Circulating Tumor Cells in Hepatocellular Carcinoma: A Comprehensive Review and Critical Appraisal

Hepatocellular carcinoma (HCC) is the fifth most common neoplasm and a major cause of cancer-related death worldwide. There is no ideal biomarker allowing early diagnosis of HCC and tumor surveillance in patients receiving therapy. Liquid biopsy, and particularly circulating tumor cells (CTCs), have emerged as a useful tool for diagnosis and monitoring therapeutic responses in different tumors. In the present manuscript, we evaluate the current evidence supporting the quantitative and qualitative assessment of CTCs as potential biomarkers of HCC, as well as technical aspects related to isolation, identification, and classification of CTCs. Although the dynamic assessment of CTCs in patients with HCC may aid the decision-making process, there are still many uncertainties and technical caveats to be solved before this methodology has a true impact on clinical practice guidelines. More studies are needed to identify the optimal combination of surface markers, to increase the efficiency of ex-vivo expansion of CTCs, or even to target CTCs as a potential therapeutic strategy to prevent HCC recurrence after surgery or to hamper tumor progression and extrahepatic spreading

Sex as a prognostic factor for mortality in critically ill adults with sepsis: a systematic review and meta-analysis.

Objective To assess the role of sex as an independent prognostic factor for mortality in patients with sepsis admitted to intensive care units (ICUs). Design Systematic review and meta-analysis. Data sources MEDLINE, Embase, Web of Science, ClinicalTrials. gov and the WHO Clinical Trials Registry from inception to 17 July 2020. Study selection Studies evaluating independent associations between sex and mortality in critically ill adults with sepsis controlling for at least one of five core covariate domains prespecified following a literature search and consensus among experts. Data extraction and synthesis Two authors independently extracted and assessed the risk of bias using Quality In Prognosis Studies tool. Meta-analysis was performed by pooling adjusted estimates. The Grades of Recommendations, Assessment, Development and Evaluation approach was used to rate the certainty of evidence. Results From 14 304 records, 13 studies (80 520 participants) were included. Meta-analysis did not find sex-based differences in all-cause hospital mortality (OR 1.02, 95% CI 0.79 to 1.32; very low-certainty evidence) and all-cause ICU mortality (OR 1.19, 95% CI 0.79 to 1.78; very low-certainty evidence). However, females presented higher 28-day all-cause mortality (OR 1.18, 95% CI 1.05 to 1.32; very low-certainty evidence) and lower 1-year all-cause mortality (OR 0.83, 95% CI 0.68 to 0.98; low-certainty evidence). There was a moderate risk of bias in the domain adjustment for other prognostic factors in six studies, and the certainty of evidence was further affected by inconsistency and imprecision. Conclusion The prognostic independent effect of sex on all-cause hospital mortality, 28-day all-cause mortality and all-cause ICU mortality for critically ill adults with sepsis was uncertain. Female sex may be associated with decreased 1-year all-cause mortality.post-print1281 K

Enumeration and Characterization of Circulating Tumor Cells in Patients with Hepatocellular Carcinoma Undergoing Transarterial Chemoembolization

Circulating tumor cells (CTCs), and particularly circulating cancer stem cells (cCSC), are prognostic biomarkers for different malignancies and may be detected using liquid biopsies. The ex vivo culture of cCSCs would provide valuable information regarding biological aggressiveness and would allow monitoring the adaptive changes acquired by the tumor in real time. In this prospective pilot study, we analyzed the presence of EpCAM+ CTCs using the IsoFlux system in the peripheral blood of 37 patients with hepatocellular carcinoma undergoing transarterial chemoembolization (TACE). The average patient age was 63.5 ± 7.9 years and 91.9% of the patients were men. All patients had detectable CTCs at baseline and 20 patients (54.1%) showed CTC aggregates or clusters in their peripheral blood. The increased total tumor diameter (OR: 2.5 (95% CI: 1.3–4.8), p = 0.006) and the absence of clusters of CTCs at baseline (OR: 0.2 (95% CI: 0.0–1.0), p = 0.049) were independent predictors of a diminished response to TACE. Culture of cCSC was successful in five out of thirty-three patients, mostly using negative enrichment of CD45− cells, ultra-low adherence, high glucose, and a short period of hypoxia followed by normoxia. In conclusion, the identification of clusters of CTCs before TACE and the implementation of standardized approaches for cCSC culture could aid to predict outcomes and to define the optimal adjuvant therapeutic strategy for a true personalized medicine in hepatocellular carcinoma

Cumulative exposure to tacrolimus and incidence of cancer after liver transplantation

Cancer is the leading cause of death after liver transplantation (LT). This multicenter case–control nested study aimed to evaluate the effect of maintenance immunosuppression on post-LT malignancy. The eligible cohort included 2495 LT patients who received tacrolimus-based immunosuppression. After 13 922 person/years follow-up, 425 patients (19.7%) developed malignancy (cases) and were matched with 425 controls by propensity score based on age, gender, smoking habit, etiology of liver disease, and hepatocellular carcinoma (HCC) before LT. The independent predictors of post-LT malignancy were older age (HR = 1.06 [95% CI 1.05–1.07]; p < .001), male sex (HR = 1.50 [95% CI 1.14–1.99]), smoking habit (HR = 1.96 [95% CI 1.42–2.66]), and alcoholic liver disease (HR = 1.53 [95% CI 1.19–1.97]). In selected cases and controls (n = 850), the immunosuppression protocol was similar (p = .51). An increased cumulative exposure to tacrolimus (CET), calculated by the area under curve of trough concentrations, was the only immunosuppression-related predictor of post-LT malignancy after controlling for clinical features and baseline HCC (CET at 3 months p = .001 and CET at 12 months p = .004). This effect was consistent for de novo malignancy (after excluding HCC recurrence) and for internal neoplasms (after excluding non-melanoma skin cancer). Therefore, tacrolimus minimization, as monitored by CET, is the key to modulate immunosuppression in order to prevent cancer after LT

Malignancy of intraductal papillary neoplasm of the bile duct.

Intraductal papillary neoplasm of the bile duct (IPNB) is an uncommon disease which was first included in the World Health Organization classification of neoplasms in 2010. A 64-year-old female was admitted to the hospital because of a hepatic lesion incidentally diagnosed during acute cholangitis. Abdominal computed tomography (CT) and magnetic resonance imaging (MRI) showed a well delimited 70 mm mass, with a predominant cystic component and hyperenhancement of papillary internal branching, consistent with a hydatid cyst. However, malignancy could not be excluded. The patient rapidly developed an acute abdomen syndrome, thus precluding a liver biopsy. A new urgent CT was performed to rule out a complication of the cystic lesion. A left hepatectomy was performed and the anatomopathological study confirmed the diagnosis of IPNB with a focus of cholangiocarcinoma therein. During follow up, the patient developed peritoneal carcinomatosis, received palliative chemotherapy and finally died

Changes in the liver transplant waiting list after expanding to the ‘Up-to-Seven’ criteria for hepatocellular carcinoma

We aimed to assess changes in the composition of the waiting list for liver transplantation (LT) after expanding from Milan to “up-to-seven” criteria in patients with hepatocellular carcinoma (HCC). A consecutive cohort of 255 LT candidates was stratified in a pre-expansion era (2016–2018; n = 149) and a post-expansion era (2019–2021; n = 106). The most frequent indication for LT was HCC in both groups (47.7% vs. 43.4%; p = 0.5). The proportion of patients exceeding the Milan criteria in the explanted liver was nearly doubled after expansion (12.5% vs. 21.1%; p = 0.25). Expanding criteria had no effect in drop-out (12.3% vs. 20.4%; p = 0.23) or microvascular invasion rates (37.8% vs. 38.7%; p = 0.93). The length on the waiting list did not increase after the expansion (172 days [IQR 74–282] vs. 118 days [IQR 67–251]; p = 0.135) and was even shortened in the post-expansion HCC subcohort (181 days [IQR 125–232] vs. 116 days [IQR 74–224]; p = 0.04). Tumor recurrence rates were reduced in the post-expansion cohort (15.4% vs. 0%; p = 0.012). In conclusion, expanding from Milan to up-to-seven criteria for LT in patients with HCC had no meaningful impact on the waiting list length and composition, thus offering the opportunity for the adoption of more liberal policies in the future

Sex as a prognostic factor for mortality in critically ill adults with sepsis: a systematic review and meta-analysis

Objective: To assess the role of sex as an independent prognostic factor for mortality in patients with sepsis admitted to intensive care units (ICUs). Design: Systematic review and meta- analysis. Data sources: MEDLINE, Embase, Web of Science, ClinicalTrials. gov and the WHO Clinical Trials Registry from inception to 17 July 2020. Study selection: Studies evaluating independent associations between sex and mortality in critically ill adults with sepsis controlling for at least one of five core covariate domains prespecified following a literature search and consensus among experts. Data extraction and synthesis: Two authors independently extracted and assessed the risk of bias using Quality In Prognosis Studies tool. Meta- analysis was performed by pooling adjusted estimates. The Grades of Recommendations, Assessment, Development and Evaluation approach was used to rate the certainty of evidence. Results: From 14 304 records, 13 studies (80 520 participants) were included. Meta- analysis did not find sex- based differences in all- cause hospital mortality (OR 1.02, 95% CI 0.79 to 1.32; very low- certainty evidence) and all- cause ICU mortality (OR 1.19, 95% CI 0.79 to 1.78; very low- certainty evidence). However, females presented higher 28- day all- cause mortality (OR 1.18, 95% CI 1.05 to 1.32; very low- certainty evidence) and lower 1- year all- cause mortality (OR 0.83, 95% CI 0.68 to 0.98; low- certainty evidence). There was a moderate risk of bias in the domain adjustment for other prognostic factors in six studies, and the certainty of evidence was further affected by inconsistency and imprecision. Conclusion: The prognostic independent effect of sex on all- cause hospital mortality, 28- day all- cause mortality and all- cause ICU mortality for critically ill adults with sepsis was uncertain. Female sex may be associated with decreased 1- year all- cause mortality

Evaluation of the role of sex as a prognostic factor in critically ill adults with sepsis : systematic review protocol

Sepsis is a leading cause of mortality in critically ill patients. Recently, it has been recognised that sex may contribute to a differential risk for developing sepsis and it remains uncertain if the prognosis of sepsis varies between the sexes. The aim of this systematic review is to summarise the available evidence to assess the role of sex as a prognostic factor in patients with sepsis managed in the intensive care unit (ICU). This is a systematic review protocol of prognostic studies of sex in patients with sepsis managed in the ICU. The primary outcomes include all-cause hospital mortality and all-cause hospital mortality during the first 28 days. The secondary outcomes include all-cause hospital mortality during the first 7 days and all-cause mortality at 1 year. We will conduct a search strategy based on the population (sepsis), the prognostic factor (sex), the outcome of interest (mortality) and prognostic study methods. We will search in the following databases up to December 2019: MEDLINE Ovid (from 1976), Embase Elsevier (from 1974), Web of Science and two trial registries. We will impose no language restrictions. Two authors will independently screen titles, abstracts and full-text articles for eligibility of studies, and subsequently extract data. Two authors will independently assess the risk of bias of each study using the Quality in Prognostic Studies (QUIPS) tool. If possible, we will carry out a meta-analysis to provide a pooled prognostic effect estimate for each outcome. We will use the Grading of Recommendations Assessment, Development and Evaluation system to assess the quality of evidence. Ethical approval will not be required. Findings from this review will be reported in a peer-reviewed scientific journal. Additionally, the results will be disseminated at conferences and in the mass media. CRD42019145054

Libro Rojo de Peces Dulceacuícolas de Colombia (2012)

En el marco del Plan Operativo Anual (2010 – 2011 - 2012) del Programa de Biología de la Conservación y Uso de la Biodiversidad del Instituto de Investigación de Recursos Biológicos Alexander von Humboldt, se llevó a cabo la actualización del Libro Rojo de peces dulceacuícolas de Colombia o proceso de evaluación del riesgo de extinción y evolución del estado de conservación de las especies de peces dulceacuícolas, como también es conocido. Esta iniciativa se llevó a cabo con el aval del Ministerio de Ambiente, Vivienda y Desarrollo Territorial – MAVT (hoy Ministerio de Ambiente y Desarrollo Sostenible – MADS) y la participación del Instituto de Ciencias Naturales de la Universidad Nacional de Colombia, WWF Colombia, y la Universidad de Manizales. En este proceso contribuyeron más de 50 investigadores, vinculados a unas 30 instituciones académicas, gubernamentales y no gubernamentales.Bogotá, D. C