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ObjectiveExplore the impact of COVID-19 on patients on the waiting list for liver transplantation (LT) and on their post-LT course.DesignData from consecutive adult LT candidates with COVID-19 were collected across Europe in a dedicated registry and were analysed.ResultsFrom 21 February to 20 November 2020, 136 adult cases with laboratory-confirmed SARS-CoV-2 infection from 33 centres in 11 European countries were collected, with 113 having COVID-19. Thirty-seven (37/113, 32.7%) patients died after a median of 18 (10–30) days, with respiratory failure being the major cause (33/37, 89.2%). The 60-day mortality risk did not significantly change between first (35.3%, 95% CI 23.9% to 50.0%) and second (26.0%, 95% CI 16.2% to 40.2%) waves. Multivariable Cox regression analysis showed Laboratory Model for End-stage Liver Disease (Lab-MELD) score of ≥15 (Model for End-stage Liver Disease (MELD) score 15–19, HR 5.46, 95% CI 1.81 to 16.50; MELD score≥20, HR 5.24, 95% CI 1.77 to 15.55) and dyspnoea on presentation (HR 3.89, 95% CI 2.02 to 7.51) being the two negative independent factors for mortality. Twenty-six patients underwent an LT after a median time of 78.5 (IQR 44–102) days, and 25 (96%) were alive after a median follow-up of 118 days (IQR 31–170).ConclusionsIncreased mortality in LT candidates with COVID-19 (32.7%), reaching 45% in those with decompensated cirrhosis (DC) and Lab-MELD score of ≥15, was observed, with no significant difference between first and second waves of the pandemic. Respiratory failure was the major cause of death. The dismal prognosis of patients with DC supports the adoption of strict preventative measures and the urgent testing of vaccination efficacy in this population. Prior SARS-CoV-2 symptomatic infection did not affect early post-transplant survival (96%).

Background & Aims: Bacterial infections can trigger the development of organ failure(s) and acute-on-chronic liver failure (ACLF). Geographic variations in bacteriology and clinical practice could lead to worldwide differences in ACLF epidemiology, phenotypes and associated outcomes. Herein, we aimed to evaluate regional differences in bacterial infection-related ACLF in patients with cirrhosis admitted to hospital. Methods: This post hoc analysis included 1,175 patients with decompensated cirrhosis (with bacterial infection on admission or nosocomial infection) from 6 geographic regions worldwide. Clinical, laboratory and microbiological data were collected from the diagnosis of infection. Patients were followed-up for organ failure(s) and ACLF development according to the EASL-CLIF criteria from enrolment to discharge/death. Results: A total of 333 patients (28%) had ACLF at diagnosis of infection, while 230 patients developed ACLF after diagnosis of infection, resulting in an overall rate of bacterial infection related-ACLF of 48%, with rates differing amongst different geographic regions (38% in Southern Europe vs. 75% in the Indian subcontinent). Bacterial infection related-ACLF more frequently developed in younger patients (55 ± 13 vs. 58 ± 14 years), males (73% vs. 62%), patients with alcohol-related cirrhosis (59% vs. 45%) and those with a higher baseline MELD score (25 ± 11 vs. 16 ± 5) (all p

Venous thrombotic events (VTEs) are a frequent complication of non-small cell lung cancer (NSCLC) and are associated with increased morbidity. Immune checkpoint inhibitors (ICIs) are revolutionizing the management of NSCLC, but little is known about their impact on thrombosis. This study aims to define the incidence and clinical relevance of VTEs in NSCLC patients receiving these treatments.A retrospective multicentric cohort study including 593 patients from three centers in Canada and France was performed. The cumulative incidence of VTEs after ICIs was estimated using competing risk analysis, and the association of these events with survival and response to treatment was determined. Finally, univariate and multivariate tests were performed to identify VTE risk factors.The cumulative incidence of VTEs in the cohort was 14.8% (95% CI = 7.4-22.2%) for an incidence rate of 76.5 (95% CI = 59.9-97.8) thrombosis per 1000 person-years, with most thromboses occurring rapidly after treatment initiation. VTEs were not correlated with overall survival, progression-free survival, or objective response to ICIs. Age ˂ 65 years old (HR = 2.00; 95% CI = 1.11-3.59) and tumors with PD-L1 1-49% (HR = 3.36; 95% CI = 1.19-9.50) or PD-L1 ≥ 50% (HR = 3.22; 95% CI = 1.21-8.57) were associated with more VTEs after 12 months of ICI initiation. Also, a delay of less than 12 months from diagnosis to the first ICI treatment (HR = 2.06; 95% CI = 1.09-3.89) and active smoking (HR = 2.00; 95% CI = 1.12-3.58) are probable risk factors of VTEs.This study suggests that the incidence of VTEs in NSCLC patients treated with ICIs is comparable to what is reported in other cohorts of patients treated with chemotherapy. In our cohort, VTEs were not associated with a decreased survival or response to therapy. Patient age 65 and tumors with PD-L1 ≥ 1% were associated with a higher risk of VTEs under ICIs.

Background & aims Porto-sinusoidal vascular liver disease (PSVD) is a rare cause of portal hypertension. PSVD is still often misdiagnosed as cirrhosis, emphasizing the need to improve PSVD diagnosis strategies. Data on liver stiffness measurement (TE-LSM) using transient elastography, in PSVD are limited. The aim of this study was to evaluate the accuracy of TE-LSM to discriminate PSVD from cirrhosis in patients with signs of portal hypertension. Approach & results Retrospective multicenter study comparing TE-LSM in patients with PSVD, according to VALDIG criteria, to patients with compensated biopsy-proven cirrhosis related to alcohol (n=117), hepatitis C virus (HCV) infection (n=110) or non-alcoholic fatty liver disease (NAFLD) (n=46). All patients had at least one sign of portal hypertension among gastroesophageal varices, splenomegaly, porto-systemic collaterals, history of ascites or platelet count Conclusions This study including a total of 155 patients with PSVD and 273 patients with cirrhosis demonstrates that TE-LSM 20 kPa, PSVD is highly unlikely.

Background: Myxofibrosarcoma is a type of soft-tissue sarcoma that is associated with high rates of local recurrence and distant metastases. The first-line treatment for metastatic soft-tissue sarcoma has conventionally been doxorubicin-based. Recent evidence suggests that myxofibrosarcoma may be molecularly similar to undifferentiated pleomorphic sarcoma (UPS), which is particularly sensitive to gemcitabine-based therapy. The goal of this study was to evaluate the activity of gemcitabine-containing regimens for the treatment of metastatic myxofibrosarcoma refractory to doxorubicin. Material and Methods: We retrospectively evaluated seven consecutive cases of metastatic myxofibrosarcoma at our institution treated with gemcitabine-based therapy in the second-line setting, after progression on doxorubicin. Baseline clinical and baseline characteristics were collected. Primary endpoints were objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). Results: After progression on first-line doxorubicin, a partial, or complete radiological response was observed in four of seven patients who received gemcitabine-based chemotherapy. With a median follow-up of 14 months, median progression-free and overall survival were 8.5 months and 11.4 months, respectively. Conclusions: Gemcitabine-based chemotherapy was associated with encouraging response rates in this cohort, similar to those seen in UPS. Both entities could be studied together for novel gemcitabine-based regimens.

The PACIFIC trial demonstrated that durvalumab therapy following chemoradiation (CRT) was associated with improved overall survival (OS) in patients with stage III non-small cell lung cancer (NSCLC). It is unclear whether the results obtained as part of randomised controlled trials are a reflection of real-world (RW) data. Several questions remain unanswered with regard to RW durvalumab use, such as optimal time to durvalumab initiation, incidence of pneumonitis and response in PD-L1 subgroups.In this multicentre retrospective analysis, 147 patients with stage III NSCLC treated with CRT followed by durvalumab were compared with a historical cohort of 121 patients treated with CRT alone. Survival curves were estimated using the Kaplan-Meier method and compared with the log-rank test in univariate analysis. Multivariate analysis was performed to evaluate the effect of standard prognostic factors for durvalumab use.Median OS was not reached in the durvalumab group, compared with 26.9 months in the historical group (hazard ratio [HR]: 0.56, 95% confidence interval [CI]: 0.37-0.85, p = 0.001). In the durvalumab group, our data suggest improved 12-month OS in patients with PD-L1 expression ≥50% (100% vs 86%, HR: 0.25, 95% CI: 0.11-0.58, p = 0.007). There was no difference in OS between patients with a PD-L1 expression of 1-49% and patients with PD-L1 expression1%. Delay in durvalumab initiation beyond 42 days did not impact OS. Incidence of pneumonitis was similar in the durvalumab and historical groups. In the durvalumab group, patients who experienced any-grade pneumonitis had a lower 12-month OS than patients without pneumonitis (85% vs 95%, respectively; HR: 3.3, 95% CI: 1.2-9.0, p = 0.006).This multicentre analysis suggests that PD-L1 expression ≥50% was associated with favourable OS in patients with stage III NSCLC treated with durvalumab after CRT, whereas the presence of pneumonitis represented a negative prognostic factor.

International audience; Treatment with combined immune checkpoint blockade (CICB) targeting CTLA-4 and PD-1 is associated with clinical benefit across tumor types, but also a high rate of immune-related adverse events. Insights into biomarkers and mechanisms of response and toxicity to CICB are needed. To address this, we profiled the blood, tumor and gut microbiome of 77 patients with advanced melanoma treated with CICB, with a high rate of any ≥grade 3 immune-related adverse events (49%) with parallel studies in pre-clinical models. Tumor-associated immune and genomic biomarkers of response to CICB were similar to those identified for ICB monotherapy, and toxicity from CICB was associated with a more diverse peripheral T-cell repertoire. Profiling of gut microbiota demonstrated a significantly higher abundance of Bacteroides intestinalis in patients with toxicity, with upregulation of mucosal IL-1β in patient samples of colitis and in pre-clinical models. Together, these data offer potential new therapeutic angles for targeting toxicity to CICB.

OBJECTIVES The determinants of refractory ascites have not been fully characterized. The aims of this study were to assess liver histopathological alterations associated with refractory ascites and their relationship with comorbidities. METHODS Consecutive patients with cirrhosis who underwent liver transplantation were retrospectively included. Patients' characteristics at the time of listing were analysed. The native livers were reviewed and lesions associated with refractory ascites were examined. RESULTS Out of the 89 patients included, 30 had refractory ascites and 59 did not (including 35 without ascites and 24 with diuretic-sensitive ascites). Patients with and without refractory ascites had a similar amount of fibrous tissue and features of fatty liver disease. By contrast, microvascular changes, namely sinusoidal dilatation (P < 0.001), diffuse perisinusoidal fibrosis (P = 0.001), hepatic venous thromboses (P = 0.004) and vascular proliferation (P = 0.01) were more frequently observed in the livers of patients with refractory ascites. Diabetes (57% vs. 31%, P = 0.02) and alcohol as a causal factor for cirrhosis (80% vs. 42%, P = 0.001) were more frequent in patients with refractory ascites than in those without. By multivariate analysis, refractory ascites was independently associated with diabetes mellitus [odds ratio (OR) (95% confidence interval, CI) 6.15 (1.47-25.71); P = 0.01], alcohol as a causal factor for cirrhosis [OR (95% CI) 4.63 (1.07-20.02); P = 0.04], higher Model For End Stage Liver Diseases [OR (95% CI) 1.21 (1.05-1.38); P = 0.008] and lower serum sodium [OR (95% CI) 0.87 (0.78-0.98); P = 0.03]. CONCLUSION Liver microcirculatory changes are associated with refractory ascites. Diabetes and alcohol may explain refractory ascites by causing microangiopathy.

Immune checkpoint inhibitors (ICI) represent the backbone treatment for advanced non-small cell lung cancer (NSCLC). Emerging data suggest that increased gut microbiome diversity is associated with favorable response to ICI and that antibiotic-induced dysbiosis is associated with deleterious outcomes. 18F-FDG physiologic colonic uptake on PET/CT increases following treatment with antibiotics (ATB) and could act as a surrogate marker for microbiome composition and predict prognosis. The aim of this study was to determine if 18F-FDG physiologic colonic uptake prior to ICI initiation correlates with gut microbiome profiling and clinical outcomes in patients with advanced NSCLC. Seventy-one patients with advanced NSCLC who underwent a PET/CT prior to ICI were identified. Blinded colonic contouring was performed for each colon segment and patients were stratified according to the median of the average colon SUVmax as well as for each segment in low vs. high SUVmax groups. Response rate, progression-free survival (PFS), and overall survival (OS) were compared in the low vs. high SUVmax groups. Gut microbiome composition was analyzed for 23 patients using metagenomics sequencing. The high colon SUVmax group had a higher proportion of non-responders (p = 0.033) and significantly shorter PFS (4.1 vs. 11.3 months, HR 1.94, 95% CI 1.11–3.41, p = 0.005). High caecum SUVmax correlated with numerically shorter OS (10.8 vs. 27.6 months, HR 1.85, 95% CI 0.97–3.53, p = 0.058). Metagenomics sequencing revealed distinctive microbiome populations in each group. Patients with low caecum SUVmax had higher microbiome diversity (p = 0.046) and were enriched with Bifidobacteriaceae, Lachnospiraceae, and Bacteroidaceae. Lower colon physiologic 18F-FDG uptake on PET/CT prior to ICI initiation was associated with better clinical outcomes and higher gut microbiome diversity in patients with advanced NSCLC. Here, we propose that 18F-FDG physiologic colonic uptake on PET/CT could serve as a potential novel marker of gut microbiome composition and may predict clinical outcomes in this population.

Summary Background Data on patients with COVID-19 who have cancer are lacking. Here we characterise the outcomes of a cohort of patients with cancer and COVID-19 and identify potential prognostic factors for mortality and severe illness. Methods In this cohort study, we collected de-identified data on patients with active or previous malignancy, aged 18 years and older, with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection from the USA, Canada, and Spain from the COVID-19 and Cancer Consortium (CCC19) database for whom baseline data were added between March 17 and April 16, 2020. We collected data on baseline clinical conditions, medications, cancer diagnosis and treatment, and COVID-19 disease course. The primary endpoint was all-cause mortality within 30 days of diagnosis of COVID-19. We assessed the association between the outcome and potential prognostic variables using logistic regression analyses, partially adjusted for age, sex, smoking status, and obesity. This study is registered with ClinicalTrials.gov, NCT04354701, and is ongoing. Findings Of 1035 records entered into the CCC19 database during the study period, 928 patients met inclusion criteria for our analysis. Median age was 66 years (IQR 57–76), 279 (30%) were aged 75 years or older, and 468 (50%) patients were male. The most prevalent malignancies were breast (191 [21%]) and prostate (152 [16%]). 366 (39%) patients were on active anticancer treatment, and 396 (43%) had active (measurable) cancer. At analysis (May 7, 2020), 121 (13%) patients had died. In logistic regression analysis, independent factors associated with increased 30-day mortality, after partial adjustment, were: increased age (per 10 years; partially adjusted odds ratio 1·84, 95% CI 1·53–2·21), male sex (1·63, 1·07–2·48), smoking status (former smoker vs never smoked: 1·60, 1·03–2·47), number of comorbidities (two vs none: 4·50, 1·33–15·28), Eastern Cooperative Oncology Group performance status of 2 or higher (status of 2 vs 0 or 1: 3·89, 2·11–7·18), active cancer (progressing vs remission: 5·20, 2·77–9·77), and receipt of azithromycin plus hydroxychloroquine (vs treatment with neither: 2·93, 1·79–4·79; confounding by indication cannot be excluded). Compared with residence in the US-Northeast, residence in Canada (0·24, 0·07–0·84) or the US-Midwest (0·50, 0·28–0·90) were associated with decreased 30-day all-cause mortality. Race and ethnicity, obesity status, cancer type, type of anticancer therapy, and recent surgery were not associated with mortality. Interpretation Among patients with cancer and COVID-19, 30-day all-cause mortality was high and associated with general risk factors and risk factors unique to patients with cancer. Longer follow-up is needed to better understand the effect of COVID-19 on outcomes in patients with cancer, including the ability to continue specific cancer treatments. Funding American Cancer Society, National Institutes of Health, and Hope Foundation for Cancer Research.

The enhancement of immune responses upon treatment with immune checkpoint inhibitors can have the desired outcome of reinvigorating antitumour immune surveillance, but often at the expense of immune-related adverse events (irAEs). This novel disease entity often prompts comparisons with, and extrapolation of treatment approaches from, primary autoimmune disorders. Accordingly, current treatment guidelines for irAEs make generic recommendations adapted from the literature describing primary autoimmune diseases, without taking into consideration the substantial disparity of the immunohistopathological findings within each organ affected by an irAE. The treatment modalities themselves are complex and have many potential drawbacks, such as serious and rarely fatal infections, drug toxicities overlapping with irAEs and the risk of compromising cancer immune surveillance. Herein, we provide an overview of key cellular and soluble immunological factors mediating irAEs and propose a model integrating this knowledge with the immunohistopathological findings of the affected organs for a personalized decision-making process for each patient. The treatment of immune-related adverse events (irAEs) in patients receiving immune checkpoint inhibitors has mostly been based on adapting therapeutic approaches used in the management of primary autoimmune diseases. The authors of this Review provide an overview of the different cellular and soluble immune factors involved in the pathogenesis of irAEs in order to help clinicians deliver personalized immunopathologically guided treatment to manage these adverse events.

Acute decompensation (AD) of cirrhosis may present without acute-on-chronic liver failure (ACLF) (AD-No ACLF), or with ACLF phenotype (AD-ACLF) defined by organ failure(s). Precipitants may induce AD. This multicenter, prospective, observational PREDICT study (NCT03056612) analyzes and characterizes the precipitants leading to both of these AD phenotypes., info:eu-repo/semantics/published

Immunocompromised patients may be at increased risk for complications of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection. However, comprehensive data of SARS‐CoV‐2 infection in solid organ transplant (SOT) recipients are still lacking. We performed a multicenter nationwide observational study within the Swiss Transplant Cohort Study (STCS) to describe the epidemiology, clinical presentation, treatment and outcomes of the first microbiologically documented SARS‐CoV‐2 infection among SOT recipients. Overall, 21 patients were included with a median age of 56 years (10 kidney, 5 liver, 1 pancreas, 1 lung, 1 heart and 3 combined transplantations). The most common presenting symptoms were fever (76%), dry cough (57%), nausea (33%) and diarrhea (33%). Ninety‐five percent and 24% of patients required hospital and ICU admission, respectively, and 19% were intubated. After a median of 33 days of follow‐up, 16 patients were discharged, 3 were still hospitalized and 2 patients died. These data suggest that clinical manifestations of SARS‐CoV‐2 infection in middle‐aged SOT recipients appear to be similar to the general population without an apparent higher rate of complications. These results need to be confirmed in larger cohorts.

Allergy transfer upon solid organ transplantation has been reported in the literature, although only few data are available as to the frequency, significance, and management of these cases. Based on a review of 577 consecutive deceased donors from the Swisstransplant Donor‐Registry, 3 cases (0.5%) of fatal anaphylaxis were identified, 2 because of peanut and 1 of wasp allergy. The sera of all 3 donors and their 10 paired recipients, prospectively collected before and after transplantation for the Swiss Transplant Cohort Study, were retrospectively processed using a commercial protein microarray fluorescent test. As early as 5 days posttransplantation, newly acquired peanut‐specific IgE were transiently detected from 1 donor to 3 recipients, of whom 1 liver and lung recipients developed grade III anaphylaxis. Yet, to define how allergy testing should be performed in transplant recipients and to better understand the impact of immunosuppressive therapy on IgE sensitization, we prospectively studied 5 atopic living‐donor kidney recipients. All pollen‐specific IgE and >90% of skin prick tests remained positive 7 days and 3 months after transplantation, indicating that early diagnosis of donor‐derived IgE sensitization is possible. Importantly, we propose recommendations with respect to safety for recipients undergoing solid‐organ transplantation from donors with a history of fatal anaphylaxis., Based on the Swisstransplant donor registry, the Swiss‐Transplant‐Cohort‐Study, and a prospective analysis on allergy maintenance in atopic recipients, this study makes new recommendations for the management of allergy transfer upon solid organ transplantation, emphasizing the poor effect of immunosuppression on IgE sensitization and the need of early allergological investigation in the donor and respective recipients.

Acute decompensation (AD) of cirrhosis is defined as the acute development of ascites, gastrointestinal hemorrhage, hepatic encephalopathy, infection or any combination thereof, requiring hospitalization. The presence of organ failure(s) in patients with AD defines acute-on-chronic liver failure (ACLF). The PREDICT study is a European, prospective, observational study, designed to characterize the clinical course of AD and to identify predictors of ACLF., info:eu-repo/semantics/published

Background & Aims: Liver stiffness measured with 2-dimensional shear wave elastography by Supersonic Imagine (2DSWE-SSI) is well-established for fibrosis diagnostics, but non-conclusive for portal hypertension. Methods: We performed an individual patient data meta-analysis of 2DSWE-SSI to identify clinically significant portal hypertension (CSPH), severe portal hypertension and large varices in cirrhosis patients, using hepatic venous pressure gradient and upper endoscopy as reference. We used meta-analytical integration of diagnostic accuracies with optimized rule-out (sensitivity-90%) and rule-in (specificity-90%) cut-offs. Results: Five studies from seven centres shared data on 519 patients. After exclusion, we included 328 patients. Eighty-nine (27%) were compensated and 286 (87%) had CSPH. 2DSWE-SSI&nbsp

International audience; Vascular disorders of the liver are rare diseases, some of which are diagnosed mainly with non-invasive tests and others by liver biopsy. Non-invasive methods can be used to diagnose and monitor these diseases. However, their evaluation needs to be performed by expert centers. Liver biopsy is needed each time there is an unexplained abnormality.

Immune-checkpoint inhibitors (ICI) now represent the standard of care for several cancer types. In pre-clinical models, absence of an intact gut microbiome negatively impacted ICI efficacy and these findings permitted to unravel the importance of the commensal microbiota in immuno-oncology. Recently, multiple clinical studies including more than 1800 patients in aggregate demonstrated the negative predictive impact of treatments with broad-spectrum antibiotics (ATB) on cancer patients receiving ICI. Altogether, these results have led to the hypothesis that ATB-induced dysbiosis might influence the clinical response through the modulation of the gut microbiome. Controversy still remains, as ATB treatment might simply constitute a surrogate marker of unfit or immunodeficient patients. In this review, we summarize recent publications addressing the impact of the gut microbiome on ICI efficacy, discuss currently available data on the effect of ATB administered in different time-frames respect to ICI initiation, and finally, evoke the therapeutic implications of these findings.

Portal hypertension in the absence of portal vein thrombosis and without cirrhosis, but with mild or moderate alterations of liver histology (eg, obliterative venopathy, nodular regenerative hyperplasia, or incomplete septal cirrhosis) is being increasingly recognised. Owing to the heterogeneity of causes and histological findings, a substantial number of terms have been used to describe such idiopathic non-cirrhotic portal hypertension. Patients with the same clinical and histological features exist, but without portal hypertension at the time of diagnosis. Therefore, improved criteria are needed to define this form of liver disease. Here, we propose the term porto-sinusoidal vascular disease, since all lesions found involve the portal venules or sinusoids. The definition of this entity is based on the characteristic absence of cirrhosis with or without signs of portal hypertension or histological lesions. The presence of known causes of liver disease does not rule out porto-sinusoidal vascular disease, but specific causes of vascular liver disease are excluded from its definition. The diagnosis of porto-sinusoidal vascular disease is based on liver biopsy and might include signs specific for portal hypertension with normal or mildly elevated liver stiffness values and no complete portal vein thrombosis. We provide simple diagnostic criteria, because agreement on a uniform nomenclature is an essential requirement for future collaborative studies.

Patients with cancer are at higher risk of severe coronavirus infectious disease 2019 (COVID-19), but the mechanisms underlying virus-host interactions during cancer therapies remain elusive. When comparing nasopharyngeal swabs from cancer and non-cancer patients for RT-qPCR cycle thresholds measuring acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in 1063 patients (58% with cancer, 89% COVID-19+), we found that malignant disease favors the magnitude and duration of viral RNA shedding concomitant with prolonged serum elevations of type 1 IFN that anticorrelated with anti-RBD IgG antibodies. Chronic viral RNA carriers exhibited the typical immunopathology of severe COVID-19 at the early phase of infection including circulation of immature neutrophils, depletion of non-conventional monocytes and a general lymphopenia that, however, was accompanied by a rise in plasmablasts, activated follicular T helper cells, and non-naive Granzyme B+ FasL+, EomehighTCF-1high, PD-1+CD8+ Tc1 cells. Virus-induced lymphopenia worsened cancer-associated lymphocyte loss, and low lymphocyte counts correlated with chronic SARS-CoV-2 RNA shedding, COVID-19 severity and a higher risk of cancer-related death in the first and second surge of the pandemic. Lymphocyte loss correlated with significant changes in metabolites from the polyamine and biliary salt pathways as well as increased blood DNA from Enterobacteriaceae and Micrococcaceae gut family members in long term viral carriers. We surmise that cancer therapies may exacerbate the paradoxical association between lymphopenia and COVID-19-related immunopathology, and that the prevention of COVID-19-induced lymphocyte loss may reduce cancer-associated death.

Genetic markers of the endocannabinoid system have been linked to a variety of addiction-related behaviors that extend beyond cannabis use. In the current study we investigate the relationship between endocannabinoid (eCB) genetic markers and alcohol use disorder (AUD) in European adolescents (14–18 years old) followed in the IMAGEN study (n = 2,051) and explore replication in a cohort of North American adolescents from Canadian Saguenay Youth Study (SYS) (n = 772). Case-control status is represented by a score of more than 7 on the Alcohol Use Disorder Identification Test (AUDIT). First a set-based test method was used to examine if a relationship between the eCB system and AUDIT case/control status exists at the gene level. Using only SNPs that are both independent and significantly associated to case-control status, we perform Fisher's exact test to determine SNP level odds ratios in relation to case-control status and then perform logistic regressions as post-hoc analysis, while considering various covariates. Generalized multifactor dimensionality reduction (GMDR) was used to analyze the most robust SNP×SNP interaction of the five eCB genes with positive AUDIT screen. While no gene-sets were significantly associated to AUDIT scores after correction for multiple tests, in the case/control analysis, 7 SNPs were significantly associated with AUDIT scores of > 7 (p < 0.05; ORCNR1 (pcorrected =0.042, OR = 0.73) and rs507961 in MGLL (pcorrected = 0.043, OR = 0.78). Logistic regression showed that both rs9353525 (CNR1) and rs507961 (MGLL) remained significantly associated with positive AUDIT screens (p < 0.01; OR < 1) after correction for multiple covariables and interaction of covariable × SNP. This result was not replicated in the SYS cohort. The GMDR model revealed a significant three-SNP interaction (p = 0.006) involving rs484061 (MGLL), rs4963307 (DAGLA), and rs7766029 (CNR1) predicted case-control status, after correcting for multiple covariables in the IMAGEN sample. A binomial logistic regression of the combination of these three SNPs by phenotype in the SYS cohort showed a result in the same direction as seen in the IMAGEN cohort (BETA = 0.501, p = 0.06). While preliminary, the present study suggests that the eCB system may play a role in the development of AUD in adolescents.

PurposeAdjuvant chemotherapy within 56 or 84 days following curative resection is globally accepted as the standard of care for stage III colon cancer as it has been associated with improved overall survival. Initiation of adjuvant chemotherapy within this time frame is therefore recommended by clinical practice guidelines, including the European Society for Medical Oncology. The objective of this study was to evaluate adherence to these clinical practice guidelines for patients with stage III colon cancer across the Rossy Cancer Network (RCN); a partnership of McGill University’s Faculty of Medicine, McGill University Health Centre, Jewish General Hospital and St Mary’s Hospital Center.Patients and methods187 patients who had been diagnosed with stage III colon cancer and received adjuvant chemotherapy within the RCN partner hospitals from 2012 to 2015 were included. Patient and treatment information was retrospectively determined by chart review. Χ2 and Wilcoxon rank-sum tests were used to measure associations and a multivariate Cox regression model was used to determine risk factors contributing to delays in administration of adjuvant chemotherapy.ResultsThe median turnaround time between surgery and adjuvant chemotherapy was 69 days. Importantly, only 27% of patients met the 56-day target, and 71% met the 84-day target. Increasing age, having more than one surgical complication and being diagnosed between 2013–2014 and 2014–2015 reduced the likelihood that patients met these targets. Furthermore, delays were observed at most intervals from surgery to first adjuvant chemotherapy treatment.ConclusionOur study found that within these academic hospital settings, 27% of patients met the 56-day target, and 71% met the 84-day target. Delays were associated with hospital, surgeon and patient-related factors. Initiatives in quality improvement are needed in order to improve adherence to recommended treatment guidelines for prompt administration of adjuvant chemotherapy for stage III colon cancer.

BACKGROUND: Patients with cancer may be at high risk of adverse outcomes from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We analyzed a cohort of patients with cancer and coronavirus 2019 (COVID-19) reported to the COVID-19 and Cancer Consortium (CCC19) to identify prognostic clinical factors, including laboratory measurements and anticancer therapies. PATIENTS AND METHODS: Patients with active or historical cancer and a laboratory-confirmed SARS-CoV-2 diagnosis recorded between 17 March and 18 November 2020 were included. The primary outcome was COVID-19 severity measured on an ordinal scale (uncomplicated, hospitalized, admitted to intensive care unit, mechanically ventilated, died within 30 days). Multivariable regression models included demographics, cancer status, anticancer therapy and timing, COVID-19-directed therapies, and laboratory measurements (among hospitalized patients). RESULTS: A total of 4966 patients were included (median age 66 years, 51% female, 50% non-Hispanic white); 2872 (58%) were hospitalized and 695 (14%) died; 61% had cancer that was present, diagnosed, or treated within the year prior to COVID-19 diagnosis. Older age, male sex, obesity, cardiovascular and pulmonary comorbidities, renal disease, diabetes mellitus, non-Hispanic black race, Hispanic ethnicity, worse Eastern Cooperative Oncology Group performance status, recent cytotoxic chemotherapy, and hematologic malignancy were associated with higher COVID-19 severity. Among hospitalized patients, low or high absolute lymphocyte count; high absolute neutrophil count; low platelet count; abnormal creatinine; troponin; lactate dehydrogenase; and C-reactive protein were associated with higher COVID-19 severity. Patients diagnosed early in the COVID-19 pandemic (January-April 2020) had worse outcomes than those diagnosed later. Specific anticancer therapies (e.g. R-CHOP, platinum combined with etoposide, and DNA methyltransferase inhibitors) were associated with high 30-day all-cause mortality. CONCLUSIONS: Clinical factors (e.g. older age, hematological malignancy, recent chemotherapy) and laboratory measurements were associated with poor outcomes among patients with cancer and COVID-19. Although further studies are needed, caution may be required in utilizing particular anticancer therapies. CLINICAL TRIAL IDENTIFIER: NCT04354701.

Background: The impact of COVID-19 on patients on the waiting list for liver transplantation (LT) and on their post-LT course is presently unknown. Methods: Data from consecutive adult LT candidates with COVID-19 were collected across Europe in a dedicated registry and analyzed. Findings: From February 21st to November 20th, 2020, 136 adult cases with laboratory confirmed SARS-CoV-2 infection from 33 centers in 11 European countries were collected, with 113 having COVID-19. Thirty-seven (37/113, 32·7%) patients died after a median of 18 (10-30) days, respiratory failure being the major cause (33/37, 89·2%). The 60-day mortality risk did not significantly change between first (35·3%, 95% CI 23·9-50·0) and second wave (26·0%, 95% CI 16·2-40·2). Multivariable Cox regression analysis showed lab-MELD score ≥15 (MELD 15-19 HR 6·09, 95% CI 2·01-18·45; MELD ≥20 HR 5·21, 95% CI 1·76-15·45) and dyspnea on presentation (HR 4·10, 95% CI 2·09-8·06) being the two negative independent factors for mortality. The mortality risk reached 49·2% (31/63) in patients with decompensated cirrhosis and lab-MELD score ≥15. Twenty-six patient received a LT after a median time of 78.5 (IQR 44-102) days and 25 (96%) are alive after median follow-up of 118 days (IQR 31-170). Interpretation: Increased mortality in LT candidates with COVID-19 (32·7%), reaching 49·2% in those with decompensated cirrhosis and lab-MELD score ≥15, with no significant difference between first and second wave of the pandemic. Respiratory failure was the major cause of death. The dismal prognosis of patients with decompensated cirrhosis supports the adoption of strict preventative measures and the urgent testing of vaccination efficacy in this population. Prior SARS-CoV-2 symptomatic infection did not affect early post-transplant survival (96%). Funding: No funding source. Declaration of Interests: None to declare. Ethics Approval Statement: Data was collected in accordance with General Data Protection Regulation (GDPR), the European Union legislation and the ELTR privacy policy. Reg. HCB/2020/0479 released by CLINICAL RESEARCH ETHICS COMMITTEE from Hospital Clinic Barcelona

BackgroundPatients with cancer who are infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are more likely to develop severe illness and die compared with those without cancer. The impact of immune checkpoint inhibition (ICI) on the severity of COVID-19 illness is unknown. The aim of this study was to investigate whether ICI confers an additional risk for severe COVID-19 in patients with cancer.MethodsWe analyzed data from 110 patients with laboratory-confirmed SARS-CoV-2 while on treatment with ICI without chemotherapy in 19 hospitals in North America, Europe and Australia. The primary objective was to describe the clinical course and to identify factors associated with hospital and intensive care (ICU) admission and mortality.FindingsThirty-five (32%) patients were admitted to hospital and 18 (16%) died. All patients who died had advanced cancer, and only four were admitted to ICU. COVID-19 was the primary cause of death in 8 (7%) patients. Factors independently associated with an increased risk for hospital admission were ECOG ≥2 (OR 39.25, 95% CI 4.17 to 369.2, p=0.0013), treatment with combination ICI (OR 5.68, 95% CI 1.58 to 20.36, p=0.0273) and presence of COVID-19 symptoms (OR 5.30, 95% CI 1.57 to 17.89, p=0.0073). Seventy-six (73%) patients interrupted ICI due to SARS-CoV-2 infection, 43 (57%) of whom had resumed at data cut-off.InterpretationCOVID-19–related mortality in the ICI-treated population does not appear to be higher than previously published mortality rates for patients with cancer. Inpatient mortality of patients with cancer treated with ICI was high in comparison with previously reported rates for hospitalized patients with cancer and was due to COVID-19 in almost half of the cases. We identified factors associated with adverse outcomes in ICI-treated patients with COVID-19.

International audience; Background: Chronic hepatitis B virus (HBV) infection may evolve into cirrhosis and hepatocellular carcinoma, and this progression may be accelerated by specific risk factors, including overweight and obesity. Although evidence for a protective effect of cannabis use on elevated body weight has been found for other populations, no data are available for HBV-infected patients.Aims: We aimed to identify risk factors (including cannabis use) for overweight and obesity in patients with HBV chronic infection.Methods: Using baseline data from the French ANRS CO22 Hepather cohort, we performed two separate analyses, one using “central obesity” (based on waist circumference) and the other “overweight” and “obesity” (based on body mass index) as outcomes. Logistic and multinomial regressions were used to model central obesity and overweight/obesity, respectively.Results: Among the 3706 patients in the study population, 50.8% had central obesity, 34.7% overweight, and 14.4% obesity. After multivariable adjustment, current cannabis use was associated with a 59% lower risk of central obesity compared with no lifetime use (adjusted odds ratio [95% CI]: 0.41 [0.24 to 0.70]). It was also associated with a 54% and 84% lower risk of overweight (adjusted relative risk ratio [95% CI]: 0.46 [0.27 to 0.76]) and obesity (0.16 [0.04 to 0.67]), respectively.Conclusions: Cannabis use was associated with lower risks of overweight and obesity in patients with HBV chronic infection. Future studies should test whether these potential benefits of cannabis and cannabinoid use translate into reduced liver disease progression in this high-risk population.

International audience

Background & Aims: Bacterial infections are common and life-threatening in patients with cirrhosis. Little is known about the epidemiology of bacterial infections in different regions. We performed a multicenter prospective intercontinental study to assess the prevalence and outcomes of bacterial and fungal infections in patients with cirrhosis. Methods: We collected data from 1302 hospitalized patients with cirrhosis and bacterial or fungal infections at 46 centers (15 in Asia, 15 in Europe, 11 in South America, and 5 in North America) from October 2015 through September 2016. We obtained demographic, clinical, microbiology, and treatment data at time of diagnosis of infection and during hospitalization. Patients were followed until death, liver transplantation, or discharge. Results: The global prevalence of multidrug-resistant (MDR) bacteria was 34% (95% confidence interval 31%–37%). The prevalence of MDR bacteria differed significantly among geographic areas, with the greatest prevalence in Asia. Independent risk factors for infection with MDR bacteria were infection in Asia (particularly in India), use of antibiotics in the 3 months before hospitalization, prior health care exposure, and site of infection. Infections caused by MDR bacteria were associated with a lower rate of resolution of infection, a higher incidence of shock and new organ failures, and higher in-hospital mortality than those caused by non-MDR bacteria. Administration of adequate empirical antibiotic treatment was independently associated with improved in-hospital and 28-day survival. Conclusions: In a worldwide study of hospitalized patients, we found a high prevalence of infection with MDR bacteria in patients with cirrhosis. Differences in the prevalence of MDR bacterial infections in different global regions indicate the need for different empirical antibiotic strategies in different continents and countries. While we await new antibiotics, effort should be made to decrease the spread of MDR bacteria in patients with cirrhosis.

When the COVID-19 pandemic began, formal frameworks to collect data about affected patients were lacking. The COVID-19 and Cancer Consortium (CCC19) was formed to collect granular data on patients with cancer and COVID-19 at scale and as rapidly as possible. CCC19 has grown from five initial institutions to 125 institutions with >400 collaborators. More than 5,000 cases with complete baseline data have been accrued. Future directions include increased electronic health record integration for direct data ingestion, expansion to additional domestic and international sites, more intentional patient involvement, and granular analyses of still-unanswered questions related to cancer subtypes and treatments.

Entecavir treatment failure can be observed in compliant patients despite an absence of detectable resistance mutations by Pol/RT Sanger sequencing. We hypothesized that these unexplained treatment failures could rely on other mechanisms of viral resistance, especially on mutations selected outside of the Pol/RT domain. Partial virological response to entecavir was observed in three patients treated with immunosuppressive drugs, without selection of Pol/RT resistance mutations. Mutations selected in the whole HBV genome during entecavir treatment and potentially associated with resistance were searched for using deep sequencing and characterized using a phenotypic resistance assay. Mutations Q206K (pre-core/core), Q120K (pre-S1/pre-S2, T-cell epitope) and A300E (spacer domain) were selected during entecavir treatment in patient #1 but were not associated with an increased level of resistance to entecavir or an increase in HBV replication capacity. Core promoter mutations T1753G, A1762T and G1764A were present as major mutations before and after treatment in patient #1. HBs Ag immune escape mutations were present as major mutations before and after treatment in patients #2 (sK122R, sT126I, sP127S and sG145R) and #3 (sM133I). We demonstrated that PVR to entecavir does not require selection of any resistance mutation in the whole HBV genome. Our results demonstrate that major mutations can be selected outside of the Pol/RT domain before or during entecavir treatment. These mutations could contribute to entecavir treatment failure by other mechanisms than an increased level of resistance.

This prospective observational study assesses changes in treatment plans for patients with lung cancer and qualifies the types of changes observed as a direct result of the coronavirus disease 2019 pandemic.

Background The gut microbiome plays a key role in immune checkpoint inhibitors (ICI) efficacy and several strategies are currently being investigated to improve microbiome composition. The impact of a specific diet on microbiome modulation and clinical outcomes remains unknown. In this study, we assessed the effects of a high fiber diet on clinical outcomes as well as on microbiome composition, production of fecal metabolites, and intratumor immune infiltration in metastatic non-small cell lung cancer (mNSCLC) patients amenable to ICI. Methods In this prospective study, 39 chemotherapy-refractory or naive patients with mNSCLC treated with ICI alone or in combination with chemotherapy completed a validated dietary survey. Based on the total fiber intake, patients were divided into high vs low fiber groups (HF vs LF). Objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) were compared between both groups. In addition, fecal and tumor samples were collected prior to ICI initiation. Fecal metagenomic sequencing was performed and fecal short-chain fatty acids (SCFA) were measured by LC-MS/MS. Tumoral transcriptome profiling was performed through RNA sequencing to define differentially expressed pathways. Results Baseline characteristics were well balanced between both groups, including body mass index (BMI) and PD-L1 status. Median PFS for the HF group was longer compared to the LF group (27.4 vs 12.6 months). Microbiome metagenomic profiling revealed higher baseline alpha diversity (p=0.048) in the HF group compared to the LF group. Bifidobacterium, Alistipes, and Bacteroides salyersiae were enriched in the HF group while Fusobacterium was overrepresented in the LF group. SCFA measurement revealed that a high level of propionate correlated with a significantly longer OS (not reached vs 18.4. months, p=0.02) in the entire cohort. Moreover, propionate levels were significantly higher in the HF vs LF group (p=0.02). At the tumor level, RNA sequencing demonstrated a downregulation of DNA repair mechanisms and an upregulation of humoral and adaptive immune responses in the HF group. Conclusions In this study, we demonstrated that a HF diet in patients with mNSCLC was associated with better clinical outcomes. Importantly, HF was associated with an enrichment of previously reported beneficial gut bacteria. Moreover, propionate correlated with longer OS and was increased in the HF group. This study provides further insights into how the diet can beneficially shift the microbiome composition and intratumor immune responses in patients with mNSCLC treated with ICI and this may lead to novel, dietary-geared therapeutic avenues in the oncomicrobiome arena. Ethics Approval The study was approved by CRCHUM Institution,s Ethics Board, approval number 17.035.

Introduction Studies suggest that patients with cancer are more likely to experience severe outcomes from COVID-19. Therefore, cancer centers have undertaken efforts to care for patients with cancer in COVID-free units. Nevertheless, the frequency and relevance of nosocomial transmission of COVID-19 in patients with cancer remain unknown. The goal of this study was to determine the incidence and impact of hospital-acquired COVID-19 in this population and identify predictive factors for COVID-19 severity in patients with cancer. Methods Patients with cancer and a laboratory-confirmed diagnosis of COVID-19 were prospectively identified using provincial registries and hospital databases between March 3rd and May 23rd, 2020 in the provinces of Quebec and British Columbia in Canada. Patient’s baseline characteristics including age, sex, comorbidities, cancer type, and type of anti-cancer treatment were collected. The exposure of interest was incidence of hospital-acquired infection defined by diagnosis of SARS-CoV-2 ≥ 5 days after hospital admission for COVID-unrelated cause. Co-primary outcomes were death or composite outcomes of severe illness from COVID-19 such as hospitalization, supplemental oxygen, intensive-care unit (ICU) admission and/or mechanical ventilation. Results A total of 252 patients (N=249 adult, and N=3 pediatric) with COVID-19 and cancer were identified, and the majority were residents of Quebec (N=233). One-hundred-and-six patients (42.1%) received active anti-cancer treatment in the last 3 months prior to COVID-19 diagnosis. During a median follow-up of 25 days, 33 (13.1%) required admission to the ICU, and 71 (28.2%) died. Forty-seven (19.1%) had a diagnosis of hospital-acquired COVID-19. Median overall survival was shorter in those with hospital-acquired infection, compared to a contemporary community-acquired population (27 days vs unreached, HR 2.3, 95% CI 1.2-4.4, p=0.0006). Multivariate analysis demonstrated that hospital-acquired COVID-19, age, ECOG status, and advanced stage of cancer were independently associated with death. Interpretation Our study demonstrates a high rate of nosocomial transmission of COVID-19, associated with increased mortality in both univariate and multivariate analysis in the cancer population, reinforcing the importance of treating patients with cancer in COVID-free units. We also validated that age and advanced cancer were negative predictive factors for COVID-19 severity in patients with cancer., Highlights • We found a high rate of nosocomial transmission of COVID-19 in patients with cancer. • Nosocomial COVID-19 increased mortality compared to community-acquired infection. • Nosocomial COVID-19, age, ECOG, and stage were independently associated with death. • COVID-free units and infection control procedures are required to protect patients.

International audience; Introduction: The treatment of symptomatic hernia in cirrhotic patients with refractory ascites is critical but challenging. The objective of this study was to assess the feasibility and safety of the implantation of alfapump (R) combined with concomitant hernia repair in cirrhotic patients with refractory ascites. Methods: Using data from six European centres, we retrospectively compared patients treated with alfapump (R) system implantation and concomitant hernia repair [the combined treatment group (CT group, n = 12)] or with intermittent paracentesis hernia repair [the standard treatment group (ST group, n = 26)]. Some patients of the ST group had hernia repair in an elective setting (STel group) and others in emergency (STem group). The endpoints were requirement of peritoneal drainage, the rate of infectious complications, the in-hospital mortality, the length of stay, paracentesis-free survival. Results: Postoperatively, none of the patients in the CT group and 21 patients (80%) in the ST group underwent peritoneal drainage for the evacuation of ascites fluid (P < 0.0001). The overall incidence of infectious complications was not different between groups but there were fewer infections in the CT group than in the STem group (33% vs. 81%; P = 0.01). There was no difference for in-hospital mortality. The length of stay was shorter in the CT group (P = 0.03). Paracentesis-free survival was significantly better (P = 0.0003) in the CT group than in the ST group. Conclusion: Implantation of alfapump combined with concomitant hernia repair seems feasible and safe in cirrhotic patients; however, larger and randomized study are required. (C) 2020 Published by Elsevier Masson SAS.

Radiation therapy (RT) is an essential component of therapy either curative or palliative armamentarium in oncology, but its efficacy varies considerably among patients through many extrinsic and intrinsic mechanisms of the tumour, which are beginning to be better understood. Recent studies have shown that the gut microbiome represents a key factor in the modulation of the systemic immune response and consequently on patients' outcome. Moreover, the emergence of biomarkers that are derived from the gut microbiota has fuelled the development of adjuvant strategies for patients treated with immunotherapy in combination or not with RT. Despite progress in development of more precise radiotherapy techniques, almost all patients undergoing RT to the abdomen, pelvis, or rectum develop acute adverse events as a consequence of several dose-limiting parameters such as the location of irradiation that may subsequently damage normal tissue including the intestinal epithelium. Several lines of evidence in preclinical models identified that vancomycin improves RT-induced gastrointestinal toxicities such as diarrhea and oral mucositis. In order to gain further insight into this rapidly evolving field, we have systematically reviewed the studies that have described how the gut microbiome may directly or indirectly modulate RT efficacy and its gastro-intestinal toxicities. Lastly, we outline current knowledge gaps and discuss potentially more satisfactory therapeutic options to restore the functionality of the gut microbiome of patients treated with RT.

The gut microbiome (GM) plays an important role in shaping systemic immune responses and influences immune checkpoint inhibitor (ICI) efficacy. Antibiotics worsen clinical outcomes in patients receiving ICI. However, whether GM profiling and baseline antibiotic can be a biomarker of ICI efficacy in advanced non–small cell lung cancer (NSCLC) remains unknown. We prospectively collected baseline (pre-ICI) fecal samples and clinical data of 70 Japanese patients suffering from advanced NSCLC and treated them with anti–PD-1/PD-L1 antibodies as a first-line or treatment-refractory therapy. We performed 16S rRNA V3–V4 sequencing of gene amplicons of fecal samples, and bacteria diversity and differential abundance analysis was performed. The clinical endpoints were objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and immune-related adverse events (irAE). ORR was 34%, and median PFS and OS were 5.2 and 16.2 months, respectively. Patients who received pre-ICI antibiotic had lower alpha diversity at baseline and underrepresentation of Ruminococcaceae UCG 13 and Agathobacter. When analyzing antibiotic-free patients, alpha diversity correlated with OS. In addition, Ruminococcaceae UCG 13 and Agathobacter were enriched in patients with favorable ORR and PFS >6 months. Ruminococcaceae UCG 13 was enriched in patients with OS >12 months. GM differences were observed between patients who experienced low- versus high-grade irAE. We demonstrated the negative influence of antibiotic on the GM composition and identified the bacteria repertoire in patients experiencing favorable responses to ICI. See articles by Tomita et al., p. 1236, and Peng et al., p. 1251

Chronic non cirrhotic extrahepatic portal vein obstruction (EHPVO) refers to the cavernomatous transformation of the portal vein (the so-called "portal cavernoma") which occurs following acute thrombosis of the portal vein in the absence of recanalization. In adults, EHPVO mainly occurs following thrombosis, while in children it may be related to congenital malformations and/or neonatal umbilical venous catheterization. However, 50% of the cases of EHPVO remain idiopathic [1]. Risk factors and associated diseases should be investigated (chapter 1). Indeed, the presence of a thrombophilic alteration, in particular myeloproliferative neoplasm impacts prognosis and determine a causal treatment.

Lung cancer is the most commonly diagnosed cancer in Canada and remains associated with high mortality. Nevertheless, recent advances in the fields of immuno-oncology and precision medicine have led to significant improvements in clinical outcome in metastatic non-small-cell lung cancer (nsclc). Those improvements were facilitated by a greater understanding of the biologic classification of nsclc, which catalyzed discoveries of novel therapies. Here, we present a comprehensive review of the recent avalanche of practice-changing trials in metastatic nsclc, and we offer an approach to the management of this disease from a Canadian perspective. We begin with an overview of the pathologic and molecular characterization of metastatic nsclc. Next, we review the indications for currently approved immune checkpoint inhibitors, and we provide an approach to the management of disease with a driver mutation. Finally, we address future avenues in both diagnostics and therapeutics for patients with advanced and metastatic nsclc.

Angiotensin-converting enzyme (ACE) inhibitors are frequently used to treat hypertension and congestive heart failure. Preclinical data show that ACE plays a role on both innate and adaptive immune responses. Since interactions between ACE inhibitors and immune checkpoint inhibitors (ICIs) have not been reported, the aim of this study is to investigate the influence of ACE inhibitors on non-small cell lung cancer (NSCLC) patients treated with programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) inhibitors. We conducted a retrospective cohort analysis of NSCLC patients treated with PD-1/PD-L1 inhibitors. Clinical and co-medication data as well as tumor biopsies were collected. Groups were defined according to patients’ co-medications at the time of ICI initiation. Among the 178 patients included, 22 (13.1%) received ACE inhibitors. While baseline characteristics were similar in both groups, ACE inhibitors group had a shorter median PFS (Progression-Free Survival) compared to the control group: 1.97 vs. 2.56 months, p = .01 (HR = 1.8 CI95% 1.1–2.8). Using CIBERSORT, RNA sequencing suggested that tumors from the ACE inhibitors group had less M1 macrophages, activated mast cells, NK cells and memory activated T cells, thus suggesting an immunosuppressed state. In vitro, the ACE inhibitor, captopril, induced M2 marker at the cell surface of monocytes engaged into M1 differentiation. Thus, ACE inhibitors prescription concomitant to PD-1/PD-L1 inhibitors treatment seems to be associated with impaired outcome and with a tumor immunosuppressed state in patients with advanced NSCLC. These results should be validated in larger prospective cohorts.

Background and aims Anticoagulant therapy has been recommended in patients with cirrhosis and portal vein thrombosis especially in candidates for liver transplantation. These patients are also likely to need variceal band ligation. This study aimed to assess the incidence of upper gastrointestinal bleeding after elective variceal band ligation in patients with cirrhosis receiving anticoagulant therapy for portal vein thrombosis. Methods Patients with cirrhosis and nontumoral portal vein thrombosis treated with anticoagulant therapy undergoing elective variceal band ligation were retrospectively included. We recorded upper gastrointestinal bleeding events occurring within two weeks after variceal band ligation. Postvariceal band ligation bleeding was defined as active bleeding on at least one site of previous ligation at endoscopy. Results Between 2014 and 2017, 32 patients with cirrhosis had scheduled variceal band ligations while on anticoagulant therapy [men 75%; median age 59 years; aetiology of cirrhosis: alcohol (50%), viral (34%), alcohol and viral (16%); and Child-Pugh score: A (31%), B (44%), and C (25%)]. Three (9%) patients presented postvariceal band ligation bleeding during the follow-up. None of these events led to haemorrhagic shock or death. Factors associated with postvariceal band ligation bleeding included variceal band ligation performed as secondary prophylaxis (P = 0.05) and previous decompensation of cirrhosis (P = 0.03). Conclusion In this small group of patients under anticoagulation therapy undergoing variceal band ligation, only a minority presented postendoscopic bleeding of minor importance. Nevertheless, particular attention should be paid to patients with previous decompensation of cirrhosis.

Purpose To determine whether quantification of liver surface nodularity (LSN) provides an estimate of the presence of clinically significant portal hypertension (CSPH) in patients with cirrhosis. Materials and Methods This retrospective study included a training cohort (n = 189) and separate external validation cohort (n = 78), both composed of patients with cirrhosis who underwent abdominal CT and hepatic venous pressure gradient (HVPG) measurement between 2010 and 2016. The LSN score, liver and spleen volumes, liver-to-spleen volume ratio, platelet count to spleen diameter ratio, Iranmanesh score, aspartate amino transferase-to-platelet ratio index, and Fibrosis-4 index were derived from CT images and serum laboratories. The accuracy of the various tests for predicting CSPH was evaluated with area under the receiver operating characteristic curve (AUROC) and compared by using the DeLong test. Student t test and Pearson correlation coefficient were used. Results One hundred eighty-nine patients were analyzed (119 men [mean age ± standard deviation, 57 years ± 11; range, 29-81 years] and 70 women [mean age, 61 years ± 10; range, 34-83 years]; overall mean age, 58 years ± 10; range, 29-83 years). A total of 102 patients (54%) had CSPH. LSN score correlated with HVPG (r = 0.75; P < .001). Patients with CSPH had a higher LSN score than did those without CSPH (3.2 ± 0.6 vs 2.4 ± 0.3; P < .001). A cutoff value of 2.8 had a positive predictive value of 88% for CSPH; the AUROC of LSN was 0.88 ± 0.03. This was higher than that of other available noninvasive tests (DeLong, all P < .001). In the validation cohort, LSN score of 2.8 had a positive predictive value of 86% for CSPH; the AUROC was 0.87 ± 0.04. Conclusion The CT-based liver surface nodularity score demonstrated high diagnostic performance for detecting clinically significant portal hypertension and outperformed multiple other noninvasive tests. © RSNA, 2018 Online supplemental material is available for this article.

Key points Chronic obstructive pulmonary disease (COPD) is largely caused by smoking, and patient limb muscle exhibits a fast fibre shift and atrophy. We show that this fast fibre shift is associated with type grouping, suggesting recurring cycles of denervation-reinnervation underlie the type shift. Compared to patients with normal fat-free mass index (FFMI), patients with low FFMI exhibited an exacerbated fibre type shift, marked accumulation of very small persistently denervated muscle fibres, and a blunted denervation-responsive transcript profile, suggesting failed denervation precipitates muscle atrophy in patients with low FFMI. Sixteen weeks of passive tobacco smoke exposure in mice caused neuromuscular junction degeneration, consistent with a key role for smoke exposure in initiating denervation in COPD. Abstract A neurological basis for the fast fibre shift and atrophy seen in limb muscle of patients with chronic obstructive pulmonary disease (COPD) has not been considered previously. The objective of our study was: (1) to determine if denervation contributes to fast fibre shift and muscle atrophy in COPD; and (2) to assess using a preclinical smoking mouse model whether chronic tobacco smoke (TS) exposure could initiate denervation by causing neuromuscular junction (NMJ) degeneration. Vastus lateralis muscle biopsies were obtained from severe COPD patients [n = 10 with low fat-free mass index (FFMI), 65 years; n = 15 normal FFMI, 65 years) and healthy age- and activity-matched non-smoker control subjects (CON; n = 11, 67 years), to evaluate morphological and transcriptional markers of denervation. To evaluate the potential for chronic TS exposure to initiate these changes, we examined NMJ morphology in male adult mice following 16 weeks of passive TS exposure. We observed a high proportion of grouped fast fibres and a denervation transcript profile in COPD patients, suggesting that motor unit remodelling drives the fast fibre type shift in COPD patient limb muscle. A further exacerbation of fast fibre grouping in patients with low FFMI, coupled with blunted reinnervation signals, accumulation of very small non-specific esterase hyperactive fibres and neural cell adhesion molecule-positive type I and type II fibres, suggests denervation-induced exhaustion of reinnervation contributes to muscle atrophy in COPD. Evidence from a smoking mouse model showed significant NMJ degeneration, suggesting that recurring denervation in COPD is probably caused by decades of chronic TS exposure.

Two algorithms based on sequential measurements of liver and spleen stiffness using two-dimensional shearwave elastography (2D-SWE) have been recently proposed to estimate clinically significant portal hypertension (hepatic venous pressure gradient [HVPG] ≥10 mm Hg) in patients with cirrhosis, with excellent diagnostic accuracy.To validate externally these algorithms in a large cohort of patients with cirrhosis.One hundred and ninety-one patients with stable cirrhosis (Child-Pugh class A 39%, B 29% and C 31%) who underwent liver and spleen stiffness measurements using 2D-SWE at the time of HVPG measurement were included. Diagnostic accuracy of the 2 algorithms was assessed by calculating sensitivity, specificity, positive and negative predictive values.The first algorithm, using liver stiffness16.0 kilopascals (kPa) and then spleen stiffness26.6 kPa, was used to rule-out HVPG ≥10 mm Hg. In our population, its sensitivity and negative predictive value were 95% and 63% respectively. The second algorithm, using liver stiffness38.0 kPa, or liver stiffness ≤38.0 kPa but spleen stiffness27.9 kPa, was used to rule-in HVPG ≥10 mm Hg. In our population, its specificity and positive predictive value were 52% and 83% respectively. Restricting the analyses to the 74 patients without any history of decompensation of cirrhosis or to the 65 patients with highly reliable liver stiffness measurement did not improve the results.In our population, diagnostic accuracies of non-invasive algorithms based on sequential measurements of liver and spleen stiffness using 2D-SWE were acceptable, but not good enough to replace HVPG measurement or to base clinical decisions.

An unfavourable gut bacterial composition has been shown to reduce the likelihood of clinical benefit from immune-checkpoint inhibitors (ICIs). The results of two first-in-human studies of faecal microbiota transplantation in patients with melanoma refractory to anti-PD-1 antibodies validate preclinical evidence that this approach can improve the gut microbiota and overcome resistance to ICIs; however, many questions remain.

OBJECTIVE: To evaluate the European experience after Adult-to-adult living donor liver transplantation using the left liver (LL-aLDLT). SUMMARY BACKGROUND DATA: LL-aLDLT decreases donor risk but provides a smaller graft that increases recipient risk as compared with right liver (RL-aLDLT). However, there is little knowledge of results obtained after LL-aLDLT in Europe. METHODS: This is a European multicenter retrospective study which aims to analyze donor and recipient outcomes after 46 LL-aLDLT. RESULTS: Seventy-six percent of the grafts were harvested by minimally invasive approach. Mean donor hospital stay was 7.5 ± 3.5 days. Donor liver function was minimally impaired, with 36 donors (78.3%) without any 90-day complication, and 4 (8.7%) presenting major complications. One, 3, and 5-year recipient survival was 90.9%, 82.7%, and 82.7%, respectively. However, graft survival was of 59.4%, 56.9%, and 56.9% at 1, 3, and 5 years respectively, due to a 26.1% urgent liver retransplantation (ReLT) rate, mainly due to SFSS (n = 5) and hepatic artery thrombosis (HAT, n = 5). Risk factor analysis for ReLT and HAT showed an association with a graft to body weight ratio (GBWR) 0.6% was associated with a lower ReLT rate (0% vs. 33%, P = 0.044). CONCLUSIONS: Our analysis showed low donor morbidity and preserved liver function. Recipient outcomes, however, were hampered by a high ReLT rate. A strict selection of both donor and recipients is the key to minimize graft loss.

We report the case of a liver transplant recipient, cytomegalovirus (CMV) donor-positive (D+), recipient-negative (R−), with primary multidrug-resistant CMV infection treated with a combination therapy of letermovir and (val)ganciclovir.