Telomeres in ICF syndrome cells are vulnerable to DNA damage due to elevated DNA:RNA hybrids.

DNA:RNA hybrids, nucleic acid structures with diverse physiological functions, can disrupt genome integrity when dysregulated. Human telomeres were shown to form hybrids with the lncRNA TERRA, yet the formation and distribution of these hybrids among telomeres, their regulation and their cellular effects remain elusive. Here we predict and confirm in several human cell types that DNA:RNA hybrids form at many subtelomeric and telomeric regions. We demonstrate that ICF syndrome cells, which exhibit short telomeres and elevated TERRA levels, are enriched for hybrids at telomeric regions throughout the cell cycle. Telomeric hybrids are associated with high levels of DNA damage at chromosome ends in ICF cells, which are significantly reduced with overexpression of RNase H1. Our findings suggest that abnormally high TERRA levels in ICF syndrome lead to accumulation of telomeric hybrids that, in turn, can result in telomeric dysfunction

RCC Real-World Data: Prognostic Factors and Risk Stratification in the Immunotherapy Era

Immunotherapy has transformed the landscape of treatment in metastatic renal cell carcinoma (mRCC) in the last decade. Currently, prognostic risk stratification is based on the model developed in the era of vascular endothelial growth factor receptor inhibitors (VEGFRi) by Heng in 2009. Our study aims to find the most relevant risk criteria for mRCC patients treated with checkpoint inhibitors (CPI). In a retrospective cohort study, laboratory, pathology, demographic, and clinical data were retrieved from electronic medical records of consecutive mRCC patients treated with CPI in a tertiary center between 2015 and 2020. An unbiased multivariate analysis was performed to define predictive variables with a bootstrap validation step. We analyzed data on 127 patients with a median follow-up of 60 months. The median overall survival (OS) since the diagnosis of metastatic disease was 57 months. The response rate for CPI was 39%. Five risk factors were correlated with worse OS: intact primary kidney tumor (HR 2.33, p = 0.012), liver metastasis (HR 3.33, p = 0.001), <one year to treatment start (HR 1.98, p = 0.029), elevated platelets (HR 3.06, p = 0.015), and Karnofsky performance status <80% (HR = 3.42, p = 0.001). The model received a C-index of 70.7 compared with a score of 62.0 for the Heng’s model. When dividing patients into “low-risk” (0–1 risk factors) and “high-risk” (2–5 risk factors), there was good separation between the groups, with an HR of 5.9 (p < 0.0001). This study presents a new prognostic model for mRCC in the immunotherapy era with improved accuracy. Further research is needed to validate this model in larger cohorts

Early death after a diagnosis of metastatic solid cancer-raising awareness and identifying risk factors from the SEER database.

BackgroundCancer death rates are declining, in part due to smoking cessation, better detection and new treatments; nevertheless, a large fraction of metastatic cancer patients die soon after diagnosis. Few studies and interventions focus on these patients. Our study aims to characterize early mortality in a wide range of metastatic solid tumors.MethodsWe retrieved data on adult patients diagnosed with pathologically confirmed de- novo metastatic solid tumors between the years 2004-2016 from the Surveillance, Epidemiology, and End Results database (SEER). Our primary outcome was cancer specific early death rate (defined as death within two months of diagnosis). Additional data extracted included socio-demographical data, tumor primary, sites of metastases, and cause of death.Results109,207 (20.8%) patients died of de-novo metastatic cancer within two months of diagnosis. The highest rates of early death were found in hepatic (36%), pancreato-biliary (31%) and lung (25%) primaries. Factors associated with early death included primary site, liver, and brain metastases, increasing age, and lower income. Cancer was the cause of death in 92.1% of all early deaths. Two-month mortality rates have moderately improved during the study period (from 22.4% in 2004 to 18.8% in 2016).ConclusionA fifth of de-novo metastatic cancer patients die soon after diagnosis, with little improvement over the last decade. Further research is required to better classify and identify patients at risk for early mortality, which patients might benefit from faster diagnostic tracks, and which might avoid invasive and futile diagnostic procedures

Correlates of hospitalizations in internal medicine divisions among Israeli adults of different ethnic groups with hypertension, diabetes and cardiovascular diseases.

BackgroundDisparities in non-communicable diseases (NCDs) may affect health care utilization. We compared the correlates of hospitalizations in internal medicine divisions, of adults with NCDs, between the main population groups in Israel.MethodsA cross-sectional study was conducted among Jews (N = 17,952) and Arabs (N = 10,441) aged ≥40 years with diabetes, hypertension or cardiovascular diseases, utilizing the computerized database of the largest health maintenance organization in Israel. Information was retrieved on sociodemographics, background diseases, hospitalizations and utilizations of other health services. Multivariable log binomial regression models were performed.ResultsOverall, 3516 (12.4%) patients were hospitalized at least once during a one-year period (2008). Hospitalization in internal medicine divisions was more common among Arab than Jewish patients; prevalence ratio 1.24 (95% CI 1.14-1.35), and increased with age (PConclusionsIn a country with universal health insurance, the correlates of hospitalizations included sociodemographics, multi-morbidity, health behaviors and health services use patterns. Socioeconomic disparities might account for ethnic differences in hospitalizations. Individuals with several NCDs, rather than one specific disease, disability and smoking should be targeted to reduce healthcare costs related to hospitalizations

Immune-Related Thyroiditis as a Predictor for Survival in Metastatic Renal Cell Carcinoma

Immune checkpoint inhibitors (CPI) are indicated for metastatic renal cell carcinoma (mRCC). Immune-related thyroiditis (irT), an immune-related adverse event (irAE), affects up to 30% of patients. We aimed to determine whether irT is associated with overall survival in mRCC. A retrospective cohort study of 123 consecutive patients treated with CPI for mRCC in a single center between 2015 and 2020 was conducted. Disease risk stratification was assessed by two methods: Heng criteria and a novel dichotomic stratification system to “Low risk” versus “High risk” adding number of metastatic sites. Thirty-eight percent of patients developed irT. In the general cohort, irT was not associated with a survival benefit. However, irT was associated with better survival in the poor risk group per Heng criteria (n = 17, HR = 0.25, p = 0.04) and in the novel “High risk” group (HR = 0.28, n = 42, p = 0.01), including after accounting for covariates in multivariate analysis (HR = 0.27, p = 0.003). Having any irAE was associated with improved survival in the whole cohort, with no significant correlation of any specific irAE, in either the whole cohort or the “High risk” group. We conclude that irT is an early and prevalent irAE, associated with prolonged survival in patients with poor/“High” risk mRCC

RCC Real-World Data: Prognostic Factors and Risk Stratification in the Immunotherapy Era

Immunotherapy has transformed the landscape of treatment in metastatic renal cell carcinoma (mRCC) in the last decade. Currently, prognostic risk stratification is based on the model developed in the era of vascular endothelial growth factor receptor inhibitors (VEGFRi) by Heng in 2009. Our study aims to find the most relevant risk criteria for mRCC patients treated with checkpoint inhibitors (CPI). In a retrospective cohort study, laboratory, pathology, demographic, and clinical data were retrieved from electronic medical records of consecutive mRCC patients treated with CPI in a tertiary center between 2015 and 2020. An unbiased multivariate analysis was performed to define predictive variables with a bootstrap validation step. We analyzed data on 127 patients with a median follow-up of 60 months. The median overall survival (OS) since the diagnosis of metastatic disease was 57 months. The response rate for CPI was 39%. Five risk factors were correlated with worse OS: intact primary kidney tumor (HR 2.33, p = 0.012), liver metastasis (HR 3.33, p = 0.001), p = 0.029), elevated platelets (HR 3.06, p = 0.015), and Karnofsky performance status p = 0.001). The model received a C-index of 70.7 compared with a score of 62.0 for the Heng’s model. When dividing patients into “low-risk” (0–1 risk factors) and “high-risk” (2–5 risk factors), there was good separation between the groups, with an HR of 5.9 (p < 0.0001). This study presents a new prognostic model for mRCC in the immunotherapy era with improved accuracy. Further research is needed to validate this model in larger cohorts

Major causes of early death in de novo diagnosed metastatic cancer patients.

All cause and cancer specific early death rates (A). Ten major causes of non-cancer early death (B). Y axes present percentages in both plots.</p