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Secretory IgA (SIgA) is critical for maintaining the intestinal barrier. A dysregulated B-cell compartment and altered Ig secretion have been well documented in Crohn’s disease (CD) patients, although their origin is unknown. To unravel the role of mucosal humoral immunity in CD pathogenesis, we in-depth phenotype colonic plasma cell (PC) differentiation in CD at the single-cell level, linked to ex vivo functional characterization and experimental mouse models with a congenital mitochondrial defect or under glucose-free high-protein dietary intervention. Here, we demonstrate that despite expanded colonic B cells, CD patients in remission present significantly diminished mucosal dimeric IgA and fecal SIgA. Colonic plasmablasts and immature CD19 + CD45 + PCs are increased at the expense of the mature CD19 - CD45 - phenotype. Accordingly, CD-derived ex vivo differentiated PCs display impaired maturation into dimeric IgA-secreting PCs. In this study, patient-derived data from colonic RNA-seq, spatial single-cell proteomics, and plasma metabolomics are combined with data from both mouse models and highlight the crucial role of mitochondrial oxidative phosphorylation in colonic IgA + -PC differentiation, suggesting promising directions for future therapeutic strategies. Crohn’s disease is associated with disturbances in the B-cell compartment and secreted antibodies. Here, the authors reveal impaired colonic dimeric IgA responses in patients with Crohn’s disease and verify this phenotype in murine models, demonstrating that mitochondrial dysfunction drives defective mucosal humoral immunity.

Background Detection of cholangiocarcinoma (CCA) remains a diagnostic challenge. We established diagnostic peptide biomarkers in bile and urine based on capillary electrophoresis coupled to mass spectrometry (CE-MS) to detect both local and systemic changes during CCA progression. In a prospective cohort study we recently demonstrated that combined bile and urine proteome analysis could further improve diagnostic accuracy of CCA diagnosis in patients with unknown biliary strictures. As a continuation of these investigations, the aim of the present study was to investigate the pathophysiological mechanisms behind the molecular determinants reflected by bile and urine peptide biomarkers. Methods Protease mapping and gene ontology cluster analysis were performed for the previously defined CE-MS based biomarkers in bile and urine. For that purpose, bile and urine peptide profiles (from samples both collected at the date of endoscopy) were investigated from a representative cohort of patients with benign ( n  = 76) or CCA-associated ( n  = 52) biliary strictures (verified during clinical follow-up). This was supplemented with a literature search for the association of the individual biomarkers included in the proteomic patterns with CCA or cancer progression. Results For most of the peptide markers, association to CCA has been described in literature. Protease mapping revealed ADAMTS4 activity in cleavage of both bile and urine CCA peptide biomarkers. Furthermore, increased chymase activity in bile points to mast cell activation at the tumor site. Gene ontology cluster analysis indicates cellular response to chemical stimuli and stress response as local and extracellular matrix reorganization by tissue destruction and repair as systemic events. The analysis further supports that the mapped proteases are drivers of local and systemic events. Conclusions The study supports connection of the CCA-associated peptide biomarkers to the molecular pathophysiology and indicates an involvement in epithelial-to-mesenchymal transition, generation of cancer-associated fibroblasts and activation of residual immune cells. Proteases, extracellular matrix components, inflammatory cytokines, proangiogenic, growth and vasoactive factors released from the tumor microenvironment are drivers of systemic early events during CCA progression.

Background Endoscopic placement of intestinal decompression tubes is a feasible technique for treatment of acute intestinal dilation. Given the heterogeneity of the underlying diseases leading to intestinal obstruction data on the significance of endoscopic procedures for treatment of these conditions are sparse. Methods In the study period from 2008 to 2019 all patients receiving a decompression tube were identified by retrospective chart review and analyzed. Results A total of 59 decompression tubes were placed in 50 patients. Technical success was achieved in 98% (58/59 tubes). As major complication one small bowel perforation occurred (1/59; 1.7%). Causes for impaired intestinal transit comprised tumor stenoses 22% (11/50), infections 18% (9/50), post-operative paralysis 14% (7/50), neurological diseases 8% (4/50), trauma 2% (1/50) and others 36% (18/50). Most patients (74%; 37/50) were critically ill and treated on intensive care unit. Treatment response after tube insertion was documented in 76% of patients (38/50) whereas 24% (12/50) did not fulfill response criteria. Patients with treatment response showed a significantly better outcome compared to non-responders. Responders had a median survival of 113 days (95% CI 41–186) compared to 15 days (95% CI 6–24) in non-responders ( p  = 0.002). Analysis of laboratory parameters after stratification in responders and non-responders to endoscopic therapy showed that non-responders had significantly higher levels of CRP and lower platelet count at baseline (CRP 262 mg/L (IQR 101–307) vs. 94 mg/L (IQR 26–153): p  = 0.027; platelets 69 thsd/μL (IQR 33–161) vs. 199 thsd/μL (IQR 138–289): p  = 0.009). Conclusions Endoscopic decompression is a safe procedure for acute management of impaired intestinal transit even in critically ill patients. Response to therapy is associated with improved outcome and markers of inflammation and organ function such as CRP, platelet count and serum lactate have to be taken into account for therapy monitoring and evaluation of prognosis.

Prophylactic treatment with acetylsalicylic acid does not only reduce the risk of cancer development [5] but may also reduce the risk of distant metastasis formation [6]. See PDF.] Comparison of OS between patients with thrombocytopenia (platelet count <150 g/L), normal platelet count (150–300 g/L) as well as thrombocytosis (platelet count ≥300 g/L) Additionally, and in line with these findings, a large body of preclinical evidence shows the various implications of anti-platelet therapy (acetylsalicylic acid [7] as well as adenosine diphosphate receptor P2Y12 antagonists [8]) in cancer. [...]we agree that a prospective randomized trial on the additive effect of anti-platelet therapy in patients with hepatocellular carcinoma is eagerly awaited. 1 Huo T-I, Liu P-H. Short-term effects of daily aspirin on cancer incidence, mortality, and non-vascular death: analysis of the time course of risks and benefits in 51 randomised controlled trials.

ObjectivesVariants in patatin-like phospholipase domain-containing 3 (PNPLA3; rs738409), transmembrane 6 superfamily member 2 (TM6SF2; rs58542926), and membrane bound O-acyltransferase domain containing 7 (MBOAT7; rs641738) are risk factors for the development of alcohol-related cirrhosis. Within this population, PNPLA3 rs738409 is also an established risk factor for the development of hepatocellular carcinoma (HCC). The aim of this study was to explore possible risk associations of TM6SF2 rs58542926 and MBOAT7 rs641738 with HCC.MethodsRisk variants in PNPLA3, TM6SF2, and MBOAT7 were genotyped in 751 cases with alcohol-related cirrhosis and HCC and in 1165 controls with alcohol-related cirrhosis without HCC. Association with the risk of developing HCC was analyzed using multivariate logistic regression.ResultsThe development of HCC was independently associated with PNPLA3 rs738409 (ORadjusted 1.84 [95% CI 1.55-2.18], p = 1.85 × 10-12) and TM6SF2 rs58542926 (ORadjusted 1.66 [1.30-2.13], p = 5.13 × 10-05), using an additive model, and controlling the sex, age, body mass index, and type 2 diabetes mellitus; the risk associated with carriage of MBOAT7 rs641738 (ORadjusted 1.04 [0.88-1.24], p = 0.61) was not significant. The population-attributable fractions were 43.5% for PNPLA3 rs738409, 11.5% for TM6SF2 rs58542926, and 49.9% for the carriage of both the variants combined.ConclusionsCarriage of TM6SF2 rs58542926 is an additional risk factor for the development of HCC in people with alcohol-related cirrhosis. Carriage of both PNPLA3 rs738409 and TM6SF2 rs58542926 accounts for half of the attributable risk for HCC in this population. Genotyping will allow for more precise HCC risk-stratification of patients with alcohol-related cirrhosis, and genotype-guided screening algorithms would optimize patient care.

BackgroundSegmented self-expanding metal stents (SEMS) are an alternative to conventional unsegmented SEMS in the treatment of esophageal strictures. Due to their segmented design, they may adapt better to the surrounding structures making them less likely to migrate or cause trauma. We examined if there are clinically relevant differences between segmented and conventional esophageal SEMS in benign and malignant stenosis in terms of their functionality and safety.Patients and methodsWe performed a multicenter, retrospective case–control study of segmented and conventional SEMS implantations in esophageal stenosis. Outcome parameters were adverse events such as migration, occlusion, and severe complications (i.e., bleeding and perforation).Results79 segmented SEMS were identified and compared to 79 conventional SEMS implantations. Groups were similar in terms of age, gender, and etiology. We observed 13.9% severe complications (SEMS-associated clinically significant bleeding or perforation) in the conventional SEMS group compared to 3.8% in the segmented SEMS group. This difference was statistically significant (p = 0.025). Rates of migration and occlusion were similar between both groups. Likewise, there was no significant difference in terms of short-term (30 days) clinical success.ConclusionIn this first controlled analysis, segmented SEMS were associated with fewer severe clinical complications compared to conventional SEMS.

Background: Transarterial chemo-embolisation (TACE) is recommended for patients with BCLC intermediate stage hepatocellular carcinoma (stage B), particularly in patients with good underlying liver function and minimal symptoms. The hepatoma arterial embolisation prognostic (HAP) score combines measures of liver function and tumour-related factors to offer a simple prognostic scoring system. The Albumin-Bilirubin (ALBI) grade permits assessment of the impact of liver function on survival. We aimed to investigate these two models and vascular invasion (VI). Methods: In an international cohort of 3030 patients undergoing TACE, we examined the impact of liver function as assessed by the ALBI score, the HAP score and VI on survival. Results: Classification according to ALBI grade resulted in non-overlapping survival curves in the overall data set and all regional cohorts. The HAP score was also validated. Tumour number, aetiology and VI were identified as additional independent prognostic risk factors not currently included in the HAP score. Survival was particularly poor for patients with VI. Conclusions: The ALBI grade categorised patients receiving TACE into three clear prognostic groups, thereby emphasising the importance of underlying liver function in the outcome of TACE. The HAP score has been validated internationally and the serious adverse impact of VI is clearly shown.

BackgroundChemosaturation with percutaneous hepatic perfusion (CS-PHP; Hepatic CHEMOSAT® Delivery System; Delcath Systems Inc, USA) is a novel interventional procedure, which delivers high doses of melphalan directly to the liver in patients with liver tumors while limiting systemic toxicity through hemofiltration of the hepatic venous blood. We have previously shown promising efficacy for patients with ocular melanoma (OM) and cholangiocarcinoma (CCA) within our single-center and multi-center experiences. The aim of this study was to analyze the safety and efficacy of CS-PHP after 141 treatments at Hannover Medical School, Germany.MethodsOverall response rates (ORR) were assessed according to Response Evaluation Criteria In Solid Tumors (RECIST1.1). Median Overall survival (mOS), median progression-free survival (mPFS), and median hepatic PFS (mhPFS) were analyzed using the Kaplan–Meier estimation.ResultsOverall, 60 patients were treated with CS-PHP in the salvage setting from October 2014 until January 2019 at Hannover Medical School with a total of 141 procedures. Half of the patients were patients with hepatic metastases of ocular melanoma (OM) (n = 30), 14 patients had CCA (23.3%), 6 patients had hepatocellular carcinoma (10%), and 10 patients were treated for other secondary liver malignancies (16.7%). In total, ORR and disease stabilization rate were 33.3% and 70.3% (n = 25), respectively. ORR was highest for patients with OM (42.3%), followed by patients with CCA (30.8%). Independent response-associated factors were normal levels of lactate dehydrogenase (odds ratio (OR) 13.7; p = 0.015) and diagnosis with OM (OR 9.3; p = 0.028). Overall, mOS was 9 months, mPFS was 4 months, and mhPFS was 5 months. Patients with OM had the longest mOS, mPFS, and mhPFS with 12, 6, and 6 months, respectively. Adverse events included most frequently significant, but transient, hematologic toxicities (80% of grade 3/4 thrombopenia), less frequently hepatic injury up to liver failure (3.3%) and cardiovascular events including two cases of ischemic insults (5%).ConclusionSalvage treatment with CS-PHP is safe and effective particularly in patients OM and CCA. Careful attention should be paid to possible, serious hepatic, and cardiovascular complications.

ObjectivesCholangiocarcinoma is the second most common primary liver tumour with a poor overall prognosis. Percutaneous hepatic perfusion (PHP) is a directed therapy for primary and secondary liver malignancies, and its efficacy and safety have been shown in different entities. The purpose of this study was to prove the safety and efficacy of PHP in patients with unresectable intrahepatic cholangiocarcinoma (iCCA).Patients and methodsWe retrospectively reviewed data from 15 patients with unresectable iCCA treated with PHP in nine different hospitals throughout Europe. Overall response rates (ORR) were assessed according to response evaluation criteria in solid tumours (RECIST1.1). Overall survival (OS), progression-free survival (PFS) and hepatic PFS (hPFS) were analysed using the Kaplan-Meier estimation. Adverse events (AEs) and toxicity were evaluated.ResultsFifteen patients were treated with 26 PHPs. ORR was 20%, disease control was achieved in 53% after the first PHP. Median OS was 26.9 months from initial diagnosis and 7.6 months from first PHP. Median PFS and hPFS were 122 and 131 days, respectively. Patients with liver-only disease had a significantly longer median OS compared to patients with locoregional lymph node metastases (12.9 vs. 4.8 months, respectively; p < 0.01). Haematological toxicity was common, but manageable. No AEs of grade 3 or 4 occurred during the procedures.DiscussionPHP is a standardised and safe procedure that provides promising response rates and survival data in patients with iCCA, especially in non-metastatic disease.Key Points• Percutaneous hepatic perfusion (PHP) offers an additional locoregional therapy strategy for the treatment of unresectable primary or secondary intrahepatic malignancies.• PHP is a standardised and safe procedure that provides promising response rates and survival data in patients with intrahepatic cholangiocarcinoma (iCCA), especially in non-metastatic disease.• Side effects seem to be tolerable and comparable to other systemic or local treatment strategies.

Background Chemosaturation with percutaneous hepatic perfusion (CS-PHP; hepatic CHEMOSAT ® delivery system; Delcath Systems Inc, USA) is a novel medical device, which delivers high doses of melphalan directly to the liver in patients with primary and secondary liver tumors while limiting systemic toxicity through hemofiltration of the hepatic venous blood. The aim of this study was to analyze the safety and efficacy of the second-generation CS-PHP after 54 treatments at Hannover Medical School, Germany. Methods Overall response rates (ORR) were assessed according to response evaluation criteria in solid tumors (RECIST1.1). Overall survival (OS), progression-free survival (PFS), and hepatic PFS (hPFS) were analyzed using the Kaplan–Meier estimation. Results 29 patients were treated with CS-PHP as last-line therapy up to five sessions. 19 patients had unresectable hepatic metastases from solid tumors [ocular melanoma (OM) n  = 11; colorectal carcinoma n  = 2; pancreatic adenocarcinoma n  = 2; periampular carcinoma n  = 2; breast and endometrial cancer each n  = 1] and 10 patients were diagnosed with hepatocellular or cholangiocarcinoma (HCC/CCA). ORR was 19.2%. Patients with OM had the highest ORR (33.3%). Similar to patients with OM, patients with hepatobiliary tumors had durable disease stabilization (40%). Median OS, PFS, and hPFS were 261, 117, and 135 days, respectively. Tumor volume negatively correlated with OS. Complications and toxicities included thrombocytopenia, cardiovascular events, ulcerous bleeding, and edema. Conclusion Second-generation CS-PHP seems to be effective and tolerable. Patient selection based on tumor volume and entity is of importance. Particularly, patients with OM and hepatobiliary tumors represent promising candidates for CS-PHP.