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Microsatellite instability determines whether patients with gastrointestinal cancer respond exceptionally well to immunotherapy. However, in clinical practice, not every patient is tested for MSI, because this requires additional genetic or immunohistochemical tests. Here we show that deep residual learning can predict MSI directly from H&E histology, which is ubiquitously available. This approach has the potential to provide immunotherapy to a much broader subset of patients with gastrointestinal cancer.A deep residual learning framework identifies microsatellite instability in histology slides from patients with cancer and can be used to guide immunotherapy.

Screening drugs on patient biopsies from solid tumours has immense potential, but is challenging due to the small amount of available material. To address this, we present here a plug-based microfluidics platform for functional screening of drug combinations. Integrated Braille valves allow changing the plug composition on demand and enable collecting >1200 data points (56 different conditions with at least 20 replicates each) per biopsy. After deriving and validating efficient and specific drug combinations for two genetically different pancreatic cancer cell lines and xenograft mouse models, we additionally screen live cells from human solid tumours with no need for ex vivo culturing steps, and obtain highly specific sensitivity profiles. The entire workflow can be completed within 48 h at assay costs of less than US$ 150 per patient. We believe this can pave the way for rapid determination of optimal personalized cancer therapies. Cancer patients exhibit specific sensitivities toward drug combinations that cannot be easily predicted. Here the authors setup a microfluidic platform that allows testing of multiple drug combinations correctly predicting sensitivity in vivo and they use it on patients biopsies to define effective drugs.

Hepatocellular carcinoma (HCC) is the most common primary tumor of the liver and its mortality is third among all solid tumors, behind carcinomas of the lung and the colon. Despite continuous advancements in the management of this disease, the prognosis for HCC remains inferior compared to other tumor entities. While orthotopic liver transplantation (OLT) and surgical resection are the only two curative treatment options, OLT remains the best treatment strategy as it not only removes the tumor but cures the underlying liver disease. As the applicability of OLT is nowadays limited by organ shortage, major liver resections—even in patients with underlying chronic liver disease—are adopted increasingly into clinical practice. Against the background of the oftentimes present chronical liver disease, locoregional therapies have also gained increasing significance. These strategies range from radiofrequency ablation and trans-arterial chemoembolization to selective internal radiation therapy and are employed in both curative and palliative intent, individually, as a bridging to transplant or in combination with liver resection. The choice of the appropriate treatment, or combination of treatments, should consider the tumor stage, the function of the remaining liver parenchyma, the future liver remnant volume and the patient’s general condition. This review aims to address the topic of multimodal treatment strategies in HCC, highlighting a multidisciplinary treatment approach to further improve outcome in these patients.

Cholangiocarcinoma (CCA) is the second most common primary liver cancer and associated with a dismal prognosis due to the lack of an efficient systemic therapy. In contrast to other cancers, new immunotherapies have demonstrated unsatisfactory results in clinical trials, underlining the importance of a deeper understanding of the special tumor microenvironment of CCA and the role of immune cells interacting with the tumor. Tumor-infiltrating lymphocytes (TILs) are an important component of the adaptive immune system and the foundation of current immunotherapy. Therefore, the aim of this systemic review is to summarize the current literature focusing on the proportions and distribution, molecular pathogenesis, prognostic significance of TILs and their role in immunotherapy for CCA patients. In CCA, CD8+ and CD4+ T lymphocytes represent the majority of TILs and are mostly sequestered around the cancer cells. CD20+ B lymphocytes and Natural Killer (NK) cells are less frequent. In contrast, Foxp3+ cells (regulatory T cells, Tregs) are observed to infiltrate into the tumor. In the immune microenvironment of CCA, cancer cells and stromal cells such as TAMs, TANs, MSDCs and CAFs inhibit the immune protection function of TILs by secreting factors like IL-10 and TGF-β. With respect to molecular pathogenesis, the Wnt/-catenin, TGF-signaling routes, aPKC-i/P-Sp1/Snail Signaling, B7-H1/PD-1Pathway and Fas/FasL signaling pathways are connected to the malignant potential and contributed to tumor immune evasion by increasing TIL apoptosis. Distinct subtypes of TILs show different prognostic implications for the long-term outcome in CCA. Although there are occasionally conflicting results, CD8+ and CD4+ T cells, and CD20+ B cells are positively correlated with the oncological prognosis of CCA, while a high number of Tregs is very likely associated with worse overall survival. TILs also play a major role in immunotherapy for CCA. In summary, the presence of TILs may represent an important marker for the prognosis and a potential target for novel therapy, but more clinical and translational data is needed to fully unravel the importance of TILs in the treatment of CCA.

Clostridium difficile infection (CDI) represents one of the most common healthcare-associated infections. Due to increasing numbers of recurrences and therapy failures, CDI has become a major disease burden. Studies have shown that fecal microbiota transplantation (FMT) can both be a safe and highly efficacious therapy for patients with therapy-refractory CDI. However, patients undergoing solid organ transplantation are at high risk for CDI due to long-term immunosuppression, previous antibiotic therapy, and proton pump inhibitor use. Additionally, these patients may be especially prone to adverse events related to FMT. Here, we report a successful FMT in a patient with severe therapy-refractory CDI after liver transplantation.

Combined hepatocellular-cholangiocarcinoma (cHCC/CCA) represents a rare type of primary liver cancer with a very limited prognosis. Although just recently genomic studies have contributed to a better understanding of the disease’s genetic landscape, therapeutic options, especially for advanced-stage patients, are limited and often experimental, as no standardized treatment protocols have been established to date. Here, we report the case of a 38-year-old male patient who was diagnosed with extensive intrahepatic cHCC/CCA in an otherwise healthy liver without signs of chronic liver disease. An interdisciplinary stepwise therapeutic approach including locoregional liver-targeted therapy, systemic chemotherapy, liver transplantation, surgical pulmonary metastasis resection, and next-generation sequencing-based targeted therapy led to a prolonged overall survival beyond 5 years with an excellent quality of life. This case report comprises several provocative treatment decisions that are extensively discussed in light of the existing literature on this rare but highly aggressive malignancy.

Non-alcoholic fatty liver disease (NAFLD) is a major cause of morbidity and mortality in developed countries, resulting in steatohepatitis (NASH), fibrosis and eventually cirrhosis. Modulating inflammatory mediators such as chemokines may represent a novel therapeutic strategy for NAFLD. We recently demonstrated that the chemokine receptor CXCR6 promotes hepatic NKT cell accumulation, thereby controlling inflammation in experimental NAFLD. In this study, we first investigated human biopsies (n = 20), confirming that accumulation of inflammatory cells such as macrophages is a hallmark of progressive NAFLD. Moreover, CXCR6 gene expression correlated with the inflammatory activity (ALT levels) in human NAFLD. We then tested the hypothesis that pharmacological inhibition of CXCL16 might hold therapeutic potential in NAFLD, using mouse models of acute carbon tetrachloride (CCl4)- and chronic methionine-choline-deficient (MCD) diet-induced hepatic injury. Neutralizing CXCL16 by i.p. injection of anti-CXCL16 antibody inhibited the early intrahepatic NKT cell accumulation upon acute toxic injury in vivo. Weekly therapeutic anti-CXCL16 administrations during the last 3 weeks of 6 weeks MCD diet significantly decreased the infiltration of inflammatory macrophages into the liver and intrahepatic levels of inflammatory cytokines like TNF or MCP-1. Importantly, anti-CXCL16 treatment significantly reduced fatty liver degeneration upon MCD diet, as assessed by hepatic triglyceride levels, histological steatosis scoring and quantification of lipid droplets. Moreover, injured hepatocytes up-regulated CXCL16 expression, indicating that scavenging functions of CXCL16 might be additionally involved in the pathogenesis of NAFLD. Targeting CXCL16 might therefore represent a promising novel therapeutic approach for liver inflammation and steatohepatitis.

Non‐alcoholic fatty liver disease (NAFLD) represents the most common liver disease in Western countries and often progresses to non‐alcoholic steatohepatitis (NASH) leading ultimately to liver fibrosis and liver cancer. The occurrence of hepatocyte cell death—so far characterized as hepatocyte apoptosis—represents a fundamental step from benign steatosis toward progressive steatohepatitis. In contrast, the function of RIP3‐dependent “necroptosis” in NASH and NASH‐induced fibrosis is currently unknown. We show that RIP3 is upregulated in human NASH and in a dietary mouse model of steatohepatitis. RIP3 mediates liver injury, inflammation, induction of hepatic progenitor cells/activated cholangiocytes, and liver fibrosis through a pathway suppressed by Caspase‐8. This function of RIP3 is mediated by a positive feedback loop involving activation of Jun‐(N)‐terminal Kinase (JNK). Furthermore, RIP3‐dependent JNK activation promotes the release of pro‐inflammatory mediators like MCP‐1, thereby attracting macrophages to the injured liver and further augmenting RIP3‐dependent signaling, cell death, and liver fibrosis. Thus, RIP3‐dependent necroptosis controls NASH‐induced liver fibrosis. This pathway might represent a novel and specific target for pharmacological strategies in patients with NASH. Synopsis RIP3‐dependent necroptosis mediates NASH‐induced liver fibrosis via activation of JNK, MCP‐1‐mediated recruitment of monocytes, and an expansion of intrahepatic biliary/progenitor cells. Caspase‐8 appears to suppress the deleterious effect of RIP3. RIP3 mediates liver injury in MCD‐diet‐induced NASH. RIP3—similar to Caspase‐8—does not affect CCl4‐induced liver fibrosis and thus might be a specific target in metabolic liver disease. Human NASH livers strongly express RIP3. Targeting RIP3 might represent a novel‐specific approach in human NASH. Graphical Abstract RIP3‐dependent necroptosis mediates NASH‐induced liver fibrosis via activation of JNK, MCP‐1‐mediated recruitment of monocytes, and an expansion of intrahepatic biliary/progenitor cells. Caspase‐8 appears to suppress the deleterious effect of RIP3.

In an attempt to further improve liver allograft utilization and outcome in orthotopic liver transplantation (OLT), a variety of clinical scoring systems have been developed. Here we aimed to comparatively investigate the association of the Balance-of-Risk (BAR), Survival-Outcomes-Following-Liver-Transplant (SOFT), Preallocation-Survival-Outcomes-Following-Liver-Transplant (pSOFT), Donor-Risk-Index (DRI), and the Eurotransplant-Donor-Risk-Index (ET-DRI) scores with short- and long-term outcome following OLT. We included 338 consecutive patients, who underwent OLT in our institution between May 2010 and November 2017. For each prognostic model, the optimal cutoff values were determined with the help of the Youden-index and their diagnostic accuracy for 90-day post OLT-mortality and major postoperative complications was measured by the area under the receiver operating characteristic curve (AUROC). Patient- and graft survival were analyzed using the Kaplan-Meier method and the log-rank test. Morbidity was assessed using the Clavien-Dindo classification and the Comprehensive-Complication-Index. BAR, SOFT, and pSOFT performed well above the conventional AUROC-threshold of 0.70 with good prediction of early mortality. Only BAR showed AUC>0.70 for both mortality and major morbidity. With the cutoffs of 14, 31, and 22 respectively for BAR, SOFT, and pSOFT, subgroup analysis showed significant differences (p<0.001) in morbidity and mortality, length of intensive care- and hospital-stay and early allograft dysfunction rates. Five-years patient survival was inferior in the high BAR, pSOFT, and SOFT groups. Out of all scores tested, the BAR-score had the best value in predicting both 90-day morbidity and mortality after OLT showing the highest AUCs. The pSOFT and SOFT scores demonstrated an acceptable accuracy in predicting 90-day morbidity and mortality. The used BAR, SOFT, and pSOFT cutoffs allowed the identification of patients at risk in terms of five-year patient survival. The DRI and ET-DRI scores have failed to predict recipient outcomes in the present setting.

This study aimed to observe the impact of the COVID-19 outbreak on acute general surgery in the first German “hotspot” regions of Heinsberg and Aachen, during the first months of the pandemic. The incidence and severity of acute appendicitis, acute cholecystitis and mechanical bowel obstruction, were compared between March and May 2020 and a control period (same months of the previous three years). Pre-, intra- and postoperative data was compared between three regional hospitals of Heinsberg and the closest maximum care, university hospital. A total of 592 operated patients were included, 141 belonging to the pandemic cohort and 451 to the historic cohort. The pandemic group showed higher rates of clinical peritonitis (38% vs. 27%, p = 0.015), higher rates of mean white blood cell count (13.2±4.4 /nl vs. 12.3±4.7 /nl, p = 0.044) and mean C-reactive protein (60.3±81.1 mg/l vs. 44.4±72.6 mg/l, p = 0.015) preoperatively. Specifically in patients with acute appendicitis, there were less patients with catarrhal appendicitis (23% vs. 35%, p = 0.021) and a tendency towards more advanced histological findings in the pandemic cohort. In the university hospital, a 42% reduction in acute operated cases was observed at the onset of the pandemic (n = 30 in 2020 vs. n = 52 in 2019), whereas in the peripheral hospitals of Heinsberg there was only a 10% reduction (n = 111 in 2020 vs. n = 123 in 2019). The onset of the COVID-19 pandemic in our region was accompanied by advanced preoperative and intraoperative findings in patients undergoing emergency general surgery. A greater reduction in acute operated surgical cases was observed at the university hospital, in contrast to the smaller hospitals of Heinsberg, suggesting a possible shift of emergency patients, requiring immediate operation, from maximum care hospital to the periphery.