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Cancer arises from stress-induced breakdown of tissue homeostasis
Abstract
Abstract
Part-I: I critically review the context of cancer research, where it has been advanced that most published research findings are false, that medicine itself is the third leading cause of death in the Western world, and that experienced stress arising from an individual’s position in society’s dominance hierarchy is the primary determinant of individual health.
Part-II: I critically review the randomized trials for treatments and screening, especially for breast cancer. It has been advanced that screening does more harm than good, and that treatment protocols have little effect on net population mortality from cancer. There is no robust demonstration that the treatment protocols for the common cancers do more good than harm to individual patients.
Part-III: I critically review the mutation-centric metastasis dominant paradigm of cancer, and various efforts to somewhat or definitively challenge the dominant paradigm, with an eye to answering the question “What is cancer?”
Final section: I propose a conceptual model of cancer, which incorporates the leading criticisms of the dominant paradigm, and which is testable. In my model, cancer is an age-dependent and tissue-specific stress-induced breakdown of tissue-shape homeostasis. My model is aided by a graphical picture depicting age-specific and tissue-specific curves of steady-state nodule size (DT) versus experienced stress level (S). A given curve has a critical stress (SC) beyond which there is runaway tumour growth due to tissue-response feedback. Here, “metastasis” is the simple consequence of the individual’s tissue susceptibility to loss of shape homeostasis having gone supercritical for a cluster of tissue-specific DT v. S curves. The model provides treatment strategies on three branches: Psychological, tissue-surface-shape homeostasis, and tumour growth feedback attenuation.
... For example, see Sapolsky's influential 2005 review of primate studies [1], and my critical review of medicine [2]. The metabolism of the monoamine neurotransmitter serotonin and the associated evolutionary biology is now an established area of science [3] [4][5] [6]. ...
I propose that the animal has two modes of being, which are binary end-points on an attitudinal, self-image and behavioural psychological-state-scape. The psychological-state-scape is binary in the two modes because the metabolic physiologies of the two modes are incompatible. The holistic state of being cannot be both simultaneously. Different blood biochemistries and tissue and organ responses are in play. It’s one or the other: Vying for dominance or accepting subservience.
... I have previously explained how the stress from dominance enforcement is a pivotal biopsychological mechanism that stabilizes human hierarchies, and how the costs to individuals moderate increases in hierarchical gradient [3]. I have also described how physiological stress is the dominant causal factor in individual health [7]. ...
I show that the de facto police practice of constant random harassment by carding (demanding identification) and a spectrum of other means, combined with less frequent unprovoked executions and prosecutions using false charges, in containing groups targeted for containment is exactly the most effective and efficient strategy for hierarchical containment developed by evolution and described by primate anthropologists. As such, the said practice should be understood to be an intrinsic and voluntary feature of the state's domination over occupied groups. This applies both to para-military occupation such as US and Canada's containment of ghettoized groups in cities, and to military occupation such as the occupation of Palestinians by Israel. The self-defence strategies are also derived from evolutionary anthropology, which provides the bio-psychological basis of their effectiveness.
Recent discoveries suggest that aging is neither driven by accumulation of molecular damage of any cause, nor by random damage of any kind. Some predictions of a new theory, quasi-programmed hyperfunction, have already been confirmed and a clinically-available drug slows aging and delays diseases in animals. The relationship between diseases and aging becomes easily apparent. Yet, the essence of aging turns out to be so startling that the theory cannot be instantly accepted and any possible arguments are raised for its disposal. I discuss that these arguments actually support a new theory. Are any questions remaining? And might accumulation of molecular damage still play a peculiar role in aging?
To conduct meta-analyses of randomized trials of aromatase inhibitors (AIs) compared with tamoxifen either as initial monotherapy (cohort 1) or after 2 to 3 years of tamoxifen (cohort 2).
Data submitted to the Early Breast Cancer Trialists' Collaborative Group were used in separate meta-analyses of two cohorts. Primary analyses involve postmenopausal women with tumors reported to be estrogen receptor positive. Log-rank P values are two-sided.
Cohort 1 comprised 9,856 patients with a mean of 5.8 years of follow-up. At 5 years, AI therapy was associated with an absolute 2.9% (SE = 0.7%) decrease in recurrence (9.6% for AI v 12.6% for tamoxifen; 2P < .00001) and a nonsignificant absolute 1.1% (SE = 0.5%) decrease in breast cancer mortality (4.8% for AI v 5.9% for tamoxifen; 2P = .1). Cohort 2 comprised 9,015 patients with a mean of 3.9 years of follow-up. At 3 years from treatment divergence (ie, approximately 5 years after starting hormonal treatment), AI therapy was associated with an absolute 3.1% (SE = 0.6%) decrease in recurrence (5.0% for AI v 8.1% for tamoxifen since divergence; 2P < .00001) and an absolute 0.7% (SE = 0.3%) decrease in breast cancer mortality (1.7% for AI v 2.4% for tamoxifen since divergence; 2P = .02). There was no convincing heterogeneity in the proportional recurrence reduction with respect to age, nodal status, tumor grade, or progesterone receptor status and no indication of an increase in nonbreast deaths with AIs in either cohort. CONCLUSION AIs produce significantly lower recurrence rates compared with tamoxifen, either as initial monotherapy or after 2 to 3 years of tamoxifen. Additional follow-up will provide clearer information on long-term survival.
The Swedish two county trial of breast cancer screening is now in its tenth year. This paper presents detailed results on mortality from breast cancer and from all other causes, and on the population denominators at risk for each of the first 8 years of follow up, for each county separately. These data represent a two year update on the last major report. Results show an increasingly significant deficit in deaths from breast cancer among the 77,092 women invited to screening relative to the 56,000 not invited (RR = 0.68, p = 0.002), with no significant difference between the effects of screening in the two counties (p = 0.5). These results remain the same when adjusted for age. Analysis of all cause deaths shows no significant effect of screening (p = 0.5), nor was there any significant effect of screening on deaths from all causes other than breast cancer (p = 0.9). The rates of deaths from intercurrent illness in breast cancer cases were almost identical in the group invited to screening and the group not invited (p = 0.7). This result remained the same when adjusted for age. We calculate that in the age group 50-69 at entry, one breast cancer death was prevented per 4000 woman/years, per 1460 mammographic examinations, per 13.5 biopsies, and per 7.4 breast cancers detected.
A randomised controlled trial to investigate the efficacy of mass screening with single-view mammography in reducing mortality from breast cancer was started in Sweden in 1977. 162 981 women aged 40 years or more and living in the counties of Kopparberg and Ostergötland were enrolled in the study and divided at random into 2 groups. Each woman in the study group was offered screening every 2 or 3 years depending on age. Women in the control group were not offered screening. This report is confined to the 134 867 women aged 40-74 years at date of entry. The results to the end of 1984 show a 31% reduction in mortality from breast cancer and a 25% reduction in the rate of stage II or more advanced breast cancers in the group invited to screening. 7 years after the start of the study the excess of stage I cancers in the study group largely outweighs the deficit of advanced cancers.
The contribution of hereditary factors to the causation of sporadic cancer is unclear. Studies of twins make it possible to estimate the overall contribution of inherited genes to the development of malignant diseases.
We combined data on 44,788 pairs of twins listed in the Swedish, Danish, and Finnish twin registries in order to assess the risks of cancer at 28 anatomical sites for the twins of persons with cancer. Statistical modeling was used to estimate the relative importance of heritable and environmental factors in causing cancer at 11 of those sites.
At least one cancer occurred in 10,803 persons among 9512 pairs of twins. An increased risk was found among the twins of affected persons for stomach, colorectal, lung, breast, and prostate cancer. Statistically significant effects of heritable factors were observed for prostate cancer (42 percent; 95 percent confidence interval, 29 to 50 percent), colorectal cancer (35 percent; 95 percent confidence interval, 10 to 48 percent), and breast cancer (27 percent; 95 percent confidence interval, 4 to 41 percent).
Inherited genetic factors make a minor contribution to susceptibility to most types of neoplasms. This finding indicates that the environment has the principal role in causing sporadic cancer. The relatively large effect of heritability in cancer at a few sites suggests major gaps in our knowledge of the genetics of cancer.
To assess the impact of the NHS breast screening programme on mortality from breast cancer in women aged 55-69 years over the period 1990-8.
Age cohort model with data for 1971-89 used to predict mortality for 1990-8 with assumption of no major effect from screening or improvements in treatment until after 1989. Effect of screening and other factors on mortality estimated by comparing three year moving averages of observed mortality with those predicted (by five year age groups from 50-54 to 75-79), the effect of screening being restricted to certain age groups.
England and Wales.
Women aged 40 to 79 years.
Compared with predicted mortality in the absence of screening or other effects the total reduction in mortality from breast cancer in 1998 in women aged 55-69 was estimated as 21.3%. Direct effect of screening was estimated as 6.4% (range of estimates from 5.4-11.8%). Effect of all other factors (improved treatment with tamoxifen and chemotherapy, and earlier presentation outside the screening programme) was estimated as 14.9% (range 12.2-14.9%).
By 1998 both screening and other factors, including improvements in treatment, had resulted in substantial reductions in mortality from breast cancer. Many deaths in the 1990s will be of women diagnosed in the 1980s and early 1990s, before invitation to screening. Further major effects from screening and treatment are expected, which together with cohort effects should result in further substantial reductions in mortality from breast cancer, particularly for women aged 55-69, over the next 10 years.
Randomized trials have demonstrated that mammographic screening can reduce breast cancer mortality. Our aim was to estimate the reduction in mortality expected from the East Anglian Breast Screening Programme. Breast screening achieves benefit by improving cancer prognosis (reducing tumour size, nodal involvement and possibly grade) through earlier diagnosis. We compared cancer prognosis between women invited for screening and those not yet invited in East Anglia, UK, in order to predict the mortality reduction achievable by screening, independently of any reduction due to changes in treatment and underlying disease. Participants (both invited and not-yet invited) were women eligible for invitation to first and second screens and diagnosed with invasive breast cancer in 1989-96. Death rates were predicted based on the observed distribution of tumour grade, size and node status amongst 950 cancers diagnosed following first invitation, up to and including at second screen (excluding those detected at first screening), and 451 cancers presenting symptomatically in women awaiting first invitation during the staggered introduction of screening, after adjustment for lead time amongst screen detected cases. For all ages, the ratio of predicted breast cancer mortality in the invited compared with the uninvited group was 0.85 (95% CI 0.78, 0.93). It was 0.93 (0.80, 1.08) for women aged 50-54 at diagnosis and 0.81 (0.72, 0.91) for those aged 55-64. We conclude that, by 2004, the second round of screening in East Anglia should reduce mortality by around 7% in women below age 55 at diagnosis, and by around 19% in those aged 55-64.
Some tissue types give rise to human cancers millions of times more often than other tissue types. Although this has been
recognized for more than a century, it has never been explained. Here, we show that the lifetime risk of cancers of many different
types is strongly correlated (0.81) with the total number of divisions of the normal self-renewing cells maintaining that
tissue’s homeostasis. These results suggest that only a third of the variation in cancer risk among tissues is attributable
to environmental factors or inherited predispositions. The majority is due to “bad luck,” that is, random mutations arising
during DNA replication in normal, noncancerous stem cells. This is important not only for understanding the disease but also
for designing strategies to limit the mortality it causes.
To analyze the print news media's coverage of sentinel events involving cancer patients.
Using LexisNexis, we identified English-language newspaper articles covering medical errors in cancer care between January 1, 2000, and December 31, 2010. Articles were coded for 3 major themes using a standardized abstraction instrument: narrative statements and point of view most prominently represented, attribution of blame, and orientation toward patient safety. We also abstracted country where the newspaper was published, type of error event, and extent of patient harm.
We analyzed 64 articles from 37 print newspaper syndications that circulated in 6 countries/regions. Reports of medical errors rarely were framed from the point of view of a safety expert or the responsible clinician (13% and 3%, respectively) compared with the patient and legal points of view (both 30%). Articles held individual clinicians (41%) and hospital systems (28%) responsible for most errors. Four in 10 articles failed to present medical errors as "systems" problems. Article perspective varied considerably by country, with 53% of articles from the UK and 63% from Australia and New Zealand judged as negatively slanted compared with 14% in the United States and Canada.
In reports of medical errors involving cancer patients, the news media regularly blame individual clinicians for mistakes and fail to present a systems-based understanding of these events.
Despite recent advances in molecular biology and genetics, the mysteries that control human lifespan are yet to be unraveled. Many theories, which fall into two main categories: programmed and error theories, have been proposed to explain the process of aging, but neither of them appears to be fully satisfactory. These theories may interact with each other in a complex way. By understanding and testing the existing and new aging theories, it may be possible to promote successful aging.
Patterns of incidence of breast, endometrial and ovarian cancer show strong similarities in both international and inter-regional comparisons, similarities readily confirmed by the calculation of coefficients of correlation. Migrant studies suggest that environmental factors are more important than genetic differences between populations. Correlation studies have shown that dietary factors can explain much of the international variation, and most suspicion has fallen on dietary fat. Differences in fertility between populations also correlate with the variations in incidence. For breast cancer, the latter may be an important determinant of variation within countries in the pre-menopausal age group, with dietary differences accounting for variations in post-menopausal rates internationally. There is scope for improving upon earlier studies, and for investigating the relative contributions of diet and fertility to the geographic patterns of endometrial and ovarian cancers.
Two of the most important prognostic indicators for breast cancer are tumor size and extent of axillary lymph node involvement. Data on 24,740 cases recorded in the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute were used to evaluate the breast cancer survival experience in a representative sample of women from the United States. Actuarial (life table) methods were used to investigate the 5-year relative survival rates in cases with known operative/pathologic axillary lymph node status and primary tumor diameter. Survival rates varied from 45.5% for tumor diameters equal to or greater than 5 cm with positive axillary nodes to 96.3% for tumors less than 2 cm and with no involved nodes. The relation between tumor size and lymph node status was investigated in detail. Tumor diameter and lymph node status were found to act as independent but additive prognostic indicators. As tumor size increased, survival decreased regardless of lymph node status; and as lymph node involvement increased, survival status also decreased regardless of tumor size. A linear relation was found between tumor diameter and the percent of cases with positive lymph node involvement. The results of our analyses suggest that disease progression to distant sites does not occur exclusively via the axillary lymph nodes, but rather that lymph node status serves as an indicator of the tumor's ability to spread.
Aspirin and nonaspirin nonsteroidal antiinflammatory drugs (NSAIDs) inhibit platelet cyclooxygenase, thereby blocking the formation of thromboxane A2. These drugs produce a systemic bleeding tendency by impairing thromboxane-dependent platelet aggregation and consequently prolonging the bleeding time. Aspirin exerts these effects by irreversibly blocking cyclooxygenase and, therefore, its actions persist for the circulating lifetime of the platelet. Nonaspirin NSAIDs inhibit cyclooxygenase reversibly and, therefore, the duration of their action depends on specific drug dose, serum level, and half-life. The clinical risks of bleeding with aspirin or nonaspirin NSAIDs are enhanced by the concomitant use of alcohol or anticoagulants and by associated conditions, including advanced age, liver disease, and other coexisting coagulopathies.
Information concerning the deficiencies of US medical care has been
accumulating. The fact that more than 40 million people have no health insurance
is well known. The high cost of the health care system is considered to be
a deficit, but seems to be tolerated under the assumption that better health
results from more expensive care, despite evidence from a few studies indicating
that as many as 20% to 30% of patients receive contraindicated care.1 In addition, with the release of the Institute of
Medicine (IOM) report "To Err Is Human,"2 millions
of Americans learned, for the first time, that an estimated 44,000 to 98,000
among them die each year as a result of medical errors.
The interactions between cancer cells and their micro- and macroenvironment create a context that promotes tumour growth and protects it from immune attack. The functional association of cancer cells with their surrounding tissues forms a new 'organ' that changes as malignancy progresses. Investigation of this process might provide new insights into the mechanisms of tumorigenesis and could also lead to new therapeutic targets.
We used modeling techniques to assess the relative and absolute contributions of screening mammography and adjuvant treatment to the reduction in breast-cancer mortality in the United States from 1975 to 2000.
A consortium of investigators developed seven independent statistical models of breast-cancer incidence and mortality. All seven groups used the same sources to obtain data on the use of screening mammography, adjuvant treatment, and benefits of treatment with respect to the rate of death from breast cancer.
The proportion of the total reduction in the rate of death from breast cancer attributed to screening varied in the seven models from 28 to 65 percent (median, 46 percent), with adjuvant treatment contributing the rest. The variability across models in the absolute contribution of screening was larger than it was for treatment, reflecting the greater uncertainty associated with estimating the benefit of screening.
Seven statistical models showed that both screening mammography and treatment have helped reduce the rate of death from breast cancer in the United States.
- See The Chambers
See the Chambers et al. review of 2002; and Milas et al., 1983.
Nonsteroidal anti-inflammatory drugs and colorectal cancer: Evolving concepts of their chemopreventative actions 1992-1998; and Editorial — Aspirin, NSAIDs, and colon cancer prevention: Mechanisms? Gastroenterology
- S J Shiff
- B Rigas
example: S.J. Shiff and B. Rigas. Nonsteroidal anti-inflammatory drugs and colorectal cancer: Evolving
concepts of their chemopreventative actions. Gastroenterology, 1997, vol. 113, pages 1992-1998; and Editorial —
Aspirin, NSAIDs, and colon cancer prevention: Mechanisms? Gastroenterology, 1998, vol. 114, pages 1095-1100.
Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy: 133 randomized trials involving 31,000 recurrences and 24,000 deaths among 75,000 women
Early Breast Cancer Trialist's Collaborative Group. Systemic treatment of early breast cancer by hormonal,
cytotoxic, or immune therapy: 133 randomized trials involving 31,000 recurrences and 24,000 deaths among
75,000 women. Lancet, 4 January 1992, vol. 339, no. 8784, pages 1-15.
Early Breast Cancer Trialist's Collaborative Group. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomized trials
Early Breast Cancer Trialist's Collaborative Group. Effects of chemotherapy and hormonal therapy for early
breast cancer on recurrence and 15-year survival: an overview of the randomized trials. Lancet, 14 may 2005, vol.
365, pages 1687-1717.