Meeting Report: Translational Advances in Cancer Prevention Agent Development Meeting

The Division of Cancer Prevention of the National Cancer Institute (NCI) and the Office of Disease Prevention of the National Institutes of Health co-sponsored the Translational Advances in Cancer Prevention Agent Development Meeting on August 27 to 28, 2020. The goals of this meeting were to foster the exchange of ideas and stimulate new collaborative interactions among leading cancer prevention researchers from basic and clinical research; highlight new and emerging trends in immunoprevention and chemoprevention as well as new information from clinical trials; and provide information to the extramural research community on the significant resources available from the NCI to promote prevention agent development and rapid translation to clinical trials. The meeting included two plenary talks and five sessions covering the range from pre-clinical studies with chemo/immunopreventive agents to ongoing cancer prevention clinical trials. In addition, two NCI informational sessions describing contract resources for the preclinical agent development and cooperative grants for the Cancer Prevention Clinical Trials Network were also presented.

Meeting Report: Translational Advances in Cancer Prevention Agent Development Meeting

The Division of Cancer Prevention of the National Cancer Institute (NCI) and the Office of Disease Prevention of the National Institutes of Health co-sponsored the Translational Advances in Cancer Prevention Agent Development Meeting on August 27 to 28, 2020. The goals of this meeting were to foster the exchange of ideas and stimulate new collaborative interactions among leading cancer prevention researchers from basic and clinical research; highlight new and emerging trends in immunoprevention and chemoprevention as well as new information from clinical trials; and provide information to the extramural research community on the significant resources available from the NCI to promote prevention agent development and rapid translation to clinical trials. The meeting included two plenary talks and five sessions covering the range from pre-clinical studies with chemo/immunopreventive agents to ongoing cancer prevention clinical trials. In addition, two NCI informational sessions describing contract resources for the preclinical agent development and cooperative grants for the Cancer Prevention Clinical Trials Network were also presented.

Relative Abundance of SARS-CoV-2 Entry Genes in the Enterocytes of the Lower Gastrointestinal Tract

COVID-19, the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly spread throughout the world and was declared a pandemic by the World Health Organization, thus leading to a rapid surge in the efforts to understand the mechanisms of transmission, methods of prevention, and potential therapies. While COVID-19 frequently manifests as a respiratory infection,1 there is evidence for infection of the gastrointestinal (GI) tract1-4 with documented viral RNA shedding in the stool of infected patients.2,4 In this study, we aimed to investigate the expression of ACE2 and TMPRSS2, which are required for SARS-CoV-2 entry into mammalian cells,5 from single-cell RNA sequencing (scRNA-seq) datasets of five different parts of the GI tract: esophagus, stomach, pancreas, small intestine, and colon/rectum.

Non-selective beta blocker use is associated with improved short-term survival in patients with cirrhosis referred for liver transplantation.

BACKGROUND: Recent evidence cautions against the use of non-selective beta-blockers (NSBB) in patients with refractory ascites or spontaneous bacterial peritonitis while other data suggests a survival benefit in patients with advanced liver disease. The aim of this study was to describe the use and impact of NSBB in patients with cirrhosis referred for liver transplantation. METHODS: A single-center cohort of patients with cirrhosis, who were referred and evaluated for liver transplantation between January and June 2012 were studied for baseline characteristics and clinical outcomes. Patients were grouped according to the use of NSBB at initial evaluation, with the endpoint of 90-day mortality. RESULTS: Sixty-five (38%) of 170 consecutive patients evaluated for liver transplantation were taking NSBB. Patients taking NSBB had higher MELD and Child Pugh score. NSBB use was associated with lower 90-day mortality (6% vs. 15%) with a risk adjusted hazard ratio of 0.27 (95%CI .09-0.88, p = .03). Patients taking NSBB developed acute kidney injury (AKI) within 90 days more frequently than patients not taking NSBB (22% vs 11%), p = 0.048). However, this was related to increased stage 1 AKI episodes, all of which resolved. Twelve (27%) of 45 patients with > 90 day follow up discontinued NSBB, most commonly for hypotension and AKI, had increased subsequent MELD and mortality. CONCLUSIONS: NSBB use in patients with cirrhosis undergoing liver transplant evaluation is associated with better short-term survival. Nevertheless, ongoing tolerance of NSBB in this population is dynamic and may select a subset of patients with better hemodynamic reserve.

Arterial blood pressure is closely related to ascites development in compensated HCV-related cirrhosis.

BACKGROUND: Arterial blood pressure (BP) is a reliable marker of circulatory dysfunction in cirrhotic patients. There are no prospective studies evaluating the association between different levels of arterial BP and ascites development in compensated cirrhotic patients. Therefore, we evaluated the relationship between arterial BP and ascites development in compensated cirrhotic patients. MATERIALS AND METHODS: A total of 402 patients with compensated HCV-related cirrhosis were prospectively followed during 6 years to identify ascites development. At baseline, patients underwent systolic, diastolic and mean arterial pressure (MAP) measurements. Any history of arterial hypertension was also recorded. The occurrence of events such as bleeding, hepatocellular carcinoma, death and liver transplantation prior to ascites development were considered as competing risk events. RESULTS: Over a median of 156 weeks, ascites occurred in 54 patients (13%). At baseline, MAP was significantly lower in patients with ascites development (75.9 mm/Hg [95%CI, 70.3-84.3]) than those without ascites (93.6 mm/Hg [95% CI: 86.6-102.3]). After adjusting for covariates, the 6-year cumulative incidence of ascites was 40% (95%CI, 34%-48%) for patients with MAP<83.32 mm/Hg. In contrast, cumulative incidences of ascites were almost similar among patients with MAP values between 83.32 mm/Hg and 93.32 mm/Hg (7% [95% CI: 4%-12%]), between 93.32 mm/Hg and 100.31 mm/Hg (5% [95% CI: 4%-11%]) or higher than 100.31 mm/Hg (3% [95% CI: 1%-6%]). The MAP was an independent predictor of ascites development. CONCLUSIONS: The MAP is closely related to the development of ascites in compensated HCV-related cirrhosis. The risk of ascites development increases in 4.4 fold for subjects with MAP values <83.32 mm/Hg.

The natural history of HCV-related cirrhosis and its temporal progression across the different clinical stages.

PURPOSE: The clinical course of hepatitis C virus-related cirrhosis and its temporal progression across the different clinical stages has not been completely investigated. Our study evaluated the cumulative incidences (CIs) of clinical outcomes marking disease progression across the different clinical stages. METHODS: At baseline, 660 patients were classified as compensated [absence (294), or presence (108) of gastroesophageal varices] or decompensated [ascites (144), variceal bleeding alone (45) or in combination with ascites (17) and encephalopathy alone or together with bleeding and/or ascites (52)]. Subjects were followed for 312 weeks to identify time to a first event marking disease progression. RESULTS: Among compensated patients without varices, the 312-week CIs for developing varices, ascites, and encephalopathy were 37.4, 13.6 and 3.5 %, respectively. The 312-week CIs of development of ascites, bleeding and encephalopathy were 24, 12.5 and 9.9 % for compensated subjects with varices, respectively. Among patients with ascites, the 312-week CIs of bleeding, liver-related deaths/transplant and encephalopathy were 23.5, 27.8, and 47.3 %, respectively. The 312-week CIs of ascites, liver-related deaths/transplant and encephalopathy were 22.5, 14.7 and 5.7 % among patients with bleeding; however, CIs of liver-related deaths were significantly higher in those with ascites plus bleeding (77.6 %). Patients with encephalopathy alone or in combination with ascites and/or bleeding displayed the highest rates of deaths (312 weeks, 90 %). CONCLUSIONS: Among compensated patients, the presence of varices suggests a more accelerated course of the disease. Decompensated patients show the most severe clinical course, particularly in those with a combination of two or more clinical events.

The natural history of compensated HCV-related cirrhosis: a prospective long-term study.

BACKGROUND & AIMS: The natural history of HCV-related compensated cirrhosis has been poorly investigated in Latin-American countries. Our study evaluated mortality and clinical outcomes in compensated cirrhotic patients followed for 6 years. METHODS: Four hundred and two patients with compensated HCV-related cirrhosis were prospectively recruited in a tertiary care academic center. At the time of admission, patients were stratified as compensated (absence [stage 1] or presence [stage 2] of esophageal varices) as defined by D'Amico et al. Subjects were followed to identify overall mortality or liver transplantation and clinical complication rates. RESULTS: Among 402 subjects, 294 were categorized as stage 1 and 108 as stage 2. Over a median of 176 weeks, 42 deaths occurred (10%), of which 30 were considered liver-related (7%) and 12 non-liver-related (3%); eight individuals (2%) underwent liver transplantation; 30 patients (7%) developed HCC, 67 individuals in stage 1 (22%) developed varices and any event of clinical decompensation occurred in 80 patients (20%). The 6-year cumulative overall mortality or liver transplantation was 15% and 45%, for stages 1 and 2, respectively (p<0.001). The cumulative 6-year HCC incidence was significantly higher among patients with varices (29%) than those without varices (9%), p<0.001. Similarly, the cumulative 6-year incidence of any clinical liver-related complication was higher in patients with stage 2 (66%) as compared to 26% in those with stage 1, respectively (p<0.001). CONCLUSIONS: Our results indicate significant morbidity and mortality and clinical outcome rates in compensated cirrhotic patients with varices (stage 2).

Model for End-Stage Liver Disease and liver cirrhosis-related complications.

The Model for End-Stage Liver Disease (MELD) score has gained wide acceptance for predicting survival in patients undergoing liver transplantation. The strength of this score remains in the mathematical formula derived from a multivariate Cox regression analysis; it is a continuous scale and lacks a ceiling or a floor effect with a wide range of discrimination. It is based on objective, reproducible, and readily available laboratory data and the wide range of samples which have been validated. Liver cirrhosis complications such as ascites, encephalopathy, spontaneous bacterial peritonitis and variceal bleeding were not considered in the MELD score underestimating their direct association with the severity of liver disease. In this regard, several recent studies have shown that clinical manifestations secondary to portal hypertension are good prognostic markers in cirrhotic patients and may add additional useful prognostic information to the current MELD. We review the feasibility of MELD score as a prognostic predictor in patients with liver cirrhosis-related complications.

Antioxidant and immunomodulatory effects of Viusid in patients with chronic hepatitis C.

AIM: To investigate the efficacy of Viusid, a nutritional supplement, as an antioxidant and an immunomodulator in patients with chronic hepatitis C. METHODS: Sixty patients with chronic hepatitis C who were non-responders to standard antiviral treatment were randomly assigned to receive Viusid (3 sachets daily, n = 30) or placebo (n = 30) for 24 wk. The primary outcome was the change in serum malondialdehyde and 4-hydroxyalkenals (lipid peroxidation products). Secondary outcomes were changes in serum tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma) and interleukin-10 (IL-10). RESULTS: Statistically significant reductions in serum 4-hydroxyalkenals and malondialdehyde levels were observed in both groups in comparison with pretreatment values, but the patients who received Viusid showed a more marked reduction as compared with the control group (P = 0.001). TNF-alpha levels significantly increased from 6.9 to 16.2 pg/mL (P < 0.01) in the patients who received placebo in comparison with almost unchanged levels, from 6.6 to 7.1 pg/mL (P = 0.26), in the patients treated with Viusid (P = 0.001). In addition, IL-10 levels were markedly increased in the patients treated with Viusid (from 2.6 to 8.3 pg/mL, P = 0.04) in contrast to the patients assigned to placebo (from 2.8 to 4.1 pg/mL, P = 0.09) (P = 0.01). Likewise, the administration of Viusid markedly increased mean IFN-gamma levels from 1.92 to 2.89 pg/mL (P < 0.001) in comparison with a reduction in mean levels from 1.80 to 1.68 pg/mL (P = 0.70) in the placebo group (P < 0.0001). Viusid administration was well tolerated. CONCLUSION: Our results indicate that treatment with Viusid leads to a notable improvement of oxidative stress and immunological parameters in patients with chronic hepatitis C.

Application of a biochemical and clinical model to predict individual survival in patients with end-stage liver disease.

AIM: To investigate the capability of a biochemical and clinical model, BioCliM, in predicting the survival of cirrhotic patients. METHODS: We prospectively evaluated the survival of 172 cirrhotic patients. The model was constructed using clinical (ascites, encephalopathy and variceal bleeding) and biochemical (serum creatinine and serum total bilirubin) variables that were selected from a Cox proportional hazards model. It was applied to estimate 12-, 52- and 104-wk survival. The model's calibration using the Hosmer-Lemeshow statistic was computed at 104 wk in a validation dataset. Finally, the model's validity was tested among an independent set of 85 patients who were stratified into 2 risk groups (low risk 8). RESULTS: In the validation cohort, all measures of fit, discrimination and calibration were improved when the biochemical and clinical model was used. The proposed model had better predictive values (c-statistic: 0.90, 0.91, 0.91) than the Model for End-stage Liver Disease (MELD) and Child-Pugh (CP) scores for 12-, 52- and 104-wk mortality, respectively. In addition, the Hosmer-Lemeshow (H-L) statistic revealed that the biochemical and clinical model (H-L, 4.69) is better calibrated than MELD (H-L, 17.06) and CP (H-L, 14.23). There were no significant differences between the observed and expected survival curves in the stratified risk groups (low risk, P = 0.61; high risk, P = 0.77). CONCLUSION: Our data suggest that the proposed model is able to accurately predict survival in cirrhotic patients.

Correlação entre a sintomatologia, os achados endoscópicos e o diagnóstico anatomopatológico da doença do refluxo gastroesofágico / Correlation between symptoms and endoscopic and microscopic findings in GERD

Introdução: A doença do refluxo gastroesofágico (DRGE) apresenta-se como uma das afecções crônicas mais importan»tes na prática médica, devido à alta morbidade e ao prejuízo na qualidade de vida dos pacientes. Embora seja estabelecida a importância do diagnóstico endoscópico de esofagite na DRGE, o papel do exame anatomopatológico, isolado ou associado a outros métodos, ainda nâo é bem definido, assim como a cor-relação entre eles. Objetivo: O objetivo do presente estudo éavaliar a concordância entre a sintomatologia, achados endos-cópicos e microscópicos da DRGE. Métodos: A amostra foi com»posta por 93 indivíduos, portadores ou não de DRGE, com indi»cação para realização de endoscopia digestiva alta (EDA), na cidade de Barbacena, no período de fevereiro a dezembro de 2006. Foi aplicado a esses pacientes um questionário padroni»zado e estruturado a fim de obter as informações clínicas e epi»demiológicas e registrar os achados da endoscopia digestiva alta e da análise anatomopatológica da biópsia do esôfago. Resul»tados: Do total de 93 pacientes, a biópsia foi realizada em 66 (70,96%). Nos demais, 27 (29,04%), não foi possível obter ma»terial para esse tipo de exame. Na comparação entre a sinto»matologia e os achados endoscópicos e entre a sintomatologia e os achados microscópicos, o teste de concordância aplicado demonstra baixa correlação entre esses métodos (kappa = 0,22 e 0,25, respectivamente). Entretanto, os resultados apontam forte concordância entre o exame endoscópico e o anato mopa»tológico (p < 0,001; kappa = 0,69). Conclusão: A forte concor»dância entre esses dois métodos sugere que a análise microscó»pica não mostra vantagem diagnóstica na DRGE nos casos de esofagite identificada à EDA.