Cholangiocarcinoma landscape in Europe: Diagnostic, prognostic and therapeutic insights from the ENSCCA Registry.

BACKGROUND & AIMS: Cholangiocarcinoma (CCA) is a rare and heterogeneous biliary cancer, whose incidence and related mortality is increasing. This study investigates the clinical course of CCA and subtypes (intrahepatic [iCCA], perihilar [pCCA], and distal [dCCA]) in a pan-European cohort. METHODS: The ENSCCA Registry is a multicenter observational study. Patients were included if they had a histologically proven diagnosis of CCA between 2010-2019. Demographic, histomorphological, biochemical, and clinical studies were performed. RESULTS: Overall, 2,234 patients were enrolled (male/female=1.29). iCCA (n = 1,243) was associated with overweight/obesity and chronic liver diseases involving cirrhosis and/or viral hepatitis; pCCA (n = 592) with primary sclerosing cholangitis; and dCCA (n = 399) with choledocholithiasis. At diagnosis, 42.2% of patients had local disease, 29.4% locally advanced disease (LAD), and 28.4% metastatic disease (MD). Serum CEA and CA19-9 showed low diagnostic sensitivity, but their concomitant elevation was associated with increased risk of presenting with LAD (odds ratio 2.16; 95% CI 1.43-3.27) or MD (odds ratio 5.88; 95% CI 3.69-9.25). Patients undergoing resection (50.3%) had the best outcomes, particularly with negative-resection margin (R0) (median overall survival [mOS] = 45.1 months); however, margin involvement (R1) (hazard ratio 1.92; 95% CI 1.53-2.41; mOS = 24.7 months) and lymph node invasion (hazard ratio 2.13; 95% CI 1.55-2.94; mOS = 23.3 months) compromised prognosis. Among patients with unresectable disease (49.6%), the mOS was 10.6 months for those receiving active palliative therapies, mostly chemotherapy (26.2%), and 4.0 months for those receiving best supportive care (20.6%). iCCAs were associated with worse outcomes than p/dCCAs. ECOG performance status, MD and CA19-9 were independent prognostic factors. CONCLUSION: CCA is frequently diagnosed at an advanced stage, a proportion of patients fail to receive cancer-specific therapies, and prognosis remains dismal. Identification of preventable risk factors and implementation of surveillance in high-risk populations are required to decrease cancer-related mortality. LAY SUMMARY: This is, to date, the largest international (pan-European: 26 hospitals and 11 countries) observational study, in which the course of cholangiocarcinoma has been investigated, comparing the 3 subtypes based on the latest International Classification of Diseases 11th Edition (ICD-11) (i.e., intrahepatic [2C12], perihilar [2C18], or distal [2C15] affected bile ducts), which come into effect in 2022. General and tumor-type specific features at diagnosis, risk factors, biomarker accuracy, as well as patient management and outcomes, are presented and compared, outlining the current clinical state of cholangiocarcinoma in Europe.

Incidence of venous thromboembolism in patients with non-hematological cancer admitted for COVID-19 at a third-level hospital in Madrid.

An increased risk of venous thromboembolism (VTE) in hospitalized patients with COVID-19 has been reported. We aimed to describe the incidence rate of VTE on patients with non-hematological cancer who required hospitalization due to COVID-19 at our center. In this prospective study, non-hematological cancer patients hospitalized for confirmed COVID-19 at our institution from 1st March to 30th April 2020, were evaluated daily for VTE complications during their hospital stay, and after discharge until 30th June 2020. Furthermore, Doppler ultrasound of lower limbs was routinely performed in asymptomatic patients based on D-dimer levels and current active cancer therapy. The primary outcome of this study was the cumulative incidence of VTE. Secondary outcomes were the cumulative incidence of bleeding and mortality. A total of 58 hospitalized non-hematological cancer patients and confirmed COVID-19 were identified. Median follow-up since initial symptoms of COVID-19 was 91 days (IQR 19-104). Pulmonary embolism was diagnosed in three (5%) patients. Symptomatic catheter-related deep vein thrombosis (DVT) was observed in one patient. Doppler ultrasound of lower limbs was done in 11 asymptomatic patients, showing distal DVT in two of them (18%). The cumulative incidence of VTE on day 14 after admission was 10%, without new VTE events after hospital discharge and up to 90 days follow-up. No bleeding complication was observed. Seventeen patients (29%) died in the first 14 days after COVID-19 diagnosis. Four patients died after discharge due to malignancy progression. The cumulative incidence of VTE in non-hematological cancer patients under active treatment was 10% at day 14 after admission, with no further new events in the following 12 weeks.

Is there a preferred platinum and fluoropyrimidine regimen for advanced HER2-negative esophagogastric adenocarcinoma? Insights from 1293 patients in AGAMENON-SEOM registry.

BACKGROUND: The optimal chemotherapy backbone for HER2-negative advanced esophagogastric cancer, either in combination with targeted therapies or as a comparator in clinical trials, is uncertain. The subtle yet crucial differences in platinum-based regimens' safety and synergy with combination treatments need consideration. METHODS: We analyzed cases from the AGAMENON-SEOM Spanish registry of HER2-negative advanced esophagogastric adenocarcinoma treated with platinum and fluoropyrimidine from 2008 to 2021. This study focused exclusively on patients receiving one of the four regimens: FOLFOX (5-FU and oxaliplatin), CAPOX (capecitabine and oxaliplatin), CP (capecitabine and cisplatin) and FP (5-FU and cisplatin). The aim was to determine the most effective and tolerable platinum and fluoropyrimidine-based chemotherapy regimen and to identify any prognostic factors. RESULTS: Among 1293 patients, 36% received either FOLFOX (n = 468) or CAPOX (n = 466), 20% CP (n = 252), and 8% FP (n = 107). FOLFOX significantly increased PFS (progression free survival) compared to CP, with a hazard ratio of 0.73 (95% CI 0.58-0.92, p = 0.009). The duration of treatment was similar across all groups. Survival outcomes among regimens were similar, but analysis revealed worse ECOG-PS (Eastern Cooperative Oncology Group-Performance Status), > 2 metastatic sites, bone metastases, hypoalbuminemia, higher NLR (neutrophil-to-lymphocyte ratio), and CP regimen as predictors of poor PFS. Fatigue was common in all treatments, with the highest incidence in FOLFOX (77%), followed by FP (72%), CAPOX (68%), and CP (60%). Other notable toxicities included neuropathy (FOLFOX 69%, CAPOX 62%), neutropenia (FOLFOX 52%, FP 55%), hand-foot syndrome in CP (46%), and thromboembolic events (FP 12%, CP 11%). CONCLUSIONS: FOLFOX shown better PFS than CP. Adverse effects varied: neuropathy was more common with oxaliplatin, while thromboembolism was more frequent with cisplatin.

[Cytomegalovirus reactivation in patients with immune-mediated gastritis]. / Reactivación de citomegalovirus en pacientes con gastritis inmunomediada.

INTRODUCTION: Reactivation of cytomegalovirus can complicate the evolution of patients with gastritis induced by immune checkpoint inhibitors. METHODS: The experience in our center is described and a review of the literature is performed. RESULTS: A case of severe gastritis induced by treatment with a programmed cell death receptor-1 (anti-PD1) inhibitor, associated with reactivation of cytomegalovirus (CMV) is described. In the systematic review, we identified 5 cases of immune-related gastritis associated with CMV reactivation. Ganciclovir treatment contributed to clinical improvement in most patients. CONCLUSION: The early identification of a CMV infection in patients with severe or refractory immune-related gastritis will allow the initiation of targeted treatment, and may avoid increasing immunosuppressive therapy.

Impact of Positive Lymph Nodes and Resection Margin Status on the Overall Survival of Patients with Resected Perihilar Cholangiocarcinoma: The ENSCCA Registry.

Background: Lymph node metastasis and positive resection margins have been reported to be major determinants of overall survival (OS) and poor recurrence-free survival (RFS) for patients who underwent resection for perihilar cholangiocarcinoma (pCCA). However, the prognostic value of positive lymph nodes independently from resection margin status on OS has not been evaluated. Methods: From the European Cholangiocarcinoma (ENSCCA) registry, patients who underwent resection for pCCA between 1994 and 2021 were included in this retrospective cohort study. The primary outcome was OS stratified for resection margin and lymph node status. The secondary outcome was recurrence-free survival. Results: A total of 325 patients from 11 different centers and six European countries were included. Of these, 194 (59.7%) patients had negative resection margins. In 113 (34.8%) patients, positive lymph nodes were found. Lymph node status, histological grade, and ECOG performance status were independent prognostic factors for survival. The median OS for N0R0, N0R1, N+R0, and N+R1 was 38, 30, 18, and 12 months, respectively (p < 0.001). Conclusion: These data indicate that in the presence of positive regional lymph nodes, resection margin status does not determine OS or RFS in patients with pCCA. Achieving negative margins in patients with positive nodes should not come at the expense of more extensive surgery and associated higher mortality.

DPYD Exome, mRNA Expression and Uracil Levels in Early Severe Toxicity to Fluoropyrimidines: An Extreme Phenotype Approach.

Dihydropyrimidine dehydrogenase deficiency is a major cause of severe fluoropyrimidine-induced toxicity and could lead to interruption of chemotherapy or life-threatening adverse reactions. This study aimed to characterize the DPYD exon sequence, mRNA expression and in vivo DPD activity by plasma uracil concentration. It was carried out in two groups of patients with extreme phenotypes (toxicity versus control) newly treated with a fluoropyrimidine, during the first three cycles of treatment. A novel nonsense gene variant (c.2197insA) was most likely responsible for fluoropyrimidine-induced toxicity in one patient, while neither DPYD mRNA expression nor plasma uracil concentration was globally associated with early toxicity. Our present work may help improve pharmacogenetic testing to avoid severe and undesirable adverse reactions to fluoropyrimidine treatment and it also supports the idea of looking beyond DPYD.

SARS-CoV-2 infection in cancer patients undergoing active treatment: analysis of clinical features and predictive factors for severe respiratory failure and death.

AIM: Previous studies have suggested a more frequent and severe course of novel coronavirus SARS-CoV-2 infection in cancer patients undergoing active oncologic treatment. Our aim was to describe the characteristics of the disease in this population and to determine predictive factors for poor outcome in terms of severe respiratory distress (acute respiratory distress syndrome [ARDS]) or death. PATIENTS AND METHODS: Patients consecutively admitted for SARS-CoV-2 infection were prospectively collected, and retrospective statistical analysis was performed. Univariate and multivariate analyses were performed to assess potential factors for poor outcomes defined as ARDS or death. RESULTS: Sixty-three patients were analysed, and 34 of them developed respiratory failure (70% as ARDS). Lymphocytes/mm3 (412 versus 686; p = 0.001), serum albumin (2.84 versus 3.1); lactate dehydrogenase (LDH) (670 versus 359; p < 0.001) and C-reactive protein (CRP) levels (25.8 versus 9.9; p < 0.001) discriminate those that developed respiratory failure. Mortality rate was 25%, significantly higher among ARDS, neutropenic patients (p = 0.01) and in those with bilateral infiltrates (44% versus 0%; p < 0.001). Multivariate logistic analyses model confirmed the predictive value of severe neutropenia (odds ratio [OR] 16.54; 95% confidence interval [CI] 1.43-190.9, p 0.025), bilateral infiltrates (OR 32.83, CI 95% 3.51-307, p 0.002) and tumour lung involvement (OR 4.34, CI 95% 1.2-14.95, p 0.02). CONCLUSION: Cancer patients under active treatment admitted for SARS-CoV-2 infection have worse outcomes in terms of mortality and respiratory failure rates compared with COVID-19 global population. Lymphopenia, LDH, CRP and albumin discriminate illness severity, whereas neutropenia, bilateral infiltrates and tumour pulmonary involvement are predictive of higher mortality.