Understanding the increasing incidence of neuroendocrine tumors

Genetic Basis

Large interindividual variations in drug response can arise from multiple genetic and environmental factors affecting drug absorption, distribution, biotransformation, excretion, interaction with receptor sites, or combinations of these. Twin and family studies disclosed that for several commonly used drugs genetic factors are predominantly responsible for large interindividual variations in drug disposition that occur in normal volunteers under basal conditions. Environmental contributions were surprisingly small. While it has been convenient in such studies to separate genetic from environmental contributions as though they were discrete, unrelated entities, the transcriptional and translational mechanisms by which genetic information is expressed require environmental participation. Conversely, many environmental factors that alter rates of drug disposition do so by affecting genetic mechanisms (for example, phenobarbital induction of human hepatic antipyrine metabolism and benzpyrene induction of aryl hydrocarbon hydroxylase [AHH] activity in cultured human lymphocytes). Environmental chemicals, such as DDT, polychlorinated biphenyls, and polycyclic hydrocarbons, can alter, through induction, basal, genetically controlled hepatic drug‐metabolizing enzyme activity. Disease states can markedly change an individual's basal, genetically controlled rate of drug elimination. Assurance of a truly basal, uninduced, or uninhibited state can never be complete but is partially attainable through repeated measurements of the rate of elimination of a particular drug and through a careful history of exposures at work and at home to potential compounds or conditions that could alter the basal rate of drug elimination. The existence and operation of numerous environmental factors, each with differing capability of altering the basal, genetically controlled level of drug metabolism, make it exceedingly difficult to attribute quantitatively different portions of the total interindividual variation to specific single environmental factors. In this regard, a major problem in man is that most populations are markedly heterogeneous with respect both to environmental and genetic factors that influence drug disposition. The task of partitioning the total interindividual variation in drug elimination of such heterogeneous populations into component parts is further complicated because some seemingly pure “environmental” factors (smoking and diet) are closely associated with other

Chapter 15 - Familial Arteriosclerosis

Chapter 15 - Atherosclerosis Risk Factors: Familial Arteriosclerosis

The incidence of neuroendocrine tumors (NET) has been increasing globally for several decades. The objective of the study was to examine the most recent trend in the incidence of NET as well as disparities by sex and race/ethnicity in adults in the USA. Patients with NET aged ≥20 years were identified from the SEER 22 Registries from 2000 to 2020. The age-adjusted incidence rate was calculated for overall NET and by primary site. The incidence trend was assessed by annual percent change. Disparities by sex and race/ethnicity were examined using the incidence rate ratio. Age-adjusted incidence rate of overall NET in adults was 9.39 per 100 000 in 2000-2020. The incidence rate increased from 2000 but reached a plateau with no significant change since 2015. The lung and bronchus, small intestine, and rectum were the most common primary sites. Sex and racial/ethnic disparities in NET incidence varied by primary sites. For example, there was a female excess in NET of the lung and bronchus, stomach, and appendix; and there was a male excess in the small intestine, pancreas, colon, rectum and other/unknown NET. Compared to non-Hispanic white, non-Hispanic black had higher incidences of stomach, small intestine, liver, pancreas, colon, rectum, and other/unknown NET; they had lower incidences of lung and bronchus, and appendix NET than non-Hispanic white. Age-adjusted incidence rate of overall NET has reached a plateau since 2015. However, there were sex and racial/ethnic disparities in such incidence, which varied depending on the primary site of NET.

Neuroendocrine tumors metastatic to the liver: How to select patients for liver transplantation?

BackgroundEpigenetic aging estimators commonly track chronological and biological aging, quantifying its accumulation (i.e., epigenetic age acceleration) or speed (i.e., epigenetic aging pace). Their scores reflect a combination of inherent biological programming and the impact of environmental factors, which are suggested to vary at different life stages. The transition from adolescence to adulthood is an important period in this regard, marked by an increasing and, then, stabilizing epigenetic aging variance. Whether this pattern arises from environmental influences or genetic factors is still uncertain. This study delves into understanding the genetic and environmental contributions to variance in epigenetic aging across these developmental stages. Using twin modeling, we analyzed four estimators of epigenetic aging, namely Horvath Acceleration, PedBE Acceleration, GrimAge Acceleration, and DunedinPACE, based on saliva samples collected at two timepoints approximately 2.5 years apart from 976 twins of four birth cohorts (aged about 9.5, 15.5, 21.5, and 27.5 years at first and 12, 18, 24, and 30 years at second measurement occasion).ResultsHalf to two-thirds (50–68%) of the differences in epigenetic aging were due to unique environmental factors, indicating the role of life experiences and epigenetic drift, besides measurement error. The remaining variance was explained by genetic (Horvath Acceleration: 24%; GrimAge Acceleration: 32%; DunedinPACE: 47%) and shared environmental factors (Horvath Acceleration: 26%; PedBE Acceleration: 47%). The genetic and shared environmental factors represented the primary sources of stable differences in corresponding epigenetic aging estimators over 2.5 years. Age moderation analyses revealed that the variance due to individually unique environmental sources was smaller in younger than in older cohorts in epigenetic aging estimators trained on chronological age (Horvath Acceleration: 47–49%; PedBE Acceleration: 33–68%). The variance due to genetic contributions, in turn, potentially increased across age groups for epigenetic aging estimators trained in adult samples (Horvath Acceleration: 18–39%; GrimAge Acceleration: 24–43%; DunedinPACE: 42–57%).ConclusionsTransition to adulthood is a period of the increasing variance in epigenetic aging. Both environmental and genetic factors contribute to this trend. The degree of environmental and genetic contributions can be partially explained by the design of epigenetic aging estimators.

Background: Epidemiological studies show an increasing trend in the incidence of neuroendocrine neoplasms (NENs). A significant number of NENs occur in less common primary sites, but they are often excluded from the population-based studies. We studied the incidence trends of all NENs in Norway according to different primary sites. Materials and Methods: Our analyses were based on cancer cases diagnosed between 1993 and 2010 and reported to the national population-based Cancer Registry of Norway. A total of 65 morphological codes were identified as neuroendocrine and stratified into 3 different groups of aggressiveness: low, intermediate and high. Results: We identified 16,075 NENs of which 49.5% were in women. The median age at diagnosis was 65 years. The most common primary sites were the lung (48.1%) and the gastroenteropancreatic system (18.0%). Stage at diagnosis was local in 40.4% of the cases, regional in 17.5% and distant in 42.1%. The stage distribution was stable throughout the study period. The age-standardized (European) incidence rate (per 100,000 person-years) increased from 13.3 in 1993 to 21.3 in 2010 with an estimated annual increase of 5.1% in women and 2.1% in men. The increase was most pronounced for tumors of intermediate aggressiveness from 3.3 in 1993 to 7.3 in 2010. The largest annual increases were estimated for the adrenal gland (8.8%), the pancreas (6.9%) and the lungs (6.1%). Conclusion: The incidence of NENs increased. Most primary tumors were found in the lungs or in the gastroenteropancreatic system. The increase in the incidence differed according to the primary site, gender and tumor aggressiveness.

PurposeThe incidence of neuroendocrine neoplasms is increasing. This work aimed at: (i) establishing worldwide incidence trend of low-grade neuroendocrine neoplasms; (ii) defining the incidence and temporal trend of high-grade neuroendocrine neoplasms in USA utilizing the Surveillance Epidemiology and End Results database; (iii) comparing trends for low-grade vs. high-grade neuroendocrine neoplasms.MethodsWe conducted a literature search on MEDLINE and Scopus databases and incidence trends were plotted for 1973-2012. The Surveillance Epidemiology and End Results database was used to identify incidence rates in USA for 1973-2012. Incidence rates were stratified according to histological grade, gender and ethnicity. Trends were summarized as annual percent change and corresponding 95% confidence interval.Results11 studies were identified involving 72,048 cases; neuroendocrine neoplasm incidence rates increased over time in all countries for all sites, except for appendix. In Surveillance Epidemiology and End Results low-grade neuroendocrine neoplasm incidence rate increased from 1.09 in 1973 to 3.51 per 100,000 in 2012. During this interval, high-grade neuroendocrine neoplasm incidence rate increased from 2.54 to 10.52 per 100,000. African Americans had the highest rates of digestive neuroendocrine neoplasms with male prevalence in high-grade.ConclusionsOur data indicate an increase in the incidence of neuroendocrine neoplasms as a worldwide phenomenon, affecting most anatomical sites and involving both low-grade and high-grade neoplasms.

Since the advent of genotyping, recognition of heritable disease has been perceived as an opportunity for genetic diagnosis or new gene identification studies to advance understanding of pathogenesis. Until recently, however, clinical application of DNA-based testing was confined largely to Mendelian disorders. Even within this remit, predictive testing of relatives is cost-effective only in diseases in which the majority of families harbor mutations in known causal genes, such as adult polycystic kidney disease and hypertrophic cardiomyopathy, but not dilated cardiomyopathy. Confirmatory genetic testing of index cases with borderline clinical features may be economic in the still smaller subset of diseases with limited locus heterogeneity, such as Marfan syndrome. Furthermore, Mendelian diseases account for ≈5% of total disease burden.1 Genome-wide association studies have made headway in elucidating the genetic contribution to the more common, complex diseases, and high throughput techniques promise to facilitate integration of genetic analysis into clinical practice. Nevertheless, many genes remain to be identified and implementation of genomic profiling as a population screening tool would not be cost-effective at present. The implications of heredity, however, extend beyond serving as a platform for genetic analysis, influencing diagnosis, prognostication, and treatment of both index cases and relatives, and enabling rational targeting of genotyping resources. This review covers acquisition of a family history, evaluation of heritability and inheritance patterns, and the impact of inheritance on subsequent components of the clinical pathway. Eliciting a family history is the first step to determining whether a known diagnosis is heritable or symptoms of unknown etiology have a hereditary basis. Both narrative and diagrammatic approaches are integral to data collection, the former including questioning for diseases that recur within the family and the latter involving construction of a pedigree or family tree. Incorporation of psychosocial and interactional data, such as emotional relationships (harmony, apathy, …

The prevalence of obesity has increased substantially in the past 3 decades and is projected to increase further in the years ahead. It increases the risk of diabetes mellitus, dyslipidemia, hypertension, cardiovascular disease, sleep apnea, nonalcoholic hepatic steatosis, gallbladder disease, osteoarthritis, and cancer. The prevention and treatment of obesity is, therefore, a leading challenge facing public health and medicine in the 21st century. Two stereotypes have dominated thinking in public health, medicine, and the media about obesity. The first stereotype is that the recent surge in prevalence of obesity reflects almost entirely environmental and psychological factors and excludes an important contribution of genetic biological factors. The second stereotype is that obesity should and can be treated primarily by diet and behavioral modification. In this review, I challenge these tenets. I summarize evidence for a strong genetic neurobiological contribution to adiposity and body weight and assert that common human obesity is, like essential hypertension, a complex multifactorial disease where genetic factors promote sensitivity or resistance to obesity in a toxic environment. This concept of a genetic resistance versus sensitivity to obesity helps explain why many people remain thin in a toxic environment whereas others develop profound obesity. I then discuss evidence that dietary therapy for obesity generally fails to achieve weight loss maintenance. There is mounting indication that the high rate of relapse from weight loss during dietary therapy occurs because of compensatory biological adaptations that promote lack of compliance and effectiveness. Relapse from weight loss during dietary therapy is not caused simply by lack of discipline and will power. Finally, I briefly discuss the alternatives to dietary and behavioral therapy, namely bariatric surgery and pharmacotherapy. As a prelude to my critique of dietary therapy, I begin with a discussion of the role of genetic neurobiological factors in obesity. The surge …

T1 rectal NET resection: Does size really matter?

Skin characteristics show great variation from person to person and are affected by multiple factors, including genetic, environmental, and physical factors, but details of the involvement and contributions of these factors remain unclear. We aimed to characterize genetic, environmental, and physical factors affecting 16 skin features by developing models to predict personal skin characteristics. We analyzed the associations of skin phenotypes with genetic, environmental, and physical features in 1472 Japanese females aged 20-80 years. We focused on 16 skin characteristics, including melanin, brightness/lightness, yellowness, pigmented spots, wrinkles, resilience, moisture, barrier function, texture, and sebum amount. As genetic factors, we selected 74 single-nucleotide polymorphisms of genes related to skin color, vitamin level, hormones, circulation, extracellular matrix (ECM) components and ECM-degrading enzymes, inflammation, and antioxidants. Histories of ultraviolet (UV) exposure and smoking as environmental factors and age, height, and weight as physical factors were acquired by means of a questionnaire. A linear association with age was prominent for increase in the area of crow's feet, increase in number of pigmented spots, decrease in forehead sebum, and increase in VISIA wrinkle parameters. Associations were analyzed by constructing linear regression models for skin feature changes and logistic regression models to predict whether subjects show lower or higher skin measurement values in the same age groups. Multiple genetic factors, history of UV exposure and smoking, and body mass index were statistically selected for each skin characteristic. The most important association found for skin spots, such as lentigines and wrinkles, was adolescent sun exposure. Genetic, environmental, and physical factors associated with interindividual differences of the selected skin features were identified. The developed models should be useful to predict the skin characteristics of individuals and their age-related changes.

BackgroundMonitoring trends in lung cancer incidence and mortality is important for the evaluation of cancer control activities. We investigated recent trends in age-standardized incidence rates by histological type of lung cancer in Osaka, Japan.MethodsCancer incidence data for 1975–2008 were obtained from the Osaka Cancer Registry. Lung cancer mortality data with population data in Osaka during 1975–2012 were obtained from vital statistics. We examined trends in age-standardized incidence and mortality rates for all histological types and age-standardized incidence rates by histological type and age group using a joinpoint regression model.ResultsThe age-standardized incidence rate of lung cancer levelled off or slightly increased from 1975–2008, with an annual percentage change of 0.3% (95% confidence interval [CI], 0.1%–0.4%) for males and 1.1% (95% CI, 0.9%–1.3%) for females, and the mortality rate decreased by 0.9% (95% CI, 1.2%–0.7%) for males and 0.5% (95% CI, 0.8%–0.3%) for females. The incidence rates of squamous cell carcinoma (SQC) and small cell carcinoma (SMC) significantly decreased for both genders, whereas that of adenocarcinoma (ADC) significantly increased among almost all age groups in both genders.ConclusionsThe incidence rates of SQC and SMC decreased with the decline in smoking prevalence, which probably explains the change in trends in the incidence rates of lung cancer from the mid-1980s. However, the reason for the increase in ADC remains unclear. Therefore, trends in incidence rates of lung cancer should be carefully monitored, especially for ADC, and the associations between ADC and its possible risk factors should be studied.

Atherosclerosis, the primary cause of coronary artery disease (CAD) and stroke, is a disorder with multiple genetic and environmental contributions. Genetic-epidemiologic studies have identified a surprisingly long list of genetic and nongenetic risk factors for CAD. However, such studies indicate that family history is the most significant independent risk factor (15, 52, 77). Many Mendelian disorders associated with atherosclerosis, such as familial hypercholesterolemia (FH), have been characterized, but they explain only a small percentage of disease susceptibility (although a substantial fraction of early CAD). Most cases of myocardial infarction (MI) and stroke result from the interactions of multiple genetic and environmental factors, none of which can cause disease by itself. Successful discovery of these genetic factors will require using complementary approaches with animal models, large-scale human genetic studies, and functional experiments. This review emphasizes the common, complex forms of CAD.