“The use of biomarkers in basic and clinical research has become routine in many areas of medicine. They are accepted as molecular signatures that have been well characterized and repeatedly shown to be capable of predicting relevant disease states or clinical outcomes. In Role of Biomarkers in Medicine, expert researchers in their individual field have reviewed many biomarkers or potential biomarkers in various types of diseases. The topics address numerous aspects of medicine, demonstrating the current conceptual status of biomarkers as clinical tools and as surrogate endpoints in clinical research.”
The above quote is from the preface of the book. Here’s my goodreads review. I have read about biomarkers before – for previous posts on this topic, see this link. I added the link in part because the coverage provided in this book is in my opinion generally of a somewhat lower quality than is the coverage that has been provided in some of the other books I’ve read on these topics. However the fact that the book is not amazing should probably not keep me from sharing some observations of interest from the book, which I have done in this post.
“we suggest more precise studies to establish the exact role of this hormone […] additional studies are necessary […] there are conflicting results […] require further investigation […] more intervention studies with long-term follow-up are required. […] further studies need to be conducted […] further research is needed“ (There are a lot of comments like these in the book, I figured I should include a few in my coverage…)
“Cancer biomarkers (CB) are biomolecules produced either by the tumor cells or by other cells of the body in response to the tumor, and CB could be used as screening/early detection tool of cancer, diagnostic, prognostic, or predictor for the overall outcome of a patient. Moreover, cancer biomarkers may identify subpopulations of patients who are most likely to respond to a given therapy […] Unfortunately, […] only very few CB have been approved by the FDA as diagnostic or prognostic cancer markers […] 25 years ago, the clinical usefulness of CB was limited to be an effective tool for patient’s prognosis, surveillance, and therapy monitoring. […] CB have [since] been reported to be used also for screening of general population or risk groups, for differential diagnosis, and for clinical staging or stratification of cancer patients. Additionally, CB are used to estimate tumor burden and to substitute for a clinical endpoint and/or to measure clinical benefit, harm or lack of benefit, or harm [4, 18, 30]. Among commonly utilized biomarkers in clinical practice are PSA, AFP, CA125, and CEA.”
“Bladder cancer (BC) is the second most common malignancy in the urologic field. Preoperative predictive biomarkers of cancer progression and prognosis are imperative for optimizing […] treatment for patients with BC. […] Approximately 75–85% of BC cases are diagnosed as nonmuscle-invasive bladder cancer (NMIBC) […] NMIBC has a tendency to recur (50–70%) and may progress (10–20%) to a higher grade and/or muscle-invasive BC (MIBC) in time, which can lead to high cancer-specific mortality . Histological tumor grade is one of the clinical factors associated with outcomes of patients with NMIBC. High-grade NMIBC generally exhibits more aggressive behavior than low-grade NMIBC, and it increases the risk of a poorer prognosis […] Cystoscopy and urine cytology are commonly used techniques for the diagnosis and surveillance of BC. Cystoscopy can identify […] most papillary and solid lesions, but this is highly invasive […] urine cytology is limited by examiner experience and low sensitivity. For these reasons, some tumor markers have been investigated […], but their sensitivity and specificity are limited  and they are unable to predict the clinical outcome of BC patients. […] Numerous efforts have been made to identify tumor markers. […] However, a serum marker that can serve as a reliable detection marker for BC has yet to be identified.”
“Endometrial cancer (EmCa) is the most common type of gynecological cancer. EmCa is the fourth most common cancer in the United States, which has been linked to increased incidence of obesity. […] there are no reliable biomarker tests for early detection of EmCa and treatment effectiveness. […] Approximately 75% of women with EmCa are postmenopausal; the most common symptom is postmenopausal bleeding […] Approximately 15% of women diagnosed with EmCa are younger than 50 years of age, while 5% are diagnosed before the age of 40 . […] Roughly, half of the EmCa cases are linked to obesity. Obese women are four times more likely to develop EmCa when compared to normal weight women […] Obese individuals oftentimes exhibit resistance to leptin and show high levels of the adipokine in blood, which is known as leptin resistance […] prolonged exposure of leptin damages the hypothalamus causing it to become insensitive to the effects of leptin […] Evidence shows that leptin is an important pro-inflammatory, pro-angiogenic, and mitogenic factor for cancer. Leptin produced by cancer cells acts in an autocrine and paracrine manner to promote tumor cell proliferation, migration and invasion, pro-inflammation, and angiogenesis [58, 70]. High levels of leptin […] are associated with metastasis and decreased survival rates in breast cancer patients . […] Metabolic syndrome including obesity, hypertension, insulin resistance, diabetes, and dyslipidemia increase the risk of developing multiple malignancies, particularly EmCa . Younger women diagnosed with EmCa are usually obese, and their carcinomas show a well-differentiated histology .”
“Normally, tumor suppressor genes act to inhibit or arrest cell proliferation and tumor development . However; when mutated, tumor suppressors become inactive, thus permitting tumor growth. For example, mutations in p53 have been determined in various cancers such as breast, colon, lung, endometrium, leukemias, and carcinomas of many tissues. These p53 mutations are found in approximately 50% of all cancers . Roughly 10–20% of endometrial carcinomas exhibit p53 mutations . […] overexpression of mutated tumor suppressor p53 has been associated with Type II EmCa (poor histologic grade, non-endometrioid histology, advanced stage, and poor survival).”
“Increasing data indicate that oxidative stress is involved in the development of DR [diabetic retinopathy] [16–19]. The retina has a high content of polyunsaturated fatty acids and has the highest oxygen uptake and glucose oxidation relative to any other tissue. This phenomenon renders the retina more susceptible to oxidative stress . […] Since long-term exposure to oxidative stress is strongly implicated in the pathogenesis of diabetic complications, polymorphic genes of detoxifying enzymes may be involved in the development of DR. […] A meta-analysis comprising 17 studies, including type 1 and type 2 diabetic patients from different ethnic origins, implied that the C (Ala) allele of the C47T polymorphism in the MnSOD gene had a significant protective effect against microvascular complications (DR and diabetic nephropathy) […] In the development of DR, superoxide levels are elevated in the retina, antioxidant defense system is compromised, MnSOD is inhibited, and mitochondria are swollen and dysfunctional [77,87–90]. Overexpression of MnSOD protects [against] diabetes-induced mitochondrial damage and the development of DR [19,91].”
“Continuous high level of blood glucose in diabetes damages micro and macro blood vessels throughout the body by altering the endothelial cell lining of the blood vessels […] Diabetes threatens vision, and patients with diabetes develop cataracts at an earlier age and are nearly twice as likely to get glaucoma compared to non-diabetic[s] . More than 75% of patients who have had diabetes mellitus for more than 20 years will develop diabetic retinopathy (DR) . […] DR is a slow progressive retinal disease and occurs as a consequence of longstanding accumulated functional and structural impairment of the retina by diabetes. It is a multifactorial condition arising from the complex interplay between biochemical and metabolic abnormalities occurring in all cells of the retina. DR has been classically regarded as a microangiopathy of the retina, involving changes in the vascular wall leading to capillary occlusion and thereby retinal ischemia and leakage. And more recently, the neural defects in the retina are also being appreciated […]. Recently, various clinical investigators [have detected] neuronal dysfunction at very early stages of diabetes and numerous abnormalities in the retina can be identified even before the vascular pathology appears [76, 77], thus suggesting a direct effect of diabetes on the neural retina. […] An emerging issue in DR research is the focus on the mechanistic link between chronic low-grade inflammation and angiogenesis. Recent evidence has revealed that extracellular high-mobility group box-1 (HMGB1) protein acts as a potent proinflammatory cytokine that triggers inflammation and recruits leukocytes to the site of tissue damage, and exhibits angiogenic effects. The expression of HMGB1 is upregulated in epiretinal membranes and vitreous fluid from patients with proliferative DR and in the diabetic retina. […] HMGB1 may be a potential biomarker [for diabetic retinopathy] […] early blockade of HMGB1 may be an effective strategy to prevent the progression of DR.”
“High blood pressure is one of the leading risk factors for global mortality and is estimated to have caused 9.4 million deaths in 2010. A meta‐analysis which includes 1 million individuals has indicated that death from both CHD [coronary heart disease] and stroke increase progressively and linearly from BP levels as low as 115 mmHg systolic and 75 mmHg diastolic upwards . The WHO [has] pointed out that a “reduction in systolic blood pressure of 10 mmHg is associated with a 22% reduction in coronary heart disease, 41% reduction in stroke in randomized trials, and a 41–46% reduction in cardiometabolic mortality in epidemiological studies” .”
“Several reproducible studies have ascertained that individuals with autism demonstrate an abnormal brain 5-HT system […] peripheral alterations in the 5-HT system may be an important marker of central abnormalities in autism. […] In a recent study, Carminati et al.  tested the therapeutic efficacy of venlafaxine, an antidepressant drug that inhibits the reuptake of 5-HT, and [found] that venlafaxine at a low dose [resulted in] a substantial improvement in repetitive behaviors, restricted interests, social impairment, communication, and language. Venlafaxine probably acts via serotonergic mechanisms […] OT [Oxytocin]-related studies in autism have repeatedly reported lower blood OT level in autistic patients compared to age- and gender-matched control subjects […] autistic patients demonstrate an altered neuroinflammatory response throughout their lives; they also show increased astrocyte and microglia inflammatory response in the cortex and the cerebellum [47, 48].”
Here are my first two posts about the book, which I have now finished. I gave the book three stars on goodreads, but I’m close to a four star rating and I may change my opinion later – overall it’s a pretty good book. I’ve read about many of the topics covered before but there was also quite a bit of new stuff along the way; as a whole the book spans very widely, but despite this the level of coverage of individual topics is not bad – I actually think the structure of the book makes it more useful as a reference tool than is McPhee et al. (…in terms of reference books which one might find the need to refer to in order to make sense of medical tests and test results, I should of course add that no book can beat Newman & Kohn). I have tried to take this into account along the way in terms of the way I’ve been reading the book, in the sense that I’ve tried to make frequent references in the margin to other relevant works going into more detail about specific topics whenever this seemed like it might be useful, and I think if one does something along those lines systematically a book like this one can become a really powerful tool – you get the short version with the most important information (…or at least what the authors considered to be the most important information) here almost regardless of what topic you’re interested in – I should note in this context that the book has only very limited coverage of mental health topics, so this is one area where you definitely need to go elsewhere for semi-detailed coverage – and if you need more detail than what’s provided in the coverage you’ll also know from your notes where to go next.
In my last post I talked a bit about which topics were covered in the various chapters in the book – I figured it might make sense here to list the remaining chapter titles in this post. After the (long) surgery chapter, the rest of the chapters deal with epidemiology (I thought this was a poor chapter and the authors definitely did not consider this topic to be particularly important; they spent only 12 pages on it), clinical chemistry (lab results, plasma proteins, topics like ‘what is hypo- and hypernatremia’, …), eponymous syndromes (a random collection of diseases, many of which are quite rare), radiology (MRI vs X-ray? When to use, or not use, contrast material? Etc.), ‘reference intervals etc.‘ (the ‘etc.’ part covered drug therapeutic ranges for some commonly used drugs, as well as some important drug interactions – note to self: The effects of antidiabetic drugs are increased by alcohol, beta-blockers, bezafibrate, and MAOIs, and are decreased by contraceptive steroids, corticosteroids, diazoxide, diuretics, and possibly also lithium), practical procedures (I was considering skipping this chapter because I’m never going to be asked to e.g. insert a chest drain and knowing how to do it seems to be of limited benefit to me, but I figured I might as well read it anyway; there were some details about what can go wrong in the context of specific procedures and what should be done when this happens, and this seemed like valuable information. Also, did you know that “There is no evidence that lying flat post procedure prevents headache” in the context of lumbar punctures? I didn’t, and a lot of doctors probably also don’t. You can actually go even further than that: “Despite years of anecdotal advice to the contrary, none of the following has ever been shown to be a risk factor [for post-LP headache]: position during or after the procedure; hydration status before, during, or after; amount of CSF removed; immediate activity or rest post-LP.”), and emergencies.
In this post I won’t cover specific chapters of the book in any detail, rather I’ll talk about a few specific topics and observations I could be bothered to write some stuff about here. Let’s start with some uplifting news about the topic of liver tumours: Most of these (~90%) are secondary (i.e. metastatic) tumours with an excellent prognosis (“Often <6 months”). No, wait just a minute… Nope, you definitely do not want cancer cells to migrate to your liver. Primary tumors, the most common cause of which is hepatitis B infection (…they say in that part of the coverage – but elsewhere in the book they observe that “alcohol is the prime cause of any liver disease”), also don’t have great outcomes, especially not if you don’t get a new liver: “Resecting solitary tumours <3cm across ↑3yr survival to 59% from 13%; but ~50% have recurrence by 3yrs. Liver transplant gives a 5yr survival rate of 70%.” It should be noted in a disease impact context that this type of cancer is far more common in areas of the world with poorly developed health care systems like Africa and China.
Alcoholism is another one of the causes of liver tumors. In the book they include the observation that the lifetime prevalence of alcoholism is around 10% for men and 4% for women, but such numbers are of course close to being completely meaningless almost regardless of where they’re coming from. Alcoholism is dangerous; in cases with established cirrhosis roughly half (52%) of people who do not stop drinking will be dead within 5 years, whereas this is also the case for 23% of the people who do stop drinking. Excessive alcohol consumption can cause alcoholic hepatitis; “[m]ild episodes hardly affect mortality” but in severe cases half will be dead in a month, and in general 40% of people admitted to the hospital for alcoholic hepatitis will be dead within one year of admission. Alcohol can cause portal hypertension (80% of cases are caused by cirrhosis in the UK), which may lead to the development of abnormal blood vessels e.g. in the oesophagus which will have a tendency to cause bleeding, which can be fatal. Roughly 30% of cirrhotics with varices bleed, and rebleeding is common: “After a 1st variceal bleed, 60% rebleed within 1yr” and “40% of rebleeders die of complications.” Alcoholism can kill you in a variety of different ways (acute poisonings and accidents should probably also be included here as well), and many don’t survive long enough to develop cancer.
As mentioned in the first post about the book acute kidney injury is common in a hospital setting. In the following I’ve added a few more observations about renal disease. “Renal pain is usually a dull ache, constant and in the loin.” But renal disease don’t always cause pain, and in general: “There is often a poor correlation between symptoms and severity of renal disease. Progression [in chronic disease] may be so insidious that patients attribute symptoms to age or a minor illnesses. […] Serious renal failure may cause no symptoms at all.” The authors note that odd chronic symptoms like fatigue should not be dismissed without considering a renal function test first. The book has a nice brief overview of the pathophysiology of diabetic nephropathy – this part is slightly technical, but I decided to include it here anyway before moving on to a different topic:
“Early on, glomerular and tubular hypertrophy occur, increasing GFR [glomerular filtration rate, an indicator variable used to assess kidney function] transiently, but ongoing damage from advanced glycosylation end-products (AGE—caused by non-enzymatic glycosylation of proteins from chronic hyperglycaemia) triggers more destructive disease. These AGE trigger an inflammatory response leading to deposition of type IV collagen and mesangial expansion, eventually leading to arterial hyalinization, thickening of the mesangium and glomerular basement membrane and nodular glomerulosclerosis (Kimmelstiel–Wilson lesions). Progression generally occurs in four stages:
1 GFR elevated: early in disease renal blood flow increases, increasing the GFR and leading to microalbuminuria. […]
2 Glomerular hyperfiltration: in the next 5–10yrs mesangial expansion gradually occurs and hyperfiltration at the glomerulus is seen without microalbuminuria.
3 Microalbuminuria: as soon as this is detected it indicates progression of disease, GFR may be raised or normal. This lasts another 5–10yrs.
4 Nephropathy: GFR begins to decline and proteinuria increases.
Patients with type 2 DM may present at the later stages having had undetected hyperglycaemia for many years before diagnosis.”
Vitamin B12 deficiency is quite common, the authors note that it occurs in up to 15% of older people. Severe B12 deficiency is not the sort of thing which will lead to you feeling ‘a bit under the weather’ – it can lead to permanent brain damage and damage to the spinal cord. “Vitamin B12 is found in meat, fish, and dairy products, but not in plants.” It’s important to note that “foods of non-animal origin contain no B12 unless fortified or contain bacteria.” The wiki article incidentally includes even higher prevalence estimates (“It is estimated to occur in about 6% of those under the age of 60 and 20% of those over the age of 60. Rates may be as high as 80% in parts of Africa and Asia.”) than the one included in the book – this vitamin deficiency is common, and if severe it can have devastating consequences.
On bleeding disorders: “After injury, 3 processes halt bleeding: vasoconstriction, gap-plugging by platelets, and the coagulation cascade […]. Disorders of haemostasis fall into these 3 groups. The pattern of bleeding is important — vascular and platelet disorders lead to prolonged bleeding from cuts, bleeding into the skin (eg easy bruising and purpura), and bleeding from mucous membranes (eg epistaxis [nose bleeds], bleeding from gums, menorrhagia). Coagulation disorders cause delayed bleeding into joints and muscle.” An important observation in the context of major bleeds is incidentally this: “Blood should only be given if strictly necessary and there is no alternative. Outcomes are often worse after a transfusion.” The book has some good chapters about the leukaemias, but they’re relatively rare diseases and some of them are depressing (e.g. acute myeloid leukaemia: according to the book coverage death occurs in ~2 months if untreated, and roughly four out of five treated patients are dead within 3 years) so I won’t talk a lot about them. One thing I found somewhat interesting about the blood disorders covered in the book is actually how rare they are, all things considered: “every day each of us makes 175 billion red cells, 70 billion granulocytes, and 175 billion platelets”. There are lots of opportunities for things to go wrong here…
Some ways to prevent traveller’s diarrhea: “If in doubt, boil all water. Chlorination is OK, but doesn’t kill amoebic cysts (get tablets from pharmacies). Filter water before purifying. Distinguish between simple gravity filters and water purifiers (which also attempt to sterilize chemically). […] avoid surface water and intermittent tap supplies. In Africa assume that all unbottled water is unsafe. With bottled water, ensure the rim is clean & dry. Avoid ice. […] Avoid salads and peel your own fruit. If you cannot wash your hands, discard the part of the food that you are holding […] Hot, well-cooked food is best (>70°C for 2min is no guarantee; many pathogens survive boiling for 5min, but few last 15min)”
An important observation related to this book’s coverage about how to control hospital acquired infection: “Cleaning hospitals: Routine cleaning is necessary to ensure that the hospital is visibly clean and free from dust and soiling. 90% of microorganisms are present within ‘visible dirt’, and the purpose of routine cleaning is to eliminate this dirt. Neither soap nor detergents have antimicrobial activity, and the cleaning process depends essentially on mechanical action.”
Falciparum malaria causes one million deaths/year, according to the book, and mortality is close to 100% in untreated severe malaria – treatment reduces this number to 15-20%. Malaria in returning travellers is not particularly common, but there are a couple thousand cases in the UK each year. Malaria prophylaxis does not give full protection, and “[t]here is no good protection for parts of SE Asia.” Multidrug resistance is common.
Yesterday I gave some of the reasons I had for disliking the book; in this post I’ll provide some of the reasons why I kept reading. The book had a lot of interesting data. I know I’ve covered some of these topics and numbers before (e.g. here), but I don’t mind repeating myself every now and then; some things are worth saying more than once, and as for the those that are not I must admit I don’t really care enough about not repeating myself here to spend time perusing the archives in order to make sure I don’t repeat myself here. Anyway, here are some number from the coverage:
“Twenty-two high-burden countries account for over 80 % of the world’s TB cases […] data referring to 2011 revealed 8.7 million new cases of TB [worldwide] (13 % coinfected with HIV) and 1.4 million people deaths due to such disease […] Around 80 % of TB cases among people living with HIV were located in Africa. In 2011, in the WHO European Region, 6 % of TB patients were coinfected with HIV […] In 2011, the global prevalence of HIV accounted for 34 million people; 69 % of them lived in Sub-Saharan Africa. Around five million people are living with HIV in South, South-East and East Asia combined. Other high-prevalence regions include the Caribbean, Eastern Europe and Central Asia . Worldwide, HIV incidence is in downturn. In 2011, 2.5 million people acquired HIV infection; this number was 20 % lower than in 2001. […] Sub-Saharan Africa still accounts for 70 % of all AIDS-related deaths […] Worldwide, an estimated 499 million new cases of curable STIs (as gonorrhoea, chlamydia and syphilis) occurred in 2008; these findings suggested no improvement compared to the 448 million cases occurring in 2005. However, wide variations in the incidence of STIs are reported among different regions; the burden of STIs mainly occurs in low-income countries”.
“It is estimated that in 2010 alone, malaria caused 216 million clinical episodes and 655,000 deaths. An estimated 91 % of deaths in 2010 were in the African Region […]. A total of 3.3 billion people (half the world’s population) live in areas at risk of malaria transmission in 106 countries and territories”.
“Diarrhoeal diseases amount to an estimated 4.1 % of the total disability-adjusted life years (DALY) global burden of disease, and are responsible for 1.8 million deaths every year. An estimated 88 % of that burden is attributable to unsafe supply of water, sanitation and hygiene […] It is estimated that diarrhoeal diseases account for one in nine child deaths worldwide, making diarrhoea the second leading cause of death among children under the age of 5 after pneumonia”
“NCDs [Non-Communicable Diseases] are the leading global cause of death worldwide, being responsible for more
deaths than all other causes combined. […] more than 60 % of all deaths worldwide currently stem from NCDs .
In 2008, the leading causes of all NCD deaths (36 million) were:
• CVD [cardiovascular disease] (17 million, or 48 % of NCD deaths) [nearly 30 % of all deaths];
• Cancer (7.6 million, or 21 % of NCD deaths) [about 13 % of all deaths]
• Respiratory diseases (4.2 million, or 12 % of NCD deaths) [7 % of all deaths]
• Diabetes (1.3 million, 4 % of NCD deaths) .” [Elsewhere in the publication they report that: “In 2010, diabetes was responsible for 3.4 million deaths globally and 3.6 % of DALYs” – obviously there’s a lot of uncertainty here. How to avoid ‘double-counting’ is one of the major issues, because we have a pretty good idea what they die of: “CVD is by far the most frequent cause of death in both men and women with diabetes, accounting for about 60 % of all mortality”].
“Behavioural risk factors such as physical inactivity, tobacco use and unhealthy diet explain nearly 80 % of the CVD burden”
“nearly 80 % of NCD deaths occur in low- and middle-income countries , up sharply from just under 40 % in 1990 […] Low- and lower-middle-income countries have the highest proportion of deaths from NCDs under 60 years. Premature deaths under 60 years for high-income countries were 13 and 25 % for upper-middle-income countries. […] In low-income countries, the proportion of premature NCD deaths under 60 years is 41 %, three times the proportion in high-income countries . […] Overall, NCDs account for more than 50 % of DALYs [disability-adjusted life years] in most counties. This percentage rises to over 80 % in Australia, Japan and the richest countries of Western Europe and North America […] In Europe, CVD causes over four million deaths per year (52 % of deaths in women and 42 % of deaths in men), and they are the main cause of death in women in all European countries.”
“Overall, age-adjusted CVD death rates are higher in most low- and middle-income countries than in developed countries […]. CHD [coronary heart disease] and stroke together are the first and third leading causes of death in developed and developing countries, respectively. […] excluding deaths from cancer, these two conditions were responsible for more deaths in 2008 than all remaining causes among the ten leading causes of death combined (including chronic diseases of the lungs, accidents, diabetes, influenza, and pneumonia)”.
“The global prevalence of diabetes was estimated to be 10 % in adults aged 25 + years […] more than half of all nontraumatic lower limb amputations are due to diabetes [and] diabetes is one of the leading causes of visual impairment and blindness in developed countries .”
“Almost six million people die from tobacco each year […] Smoking is estimated to cause nearly 10 % of CVD […] Approximately 2.3 million die each year from the harmful use of alcohol. […] Alcohol abuse is responsible for 3.8 % of all deaths (half of which are due to CVD, cancer, and liver cirrhosis) and 4.5 % of the global burden of disease […] Heavy alcohol consumption (i.e. ≥ 4 drinks/day) is significantly associated with an about fivefold increased risk of oral and pharyngeal cancer and oesophageal squamous cell carcinoma (SqCC), 2.5-fold for laryngeal cancer, 50 % for colorectal and breast cancers and 30 % for pancreatic cancer . These estimates are based on a large number of epidemiological studies, and are generally consistent across strata of several covariates. […] The global burden of cancer attributable to alcohol drinking has been estimated at 3.6 and 3.5 % of cancer deaths , although this figure is higher in high-income countries (e.g. the figure of 6 % has been proposed for UK  and 9 % in Central and Eastern Europe).”
“At least two million cancer cases per year (18 % of the global cancer burden) are attributable to chronic infections by human papillomavirus, hepatitis B virus, hepatitis C virus and Helicobacter pylori. These infections are largely preventable or treatable […] The estimate of the attributable fraction is higher in low- and middle-income countries than in high-income countries (22.9 % of total cancer vs. 7.4 %).”
“Information on the magnitude of CVD in high-income countries is available from three large longitudinal studies that collect multidisciplinary data from a representative sample of European and American individuals aged 50 and older […] according to the Health Retirement Survey (HRS) in the USA, almost one in three adults have one or more types of CVD [11, 12]. By contrast, the data of Survey of Health, Ageing and Retirement in Europe (SHARE), obtained from 11 European countries, and English Longitudinal Study of Aging (ELSA) show that disease rates (specifically heart disease, diabetes, and stroke) across these populations are lower (almost one in five)”
“In 1990, the major fraction of morbidity worldwide was due to communicable, maternal, neonatal, and nutritional disorders (47 %), while 43 % of disability adjusted life years (DALYs) lost were attributable to NCDs. Within two decades, these estimates had undergone a drastic change, shifting to 35 % and 54 %, respectively”
“Estimates of the direct health care and nonhealth care costs attributable to CVD in many countries, especially in low- and middle-income countries, are unclear and fragmentary. In high-income countries (e.g., USA and Europe), CVD is the most costly disease both in terms of economic costs and human costs. Over half (54 %) of the total cost is due to direct health care costs, while one fourth (24 %) is attributable to productivity losses and 22 % to the informal care of people with CVD. Overall, CVD is estimated to cost the EU economy, in terms of health care, almost €196 billion per year, i.e., 9 % of the total health care expenditure across the EU”
“In the WHO European Region, the Eastern Mediterranean Region, and the Region of the Americas, over 50 % of women are overweight. The highest prevalence of overweight among infants and young children is in upper-to-middle-income populations, while the fastest rise in overweight is in the lower-to-middle-income group . Globally, in 2008, 9.8 % of men and 13.8 % of women were obese compared to 4.8 % of men and 7.9 % of women in 1980 .”
“In low-income countries, around 25 % of adults have raised total cholesterol, while in high-income countries, over 50 % of adults have raised total cholesterol […]. Overall, one third of CHD disease is attributable to high cholesterol levels” (These numbers seem very high to me, but I’m reporting them anyway).
“interventions based on tobacco taxation have a proportionally greater effect on smokers of lower SES and younger smokers, who might otherwise be difficult to influence. Several studies suggest that the application of a 10 % rise in price could lead to as much as a 2.5–10 % decline in smoking [20, 45, 50, 56].”
“The decision to allocate resources for implementing a particular health intervention depends not only on the strength of the evidence (effectiveness of intervention) but also on the cost of achieving the expected health gain. Cost-effectiveness analysis is the primary tool for evaluating health interventions on the basis of the magnitude of their incremental net benefits in comparison with others, which allows the economic attractiveness of one program over another to be determined [More about this kind of stuff here]. If an intervention is both more effective and less costly than the existing one, there are compelling reasons to implement it. However, the majority of health interventions do not meet these criteria, being either more effective but more costly, or less costly but less effective, than the existing interventions [see also this]. Therefore, in most cases, there is no “best” or absolute level of cost-effectiveness, and this level varies mainly on the basis of health care system expenditure and needs .”
“The number of new cases of cancer worldwide in 2008 has been estimated at about 12,700,000 . Of these, 6,600,000 occurred in men and 6,000,000 in women. About 5,600,000 cases occurred in high-resource countries […] and 7,100,000 in low- and middle-income countries. Among men, lung, stomach, colorectal, prostate and liver cancers are the most common […], while breast, colorectal, cervical, lung and stomach are the most common neoplasms among women […]. The number of deaths from cancer was estimated at about 7,600,000 in 2008 […] No global estimates of survival from cancer are available: Data from selected cancer registries suggest wide disparities between high- and low-income countries for neoplasms with effective but expensive treatment, such as leukaemia, while the gap is narrow for neoplasms without an effective therapy, such as lung cancer […]. The overall 5-year survival of cases diagnosed during 1995– 1999 in 23 European countries was 49.6 % […] Tobacco smoking is the main single cause of human cancer worldwide […] In high-income countries, tobacco smoking causes approximately 30 % of all human cancers .”
“Systematic reviews have concluded that nutritional factors may be responsible for about one fourth of human cancers in high-income countries, although, because of the limitations of the current understanding of the precise role of diet in human cancer, the proportion of cancers known to be avoidable in practicable ways is much smaller . The only justified dietary recommendation for cancer prevention is to reduce the total caloric intake, which would contribute to a decrease in overweight and obesity, an established risk factor for human cancer. […] The magnitude of the excess risk [associated with obesity] is not very high (for most cancers, the relative risk (RR) ranges between 1.5 and 2 for body weight higher than 35 % above the ideal weight). Estimates of the proportion of cancers attributable to overweight and obesity in Europe range from 2 %  to 5 % . However, this figure is likely to be larger in North America, where the prevalence of overweight and obesity is higher.”
“Estimates of the global burden of cancer attributable to occupation in high-income countries result in the order of 1–5 % [9, 42]. In the past, almost 50 % of these were due to asbestos alone […] The available evidence suggests, in most populations, a small role of air, water and soil pollutants. Global estimates are in the order of 1 % or less of total cancers [9, 42]. This is in striking contrast with public perception, which often identifies pollution as a major cause of human cancer.”
“Avoidance of sun exposure, in particular during the middle of the day, is the primary preventive measure to reduce the incidence of skin cancer. There is no adequate evidence of a protective effect of sunscreens, possibly because use of sunscreens is associated with increased exposure to the sun. The possible benefit in reducing skin cancer risk by reduction of sun exposure, however, should be balanced against possible favourable effects of UV radiation in promoting vitamin D metabolism.”
Despite not actually having reading all that many books this year I’m way behind on blogging the books I’ve read, so I thought I might as well try to catch up a bit. You can find my previous coverage of the book here and here.
In this post I’ll cover the chapters about the musculoskeletal system, the endocrine system, and the breast.
“Disorders of the musculoskeletal system make up 20–25 per cent of a general practitioner’s workload and account for significant disability in the general population. […] The chief symptoms to identify in the musculoskeletal assessment are: *pain *stiffness *swelling *impaired function *constitutional [regarding constitutional symptoms, “Patients with arthritis may describe symptoms of fatigue, fever, sweating and weight loss”]. […] As a rule mechanical disorders (e.g. OA [Osteoarthritis], spondylosis, and tendinopathies) are worsened by activity and relieved by rest. In severe degenerative disease the pain may, however, be present at rest and disturb sleep. Inflammatory disorders tend to be painful both at rest and during activity and are associated with worsened stiffness after periods of prolonged rest. The patient may note that stiffness is relieved somewhat by movement. Both mechanical and inflammatory disorders may be worsened by excessive movement.”
“The lifetime incidence of lower back pain is about 60 per cent and the greatest prevalence is between ages 45 and 65 years. Over 90 per cent of low back pain is mechanical and self-limiting. […] Indicators of serious pathology in lumbar pain: ‘red flags’ of serious pathology that requires further investigation […] are: *presenting under age 20 and over age 55 years *prolonged stiffness (>6 weeks) *sudden onset of severe pain *pain that disturbs sleep (>6 weeks) *thoracic pain *nerve root symptoms – including spinal claudication (pain on walking resolved by rest), saddle numbness, and loss of bladder or bowel control *chronic persistent pain (>12 weeks) *weight loss *history of carcinoma.”
“Osteoarthritis is a chronic degenerative and mechanical disorder characterized by cartilage loss. It is the most common form of arthritis, estimated to affect 15 per cent of the population of the UK over the age of 55 years. It is second only to cardiovascular disease as a cause of disability. Weight-bearing joints are chiefly involved (e.g. facets in the spine, hip and knee). […] There is little evidence to link OA with repetitive injury from occupation, except perhaps knee bending in men. Dockers and miners have a higher incidence of knee OA.”
“Rheumatoid arthritis […] is the most common ARD [Autoimmune Rheumatic Diseases] and is characterized by the presence of a symmetrical destructive polyarthritis with a predisposition for the small joints of the hands, wrists and feet. It is more common in women than men and may present at any age though most often in the third to fourth decade. […] Onset is typically insidious and progressive pain, stiffness and symmetrical swelling of small joints occurs. Up to a third of patients may have a subacute onset with symptoms of fatigue, malaise, weight loss, myalgia, morning stiffness and joint pain without overt signs of swelling. A mono- or bilateral arthropathy of the shoulder or wrist may account for up to 30–40 per cent of initial presentations”
“[Osteoporosis] remains a significant cause of morbidity and mortality. Peak bone mass is usually achieved in the third decade and is determined by both genetic and environmental factors. After the age of 35 the amount of bone laid down is less than that reabsorbed during each remodelling cycle. The net effect is age-related loss of bone mass. Up to 15 per cent of bone mass can also be lost over the 5-year period immediately post menopause. Symptomless reduction in bone mass and strength results in an increased risk of fracture; it is the resulting fractures that lead to pain and morbidity. Major risk factors to be considered in osteoporosis are: *race (white or Asian > African Caribbean) *age *gender *family history of maternal hip fracture *previous low trauma fracture (low trauma defined as no greater than falling from standing height) *long-term use of corticosteroids *malabsorption disorders *endocrinopathies […] *inflammatory arthritis […] Other risk factors include: *low body mass index […] *late menarche and early menopause *nulliparity *reduced physical activity *low intake of calcium (below 240 mg daily) *excess alcohol intake *smoking *malignancy (multiple myeloma).”
“Infection may give rise to systemic inflammatory arthritis or vasculitis. The condition ‘reactive arthritis’ is also recognized. […] It is usually triggered by sexually transmitted infection such as with Chlamydia trachomatis. The acute inflammatory reaction is treated with NSAIDs and corticosteroids and often ‘burns out’ after 6–18 months [Had to read that one twice: 18 months…]. It may leave lasting joint damage. […] Septic arthritis constitutes an acute emergency. The presentation is usually one of a rapid onset of severe pain in a hot swollen joint, the pain so severe that the patient cannot bear for it to be touched or moved.”
“Focal pain, swelling, or a low trauma fracture in the spine or long bones should alert suspicion [of neoplasia]. Primary tumours of bone include the benign (but often very painful) osteoid-osteoma, chondromas, and malignant osteosarcoma. Metastatic carcinoma may be secondary to a primary lesion in the lung, breast, prostate, kidney or thyroid. Haematological malignancies including lymphomas and leukaemias may also lead to diffuse bone involvement.”
“Diabetes mellitus is becoming a major public health problem. This is particularly true for type 2 diabetes, the prevalence of which is increasing rapidly due to the association with obesity and physical inactivity. Much of the morbidity, and cost, of diabetes care is due to the associated complications, rather than directly to hyperglycaemia and its management. Thyroid disease and polycystic ovarian syndrome are also prevalent [endocrine] conditions. Most other endocrine disorders are uncommon”
“The classic triad of symptoms associated with diabetes mellitus consists of: *thirst *polyuria (often nocturia) *weight loss.
Many patients will also experience pruritus or balanitis, fatigue and blurred vision. Some people, particularly those with newly presenting type 1 diabetes diabetes mellitus (T1DM) or with marked hyperglycaemia in type 2 diabetes mellitus (T2DM), may have a ‘full house’ of symptoms, in which case it is generally not difficult to suspect the diagnosis. However, other patients, particularly those with only modestly elevated blood glucose concentrations in T2DM, will have fewer, milder symptoms, and some may be entirely asymptomatic. […] symptoms potentially suggestive of diabetes may have alternative causes, particularly in elderly people, for example, frequency and nocturia in an older man may be due to bladder outflow obstruction, and many medical disorders are associated with weight loss. The symptom complex of thirst, polydipsia and polyuria most commonly suggests a diagnosis of uncontrolled diabetes mellitus but can occur in other settings. Some patients taking diuretics will experience similar symptoms. A dry mouth, perhaps associated with drug usage (e.g. tricyclic antidepressants) or certain medical conditions (e.g. Sjögren’s syndrome), may lead to increased fluid intake in an attempt at symptom relief.”
“The blood glucose concentration at diagnosis is not useful as a guide to whether an individual patient has T1DM or T2DM. Patients with T1DM can be in severe ketoacidosis with a blood glucose less than 20 mmol/L, and even below 10 mmol/L on occasions, whereas T2DM can present with a hyperosmolar state with blood glucose levels over 50 mmol/L.”
“30–50 per cent of patients with newly diagnosed T2DM will already have tissue complications at diagnosis due to the prolonged period of antecedent moderate and asymptomatic hyperglycaemia. […] Diabetes mellitus is much more than a disorder of glucose metabolism. The complications of diabetes can affect many of the organ systems leading to associated cardiac, vascular, renal, retinal, neurological and other disorders.”
“Pain is one of the commonest presenting disorders in the female breast, occurring in both pre-and postmenopausal women. […] In most women, there is no obvious or serious underlying breast pathology present […] In males, pain is not uncommon in gynaecomastia (swelling of male breast). […] A discrete lump, nodularity or thickening is the next most common mode of presentation. Size may vary (frequently ‘pea-sized’), but can be large. Onset may be acute (several days) or longstanding (several months). Fluctuation with the menstrual cycle is common in young women. Pain and tenderness are features of cysts, less common with fibroadenomas (unless rapidly growing or phylloides tumours), uncommon with cancer, except with rapidly expanding, aggressive (grade 3) and inflammatory tumours. The commonest lump in women below 30 years is a fibroadenoma; in women 30–45 years, a cyst and those over 45 years, cancer. […] Careful assessment of a lump can indicate whether the breast lesion is benign or malignant: *if it is rounded, smooth, mobile, tense and tender it is most likely to be a cyst (30 to 45 years of age) *if it is rounded, smooth, mobile, firm and non-tender it is most likely to be a fibroadenoma (under 30 years of age) *malignant lumps are rare in women under 30 years and uncommon under 40 years (4 per cent of breast cancers). Cancers are usually irregular, firm or hard, with variable involvement of overlying skin or deeper structures.”
“Retraction (intermittent, partial or chronic) is often a concern to women. It can be idiopathic or associated with malignancy in the retroareolar region, but usually is seen in the postmenopausal breast and is secondary to glandular atrophy and replacement by fibrosis and major duct ectasia. Congenital absence is very rare, whereas accessory nipples are seen in 2 per cent of women.” [Again, I had to read that one twice. 2 %! Who knew! Also, this condition seems to be even more common in males (see the link above).]
“Five to 10 per cent of women will, at some stage, present with a macrocyst. Microcysts are more common but tend to be occult. Breast cysts are commonest between the ages of 35 and 50, but can occur outside this age range, particularly in women who have been taking HRT. […] Patients present with a palpable lump or nodularity. When acute and large, the lump can be tender and the patient complains of pain. Typically cysts are well-circumscribed, smooth, mobile and, on occasion, tender lumps.”
“Nipple discharge in premenopausal women is likely to be associated with, or be due to, benign disease. It is the predominant clinical feature in up to 10 per cent of women presenting with breast cancer. […] *Purulent and coloured discharges are usually indicative of benign disease (infection and fibrocystic disease, respectively). *Spontaneous bilateral milky discharge (multiple ducts) most commonly occurs in women of reproductive age and is called galactorrhoea. […] *Clear, serous or bloodstained discharges are not infrequently associated with neoplastic disease”
“Carcinoma of the breast is one of the most common cancers (23 per cent of all female malignancies in the developed world) […]. One in 10 women develops breast cancer during her lifetime. […] Breast cancer is very rare in women under the age of 25. About 4 per cent occur under the age of 40. There is a plateau in incidence between the ages of 45 and 55, and beyond 55 years it continues to increase steadily into the 80s. […] The most common (70 per cent) presentation is a palpable lump, nodularity or thickening in the breast, usually detected by the patient. Typically the lump is firm or hard, well defined, with an irregular surface. […] About 25 per cent of women in the UK present with large primary tumours […], or locally advanced breast cancers […]. In some cases, particularly elderly patients, the tumour may have been present for some time, but hidden by the patient from her relatives due to fear and anxiety […]. Occasionally patients may even deny the presence of a tumour as a psychological coping strategy. […] Breast cancer is the most common malignant condition occurring during pregnancy. The incidence is approximately 1 in 2500 pregnancies, and poses many medical and psychological problems, both for the woman and her relatives.”
“The student of medicine has to learn both the ‘bottom up’ approach of constructing a differential diagnosis from individual clinical findings, and the ‘top down’ approach of learning the key features pertaining to a particular diagnosis. In this textbook we have integrated both approaches into a coherent working framework that will assist the reader in preparing for academic and professional examinations, and in every day practice. […] We have split this textbook into three sections. The first section introduces the basic skills underpinning much of what follows – how to take a history and perform an examination, how to devise a differential diagnosis and select appropriate investigations, and how to record your findings in the case notes and present cases on ward rounds. The second section takes a systems-based approach to history taking and examining patients, and also includes information on relevant diagnostic tests and common diagnoses for each system. Each chapter begins with the individual ‘building blocks’ of the history and examination, and ends by drawing these elements together into relevant diagnoses. […] The third and final section of the book covers ‘special situations’, including the assessment of the newborn, infants and children, the acutely ill patient, the patient with impaired consciousness, the older patient and death and the dying patient.”
The above quote is from the preface of the book. This is a medical textbook with 500 pages and 26 chapters written by 27 contributors, so it has a lot of stuff; I’ve been conflicted about how to blog it for this reason. It has as lot of stuff which is useful to know but which most people don’t, and I think it’s the sort of book I might be tempted to ‘consult’ later on; the various 100 Cases… books I’ve read include some similar useful observations, but I think it’d be more natural to consult this book first because it’s much more likely that this book will at least have something about the medical condition you’re curious/can’t remember the details about. I think it was somewhat easier to read than was McPhee et al., and I’m not sure this is only because I read the former first (while I was reading McPhee et al. I was learning part of the vocabulary which is needed to read this book).
In the coverage below I have not talked about the stuff included in the first part; I don’t need to e.g. be able to take a medical history and navigate medical records, and if some of my readers do I’ll assume they have the necessary skills already, or know where/how to obtain such skills. In this post I’ll focus on the coverage of major systems in part two, with my coverage focused on ‘key variables’, and, well, ‘stuff I found interesting’ – which also means that I won’t talk about stuff like ‘this is how you palpate a liver’ and ‘this is how you grade heart murmurs’ (the book also covers that kind of stuff in some detail). Nor will I tell you what Buerger’s test or Trendelenburg’s test are used for, or give you a full account of the many, many different types of ‘named medical signs’ included and described in the book (Charcot’s triad, Cullen’s sign, Grey Turner’s sign, Murphy’s sign, Courvoisier’s sign, Kussmaul’s sign, Levine’s sign, etc. …).
I may in my coverage of this book tend to focus more on acute conditions than on chronic conditions, in part because it seems more useful to me to know/remember whether or not someone is, say, having a heart attack than whether or not someone with chronic kidney failure will be bothered by pitting edema. I think this approach makes sense.
The book has split the systems coverage in part 2 up into 15 chapters – there are specific chapters about: *The cardiovascular system, *the respiratory system, *the gastrointestinal system, *the renal system, *the genitourinary system, *the nervous system, *psychiatric assessment, *the musculoskeletal system, *the endocrine system, *the breast, *the haematological system, *skin, nails and hair, *the eye, *ear, nose and throat, and *infectious and tropical diseases. Most of the book coverage is devoted to this treatment of individual systems, as these 15 chapters make up roughly 350 pages of the total. I found it, interesting, that there was close to zero overlap between the coverage in this book and Newman and Kohn’s text; I’m not quite sure what to think about that.
In this post I’ll mostly talk about the first three ‘systems’ chapters. When dealing with cardiovascular disease, the major symptoms are chest discomfort, breathlessness, palpitation (an awareness of the heartbeat), dizziness and syncope (‘transient loss of consciousness resulting from transient global cerebral hypoperfusion’), and peripheral oedema (usually ankle swelling, most often associated with heart failure, often worse in the evening). An important observation is that myocardial ischemia (‘the heart muscle doesn’t get enough blood/oxygen’) can cause breathlessness and chest discomfort, and “in many cases breathlessness is the predominant symptom (particularly in women).” Deep vein thrombosis can be asymptomatic, but it commonly causes pain and swelling in the affected leg – the main acute risk factor associated with the condition (which is not particularly rare among elderly people) is that the blood clot travels to the lungs and causes a pulmonary embolism.
Next, the respiratory system: “respiratory conditions are common – accounting for more than 13 per cent of all emergency admissions and more than 20 per cent of general practitioner consultations”. I was very surprised the number was that high! I can’t provide a source as the authors did not provide a source; there are no inline citations in this book, which is part of the reason why the book did not get five stars on goodreads. Six key symptoms of respiratory diseases are chest pain (that may be extended to chest sensations), dyspnoea (shortness of breath/breathlessness), cough (“the commonest symptom that is associated with pure respiratory disease”), wheeze, sputum production, and haemoptysis (coughing up blood/blood in the sputum – this is, perhaps unsurprisingly, often, but not always, a ‘red flag symptom’: “Current recommendations indicate that urgent referral to a hospital clinic should be made when patients have haemoptysis, are over the age of 40, and are current or ex-smokers. However, a young patient who has a small amount of streak (lines in sputum) haemoptysis in the context of an upper respiratory tract infection usually will not require referral”).
In respiratory medicine, cough duration is an important variable in the diagnostic context; I was surprised that even simple respiratory tract infections may cause cough for up to three weeks, and that this is not necessarily something to worry about. Longer than that and it’s however less likely to be due to a self-limiting condition, and is more likely to be due to either lung cancer or one of the many causes of chronic cough (cough is not chronic until it’s lasted longer than 6 months) – these causes include, but are not limited to, astma, COPD, and GERD. As should be clear from the above, both heart and lung conditions may cause shortness of breath, so you can’t always conclude that shortness of breath is a lung issue. This is of course far from the only symptom which may present in different disease contexts, and the heart and lungs are connected in other ways as well; for example problems in both systems may cause clubbing. When dealing with a case of pneumonia it’s useful to be familiar with the CURB 65 score to assess risk/severity. Lung cancer can be either ‘non-small cell’ or ‘small cell’ lung cancer – in terms of presenting symptoms they’re reasonably similar, but the latter is more often associated with paraneoplastic syndromes (though these are still rare in an absolute sense, presenting in 5% of small cell lung cancers and 1% of non-small cell lung cancers, according to the book). The most common symptom is a cough, followed by persistent ‘chest infections’ (which are of course not infections) and bloody sputum/coughing up blood – but “some patients have remarkably few signs.” In the context of acute conditions affecting the lungs, pleuritic chest pain is an important symptom; this means pain which is made worse by breathing and which often has a sharp and stabbing quality to it – acute onset pleuritic chest pain can be due to a pulmonary embolism (60% of patients with PE have acute onset pleuritic chest pain; in another 25% there is a sudden onset of acute breathlessness) or a pneumothorax (‘collapsed lung’ – may also cause acute breathlessness). Although the two conditions are different, if you have either of them you want to get to a hospital, fast – sudden onset pleuritic chest pain seems to me a very good reason to call for an ambulance/visit the local emergency department.
“The gastrointestinal system includes the alimentary tract from mouth to anus, the liver, hepatobiliary structures including the gallbladder, pancreas and the biliary and pancreatic ductal systems.” This is a big system. And it’s often hard to get a good look at what’s the problem: “Almost half of gastrointestinal problems are not associated with physical signs or positive test results. Hence, the diagnosis and management is often based entirely on the inferences drawn from a patient’s symptoms.” Difficulty swallowing is a ‘red flag’ symptom, because “many patients with this symptom will have clinically significant pathology.” Weight loss combined with worsening difficulty swallowing (solids first, liquids later) means that oesophageal cancer is likely to be the cause (this one has a really bad prognosis). A useful observation when it comes to distinguishing between angina (‘heart issue’) and heartburn (‘gastrointestinal issue’), which may cause somewhat similar symptoms, is that whereas angina is often worsened by physical exertion, heartburn is not and often occurs at rest. It’s worth noting that when dealing with gastrointestinal disorders, you can learn a lot by figuring out where exactly the pain is coming from – stomach pain isn’t just stomach pain. Pain localized to one specific section of the stomach is much more likely to be due to condition X than condition Y (e.g., pain in the right upper quadrant = maybe biliary obstruction or hepatomegaly; pain in the left lower quadrant = maybe diverticulitis or infectious colitis). This may not be particularly useful for people in general to know, but I thought it was interesting. Duration of pain is a key variable: “Sudden onset of well-localized severe pain is likely to be due to catastrophic events [and] [p]ain present for weeks to months is often less life-threatening than pain presenting within hours of symptom onset.” The authors point out that the severity of abdominal pain can be underestimated in elderly people, very young patients, people who are immunosuppressed and diabetics (the latter presumably due to autonomous-/diabetes-associated enteric neuropathy). “Presence of blood in the stool points towards either inflammatory bowel disease or malignancy, but in those with infective diarrhoea it is highly specific for infections with a invasive organism.” The authors mention a few pointers to specific nutritional deficiencies which are probably useful to know about – iron deficiency may cause a flat angle or ‘spooning‘ of the nails, and it may also (together with vitamin B12-deficiency) cause soreness/redness of the tongue. Redness and cracks at the angles of the mouth are also associated with deficiencies of iron and vitamin-B12, as well as deficiencies of riboflavin, and folate.
This book is another publication from the 100 Cases … series which I’ve talked about before – I refer to these posts for some general comments about what this series is like and some talk about the other books in the series which I’ve read. The book is much like the others, though of course the specific topics covered are different in the various publications. I liked this book and gave it 3 stars on goodreads. The book has three sections: a section dealing with ‘chemical pathology, immunology and genetics’; a section dealing with ‘histopathology’; and a section dealing with ‘haematology’. As usual I knew a lot more about some of the topics covered than I did about some of the others. Some cases were quite easy, others were not. Some of the stuff covered in Greenstein & Wood’s endocrinology text came in handy along the way and enabled me for example to easily identify a case of Cushing’s syndrome and a case of Graves’ disease. I don’t think I’ll spoil anything by noting that two of the cases in this book involved these disorders, but if you plan on reading it later on you may want to skip the coverage below, as I have included some general comments from the answer sections of the book in this post.
As someone who’s not working in the medical field and who will almost certainly never need to know how to interpret a water deprivation test (also covered in detail in Greenstein and Wood, incidentally), there are some parts of books like this one which are not particularly ‘relevant’ to me; however I’d argue that far from all the stuff included in a book like this one is ‘stuff you don’t need to know’, as there are also for example a lot of neat observations included about how specific symptoms (and symptom complexes) are linked to specific disorders, some related ideas about which other medical conditions might cause similar health problems, and which risk factors are potentially important to have in mind in specific contexts. If you’ve had occasional fevers, night sweats and experienced weight loss over the last few months, you should probably have seen a doctor a while ago – knowledge included in books like this one may make the reader perhaps a bit less likely to overlook an important and potentially treatable health problem, and/or increase awareness of potential modifiable risk factors in specific contexts. A problem is however that the book will be hard to read if you have not read any medical textbooks before, and in that case I would probably advise you against reading it as it’s almost certainly not worth the effort.
I have added a few observations from the book below.
“After a bone marrow transplant (and any associated chemotherapy), the main risks are infection (from low white cell counts and the use of immunosuppressants, such as cyclosporin), bleeding (from low platelet counts) and graft versus host disease (GVHD). […] An erythematous rash that develops on the palms or soles of the feet of a patient 10–30 days after a bone marrow transplant is characteristic of GVHD. […] GVHD is a potentially life-threatening problem that can occur in up to 80% of successful allogeneic bone marrow transplants. […] Clinically, GVHD manifests like an autoimmune disease with a macular-papular rash, jaundice and hepatosplenomegaly and ultimately organ fibrosis. It classically involves the skin, gastrointestinal tract and the liver. […] Depending on severity, treatment of acute GVHD may involve topical and intravenous steroid therapy, immunosuppression (e.g. cyclosporine), or biologic therapies targeting TNF-α […], a key inflammatory cytokine. […] Prognosis is related to response to treatment. The mortality of patients who completely respond can still be around 20%, and the mortality in those who do not respond is as high as 75%.”
“The leading indication for a liver transplant is alcoholic cirrhosis in adults and biliary atresia in children. […] The overall one-year survival of a liver transplant is over 90%, with 10-year survival of around 70%. […] Transplant rejection can be classified by time course, which relates to the underlying immune mechanism: • Hyperacute organ rejection occurs within minutes of the graft perfusion in the operating theatre. […] The treatment for hyperacute rejection is immediate removal of the graft. • Acute organ rejection take place a number of weeks after the transplant […] The treatment for acute rejection includes high dose steroids. • Chronic organ rejection can take place months to years after the transplant. […] As it is irreversible, treatment for chronic rejection is difficult, and may include re-transplantation.”
“Chronic kidney disease (CKD) is characterized by a reduction in GFR over a period of 3 or more months (normal GFR is >90–120 mL/min). It arises from a progressive impairment of renal function with a decrease in the number of functioning nephrons; generally, patients remain asymptomatic until GFR reduces to below 15 mL/min (stage V CKD). Common causes of CKD are (1) diabetes mellitus, (2) hypertension, (3) glomerulonephritis, (4) renovascular disease, (5) chronic obstruction or interstitial nephritis, and (6) hereditary or cystic renal disease”
“The definition of an aneurysm is an abnormal permanent focal dilatation of all the layers of a blood vessel. An AAA [abdominal aortic aneurysm] is defined when the aortic diameter, as measured below the level of the renal arteries, is one and a half times normal. Women have smaller aortas, but for convenience, more than 3 cm qualifies as aneurysmal. The main risk factors for aneurysm formation are male gender, smoking, hypertension, Caucasian/European descent and atherosclerosis. Although atherosclerosis is a risk factor and both diseases share common predisposing factors, there are also differences. Atherosclerosis is primarily a disease of the intima, the innermost layer of the vessel wall, whereas in aneurysms there is degeneration of the media, the middle layer. […] The annual risk of rupture equals and begins to outstrip the risk of dying from surgery when the aneurysm exceeds 5.5 cm. This is the size above which surgical repair is recommended, comorbidities permitting. […] Catastrophic rupture, as in this case, presents with hypovolaemic shock and carries a dismal prognosis.” [The patient in the case history died soon after having arrived at the hospital]
“Stroke refers to an acquired focal neurological deficit caused by an acute vascular event. The neurological deficit persists beyond 24 hours, in contrast to a transient ischaemic attack (TIA) where symptoms resolve within 24 hours, although the distinction is now blurred with the advent of thrombolysis. […] Strokes are broadly categorized into ischaemic and haemorrhagic types, the majority being ischaemic. The pathophysiology in a haemorrhagic stroke is rupture of a blood vessel causing extravasation of blood into the brain substance with tissue damage and disruption of neuronal connections. The resulting haematoma also compresses surrounding normal tissue. In most ischaemic strokes, there is thromboembolic occlusion of vessels due to underlying atherosclerosis of the aortic arch and carotid arteries. In 15–20% of cases, there is atherosclerotic disease of smaller intrinsic blood vessels within the brain[…]. A further 15–20% are due to emboli from the heart. […] The territory and the extent of the infarct influences the prognosis; [for example] expressive dysphasia and right hemiparesis are attributable to infarcts in Broca’s area and the motor cortex, both frontal lobe territories supplied by the left middle cerebral artery.”
“The stereotypical profile of a gallstone patient is summed up by the 4Fs: female, fat, fertile and forty. However, while gallstones are twice as common in females, increasing age is a more important risk factor. Above the age of 60, 10–20% of the Western population have gallstones. […] Most people with cholelithiasis are asymptomatic, but there is a 1–4% annual risk of developing symptoms or complications. […] Complications depend on the size of the stones. Smaller stones may escape into the common bile duct, but may lodge at the narrowing of the hepatopancreatic sphincter (sphincter of Oddi), obstructing the common bile duct and pancreatic duct, leading to obstructive jaundice and pancreatitis respectively. […] In most series, alcohol and gallstones each account for 30–35% of cases [of acute pancreatitis]. […] Once symptomatic, the definitive treatment of gallstone disease is generally surgical via a cholecystectomy.”
“Breast cancer affects 1 in 8 women (lifetime risk) in the UK. […] Between 10 and 40% of women who are found to have a mass by mammography will have breast cancer. […] The presence of lymphovascular invasion indicates the likelihood of spread of tumour cells beyond the breast, thereby conferring a poorer outlook. Without lymph node involvement, the 10-year disease-free survival is close to 70–80% but falls progressively with the number of involved nodes.”
“Melanoma is a cancer of melanocytes, the pigmented cells in the skin, and is caused by injury to lightly pigmented skin by excessive exposure to ultraviolet (UV) radiation […] The change in colour of a pre-existing pigmented lesion with itching and bleeding and irregular margins on examination are indicators of transformation to melanoma. Melanomas progress through a radial growth phase to a vertical growth phase. In the radial growth phase, the lesion expands horizontally within the epidermis and superficial dermis often for a long period of time. Progression to the vertical phase is characterized by downward growth of the lesion into the deeper dermis and with absence of maturation of cells at the advancing front. During this phase, the lesion acquires the potential to metastasize through lymphovascular channels. The probability of this happening increases with increasing depth of invasion (Breslow thickness) by the melanoma cells. […] The ABCDE mnemonic aids in the diagnosis of melanoma: Asymmetry – melanomas are likely to be irregular or asymmetrical. Border – melanomas are more likely to have an irregular border with jagged edges. Colour – melanomas tend to be variegated in colour […]. Diameter – melanomas are usually more than 7 mm in diameter. Evolution – look for changes in the size, shape or colour of a mole.”
“CLL [chronic lymphocytic leukaemia] is the most common leukaemia in the Western world. Typically, it is picked up via an incidental lymphocytosis in an asymptomatic individual. […] The disease is staged according to the Binet classification. Typically, patients with Binet stage A disease require no immediate treatment. Symptomatic stage B and all stage C patients receive chemotherapy. […] cure is rare and the aim is to achieve periods of remission and symptom control. […] The median survival in CLL is between four and six years, though some patients survive a decade or more. […] There is […] a tendency of CLL to transform into a more aggressive leukaemia, typically a prolymphocytic transformation (in 15–30% of patients) or, less commonly (<10% of cases), transformation into a diffuse large B-cell lymphoma (a so-called Richter transformation). Appearance of transformative disease is an ominous sign, with few patients surviving for more than a year with such disease.”
“Pain, swelling, warmth, tenderness and immobility are the five cardinal signs of acute inflammation.”
“Osteomyelitis is an infection of bone that is characterized by progressive inflammatory destruction with the formation of sequestra (dead pieces of bone within living bone), which if not treated leads to new bone formation occurring on top of the dead and infected bone. It can affect any bone, although it occurs most commonly in long bones. […] Bone phagocytes engulf the bacteria and release osteolytic enzymes and toxic oxygen free radicals, which lyse the surrounding bone. Pus raises intraosseus pressure and impairs blood flow, resulting in thrombosis of the blood vessels. Ischaemia results in bone necrosis and devitalized segments of bone (known as sequestra). These sequestra are important in the pathogenesis of non-resolving infection, acting as an ongoing focus of infection if not removed. Osteomyelitis is one of the most difficult infections to treat. Treatment may require surgery in addition to antibiotics, especially in chronic osteomyelitis where sequestra are present. […] Poorly controlled diabetics are at increased risk of infections, and having an infection leads to poor control of diabetes via altered physiology occurring during infection. Diabetics are prone to developing foot ulcers, which in turn are prone to becoming infected, which then act as a source of bacteria for infecting the contiguous bones of the feet. This process is exacerbated in patients with peripheral neuropathy, poor diabetic control and peripheral vascular disease, as these all increase the risk of development of skin breakdown and subsequent osteomyelitis.” [The patient was of course a diabetic…]
“Recent onset fever and back pain suggest an upper UTI [urinary tract infection]. UTIs are classified by anatomy into lower and upper UTIs. Lower UTIs refer to infections at or below the level of the bladder, and include cystitis, urethritis, prostatitis, and epididymitis (the latter three being more often sexually transmitted). Upper UTIs refer to infection above the bladder, and include the ureters and kidneys. Infection of the urinary tract above the bladder is known as pyelonephritis [which] may be life threatening or lead to permanent kidney damage if not promptly treated. UTIs are also classified as complicated or uncomplicated. UTIs in men, the elderly, pregnant women, those who have an indwelling catheter, and anatomic or functional abnormality of the urinary tract are considered to be complicated. A complicated UTI will often receive longer courses of broader spectrum antibiotics. Importantly, the clinical history alone of dysuria and frequency (without vaginal discharge) is associated with more than 90% probability of a UTI in healthy women. […] In women, a UTI develops when urinary pathogens from the bowel or vagina colonize the urethral mucosa, and ascend via the urethra into the bladder. During an uncomplicated symptomatic UTI in women, it is rare for infection to ascend via the ureter into the kidney to cause pyelonephritis. […] Up to 40% of uncomplicated lower UTIs in women will resolve spontaneously without antimicrobial therapy. The use of antibiotics in this cohort is controversial when taking into account the side effects of antibiotics and their effect on normal flora. If prescribed, antibiotics for uncomplicated lower UTIs should be narrow-spectrum […] Most healthcare-associated UTIs are associated with the use of urinary catheters. Each day the catheter remains in situ, the risk of UTI rises by around 5%. Thus inserting catheters only when absolutely needed, and ensuring they are removed as soon as possible, can prevent these.”
The stuff below covers material from the last half of part V in Holmes et al. This previous post also dealt with this topic (the title of this post is the title of part 5 of the book, which if not hidden away in a 2000+ page textbook might well have been a book of its own; I’m quite sure you can find entire books on these topics which go into much less detail than does part 5 of this book). Some of the stuff was really hard to read; I’ve tried to include in this post mainly stuff people who have not read the rest of the coverage might be expected to understand without too much difficulty.
“Antibody to EBV [Epstein-Barr Virus] can be detected in 90-95% of the population by adulthood.10 Primary exposure often occurs in the first years of life, with seroconversion evident before the age of 5 years in 50% of children studied in the United States and Great Britain.22,23 In economically advantaged communities, primary infection may be delayed until adolescence or early adulthood,24 at which time acquisition of virus produces the clinical syndrome acute infectious mononucleosis. […] Primary EBV infection in infancy or early childhood is usually subclinical, but when delayed until the second decade of life, it manifests as infectious mononucleosis in up to 50% of patients. A self-limiting lymphoproliferative disease, the syndrome consists of fever, headache, pharyngitis, lymphadenopathy, and general malaise. Resolution of symptoms may take weeks to months, but primary infection is always followed by the establishment of a permanent viral carrier state.”
“a highly significant correlation between seropositivity for EBV, sexual intercourse, and an increasing number of sexual partners was found in a cross-sectional analysis of 1006 new University students.50 In this study, two-thirds of infectious mononucleosis cases were statistically attributable to sexual intercourse, whereas only a tenth of asymptomatic primary infections were linked to sexual activity.” [This is of course just a cross-sectional analysis, but even so – ‘kissing disease‘ may perhaps be a slightly inaccurate term…]
“The overall size of the EBV-infected B cell reservoir is largely controlled by CD8+, HLA class I-restricted, EBV-specific cytotoxic T lymphocytes (CTLs). Up to 5% of the total circulating CD8+ T cell pool may be committed to this single virus in the EBV-carrier state,110 indicating the critical role for T-cell surveillance in maintaining the host: virus balance. Impaired CTL responses in immunosuppressed patients such as transplant recipients or HIV-1-infected individuals32,111 leads to an expansion of the infected B cell population and potentially fatal lymphoproliferative disease. The contribution of virus-specific CTLs in immune regulation of EBV-induced lymphoproliferation has been made clear by recent therapeutic interventions involving adoptive transfer of virus-specific T lymphocytes to restore immunity against EBV infection in bone marrow transplant recipients.112, 113, 114”
“Non-Hodgkin’s lymphoma, an AIDS-defining cancer some 60 times more common in AIDS patients than in the general population,122 can be divided morphologically into Burkitt-like and immunoblastic lymphomas […]. Both have a higher association with EBV (30-40% and 75-80%, respectively) in AIDS than in non-AIDS groups.123,124 […] Burkitt’s lymphomas appear early in the course of AIDS, prior to profound immunosuppression, whereas immunoblastic lymphomas typically occur in late-stage AIDS when cellular immunity is compromised. […] Hodgkin’s lymphomas in the setting of AIDS contain EBV in 75-90% of the cases,140,141 reflecting the unusually high frequency in the HIV-infected population of mixed-cellularity and lymphocyte-depletion subtypes142 known to be most closely associated with EBV in the general population.15,16 Although not considered an AIDS-defining illness, Hodgkin’s lymphoma occurs with increased frequency in the setting of HIV infection. […] Our understanding of the precise role of EBV in the biology of each malignancy remains rudimentary.”
“Papillomaviruses are a group of small DNA viruses that primarily induce epithelial cell proliferation, or papillomas, in higher vertebrates. Infections are strictly genus or species specific and there is considerable tropism among the viruses for particular anatomic sites. […] The genomes of over 100 human papillomavirus (HPV) types have been molecularly cloned and completely sequenced and partial sequences for potentially up to another hundred types have been detected by PCR-based assays.9,10”
[You can skip this part without missing out on anything important:] “A basal level of transcription from the p97/p105 promoter is regulated by the keratinocyte-dependent enhancer in the NCR and can be repressed by binding of E2 to its cognate recognition sequences located adjacent to the p97/p105 TATA boxes.82,87 E2 has a role in repressing transcription from the viral promoter and its loss on viral DNA integration allows increased expression of the oncogenic proteins E6 and E7. E2 also activates transcription under some circumstances.88 Variations in binding to four different E2 binding sites may contribute to transcriptional regulation.89 Interestingly, the E8E2C protein of HPV-31 had an ability to repress transcription from a single promoter-distal E2 binding site. This activity was lacking in the full-length E2, suggesting that E8E2C has a role in regulating transcription.90 E2 binds the general transcription factor TFIIB91 and is thought to directly inhibit HPV transcription at a step subsequent to binding of TBP or TFIID to the TATA box.92 It interacts with numerous other transcription factors and chromatin modification factors including CBP,93 p/CAF,94 C/EBP,95 nucleosome assembly protein 1,96 and Top BP1.97 An interaction between bromodomain protein 4 and E2 is required for transcriptional activation by E2.98 Two crystal structure studies of the amino terminal transcription activation domain of E2 suggested that dimerization of E2 helps recruit distal transcription factors to the viral transcription complex99 …” [I decided to include a quote like this as well to indicate what kind of stuff the book is also full of, and illustrate why it was hard to read. There’s a lot of stuff in some of these chapters which I had a really hard time following.]
“Predictions about the role of HPV in neoplasia obtained from experimental studies are consistent with the natural history of cervical cancer. Among women who develop squamous intraepithelial lesions, the time from first detection of viral DNA to lesions is short, ~2 years, though factors like number of partners and infection with other STDs may influence the interval […]. Even mildly dysplastic lesions show an increase in proliferation and polyploidization. These changes result as a direct consequence of expression of E6/E7. The median age of carcinoma in situ (CIS) in the United States is 29,223,224 indicating that approximately a decade has elapsed between the initial infection and severe dysplasia. CIS lesions are characterized by their aneuploid DNA content and thus reflect the genetic instability that accompanies prolonged expression of E6/E7. The preneoplastic lesions can regress spontaneously. One principle explanation for their regression is likely to be an effective immune response, and generalized T-cell deficiency has been associated with increased dysplasia […]. Other explanations may include the fact that some, perhaps most, alterations will be deleterious, resulting in cell death. The median age of invasive cervical cancer in the United States is 49, indicating that additional changes required for invasion and metastasis are acquired slowly over time.”
“All HPV types are linked to the development of low-grade cervical SILs [squamous intraepithelial lesions],16 whereas high-grade cervical SILs are usually positive for oncogenic HPV types.272 In a cohort of young women in the United States, Moscicki et al.155 reported that 15% developed LSIL within 3 years after initial HPV infection, and in the UK, Woodman et al.70 reported that the 3-year cumulative incidence of any cytologic abnormality after initial infection was 33%. In another cohort of young women in the United States, Winer et al.132 reported that approximately 50% developed a low-grade lesion within 3 years after initial HPV infection […]. The latter study also reported that rates of lesion detection tend to increase with increased screening frequency, due to spontaneous regression of most low-grade lesions. Therefore, the shorter interval between follow-up visits (4 vs. 6 months) may explain why that study detected LSIL in a higher proportion of women. Half of newly detected low-grade lesions appear to regress within 6-9 months.70,132,273 It also appears that vaginal SIL is not uncommon among women with incident HPV infections. While less commonly detected than cervical SIL, one study reported that almost 30% of women with incident HPV infections developed vaginal SIL within 3 years (Fig. 28-3B), and the median duration of these lesions was less than 5 months.132
Results from natural history studies suggest that LSILs are transient manifestations of productive HPV infections, whereas HSILs are cervical cancer precursor lesions. This is in contrast to the previously held theory that cervical carcinogenesis always follows a progression from persistent HPV infection to development of low- and then high-grade lesions. Several recent studies have shown that cervical highgrade lesions are a relatively early manifestation of HPV infections in young women. Woodman et al.70 reported that the risk of high-grade lesions was highest in the first 6 months after initial HPV infection. It has also been shown that histologically confirmed high-grade lesions are common after infection with HPV 16 and 18 infections,132,274 with one study reporting that 27% of women with incident HPV 16 or 18 infections developed histologically confirmed CIN grade 2 or 3 within 3 years […] and that the median time to development was 14 months.132”
“Although viral hepatitis is unquestionably an ancient disease, it is only in the past 40 years that an appreciation has emerged of the diversity of infectious agents capable of causing the clinical syndrome of acute hepatitis. […] at least five distinctly different human viruses (classified as hepatitis A through E) are now generally recognized to be causative agents of acute and/or chronic viral hepatitis […].
Hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis delta virus (HDV), and hepatitis E virus (HEV) all share a remarkable tropism for the liver despite profound differences in their physical structure, pathobiology, and epidemiology. Each of these viruses is a cause of clinically overt acute hepatitis associated with frank jaundice. The severity of the liver disease, which frequently accompanies acute infection with these viruses, generally distinguishes them from cytomegalovirus and Epstein-Barr virus, which typically cause much milder liver dysfunction during primary infections. Within the United States, almost all cases of acute hepatitis are caused by infection with HAV (51%), HBV (40%), or HCV (9%).3 These acute hepatitis virus infections cannot be distinguished from each other without serologic testing. Acute hepatitis represents a considerable disease burden within the United States, with an estimated 40,000-60,000 clinical cases occurring annually during the past 5 years. Only a fraction of these cases are reported to public health authorities, and a substantial number of additional infections do not come to medical attention because they are asymptomatic. Fulminant hepatic failure and death occur in a very small proportion of patients with acute hepatitis A or B, but these clinical endpoints are rarely associated with acute HCV infection in the United States.4,5”
“The major burden of disease due to hepatitis virus infections stems from the chronic liver damage that occurs in individuals who develop persistent infections. The proportion of persons who become persistently infected is highly dependent on the infecting virus. Persistent infections with HAV are not well documented and may never occur. On the other hand, more than 50% of persons infected with HCV fail to clear the virus and most eventually develop biochemical and histologic evidence of chronic liver disease.6 HBV has an intermediate tendency to establish persistence, with the risk of persistent infection being highly dependent on the age at the time of infection and immunologic competence of the individual.
It is appropriate to focus attention on the hepatitis viruses in a textbook concerned with sexually transmitted diseases (STDs). Although these are systemic infections that are also commonly transmitted by other means, HBV is a sexually transmitted infection, and sexual activity may profoundly influence the risks for acquisition of HAV. To a lesser extent, sexual behavior may also influence the risk of infection with HCV and HDV.”
“Several factors account for the high risk of HBV infection among MSM [Males who have Sex with Males], which was noted in […] early studies. One of the most important factors was the number of sexual partners. The typical homosexually active male frequenting Denver’s steam baths in the late 1970s had eight different male sexual contacts per month.206 These contacts were largely anonymous and could total as many as 1000 over the lifetime of a gay man.”
“The endemicity of HBV infection varies greatly worldwide and is influenced primarily by the predominant age at which infection occurs.121,190 Endemicity of infection is considered high in those parts of the world where at least 8% of the population is HBsAg positive, and 70-90% of the population has serological evidence of previous HBV infection. Almost all infections occur during either the perinatal period or early in childhood, which accounts for the high rates of chronic HBV infection in these populations. Risk of HBV infection continues after the first 5 years of life, but its eventual contribution to the high rate of chronic infection is less significant. Chronic infection with HBV is strongly associated with HCC [liver cancer], and areas with a high endemicity of chronic HBV infection have the highest death rates from this neoplasm. […]
In most developed parts of the world, including the United States and Western Europe, the prevalence of chronic HBV infection is <1%, and the overall infection rate is 5-7%. The highest incidence of acute hepatitis B is among young adults, and high-risk sexual activity and injectable drug use account for most cases of newly acquired hepatitis B.191, 192, 193, 194 In the United States, heterosexual activity accounts for 40% of new hepatitis B cases, while MSM represent 15% of new cases.”
“HCV infection accounts for 15% of acute viral hepatitis cases within the United States. However, it is by far the leading cause of chronic viral hepatitis and is present in over 40% of persons with chronic liver disease. The morbidity and mortality associated with HCV infection are due to its unique propensity to cause persistent infection in most persons, a feature that distinguishes this virus from other hepatitis viruses. The specific mechanisms underlying viral persistence are not known.
Although it has been controversial, the balance of evidence now favors the occasional sexual transmission of HCV. The risk of infection with HCV, like HBV, has been independently related to numbers of sexual partners in some STD clinic studies.226,285 Although the risk of HCV infection has been shown to correlate with numbers of partners and/or specific sexual practices in some studies of homosexual men,286,287 the risk of infection is overwhelmingly more closely tied to injection drug use. […] About 60-85% of all infections lead to virus persistence, and this is often associated with evidence of chronic liver disease […]. After many years, this process may culminate in cirrhosis and liver failure, or the development of hepatocellular carcinoma. These end-stage events in chronic hepatitis C may claim as many as 10,000 lives annually in the United States.326 […] As many as a third of patients found to have chronic hepatitis C will ultimately develop cirrhosis6,284,333,334; although it is not well defined, the fraction of all patients who are infected with the virus and progress to cirrhosis is undoubtedly far lower. Cirrhosis may be present within as little as 60 months of the initial infection but is identified typically in persons who have been infected for decades. Factors associated with disease progression include age at infection, regular alcohol consumption, coinfection with HIV or HBV, and more recently obesity and insulin resistance.335, 336 Some patients, usually with well-established cirrhosis, develop primary hepatocellular carcinoma.283 Chronic HCV infection is the most important etiology of hepatocellular carcinoma in western countries.
The major challenge to clinical investigators has been the discovery of specific markers that are predictive of progression of chronic hepatitis C to a clinically significant disease state. This remains an exceptionally difficult problem. There is no good correlation between biochemical markers and the extent of fibrosis or the presence or absence of cirrhosis. Indeed, many patients with cirrhosis have no obvious laboratory abnormalities.333 In addition, quantitative measurements of the viremia (“virus load”) are not useful in determining the extent of disease resistance.335, 336”
“[H]uman papilloma virus, hepatitis B virus, hepatitis C virus, Epstein-Barr virus, human herpes virus 8, human T-cell lymphotropic virus 1, human immunodeficiency virus, Merkel cell polyomavirus, Helicobacter pylori, Opisthorchis viverrini, Clonorchis sinensis, Schistosoma haematobium […] are recognized as carcinogens and probable carcinogens by [the] International Agency for Research on Cancer (IARC). They are not considered in this book […] The aim of this monograph is to analyze associations of other infectious agents with cancer risk […] virology is not considered in our monograph: although there are some viruses that can be connected with cancer but are not included into the IARC list (John Cunningham virus, herpes simplex virus-1 and -2, human cytomegalovirus, simian virus 40, xenotropic murine leukemia virus-related virus), we decided to leave them for the virologists and to concentrate our efforts on other infectious agents (bacteria, protozoa, helminths and fungi) […] To the best of our knowledge, this is the first book devoted to this problem”
Here’s what I wrote on goodreads:
“This book is written by three Russian researchers, and you can tell; the language is occasionally hilariously bad, but it’s not too difficult to figure out what they’re trying to say. The content partially made up for the poor language, as the book covers quite a bit of ground considering the low page count.”
I gave the book two stars. I’m glad they wrote the book, because it covered some stuff I didn’t know much about. I think I’m closer to one star than three, but it’s mostly because it’s terribly written, not because I have major objections to the coverage as such. What I mean by this is that they talk about a lot of studies and they include a lot of data – they’re scientists who write about scientific research, they just happen to be Russian scientists who are not very good at English. It’s terribly written, but the stuff is interesting.
As mentioned above there are quite a few viruses which we know may lead to cancer in humans. I’ve recently read a lot of stuff about this topic as it was covered in both Boffetta at el. and also rather extensively in part 5 of the Sexually Transmitted Diseases text, which covered sexually transmitted viral pathogens (that section of the book was with its 230 pages actually a ‘book-length section’; it was significantly longer than this book is..). I’ve even covered some of that stuff here on the blog, e.g. here. I may incidentally write more about these things and related stuff later, as I’m quite far behind in terms of my intended coverage of the STD book at the moment.
Anyway, viruses aren’t the only bad guys around. So these guys decided to write a book about some other infectious diseases affecting humans, and how these infectious diseases may relate to cancer risk. As they point out in the book, “there is only one bacterium, Helicobacter pylori, which is recognized by IARC as an established human carcinogen.” After reading this book you’ll realize that there are some others which perhaps look a bit suspicious as well. In some cases a lot of studies have been done and you have both animal-models, lab-analyses, case-control studies, cohort studies, … In other cases you have just a few small studies to judge from. As is always the case when people have a close look at epidemiological research, this stuff is messy. Sometimes studies that looked really convincing turn out to not replicate in larger samples, sometimes dramatically different effect sizes are found in different areas of the world (which may of course both be interpreted as an indicator that the ‘true’ effect sizes are different in the different subpopulations, or it may be interpreted as a result e.g. of faulty study design which makes those Swedish data look really fishy..), sometimes different results can be explained by differences in data quality/type of data applied/etc. (classic cases are different effects based on whether you rely on self reports or biological disease markers, and different results from analyses of bacterial cultures vs PCR analyses), and so on and so forth. There are a lot of details, and they cover them in the book. I occasionally see people criticize epidemiological research online on the grounds that many (‘all?’) results published in this area are just random correlations without any deeper meaning. Sometimes this criticism may well be warranted, and the authors of this book certainly in some cases seem to go quite a bit further than I would do based on the same data. But there’s another part of the story here. When you start out with a couple of case-control studies indicating that guys with cancer type X are more likely to have positive lab cultures for this specific micro-organism, that may not be a big deal. But perhaps then a few microbiologists show up and tell you that it would actually make a lot of sense if there was a connection here (and they might start talking about fancy stuff like various ‘modulations of host immune responses’, ‘inflammatory markers’, ‘the role of nitric oxides’, …). They conduct some studies as well and perhaps one of the things they find is that the observed cancer grades in the patients seem to depend quite a lot upon which of the pathogen subtypes the individual happen to be infected with (perhaps suddenly also providing an explanation for some previously surprising negative results in specific cases). And then perhaps you get a couple of animal studies that show that these animals get cancer when you infect them with these bugs and don’t treat the infection. Perhaps you have a few more studies as well in different populations, because Chinese people get cancer too, and you start seeing that people around the world who happen to be infected with these bugs are all more likely to get cancer, compared to the locals who are not infected (…or perhaps not, and then it just gets more fun…). This process goes on for a while, until at some point it starts getting really hard to think these positive correlations are all just the result of random p-value hunting done by bored researchers who don’t know what else to do with their time, and you start asking yourself if perhaps this idea is not as stupid as it was when you first encountered it. Most of the time the process stops before then because the proposed link isn’t there, but modern epidemiology is not just random collections of correlations.
In the context of the specific infectious diseases covered in the book the people who have in some sense the final say in these things (the IARC) think we’re not quite there yet, but you have some cases where some different lines of evidence all seem to indicate that a link may be present and relevant. It would be highly surprising to me if in 20 years time we’d have realized that none of the infectious diseases they talk about in this book are at all involved in cancer pathogenesis. A related point is that most likely we’ve missed some ‘true connections’ along the way, and will continue to do so in the future, because even if a link is there, it’s sometimes really hard to find it and easy to overlook it, for many different reasons.
I have quoted a bit from the book below and added some comments here and there. I have corrected some of the spelling/language errors the authors made to ease reading; if a word is placed in brackets, it’s an indicator that I’ve replaced a misspelled word by the correct one (‘they meant to use’). The authors do not even have any clue how and when to use the word ‘the’, often using it when it’s not needed and forgetting to use it in cases where it is needed, which made quoting from the book painful. Read it for the content.
“Chronic inflammation substantially increases the probability of neoplastic transformation of the surrounding cells, inducing mutations and epigenetic alterations by the activity of inflammatory molecules […] through the formation of free radicals and DNA damage […] Since infectious agents persisting in the organism may cause chronic inflammation, they can also promote local carcinogenesis. […] Chronic inflammation can also specifically affect the functioning of [an] organ, for instance, promoting cholelithiasis and urolithiasis that increase the time of exposure of the gallbladder, bile ducts, urinary bladder and ureters to chemical carcinogens and carcinogenic bacteria. […] In addition to […] metabolic and immune mechanisms, a number of bacteria […] and protozoa […] [produce] or [contain] in their cell wall their own toxins […] possessing [carcinogenic] activity, affecting cell-cell interactions, intracellular signal transduction or induction of mutations and epigenetic alterations that can influence vital cell processes (apoptosis, proliferation, survival, growth, differentiation, invasion). Intracellular protozoan (Toxoplasma gondii) may induce resistance to multiple mechanisms of apoptosis […]. So, bacterial and [protozoan toxins] may function like initiating or like promoting agents.”
“Typhoid fever, which is a systemic infection caused by Salmonella enterica serovar Typhi (S. typhi), is a major health problem in developing countries. There are approximately 21.6 million cases of typhoid fever worldwide and an estimated 200,000 deaths every year. It is known that S. typhi may colonize the gallbladder, causing […] chronic inflammation. Welton et al. (1979) were the very first to [establish] an association between the typhoid-carrier state and death due to malignancies of the hepatobiliary tract. They recruited 471 U.S. carriers of [S. typhi] , matched them with 942 controls and demonstrated that chronic typhoid carriers died of hepatobiliary cancer six times more often than the controls. […] The absence of basic research analyzing the carcinogenic properties of S. typhi does not allow placing it in the short list of the infectious agents that may be a cause of cancer development but are not included in the IARC roster, but this bacterium undoubtedly should be [on] the extended list. If [basic] studies on cell lines and animal models [support] the results of [the] epidemiological investigations, S. typhi can be placed [on] the short list.” [I included this in part because it is one of several examples in the book of how even strong correlations and high relative risks are not considered sufficient on their own by epidemiologists to settle matters. Some relative risks in other studies have been even higher – a study on gall-bladder cancer found an RR of 12.7].
“Tuberculosis (TB), a destructive disease [affecting] the lungs […] is a major global health burden, with about nine million of new cases and 1.1 million deaths annually. When the host protective immunity fails to control M. tuberculosis growth, progression to active disease occurs. […] According to the data of the last comprehensive systematic review and [meta-analysis] published by Brenner et al. (2011), there were 30 studies […] conducted in North America, Europe and Asia, which investigated the association of tuberculosis on lung cancer risk with adjustment for smoking. The relative risk (RR) of lung cancer development among patients with TB history was 1.76 (95% CI = 1.49–2.08).”
“22 studies from North America, Europe and East Asia [have] investigated the association between pneumonia and lung cancer risk while adjusting for smoking […] A significant increase in lung cancer risk was observed among all studies (RR = 1.43, 95% CI = 1.22–1.68). […] To sum up, there are basic as well as extensive epidemiological evidence that С. pneumoniae may cause lung cancer” [However effect sizes seem to be different in different countries. I was skeptical about this one in part because a non-smoker’s absolute risk of getting lung cancer is very low, meaning that relative risks in the neighbourhood reported above although statistically significant probably are clinically insignificant. How pneumonia and smoking interact seems to me a much more important question. Then again we haven’t got an explanation for all of the non-smoking-related lung cancers yet, and they are caused by something, so it’s also not like researching this is a complete waste of time.]
“Primary infection with C. trachomatis [Chlamydia], the most prevalent sexually transmitted bacterium worldwide with an estimated 90 million new cases occurring each year, is often asymptomatic and may persist for several months or years. The first study analyzing possible association of C. trachomatis with cervical cancer was carried out by Schachter et al. (1975) who assessed the prevalence of antibodies to TRIC (trachoma-inclusion conjunctivitis) agents in women with cervical dysplasia and in women attending selected clinics […]. According to this investigation, antibodies to chlamydiae were identified in 77.6% of the women with dysplasia or cervical cancer whereas antichlamydial antibodies were less prevalent in the other clinic populations. Four years later, Paavonen et al. (1979) obtained [similar] results in 93 of patients with cervical dysplasia comparing them to the controls. […] Smith et al. (2001, 2002) examined 499 women with incident invasive cervical cancer cases and 539 control patients from Brazil and the Philippines, detecting that C. trachomatis increased risk of squamous cervical cancer among HPV-positive women (OR=2.1; 95% CI=1.1–4.0). The results were similar in both countries.” [As I recently pointed out elsewhere, “Chronic infection with HPV is a necessary cause of cervical cancer. Using sensitive molecular techniques, virtually all tumours are positive for the virus.” But as this finding (and other related findings) indicate, other infectious processes may play a role as well in HPV-related cancers. Synergistic effects are common in this area (recall for example also the herpes simplex virus-HIV link).]
“Trichomonas vaginalis (T. vaginalis), a protozoan parasite, is the causative agent of trichomoniasis, the most common nonviral sexually transmitted disease in humans. This parasite has a worldwide distribution and it infects 250–350 million people worldwide. [wiki says ~150 mil, but these guesstimates should always be taken with a grain of salt. Either way it affects a lot of people] […] Zhang et al. (1995) observed a relationship between T. vaginalis infection and cervical cancer in [their] prospective study in a cohort of 16,797 Chinese women. T. vaginalis-infection correlated with higher cervical cancer risk (RR=3.3, 95% CI=1.5–7.4). In a large cohort study conducted in Finland by Viikki et al. (2000) T. vaginalis was associated with a high RR of cervical cancer, 6.4 (95% CI = 3.7–10) and SIR [standardized incidence ratio]=5.5 (95% CI=4.2–7.2s), respectively. […] Mekki and Ivić (1979), detected that T. vaginalis were of a significantly smaller diameter in invasive carcinoma and carcinoma in situ in comparison with dysplasia. In the control group with trichomoniasis alone, the diameter of T. vaginalis was twice as large as that in carcinoma and larger compared to dysplasia, indicating that small forms of T. vaginalis are more carcinogenic than large ones. […] To sum up, there are basic as well as epidemiological evidence that T. vaginalis may be a cause of cervical and prostate cancer […] For cervical cancer it is evident, for prostate cancer it is arguable. According to our criteria, it is possible to include it in the short list of the infectious agents that may be a cause of cancer development but are not placed in the IARC roster.”
“At the moment of publication, IARC [recognizes] Schistosoma haematobium [and] [S. mansoni], Opisthorchis viverrini, and Clonorchis sinensis as causative agents of cancer, leaving a possibility to enlarge this list by [Schistosoma japonicum] [and] Opisthorchis felineus.” [The authors think the list should be enlarged even more, but I did not find their helmith data/coverage very convincing (not much research has been done in this area), so I decided not to cover these things here].
“Neoplasms include several hundreds of diseases, which can be distinguished by localization, morphology, clinical behaviour and response to therapy. […] Malignant neoplasms are characterized by progressive growth of tissue with structural and functional alterations with respect to the normal tissue. In some cases, the alterations can be so important that it becomes difficult to identify the tissue of origin. A peculiarity of most malignant tumours is the ability to migrate and colonize other organs (metastatization) via blood and lymph vessel penetration. The presence and extension of metastases are often the critical factors to determine the success of therapy and the survival of cancer patients. The pace of growth of malignant neoplasms varies widely, and asymptomatic neoplasms are often found at autopsy of individuals deceased from other causes. […] Most malignant neoplasms (about 90 %) in adults arise from epithelial tissues and are defined as carcinomas. […] Knowledge about the causes and the possible preventive strategies for malignant neoplasms has greatly advanced during the last decades. This has been largely based on the development of cancer epidemiology.”
I finished this book yesterday. I complained in my coverage of Managing Cardiovascular Complications in Diabetes that that book was full of formatting errors and that it seemed that nobody had proofread the book before publication, and I said in that post that ‘It’s much rarer, I think, to see stuff like that in Springer publications.’ I might be wrong about this, or at least I’ve updated my priors on that one; this specific book was even worse than the Managing Cardiovascular complications book in that respect – errors are all over the place. It’s odd and also slightly annoying, because if not for that problem I would consider this book to be a really nice little resource.
The book deals mainly with the data, and it is not a methodology text. Occasionally how we know what we know is important and the limits of our knowledge is important, so methodological questions are addressed here and there; but you certainly don’t need to have read a book like this to understand it, and although many specific details in the book presumably would not be understood by a random guy who’d just finished high school, most of the book is relatively easy to follow. This disease is this common in this area and that common in that area and the difference between these two areas may be due to these things; it kills this many people; these are some of the risk factors we know about, and the role they play is this – most of the book deals with questions such as these, and there are only so many ways you can make stuff like that impossible to understand by using a lot of fancy medical terms.
The book provides an excellent overview and the data and the level of coverage is actually quite excellent considering the length of the book – if not for the many errors and general sloppiness I’d feel tempted to give it a high rating. We know more than I thought we knew about these things, which is nice, and a few of the observations included were surprising to me. Of course a lot of details are missing but this is to be expected – people have written books about topics covered in a few pages here (e.g. this). If you read Mukherjee and this book, I think you’ll be off to a great start in terms of understanding cancer better; the obvious next step would be a book like this, but most people are probably not going to read stuff like that.
I should point out that perhaps I was a bit too hard on the lecture about the UK million women study in the recent Open Thread – I find it important to note in particular that specific topics also covered in this book, such as the role of birth control and hormone replacement therapy in cancer development, are covered in more detail in that lecture than they are in this book; so I refer you to that lecture, rather than covering that stuff below. Some of this stuff is the sort of stuff I’d probably want to know about if I were of the opposite gender. I should point out as well here that one of the reasons I did not think too highly of her lecture relates to her comments about cancer screening during the lecture (I think it’s around the 35 minute mark or so). Those comments annoyed me because I think she’s being intellectually dishonest during her lecture by not addressing the main problems with the pro-screening position, but only presents a weaker argument (to an audience unlikely to know any better) which is much easier to knock down – in the context of breast cancer screening the main argument against them, from what I’ve gathered, is not that these things do not save any lives (though there’s also a lively debate about how many lives are actually saved and how you should go about estimating this number), but rather that the costs – both monetary and non-monetary (the latter e.g. relating to the mental anguish experienced by the many, many women who get a false positive test result) – are not justified; there’s much more about these and related things in this book. In general it’s safe to say that it’s quite a bit harder to ‘properly justify’ screening programmes than many doctors often seem to think it is. Anyway the book doesn’t go into much detail about these things, and you’ll have to look elsewhere (e.g. Juth and Munthe) for detailed coverage of stuff like that.
I have added some observations from the book below and a few comments.
“Analytical studies (case–control and cohort) have shown the causal role of specific exposures in the aetiology of several malignant neoplasms. One limitation of the epidemiological approach, which may prove of critical importance in trying to detect comparatively small increases in risk, as in the case of environmental pollutants, is that even in the best conditions it is impossible to confidently identify by epidemiological means an increase in risk smaller than say 10–20 % (and serious problems arise in the interpretation of increases below 50 %), as the biases inherent in any observational study are of at least this order of magnitude (Adami et al. 2008).”
“In addition to lead-time bias, three types of bias are peculiar to the assessment of screening programmes. Because of self-selection, persons who elect to receive early detection may be different from those who do not: for instance, they may belong to better educated classes, be generally healthier and health conscious, and this could produce a longer survival independent of any effect of early detection. In addition, cancers with longer pre-clinical phases, which may mean less biological aggressiveness and better prognosis, are, in any case, more likely to be intercepted by a programme of periodical screening than cancers with a short pre-clinical phase, and a rapid, aggressive clinical course (length bias). Finally, because of criteria of positivity adopted to maximize yield of early cases, a number of lesions which in fact would never become malignant growths are included as ‘cases’, thus falsely improve the survival statistics (over-diagnosis bias).”
“The number of new cases of cancer which occurred worldwide in 2008 has been estimated at about 12,700,000 […]. Of these, 6,600,000 occurred in men and 6,000,000 in women. About 5,600,000 cases occurred in high-resource countries (North America, Japan, Europe including Russia, Australia and New Zealand) and 7,100,000 in low- and medium-resource countries. Among men, lung, stomach, colorectal, prostate and liver cancers are the most common malignant neoplasms […], while breast, colorectal, cervical, lung and stomach are the most common neoplasms among women […] The number of deaths from cancer was estimated at about 7,600,000 in 2008 […] No global estimates of survival from cancer are available: data from selected cancer registries suggest wide disparities between high- and low-resource countries for neoplasms with effective but expensive treatment, such as leukaemia, while the gap is narrow for neoplasms without an effective therapy, such as lung cancer […] The overall 5-year survival of cases diagnosed during 1995–1999 in 23 European countries was 49.6 % (Sant et al. 2009).”
“Survival from breast cancer has slowly increased in high-resource countries, where it now achieves 85 %, following improvements in screening practices and treatments. Survival in low-resource countries remains poor, in the order of 50–60 %. Breast cancer is the most common cancer among women worldwide: the estimated number of new cases in 2012 was 1,680,000” [I had no idea survival rates were that high in ‘high-resource countries’, though it’s a bit problematic that it is not spelled out what is actually meant by ‘survival’; I gather from this link that it’s the 5-year survival rate.]
“Tobacco smoking is the main single cause of human cancer worldwide (IARC 2004) and the largest cause of death and disease. It is the key cause of lung cancer, and a major cause of cancers of the oral cavity, pharynx, nasal cavity, larynx, oesophagus, stomach, pancreas, uterine cervix, kidney and bladder, as well as of myeloid leukemia. In high-resource countries, tobacco smoking causes approximately 30 % of all human cancers (Doll and Peto 2005). […] A benefit of quitting tobacco smoking in adulthood has been shown for all major cancers causally associated with the habit. Smokers who stop around age 50 avoid over 50 % of overall excess mortality from all causes (Doll et al. 2004; Jha et al. 2013; Pirie et al. 2013), from lung cancers (Peto et al. 2000) and well as from other tobacco-related cancers (Bosetti et al. 2008a), and those who stop around age 40 or earlier avoid most of their tobacco-related cancer risk. […] “The risk of lung cancer among smokers relative to the risk among never-smokers is in the order of over 20-fold […] In the UK million women study, the RRs [relative risks] of lung cancer were 10.5 for current smokers of 10 cigarettes per day, 22.0 for 15, and 36.0 for ≥20 cigarettes per day. […] An association has been shown in many studies between exposure to involuntary smoking and lung cancer risk in non-smokers. The magnitude of the excess risk among non-smokers exposed to involuntary smoking is in the order 20 % (IARC 2004).” [You have a 20% risk increase from passive smoking and a twenty-fold increase from smoking. My conclusion from these observations would be that in terms of cancer risk passive smoking doesn’t really matter in the big picture, and that it is overhyped as a disease risk factor – the excess cancer risk attributable to smoking probably causes more than 100 cancers in smokers for each cancer case in a non-smoker, and most of the non-smokers who develop cancerous lesions will have been exposing themselves for years – questioning the assumption that they did not willingly take on this risk]. Lung cancer is “the most important cause of cancer death worldwide. It accounts for an estimated 1,250,000 new cases and 1,100,000 deaths each year among men and 580,000 cases and 500,000 deaths among women […]. Survival from lung cancer is poor (around 10 % at 5 years).”
“The role of dietary factors in causing human cancer remains largely obscure. For no dietary factor other than alcohol […] and aflatoxin (a carcinogen produced by some fungi in certain tropical areas) there is sufficient evidence of an increased or decreased risk of cancer. […] Alcohol drinking increases the risk of cancers of the oral cavity, pharynx, larynx, oesophagus and liver, colorectum and female breast (Baan et al. 2007). For all cancer sites, risk is a function of the amount of alcohol consumed […] The global burden of cancer attributable to alcohol drinking has been estimated at 3.6 and 3.5 % of cancer deaths (Boffetta 2006), although this figure is higher in high-resource countries (e.g., the figure of 6 % has been proposed for United Kingdom (Doll and Peto 2005) , and 9 % in Central and Eastern Europe). These included over 5 % of cancers and cancer deaths in men and about 1.5 % of cancers and cancer deaths in women. […] Systematic reviews have concluded that nutritional factors may be responsible for about one-fourth of human cancers in high-resource countries, although, because of the limitations of the current understanding of the precise role of diet in human cancer, the proportion of cancers known to be avoidable in practicable ways is much smaller (Doll and Peto 2005). The only justified dietary recommendation for cancer prevention is to reduce total caloric intake, which would contribute to a decrease in obesity, an established risk factor for human cancer […] There is sufficient evidence for a cancer preventive effect of avoidance of weight gain, based on a decreased risk of cancers of the colon, gallbladder, post- menopausal breast, endometrium, kidney and esophagus (adenocarcinoma) […] Estimates of the proportion of cancers attributable to overweight and obesity in Europe range from 2 % (Doll and Peto 2005) to 5 % (Bergstrom et al. 2001).”
“There is growing evidence that chronic infection with some viruses, bacteria and parasites represents a major risk factor for human cancer, in particular in low-income countries […] The population attributable fraction for infectious agents was 16.1 % in 2008, meaning that around two million new cancer cases were attributable to infections. HBV and HCV-related liver cancer, HPV-related cervical cancer and Helicobacter pylori-related stomach cancer overall are responsible for 95 % of the total number of infection-related cancers. The estimate of the attributable fraction is higher in less developed countries than in high-resource countries (22.9 % of total cancer versus 7.4 %). […] Cervical cancer is a major public health problem in many low and middle income countries. Incidence rates are high (20–40/100,000) in sub-Saharan Africa and Latin America countries, as well as in India and southern Asia. […] Chronic infection with HPV is a necessary cause of cervical cancer. Using sensitive molecular techniques, virtually all tumours are positive for the virus […]. Different types of HPV exist, and those associated with cervical cancer are mainly types 16, 18, 31, 45 and 58. In particular, HPV 16 is the main cervical carcinogen in most populations”.
“Approximately 40 occupational agents, groups of agents and mixtures have been classified as carcinogenic by IARC […] Estimates of the global burden of cancer attributable to occupation in high-income countries result in figures in the order of 1–5 % (Doll and Peto 2005 ; Schottenfeld et al. 2013). In the past, almost 50 % of these were due to asbestos alone, while in recent years the impact of asbestos on lung cancer […] is levelling off […] However, these cancers concentrate in some sectors of the population (mainly male blue-collar workers), among whom they may represent a sizable proportion of total cancers […] The available evidence suggests, in most populations, a small role of air, water, and soil pollutants. Global estimates are in the order of 1 % or less of total cancers (Doll and Peto 2005; Schottenfeld et al. 2013). This is in striking contrast with public perception, which often identifies pollution as a major cause of human cancer. However, in selected areas (e.g., residence near asbestos processing plants or in areas with drinking water contaminated by arsenic), environmental exposure to carcinogens may represent an important cancer hazard.”
“No precise estimates are available for the global contribution of drug use to human cancer. It is unlikely, however, that they represent more than 1 % in high-resource countries (Doll and Peto 2005). Furthermore, the benefits of therapies are usually much greater than the potential cancer risk.”
“A number of inherited mutations of a high-penetrance cancer gene increase dramatically the risk of some neoplasms. However, these are rare conditions in most populations and the number of cases attributable to them is rather small.” [An example: “breast cancer risk is greatly increased in carriers of mutations of several high-penetrance genes, in particular BRCA1, BRCA2, ATM, CHECK2 and p53. Although the cumulative lifetime risk in carriers of these genes is over 50 %, they are rare in most populations and explain only a small fraction (2–5 %) of total cases.”]
Warning: Long post.*
Okay, I’ve finished the book. I gave it five stars on goodreads – it’s come to my attention that I may be judging scientific publications like this one way too harshly, when you compare them with most other books. But then again I’d probably have given it four or five stars anyway; this book is an excellent source of information about the stuff it covers, and it covers a lot of stuff. In a way it’s hard to evaluate a book like this, because on the one hand you have a pretty good idea whether it’s enjoyable to read it or not, but on the other there are small chunks of it (or huge portions of it, or entire chapters, in the case of some readers…) which you are really not at all qualified to evaluate in the first place because you’re not actually sure precisely what they’re talking about**. Oh well.
As mentioned this book has a lot of stuff, and I can’t cover it all here. I’m annoyed about this, because it’s a great book. Some of this stuff is quite technical and there were parts of a few of the chapters I will not pretend to have really understood, but most of the stuff is okay in terms of the difficulty level – the book isn’t any harder to deal with than are most of Springer’s medical textbooks – and it’s interesting. In the first post I talked a little about sleeping patterns and a bit about cancer. The book has a lot of other stuff, and it has a lot of additional stuff about those things as well. Writing posts where I go into the details of books like these takes a lot of time and it’s not always something I have a great desire to do because it’s really hard to know where to stop. Let’s say for example that I were to decide to cover this book in great detail, and that I were to start out in chapter two, dealing with ‘Effects of Sleep Deficiency on Hormones, Cytokines, and Metabolism’. In that case I might decide to start out with these observations:
“Laboratory studies of both chronic and acute partial sleep restriction indicate that insufficient sleep can lead to increased hunger and caloric intake.”
“Many studies […] report that sleep independently relates to diabetes risk, even after controlling for the confounding effects of obesity and overweight. […] Cappuccio et al.  analyzed ten prospective studies with a pool of over 100,000 adults to ascertain the association of type 2 diabetes with sleep duration and quality. After controlling for BMI, age, and other confounding factors, they found [that] sleeping less than 6 h per night conferred an RR of 1.28 in predicting the incidence of type 2 diabetes, and prolonged duration (>8–9 h) had a higher RR of 1.48. As for sleep quality, Cappuccio et al. found that difficulty falling and staying asleep were highly correlated with type 2 diabetes risk with RRs of 1.48 and 1.84, respectively. […] a 3-year prospective study show[ed] that of workers with prediabetic indices, such as elevated fasting glucose, night-shift workers [were] at fivefold risk for developing overt diabetes compared to day workers .”
And I’d move on from there. So already here we’ve established not only that sleep problems may lead to changes in appetite which may lead to weight gain; that sleep problems and type 2 diabetes may be related, and perhaps not only because of the weight gain; that different aspects of sleep may play different roles (difficulty falling asleep doesn’t seem to have the same effect as does difficulty staying asleep); and that the time course from pre-diabetes to overt diabetes may be drastically accelerated in people who work night shifts. This is a lot of information, and we’re still only scratching the surface of that chapter (there are 11 chapters in the book). If I were to go into details about the diabetes thing I might be tempted to talk about how in another chapter they describe a study where three out of eight completely healthy young men were basically (temporarily) converted into prediabetics just by messing around a bit with their circadian clock in order to cause it to get out of sync with their sleep-wake cycle (a common phenomenon in people suffering from jetlag, and actually also a common problem, it seems, in blind people, as they’re generally not capable of using light to adjust melatonin release patterns and keep the circadian clock ‘up to date’, so to speak), but I really wouldn’t need to look to other chapters to talk more about that kind of stuff as the chapter also has some coverage of studies on hormonal pathways such as those involving leptin [a ‘satiety hormone’] and ghrelin [a ‘hunger hormone’]. The role of cortisol is also discussed in the chapter (and elaborated upon in a later chapter). I might decide to go into a bit more detail about these things and explain that the leptin-ghrelin connection isn’t perfectly clear here, as some studies find that sleep deprivation reduces leptin production and stimulates ghrelin release whereas other studies do not, but perhaps I’d also feel tempted to add that although this is the case, most studies do after all seem to find the effects you’d expect in light of the results from the weight gain studies I talked about in the first post (sleep deprivation -> less leptin, more ghrelin). But maybe then I’d feel the need to also talk about how it seems that these effects may depend on gender and may change over time (/with age). And I’d add that most of the lab studies are quite small studies with limited power, so it’s all a bit uncertain what all this ‘really means’. Perhaps I’d add the observation from the last chapter, where they talk more about this stuff, that the literature on these two hormones are not equally convincing: “Conflicting results have been presented for leptin […], although increases in ghrelin, an appetite-stimulating hormone, may be more uniformly observed.” Perhaps when discussion these things I’d opt for including a few remarks about the role of other hormones and circulating peptides as well, for example the “hypothalamic factors (e.g., neuropeptide Y and agouti-related peptide), gut hormones [such as] glucagon-like peptide-1 [GLP-1], peptide YY [PYY], and cholecystokinin), and adiposity signals (e.g., leptin and adiponectin)”, all of which are briefly covered in chapter 11 and all of which “have been demonstrated to play a role in the regulation of hunger, appetite, satiety, and food intake.”
As for the increased hunger and caloric intake observation, I might decide to talk about how there’s an ‘if you’re awake, you have more time to eat’-effect that may play a role (aside perhaps from the rare somnambulist, few people eat while they’re sleeping – and I’m not sure about the somnambulists either…) – but on the other hand staying awake requires more calories than does sleeping (“Contrary to the common belief that insufficient sleep reduces energy expenditure, sleep loss increases total daily energy expenditure by approximately ~5 % (~111 kcal/day).”). Those are sort of behavioural approaches to the problem, but of course there are many others and multiple mechanisms have been explored in order to better understand what happens when people are deprived of sleep – hormonal pathways is one way to go, I’ve talked a little about them already, and of course they’re revisited later in the chapter when dealing with type 2 diabetes. As an aside, in terms of hormonal pathways there’s incidentally an entire chapter on melatonin and the various roles it may play, as well as some stuff on insulin sensitivity and related matters, but that’s not chapter 2, the one we were talking about – however if I were to cover chapter 2 in detail I’d probably feel tempted to add a few remarks about that as well. But of course chapter 2 doesn’t limit coverage to just behavioural stuff and the exploration of hormonal pathways, as it seems that sleep deprivation also has potentially important neurological effects, in that it affects how the brain responds to food – and so in the chapter they talk about a couple of fMRI studies which have suggested this and perhaps indicated how those things might work, and they talk about a related study the results of which suggest that sleep deprivation may also induce impairments in self-control.
If I we’re to talk about the weight gain stuff in the chapter, I might as well also talk a bit about how sleep patterns may affect people when they’re trying to lose weight, as they talk a little bit about that as well. Those results are interesting – for example one study on weight loss that followed individuals for two weeks found that the individuals who were assigned to the sleep-deprivation condition (5.5 hours, vs 8,5 hours in the control group) had higher respiratory rates than those who did not. The higher respiratory rate the authors of the study argued was an indicator that the sleep-deprived individuals relied more on carbohydrates and less on fat than the well-rested controls, which is important if you’re dealing with weight loss regimes; however the authors in the book do not seem convinced that this was a plausible inference… Before going any further I would probably also interpose that how sleep affects breathing – and how breathing affects sleep – is really important for many other reasons as well besides weight loss stuff, so it makes a lot of sense to look at these things; stuff like intermittent hypoxia during the sleeping state, sleep disordered breathing and sleep apnea are topics important enough to have their own chapters in the book. Perhaps I’d feel tempted to mention in this context that there’s some evidence that people with sleep apnea who get cancer have a poorer prognosis than people without such sleep problems, and that we have some idea why this is the case. I actually decided to quote a bit from that part of the book below… But anyway, back to the weight loss study, an important observation from that study I might decide to include in my coverage is that: “shorter sleep duration reduced weight loss by 55 % in sleep-restricted subjects”. This is not good news, at least not for people who don’t get enough sleep and are trying to lose weight; certainly not when combined with the observation that sleep-deprived individuals in that study disproportionately lost muscle tissue, whereas individuals in the well-rested group were far more likely to lose fat. One tentative conclusion to draw is that if you’re sleep deprived while dieting your diet may be less likely to work, and if it does work the weight loss you achieve may not be nearly as healthy as you perhaps would be tempted to think it is. Another conclusion is that researchers looking at these things may miss important metabolic effects if they limit their analyses to body mass measures without taking into account e.g. tissue composition responses as well.
Actually if I were to talk about the stuff covered in chapter 2 I wouldn’t really be finished talking the type 2 diabetes and sleep problems even though I talked a little bit about that above, and so I’d probably feel tempted to say a bit more about that stuff. Knowing that sleep disorders may lead to a higher type 2 diabetes risk doesn’t tell you much if you don’t know why. So you could perhaps talk a bit about whether this excess risk only relates to insulin sensitivity? Or maybe beta cell function is implicated as well? We probably shouldn’t limit the analysis to insulin either – cortisol is important in glucose homeostasis, and perhaps that one plays a role? – yep, they’ve looked at that stuff as well. And so on and so forth … for example what role does the sympathetic nervous system and the catecholamines play in the diabetes-sleep link? The one you’d expect, or at least what you’d expect if you knew a bit of stuff about these things. A few conclusions from the chapter:
“Overall, studies suggest a strong relationship between insufficient sleep and impaired glucose homeostasis and cortisol regulation. These proximal outcomes may explain observed associations between sleep and the diabetes epidemic.” […] “The relationship suggested between sleep loss and sympathetic nervous system dysfunction [‘increased catecholamine levels’, US] proposes another likely mediator of several of the negative metabolic effects of sleep loss and sleep disorders, including insulin resistance, decreased glucose tolerance, and reduced leptin signaling”).
I’d still leave out a bit of stuff from chapter two if I were to cover it in the amount of detail ‘outlined’ above, but I hope you sort of get the picture. There are a lot of connections to be made here all over the place, a lot of observations which you can sort of try to add together to get something resembling a full picture of what’s going on, and it gets really hard to limit your coverage to ‘the salient points’ of a specific topic without excluding many important links to other parts of the picture and overlooking a lot of crucial details. There’s way too much stuff in books like these for me to really provide a detailed coverage of all of it – most of the time I don’t even try, though I sort of did in this post, in a way. I encourage you to ask questions if there’s something specific you’d like to know about these things which might be covered in the book; if you do, I’ll try to answer. Of course it’s rather easy for me to say that you can just ask questions about stuff like this which you’d like to know more about, as part of the reason why people read books like these in the first place is so that they can get at least some idea which questions it makes sense to ask. On the other hand people who don’t know very much about science occasionally manage to ask some rather interesting questions with interesting answers on the askscience-subreddit, so…
I’ve added some additional observations from the book below, as well as some further observations and comments.
“Over the past few decades, the drastic increase in the prevalence of obesity has been reflected by substantial decreases in the amount of sleep being obtained. For example, whereas in 1960 modal sleep duration was observed to be 8–8.9 h/night, by 2004 more than 30 % of adults aged 30–64 years reported sleeping <6 h/night . More recently, the results of a large, cross-sectional population-based study of adults in the United States showed that 7.8 % report sleeping <5 h/night, 28.3 % report sleeping ≤6 h/night, and 59.1 % of those surveyed report sleeping ≤7 h/night .”
Regardless of the extent to which you think these two variables are related (and how they’re related), this development is interesting to me. I’m pretty sure some of the authors of the book consider the (causal part of the?) link to be stronger than I do. I had no idea things had changed that much. Okay, let’s move on…
“For many years, it has been known that the timing of onset of severe adverse cardiovascular events, such as myocardial infarction, sudden cardiac death, cardiac arrest, angina, stroke, and arrhythmias, exhibits a diurnal rhythm with peak levels occurring between 6 am and noon […] It is clear that many variables and parameters within the cardiovascular system are under substantial regulation by the circadian clock, highlighting the relevance of circadian organization for cardiovascular disease. Shift work has consistently been associated with increased cardiovascular disease risk [68–71].”
“Molecular oxygen (O2) is essential for the survival of mammalian cells because of its critical role in generating ATP via oxidative phosphorylation [the link is to a featured article on the topic, US]. Hypoxia, i.e., low levels of O2, is a hallmark phenotype of tumors. As early as 1955, it was reported that tumors exhibit regions of severe hypoxia . Oxygen diffuses to a distance of 100–150 μm from blood vessels. Cancer cells located more than 150 μm exhibit necrosis. The uncontrolled cell proliferation causes tumors to outgrow their blood supply, limiting O2 diffusion resulting in chronic hypoxia. In addition, structural abnormalities in tumor blood vessels result in changes in blood flow leading to cyclic hypoxia [17,18]. Measurement of blood flow fluctuations in murine [rats and mice, US – a lot of our knowledge about some of these things come from animal studies, and they’re covered in some detail in some of the chapters in the book] and human tumors by different methods have shown that the fluctuations in oxygen levels in tumors vary from several minutes to more than 1 h in duration. Hypoxia in tumors was shown to be associated with increased metastasis and poor survival in patients suffering from squamous tumors of head and neck, cervical, or breast cancers [19,20]. Tumor hypoxia is associated with resistance to radiation therapy and chemotherapy and poor outcome regardless of treatment modality. Cancer cells have adapted a variety of signaling pathways that regulate proliferation, angiogenesis, and death allowing tumors to grow under hypoxic conditions. Cancer cells shift their metabolism from aerobic to anaerobic glycolysis under hypoxia  and produce growth factors that induce angiogenesis [22,23]. […] It is increasingly recognized that hypoxia in cancer cells initiates a transcription program that promotes aggressive tumor phenotype. Hypoxia-inducible factor-1 (HIF-1) is a major activator of transcriptional responses to hypoxia . […] It is now well recognized that HIF-1 activation is a key element in tumor growth and progression.”
“the existing epidemiologic evidence linking OSA [Obstructive Sleep Apnea] and cancer progression fits some of the key classic causality criteria : the association is biologically plausible (in view of the existing pathophysiologic knowledge and in vitro evidence); the existing longitudinal evidence supports the existence of temporality in the cause-effect association; the effects are strong; there is evidence of a dose-response relationship; and it is consistent with animal experimental models and other evidence. Lacking is evidence regarding another important criterion: that treatment of OSA will result in a decrease in cancer mortality. Future studies in this area are critical.
If verified in future studies, the implications of the evidence presented here are profound. OSA might be one of the mechanisms by which obesity is a detrimental factor in cancer etiology and natural history. From a clinical standpoint, assessing the presence of OSA (particularly in overweight or obese patients) and treating it if present might have to become a routine part of the clinical management of cancer patients.”
It’s perhaps worth mentioning here that this is but one of presumably a number of areas of oncology where sleep research has shown promise in terms of potential treatment protocol optimization. It’s observed in the book that the effectiveness of- and side effect profile of chemotherapies may depend upon which time during the day (/night?) the treatment is given, which also seems like something oncologists may want to look into (unfortunately it does not however seem like they’ve made a lot of progress over the years):
“Arguably, a field in which little progress has been made in linking circadian rhythms to pathology, disease pathogenesis, and/or clinical medicine at the molecular and genetic levels is cancer. This is unfortunate given that a diurnal rhythm in efficacy and sensitivity to chemotherapeutic agents was reported in mice over 40 years ago . More recently, screening studies in rodents have demonstrated clear circadian rhythmicity in the antitumor activity and side effect profile of many anticancer agents, although at present, it is not possible to predict a priori at which time of day a given drug will be maximally effective (i.e., although rhythms are clearly present, little is known of their mechanistic underpinnings) . Results such as these have given rise to the concept of “chronotherapeutics,” in which the time of drug administration is taken into consideration in the treatment plan in order to maximize efficacy and minimize toxicity […] Although some progress has been made, by and large, this approach has not made significant inroads into clinical oncology”
The stuff above is probably closely related to discoveries made by other contributors, described elsewhere in the book:
“Our laboratory used actigraphy to measure circadian activity rhythms, fatigue, and sleep/wake patterns in breast cancer patients. We found that circadian rhythms were robust at baseline, but became desynchronized during chemotherapy […] desynchronization was correlated with fatigue, low daytime light exposure, and decreased quality of life [21,32].”
Here’s some more stuff on related matters:
“A diagnosis of cancer and the subsequent cancer treatments are often associated with sleep disturbances. […] Prevalence rates for sleep disturbance among oncology patients range from 30% to 55% [in another chapter it’s 30% to 75% – either way these numbers are high, US] […] These sleep disturbances can last for years after the end of the cancer treatment. In cancer patients and survivors, sleep disturbances are associated with anxiety, depression, cognitive impairment, increased sensitivity to physical pain, impaired immune system functioning, lowered quality of life, and increased mortality. Given these associations and the high prevalence of sleep disturbance in cancer patients, it is paramount that clinicians assess sleep disturbances and treat sleep disorders in cancer patients and survivors. […] The effects of chemotherapy and anxiety on sleep quality in [cancer] patients have been well studied, and interventions to improve sleep quality and/or duration among cancer patients have shown widespread improvements in cancer mortality and outcomes, as well as mental health, and overall quality of life” [for more on quality of life aspects related to cancer, see incidentally Goerling et al.]
“We have previously demonstrated an inverse association of self-reported typical hours of sleep per night with likelihood of incident colorectal adenomas in a prospective screening colonoscopy-based study of colorectal adenomas . Compared to individuals reporting at least 7 h of sleep per night, those individuals reporting fewer than 6 h of sleep per night had an estimated 50 % increase risk in colorectal adenomas […] A recent study as part of the Women’s Health Initiative (WHI) has shown similar results with regard to risk of colorectal cancer .”
Remember here that colorectal cancer is one of the most common types of cancer in industrialized countries – “[t]he lifetime risk of being diagnosed with cancer of the colon or rectum is about 5% for both men and women in the US” – some more neat numbers here. The more people are affected by the disease, in some sense the ‘bigger’ these ’50 % increases’ get.
“Probably, the cancer for which sleep duration has been studied most with regard to risk is breast cancer. There are also a number of epidemiological studies that have investigated the association of sleep duration and risk of breast cancer. In these studies, the association of short sleep duration and incidence of breast cancer has been mixed […] In a large, prospective cohort of over 20,000 men, Kakizaki et al. found that sleeping 6 or fewer hours was associated with an approximately 38 % increased risk of prostate cancer, compared with those reporting 7–8 h of sleep […] New evidence is also emerging on the role of sleep duration in cancer phenotype […] Breast cancer patients who reported less than 6 h of sleep per night prior to diagnosis were about twice as likely to fall into the “high-risk” recurrence category compared to women who reported at least 7 h of sleep per night before diagnosis. This suggests that short sleep may lead to a more aggressive breast cancer phenotype.”
“Pain in cancer patients is most often treated with opioids, and sedation is a common side effect of opioids. However, the relationship between opioid use and sleep has not been well studied. Limited PSG data show that opioids decrease REM sleep and slow-wave sleep , suggesting that rather than improving sleep by being sedated, opioids may actually contribute to the sleep disturbances in cancer patients with chronic pain. In addition, the most serious adverse effect of opioids is respiratory depression which may exacerbate the hypoxemia in those individuals with SDB [Sleep Disordered Breathing] and thus lead to more interrupted sleep […it may also promote tumor growth and/or lead to poorer treatment outcomes – see above. On the other hand not treating pain in cancer patients is also … problematic (yet probably still widespread, at least judging from the data in Clark & Treisman’s book)]. […] Although pharmacotherapy is the most prescribed therapy for cancer patients with sleep disturbances [10,35], there is a paucity of studies related to pharmacologic interventions in cancer patients. A recent review concluded that evidence is not sufficient to recommend specific pharmacologic interventions for sleep disturbances in cancer patients . […] As several studies have now confirmed the beneficial effects of cognitive behavioral therapy for insomnia (CBT-I) in cancer patients (mostly breast cancer) and survivors, CBT-I needs to be considered as the first-line treatment. Hypnotics are commonly prescribed to cancer patients. Despite this common use, little to nothing is known about the safety of these drugs in cancer patients. Given the possible interaction effects of the hypnotic/sedatives with cancer treatment agents, the side effects, and potential tolerance and addiction issues, the common use of these drugs in cancer patients is concerning.”
The book is not only about sleep, and this part I found interesting:
“Emerging evidence supports the hypothesis […] that shared mechanisms exist for the co-occurrence of common [cancer] symptoms […] an increased understanding of the mechanisms that underlie the co-occurrence of multiple symptoms may prove crucial to the development of successful interventions […] The study of multiple co-occurring symptoms in cancer patients has led to the emergence of “symptom cluster” research. […] Although awareness of the co-occurrence of symptoms has existed for over two decades […], the study of symptom clusters is considerably more recent . An enduring challenge in the study of symptom clusters remains the lack of consistency in the methods used to cluster symptoms . Currently, the analytic methods used to cluster co-occurring symptoms include correlation, regression modeling [120,121], factor analysis , principal component analysis [121,123], cluster analysis [104,111], and latent variable modeling . […] the decisions that dictate the use of a specific approach are beyond the scope of this chapter […] Symptom cluster research can be grouped into two categories: de novo identification of symptom clusters (i.e., clustering symptoms) and the identification of subgroups of patients based on a specific symptom cluster (i.e., clustering patients ) […] De novo identification of symptom clusters is the most common type of symptom cluster research that occurs with oncology patients.”
A lot of stuff didn’t make it into this post, but I’ll stop here. Or should I also mention that aside from what you eat, it may also matter a lot when you eat (“a study in mice showing that animals fed a high-fat diet during their inactive phase gained more weight than mice fed during their habitual active phase”)? Or should I mention that “individuals with later sleep schedules tended” … in one study … “to have higher energy intakes throughout the day than those whose midpoint of sleep was earlier?” No, probably not. I wouldn’t know where to stop…
[This is a big part of the reason why I often limit my coverage of books to mostly just quotes. Posts like these have a tendency to blow up in my face, and if they don’t I often still find myself having spent a lot of time on them.]
*Or maybe it isn’t actually all that long, perhaps it’s just slightly longer than average? Anyway now that you’ve scrolled down from the top of the post to the buttom in order to figure out what that asterisk meant (if you didn’t scroll down and are now only reading this after you’ve read the entire post above, that’s your fault, not mine…), you’ll know whether you think it’s long. The warning seemed to carry more weight this way. That a warning like this should carry some weight seems quite important to me, considering that I’m blogging a book about obesity. A book about obesity which covers dietary aspects in some detail, yet is occasionally itself a bit hard to digest. [Permission to groan: Granted.]
“Prolyl hydroxylase (PHD) is a tetrameric enzyme containing two hydroxylase units and two protein disulphide isomerase subunits, which requires O2, ferrous iron, and 2-oxoglutarate for PHD enzyme activity. In the presence of O2, PHD covalently modifies the HIFα subunit to a hydroxylated form, which by interacting with Von Hippel-Lindau (VHL) protein, a tumor suppressor, is subjected to ubiquitylation and targeted to proteasome, where it gets degraded . Hypoxia inhibits PHD activity resulting in accumulation of HIF-1α subunit, which dimerizes with HIF-1β subunit.”
Yeah, that sounds about right to me…
There isn’t much of this kind of stuff in the book; if there had been I would not have given it five stars, because in that case I would not have found it at all interesting/enjoyable to read.
“Sleep has recently been recognized as a critical determinant of energy balance, regulating restoration and repair of many of the physiological and psychological processes involved in modulating energy intake and utilization. Emerging data indicate that sleep can now be added to caloric intake and physical activity as major determinants of energy balance with quantitative and qualitative imbalances leading to under- or overnutrition and associated comorbidities. Considerable research is now focused on disorders of sleep and circadian rhythm and their contribution to the worldwide obesity pandemic and the associated comorbidities of diabetes, cardiovascular disease, and cancer. In addition to having an impact on obesity, sleep and circadian rhythm abnormalities have been shown to have significant effects on obesity-associated comorbidities, including metabolic syndrome, premalignant lesions, and cancer. In addition to the observation that sleep disturbances are associated with increased risk for developing cancer, it has now become apparent that sleep disturbances may be associated with worse cancer prognosis and increased mortality. […] circadian misalignment, such as that experienced by “shift workers,” has been shown to be associated with an increased incidence of several malignancies, including breast, colorectal, and prostate cancer, consistent with the increasing recognition of the role of clock genes in metabolic processes […] This volume […] review[s] current state-of-the-art studies on sleep, obesity, and cancer, with chapters focusing on molecular and physiologic mechanisms by which sleep disruption contributes to normal and abnormal physiology, related clinical consequences, and future research needs for laboratory, clinical, and translational investigation.”
I’m currently reading this book. I probably shouldn’t be reading it; I realized a couple of weeks ago that if I continue at the present rate I’ll get to something like 100 books this year, and despite some of these books being rather short and/or fiction books I don’t think this is a healthy amount of reading. It’s probably worth noting in this context that despite the fact that the number of ‘books read’ is now much higher than it used to be, I incidentally am far from sure if I actually read any more stuff now than I did in the past; it may just be that these things have become easier to keep track of as I now read a lot more books and a lot less ‘unstructured online stuff’. It’s not a new problem, but it’s getting rather obvious.
But anyway I’m reading the book, and although it may not be a good way for me to spend my time I am at least learning some stuff I did not know. The book is a standard Springer publication, with 11 chapters each of which deals with a specific topic of interest (a few examples: ‘Effects of Sleep Deficiency on Hormones, Cytokines, and Metabolism’, ‘Biomedical Effects of Circadian Rhythm Disturbances’, and ‘Shift Work, Obesity, and Cancer’). I’ve added some observations from the book below as well as some comments – I’ll probably post another post about the book later on once I’ve finished reading it. The very short version is that insufficient sleep may be quite bad for you.
“Insomnia, identified by complaints of problems initiating and/or maintaining sleep, is common, especially among women. Insomnia is often associated with a state of hyperarousal and has been linked to increased risk of depression, myocardial infarction, and cardiovascular mortality . Relative risks for cardiovascular disease for insomnia have been estimated to vary from 1.5 to 3.9; a dose-dependent association between frequency of insomnia symptoms and acute myocardial infarction has been demonstrated . Insomnia may be particularly problematic at certain times in the lifespan, especially in the perimenopause period and in association with acute life stresses, such as loss of a loved one. The occurrence of insomnia during critical periods, such as menopause, may contribute to increased cardiometabolic risk factors at those times. Short sleep duration may occur secondary to a primary sleep disorder or secondary to behavioral/social issues. Regardless of etiology, short sleep duration has been associated with increased risk of obesity, weight gain, diabetes, cardiovascular disease, and premature mortality [17,18].”
“Sleep is characterized not only by its presence or absence (and timing) but by its quality. Sleep is composed of distinct neurophysiological stages […] associated with differences in arousal threshold, autonomic and metabolic activity, chemosensitivity, and hormone secretion  […] Each sleep stage is characterized by specific patterns of EEG activity, described by EEG amplitude (partly reflecting the synchronization of electrical activity across the brain) and EEG frequency. Lighter sleep (stages N1, N2) displays relatively low-amplitude and high-frequency EEG activity, while deeper sleep (slow-wave sleep, N3) is of higher amplitude and lower frequency. Stages N1, N2, and N3 comprise non-rapid eye movement (REM) sleep (NREM). In contrast, rapid eye movement (REM) sleep is a variable frequency, low-amplitude stage, in which rapid eye movements occur and muscle tone is low. […] In adults, over the course of the night, NREM and REM sleep cycles recur approximately every 90 min, although their composition differs across the night: early cycles typically have large amounts of N3, while later cycles have large amounts of REM. The absolute and percentage times in given sleep stages, as well as the pattern and timing of progression from one stage to another, provide information on overall sleep architecture and are used to quantify the degree of sleep fragmentation. Sleep characterized by frequent awakenings, arousals, and little N3 is considered to be lighter or non-restorative and contributes to daytime sleepiness and impaired daytime function. Higher levels of N3 are thought to be “restorative.””
“The circadian rhythm changes with age and one important change is a general shift to early sleep times (advanced sleep phase) with advancing age. While teenagers and college students have a tendency due to both intrinsic rhythm and external pressures to have later bedtimes, this starts to wane in young adulthood. This phase advance to an earlier sleep time has been referred to as “an end to adolescence” and happens at a younger age for women than for men . […] During the transition from adolescence to adult, several changes occur to the sleep architecture. Most notably is the significant reduction in stage N3 sleep by approximately 40 % as the child progresses through the teenage years […] This means that other stages of NREM (N1 and N2) take up more of the sleep time. Functionally this translates to the child having lighter sleep during the night and therefore is easier to arouse and awaken. […] The sleep architecture of young adults is […] in a 90-min cycle with all sleep stages represented. The amount of stage N3 sleep continues to reduce at this time, at a rate of approximately 2 % per decade up to age 60 years. There is also a smaller reduction in REM sleep during early and mid-adulthood. Once through puberty and into the 20s, most adults sleep approximately 7–8 h per night. This remains relatively constant through mid-adulthood. Young adults may still sleep a bit longer, 8–9 h for a few years. The need for sleep does not change as people progress to mid-adulthood, but the ability to maintain sleep may be affected by medical conditions and environmental influences. […] although average sleep duration does not change over adulthood, there is a large degree of inter- and intraindividual variability in sleep duration. Individuals who are consistently short sleepers (e.g., <6 h per night) and long sleepers (>9 h per night) and who demonstrate high between-day variability in sleep duration are at increased risk for weight gain, diabetes, and other metabolic dysfunction and chronic disease.”
“Nine retrospective studies have indicated that shift work might be associated with a higher risk of breast cancer, including three studies in Denmark, three studies in Norway, two studies in France, and one study in the United States. […] Three of four prospective studies have provided evidence in favor of an association between shift work and breast cancer. […] evidence for a relation between shift work and prostate cancer is very limited, both by the small number of studies and by major limitations involved in those studies that have been conducted”
The increased risk of breast cancer may well be quite significant not only in the statistical sense of the word, but also in the normal, non-statistical, sense of the word; for example the estimated breast cancer odds ratio of Norwegian nurses who’d worked 30+ years of nightwork, compared to those who hadn’t done any nightwork, was 2.21 (1.10-4.45) – and that study involved more than 40.000 nurses. Another study dealing with the same cohort found that the nurses who’d worked more than five years with schedules involving more than 5 consecutive night shifts also had an elevated risk of breast cancer (odds ratio: 1.6 (1.0-2.4)). It’s noteworthy that many of the studies on this topic according to the authors suffer from identification problems which if anything are likely to bias the estimates towards zero. As you should be able to tell from the reported CIs above, the numbers are somewhat uncertain, but that doesn’t exactly make them irrelevant or useless; roughly 1 in 8 women at baseline can expect to get breast cancer during their lifetime (link), so an odds ratio of, say, 2 is actually a really big deal – and even if we don’t know precisely what the correct number is, the risk certainly seems to be high enough to warrant some attention. One mechanism proposed in the shift work chapter is that the altered sleep patterns of shift workers lead to weight gain, and that weight gain is then part of the explanation for the increased cancer risk. I’ve read about and written about the obesity-cancer link before so this is stuff I know a bit about, and that idea seems far from far-fetched to me. And actually it turns out that the link between shift work and weight gain seems significantly stronger than does the link between shift work and cancer – which is precisely what you’d expect if it’s not the altered sleep patterns per se which increase cancer risk, but rather the excess adipose tissue which so often follows in its wake:
“Numerous epidemiologic studies have examined the association between shift work and obesity in various different countries. Most of these studies have utilized existing data from employment records in particular companies, which provide convenient but typically limited information on shift work and health-related variables because this information was not originally collected for research purposes. As a result, many of these studies have methodological issues that potentially limit the interpretation of their results. Still, 22 of 23 currently published studies found some evidence that obesity is significantly more common among individuals with shift work experience compared to those without such experience [36–57]; only one study did not identify a possible link . […] many analyses of shift work and obesity lack adjustment for potentially important confounding variables (e.g., other health and lifestyle factors), and therefore prospective studies with more extensive information on these variables have provided critical insight. Four such prospective studies have been conducted, all of which indicate that individuals who perform shift work tend to experience significant weight gain over time — including two studies in Japan, one study in Australia, and one study in the United States. […] in the largest and most detailed analysis to date, each 5-year increase in rotating shift work experience was associated with a gain of 0.17 kg/m2 in body mass index (95 % CI = 0.14–0.19) or 0.45 kg in weight (95 % CI = 0.38–0.53), among 107,663 women who were followed over 18 years in the US Nurses’ Health Study 2 . Statistical models were adjusted extensively for age, baseline body mass index, alcohol intake, smoking, physical activity, and other health and lifestyle indicators.”
A major problem with the ‘shift work -> obesity -> cancer’ -story is however that the identified weight gain effect sizes seem really small (one pound over five years is not very much, and despite how dangerous excess adipose tissue may be, those kinds of weight differences certainly aren’t big enough to explain e.g. the breast cancer odds ratio of 1.6 mentioned above) – the authors don’t spell this out explicitly, but it’s obvious from the data. It may be slightly misleading to consider only the average effects, as some women may be more sensitive than others to these effects and outliers may be important, but not that misleading; I don’t think it’s plausible to argue that this is all about body mass. In the few studies where they have actually looked at obesity as a potential effect modifier, the results have not been convincing:
“Although it is possible that obesity predicts both shift work and cancer risk — as would be required for obesity to be a potential confounding factor of this relation — it is probably more likely that shift work predicts obesity, in addition to obesity being a risk factor for many types of cancer. This scenario is suggested by the prospective studies of shift work and obesity described above; that is, obesity is a stronger candidate for effect modification than confounding of the association between shift work and cancer, as shift work appears to influence the risk of obesity over time. Yet, only three prior studies have conducted stratified analyses based on obesity status to evaluate the possibility of effect modification. Two of these studies focused on shift work and breast cancer, but they found no evidence of effect modification by obesity [24,26]; a third study of shift work and endometrial cancer did identify obesity as an effect modifier . […] Clearly, additional studies need to carefully consider the role of body mass index—a possible confounding factor, but more likely effect modifying factor—in the association between shift work and obesity.”
I should make clear that although it makes sense to assume that obesity is a potentially major variable in the sleep-cancer risk relation, there are a lot of other variables that likely play a role as well, and that the book actually talks about these things as well even though I haven’t covered them here:
“Although the exact mechanisms by which various sleep disorders may affect the initiation and progression of cancer are largely unknown, disruption of circadian rhythm, pervasive in individuals with sleep disorders, is thought to be the underlying denominator linking sleep disorders, as well as shift work and sleep deprivation, to cancer. The circadian system synchronizes the host’s daily cyclical physiology from gene expression to behavior . Disruption of circadian rhythm may influence tumorigenesis through a number of mechanisms, including disturbed homeostasis and metabolism (details provided in Chap. 2), suppression of melatonin secretion (details provided in Chap. 3), intermittent hypoxia and oxidative stress (details provided in Chap. 5), reduced capacity in DNA repair, and energy imbalance.”
The obesity link relates to a few of these, but there’s a lot of other stuff going on as well. I may talk about some of those things later – I thought chapter 7 was quite interesting, so I’ve ended up talking quite a bit about that chapter in this post, and neglected to cover some of the earlier stuff covered in the book.
This book actually probably didn’t really merit two posts, but given that I wrote a part one earlier on I felt I had to write a part two as well now that I’ve finished it. I’ve also recently read Josephine Tey’s The Daughter of Time and Agatha Christie’s Cards on the Table, but as mentioned earlier I’ve been thinking about getting rid of the fiction coverage here and so I won’t cover those here in any detail – all I’ll say is that Cards on the Table was awesome (5 stars on goodreads), and Tey was an enjoyable read (4 stars … do recall if you read it that it’s a work of fiction).
Goerling’s book is a neat little book – I liked it. It’s not super comprehensive, but it’s the kind of book that can be read without problems by both patients and their caregivers as well as doctors and other health care professionals. Many people will/would probably benefit from reading this book. Occasional talk about stuff like ‘Mindfulness-Based Stress Reduction’ and similar stuff subtracted a star or two along the way, but most of the stuff is actually quite interesting. I’ve added a few observations from the second half of the book below:
“With the favorable trend regarding survival of cancer in the Western world, there is an increasing focus among patients, clinicians, researchers, and politicians regarding cancer survivors’ health and well-being. Their number is rapidly growing and more than 3 % of the adult populations in Western countries have survived cancer for 5 years or more. Cancer survivors are at increased risk for a variety of late effects after treatment, some life-threatening such as secondary cancer and cardiac diseases, others might negatively impact on their daily functioning and quality of life. The latter might include fatigue, anxiety disorders and difficulties returning to work while depression does not seem to be more common among survivors than in the general population. […] Today, the relative 5-year survival is 60–65 % for patients diagnosed with cancer (American Cancer Society 2012, Verdecchia et al. 2007). In Norway, cancer survivors alive ≥5 years from diagnosis represent 3.3 % of the total population (The Cancer Registry of Norway 2010). For some cancer types such as testicular cancer, breast cancer, and Hodgkin’s lymphoma, the 5-year relative survival exceeds 90 %. According to cancer types the most common survivor groups are survivors of female breast, prostate, colorectal, and gynecologic cancer (American Cancer Society 2012).”
“Treatment-related solid second cancers are usually diagnosed at a latency of 10–30 years after radiotherapy, and their development is related to the radiation dose within the target field, but also to scattered irradiation beyond the field borders. […] During the last two decades increasing documentation has emerged that cytotoxic drugs in a dose-dependent manner are carcinogenic leading to an increased risk of leukemia […], but also of solid tumors […] Dependent of their previous treatment long-term cancer survivors may develop asymptomatic or symptomatic left ventricle dysfunction, heart failure, premature coronary atherosclerosis, arrhythmia, or sudden cardiac death, most often due to myocardial infarction (Lenihan et al. 2013). Mediastinal radiotherapy and treatment with certain cytotoxic drugs (antracyclines, trastuzumab) represent well-known cardiotoxic risk factors, with clear dose–effect associations to cardiac dysfunction.” [treatment for cancer can be really bad for you, but often the alternative isn’t great either…]
“For the cancer survivor to be able to make the optimal decisions regarding own present and future health, they need information regarding the long-term health risks they face and how to best handle them. The literature indicates that today’s cancer survivors are not aware of their risks for later adverse health events […] These findings might not only relate to lacking information per se. We must also assume that the survivors have an ambivalent wish for information about future health risks.”
“CBT strives to be evidence based and much effort has been put in scientific research, including large randomized controlled studies. In patients suffering from cancer, CBT has been demonstrated to improve anxiety and depressive symptoms, self-esteem, immune functions, quality of life, optimism, self-efficacy, compliance, coping effectiveness and satisfaction, and to decrease cancer-related fatigue, cortisol levels, pain, and distress (Andersen et al. 2007; Daniels and Kissane 2008; Greer et al. 1992; Hopko et al. 2005; Lee et al. 2006; Manne et al. 2007; Mefford et al. 2007; Moorey et al. 1998; Osborn et al. 2006; Penedo et al. 2007; Tatrow 2006; Witek-Janusek et al. 2008; Wojtyna et al. 2007).”
“psycho-oncological interventions seem to influence treatment adherence, but its relevance for survival is controversial (Chow et al. 2004; Smedslund and Ringdal 2004; Spiegel et al. 1989). A systematic Cochrane review examining the effectiveness of psychosocial interventions in breast cancer patients on survival outcome showed insufficient evidence for such an effect (Edwards et al. 2008).”
“In a very impressive paper Laurie Lyckholm (2001) reports on handling stress, burnout, and grief in the practice of oncology. Causes of stress are seen in insufficient personal or vacation time, a sense of failure, unrealistic expectations, anger, frustration, as well as feelings of inadequacy or self preservations, reimbursement, and other issues related to managed care and third party payers, and last but not least grieving. Burnout can manifest itself in substance abuse, marital conflict, overeating and substantial weight gain, higher frequency of mistakes in clinical care, inappropriate emotional outbursts, interaction problems, depression and anxiety disorders, and even suicide. Lack of or inadequate training of communication and management skills are also considered causes of burnout (Ramirez et al. 1996). In a survey of 7,288 physicians in the United States, 45.8 % reported at least one of the following symptoms of burnout: loss of enthusiasm for work, feelings of cynicism (depersonalisation), and low sense of personal accomplishment (Shanafelt et al. 2012).”
I finished Lloyd et. al, but I’ll cover that one later – I’m a bit behind on the book blogging as there are a few books I haven’t covered, but I don’t really give a crap about that right now. I might get to those books or I might not. On a related note I’ve been thinking about dropping the fiction book blogging altogether and just limit coverage of those books to whatever I can be arsed to write on goodreads.
I usually don’t find it hard to justify spending time reading a specific book – I don’t have many non-inferior ways to spend my time – but in the grand scheme of things this one was/is particularly easy to justify reading. I consider it not particularly likely that I’ll get cancer (other causes of death are statistically much more likely, and many of them can be expected to kill me before, say, those prostate basal cells start acting up enough for me to get a cancer diagnosis), but assuming I’m still alive in a decade or so there’s a high likelihood someone in my family and/or social circle will have gotten cancer in the meantime. When that happens, it’s probably a good idea to have read a book like this. At least it can’t hurt. I should note that although I did not know this when I started out, some of the observations in the book are quite relevant to areas outside the cancer setting. For instance I behaved like a jerk towards a good friend last week, and I’d have at least to some extent decreased the likelihood of behaving in such a manner if I’d read and taken to heart the remarks on how to optimize communication strategies included in chapter 3 of this book before that specific social exchange took place.
On a related note, “Those who suffer from depression tend to withdraw from friendships and relationships, causing loneliness and isolation. Maintaining networks of family and friends may prevent this from happening.” This quote is actually from Lloyd et al. but I figured I should include it here; as that book also makes clear, the mental health profile of people with chronic diseases like DM is somewhat complicated and I’m not sure how to categorize my current state of mind, but there are some depressive thoughts there and I’m really trying to remind myself of stuff like this these days. Yesterday I went to the chess club despite having absolutely no desire to go at all, and today I went to a Mensa meeting for the first time in a few months – not because I wanted to, but because my social interaction patterns over the last few weeks in particular have been deeply problematic (i.e., I have had pretty much no social interaction).
Anyway, enough blather – below some observations from the first half of the book:
“Several meta-analyses and large multi-centre studies have shown that, during the time of cancer diagnosis, about 30 % of the patients suffer from a mental health condition (Mitchell et al. 2011; Singer et al. 2010, 2013a; Vehling et al. 2012). Less is known however about the course of those conditions during the cancer trajectory. Available evidence suggests that their frequency does not decrease considerably over time (Bringmann et al. 2008).
Known risk factors for mental disorders in cancer patients are pain, high symptom burden, fatigue, mental health problems in the past and disability […] There are no consistent correlates of depression in cancer patients (Mitchell et al. 2011).”
“Vocational rehabilitation of cancer patients differs remarkably between countries. For example, while in Scandinavia about 63 % of all patients returned to work after a total laryngectomy (Natvig 1983) and 50 % did so in France (Schraub et al. 1995) only 11 % could return in Spain (Herranz et al. 1999). Predictors of successful return to work are flexible working arrangements, counseling, training and rehabilitation services, younger age, educational attainment, male gender, less physical symptoms and continuity of care (Mehnert 2011).”
“Although the data reviewing sex and/or gender as a primary variable in cancer is quite limited there is a body of literature that is highly informative and is worth a brief review. As it relates to psychological distress, women report more psychological distress overall than do men. This information has been confirmed by many international studies using a wide variety of screening instruments and in diverse cancer populations […] In terms of willingness to report vulnerabilities based on gender, women do report more requests for help (Merckaert et al. 2010) and accept more help (Curry et al. 2002)”
“Pistrang and Barker found that male partner support (high empathy and low withdrawal) plays a pivotal role in the woman’s adaptation and psychological well-being (Pistrang and Barker 1995). […] in a large study of caregivers, Kim et al. (2006) reported that female cancer patients felt that their male partners were very supportive when it came to practical tasks but that they did not provide the emotional support that was so important to them. In essence, men were much more comfortable with demanding and ongoing practical and physical tasks than with the emotional components of the experience. This misalignment has significant implications not only for couples but whenever men and women try to support and connect with each other during times of stress or crisis. […]
“One of the well-documented gender differences found in the literature is the stress response. When under stress, women have been shown to reach out to others and to ‘‘tend and befriend,’’ (Taylor et al. 2000) as an initial response to control their sense of danger and fear. Women feel secure in reaching out to others when trying to manage the stress associated to their vulnerability and do not experience any diminution of self-esteem by asking for help. […] Unlike women, men may experience a sense of diminished self-esteem by sharing their vulnerabilities with others. Although women are adept at prospectively sharing their emotional concerns to reduce their immediate sense of threat, it is only in retrospect that men are generally comfortable sharing their fears and concerns with others, once the sense of threat is reduced to manageable levels. The ways in which many women and men manage their vulnerabilities (women seeking emotional connection and men seeking space and time to think) have significant implications within the context of caregiving. […] when people are under stress they are more likely to revert into their habitual behavioral patterns. In essence, they become more like caricatures of themselves. There are some common behaviors that men and women produce in different frequencies that are generalizations (to be at least considered but never assumed) in the clinical setting.”
“although women are still the primary caregivers for seriously ill family members, men are increasingly taking on the role as primary caregiving role from 25 % in 1987 to 39 % in 2004, (Kim et al. 2006, 2007).”
“There is growing evidence that early integration of palliative care—several months prior to death—not only reduces distress and improves quality of life, but also decreases health care utilization and lastly costs (Temel et al. 2010, 2011; Zhang et al. 2009). Evidence seems to be sufficient for the American Society for Clinical Oncology (ASCO) to recommend early palliative care as best practice in some cancer diagnoses (Smith et al. 2012).”
“Anxiety […] plays an important if not dominant role in symptom perception and expression especially in pain. It is well known from multiple studies in neuropsychology and -physiology that uncertainty and pain are directly linked (Brown et al. 2008; Yoshida et al. 2013).”
“The lack of a common metric makes it difficult to precisely assess the extent of psychological impairment among cancer family caregivers, and the subgroup of caregivers who are at greatest risk; however, it is noteworthy that, across almost all metrics, caregivers consistently have anxiety, depression, and psychological distress rates two or more times that of the general population (Kurtz et al. 2004; Grov et al. 2005; Grunfeld et al. 2004; Northouse et al. 2001; Williams et al. 2013). The lack of precision in the research literature around caregiver psychological impairment in no way obscures what is undoubtedly a major burden for cancer family caregivers. Several studies which concurrently measured psychological impairment in patients and family caregivers, found the family caregivers had higher rates of impairment than the patients with cancer (Braun et al. 2007; Kim et al. 2005; Matthews 2003; Mellon et al. 2006).”
The book is a Springer publication by Niklas Juth and Christian Munthe. Here’s what I wrote in my goodreads review:
“I don’t think it’s a bad book, and it’s likely one of the best on the topic. I generally liked the book and I was at three stars throughout much of it. Different ethical approaches to problems in this area are described and applied to a variety of contexts.
If you want to know why I didn’t go higher [than 3 stars], here are some relevant points of criticism: 1) Some of the concluding analysis in the last chapter was so weak that I ended up writing some relatively nasty stuff in the margin of the book. I decided at one point to subtract a star because of that stuff, but I later decided that it was probably wrong to do that, and so I ended up back at three stars. However I still find their analysis and conclusions related to DTC genetic testing poorly argued. No, not poorly argued – stupid. 2) I also very much disagree with their take on prenatal screening in general, especially when it comes to the decision-relevant parameters to be included in a discussion like that.”
If I’d gone into more detail about 2, there would be more than 2 points of criticism, but the major problem I have is with the DTC genetic testing analysis – primarily because that’s what’s coming next, and so this is where you want the analysis to be as accurate as possible as it actually may have decision-impacting consequences. Razib Khan has written more than a few posts on that topic (23andme-posts) in the past, and as I’ve read him I broadly agree with him regarding the general principles; on the other hand these guys basically seem to consider an outcome where such services are regulated out of existence to be completely fine. The basic argument they present is that they believe (for various bad reasons) that similar principles should be applied to evaluate the ethical framework of these testing measures and the ethics of screening programmes containing tests such as the ones on offer by the private companies (this I incidentally find completely mindboggling, given their repeated emphasis on the differences between voluntary patient-directed health initiatives and screening – see also below), which would mean that counseling requirements would have to be quite strict to justify them – almost certainly too strict for it to make much sense for firms to stay in countries where such requirements are imposed (RK has talked about this aspect before as well). Here’s a relevant quote:
“There is no reason not to apply exactly the same ethical requirements to DTC genetic testing as to genetic screening programmes run by hospitals and other public health institutions. If DTC genetic testing providers can meet these requirements and still make a profit, fine. If not, we may conclude that the very idea of a sustainable business of DTC genetic testing was a fantasy to begin with.”
No thought is given to the problem that the level of counseling provided to actual people using these services may well go down with the formal counseling requirements required (because people buy the services abroad instead, where requirements are laxer). Close to no thought is given to intra-industry dynamics and if one were to take the implicit sketched incentives model of major industry players in chapter 6 seriously one would surely consider it a miracle that there’s such a thing as used car salesmen, or estate agents.
But enough with the criticism, there’s a lot of good stuff as well. They talk quite a bit along the way about the Wilson and Jungner criteria, which is a natural starting point for the analysis. Stuff like that you need to know about if you want to discuss such matters, so here is one version of the criteria, and here’s the 1968 paper (it’s quite long, I haven’t read it). I should point out that the formulation of the principles in the book diverges a bit from those in the link, but it seems that many of the key principles are preserved in the linked version (the book version has 10 points rather than 9, and is a bit more detailed). The main take-away I got from this book is that it’s actually quite a bit harder to justify screening programmes than I’d have thought beforehand – not all the reasons they provide for being cautious about these things I find convincing, but some of them are clearly worth having in mind. Some quotes from the book:
“we will in the rest of this book use the following working definition of the term “screening”:
The use of medical investigation or testing methods at the initiative of health care or society for the purpose of investigating the health status of individuals with the aim of selecting some of these for possible further treatment from a large population of people that is not united by previously recognised risk or symptoms of disease.” […]
“roughly, there are three kinds of goals or values that can provide the rationale for introducing screening programmes:
1. Improvement of (physiological) health, reduction of disease or amelioration of symptoms of disease.
2. Improvement of psychological well-being or reduction of suffering.
3. Promotion of autonomy.
[…] these goals may conflict in various ways.” […]
“The most straightforward way in which an individual may be better off regarding her psychological wellbeing is by having her anxiety or uncertainty regarding her future health status removed – e.g. by having an initial assessment of risk of disease adjusted by having some test. However, the appearance of this possible benefit presupposes that the individual in question has been suspecting that she (or her offspring) is at risk for the disease(s) screened for in the first place (otherwise, there is no initial risk assessment to adjust). Since, by definition, in the case of screening, the initiative to having the test does not come from the individual herself, this cannot be presupposed here. We do not question that reducing anxiety or worry is a valid objective of health care, but this objective is primarily an argument for health care to offer medical investigations if requested by individuals, not for screening. On the contrary, screening runs the evident risk of creating more anxiety than it reduces […] Thus, in terms of well-being, screening programmes (in contrast to the offering of testing to concerned individuals approaching health care with some initial worry) must primarily be justified with reference to their potency for resulting in some kind of improvement of physiological health.”
“since screening programmes tend to target large and unprepared populations, setting up organisations for appropriate counselling is particularly complicated and challenging and usually requires substantial resources. Thus, the room for serious mistakes is larger, and meeting this challenge makes it more difficult for a screening programme to justify its costs compared to less proactive ways of organising the offering of health care services.”
“The line of reasoning underlying the idea that screening improves autonomy is roughly the following: if individuals possess the knowledge that they or their offspring have an increased risk of contracting some disease, they are in a better position to plan their lives in accordance with their own conception of a good life, to live in accordance with their own values […] Traditionally in ethics, autonomy has not been considered primarily as a value to promote, but rather as something that gives rise to moral restrictions on how we are allowed to treat each other when trying to promote other things found valuable […] according to this line of thought, there is a moral obligation to respect autonomy but not necessarily to promote it. […] a central characteristic of screening is that the initiative to the investigation is not coming from the individuals themselves, but from society or large societal institutions. This is potentially problematic already from the point of view of the idea of respecting autonomy, since that idea makes pressure to accept or abstain from medical procedures at least questionable. Respect for autonomy is usually not only taken to mean that informed consent should be obtained in order for an investigation to be justified, but also that the individual should not be pressured or subjected to more subtle manipulative efforts. […] The more that participation is taken for granted in the offer of entering a screening programme, the more pressure there is to participate. The more benefits are emphasised and the less drawbacks are mentioned, the more pressure to participate. The more active the patient has to be in order to refuse investigation, the more pressure to participate. And the more pressure to participate, the more problematic from the point of view of autonomy.35 Although pressure can be reduced in various ways, the general point remains: the very fact that the initiative comes from society always presents some problem from the point of view of autonomy. […] there are practical problems related to screening regarding the need for counselling in order to promote autonomy. […] There is, in effect, always a counter proportionality between pursuing the promotion of autonomy as a goal and economic viability in the context of screening.” […]
“there is no empirical evidence in support of the position that more prenatal testing leads to more discrimination and stigmatisation of the disabled.20 Rather, the trend in many countries seems to be the opposite: in tandem with the development of prenatal diagnosis, more resources have been invested in improving both the quality of life and the societal opportunities of disabled people.” [But this observation did not stop them from arguing as if the stigmatisation argument was valid in chapter 5, while discussing non-invasive prenatal diagnosis, even though there’s absolutely no reason to assume it’s a problem. This fact annoyed me.] […]
“Both prenatal and neonatal screening programmes […] have good chances of being efficient in terms of uptake, i.e. testing a large part of the populations of foetuses and newborns respectively. This is so, since most (prospective) parents are in contact with health care during pregnancy and birth anyway […] this is cost reducing and probably one contributing explanation of the fact that all developed countries have more or less ambitious pre- and neonatal screening programmes.” […]
“regarding these kinds of tests, there always must be a tradeoff between sensitivity and specificity – one cannot increase the one without decreasing the other. […] the case for the importance of high specificity is strengthened if there are no effective treatments […] or if existing treatments are very burdensome […] In contrast, it seems more reasonable to opt for high sensitivity if there is an effective treatment and there are severe consequences for the individual in terms of health without early diagnosis […] Traditionally, among screening specialists, high sensitivity has been seen as a more important feature of a screening programme than high specificity. […] Plausibly, the ethical assessment of how sensitivity and specificity should be balanced cannot be decided by a simple rule. Rather, such assessments would have to be done by careful consideration of each suggested screening programme in a broader context” […] as a rule, the less predictive value, the stronger the reason to abstain to use the test in a screening program.” […]
“These are very good reasons indeed not to use relative risk in the presentation of either what sort of information that may be provided by a screening test, or when informing about the actual result of a test. […] What the patient needs to know both for deciding whether or not to enter a screening programme and what to do on the basis of the test result are the absolute risk figures. In spite of this, there is a widespread tendency in the practice of screening, as well as medical testing in general, for health professionals to press more strongly on relative risk figures when the absolute risks are low or uncertain. […] Since different genes have different penetrance and expressivity […] a genetic test [in many cases] cannot even result in a precise risk-figure. Rather, if a useful test can be construed at all, the result it will present will be in terms of a range of risk, like 5–35% increased risk in comparison to the general population. If the risk-level is low to begin with, the predictive value of such a test, and thus the value as a tool for guidance for health care measures or private decision-making, is virtually non-existing. […] It is […] safe to say, that the threat to the quality of screening programmes created by the fact that the methods for testing and analysis used provide unclear information potentially affects all types of screening programmes in terms of the groups and diseases targeted.” […]
“The extent of false positives [in mammography screening] is debated […] However, Cochrane Collaboration estimates that one in ten during a 10 year period of mammography screening is a false positive. […] When treatment is initiated due to overdiagnosis, it is called overtreatment. One question in the debate regards the magnitude of overtreatment. Figures cited vary from 10% increase of overtreatment due to the initiation of mammography screening programmes,52 to 30% […] Our conclusion from all of this is that the debate regarding overdiagnosis and -treatment, while being cast in the language of scientific facts, is powered mainly by deep ethical disagreements. Positions with regard to this disagreement range from the idea that overdiagnosis and -treatment is not a great problem at all, to the notion that it is a conclusive argument against a screening programme. These positions can, of course, be upheld almost regardless of the magnitude of overtreatment. However, as pointed out, it is difficult to free oneself from the suspicion that this ethical disagreement has been allowed (by one or both parties) to leak into also what is supposed to be the purely scientific part of the discussion. […] the debate would probably gain from bringing implicit value-judgements into the open.”
“the self-reinforcing nature of screening programmes has an important consequence: unless blatantly flawed, they will probably be very difficult to roll back once in place. This has nothing to do with what is medically or ethically well-founded, but follows from the pragmatics of institutions and realpolitik. This should be kept in mind when new screening programmes are proposed. […] if we were to imagine the situation that mammography screening was proposed to be initiated today on the basis of present evidence (including the confusing scientific debate), it would not be an easy task to find it to be warranted. First, partly due to the lack of methodological consensus, the scientific basis of information is much too uncertain and difficult to interpret. Second, if counselling procedures of an appropriate nature were to be included, this would presumably seriously elevate the cost of the programme.” […]
“In 2008, The Cochrane Collaboration published a review: Screening for prostate cancer.71 The review found only two trials that were eligible for inclusion to start with. […] However, in recent years, this scientific vacuum is starting to be remedied. The most ambitious study is The European Randomized Study of Screening for Prostate Cancer (ERSPC), which was initiated in the early 1990s and includes 182,000 men from seven European countries between the ages of 50 and 74. Results published after a median of 9 years shows a reduced rate of death from prostate cancer of 20%.74 However, the absolute benefit (0.7/1000 reduction) was small and was associated with a 70% increase in prostate cancer diagnosis. In other words, 1410 men needs to be screened and 48 more cases needs to be treated in order to prevent one death, as compared to the non-screened population. […] most men tested positive with PSA are subsequently shown not to have prostate cancer; only 25–35% of men who have a follow-up biopsy are diagnosed with cancer […] new data suggest that the extent of the harms of being diagnosed with cancer have not been sufficiently appreciated in the debate. A large cohort study in USA indicates that a diagnosis of prostate cancer may increase the immediate risk of suicide and cardiovascular death. […] there is relatively large agreement that standards of informed consent in PSA screening, at least in the United States, have been poor. A recent survey among test subjects revealed that a majority (71.4%) were told about the upside of PSA testing, while only a minority (32%) were informed about potential drawbacks.”
I’ve finished the book.
It’s a Springer book, so those of you who’ve encountered these books before will know that this is not an easy-to-read popular-science book. The general level is high and occasionally I felt almost completely lost; chapter 8 for example was very technical. As I’ve pointed out before, I don’t like to fault authors for not taking into account the possibility that their books may also be picked up by ignorant fools who don’t know anything, but if you have a hard time understanding what the author is getting at it will affect your reading experience in a negative manner. It should be noted, though, that although it’s not an easy book to read you’ll learn a lot of stuff if you put in some effort (…and/but if you don’t put in some effort you’ll never finish it, and you’ll get nothing out of it at all).
Some of the chapters deal with similar stuff, and I got the impression a couple of times that the authors of a specific chapter had not read the other chapters. On the other hand it’s very clear in other chapters/contexts that they most certainly did, but even so there are a few things which are repeated a few times along the way which perhaps did not need to be repeated. On the third hand the book is structured in such a way that each chapter is pretty much self-contained (which is presumably part of the explanation for the occasional repetitions), and the fact that you probably don’t necessarily need to read it cover to cover from chapter one to chapter 9 the way I did to get a lot out of the book would presumably be appealing to some people.
I gave it four stars on goodreads, because of the high quality of the material included.
Some stuff from the last chapters, with some hopefully helpful links added to make the passages easier to understand (perhaps needless to say no such links are included in the book, so if you find the links helpful you’ll probably need to look up some stuff along the way if you decide to read it yourself…) as well as some comments here and there:
“Emerging studies clearly indicate that a bidirectional crosstalk is established between all cellular components of AT [adipose tissue, US] and cancer cells and that the tumor-surrounding AT contributes to inflammation, extracellular matrix remodeling as well as energy supply within the tumors. In this chapter, we present evidences showing how AT locally affects tumor progression in given types of tumors and how these results might be attractive to explain the link between obesity and the poor prognosis of some cancers. This will be preceded by the overall description of AT composition and function with special emphasis on the specificity of adipose depots, key aspects that need to be taken in account when paracrine effects of AT on tumor progression is considered. […]
The past two decades have provided substantial evidence for the major role of the tissue local environment for tumor progression. Cancer is now considered as a tissue-based disease in which malignant cells interact dynamically with the surrounding supportive tissue, the tumor stroma, composed by multiple normal cell types such as fibroblasts, infiltrating immune cells, and endothelial cells within the context of extracellular matrix . This stroma/tumor cell interaction involves constant bidirectional crosstalk between normal and malignant cells. Cancer cells usually generate a supportive microenvironment by activating the wound-healing response of the host . Conversely, the stromal cells, such as for example, cancerassociated fibroblasts (CAFs) or tumor-associated macrophages (TAMs), promote tumor progression through different mechanisms including enhancement of tumor survival, growth, and spread, by secreting growth factors, chemokines, extracellular matrix (ECM) components, and ECM-modifying enzymes [3,4]. Constituents of the tumor microenvironment can arise from two major sources: recruitment from nearby local tissue or systemic recruitment from distant tissues via circulation. Among the different cell types frequently found at close proximity of evolving tumors, little attention has been given to cells that compose the adipose tissue (AT) although a growing interest can be noted in recent years. Throughout the body, AT is mainly described as subcutaneous (i.e., superficial and deep hypodermic location) and visceral depots. Visceral adipose tissue (VAT) surrounds the inner organs and can be divided into omental, mesenteric, retroperitoneal (surrounding the kidney), gonadal, perivascular, and pericardial depots . Of note, AT is also present in the breast (mammary adipose tissue or MAT) and in the bone marrow (BM). All these specific regional depots exhibit differences in structure, function, composition, and secretion profiles . […] The cellular heterogeneity of AT adds an additional degree of complexity when AT/cancer cells crosstalk is considered. […] All the cells from adipose tissue (including mature adipocytes) produces a large number of secretory bioactive substances, such as hormones, growth factors, chemokines, proangiogenic or proinflammatory molecules , which could directly affect adjacent tumors. AT is therefore an excellent candidate to influence tumor behavior through heterotypic paracrine signaling processes and might prove to be critical for tumor survival, growth, local, and distant invasion. […] Fat depots from different region of the body have different incidence in pathology because they display distinct functional and structural properties in terms of energy metabolism and bioactive molecule (adipokines) release as well. Regional heterogeneity plays a central role in mammalian AT homeostasis.” (I talked about these aspects in the last post, but I figured I should give at least part of the ‘medical textbook version’ here..) […]
“Ovarian cancer is a highly fatal disease, with only about 40 % of women with ovarian cancer still alive more than 5 years postdiagnosis. This poor survival is largely attributable to the fact that a majority of ovarian cancer in developed countries is diagnosed with metastatic spread. The omentum, a peritoneal organ rich in AT and immune cells, has been shown to be a preferred site of metastatic dissemination in ovarian cancer patients. Omental dissemination, which is often accompanied by ascites, facilitates the further spread of the tumors .” […]
“Prostate cancer is the most common malignancy in males in Western countries, representing the second leading cause of cancer death. Prostate is surrounded by AT and tumor admixed with periprostatic fat is the most easily recognized manifestation of extraprostatic extension, a well-established adverse prognostic factor for prostate cancer [79,80]. Periprostatic AT (PPAT) is considered as VAT, but the specificities of this depot in terms of metabolism and adipokines secretion remain largely unknown. At laboratory levels, the contribution of this tissue to cancer progression has been first suggested by the report of Finley et al. that analyzed the PPAT features in patients undergoing prostatectomy for cancer . In this study, the authors found that the level of IL-6 secreted by PPAT-conditioned medium (CM) was almost 375 times greater than the circulating levels of the cytokine in the same patient. Both IL-6 levels in PPAT and activation of IL-6 related signaling pathways were correlated to tumor aggressiveness . Therefore, this study strongly suggests that PPAT represents an important source of IL-6 that favors tumor progression. Interestingly, several studies already reported that increased serum IL-6 and soluble interleukin-6 receptor levels are associated with aggressiveness of the disease and with a poor prognosis in prostate cancer patients, underlying the importance of this pathway in PC progression (for review see ). […] Recent studies suggest that, like in breast cancer, a bidirectional crosstalk exists between PC cells and surrounding AT.” […]
“During the last decade, pancreatic cancer has become the fourth leading cause of cancer-related death in the USA and the sixth leading cause in Europe. Despite major advances in surgical techniques and adjuvant therapies, overall 5-year survival remains under 5 %. While very few, if any, laboratory studies have been performed to date on the crosstalk between pancreatic cancers and AT, several clinical data have suggested that an adipose-rich environment leads to a deleterious outcome on this disease. […] it has been demonstrated that peripancreatic fat invasion is correlated to a poorer survival for pancreatic cancers . Recent epidemiologic studies also suggest that obesity doubles the relative risk of pancreatic cancer . In addition, central adiposity has been shown to be an independent risk factor in development of pancreatic cancer as well as to contribute to a poorer survival . Interestingly, it has been demonstrated that increased pancreatic fat (pancreatic steatosis) promotes dissemination and lethality of pancreatic cancer .” […]
“The relationship between AT and cancer is complex and involves both paracrine and endocrine effects whose relative contribution to tumor progression remains to be determined. Regarding paracrine effects, we have underlined in this chapter the need to consider the appropriate neighboring AT for each cancer subtypes in experimental studies. […] there is clear variations between the different AT in terms of secretion and sensitivity to lipolysis […] Nevertheless, regarding AT/cancer crosstalk, there are common features found in several cancer subtypes. […] it is very important to underline that adipose cells are not inert to their surrounding and that their phenotype are profoundly modified by cancer cell secretions.” […]
“Present data suggest caution about the clinical use of lipotransfer-derived WAT cells for breast reconstruction in patients with breast cancer [15,16].”
I thought I should make a brief stop here to cover the observation above in a little more detail, because I think it’s a good illustration of why the finer details of how these things work actually matter. Now, one might well be tempted to say that if we know that fat people get cancer more often and have worse prognoses (this is, incidentally, a gross oversimplification – as should be clear from the posts), well – do we really need to know all that much more about how it all works out at the microscopical level and so on? Why not just tell people to lose weight and just leave it at that? Findings like the ones in [15,16] above indicate that it matters what goes on in these tissues. What did the studies tell us? Well, it has been observed that female breast cancer survivors who have undergone a specific type of reconstructive surgery (‘lipotransfer procedure for esthetical purposes’) had higher cancer recurrence risk than did females who had not undergone such a procedure; this is important information with clinical relevance. One basic idea behind what may be happening is that the adipose tissue that is transplanted into the reconstructed breast(/s) may work as a fuel source for any remaining cancerous cells still hiding in the tissues (/and it may spark new tumor development through the crosstalk and paracrine signalling mechanisms already mentioned). Note that this information may not yet be well known – see e.g. this webpage about reconstructive breast surgery from the website of Johns Hopkins University, which is hardly an institution to be found at the bottom of the barrel: “we try to give women the look and feel of an actual breast, using creative techniques such as fat grafting, also known as lipofilling or fat transfer. Fat can be taken from another part of your body, possibly the abdomen or somewhere on your buttocks, through liposuction. The fat will be purified and carefully layered within the new breast to create the desired shape. Our surgeons are experienced at these techniques.” They may want to reconsider at the very least the extent to which they are using these techniques. Anyway, back to the book:
“surgical options for treatment of the severely obese population have increased in popularity over the last few decades, with an estimated 344,000 cases performed globally in 2008 [40,41]. As previously noted, lifestyle therapy for weight loss intervention is generally insufficient for extremely obese patients and effective long-term weight loss using pharmacological therapy has been limited, leaving bariatric surgery as the only medical intervention providing substantial, long-term weight loss for most severely obese patients. […] Because post-bariatric surgical patients generally experience significant and sustained weight loss [2,47], they represent a unique population to study the relationship between voluntary weight loss and cancer risk. […] Generally, 80 % of patients who seek bariatric surgery are female.” […]
“Since 2009, there have been five reviews exploring the potential relationship between bariatric surgery and subsequent cancer risk [22,40,59–61], and two additional reviews of cancer risk associated with either weight loss from bariatric surgery or nonsurgical weight loss therapies [11,20]. […] [the following are some results from these studies:] Reported cancers subsequent to bariatric surgery were 117 cancers in the surgical group compared to 169 cancers among the control groups, representing an HR of 0.67 (95 % CI 0.53–0.85; p=0.0009). For female participants only, the surgical group had a reported 79 cancers compared to 130 cancers in the control females, giving an HR value of 0.58 (95 % CI 0.44–0.77; p = 0.0001). […] After a maximum of 5-year followup, the reported number of visits to the physician/hospital that led to a cancer-related diagnosis for the weight loss surgical group was 21 visits (2.0 %) compared with 487 visits (8.5 %) among the control group. This difference was reported to have a relative risk of 0.22 (95% CI 0.14–0.35; p=0.001) . […] the relative risk for breast cancer was 0.17 (95% CI 0.01–0.31; p=0.001). […] For cancer deaths, the bariatric surgical group was 60 % lower when compared the control group ( p = 0.001; 31 deaths among surgical group compared to 73 deaths in control groups). […] For all cancers combined, there was a 24 % reduction in cancer incidence among the surgical group compared to controls (HR 0.76, 95% CI, 0.65–0.89; p=0.0006). […] Based upon these analyses, it was estimated that about 71 gastric bypass surgeries would be necessary to prevent one incident cancer . […] [And so they conclude:] there are now studies that demonstrate a reduction in cancer mortality among postbariatric patients compared to severely obese, nonoperated controls. In addition, one prospective study (SOS study) and a few observational studies have also demonstrated a reduction in cancer incidence following metabolic surgery. To date, the reduced cancer risk benefits have been limited to females and there appears to be a stronger correlation of benefit associated with cancers that are “likely” to be obesity related. Given these limitations, the general consensus is that intentional weight loss does lead to a reduction in cancer incidence .” […]
“Multiple reviews have been published on the effect of metabolic surgery on diabetes, including a meta-analysis by Buchwald et al., which reported a 78.1 % remission of diabetes and an 86.6 % improvement or remission in diabetes following bariatric surgery . The intriguing element related to diabetes remission is that a significant number of bariatric surgical patients (i.e., gastric bypass patients) have discarded their antidiabetic medication and returned to a normal blood glucose by the time they are discharged from the hospital following their metabolic surgery (i.e., 2–3 days after surgery) and long before significant weight loss has occurred . Again, mechanisms accounting for this remarkable remittance or improvement of diabetes following surgery are multiple. In an analogous way, the reduced risk of cancer following metabolic surgery is also likely to be linked with several biological mechanisms, which may or may not be directly associated with weight loss.”
I’ve read roughly two-thirds of the book by now – I like it, pretty much every page contains new stuff which I didn’t know anything about and it’s quite interesting. Some more stuff from the book below, as well as some comments. As always you can click images to view them in a higher resolution.
“Obesity increases the incidence of many cancers, such as breast, prostate, and colon cancer. However, endometrial cancer is the mostly tightly linked with obesity. Estimates suggest that nearly 40 % of cases of endometrial cancer can be attributed to obesity. […] Obese women have a threefold higher risk of developing endometrial cancer than lean women . […] every increase in BMI of 5 kg/m^2 increases a woman’s risk of the developing of endometrial cancer by approximately 60 % (relative risk, 1.59; 95 % confidence interval [CI], 1.50–1.68) . Endometrial cancer in obese women is more likely to have lower risk features such as endometrioid histology and low/intermediate grade. […] An elevated waist-to-hip ratio, reflecting a preferential deposition of adipose in the abdomen, increases the risk of developing endometrial cancer by 220 % . […] Among the population as a whole, obesity increases the risk of death from endometrial cancer. In a study of 900,000 prospectively followed healthy patients, 57,145 individuals died of cancer over 16 years. The relative risk of death from endometrial cancer in this population was 6.25 for women with a BMI >40 and 2.77 with a BMI between 35 and 39 .”
“As a component of adipose tissue in obese individuals, immune cells, and specifically macrophages, secrete a variety of growth, survival, and proangiogenic factors, as well as bioactive molecules that enable tumor growth and contribute to the remodeling of the tumor microenvironment to facilitate metastases. Furthermore, reactive oxygen and nitrogen species released by activated macrophages are mutagenic and accelerate oncogenic mutations that contribute to cancer risk and progression [30,33]. So, not only does inflamed visceral adipose tissue provide an ideal milieu for the growth of metastatic endometrial cancer but proinflammatory factors also secreted by infiltrating adipose immune cells mediate systemic effects on tumor progression at distant sites, including the endometrium.”
“Taken together, current evidence suggests that through a variety of mechanisms, weight loss and physical activity reduce proproliferative signaling and counteract environmental conditions that support the initiation and progression of endometrial cancer.” […as the figure above illustrates, endometrial cancer is far from the only cancer type where behavioral factors play a large role – US.]
“Multiple epidemiologic studies demonstrate that women who use combination estrogen and progesterone oral contraceptives (OCP) decrease their risk of endometrial cancer by 50 % [78–80]. While there is no data to support a decreased efficacy in endometrial cancer protection in obese women, there are studies that suggest that obese women have a slightly decreased contraceptive efficacy compared to thin women .”
“At the cellular level, overweight and obesity are characterized by the increase in number and size of adipocytes. A lean adult has 35 million adipocytes, each containing 0.4–0.6 μg of triglycerides, whereas an extremely obese person has 125 million adipocytes, each containing 0.8–1.2 μg of triglycerides . Traditionally, adipocytes have been viewed solely as energy depots, but after the discovery of leptin in 1994 and extensive research in the field in the last decades, it has been established that the adipose tissue is an active endocrine organ. The adipocyte is a major source of secreted proteins …”
A really important point which has been repeated, explicitly or implicitly, again and again in this book, and which I thought I should emphasize here using ‘non-textbook language’, is that fat cells aren’t just inactive cells that ‘hang around’ doing nothing. They do a lot of stuff while they’re ‘hanging around’. And when you have a lot of them hanging around in the wrong places, many of the things they’re doing are really quite bad for you. As you’ve probably already inferred, the book goes into a lot more detail about mechanisms and how these things work in detail (to the extent that we even know what’s going on in the first place), but if you don’t remember much from the posts about this book this is at least, I think, one of the key points you should try to remember; adipose tissues are active tissues and they – and the secretions derived from them – play a major role in a variety of contexts, including some contexts which are highly relevant to e.g. cancer pathogenesis. There’s still a lot we don’t know because this stuff is complicated; I link to leptin above, which has been intensively studied and is also relatively intensively covered e.g. in chapter 5 of the book, and the wiki link about adipokines mentions a few others – but I should note here that there are more than 50 different types of adipokines that we know of at this point. Different types of cancer start out in different types of tissues and a diverse set of mechanisms are involved in the disease processes, and so it seems likely that different types of adipokines play different roles in different types of cancers. There are still a lot of things which are not clear, but as they put it in the conclusion of chapter 5: “There are strong epidemiological, molecular, and clinical evidences showing associations between adipokines and the incidence and clinical outcome of cancer.” It should be noted that work on this stuff is not limited to work on just ‘human data’ – lab-work using rodents, which is covered in chapter 6 of the book, has added some details and some interesting observations regarding potential mechanisms of action, and such animal models seem to support ‘a causal link’ of some sort between body weight and the development of specific types of cancers in a number of important (…to humans…) cases, including breast cancer and colon cancer. However the precise mechanisms of action are still far from clear, as they note in their conclusion in chapter 6:
“As detailed here, overweight and/or obesity is associated with an elevated risk of several cancers; however, it is clear that a common disease mechanism was not identified. Although the current literature hypothesizes at least three major components such as sex hormones, insulin-related pathologies, and adipokines, these components cannot explain every aspect of clinical features/disease courses. But as models improve both for obesity and various cancers, hopefully it will become easier to identify mechanisms of action for the relationship of body weight and cancer.”
I’ve read the first third of this book, and it’s been a quite interesting read so far. Some parts have been easier to read than others and occasionally it gets a bit technical, but overall it’s a quite readable book for someone with my background and I’m certainly learning some new stuff by reading this.
Some observations from the book:
“obesity and metabolic syndrome are linked to various chronic diseases [6,7] including cardiovascular disease, type II diabetes, and the focus of this chapter, cancer. Importantly, not all obese individuals develop the metabolic dysregulation usually associated with obesity and metabolic syndrome, and these “metabolically healthy obese” individuals do not have elevated cancer risk. An estimated 30 % of obese individuals in the USA are metabolically healthy . Conversely, some nonobese individuals can develop the metabolic perturbations usually associated with obesity, and these individuals appear to be more prone to chronic diseases including cancer . Thus, an emerging hypothesis is that the obesity-related metabolic perturbations, and not specific dietary components or increased adiposity, are at the crux of the obesity–cancer connection.” […]
“Evidence-based guidelines for cancer prevention urge maintenance of a lean phenotype . Overall, an estimated 15–20 % of all cancer deaths in the USA are attributable to overweight and obese body types . Obesity is associated with increased mortality from cancer of the prostate and stomach in men; breast (postmenopausal), endometrium, cervix, uterus, and ovaries in women; and kidney (renal cell), colon, esophagus (adenocarcinoma), pancreas, gallbladder, and liver in both genders . While the relationships between metabolic syndrome and specific cancers are less well established, first reports from the Metabolic Syndrome and Cancer Project, a European cohort study of ~580,000 adults, confirm associations between obesity (or BMI) in metabolic syndrome and risks of colorectal, thyroid, and cervical cancer .”
“During obesity, adipose tissue responds to the excess energy by increasing adipocyte size (hypertrophy) and enhancing adipocyte proliferation (hyperplasia) . Adipocyte size strongly correlates with insulin resistance and secretion of proinflammatory cytokines . Moreover, location of the adipose tissue also determines risk for metabolic diseases. […] Healthy adipose tissue must be able to rapidly respond to excess energy intake by inducing adipocyte hypertrophy and hyperplasia, remodeling of the extracellular matrix, and enhanced neovascularization to nourish the adipose tissue. In pathological states such as insulin resistance associated with obesity, rapid adipocyte hypertrophy occurs with restricted angiogenesis resulting in cellular hypoxia, and thereby resulting in local inflammation . Macrophages surrounding necrotic adipocytes phagocytize fatty acids, which are released from the adipocyte. This produces bloated, lipid overburdened macrophages, which is characteristic of chronic inflammation and often observed in obese individuals . […] inflammation is a recognized hallmark of cancer, and growing evidence continues to indicate that chronic inflammation is associated with increased cancer risk [75–77]. Several tissue-specific inflammatory lesions are established neoplastic precursors for invasive cancer, including gastritis for gastric cancer, inflammatory bowel disease for colon cancer, and pancreatitis for pancreatic cancer [78,79].”
“When lipid storage capacity in adipose tissue is exceeded, surplus lipids often accumulate within muscle, liver, and pancreatic tissue . As a consequence, hepatic and pancreatic steatosis can develop; both have been positively associated with insulin resistance and ultimately lead to impairment of lipid processing and clearance within these tissues . […] The term nonalcoholic fatty liver disease (NAFLD) refers to a disease spectrum that includes variable degrees of simple steatosis, nonalcoholic steatohepatitis (NASH), and cirrhosis [19,20]. Simple steatosis is benign, whereas NASH is defined by the presence of hepatocyte injury, inflammation, and/or fibrosis, which can lead to cirrhosis, liver failure, and hepatocellular carcinoma. […] NASH occurs in 20 % of cases of NAFLD and ~5–20 % of NASH cases progress to cirrhosis; 80 % of cryptogenic cirrhosis cases present with NASH . Of this group, ~0.5 % will eventually progress to hepatocellular carcinoma […] In Western populations, overnutrition/obesity is the most common cause of NAFLD” […] NAFLD has evolved in parallel to the obesity pandemic as the most prevalent liver disease worldwide. Whereas the fact that chronic liver inflammation as observed in nonalcoholic steatohepatitis (NASH) finally leads to the development of hepatocellular carcinoma is well accepted , its association with increased formation of adenomatous polyps and CRC has just recently been established [124,125].”
“Hyperglycemia, a hallmark of metabolic syndrome, is associated with insulin resistance, aberrant glucose metabolism, chronic inflammation, and the production of other metabolic hormones such as IGF-1, leptin, and adiponectin . […] In metabolic syndrome, the amount of bioavailable IGF-1 increases […] Elevated circulating IGF-1 is an established risk factor for many cancer types [38,39].”
VEGF [Vascular Endothelial Growth Factor], a heparin-binding glycoprotein produced by adipocytes and tumor cells, has angiogenic, mitogenic, and vascular permeability-enhancing activities specific for endothelial cells . Circulating levels of VEGF are increased in obese, relative to lean, humans and animals, and increased tumoral expression of VEGF is associated with poor prognosis in several obesity-related cancers . The need for nutrients and oxygen triggers tumor cells to produce VEGF, which leads to the formation of new blood vessels to nourish the rapidly growing tumor and may facilitate the metastatic spread of tumors cells .”
“Epidemiological studies indicate that obesity represents a significant risk factor for the development of various cancers such as prostate and breast cancer, leading cancers in the Western world. An impressive body of evidence, however, also indicates that the risk of colorectal adenoma, and cancer (CRC) is increased in subjects with obesity and related metabolic syndrome [2,3]. […] Colorectal cancer is the second leading cancer death in the Western world and its death rate correlates with body mass index . […] Recent CRC screening studies suggest that obesity and an increased body mass index are a significant additional risk factor for the development of colonic polyps with evidence that advanced adenomas arise in men almost a decade earlier than in women . […] menopausal status appears to modify the relationship between BMI and colon cancer with a strong association between BMI and colon cancer risk seen in premenopausal but not postmenopausal women . […] being obese prior to being diagnosed with colon cancer increases your risk of dying from the disease [29–32]. […] more and more studies are now demonstrating the location of body fat tissue is the best predictor of all-cause and colorectal cancer mortality […] colon cancer survival may be less likely for patients who are […] too thin at diagnosis .”
“In a meta-analysis of 52 studies (24 case–control and 28 cohort studies) examining the link between physical activity and colon cancer, a significant 24 % reduced risk of colon cancer in people who were most active compared with the least was found . This supports other reviews of the association between physical activity and colon cancer in the Asian and European populations [49,50]. […] Physical activity also appears to affect disease outcome and recurrence after diagnosis and treatment with the greatest effect on colon cancer incidence . […] new well-controlled clinical trials on obesity prevention and obesity treatment are necessary before therapeutic implications of WAT [White Adipose Tissue] reduction on cancer predisposition are completely understood. One of the possibly important considerations is the number of adipocytes and the accompanying stromal/vascular cells in WAT increasing in obesity and remaining increased even upon subsequent weight loss, which occurs via adipocyte size reduction. The pool of ASC [Adipose Stem Cells] is likely to remain intact and could contribute to cancer onset or progression despite calorie restriction and reduced adiposity.”
“There is general agreement that obesity is associated with an increased incidence of breast cancer in postmenopausal women (reviewed in [14–17]). […] The European Prospective Investigation into Cancer and Nutrition (EPIC) study , which had 57,923 postmenopausal participants, is of particular interest because of its large size, its prospective design, and the observations made concerning exogenous estrogens as a confounder. The results showed that a long-term weight gain was related to an increase in risk, but only in those who were not taking hormone replacement medication: compared with women with a stable body weight the relative risk for women who gained 15–20 kg was 1.5 with a confidence interval of 1.60–2.13. As reported by others, adiposity ceased to be a risk factor in current replacement therapy users, who were already at a high risk for breast cancer compared with nonusers. […] Preexisting obesity and postoperative weight gain are associated with poor prognosis in both premenopausal and postmenopausal breast cancer patients. […] A pivotal review of the literature by Chlebowski et al.  found that in 26 out of 34 studies individual studies, totaling 29,460 women, obesity was related to an increased risk of recurrence or reduced survival.”
“Daling et al.  have provided a major contribution to our understanding in the relationships between body fat mass and tumor biomarkers of progression in young breast cancer patients. In their study, not only was a combination of obesity and an absence of ER expression in premenopausal breast cancer patients aged younger than 45 years associated with an increased risk of dying from the disease, but those with BMI values in the highest quartile were more likely to have larger tumors of high histologic grade. This observation is particularly significant because it implies that large tumors in overweight/obese women grow at a faster rate than tumors of similar size from leaner women, rather than simply arising from delayed diagnosis due to palpation difficulty in obese women.”
“Wolf et al.  and Schott et al.  suggested that up to 16 % of breast cancer patients have diabetes, and that T2D may be associated with a 10–20 % excessive risk of breast cancer. […] There is ample epidemiological evidence that diabetes contributes to breast cancer risk [17,36–40]. […] Overall survival in cancer patients, with or without preexisting diabetes, has shown diabetes to be associated with an increased all-cause mortality risk. […] The Danish Breast Cancer Cooperative Group, with 18,762 newly diagnosed T2D cases, found that the recurrence with metastases was 46 % higher in obese women with a BMI of 30 kg/m^2 or greater beyond the first 5 years.”
The relationship between obesity and prostate cancer is a complicated one. […] The explanation for this confusion may rest, at least in part, in the reports that obesity as a positive risk factor for prostate cancer relates specifically with the aggressive phenotype [56–60] […] a meta-analysis by Discacciati et al.  of the results from 25 studies that examined disease stage and BMI showed not only a positive relationship between obesity and advanced prostate cancer but also a decrease in the risk for localized disease. The association between obesity and an aggressive prostate cancer phenotype is reflected in the relationship between the BMI and prostate cancer mortality rate. For example, in one large retrospective cohort study by Andersson et al.  […] there was a significantly larger prostate cancer mortality rate in the higher BMI categories”
Two studies have been reported in which meta-analysis was used to examine previously published investigations into the relationship between diabetes mellitus and prostate cancer risk [66,67]. […] [The first] meta-analysis showed that there was an inverse relationship between diabetes and prostate cancer risk, which translated to a 9 % reduction in risk. […] The overall conclusion […in the second meta-analysis] was the same: diabetic men have a significantly decreased risk of developing prostate cancer (RR = 0.84; 95% CI, 0.76–0.93). […] Gong et al.  reported a large prospective study of diabetes and prostate cancer from the USA after the two meta-analyses described above had been published that also took account of potential confounding by obesity. Men with diabetes had a 34 % lower risk of prostate cancer compared with men without diabetes that was not affected by adjustment for the BMI […] In contrast to these results, recently published studies have found that the presence of diabetes is positively associated with prostate cancers of high-grade [71–73] and late-stage tumors  ], a reversal in the observed relationship that needs to be considered in the context of the duration of the presence of T2D and the detection of prostate cancer by prostatic-specific antigen screening.”
My first post about the book can be found here. In this post I’ll talk a little bit the chapters 4-5, which deal with infectious diseases and neoplasia.
When reading chapter 4 – on infectious diseases – it was a great help to have read chapter 3 first – that chapter had a lot of stuff on how the body defends itself against the kind of stuff they talk about in chapter 4, and even though they recap a bit of that stuff in chapter 4 it’s probably smart to read those two chapters in the order they appear in the book. I did not find chapter 4 particularly hard to read, in part probably because this stuff is closely related to the microbiology stuff I read in the past, which dealt in much more detail with the microorganisms causing these diseases. There’s a lot of important concepts covered: transmission mechanisms; factors impacting disease susceptibility; the normal microbial flora and how it relates to this topic at hand; constitutive defences the body (‘defence mechanisms which do not require prior contact with the microorganism – such as physical and chemical barriers to colonization, inflammatory response, the complement system, and phagocytosis); disease progression (to cause disease all microorganisms must go through four stages: they must encounter the host, gain entry, multiply and spread, and cause host tissue injury. The course of an infection may vary from asymptomatic to life threatening; an important distinction is between acute (and sub-acute) and chronic infections). Chronic infection is not the only outcome of a long-term colonization; an individual may also enter a carrier state, or the infection may become latent until reactivation.).
After the ‘general stuff’ has been covered in chapter 4, they deal with the pathophysiology of some examples of infectious diseases; infective endocarditis (bacterial or fungal infection of the interior of the heart), meningitis, pneumonia, infectious diarrhea, and sepsis/sepsis syndrome/septic shock. I’ll not go into much detail about these diseases, but I should probably note here that the names we use to describe infectious diseases like these may cause people to misunderstand how they work: To be clear, there isn’t just one ‘endocarditis bacterium’ or a specific ‘meningitis bacterium’. When specific sites/organ systems are invaded by microorganisms which spread and cause tissue damage (damage which can be caused both by the toxins released by the invading microorganisms and by the host response to the invasion), we have a name for that – but many different microorganisms may cause symptoms by invading the specific site or organ system in question, though some are more likely to affect specific sites than others. Sometimes the names of the microorganisms may even add to this confusion; for example one of the most common causes of bacterial meningitis (infection of the meninges) in children aged 2 months to 15 years is H Influenzae (which kind of sounds like, well…).
Chapter 5 deals with neoplasia. If you dont’ feel like reading this stuff, at least read Mukherjee. The chapter deals briefly with colon carcinoma as an example of an epithelial neoplasia; this stuff from Khan Academy is another great resource on this subject – it also deals a bit with cancer development more generally, and it’s a lot more accessible than is this chapter.
Anyway, the chapter… It starts out with a bit of a downer: “The recognition of overt malignancy by physical examination or imaging requires the presence in the body of about 1 billion malignant cells.” It goes on to note that: “A preclinical phase may sometimes be recognized” but even so, “More commonly, the preclinical phase goes undetected until invasive cancer, occasionally with regional or distant metastases, is already present.” That’s the way it is. The chapter then goes on to talk about many of the same things Mukherjee covers in the latter half of his book, like the role of tumor suppressor genes and oncogenes, the role of environmental triggers (carcinogens), inheritance, … In the field of oncology there seems to be a big focus on the role of genetic changes taking place in the cell(s), and: “A paradigm for sequential genetic alterations has been proposed as a necessary set of events leading to tumorigenesis.” Mukherjee also has more on this, if you’re interested. There are a lot of oncogenes and tumor suppressor genes that play a role in human cancers. In terms of the phenotypic changes they cause, this table is relevant (click to view full size):
A good related quote from the first part of the chapter:
“Molecular and cellular changes in tumor cells are, in a sense, a modification of normal physiology that benefits their growth and spread. The initial alterations may be “preprogrammed” in rare inherited malignancies, or they may be acquired as a consequence of mutations brought about by environmental exposure or occuring by chance during normal cell division. In a process akin to evolution, albeit in a fast time frame, additional genetic changes occur that favor further growth, invasion, and spread. Evasion of the host’s immune system, enhanced proliferative and invasive potential, and resistance to therapy are examples of early, middle, and late changes in the progression of neoplasia.”
The simple way to think about cancer is this: Cancer cells outcompete the surrounding cells because they’re better at growing and spreading, and they cause disease because the reason why they’re better at growing and spreading is that they’re no longer doing what they’re supposed to be doing, and because they’re taking up space and nutrients from the cells that still do their jobs.
The chapter also has some stuff on breast cancer and talks a bit about the BRCA mutations. After that they talk about mesenchymal, neuroendocrine and germ cell neoplasias, which are types of neoplasias the pathophysiology of which “can be described in terms of the embryonic tissue of origin.” The examples they include are carcinoid tumors, testicular cancer, and sarcomas. Again the naming of these diseases may be a bit confusing – tissue will often migrate during development and you can actually end up with, say, a testicular neoplasm which is not located anywhere near your testes (for example, the testicular tissue may have migrated to your chest..). Then they cover hematologic neoplasms (blood, bone marrow, or lymph nodes), and here they’ve included some stuff on lymphomas (“uncontrolled proliferation and potential dissemination of lymphocytes“) and AML, a type of leukemia (Mukherjee has a lot more stuff on that). I found it surprising that they did not spend more time on the last part, the systemic effects of neoplasia – basically they only spend one page on that stuff, though they do also include a few tables to illustrate these aspects of the diseases. I’ve included one of the figures below (click to view in a higher resolution):
Indirect systemic effects of cancer which are not caused by the local presence of cancer cells are what’s called pareneoplastic syndromes.
“SUMMARY AND CONCLUSIONS
Documents provided by the Department of Energy reveal the frequent and systematic use of human subjects as guinea pigs for radiation experiments. Some experiments were conducted in the 1940s at the dawn of the nuclear age, and might be attributed to an ignorance of the long term effects of radiation exposure, or to the atomic hubris that accompanied the making of the first nuclear bombs. But other experiments were conducted during the supposedly more enlightened 1960s and 1970s. In either event, such experiments cannot be excused.
These experiments were conducted under the sponsorship of the Manhattan Project, the Atomic Energy Commission, or the Energy Research and Development Administration, all predecessor agencies of the Department of Energy. These experiments spanned roughly thirty years. This report presents the findings of the Subcommittee staff on this project.
Literally hundreds of individuals were exposed to radiation in experiments which provided little or no medical benefit to the subjects. The chief objectives of these experiments were to directly measure the biological effects of redioactive material; to measure doses from injected, ingested, or inhaled redioactive substances; or to measure the time it took radioactive substances to pass through the human body. American citizens thus became nuclear calibration devices.
In many cases, subjects willingly participated in experiments, but they became willing guinea pigs nonetheless. In some cases, the human subjects were captive audiences or populations that experimenters might frighteningly have considered “expendable”: the elderly, prisoners, hospital patients suffering from terminal diseases or who might not have retained their full faculties for informed consent. For some human subjects, informed consent was not obtained or there is no evidence that informed consent was granted. For a number of these same subjects, the government covered up the nature of the experiments and deceived the families of deceased victims as to what had transpired. In many experiments, subjects received doses that approached or even exceeded presently recognized limits for occupational radiation exposure. Doses were as great as 98 times the body burden recognized at the time the experiments were conducted.”
It seems that the Tuskegee syphilis experiment wasn’t quite as unique as I’d thought.
ii. Diuretic Treatment of Hypertension. Interesting, lots of stuff there I didn’t know.
“After adjusting for age, sex, education, and race/ethnicity, risk of death was higher in low-income than high-income group for both all-cause mortality (Hazard ratio [HR], 1.98; 95% confidence interval [CI]: 1.37, 2.85) and cardiovascular disease (CVD)/diabetes mortality (HR, 3.68; 95% CI: 1.64, 8.27). The combination of the four pathways attenuated 58% of the association between income and all-cause mortality and 35% of that of CVD/diabetes mortality. Health behaviors attenuated the risk of all-cause and CVD/diabetes mortality by 30% and 21%, respectively, in the low-income group. Health status attenuated 39% of all-cause mortality and 18% of CVD/diabetes mortality, whereas, health insurance and inflammation accounted for only a small portion of the income-associated mortality (≤6%).
Excess mortality associated with lower income can be largely accounted for by poor health status and unhealthy behaviors. Future studies should address behavioral modification, as well as possible strategies to improve health status in low-income people.”
iv. Influence of Opinion Dynamics on the Evolution of Games. I’ve only just skimmed this, but it looks interesting. Here’s the abstract:
“Under certain circumstances such as lack of information or bounded rationality, human players can take decisions on which strategy to choose in a game on the basis of simple opinions. These opinions can be modified after each round by observing own or others payoff results but can be also modified after interchanging impressions with other players. In this way, the update of the strategies can become a question that goes beyond simple evolutionary rules based on fitness and become a social issue. In this work, we explore this scenario by coupling a game with an opinion dynamics model. The opinion is represented by a continuous variable that corresponds to the certainty of the agents respect to which strategy is best. The opinions transform into actions by making the selection of an strategy a stochastic event with a probability regulated by the opinion. A certain regard for the previous round payoff is included but the main update rules of the opinion are given by a model inspired in social interchanges. We find that the fixed points of the dynamics of the coupled model are different from those of the evolutionary game or the opinion models alone. Furthermore, new features emerge such as the independence of the fraction of cooperators with respect to the topology of the social interaction network or the presence of a small fraction of extremist players.”
v. This is awesome.
“Determining the fitness consequences of sibling interactions is pivotal for understanding the evolution of family living, but studies investigating them across lifetime are lacking. We used a large demographic dataset on preindustrial humans from Finland to study the effect of elder siblings on key life-history traits. The presence of elder siblings improved the chances of younger siblings surviving to sexual maturity, suggesting that despite a competition for parental resources, they may help rearing their younger siblings. After reaching sexual maturity however, same-sex elder siblings’ presence was associated with reduced reproductive success in the focal individual, indicating the existence of competition among same-sex siblings. Overall, lifetime fitness was reduced by same-sex elder siblings’ presence and increased by opposite-sex elder siblings’ presence. Our study shows opposite effects of sibling interactions depending on the life-history stage, and highlights the need for using long-term fitness measures to understand the selection pressures acting on sibling interactions.”
Where did they get their data? Well, it was hard for people living in the 17th and 18th century to avoid death or taxes too:
“The demographic dataset from historical Finnish populations was compiled from records of the Lutheran church, which was obliged by law to document all dates of births, marriages and deaths in the population for tax purposes [25–29]. As migration events were relatively rare and the migration records maintained by the church allowed us to follow dispersers in the majority of the cases, these records provide us with relatively accurate information on individual survival and reproductive histories  (e.g. 91% of individuals with known birth date were followed to sexual maturity at age 15 years). Our study period is limited to the eighteenth and nineteenth centuries, before the transition to reduced birth and mortality rates .”
vii. I’ve posted about this topic before, here’s a new study on cancer screening procedures: Effect of Three Decades of Screening Mammography on Breast-Cancer Incidence. I think the results are depressing:
“The introduction of screening mammography in the United States has been associated with a doubling in the number of cases of early-stage breast cancer that are detected each year, from 112 to 234 cases per 100,000 women — an absolute increase of 122 cases per 100,000 women. Concomitantly, the rate at which women present with late-stage cancer has decreased by 8%, from 102 to 94 cases per 100,000 women — an absolute decrease of 8 cases per 100,000 women. With the assumption of a constant underlying disease burden, only 8 of the 122 additional early-stage cancers diagnosed were expected to progress to advanced disease. After excluding the transient excess incidence associated with hormone-replacement therapy and adjusting for trends in the incidence of breast cancer among women younger than 40 years of age, we estimated that breast cancer was overdiagnosed (i.e., tumors were detected on screening that would never have led to clinical symptoms) in 1.3 million U.S. women in the past 30 years. We estimated that in 2008, breast cancer was overdiagnosed in more than 70,000 women; this accounted for 31% of all breast cancers diagnosed.
Despite substantial increases in the number of cases of early-stage breast cancer detected, screening mammography has only marginally reduced the rate at which women present with advanced cancer. Although it is not certain which women have been affected, the imbalance suggests that there is substantial overdiagnosis, accounting for nearly a third of all newly diagnosed breast cancers, and that screening is having, at best, only a small effect on the rate of death from breast cancer.”
By Siddhartha Mukherjee. It is another one of the books I received in the mail Tuesday. I didn’t plan on reading it before this weekend, but ‘things didn’t go as planned.’ I started out with a few pages Tuesday evening and basically I just couldn’t stop reading. Now I’ve finished the book.
It’s gotten a lot of attention around the web, which was part of why I decided to have a go at it. The attention it has received is not undeserved. I’d have liked more data but then again I always want more data. Here are a few interesting observations from the book:
“In 1870, the per capita consumption in America was less than one cigarette per year. A mere thirty years later, Americans were consuming 3.5 billion cigarettes and 6 billion cigars every year. By 1953, the average annual consumption of cigarettes had reached thirty-five hundred per person. On average, an adult American smoked ten cigarettes every day, an average Englishman twelve, and a Scotsman nearly twenty. […] between 1940 and 1944, the fraction of female smokers in the United States more than doubled, from 15 to 36 percent.”
If you assume they wouldn’t have started in case there hadn’t been a World War, you can probably add another few million people to the list of war casualties right there. How about later on? “By 1994, the per capita consumption of cigarettes in America had dropped for nearly twenty straight years (from 4,141 in 1974 to 2,500 in 1994), representing the most dramatic downturn in smoking rates in history.” But before that point the results of the changed smoking habits were not hard to observe in the data:
“Between 1970 and 1994, lung cancer deaths among women over the age of fifty-five had increased by 400 percent, more than the rise in the rates of breast and colon cancer combined. This exponential upswing in mortality had effaced nearly all gains in survival not just for lung cancer, but for all other types of cancer. […] Lung cancer was still the single biggest killer among cancers, responsible for nearly one-fourth of all cancer deaths.”
A few other interesting bits:
“Prostate cancer represents a full third of all cancer incidence in men — sixfold that of leukemia and lymphoma. In autopsies of men over sixty years old, nearly one in every three specimens will bear some evidence of prostatic malignancy.” (but you already knew that first part, right?)
“Cisplatin was unforgettable in more than one sense. The drug provoked an unremitting nausea, a queasiness of such penetrating force and quality that had rarely been encountered in the history of medicine: on average, patients treated with the drug vomited twelve times a day.”
“The incidence of CML remains unchanged from the past: only a few thousand patients are diagnosed with this form of leukemia every year. But the prevalence of CML—the number of patients presently alive with the disease—has dramatically changed with the introduction of Gleevec [a new treatment option – there’s much more about it in the book and the wikipedia article also covers this]. As of 2009, CML patients treated with Gleevec are expected to survive an average of thirty years after their diagnosis. Based on that survival figure, Hagop Kantarjian estimates that within the next decade, 250,000 people will be living with CML in America, all of them on targeted therapy. Druker’s drug will alter the national physiognomy of cancer, converting a once-rare disease [people just died of it in the past] into a relatively common one”
He doesn’t cover the economics of cancer and cancer treatment in much detail and present problems and developments in this area are not covered at all. Included in the postscript is however an interview dealing with some of the stuff not covered in the book, and after reading that part I’m in a way glad he didn’t write about this stuff – when dealing with the question of the high costs of relatively recently discovered targeted therapies, he does not even mention FDA’s role in driving up costs when answering that question, which is telling me that this is a subject he simply doesn’t know enough about to cover, at least at the present point in time. If you want to know more the FDA’s role in driving up costs of new medical treatments, including new cancer treatments, Megan McArdle has written about that stuff often though I don’t have a specific link at hand; google is your friend.
The book is very USA-centric, but I didn’t consider that a big issue. It’s also ‘popular science’. That was initially a strong argument for not buying the book, but on the other hand the popular science aspect also means that the book is easy to read and won’t take you very long to get through even though the page count is significant.
It’s a wonderful read.