Chasing the immortal strand: evidence for nature's way of protecting the breast genome

Mutations arise during cell division at a predictable rate. Besides DNA repair mechanisms, the existence of cellular hierarchies that originate with a stem cell serve to reduce the number of divisions necessary for normal physiology. In a previous issue, Bussard and colleagues demonstrate that mammary stem cells have an additional remarkable trait; namely the ability to selectively retain a template DNA strand during self renewal. In doing so, they avoid the accumulation of mutations in that so called 'immortal strand'. The implications of this are discussed with reference to the development and treatment of cancer.     

Cognitive decline after major oncological surgery in the elderly

BackgroundElderly patients undergoing oncological surgery experience postoperative cognitive decline. The aims of this study were to examine the incidence of cognitive decline 3 months after surgery and identify potential patient-, disease- and surgery-related risk factors for postoperative cognitive decline in onco-geriatric patients.MethodsA consecutive series of elderly patients (≥65 years) undergoing surgery for the removal of a solid tumour were included (n = 307). Cognitive performance was assessed pre-operatively and 3 months postoperatively. Postoperative decline was defined as a decline in scores of cognitive tests of ≥25% on ≥2 of 5 tests.ResultsOf the patients who had completed the assessments, 117 (53%, 95% confidence interval [CI]: 47–60) had improved cognitive test scores, whereas 26 (12%, 95% CI: 7.6–16) showed cognitive decline at 3 months postoperatively. In patients aged >75 years, the incidence of overall cognitive decline 3 months postoperatively was 18% (95% CI: 9.3–27). In patients with lower pre-operative Mini–Mental State Examination (MMSE) score (≤26) the incidence was 37% (95% CI: 18–57), and in patients undergoing major surgery it was 18% (95% CI: 10.6–26). Of the cognitive domains, executive function was the most vulnerable to decline.ConclusionAbout half of the elderly patients show improvement in postoperative cognitive performance after oncological surgery, whereas 12% show cognitive decline. Advanced age, lower pre-operative MMSE score and major surgery are risk factors for cognitive decline at 3 months postoperatively and should be taken into account in the clinical decision-making progress. Research to develop interventions to preserve quality of life should focus on this high-risk subpopulation.     

Socioeconomic disparities in the decline in invasive breast cancer incidence

Breast cancer incidence in the United States has declined dramatically since the year 2002. To improve our understanding of the underlying factors driving breast cancer trends, we explored potential socioeconomic disparities in the recent decline in incidence. We examined the decline in breast cancer incidence according to county-level socioeconomic indicators using data from the Surveillance, Epidemiology and End Results (SEER) program. Since socioeconomic status is associated with mammography screening, we also examined the relation between incidence of ductal carcinoma in situ (DCIS; a strong marker of mammography utilization) and the decline in invasive breast cancer. The reduction in invasive breast cancer incidence between 1998–2001 and 2003–2006 in the SEER 9 registries was greatest among women living in counties with higher median household income (−16% change for ≥$85,000 vs. −4% for <$85,000 vs. −4% for <35,000; P _trend < 0.01) and a higher percentage of adults aged 25 years or older with a bachelor’s degree (−13% change for ≥40% vs. −8% for <15%; P _trend < 0.01). Counties with higher DCIS incidence during 1985–2001 had a larger decrease in invasive breast cancer incidence (absolute decrease 1.7 percentage points greater per 5 per 100,000 increase in DCIS incidence; P = 0.01). This association was present for both ER-positive and ER-negative invasive cancers (P < 0.05). In summary, the decline in breast cancer incidence has been largest in areas with high socioeconomic status and high screening utilization rates. These results are consistent with the hypothesis that a saturation of screening mammography utilization contributed to the overall decline in breast cancer incidence.     

Epigenetic alterations in the suprachiasmatic nucleus and hippocampus contribute to age-related cognitive decline

Circadian rhythm dysfunction and cognitive decline, specifically memory loss, frequently accompany natural aging. Circadian rhythms and memory are intertwined, as circadian rhythms influence memory formation and recall in young and old rodents. Although, the precise relationship between circadian rhythms and memory is still largely unknown, it is hypothesized that circadian rhythm disruption, which occurs during aging, contributes to age-associated cognitive decline, specifically memory loss. While there are a variety of mechanisms that could mediate this effect, changes in the epigenome that occur during aging has been proposed as a potential candidate. Interestingly, epigenetic mechanisms, such as DNA methylation and sirtuin1 (SIRT1) are necessary for both circadian rhythms and memory. During aging, similar alterations of epigenetic mechanisms occur in the suprachiasmatic nucleus (SCN) and hippocampus, which are necessary for circadian rhythm generation and memory, respectively. Recently, circadian rhythms have been linked to epigenetic function in the hippocampus, as some of these epigenetic mechanisms oscillate in the hippocampus and are disrupted by clock gene deletion. The current paper will review how circadian rhythms and memory change with age, and will suggest how epigenetic changes in these processes might contribute to age-related cognitive decline.     

History,heresy and radiology in scientific discovery

Nowadays, most drugs reach the market after research has established their pharmacology, safety and efficacy. That was not always the case 50 years ago. Thalidomide was used before its target cell or mode of action were known. Commencing with the thalidomide catastrophe – an epidemic of gross birth defects (1958–1962) – thalidomide's origins are revisited to show how this drug came to be made and sold in the 1950s. Thalidomide intersected with Australian radiology in the 1970s. The site and mode of action of the drug was deduced from X‐rays of thalidomide‐induced bone defects, which have classical radiological signs of sensory neuropathic osteoarthropathy. The longitudinal reduction deformities follow the distribution of segmental sensory innervation of the limb skeleton, indicating neural crest as the target organ. Injury to one level of neural crest halts normal neurotrophism and deletes the dependent segment – a previously unrecognised embryonic mechanism that explains most non‐genetic birth defects. The final common pathway is neural crest injury and failure of normal neurotrophism to result in longitudinal reduction deformities, for example, phocomelia.     

Quantifying the role of PSA screening in the US prostate cancer mortality decline

OBJECTIVE: To quantify the plausible contribution of prostate-specific antigen (PSA) screening to the nearly 30% decline in the US prostate cancer mortality rate observed during the 1990s. METHODS: Two mathematical modeling teams of the US National Cancer Institute's Cancer Intervention and Surveillance Modeling Network independently projected disease mortality in the absence and presence of PSA screening. Both teams relied on Surveillance, Epidemiology, and End Results (SEER) registry data for disease incidence, used common estimates of PSA screening rates, and assumed that screening, by shifting disease from distant to local-regional clinical stage, confers a corresponding improvement in disease-specific survival. RESULTS: The teams projected similar mortality increases in the absence of screening and decreases in the presence of screening after 1985. By 2000, the models projected that 45% (Fred Hutchinson Cancer Research Center) to 70% (University of Michigan) of the observed decline in prostate cancer mortality could be plausibly attributed to the stage shift induced by screening. CONCLUSIONS: PSA screening may account for much, but not all, of the observed drop in prostate cancer mortality. Other factors, such as changing treatment practices, may also have played a role in improving prostate cancer outcomes.     

The fifty-year decline of cancer in America.

PURPOSE: From 1950 to 1990, the overall cancer mortality rate increased steadily in the United States, a trend which ran counter to declining mortality from other major diseases. The purpose of this study was to assess the impact of lung cancer on all-cancer mortality over the past 50 years. METHODS: Data from the National Centers for Health Statistics were used to develop mortality rates for all forms of cancer combined, lung cancer, and other-cancer (all-cancer minus lung cancer) from 1950 to 1998. RESULTS: When lung cancer is excluded, mortality from all other forms of cancer combined declined continuously from 1950 to 1998, dropping 25% during this period. The decline in other-cancer mortality was approximately 0.4% annually from 1950 to 1990 but accelerated to 0.9% per year from 1990 to 1996 and to 2.2% per year from 1996 to 1998. CONCLUSION: The long-term decline is likely due primarily to improvements in medical care, including screening, diagnosis, and treatment.     

Radiotherapy practices in Sweden compared to the scientific evidence

A systematic assessment of radiotherapy for cancer was conducted by The Swedish Council on Technology Assessment in Health Care (SBU) in 2001. The assessment included a critical review of the literature on radiotherapy for cancer published in 1994-2001 and a prospective survey of radiotherapy practice in Sweden during 12 weeks in the autumn of 2001. The results of the survey were compared with the evidence derived from the scientific literature, and the following conclusions could be drawn: Radiotherapy is currently given to approximately 47% of new cancer cases This figure is on a par with rates reported from other countries. For most tumour types, curative radiotherapy practices in Sweden are generally supported by the literature. Interstitial brachytherapy has been included in the treatment of non-gynaecological malignancies, and prostate cancer is now the most common indication. Palliative radiotherapy has increased and is today given in a more rational way using single or few fractions However, it still seems to be under-utilized in Sweden. The need for radiotherapy can be expected to increase until the year 2010.     

In vivo decline of methotrexate and methotrexate polyglutamates in age-fractionated erythrocytes

Summary Methotrexate (MTX) accumulates in erythrocytes (ery) during weekly MTX administration, and the ery-MTX concentration reaches a steady state after 4–6 weeks. In order to study MTX accumulation and metabolism to polyglutamate derivatives in different age populations of red blood cells, we took erythrocytes from 12 children with ALL who were receiving maintenance treatment with MTX and 6-MP and separated them according to age on a discontinuous Percoll gradient. When the erythrocytes of these children were separated according to specific gravity a normal distribution was obtained. Age fractionation was confirmed by the exponential decline of the erythrocyte aspartate aminotransferase (ery-ASAT) and by the reticulocyte counts. The ery-MTX declined with increasing red blood cell age in an exponential manner no different from the decline of the ery-ASAT. The youngest population of red blood cells contained 2.3–5.9 (mean 3.8) times more MTX than the oldest population. By linear regression analysis the t1/2 of the ery-MTX was 19–79 days (mean 37 days). The ery-MTX t1/2 seemed to be directly related to the amount of MTX which had been metabolized to MTX-glu_3-5. The decline of the ery-MTX was predominantly due to selective disappearance of MTX-glu₁₊₂, whereas MTX-glu_3-5 changed to a much lesser extent with advancing red blood cell age. The present investigation showed that steady-state ery-MTX concentration was determined by (1) the amount of MTX added to the circulation by the reticulocytes, (2) the in vivo loss predominantly of MTX with low numbers of glutamyl derivatives from erythrocytes, and (3) the loss of MTX from destroyed red blood cells. The observed in vivo disappearance of MTX from erythrocytes offers a possible explanation of the observation that the ery-MTX steady state was reached after 4–6 weeks of unaltered weekly MTX treatment.The present work was supported by grant no. 12-6387 from the Danish Medical Research Council and by grants from the Institute of Experimental and Clinical Research, Universty of Aarhus Denmark     

The decline in cancer mortality in the European Union, 1988-1996

After the peak rate reached in 1988, moderate but steady declines were observed over the last decade in total cancer mortality rates in the European Union (EU). Such a decline was over 7% for both sexes combined over the period of 1988-1996 (i.e. from 147.0 to 136.4/100,000, world standard population). The declines in cancer mortality correspond to the avoidance of approximately 70,000 deaths in 1996 in the EU compared with the 1988 rates. The major determinants of these favourable trends were lung (-7.7%), stomach (-24.8%), intestines (-12.4%), breast (-7.1%), uterus, mainly cervix (-20.6%), and leukaemias (-8.3%) and, after 1992, a levelling off of prostate cancer rates.     

The clinical effect of recent decline in the gastric cancer mortality rate

The clinical effect of the recent decline in the gastric cancer mortality rate in Niigata Prefecture was studied. The age-adjusted death rate for gastric cancer has been declining from average 60.5 per 1,000,000 population during 1958-1967 to 38.6 in 1981. From our analysis of surgically treated gastric cancer patients registered between 1972-1981 in Niigata Prefecture, the age-adjusted rate of early gastric cancer increased from 4.6 per 1,000,000 population in 1972 to 11.5 in 1981. Therefore, we conclude that there was a surgical effect of 46.1% in the decline in the gastric cancer mortality rate as of 1981.