Spatial and Temporal Heterogeneity of Panel-Based Tumor Mutational Burden in Pulmonary Adenocarcinoma: Separating Biology From Technical Artifacts

BackgroundTumor mutational burden (TMB) is an emerging biomarker used to identify patients who are more likely to benefit from immuno-oncology therapy. Aside from various unsettled technical aspects, biological variables such as tumor cell content and intratumor heterogeneity may play an important role in determining TMB.MethodsTMB estimates were determined applying the TruSight Oncology 500 targeted sequencing panel. Spatial and temporal heterogeneity was analyzed by multiregion sequencing (two to six samples) of 24 pulmonary adenocarcinomas and by sequencing a set of matched primary tumors, locoregional lymph node metastases, and distant metastases in five patients.ResultsOn average, a coding region of 1.28 Mbp was covered with a mean read depth of 609x. Manual validation of the mutation-calls confirmed a good performance, but revealed noticeable misclassification during germline filtering. Different regions within a tumor showed considerable spatial TMB variance in 30% (7 of 24) of the cases (maximum difference, 14.13 mut/Mbp). Lymph node–derived TMB was significantly lower (p = 0.016). In 13 cases, distinct mutational profiles were exclusive to different regions of a tumor, leading to higher values for simulated aggregated TMB. Combined, intratumor heterogeneity and the aggregated TMB could result in divergent TMB designation in 17% of the analyzed patients. TMB variation between primary tumor and distant metastases existed but was not profound.ConclusionsOur data show that, in addition to technical aspects such as germline filtering, the tumor content and spatially divergent mutational profiles within a tumor are relevant factors influencing TMB estimation, revealing limitations of single-sample–based TMB estimations in a clinical context.     

Alcohol and the burden of disease

World Health Organization (WHO) lists alcohol consumption as a leading risk to health, contributing 4% to the global burden of disease. This serves as justification for far-reaching preventive interventions. The purpose of this article is to recapitulate in narrative some of the assumptions upon which WHO conclusions rest and to interpret their validity accordingly. First, it may be misleading to include ‘alcohol use’ as a risk to health. As alcohol use has beneficial, protective as well as harmful properties, burden assessment should be based on harmful aspects only, e.g., ‘hazardous patterns of alcohol use’. Second, assessments of interventions aimed at reducing risks from alcohol use to disease burden should also consider such interventions’ impact on dimensions other than health or disease–in particular, psychosocial benefits of alcohol consumption. Third, the uncertainties associated with both the database and methodology for estimating the disease burden attributable to alcohol are high and need to be considered in the interpretation of findings.     

Cadmium Levels in the Lung,Liver, Kidney Cortex,and Urine Samples from Australians without Occupational Exposure to Metals

The authors undertook this study to assess levels of cadmium exposure in the general population. Samples of lung, liver, and kidney were obtained from 61 cadavers (43 males, 18 females; 2–89 yr of age, mean age = 38.5 yr) who died from accidental causes and who were subject to postmortem examinations at the John Tonge Centre for Forensic Sciences, Queensland Health Scientific Services, Brisbane, Australia, in 1997 and 1998. Samples of bladder urine were also obtained from 22 cadavers. Tissue and urine samples were analyzed for cadmium, zinc, and copper with inductively coupled plasm (ICP) mass spectrometry. The overall mean values for cadmium in the lung, liver, and kidney cortex samples were 0.13, 0.95, and 15.45 μg/gm wet tissue weight. The average renal cadmium level in subjects with high lung-cadmium levels (n = 13) was 6 μg/gm wet tissue weight higher than that of similarly aged subjects who had medium lung-cadmium levels (n = 30). In females, the average level of cadmium in the liver was 74% greater than in males, and the average liver cadmium in females with high lung-cadmium levels was 100% higher than in males in the same age range who had the same high lung-cadmium levels. Renal cadmium accumulation tended to be greater in females than in males who were in the same age range and who had similar lung-cadmium levels, a result that suggested that there was a higher absorption rate of cadmium in females. The mean value for a urinary cadmium excretion of 2.30 μg/gm creatinine was found in a subset of samples that had a mean age of 39 yr and a renal cortex cadmium concentration of 18.6 μg/gm wet tissue weight. Urinary cadmium excretion rates were correlated more strongly with lung and kidney cadmium content than with age or liver cadmium levels. The results suggest that urinary cadmium excretion may be increased in smokers and could provide some estimate of body cadmium burdens in future Australian epidemiological studies.     

老年髋部骨折患者家庭照顾者照顾负荷的研究进展

髋部骨折通常是指股骨颈及股骨转子间骨折，它的病残率和致死率高，严重威胁老年人的生命及生存质量。相关研究报道显示：老年髋部骨折患者术后3个月是患者功能锻炼和肢体功能恢复的最佳时间。在我国，家庭照顾者是老年髋部骨折患者的主要照顾力量，而由于人口老龄化的问题和核心家庭比例的增加，家庭照顾问题和照顾者负荷显得愈加严重。