Search

Cancers of the digestive system are major contributors to global cancer-associated morbidity and mortality, accounting for 35% of annual cases of cancer deaths. The etiologies, molecular features, and therapeutic management of these cancer entities are highly heterogeneous and complex. Over the last decade, genomic and functional studies have provided unprecedented insights into the biology of digestive cancers, identifying genetic drivers of tumor progression and key interaction points of tumor cells with the immune system. This knowledge is continuously translated into novel treatment concepts and targets, which are dynamically reshaping the therapeutic landscape of these tumors. In this review, we provide a concise overview of the etiology and molecular pathology of the six most common cancers of the digestive system, including esophageal, gastric, biliary tract, pancreatic, hepatocellular, and colorectal cancers. We comprehensively describe the current stage-dependent pharmacological management of these malignancies, including chemo-, targeted, and immunotherapy. For each cancer entity, we provide an overview of recent therapeutic advancements and research progress. Finally, we describe how novel insights into tumor heterogeneity and immune evasion deepen our understanding of therapy resistance and provide an outlook on innovative therapeutic strategies that will shape the future management of digestive cancers, including CAR-T cell therapy, novel antibody-drug conjugates and targeted therapies., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Most clinical information is encoded as free text, not accessible for quantitative analysis. This study presents an open-source pipeline using the local large language model (LLM) "Llama 2" to extract quantitative information from clinical text and evaluates its performance in identifying features of decompensated liver cirrhosis. The LLM identified five key clinical features in a zero- and one-shot manner from 500 patient medical histories in the MIMIC IV dataset. We compared LLMs of three sizes and various prompt engineering approaches, with predictions compared against ground truth from three blinded medical experts. Our pipeline achieved high accuracy, detecting liver cirrhosis with 100% sensitivity and 96% specificity. High sensitivities and specificities were also yielded for detecting ascites (95%, 95%), confusion (76%, 94%), abdominal pain (84%, 97%), and shortness of breath (87%, 97%) using the 70 billion parameter model, which outperformed smaller versions. Our study successfully demonstrates the capability of locally deployed LLMs to extract clinical information from free text with low hardware requirements., (© 2024. The Author(s).)

Background: Transcutaneous point-shear wave elastography (p-SWE) performed using an acoustic radiation force impulse can be used to quantify pancreatic stiffness in chronic pancreatitis (CP). We aimed to evaluate its usefulness to diagnose and monitor CP., Methods: 175 participants were included in this prospective study including patients with CP (n = 65), liver cirrhosis (LC; n = 60), alcohol abuse (n = 10) and healthy controls (n = 40). Point-shear wave elastography of the pancreas was performed and quantified as median shear wave velocity (SWV). In the same way, p-SWE of the spleen served as a marker of portal hypertension. The M-ANNHEIM Severity score was used as global marker for disease activity in CP., Results: Compared to healthy controls, pancreatic SWV was significantly elevated in CP (1.38 vs. 0.96 m/s; p < 0.0001, MWU-test). Pancreatic SWV was increased in alcoholic CP but not in hereditary CP. Receiver operating characteristic analysis revealed 1.2 m/s as the optimal cut-off to identify non-heredity-CP subjects (90% specificity; 81% sensitivity; 92% positive predictive value). Pancreatic SWV correlated significantly with the M-ANNHEIM Severity score, severity of CP-typical complications (both p < 0.05, linear regression analysis), morphological changes of the pancreas and need for hospital treatment (both p < 0.05, MWU-test) but not with exocrine or endocrine insufficiency. Pancreatic SWV >1.7 m/s was identified to predict M-ANNHEIM Severity score ≥11 points. Pancreatic SWV was also elevated in LC (1.42 m/s; p < 0.001), correlating with increased splenic SWV., Conclusion: Transcutaneous pancreatic p-SWE represents a bedside, cost-effective and non-invasive tool which adds valuable information to the process of diagnosing and monitoring CP. By portal hypertension, an increased pancreatic SWV must be expected., (© 2024 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.)

To predict outcome to combination bevacizumab (BVZ) therapy, we employed cell-free DNA (cfDNA) to determine chromosomal instability (CIN), nucleosome footprints (NF) and methylation profiles in metastatic colorectal cancer (mCRC) patients. Low-coverage whole-genome sequencing (LC-WGS) was performed on matched tumor and plasma samples, collected from 74 mCRC patients from the AC-ANGIOPREDICT Phase II trial (NCT01822444), and analysed for CIN and NFs. A validation cohort of plasma samples from the University Medical Center Mannheim (UMM) was similarly profiled. 61 AC-ANGIOPREDICT plasma samples collected before and following BVZ treatment were selected for targeted methylation sequencing. Using cfDNA CIN profiles, AC-ANGIOPREDICT samples were subtyped with 92.3% accuracy into low and high CIN clusters, with good concordance observed between matched plasma and tumor. Improved survival was observed in CIN-high patients. Plasma-based CIN clustering was validated in the UMM cohort. Methylation profiling identified differences in CIN-low vs. CIN high (AUC = 0.87). Moreover, significant methylation score decreases following BVZ was associated with improved outcome (p = 0.013). Analysis of CIN, NFs and methylation profiles from cfDNA in plasma samples facilitates stratification into CIN clusters which inform patient response to treatment., (© 2024. The Author(s).)

Loss of hepatocyte nuclear factor 4α (HNF4α) expression is frequently observed in end-stage liver disease and associated with loss of vital liver functions, thus increasing mortality. Loss of HNF4α expression is mediated by inflammatory cytokines, such as transforming growth factor (TGF)-β. However, details of how HNF4α is suppressed are largely unknown to date. Herein, TGF-β did not directly inhibit HNF4α but contributed to its transcriptional regulation by SMAD2/3 recruiting acetyltransferase CREB-binding protein/p300 to the HNF4α promoter. The recruitment of CREB-binding protein/p300 is indispensable for CCAAT/enhancer-binding protein α (C/EBPα) binding, another essential requirement for constitutive HNF4α expression in hepatocytes. Consistent with the in vitro observation, 67 of 98 patients with hepatic HNF4α expressed both phospho-SMAD2 and C/EBPα, whereas 22 patients without HNF4α expression lacked either phospho-SMAD2 or C/EBPα. In contrast to the observed induction of HNF4α, SMAD2/3 inhibited C/EBPα transcription. Long-term TGF-β incubation resulted in C/EBPα depletion, which abrogated HNF4α expression. Intriguingly, SMAD2/3 inhibitory binding to the C/EBPα promoter was abolished by insulin. Two-thirds of patients without C/EBPα lacked membrane glucose transporter type 2 expression in hepatocytes, indicating insulin resistance. Taken together, these data indicate that hepatic insulin sensitivity is essential for hepatic HNF4α expression in the condition of inflammation., Competing Interests: Disclosure Statement None declared., (Copyright © 2024 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Introduction: The Laurén classification is widely used for Gastric Cancer (GC) histology subtyping. However, this classification is prone to interobserver variability and its prognostic value remains controversial. Deep Learning (DL)-based assessment of hematoxylin and eosin (H&E) stained slides is a potentially useful tool to provide an additional layer of clinically relevant information, but has not been systematically assessed in GC., Objective: We aimed to train, test and externally validate a deep learning-based classifier for GC histology subtyping using routine H&E stained tissue sections from gastric adenocarcinomas and to assess its potential prognostic utility., Methods: We trained a binary classifier on intestinal and diffuse type GC whole slide images for a subset of the TCGA cohort (N = 166) using attention-based multiple instance learning. The ground truth of 166 GC was obtained by two expert pathologists. We deployed the model on two external GC patient cohorts, one from Europe (N = 322) and one from Japan (N = 243). We assessed classification performance using the Area Under the Receiver Operating Characteristic Curve (AUROC) and prognostic value (overall, cancer specific and disease free survival) of the DL-based classifier with uni- and multivariate Cox proportional hazard models and Kaplan-Meier curves with log-rank test statistics., Results: Internal validation using the TCGA GC cohort using five-fold cross-validation achieved a mean AUROC of 0.93 ± 0.07. External validation showed that the DL-based classifier can better stratify GC patients' 5-year survival compared to pathologist-based Laurén classification for all survival endpoints, despite frequently divergent model-pathologist classifications. Univariate overall survival Hazard Ratios (HRs) of pathologist-based Laurén classification (diffuse type versus intestinal type) were 1.14 (95% Confidence Interval (CI) 0.66-1.44, p-value = 0.51) and 1.23 (95% CI 0.96-1.43, p-value = 0.09) in the Japanese and European cohorts, respectively. DL-based histology classification resulted in HR of 1.46 (95% CI 1.18-1.65, p-value < 0.005) and 1.41 (95% CI 1.20-1.57, p-value < 0.005), in the Japanese and European cohorts, respectively. In diffuse type GC (as defined by the pathologist), classifying patients using the DL diffuse and intestinal classifications provided a superior survival stratification, and demonstrated statistically significant survival stratification when combined with pathologist classification for both the Asian (overall survival log-rank test p-value < 0.005, HR 1.43 (95% CI 1.05-1.66, p-value = 0.03) and European cohorts (overall survival log-rank test p-value < 0.005, HR 1.56 (95% CI 1.16-1.76, p-value < 0.005))., Conclusion: Our study shows that gastric adenocarcinoma subtyping using pathologist's Laurén classification as ground truth can be performed using current state of the art DL techniques. Patient survival stratification seems to be better by DL-based histology typing compared with expert pathologist histology typing. DL-based GC histology typing has potential as an aid in subtyping. Further investigations are warranted to fully understand the underlying biological mechanisms for the improved survival stratification despite apparent imperfect classification by the DL algorithm., (© 2023. The Author(s).)

Background: During the COVID-19 pandemic, there was a decrease in the rates of diagnosis and treatment of cancer. However, only a few detailed analyses have been made to date regarding the effect of the pandemic on the care of cancer patients in Germany. Such studies are needed as the basis for well-founded recommendations on health-care delivery priorities during pandemics and other, comparable situations of crisis., Methods: This review is based on publications that were retrieved by a selective search of the literature for controlled studies from Germany on the effects of the pandemic on colonoscopies, first diagnoses of colorectal cancer (CRC), surgical procedures for CRC, and CRC-related mortality., Results: Compared to 2019, the rate of screening colonoscopies performed by physicians in private practice was 1.6% higher in 2020 and 4.3% higher in 2021. On the other hand, the rate of diagnostic colonoscopies in the inpatient setting was 15,7% lower in 2020, while that of therapeutic colonoscopies was 11.7% lower. According to the data evaluated here, first diagnoses of CRC were 2.1% less common in January to September in 2020 than they had been in 2019; according to routine data collected by the statutory health insurance provider GRK, surgery for CRC was 10% less common in 2020 than in 2019. With regard to mortality, sufficient data from Germany were lacking to draw definite conclusions. International modeling data suggest an increase in mortality due to decreased colorectal screening rates during the pandemic that may at least be partially compensated for by intensified screening strategies following the pandemic., Conclusion: Three years after the onset of the COVID-19 pandemic, there is still only a limited evidence base for an evaluation of the effects of the pandemic on medical care and on the outcomes of patients with CRC in Germany. The implementation of central data and research infrastructures will be necessary for further study of the long-term effects of this pandemic, as well as to enable optimal preparedness for future crisis situations.

The human liver has a remarkable capacity to regenerate and thus compensate over decades for fibrosis caused by toxic chemicals, drugs, alcohol, or malnutrition. To date, no protective mechanisms have been identified that help the liver tolerate these repeated injuries. In this study, we revealed dysregulation of lipid metabolism and mild inflammation as protective mechanisms by studying longitudinal multi-omic measurements of liver fibrosis induced by repeated CCl 4 injections in mice (n = 45). Based on comprehensive proteomics, transcriptomics, blood- and tissue-level profiling, we uncovered three phases of early disease development-initiation, progression, and tolerance. Using novel multi-omic network analysis, we identified multi-level mechanisms that are significantly dysregulated in the injury-tolerant response. Public data analysis shows that these profiles are altered in human liver diseases, including fibrosis and early cirrhosis stages. Our findings mark the beginning of the tolerance phase as the critical switching point in liver response to repetitive toxic doses. After fostering extracellular matrix accumulation as an acute response, we observe a deposition of tiny lipid droplets in hepatocytes only in the Tolerant phase. Our comprehensive study shows that lipid metabolism and mild inflammation may serve as biomarkers and are putative functional requirements to resist further disease progression., (© 2023. The Author(s).)

Background: Small bowel adenocarcinoma (SBA) remains a rare malignancy accounting for less than 5% of all the gastrointestinal tract cancers. However, only limited data and expert guidelines are available for this entity. As a result, treatment concepts are predominantly derived from colorectal cancer., Methods: To substantiate data on the course of disease, diagnosis and treatment of SBA, we performed a population-based analysis from a Bavarian population of 2.2 million people., Results: We identified 223 patients with SBA. Mean age at diagnosis was 67.8 years and patients were diagnosed rather late (34.5% UICC stage IV). Largest proportion of these patients were diagnosed with adenocarcinoma of the duodenum (132 patients, 59.2%) and most patients were diagnosed with late stage cancer, stage IV (70 patients, 31.4%). With respect to treatment, most patients underwent primary surgery (187 patients, 84.6%). Systemic therapy seemed to have an impact in UICC stage IV patients but not in UICC stage IIB or III. The 5-year survival rate was 29.0%. This was significantly less compared to colon cancer in the same cohort, which was 50.0%. Furthermore, median survival of patients with small bowel cancer was only 2.0 years (95% CI 1.4-2.5) compared to 4.9 years (95% CI 4.8-5.1) of patients with colon cancer., Conclusion: SBA showed a distinct epidemiology compared to colon cancer. Thus, data acquisition particularly on systemic treatment are paramount, with the objective to complement the available guidelines., (© 2022. The Author(s).)

Background and Aims: Primary liver cancer (PLC) ranks among of the most common cancers worldwide. Within this group, a minority of cases displays characteristics of both hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), known as combined hepatocellular cholangiocarcinoma (cHCC- CCA). Currently, there is no specific standardized therapy for these mixed tumors. Therefore, the aim of our study was to analyze the clinical course, treatment and outcome of cHCC-CCA patients in a European population-based registry., Methods: We investigated 9,144 patients with PLC (6,622 HCC, 2,356 iCCA, and 166 cHCC-CCA) diagnosed between 2009 and 2020. All data were obtained from Clinical Cancer Registry of Baden-Württemberg (BW), Germany., Results: In all three groups patients were predominantly male (82%, 57%, and 68% for HCC, iCCA and cHCC-CCA groups, respectively). 48% of cHCC-CCA patients were diagnosed as stage IV cancers, which was more than for HCC (31%) but less compared to CCA (64%). Overall median survival of cHCC-CCA patients was worse compared to HCC (9-13 months vs. 15.5 months, p<0.001) and rather comparable to CCA (11.8 months)., Conclusions: Our data demonstrated that cHCC-CCA tumors appear to have a distinct clinical course with worse overall survival compared to HCC. Thus, identification of these cancers by histopathology is essential in order to further characterize this tumor entity and to provide accurate treatment to these patients.

The world is witnessing a global increase in the urban population, particularly in developing Asian and African countries. Concomitantly, the global burden of non-communicable diseases (NCDs) is rising, markedly associated with the changing landscape of lifestyle and environment during urbanization. Accumulating studies have revealed the role of the gut microbiome in regulating the immune and metabolic homeostasis of the host, which potentially bridges external factors to the host (patho-)physiology. In this review, we discuss the rising incidences of NCDs during urbanization and their links to the compositional and functional dysbiosis of the gut microbiome. In particular, we elucidate the effects of urbanization-associated factors (hygiene/pollution, urbanized diet, lifestyles, the use of antibiotics, and early life exposure) on the gut microbiome underlying the pathogenesis of NCDs. We also discuss the potential and feasibility of microbiome-inspired and microbiome-targeted approaches as novel avenues to counteract NCDs, including fecal microbiota transplantation, diet modulation, probiotics, postbiotics, synbiotics, celobiotics, and precision antibiotics.

Lung carcinoids are neuroendocrine tumors representing 1 to 2% of lung cancers. This study outlines the case of a patient with a metastatic lung atypical carcinoid who presented with a pleural effusion and progression of liver metastases after developing resistance to conventional treatments. Personalized functional profiling (PFP), i.e. drug screening, was performed in ex-vivo spheroids obtained from the patient's liver metastasis to identify potential therapeutic options. The drug screening results revealed cediranib, an antiangiogenic drug, as a hit drug for this patient, from a library of 66 Food and Drug Administration (FDA)-approved and investigational drugs. Based on the PFP results and the reported evidence of clinical efficacy of bevacizumab and capecitabine combination in gastro-intestinal neuroendocrine tumors, this combination was given to the patient. Four months later, the pleural effusion and pleura carcinosis regressed and the liver metastasis did not progress. The patient experienced 2 years of a stable disease under the PFP-guided personalized treatment.

Background & Aims: We investigated the efficacy and safety of immune checkpoint inhibitor (ICI) rechallenge in patients with hepatocellular carcinoma (HCC) who received ICI-based therapies in a previous systemic line., Methods: In this international, retrospective multicenter study, patients with HCC who received at least two lines of ICI-based therapies (ICI-1, ICI-2) at 14 institutions were eligible. The main outcomes included best overall response and treatment-related adverse events., Results: Of 994 ICI-treated patients screened, a total of 58 patients (male, n = 41; 71%) with a mean age of 65.0±9.0 years were included. Median systemic treatment lines of ICI-1 and ICI-2 were 1 (range, 1-4) and 3 (range, 2-9), respectively. ICI-based therapies used at ICI-1 and ICI-2 included ICI alone (ICI-1, n = 26, 45%; ICI-2, n = 4, 7%), dual ICI regimens (n = 1, 2%; n = 12, 21%), or ICI combined with targeted therapies/anti-VEGF (n = 31, 53%; n = 42, 72%). Most patients discontinued ICI-1 due to progression (n = 52, 90%). Objective response rate was 22% at ICI-1 and 26% at ICI-2. Responses at ICI-2 were also seen in patients who had progressive disease as best overall response at ICI-1 (n = 11/21; 52%). Median time-to-progression at ICI-1 and ICI-2 was 5.4 (95% CI 3.0-7.7) months and 5.2 (95% CI 3.3-7.0) months, respectively. Treatment-related adverse events of grade 3-4 at ICI-1 and ICI-2 were observed in 9 (16%) and 10 (17%) patients, respectively., Conclusions: ICI rechallenge was safe and resulted in a treatment benefit in a meaningful proportion of patients with HCC. These data provide a rationale for investigating ICI-based regimens in patients who progressed on first-line immunotherapy in prospective trials., Impact and Implications: Therapeutic sequencing after first-line immune checkpoint inhibitor (ICI)-based therapy for advanced hepatocellular carcinoma (HCC) remains a challenge as no available second-line treatment options have been studied in immunotherapy-pretreated patients. Particularly, the role of ICI rechallenge in patients with HCC is unclear, as data from prospective trials are lacking. We investigated the efficacy and safety of ICI-based regimens in patients with HCC pretreated with immunotherapy in a retrospective, international, multicenter study. Our data provide the rationale for prospective trials investigating the role of ICI-based regimens in patients who have progressed on first-line immunotherapy., Competing Interests: BS received travel support from AbbVie, Ipsen and Gilead. DR has received advisory fees from Bayer and speakers fees as well as travel grants from Ipsen. He is an investigator for Bayer, BMS, Lilly, AstraZeneca and Roche. SP has nothing to disclose. ML has nothing to disclose. KP has nothing to disclose. TP received consulting fees from IQVIA and Bayer; and institutional research funding from Lilly, Roche, Bayer. AC has nothing to disclose. TWF has nothing to disclose. JVF has received advisory board fees from Roche. KS served as consultant for Ipsen and Bayer, and conducts studies for Bayer, Roche, Lilly, MSD, and BMS. VH has nothing to disclose. FF received travel support from Abbvie and Novartis, and speaker fees from Abbvie and MSD. AD has nothing to disclose. ARS has served at advisory boards and received consulting honoraria from AMGEN, AAA, Bayer, BMS, IPSEN, Lilly, Merck, MSD, Pfizer, Roche, Sanofi, and Servier. KS has nothing to disclose. PR has nothing to disclose. BiS has nothing to disclose. MPE received consulting honoraria from BMS and MSD. AT received consulting honoraria and/or lecture fees from Bayer, IPSEN, Lilly, BMS, Eisai Novartis, Roche, Intercept, Falk, AbbVie, and Gilead. He received travel grants from IPSEN, AbbVie, and Gilead. He is an investigator for IPSEN and GILEAD. AngD received advisory board fees from Roche and BMS, and travel support from Roche and Ipsen. FH received travel support from Bayer, Abbvie, and Gilead. LB has nothing to disclose. ABP has nothing to disclose. DH received research support from Pfizer. MV received speaker fees from Nordic Pharma, Ipsen, Merck Serono, Bayer Vital, Lilly, AstraZeneca, Merck Sharp & Dohme (MSD), Bristol-Myers Squibb (BMS), and Sirtex, advisory board fees from Roche, Ipsen, Lilly, Nordic Pharma, Bristol-Myers Squibb (BMS), Merck Sharp & Dohme (MSD), Eisai, AstraZeneca and Amgen, research grants from Sirtex. FS has nothing to disclose. MT received speaker fees from Bristol-Myers Squibb (BMS), Falk Foundation, Gilead, Intercept and Merck Sharp & Dohme (MSD); advisory board fees from Abbvie, Albireo, Boehringer Ingelheim, BiomX, Falk Pharma GmbH, GENFIT, Gilead, Intercept, Janssen, MSD, Novartis, Phenex, Regulus and Shire; travel grants from AbbVie, Falk, Gilead, and Intercept; and research grants from Albireo, CymaBay, Falk, Gilead, Intercept, MSD, and Takeda. He is also coinventor of patents on the medical use of norUDCA filed by the Medical University of Graz. ADA received travel support and consultancy fees from Roche. CAMF has nothing to disclose. DJP received lecture fees from ViiV Healthcare, Bayer Healthcare, BMS, Roche, Eisai, Falk Foundation, travel expenses from BMS and Bayer Healthcare; consulting fees for Mina Therapeutics, EISAI, Roche, DaVolterra, Mursla, Exact Sciences and Astra Zeneca; research funding (to institution) from MSD and BMS. MPR is advisor/consultant for Astra Zeneca, Bayer, BMS, Eisai, Ipsen, Lilly, MSD, and Roche; he served as a speaker for Bayer, Eisai, Ipsen, Lilly, and Roche; he is an investigator for Bayer, BMS, Eisai, Exelixis, Lilly, and Roche. JFD received compensations as a member of scientific advisory boards of Abbvie, Bayer, Bristol–Myers Squibb, Falk, Galapagos, Genfit, Genkyotex, Gilead Sciences, HepaRegenix, Intercept, Lilly, Merck, and Novartis. AW received compensations as a member of scientific advisory boards for BMS, Wako and Sanofi. He served as a speaker for Leo Pharma, Eisai, Ipsen and Roche and received travel support from Merck and Servier. AEK has received consulting fees from Abbvie, AstraZeneca, Bayer, CymaBay, Escient, FMC, Gilead, GSK, Guidepoint, Intercept, Mirum, Medscape, MSD, Myr, Viofor; lecture fees from Abbvie, AOP Orphan, Bayer, BMS, CMS, CymaBay, Eisai, Falk, Gilead, GSK, Intercept, Janssen, Newbridge, Novartis, Lilly, MSD, Zambon; and institutional research funding from Intercept. AGS served on advisory boards and as a consultant for Genentech, AstraZeneca, Eisai, Bayer, Exelixis, TARGET RWE, FujiFilm Medical Sciences, Glycotest, Exact Sciences, GRAIL, and Freenome. ENDT has served as a paid consultant for AstraZeneca, Bayer, BMS, EISAI, Eli Lilly & Co, MSD, Mallinckrodt, Omega, Pfizer, IPSEN, Terumo and Roche. He has received reimbursement of meeting attendance fees and travel expenses from Arqule, Astrazeneca, BMS, Bayer, Celsion and Roche, and lecture honoraria from BMS and Falk. He has received third-party funding for scientific research from Arqule, AstraZeneca, BMS, Bayer, Eli Lilly, and IPSEN and Roche. LR has received consulting fees from Amgen, ArQule, AstraZeneca, Basilea, Bayer, BMS, Celgene, Eisai, Exelixis, Genenta, Hengrui, Incyte, Ipsen, IQVIA, Lilly, MSD, Nerviano Medical Sciences, Roche, Sanofi, Servier, Taiho Oncology, Zymeworks; lectures fees from AbbVie, Amgen, Bayer, Eisai, Gilead, Incyte, Ipsen, Lilly, Merck Serono, Roche, Sanofi, Servier; travel expenses from AstraZeneca; and institutional research funding from Agios, ARMO BioSciences, AstraZeneca, BeiGene, Eisai, Exelixis, Fibrogen, Incyte, Ipsen, Lilly, MSD, Nerviano Medical Sciences, Roche, Zymeworks. MP is an investigator for Bayer, BMS, Eisai, Ipsen, Lilly, and Roche; he received speaker honoraria from Bayer, BMS, Eisai, Lilly, MSD, and Roche; he is a consultant for Bayer, BMS, Eisai, Ipsen, Lilly, MSD, and Roche; he received travel support from Bayer, BMS, and Roche. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2022 The Author(s).)

Background: Extraintestinal symptoms are common in inflammatory bowel diseases (IBD) and include depression and fatigue. These are highly prevalent especially in active disease, potentially due to inflammation-mediated changes in the microbiota-gut-brain axis. The aim of this study was to investigate the associations between structural and functional microbiota characteristics and severity of fatigue and depressive symptoms in patients with active IBD., Methods: We included clinical data of 62 prospectively enrolled patients with IBD in an active disease state. Patients supplied stool samples and completed the questionnaires regarding depression and fatigue symptoms. Based on taxonomic and functional metagenomic profiles of faecal gut microbiota, we used Bayesian statistics to investigate the associative networks and triangle motifs between bacterial genera, functional modules and symptom severity of self-reported fatigue and depression., Results: Associations with moderate to strong evidence were found for 3 genera (Odoribacter, Anaerotruncus and Alistipes) and 3 functional modules (pectin, glycosaminoglycan and central carbohydrate metabolism) with regard to depression and for 4 genera (Intestinimonas, Anaerotruncus, Eubacterium and Clostridiales g.i.s) and 2 functional modules implicating amino acid and central carbohydrate metabolism with regard to fatigue., Conclusions: This study provides the first evidence of association triplets between microbiota composition, function and extraintestinal symptoms in active IBD. Depression and fatigue were associated with lower abundances of short-chain fatty acid producers and distinct pathways implicating glycan, carbohydrate and amino acid metabolism. Our results suggest that microbiota-directed therapeutic approaches may reduce fatigue and depression in IBD and should be investigated in future research., (© 2022. The Author(s).)

Background and Aims: Liver involvement in sarcoidosis may occur in up to 60% of all patients. As many patients experience only minor symptoms, a high number of undiagnosed cases must be assumed. In order to successfully identify patients with hepatic sarcoidosis, a throughout characterization of these patients and their course of disease is necessary., Methods: We collected 40 patients from four German centers to evaluate current treatment standards and course of disease. All of our patients underwent liver biopsy with histologically proven granulomatous hepatitis., Results: Detailed characterization of our patients showed an overall benign course of disease. Treatment was very diverse with glucocorticoids for 1 year in 55% (22/40), 5-10 years in 18% (7/40), and permanently in 18% (7/40). Other treatments included disease-modifying anti-rheumatic drugs (DMARDs), the conventional non-biological type in 53% of all patients (of these 81% received azathioprine, 46% metotrexate, 10% hydroxychloroquine, 10% mycophenolate mofetil and 10% cyclophosphamide and biologicals in 8%. Despite these very diverse treatments, patients generally showed slow progression of the disease. Two patients died. None of our patients received a liver transplantation., Conclusions: Patients received diverse treatments and generally showed slow progression of the disease. Based on our experience, we proposed a diagnostic work up and surveillance strategy as a basis for future, prospective register studies.

In addition to the poor prognosis, excruciating abdominal pain is a major challenge in pancreatic cancer. Neurotropism appears to be the underlying mechanism leading to neuronal invasion. However, there is a lack of animal models suitable for translationally bridging in vitro findings with clinical trials. We characterized KPC (Kras G12D/+ ; Trp53 R172H/+ ; P48-Cre) and KPPC (Kras G12D/+ ; Trp53 R172H/R172H ; P48-Cre) mice with genetically determined pancreatic ductal adenocarcinoma (PDAC) and compared them with an orthotopic pancreatic cancer mouse model, healthy littermates and human tissue. We analyzed behavioral correlates of cancer-associated pain and well-being, and studied neuronal remodeling and cytokine expression. Histologically, we found similarities between KPC and KPPC tissue with human samples. Compared to healthy littermates, we detect nerve fiber hypertrophy, which was not restricted to a certain fiber type. Interestingly, while KPPC mice showed significantly reduced well-being, KPC mice emerged to be better suited for studying long-lasting cancer pain that emerges over a slow course of tumor progression. To address the neuroinflammatory correlate of loss of well-being, we studied cytokine levels in KPPC mice and observed a significant upregulation of CXCL16, TNFRSF5, CCL24, CXCL1, CCL22, CLL20 and CX2CL1. In summary, we demonstrate that the KPC mouse model is best suited to studying cancer pain, whereas the KPPC model can be employed to study cancer-associated reduction in well-being.

The human gastrointestinal tract harbours an abundance of viruses, collectively known as the gut virome. The gut virome is highly heterogeneous across populations and is linked to geography, ethnicity, diet, lifestyle, and urbanisation. The currently known function of the gut virome varies greatly across human populations, and much remains unknown. We review current literature on the human gut virome, and the intricate trans-kingdom interplay among gut viruses, bacteria, and the mammalian host underlying health and diseases. We summarise evidence on the use of the gut virome as diagnostic markers and a therapeutic target. We shed light on novel avenues of microbiome-inspired diagnosis and therapies. We also review pre-clinical and clinical studies on gut virome-rectification-based therapies, including faecal microbiota transplantation, faecal virome transplantation, and refined phage therapy. Our review suggests that future research effort should focus on unravelling the mechanisms exerted by gut viruses/phages in human pathophysiology, and on developing phage-prompted precision therapies., Competing Interests: Declaration of interests The authors declare no conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Patient-derived organoids resemble the biology of tissues and tumors, enabling ex vivo modeling of human diseases. They have heterogeneous morphologies with unclear biological causes and relationship to treatment response. Here, we use high-throughput, image-based profiling to quantify phenotypes of over 5 million individual colorectal cancer organoids after treatment with >500 small molecules. Integration of data using multi-omics modeling identifies axes of morphological variation across organoids: Organoid size is linked to IGF1 receptor signaling, and cystic vs. solid organoid architecture is associated with LGR5 + stemness. Treatment-induced organoid morphology reflects organoid viability, drug mechanism of action, and is biologically interpretable. Inhibition of MEK leads to cystic reorganization of organoids and increases expression of LGR5, while inhibition of mTOR induces IGF1 receptor signaling. In conclusion, we identify shared axes of variation for colorectal cancer organoid morphology, their underlying biological mechanisms, and pharmacological interventions with the ability to move organoids along them., (© 2022. The Author(s).)

Background: The overall survival of patients with advanced and refractory oesophageal squamous cell carcinoma, mostly aged 65 years and older, is poor. Treatment with PD-1 antibodies showed improved progression-free survival and overall survival. We assessed the safety and efficacy of combined nivolumab and ipilimumab therapy in this population., Methods: This multicentre, open-label, phase 2 trial done in 32 sites in Germany included patients aged 65 years and older with oesophageal squamous cell carcinoma and disease progression or recurrence following first-line therapy. Patients were treated with nivolumab (240 mg fixed dose once every 2 weeks, intravenously) in the safety run-in phase and continued with nivolumab and ipilimumab (nivolumab 240 mg fixed dose once every 2 weeks and ipilimumab 1 mg/kg once every 6 weeks, intravenously). The primary endpoint was overall survival, which was compared with a historical cohort receiving standard chemotherapy in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT03416244., Findings: Between March 2, 2018, and Aug 20, 2020, we screened 75 patients with advanced oesophageal squamous cell carcinoma. We enrolled 66 patients (50 [76%] men and 16 [24%] women; median age 70·5 years [IQR 67·0-76·0]), 44 (67%) of whom received combined nivolumab and ipilimumab therapy and 22 (33%) received nivolumab alone. Median overall survival time at the prespecified data cutoff was 7·2 months (95% CI 5·7-12·4) and significantly higher than in a historical cohort receiving standard chemotherapy (p=0·0063). The most common treatment-related adverse events were fatigue (12 [29%] of 42), nausea (11 [26%]), and diarrhoea (ten [24%]). Grade 3-5 treatment-related adverse events occurred in 13 (20%) of 66 patients. Treatment-related death occurred in one patient with bronchiolitis obliterans while on nivolumab and ipilimumab treatment., Interpretation: Patients aged at least 65 years, with advanced oesophageal squamous cell carcinoma might benefit from combined nivolumab and ipilimumab therapy in second-line treatment., Funding: Bristol Myers Squibb., Competing Interests: Declaration of interests MPE reports receiving funding to conduct the trial from AIO Studien, the regulatory sponsor of the trial, and serving as an advisor with Bristol Myers Squibb. NMB reports receiving research funding and receipt of equipment from Deutsche Forschungsgemeinschaft. RH reports serving as an advisor with Amgen, Astra Zeneca, Bristol Myers Squibb, Boehringer, Daichi, Lilly, Merck, MSD, Pierre Fabre, Roche, and Servier; honoraria for lectures and presentations from Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer, Daichi, Lilly, medac, Merck, MSD, Pierre Fabre, Roche, Saladax, Sanofi, and Servier; and consulting fees from Amgen, Astra Zeneca, Bayer, BMS, Boehringer, Daichi, Lilly, medac, Merck, MSD, Pierre Fabre, Roche, Saladax, Sanofi, and Servier. AV reports serving as an advisor with Roche, Bayer, Bristol Myers Squibb, Lilly, Eisai, AstraZeneca, IPSEN, MSD, Sirtex, BTG, Servier, Terumo, and Imaging Equipment; and consulting fees and honoraria for lectures from Roche, Bayer, Bristol Myers Squibb, Lilly, Eisai, Astra Zeneca, IPSEN, MSD, Sirtex, BTG, Servier, Terumo, and Imaging Equipment. RJ reports receiving consulting fees from Roche and Bayer; payments for lectures and presentations from Dr Falk Pharma and Bristol Myers Squibb; for writing of manuscripts from Boston Scientific and Springer Nature; serving as an advisor with Heidelberg University Hospital; and leading the Endoscopy section of the German Society of Gastroenterology. PTP reports receiving consulting fees from Bristol Myers Squibb, AstraZeneca, and MSD. TGa reports receiving honoraria from Bristol Myers Squibb, MSD, and Roche for presentations and advisory functions. JNK reports receiving consulting fees from Owkin and Panakeia as well as honoraria for lectures from MSD and Eisai. MM reports employment with AIO Studien, who was the regulatory sponsor of the trial. NH reports serving as an advisor with Bristol Myers Squibb. All other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Microsatellite instability (MSI)/mismatch repair deficiency (dMMR) is a key genetic feature which should be tested in every patient with colorectal cancer (CRC) according to medical guidelines. Artificial intelligence (AI) methods can detect MSI/dMMR directly in routine pathology slides, but the test performance has not been systematically investigated with predefined test thresholds., Method: We trained and validated AI-based MSI/dMMR detectors and evaluated predefined performance metrics using nine patient cohorts of 8343 patients across different countries and ethnicities., Results: Classifiers achieved clinical-grade performance, yielding an area under the receiver operating curve (AUROC) of up to 0.96 without using any manual annotations. Subsequently, we show that the AI system can be applied as a rule-out test: by using cohort-specific thresholds, on average 52.73% of tumors in each surgical cohort [total number of MSI/dMMR = 1020, microsatellite stable (MSS)/ proficient mismatch repair (pMMR) = 7323 patients] could be identified as MSS/pMMR with a fixed sensitivity at 95%. In an additional cohort of N = 1530 (MSI/dMMR = 211, MSS/pMMR = 1319) endoscopy biopsy samples, the system achieved an AUROC of 0.89, and the cohort-specific threshold ruled out 44.12% of tumors with a fixed sensitivity at 95%. As a more robust alternative to cohort-specific thresholds, we showed that with a fixed threshold of 0.25 for all the cohorts, we can rule-out 25.51% in surgical specimens and 6.10% in biopsies., Interpretation: When applied in a clinical setting, this means that the AI system can rule out MSI/dMMR in a quarter (with global thresholds) or half of all CRC patients (with local fine-tuning), thereby reducing cost and turnaround time for molecular profiling., Competing Interests: Disclosure JNK declares consulting services for Owkin, France and Panakeia, UK. TJB reports owning a company that develops mobile apps, outside the scope of the submitted work (Smart Health Heidelberg GmbH, Handschuhsheimer Landstr. 9/1, 69120 Heidelberg). PQ has had paid roles in the English NHS bowel cancer screening programme over the course of this study. SBG is co-founder of Brogent International LLC with equity, outside the scope of the submitted work. All other authors have declared no conflicts of interest., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Targeting cancer hallmarks is a cardinal strategy to improve antineoplastic treatment. However, cross-talk between signaling pathways and key oncogenic processes frequently convey resistance to targeted therapies. The p53 and Wnt pathway play vital roles for the biology of many tumors, as they are critically involved in cancer onset and progression. Over recent decades, a high level of interaction between the two pathways has been revealed. Here, we provide a comprehensive overview of molecular interactions between the p53 and Wnt pathway discovered in cancer, including complex feedback loops and reciprocal transactivation. The mutational landscape of genes associated with p53 and Wnt signaling is described, including mutual exclusive and co-occurring genetic alterations. Finally, we summarize the functional consequences of this cross-talk for cancer phenotypes, such as invasiveness, metastasis or drug resistance, and discuss potential strategies to pharmacologically target the p53-Wnt interaction.

Colorectal cancer (CRC) is a major contributor to cancer-associated morbidity worldwide and over one-third of CRC is located in the rectum. Neoadjuvant chemoradiotherapy (nCRT) followed by surgical resection is commonly applied to treat locally advanced rectal cancer (LARC). In this review, we summarize current and novel concepts of neoadjuvant therapy for LARC such as total neoadjuvant therapy and describe how these developments impact treatment response. Moreover, as response to nCRT is highly divergent in rectal cancers, we discuss the role of potential predictive biomarkers. We review recent advances in biomarker discovery, from a clinical as well as a histopathological and molecular perspective. Furthermore, the role of emerging predictive biomarkers derived from the tumor environment such as immune cell composition and gut microbiome is presented. Finally, we describe how different tumor models such as patient-derived cancer organoids are used to identify novel predictive biomarkers for chemoradiotherapy (CRT) in rectal cancer., Competing Interests: Conflict of interest statement: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2022.)

Globally, metastatic colorectal cancer is one of the leading causes for cancer-related death. Treatment limited to conventional chemotherapeutics extended life for only a few months. However, advances in surgical approaches and medical treatment regimens have greatly increased survival, even leading to long-term remission in selected patients. Advances in multiomics analysis of tumors have built a foundation for molecular-targeted therapies. Furthermore, immunotherapies are on the edge of revolutionizing oncological practice. This review summarizes recent advances in the growing toolbox of personalized treatment for patients with metastatic colorectal cancer. We provide an overview of current multimodal therapy and explain novel immunotherapy and targeted therapy approaches in detail. We emphasize clinically relevant therapies, such as inhibitors of MAPK signaling, and give recommendations for clinical practice. Finally, we describe the potential predictive impact of molecular subtypes and provide an outlook on novel concepts, such as functional precision medicine., Competing Interests: Conflict of interest statement: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2022.)

Colorectal cancer (CRC) is a high-incidence malignancy worldwide which still needs better therapy options. Therefore, the aim of the present study was to investigate the responses of normal or malignant human intestinal epithelium to bone morphogenetic protein (BMP)-9 and to find out whether the application of BMP-9 to patients with CRC or the enhancement of its synthesis in the liver could be useful strategies for new therapy approaches. In silico analyses of CRC patient cohorts (TCGA database) revealed that high expression of the BMP-target gene ID1, especially in combination with low expression of the BMP-inhibitor noggin, is significantly associated with better patient survival. Organoid lines were generated from human biopsies of colon cancer (T-Orgs) and corresponding non-malignant areas (N-Orgs) of three patients. The N-Orgs represented tumours belonging to three different consensus molecular subtypes (CMS) of CRC. Overall, BMP-9 stimulation of organoids promoted an enrichment of tumour-suppressive gene expression signatures, whereas the stimulation with noggin had the opposite effects. Furthermore, treatment of organoids with BMP-9 induced ID1 expression (independently of high noggin levels), while treatment with noggin reduced ID1. In summary, our data identify the ratio between ID1 and noggin as a new prognostic value for CRC patient outcome. We further show that by inducing ID1, BMP-9 enhances this ratio, even in the presence of noggin. Thus, BMP-9 is identified as a novel target for the development of improved anti-cancer therapies of patients with CRC., (© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Background and Aims: Colorectal adenomas are precursor lesions for colorectal cancer (CRC), a major cause of cancer-related death. Despite all molecular insights, there are still unknown variables in the development of CRC as well as uncertainties regarding adenoma recurrence after resection. We aimed to characterize the expression of docking protein 1 (DOK1) and myotubularin-related protein 7 (MTMR7), which share inhibiting functions on EGFR-RAS-signalling, a major oncogenic driver in CRC, and their association with clinical variables and adenoma recurrence., Methods: This observational study is based on clinical data obtained from patients who underwent routine endoscopy and consecutive follow-up examinations. Immunohistochemistry was conducted both in dysplastic tissue and adjacent non-dysplastic mucosa followed by microscopical assessment. Recurrence was differentiated between local, segmental and distant relapse., Results: A total of 56 patients (23 females) gathering 96 adenomas/polyps were included. 36 patients experienced a metachronous lesion, 23 patients had simultaneous lesions in their index endoscopy. Female patients showed lower levels of MTMR7 in adenomas (p=0.0318). Adenomas of young patients showed lower DOK1 than those of older patients (p=0.0469). Big adenomas showed a higher expression of DOK1 than small lesions (p=0.0044). In serrated lesions, DOK1 was reduced (p=0.0026) and correlated with the quantity of lesions (p < 0.001). MTMR7 was significantly reduced in distant (p=0.05) and local segmental recurrence (p=0.0362), while DOK1 showed higher expression in recurrence (p=0.0291)., Conclusions: We found ambivalent results regarding the role of the markers as potential tumor suppressors, implying a context-dependent function of these molecules which might change in the course of time. DOK1 may play an inhibiting role in the serrated pathway. Remarkably, molecular markers have the potential to predict recurrence, since a combined expression analysis of high DOK1 and low MTMR7 correlated with the likelihood of segmental adenoma recurrence.

Background: Response to immunotherapy in gastric cancer is associated with microsatellite instability (or mismatch repair deficiency) and Epstein-Barr virus (EBV) positivity. We therefore aimed to develop and validate deep learning-based classifiers to detect microsatellite instability and EBV status from routine histology slides., Methods: In this retrospective, multicentre study, we collected tissue samples from ten cohorts of patients with gastric cancer from seven countries (South Korea, Switzerland, Japan, Italy, Germany, the UK and the USA). We trained a deep learning-based classifier to detect microsatellite instability and EBV positivity from digitised, haematoxylin and eosin stained resection slides without annotating tumour containing regions. The performance of the classifier was assessed by within-cohort cross-validation in all ten cohorts and by external validation, for which we split the cohorts into a five-cohort training dataset and a five-cohort test dataset. We measured the area under the receiver operating curve (AUROC) for detection of microsatellite instability and EBV status. Microsatellite instability and EBV status were determined to be detectable if the lower bound of the 95% CI for the AUROC was above 0·5., Findings: Across the ten cohorts, our analysis included 2823 patients with known microsatellite instability status and 2685 patients with known EBV status. In the within-cohort cross-validation, the deep learning-based classifier could detect microsatellite instability status in nine of ten cohorts, with AUROCs ranging from 0·597 (95% CI 0·522-0·737) to 0·836 (0·795-0·880) and EBV status in five of eight cohorts, with AUROCs ranging from 0·819 (0·752-0·841) to 0·897 (0·513-0·966). Training a classifier on the pooled training dataset and testing it on the five remaining cohorts resulted in high classification performance with AUROCs ranging from 0·723 (95% CI 0·676-0·794) to 0·863 (0·747-0·969) for detection of microsatellite instability and from 0·672 (0·403-0·989) to 0·859 (0·823-0·919) for detection of EBV status., Interpretation: Classifiers became increasingly robust when trained on pooled cohorts. After prospective validation, this deep learning-based tissue classification system could be used as an inexpensive predictive biomarker for immunotherapy in gastric cancer., Funding: German Cancer Aid and German Federal Ministry of Health., Competing Interests: Declaration of interests JNK declares consulting roles for OWKIN France and Panakeia (UK) without any direct connection to this work; these roles started in April, 2021, after conducting the present study. JNK also declares honoraria from MSD and Eisai. DC declares grants from Medimmune/AstraZeneca, Clovis, Eli Lilly, 4SC, Bayer, Celgene, Leap, and Roche, and Scientific Board Membership for OVIBIO. DJ declares consulting services and advisory board participation for CureVac AG, Definiens, F Hoffmann-La Roche, Genmab A-S, Life Science Inkubator GmbH, VAXIMM AG, OncoOne Research & Development Research GmbH, and Oncolytics Biotech; payment or honoraria from SKK Kliniken Heilbronn, Georg Thieme Verlag, Terrapinn, Touch Medical Medica, BMS GmbH & Co KG, and MSD; reimbursements for expert opinion on medical questions from Wilhelm-Sander Foundation, Else-Kröner-Fresenius Foundation, Scherer Foundation, and NordForsk; meeting support (ie, for travel) from Amgen, Oryx GmbH, Roche Glycart AG, Parexel.com, IKTZ HD GmbH, and BMS; and leadership in the BMS Foundation Immunooncology. All other authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Pancreatic acinar cell carcinoma (ACC) is a rare malignant disease that displays distinct differences to pancreatic ductal adenocarcinoma. Here, we report the case of a patient with ACC and underlying breast cancer susceptibility gene 2 (BRCA2) germline mutation that developed severe pancreatic panniculitis (PP) during the course of the disease. The patient received a multimodal therapy including surgery, systemic chemotherapy, and targeted therapy with the PARP inhibitor olaparib, resulting in an overall survival of 47 months. Findings from this case are compared to the current knowledge on management of ACC and paraneoplastic PP., Competing Interests: The authors have no conflicts of interest., (Copyright © 2021 by S. Karger AG, Basel.)

Background: Hepatocellular carcinoma (HCC) is a major cause of cancer-related death. Paired related homeobox 1 (PRRX1) is a transcription factor that regulates cell growth and differentiation, but its importance in HCC is unclear., Methods: We examined the expression pattern of PRRX1 in nine microarray datasets of human HCC tumour samples (n > 1100) and analyzed its function in HCC cell lines. In addition, we performed gene set enrichment, Kaplan-Meier overall survival analysis, metabolomics and functional assays., Results: PRRX1 is frequently upregulated in human HCC. Pathway enrichment analysis predicted a direct correlation between PRRX1 and focal adhesion and epithelial-mesenchymal transition. High expression of PRRX1 and low ZEB1 or high ZEB2 significantly predicted better overall survival in HCC patients. In contrast, metabolic processes correlated inversely and transcriptional analyses revealed that glycolysis, TCA cycle and amino acid metabolism were affected. These findings were confirmed by metabolomics analysis. At the phenotypic level, PRRX1 knockdown accelerated proliferation and clonogenicity in HCC cell lines., Conclusions: Our results suggest that PRRX1 controls metabolism, has a tumour suppressive role, and may function in cooperation with ZEB1/2. These findings have functional relevance in HCC, including in understanding transcriptional control of distinct cancer hallmarks., (© 2021. The Author(s).)

Untreated non-alcoholic fatty liver disease (NAFLD) may have significant consequences including an increase in mortality and cardiovascular injury. Thus, early detection of NAFLD is currently believed not only to prevent liver-related but also cardiovascular mortality. However, almost nothing is known about coexisting NAFLD in patients with coronary artery disease (CAD). We investigated the impact of surrogate scores of fibrosis in NAFLD in a large cohort of patients referred to coronary angiography. Modeling the common NALFD and fibrosis scores, fibrosis-4 index (FIB-4) and NAFLD fibrosis score (NFS), as splines revealed significant associations with all-cause and cardiovascular mortality when Cox regression models were only adjusted for cardiovascular risk factors that were not already included in the calculation of the scores. Stratifying the scores into quartiles yielded hazard ratios [95% confidence interval (CI)] for all-cause and cardiovascular mortality for the 4th quartile versus the 1st quartile of 2.28 (1.90-2.75) and 2.11 (1.67-2.67) for FIB-4 and of 3.21 (2.61-3.94) and 3.12 (2.41-4.04) for NFS. However, we did not observe an independent association of FIB-4 or NFS with overall or cardiovascular mortality in our prospective CAD cohort after full adjustment for all cardiovascular risk factors [all-cause mortality: HR 1.13 (0.904-1.41) and 1.17 (0.903-1.52); cardiovascular mortality: HR 1.06 (0.8-1.41) and 1.02 (0.738-1.41)]. Thus, neither FIB-4 nor NFS, as surrogate markers for NAFLD/NASH, were independent risk factors for overall or cardiovascular mortality in patients with CAD. Our data show that surrogate risk scores for NAFLD-related fibrosis do not add information in assessing the CVD events in patients with CAD proven by angiography. NEW & NOTEWORTHY We investigated the impact of NAFLD surrogate markers in a large cohort of patients that had been referred to coronary angiography. In contrast to a repeatedly demonstrated increased link of cardiovascular events in patients with NALFD, we demonstrated that NAFLD surrogate markers were not independent risk factors for overall or cardiovascular mortality in patients with CAD. Thus, these markers may not be useful for primary prevention of cardiovascular events in patients with CAD.

Background: The unexpected outbreak of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused more than 49 million cases and an estimated 2,000,000 associated deaths worldwide. In Germany, there are currently more than 2,000,000 laboratory-confirmed coronavirus disease 2019 (COVID-19) cases including 51,800 deaths. However, regional differences also became apparent and with the second wave of infections, the detailed characterization of COVID-19 patients is crucial to early diagnosis and disruption of chains of infections., Methods: Handing out detailed questionnaires to all individuals tested for COVID-19, we evaluated the clinical characteristics of negative and positive tested individuals. Expression of symptoms, symptom duration and association between predictor variables (i.e. age, gender) and a binary outcome (olfactory and gustatory dysfunction) were assessed., Results: Overall, the most common symptoms among individuals who tested positive for SARS-CoV-2 were fatigue, headache, and cough. Olfactory and gustatory dysfunction were also reported by many SARS-CoV-2 negative individuals, more than 20% of SARS-CoV-2 negative tested individuals in our study reported olfactory and gustatory dysfunction. Independent of SARS-CoV-2 status, more females displayed symptoms of gustatory (29.8%, p = 0.0041) and olfactory dysfunction (22.9%, p = 0.0174) compared to men., Conclusions: Bringing early SARS-CoV-2 tests to the populations at risk must be a main focus for the upcoming months. The reliability of olfactory and gustatory dysfunction in COVID-19 negative tested individuals requires deeper investigation in the future.

Hepatocellular carcinoma (HCC) can have viral or non-viral causes 1-5 . Non-alcoholic steatohepatitis (NASH) is an important driver of HCC. Immunotherapy has been approved for treating HCC, but biomarker-based stratification of patients for optimal response to therapy is an unmet need 6,7 . Here we report the progressive accumulation of exhausted, unconventionally activated CD8 + PD1 + T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded activated CD8 + PD1 + T cells within tumours but did not lead to tumour regression, which indicates that tumour immune surveillance was impaired. When given prophylactically, anti-PD1 treatment led to an increase in the incidence of NASH-HCC and in the number and size of tumour nodules, which correlated with increased hepatic CD8 + PD1 + CXCR6 + , TOX + , and TNF + T cells. The increase in HCC triggered by anti-PD1 treatment was prevented by depletion of CD8 + T cells or TNF neutralization, suggesting that CD8 + T cells help to induce NASH-HCC, rather than invigorating or executing immune surveillance. We found similar phenotypic and functional profiles in hepatic CD8 + PD1 + T cells from humans with NAFLD or NASH. A meta-analysis of three randomized phase III clinical trials that tested inhibitors of PDL1 (programmed death-ligand 1) or PD1 in more than 1,600 patients with advanced HCC revealed that immune therapy did not improve survival in patients with non-viral HCC. In two additional cohorts, patients with NASH-driven HCC who received anti-PD1 or anti-PDL1 treatment showed reduced overall survival compared to patients with other aetiologies. Collectively, these data show that non-viral HCC, and particularly NASH-HCC, might be less responsive to immunotherapy, probably owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance. Our data provide a rationale for stratification of patients with HCC according to underlying aetiology in studies of immunotherapy as a primary or adjuvant treatment.

Background & Aims: Pancreatic ductal adenocarcinoma (PDAC) is frequently accompanied by excruciating pain, which has been associated with attraction of cancer cells and their invasion of intrapancreatic sensory nerves. Neutralization of the chemokine CCL2 reduced cancer-associated pain in a clinical trial, but there have been no systematic analyses of the highly diverse chemokine families and their receptors in PDAC., Methods: We performed an open, unbiased RNA-interference screen of mammalian chemokines in co-cultures of mouse PDAC cells (K8484) and mouse peripheral sensory neurons, and confirmed findings in studies of DT8082 PDAC cells. We studied the effects of chemokines on migration of PDAC cell lines. Orthotopic tumors were grown from K8484 cells in mice, and mice were given injections of neutralizing antibodies against chemokines, antagonists, or control antibodies. We analyzed abdominal mechanical hypersensitivity and collected tumors and analyzed them by histology and immunohistochemistry to assess neural remodeling. We collected PDAC samples and information on pain levels from 74 patients undergoing resection and measured levels of CXCR3 and CCR7 by immunohistochemistry and immunoblotting., Results: Knockdown of 9 chemokines in DRG neurons significantly reduced migration of PDAC cells towards sensory neurons. Sensory neuron-derived CCL21 and CXCL10 promoted migration of PDAC cells via their receptors CCR7 and CXCR3, respectively, which were expressed by cells in orthotopic tumors and PDAC specimens from patients. Neutralization of CCL21 or CXCL10, or their receptors, in mice with orthotopic tumors significantly reduced nociceptive hypersensitivity and nerve fiber hypertrophy and improved behavioral parameters without affecting tumor infiltration by T cells or neutrophils. Increased levels of CXCR3 and CCR7 in human PDAC specimens were associated with increased frequency of cancer-associated pain, determined from patient questionnaires., Conclusions: In an unbiased screen of chemokines, we identified CCL21 and CXCL10 as proteins that promote migration of pancreatic cancer cells toward sensory neurons. Inhibition of these chemokines or their receptors reduce hypersensitivity in mice with orthotopic tumors, and patients with PDACs with high levels of the chemokine receptors of CXCR3 and CCR7 had increased frequency of cancer-associated pain., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Psychiatric co-morbidities including depression and anxiety are common in inflammatory bowel diseases (IBD). Emerging evidence suggests that interactions between the gut microbiota and brain may play a role in the pathogenesis of psychiatric symptoms in IBD., Aim: To review the literature on microbiota-brain-gut interactions in gut inflammation, psychosocial stress and mental disorders and to discuss the putative mediating role of gut microbiota in the development of psychiatric symptoms or co-morbidities in IBD., Methods: A literature search was conducted on Ovid and Pubmed to select relevant animal and human studies reporting an association between IBD, mental disorders and gut microbiota., Results: Gut microbial alterations are frequently reported in subjects with IBD and with mental disorders. Both have been associated with reduced faecal bacterial diversity, decreased taxa within the phylum Firmicutes and increased Gammaproteobacteria. In animal studies, microbial perturbations induce behavioural changes and modulate inflammation in mice. Anxiety- and depression-like behaviours in animals can be transferred via faecal microbiota. In humans, modulation of the gut microbiota with probiotics is associated with behavioural and mood changes. Recent data show correlations in changes of faecal and mucosal microbiota and psychological distress in patients with IBD independent of disease activity., Conclusion: Both IBD and mental disorders are associated with gut microbial alterations. Preclinical and preliminary human studies have shown a mediating role of the gut microbiota in intestinal inflammation and anxiety, depression and stress. Targeting the gut microbiota may represent a useful therapeutic approach for the treatment of psychiatric co-morbidities in IBD., (© 2020 John Wiley & Sons Ltd.)

Introduction: Colorectal cancer arises in a multistep process of carcinogenesis from normal mucosa. The earliest precursor might be a morphologically inconspicuous precancerous field, harboring cancer-associated mutations., Methods: We systematically analyzed genetic alterations in 77 tissue samples from 30 patients with sporadic colorectal neoplasms (18 large adenomas and 12 adenocarcinomas) and matched adjacent normal mucosa (N = 30), as well as normal rectal tissue (N = 17). We profiled mutations associated with colorectal cancer by targeted sequencing of 46 genetic loci using 157 custom amplicons and a median depth of 42,655 reads per loci., Results: Multiple mutations were found in colorectal neoplasms, most frequently in APC, KRAS, and TP53. In a subgroup of 11 of 30 patients, alterations were also detected in non-neoplastic mucosa. These mutations were divergent from those in matched neoplasms. The total alteration count and the allele frequency of mutations were higher in neoplasms compared with those in adjacent tissues. We found that younger patients (≤70 years) are less likely affected by mutations in non-neoplastic mucosa than older patients (>70 years, P = 0.013), although no association was found for other variables, including type, location and differentiation of neoplasia, and previous history of polyps., Discussion: Our data show that cancer-associated mutations can be found in non-neoplastic tissues in a subgroup of patients with colorectal neoplasms. Further studies are needed to specify the risk of occurrence and recurrence of neoplasia in this patient population.

Chemotherapy combined with the angiogenesis inhibitor bevacizumab (BVZ) is approved as a first-line treatment in metastatic colorectal cancer (mCRC). Limited clinical benefit underpins the need for improved understanding of resistance mechanisms and the elucidation of novel predictive biomarkers. We assessed germline single-nucleotide polymorphisms (SNPs) in 180 mCRC patients (Angiopredict [APD] cohort) treated with combined BVZ + chemotherapy and investigated previously reported predictive SNPs. We further employed a machine learning approach to identify novel associations. In the APD cohort IL8 rs4073 any A carriers, compared to TT carriers, were associated with worse progression-free survival (PFS) (HR = 1.51, 95% CI:1.03-2.22, p-value = 0.037) and TBK1 rs7486100 TT carriers, compared to any A carriers, were associated with worse PFS in KRAS wild-type (wt) patients (HR = 1.94, 95% CI:1.04-3.61, p-value = 0.037), replicating previous findings. Machine learning identified novel associations in genes encoding the inflammasome protein NLRP1 and the ER protein Sarcalumenin (SRL). A negative association between PFS and carriers of any A at NLRP1 rs12150220 and AA for SRL rs13334970 in APD KRAS wild-type patients (HR = 4.44, 95% CI:1.23-16.13, p-value = 0.005), which validated in two independent clinical cohorts involving BVZ, MAVERICC and TRIBE. Our findings highlight a key role for inflammation and ER signalling underpinning BVZ + chemotherapy responsiveness.

Background: The extracellular signal-regulated kinase (ERK) pathway regulates cell growth, and is hyper-activated and associated with drug resistance in hepatocellular carcinoma (HCC). Metabolic pathways are profoundly dysregulated in HCC. Whether an altered metabolic state is linked to activated ERK pathway and drug response in HCC is unaddressed., Methods: We deprived HCC cells of glutamine to induce metabolic alterations and performed various assays, including metabolomics (with 13 C-glucose isotope tracing), microarray analysis, and cell proliferation assays. Glutamine-deprived cells were also treated with kinase inhibitors (e.g. Sorafenib, Erlotinib, U0126 amongst other MEK inhibitors). We performed bioinformatics analysis and stratification of HCC tumour microarrays to determine upregulated ERK gene signatures in patients., Findings: In a subset of HCC cells, the withdrawal of glutamine triggers a severe metabolic alteration and ERK phosphorylation (pERK). This is accompanied by resistance to the anti-proliferative effect of kinase inhibitors, despite pERK inhibition. High intracellular serine is a consistent feature of an altered metabolic state and contributes to pERK induction and the kinase inhibitor resistance. Blocking the ERK pathway facilitates cell proliferation by reprogramming metabolism, notably enhancing aerobic glycolysis. We have identified 24 highly expressed ERK gene signatures that their combined expression strongly indicates a dysregulated metabolic gene network in human HCC tissues., Interpretation: A severely compromised metabolism lead to ERK pathway induction, and primes some HCC cells to pro-survival phenotypes upon ERK pathway blockade. Our findings offer novel insights for understanding, predicting and overcoming drug resistance in liver cancer patients. FUND: DFG, BMBF and Sino-German Cooperation Project., Competing Interests: Declaration of competing interest The authors declare no competing interests with respect to this study., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Caveolin-1 (CAV1) is a crucial regulator of lipid accumulation and metabolism. Previous studies have shown that global Cav1 deficiency affects lipid metabolism and hepatic steatosis. We aimed to analyze the consequences of hepatocyte-specific Cav1 knockout under healthy conditions and upon non-alcoholic fatty liver disease (NAFLD) development. Male and female hepatocyte-specific Cav1 knockout (HepCAV1ko) mice were fed a methionine/choline (MCD) deficient diet for 4 weeks. MCD feeding caused severe hepatic steatosis and slight fibrosis. In addition, liver function parameters, i.e., ALT, AST, and GLDH, were elevated, while cholesterol and glucose level were reduced upon MCD feeding. These differences were not affected by hepatocyte-specific Cav1 knockout. Microarray analysis showed strong differences in gene expression profiles of livers from HepCAV1ko mice compared those of global Cav1 knockout animals. Pathway enrichment analysis identified that metabolic alterations were sex-dimorphically regulated by hepatocyte-specific CAV1. In male HepCAV1ko mice, metabolic pathways were suppressed in NAFLD, whereas in female knockout mice induced. Moreover, gender-specific transcription profiles were modulated in healthy animals. In conclusion, our results demonstrate that hepatocyte-specific Cav1 knockout significantly altered gene profiles, did not affect liver steatosis and fibrosis in NAFLD and that gender had severe impact on gene expression patterns in healthy and diseased hepatocyte-specific Cav1 knockout mice.

Caveolin-1 (CAV1) is a membrane protein associated with metabolism in various cell types. The transforming growth factor beta (TGF-β) is a pro-fibrogenic cytokine in the liver, but its metabolic gene signatures remain unclear to date. We have previously shown that CAV1 alters TGF-β signaling and blocks its pro-apoptotic function. Here, we defined TGF-β-induced metabolic gene signatures in hepatocytes and assessed whether CAV1 abundance affects TGF-β control of those metabolic genes. Microarray analyses of primary hepatocytes after TGF-β stimulation (48 h) showed differential expression of 4224 genes, of which 721 are metabolic genes (adjusted p < 0.001). Functional annotation analysis revealed that TGF-β mainly suppresses metabolic gene network, including genes involved in glutathione, cholesterol, fatty acid, and amino acid metabolism. TGF-β also upregulated several genes related to glycan metabolism and ion transport. In contrast to TGF-β effects, CAV1 knockdown triggered the upregulation of metabolic genes. Immortalized mouse hepatocytes (AML12 cells) were used to validate the gene changes induced by TGF-β stimulation and CAV1 knockdown. Noteworthy, of the TGF-β metabolic target genes, CAV1 modulated the expression of 228 (27%). In conclusion, we present several novel metabolic gene signatures of TGF-β in hepatocytes and show that CAV1 abundance alters almost a third of these genes. These findings could enable a better understanding of TGF-β function in normal and diseased liver especially where differential CAV1 level is implicated., (Copyright © 2020 Han, Nwosu, Piorońska, Ebert, Dooley and Meyer.)

Metastatic gastric cancer (GC) and oesophagogastric junctional (OGJ) adenocarcinoma have a poor clinical outcome with a high worldwide burden of disease. A 65-year old male patient with microcytic anemia was diagnosed with stage IV OGJ adenocarcinoma with multiple liver metastases. Immunohistochemical analysis revealed a high expression of HER2 (3+). Palliative chemotherapy with FLOT (oxaliplatin, 5-fluorouracil, leucovorin and docetaxel) in combination with trastuzumab was initiated. Due to severe adverse events, the therapy was de-escalated to trastuzumab monotherapy after six months of treatment. Initial restaging revealed partial response after the combination therapy of FLOT with trastuzumab. After reduction to trastuzumab monotherapy, the disease remained stable for two years until radiological complete response was observed. Trastuzumab monotherapy was continued for another two years to maintain complete response. Eleven months after the discontinuation of the therapy, no recurrence of the disease was detected. In conclusion, complete response can be achieved under trastuzumab monotherapy in exceptional responders.