Sublethal necroptosis signaling promotes inflammation and liver cancer.

It is currently not well known how necroptosis and necroptosis responses manifest in vivo. Here, we uncovered a molecular switch facilitating reprogramming between two alternative modes of necroptosis signaling in hepatocytes, fundamentally affecting immune responses and hepatocarcinogenesis. Concomitant necrosome and NF-κB activation in hepatocytes, which physiologically express low concentrations of receptor-interacting kinase 3 (RIPK3), did not lead to immediate cell death but forced them into a prolonged "sublethal" state with leaky membranes, functioning as secretory cells that released specific chemokines including CCL20 and MCP-1. This triggered hepatic cell proliferation as well as activation of procarcinogenic monocyte-derived macrophage cell clusters, contributing to hepatocarcinogenesis. In contrast, necrosome activation in hepatocytes with inactive NF-κB-signaling caused an accelerated execution of necroptosis, limiting alarmin release, and thereby preventing inflammation and hepatocarcinogenesis. Consistently, intratumoral NF-κB-necroptosis signatures were associated with poor prognosis in human hepatocarcinogenesis. Therefore, pharmacological reprogramming between these distinct forms of necroptosis may represent a promising strategy against hepatocellular carcinoma.

Soluble lymphocyte activation gene-3 (sLAG3) and CD4/CD8 ratio dynamics as predictive biomarkers in patients undergoing immune checkpoint blockade for solid malignancies.

BACKGROUND: The search for biomarkers to identify suitable candidates for immune checkpoint inhibitor (ICI) therapy remains ongoing. We evaluate how soluble levels of the next generation immune checkpoint Lymphocyte Activation Gene-3 (sLAG-3) and its association with circulating T lymphocyte subsets could pose as a novel biomarker to predict outcome to ICI therapy. METHODS: Circulating levels of sLAG3 were analyzed using multiplex immunoassay in n = 84 patients undergoing ICI therapy for advanced solid cancer, accompanied by flow cytometry analyses of peripheral blood mononuclear cells (PBMCs). RESULTS: Uni- and multivariate analysis shows that patients with higher sLAG3 concentrations before ICI therapy had a significantly impaired progression-free (PFS) and overall survival (OS) (HRPFS: 1.005 [95%CI: 1.000-1.009], p = 0.039; HROS: 1.006 [95%CI: 1.001-1.011], p = 0.015). The CD4/CD8 cell ratio and its dynamics during therapy were strong predictors of PFS and OS with patients with a decreasing ratio between baseline and after 1-2 cycles having an improved median OS compared to patients with increasing values (p = 0.012, HR: 3.32). An immunological score combining sLAG3 and the CD4/CD8 ratio showed the highest predictive potential (HROS: 10.3). CONCLUSION: Pending prospective validation, sLAG3 and correlating circulating T-cell subsets can be used as a non-invasive predictive marker to predict outcome to ICI therapy to help identifying ideal ICI candidates in the future.

Intubation Decision Based on Illness Severity and Mortality in COVID-19: An International Study.

OBJECTIVES: To evaluate the impact of intubation timing, guided by severity criteria, on mortality in critically ill COVID-19 patients, amidst existing uncertainties regarding optimal intubation practices. DESIGN: Prospective, multicenter, observational study conducted from February 1, 2020, to November 1, 2022. SETTING: Ten academic institutions in the United States and Europe. PATIENTS: Adults (≥ 18 yr old) confirmed with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and hospitalized specifically for COVID-19, requiring intubation postadmission. Exclusion criteria included patients hospitalized for non-COVID-19 reasons despite a positive SARS-CoV-2 test. INTERVENTIONS: Early invasive mechanical ventilation (EIMV) was defined as intubation in patients with less severe organ dysfunction (Sequential Organ Failure Assessment [SOFA] < 7 or Pa o2 /F io2 ratio > 250), whereas late invasive mechanical ventilation (LIMV) was defined as intubation in patients with SOFA greater than or equal to 7 and Pa o2 /F io2 ratio less than or equal to 250. MEASUREMENTS AND MAIN RESULTS: The primary outcome was mortality within 30 days of hospital admission. Among 4464 patients, 854 (19.1%) required mechanical ventilation (mean age 60 yr, 61.7% male, 19.3% Black). Of those, 621 (72.7%) were categorized in the EIMV group and 233 (27.3%) in the LIMV group. Death within 30 days after admission occurred in 278 patients (42.2%) in the EIMV and 88 patients (46.6%) in the LIMV group ( p = 0.28). An inverse probability-of-treatment weighting analysis revealed a statistically significant association with mortality, with patients in the EIMV group being 32% less likely to die either within 30 days of admission (adjusted hazard ratio [HR] 0.68; 95% CI, 0.52-0.90; p = 0.008) or within 30 days after intubation irrespective of its timing from admission (adjusted HR 0.70; 95% CI, 0.51-0.90; p = 0.006). CONCLUSIONS: In severe COVID-19 cases, an early intubation strategy, guided by specific severity criteria, is associated with a reduced risk of death. These findings underscore the importance of timely intervention based on objective severity assessments.

Interleukin-18 signaling promotes activation of hepatic stellate cells in mouse liver fibrosis.

BACKGROUND AND AIMS: Nucleotide-binding oligomerization domain-like receptor-family pyrin domain-containing 3 (NLRP3) inflammasome activation has been shown to result in liver fibrosis. Mechanisms and downstream signaling remain incompletely understood. Here, we studied the role of IL-18 in hepatic stellate cells (HSCs), and its impact on liver fibrosis. APPROACH AND RESULTS: We observed significantly increased serum levels of IL-18 (128.4 pg/ml vs. 74.9 pg/ml) and IL-18 binding protein (BP; 46.50 ng/ml vs. 15.35 ng/ml) in patients with liver cirrhosis compared with healthy controls. Single cell RNA sequencing data showed that an immunoregulatory subset of murine HSCs highly expresses Il18 and Il18r1 . Treatment of cultured primary murine HSC with recombinant mouse IL-18 accelerated their transdifferentiation into myofibroblasts. In vivo , IL-18 receptor-deficient mice had reduced liver fibrosis in a model of fibrosis induced by HSC-specific NLRP3 overactivation. Whole liver RNA sequencing analysis from a murine model of severe NASH-induced fibrosis by feeding a choline-deficient, L-amino acid-defined, high fat diet showed that genes related to IL-18 and its downstream signaling were significantly upregulated, and Il18-/- mice receiving this diet for 10 weeks showed protection from fibrotic changes with decreased number of alpha smooth muscle actin-positive cells and collagen deposition. HSC activation triggered by NLRP3 inflammasome activation was abrogated when IL-18 signaling was blocked by its naturally occurring antagonist IL-18BP. Accordingly, we observed that the severe inflammatory phenotype associated with myeloid cell-specific NLRP3 gain-of-function was rescued by IL-18BP. CONCLUSIONS: Our study highlights the role of IL-18 in the development of liver fibrosis by its direct effect on HSC activation identifying IL-18 as a target to treat liver fibrosis.

SuPAR, biomarkers of inflammation, and severe outcomes in patients hospitalized for COVID-19: The International Study of Inflammation in COVID-19.

Severe coronavirus disease 2019 (COVID-19) is a hyperinflammatory syndrome. The biomarkers of inflammation best suited to triage patients with COVID-19 are unknown. We conducted a prospective multicenter observational study of adult patients hospitalized specifically for COVID-19 from February 1, 2020 to October 19, 2022. Biomarkers measured included soluble urokinase plasminogen activator receptor (suPAR), C-reactive protein, interleukin-6, procalcitonin, ferritin, and D-dimer. In-hospital outcomes examined include death and the need for mechanical ventilation. Patients admitted in the United States (US, n = 1962) were used to compute area under the curves (AUCs) and identify biomarker cutoffs. The combined European cohorts (n = 1137) were used to validate the biomarker cutoffs. In the US cohort, 356 patients met the composite outcome of death (n = 197) or need for mechanical ventilation (n = 290). SuPAR was the most important predictor of the composite outcome and had the highest AUC (0.712) followed by CRP (0.642), ferritin (0.619), IL-6 (0.614), D-dimer (0.606), and lastly procalcitonin (0.596). Inclusion of other biomarkers did not improve discrimination. A suPAR cutoff of 4.0 ng/mL demonstrated a sensitivity of 95.4% (95% CI: 92.4%-98.0%) and negative predictive value (NPV) of 92.5% (95% CI: 87.5%-96.9%) for the composite outcome. Patients with suPAR < 4.0 ng/mL comprised 10.6% of the cohort and had a 0.8% probability of the composite outcome. Applying this cutoff to the validation cohort yielded a sensitivity of 93.8% (90.4%-96.7%) and NPV of 95.5% (93.1%-97.8%) for the composite outcome. Among commonly measured biomarkers, suPAR offered stronger discriminatory ability and may be useful in triaging low-risk patients with COVID-19.

Is there a link between appendicitis and the risk of diverticular disease?: a large German cohort study.

PURPOSE: Appendicitis, characterized by inflammation of the vermiform appendix, is a common abdominal emergency necessitating appendectomy. Recent evidence suggests a potential link between appendicitis and subsequent diverticular disease, yet population-based studies investigating this association are limited. METHODS: Utilizing the Disease Analyzer database encompassing data from over 1000 primary care practices in Germany, we conducted a retrospective cohort study. We included 25,379 adults diagnosed with appendicitis and an equal number of matched controls without appendicitis. The incidence of diverticular disease over a 10-year follow-up period was compared between the two cohorts. Cox regression analysis was performed to assess the association between appendicitis and diverticular disease, adjusting for potential confounders. RESULTS: Our findings revealed a significant association between appendicitis and subsequent diverticular disease (HR: 1.76; 95% CI: 1.57-1.97), with an increased risk observed across all age groups. Notably, this association was stronger in men (HR: 2.00; 95% CI: 1.68-2.37) than in women (HR: 1.58; 95% CI: 1.36-1.84). The cumulative 10-year incidence of diverticular disease was higher in patients with appendicitis (6.5%) compared to those without (3.6%). Additionally, we observed a clear age-dependent increase in the incidence of diverticular disease. CONCLUSION: This large-scale population-based study provides valuable insights into the interaction between appendicitis and diverticular disease. The study underscores the need for further research elucidating the underlying mechanisms linking appendicitis to diverticular disease. Probiotics emerge as a potential therapeutic avenue warranting exploration in the management of both conditions. These findings have important implications for clinical practice, highlighting the importance of considering appendicitis as a potential risk factor for diverticular disease, particularly in men. Further investigation is warranted to validate these findings and explore potential therapeutic interventions targeting the shared pathophysiological pathways underlying both conditions.

Helicobacter pylori infection associated with an increased incidence of cholelithiasis: A retrospective real-world cohort study of 50 832 patients.

BACKGROUND AND AIM: Helicobacter pylori (H. pylori) infection is a bacterial disease of the stomach that has been associated with an increased incidence of cholelithiasis. While the updated German guideline emphasizes the relevance of H. pylori as a pathogen and recommends eradication therapy, systematic data on the association between H. pylori infection, its eradication, and the subsequent diagnosis of cholelithiasis in Germany are missing. METHODS: A total of 25 416 patients with and 25 416 propensity score-matched individuals without H. pylori infection were identified from the Disease Analyzer database (IQVIA) between 2005 and 2021. A subsequent diagnosis of cholelithiasis was analyzed as a function of H. pylori infection as well as its eradication using Cox regression models. RESULTS: After 10 years of follow-up, 8.0% versus 5.8% of patients with and without H. pylori infection were diagnosed with cholelithiasis (P < 0.001). Regression analysis revealed a significant association between H. pylori infection and cholelithiasis (hazard ratio [HR]: 1.45; 95% confidence interval [CI]: 1.33-1.58), which was stronger in men (HR: 1.63; 95% CI: 1.41-1.90) than in women (HR: 1.36; 95% CI: 1.22-1.52). In terms of eradication therapy, both an eradicated H. pylori infection (HR: 1.48; 95% CI: 1.31-1.67) and a non-eradicated H. pylori infection (HR: 1.41; 95% CI: 1.25-1.60) were associated with a subsequent diagnosis of cholelithiasis. CONCLUSION: The present study reveals a strong association between H. pylori infection and a subsequent diagnosis of cholelithiasis in a large real-world cohort from Germany. Eradication therapy was not associated with a reduced incidence of cholelithiasis in our cohort.

German longitudinal prescription database (LRx): Description of characteristics, use in pharmacoepidemiological research, and limitations
.

Large databases have played a critical role in pharmacoepidemiological research in the last decade, with this role likely to gain further importance in the future. The aim of the present paper is to describe the characteristics, the recent use, and the limitations of the German longitudinal prescription (LRx) database. The LRx database contains patient-level data on prescriptions collected in retail pharmacies, corresponding to ~ 80% of prescriptions reimbursed by statutory health insurance funds in Germany. The LRx database includes a higher proportion of older adults and women compared to the overall German population with statutory health insurance. Coverage per family of drugs ranges from 71.8% for antiepileptics to 94.7% for urological agents. Multiple pharmacoepidemiological studies based on the data from the German LRx database have been published in the last years on topics such as patterns of prescription and treatment adherence and persistence. A large number of disorders have been investigated in this research (e.g., type 2 diabetes, inflammatory diseases, and psychiatric conditions). The major limitations of the LRx database are the lack of formal diagnoses and the absence of hospital data. In conclusion, the German LRx database could be a key source of data for future pharmacoepidemiological studies.

JNK signaling prevents biliary cyst formation through a CASPASE-8-dependent function of RIPK1 during aging.

The c-Jun N-terminal kinase (JNK) signaling pathway mediates adaptation to stress signals and has been associated with cell death, cell proliferation, and malignant transformation in the liver. However, up to now, its function was experimentally studied mainly in young mice. By generating mice with combined conditional ablation of Jnk1 and Jnk2 in liver parenchymal cells (LPCs) (JNK1/2LPC-KO mice; KO, knockout), we unraveled a function of the JNK pathway in the regulation of liver homeostasis during aging. Aging JNK1/2LPC-KO mice spontaneously developed large biliary cysts that originated from the biliary cell compartment. Mechanistically, we could show that cyst formation in livers of JNK1/2LPC-KO mice was dependent on receptor-interacting protein kinase 1 (RIPK1), a known regulator of cell survival, apoptosis, and necroptosis. In line with this, we showed that RIPK1 was overexpressed in the human cyst epithelium of a subset of patients with polycystic liver disease. Collectively, these data reveal a functional interaction between JNK signaling and RIPK1 in age-related progressive cyst development. Thus, they provide a functional linkage between stress adaptation and programmed cell death (PCD) in the maintenance of liver homeostasis during aging.

Liver transplantation meets gastrointestinal cancer.

Liver transplantation (LT) has emerged as a standard of care for patients with end-stage liver disease, providing a life-saving intervention for patients with severely compromised liver function in both the acute and chronic setting. While LT has also become a routine procedure for early-stage hepatocellular carcinoma (HCC), offering a potential cure by treating both the tumor and the underlying liver disease, its relevance in the context of other malignancies such as cholangiocellular carcinoma (CCA), combined hepatocellular-cholangiocarcinoma (cHCC-CCA) or liver metastases is still the subject of intense debate and no definite recommendations have yet been established. This review summarizes the current therapeutic standards in the context of LT for gastrointestinal malignancies and provides a reflection and outlook on current scientific and clinical developments.

Infectious mononucleosis is associated with an increased incidence of NAFLD.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) has become the leading cause of liver cirrhosis and hepatocellular carcinoma worldwide. Although various genetic and lifestyle-related risk factors have been identified, its pathophysiology has not yet been fully unravelled. While acute EBV infection in the setting of infectious mononucleosis can lead to acute hepatitis, the long-term hepatic sequelae of infectious mononucleosis are still poorly understood. METHODS: This retrospective cohort study included 13,859 patients with and 13,859 matched individuals without infectious mononucleosis from the Disease Analyzer database (IQVIA). Multivariable Cox regression analyses were used to evaluate the association between infectious mononucleosis and NAFLD. RESULTS: Within 10 years of the index date, 2.64% of patients with infectious mononucleosis and 1.78% of individuals without infectious mononucleosis had been diagnosed with NAFLD (p < .001). The incidence of NAFLD was 263.9 cases per 100,000 person-years among individuals with infectious mononucleosis and 164.5 cases per 100,000 person-years among those without. Multivariable regression analyses indicated that infectious mononucleosis was significantly associated with the incidence of NAFLD (HR: 1.73) both among women (HR: 1.73) and among men (HR: 1.70). In age-stratified analyses, the association between infectious mononucleosis and NAFLD was most pronounced for the groups aged between 41 and 50 years (HR: 2.94) and >50 years (HR: 2.68). CONCLUSION: Infectious mononucleosis is significantly associated with the incidence of NAFLD in a large cohort from Germany. These findings suggest a pathophysiological involvement of EBV in the development of NAFLD and could stimulate research efforts to better understand the pathophysiology of this emerging global medical burden.

A Systematic Analysis of Incidence, Therapeutic Strategies, and In-hospital Mortality of Mallory-Weiss Syndrome in Germany.

BACKGROUND: Mallory-Weiss syndrome (MWS) is a rare cause of upper gastrointestinal bleeding from gaging or vomiting-induced mucosal lacerations at the gastroesophageal junction. Most cases do not require urgent endoscopic intervention due to the mostly self-limiting course. For more severe cases, different hemostasis techniques have been used. In small MWS cohorts, overall mortality was ~5%, but comprehensive data, as well as population-based incidence, treatment recommendations, and outcome parameters such as in-hospital mortality and adverse events, are largely lacking. METHODS: We evaluated current epidemiological trends, therapeutic strategies, and in-hospital Mortality of MWS in Germany based on standardized hospital discharge data provided by the German Federal Statistical Office from 2010 to 2019. RESULTS: A total of 59,291 MWS cases, predominately male (62%), were included into analysis. The mean number of MWS cases in Germany was 5929/year and decreased continuously during the observation period (-4.1%/y). The overall annual incidence rate (as hospitalization cases per 100,000 persons) was 7.5 with the highest incidence rate in the New Federal States (8.7). The most common comorbidities were reflux esophagitis (23.6%), diaphragmatic hernia (19.7%), and alcohol abuse (10.9%). The most frequent complication was bleeding anemia (26%), whereas hypovolemic shock (2.9%) was rare. Endoscopic injection was the most commonly performed endoscopic therapy (13.7%), followed by endoscopic clipping (12.8%), whereas the need for surgical therapy was rare (0.1%). Endoscopic combination therapies were used predominantly as a combination of injection and clipping. The overall in-hospital mortality was 2.7% and did not differ through the observation period. The presence of hypovolemic shock, acute kidney injury, sepsis, artificial ventilation, adult respiratory distress syndrome, bleeding anemia, and female sex was associated with a significantly worse prognosis. CONCLUSION: Our study gives a detailed insight into the incidence, patient-related risk factors, endoscopic treatment, and overall in-hospital mortality as well as regional differences in a large MWS collective in Germany. Furthermore, we were able to identify mortality-associated complications and their impact.

Drug landscape in patients receiving general outpatient palliative care in Germany: results from a retrospective analysis of 10,464 patients.

BACKGROUND: According to § 27 and § 87 1b of the German Social Code, Book V, general outpatient palliative care (GOPC) aims to promote, maintain, and improve the quality of life and self-determination of seriously ill people. It should enable them to live in dignity until death in their preferred environment. Instead of a curative approach GOPC treatment focuses on the multiprofessional objective of alleviating symptoms and suffering on a case-by-case basis using medication or other measures, as well as the management of an individual treatment plan. The aim of this study was therefore to investigate to what extent medication differs from 12 months prior GOPC treatment within 12 months following GOPC treatment. METHODS: A retrospective database cross sectional study based on the IQVIA Disease Analyzer (DA) was performed, including adult patients with cancer diagnosis and at least one documentation of palliative support between January 1st, 2018 and December 31st, 2021, in 805 general practices (GP). RESULTS: The results of this study show, that in the context of general general outpatient palliative care, there is a significant increase in the prescription of opioids (18.3% vs. 37.7%), sedatives (7.8% vs. 16.2%) and antiemetics (5.3% vs. 9.7%), as well as a significant reduction in other medications such as statins (21.4% vs. 11.5%), proton pump inhibitors (PPI) (41.2% vs. 35.3%), or antihypertensives (57.5% vs. 46.6%). CONCLUSIONS: Our results support the role of GOPC as an important element in improving pharmacological symptom control and deprescription to improve quality of life of patients at the end of their life.

Clinical determinants of hospital mortality in liver failure: a comprehensive analysis of 62,717 patients.

BACKGROUND: Liver failure (LF) is characterised by a loss of the synthetic and metabolic liver function and is associated with a high mortality. Large-scale data on recent developments and hospital mortality of LF in Germany are missing. A systematic analysis and careful interpretation of these datasets could help to optimise outcomes of LF. METHODS: We used standardised hospital discharge data of the Federal Statistical Office to evaluate current trends, hospital mortality and factors associated with an unfavourable course of LF in Germany between 2010 and 2019. RESULTS: A total of 62,717 hospitalised LF cases were identified. Annual LF frequency decreased from 6716 (2010) to 5855 (2019) cases and was higher among males (60.51%). Hospital mortality was 38.08% and significantly declined over the observation period. Mortality significantly correlated with patients' age and was highest among individuals with (sub)acute LF (47.5%). Multivariate regression analyses revealed pulmonary (ORARDS: 2.76, ORmechanical ventilation: 6.46) and renal complications (ORacute kidney failure: 2.04, ORhepatorenal syndrome: 2.92) and sepsis (OR: 1.92) as factors for increased mortality. Liver transplantation reduced mortality in patients with (sub)acute LF. Hospital mortality significantly decreased with the annual LF case volume and ranged from 47.46% to 29.87% in low- or high-case-volume hospitals, respectively. CONCLUSIONS: Although incidence rates and hospital mortality of LF in Germany have constantly decreased, hospital mortality has remained at a very high level. We identified a number of variables associated with increased mortality that could help to improve framework conditions for the treatment of LF in the future.

Obesity and lipid metabolism disorders determine the risk for development of long COVID syndrome: a cross-sectional study from 50,402 COVID-19 patients.

PURPOSE: Metabolic disorders have been identified as major risk factors for severe acute courses of COVID-19. With decreasing numbers of infections in many countries, the long COVID syndrome (LCS) represents the next major challenge in pandemic management, warranting the precise definition of risk factors for LCS development. METHODS: We identified 50,402 COVID-19 patients in the Disease Analyzer database (IQVIA) featuring data from 1056 general practices in Germany. Multivariate logistic regression analysis was used to identify risk factors for the development of LCS. RESULTS: Of the 50,402 COVID-19 patients included into this analysis, 1,708 (3.4%) were diagnosed with LCS. In a multivariate regression analysis, we identified lipid metabolism disorders (OR 1.46, 95% CI 1.28-1.65, p < 0.001) and obesity (OR 1.25, 95% CI 1.08-1.44, p = 0.003) as strong risk factors for the development of LCS. Besides these metabolic factors, patients' age between 46 and 60 years (compared to age ≤ 30, (OR 1.81 95% CI 1.54-2.13, p < 0.001), female sex (OR 1.33, 95% CI 1.20-1.47, p < 0.001) as well as pre-existing asthma (OR 1.67, 95% CI 1.39-2.00, p < 0.001) and depression (OR 1.27, 95% CI 1.09-1.47, p = < 0.002) in women, and cancer (OR 1.4, 95% CI 1.09-1.95, p = < 0.012) in men were associated with an increased likelihood of developing LCS. CONCLUSION: Lipid metabolism disorders and obesity represent age-independent risk factors for the development of LCS, suggesting that metabolic alterations determine the risk for unfavorable disease courses along all phases of COVID-19.

Overlap between irritable bowel syndrome and common gastrointestinal diagnoses: a retrospective cohort study of 29,553 outpatients in Germany.

BACKGROUND: Irritable bowel syndrome (IBS) represents the most common functional disorder of the gastrointestinal tract. Many patients with IBS display complex gastrointestinal (GI) symptoms leading to overlapping diagnosis of IBS and other GI diseases in many patients. METHODS: Using the Disease Analyzer database (IQVIA) featuring patients treated within 2010 and 2019 within 1240 general practices in Germany, we analyzed the prevalence of common GI diseases within 12 months prior to and after the first diagnosis of IBS. RESULTS: 65,569 patients with an initial diagnosis of IBS were included into the analysis. Out of these, 29,553 patients had an observation time of at least 12 months prior to the first IBS diagnosis and at least 12 months after the first IBS diagnosis. Mean age was 48.8 (SD: 18.4) years, 65.0% were female. Notably, 16,164 (55%) of these patients had at least one preexisting diagnosis of another GI diseases within 12 months prior to the first IBS diagnosis. Most common overlapping diagnoses were intestinal infectious diseases (26%), gastritis/ duodenitis (21%), diseases of the esophagus (15%), non-infectious enteritis or colitis (7.4%), functional dyspepsia (6%) and ulcers (1.0%). Additionally, 12,048 (41%) received one of these diagnosis within 12 months after the first IBS diagnosis. CONCLUSION: Our data provide evidence for a high overlap between IBS and other GI diagnoses. Moreover, we show that IBS is frequently diagnosed in patients with preexisting GI diseases, potentially putting into question the validity of IBS diagnosis at least in some cases.

Elevated Serum Levels of CCL23 Are Associated with Poor Outcome after Resection of Biliary Tract Cancer.

Background: Surgical tumor resection is the only potentially curative treatment option for patients with biliary tract cancer (BTC). However, 5-year survival rates are still below 50% mainly due to tumor recurrence. The preoperative identification of ideal surgical candidates has remained a major challenge and easily accessible algorithms including parameters of the individual tumor biology are missing. Chemokine (C-C motif) ligand 23 (CCl23) has been associated with tumor progression in hepatocellular carcinoma (HCC), but its role in the context of BTC is largely unknown. Here, we evaluated circulating levels of CCL23 as potential diagnostic and prognostic biomarker in patients with resectable BTC. Methods: CCl23 serum levels were analyzed by multiplex immunoassay in a cohort of 119 BTC patients receiving surgical tumor resection as well as 50 healthy control samples and 11 patients with primary sclerosing cholangitis (PSC). Results: Baseline serum CCL23 levels were significantly elevated in BTC patients compared to PSC patients as well as healthy controls. CCL23 increased the diagnostic sensitivity and specificity of established tumor markers including CA19-9 and correlated with patients' age and makers of systemic inflammation. Elevated preoperative CCL23 levels were associated with a significantly impaired postoperative outcome. BTC patients with a preoperative CCL23 level above the optimal prognostic cut-off value of 702.4 pg/ml showed a median OS of only 110 days compared to 501 days for patients with low initial CCL23 levels. The prognostic value of circulating CCL23 was confirmed in Cox-regression analysis. Conclusion: Serum levels of CCL23 are elevated in patients with BTC, and high preoperative CCL23 levels were associated with an impaired postoperative survival. CCL23 serum levels could help to identify the ideal surgical candidates for BTC resection in the future.

Teratomatous Elements in Orchiectomy Specimens Are Associated with a Reduced Relapse-Free Survival in Metastasized Testicular Germ Cell Tumors.

INTRODUCTION: The impact of teratomatous elements in orchiectomy specimens of metastasized testicular germ cell tumors (TGCT) regarding oncological outcome is still unclear. METHODS: We performed a retrospective analysis including 146 patients with metastasized TGCT analysing patient characteristics. RESULTS: Twenty-six (18%) of all patients showed teratomatous elements in the orchiectomy specimens. TGCT with teratomatous elements showed a significantly higher frequency of clinical-stage 2C-3 disease (73 vs. 49%, p = 0.031), visceral metastases (58 vs. 32%, p = 0.015), and poor prognosis (p = 0.011) than TGCT without teratomatous elements. Teratoma-containing TGCT revealed a significantly higher rate of post-chemotherapy retroperitoneal lymph node dissection (PC-RPLND, 54 vs. 32%, p = 0.041), with teratomatous elements being more often present in the PC-RPLND specimens (43 vs. 11%, p = 0.020) than nonteratoma-containing primaries. In the Kaplan-Meier estimates, the presence of teratomatous elements in orchiectomy specimens was associated with a significantly reduced relapse-free survival (RFS) (p = 0.049) during a median follow-up of 36 months (10-115.5). CONCLUSIONS: The presence of teratomatous elements in orchiectomy specimens is associated with an advanced tumor stage, worse treatment response as well as a reduced RFS in metastasized TGCT. Consequently, the presence of teratomatous elements might act as a reliable stratification tool for treatment decision in TGCT patients.

Non-alcoholic fatty liver disease (NAFLD) is associated with an increased incidence of osteoporosis and bone fractures.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) and osteoporosis are common diseases with a rising incidence worldwide. Both diseases occur in similar patient populations, however, data on their mutual influence are conflicting. Here, we aimed to evaluate the impact of NAFLD on the incidence of osteoporosis and fractures by using the Disease Analyzer database featuring data on diagnoses, prescriptions, and demographic aspects of 7.49 million cases followed in general practices in Germany. METHODS: A total of 50,689 patients with NAFLD diagnosed between 2000 and 2015 were matched by age, sex, index year, and 3 comorbidities (obesity, diabetes mellitus, and vitamin D/calcium deficiency) to a cohort of equal size without NAFLD. Incidence of osteoporosis and bone fractures were compared between both groups within 10 years from the index date. RESULTS: Within the observation period, the incidence of osteoporosis was significantly higher in the NAFLD group (6.4%) compared to patients without NAFLD (5.1%; log-rank, p < 0.001). Similar results were observed for bone fractures (12.6 vs. 10.3 %; log-rank p < 0.001). The difference was more pronounced in women compared to men and observed in all age groups >50 years of age. CONCLUSION: Our data show that NAFLD is significantly associated with osteoporosis as well as bone fractures in a large cohort of patients followed in German general practices. This finding suggests that NAFLD patients might benefit from improved monitoring for the occurrence of bone demineralization and osteoporosis, which in turn could trigger preventive therapeutic measures.

Current epidemiological trends and in-hospital mortality of acute pancreatitis in Germany: a systematic analysis of standardized hospital discharge data between 2008 and 2017.

BACKGROUND: Acute pancreatitis (AP) represents a common gastrointestinal disorder. Complicated disease courses in particular still represent a major clinical challenge and are associated with high mortality. Evaluation of existing data sets and their careful interpretation can support a rational discussion to optimize outcomes of this common gastrointestinal disease. METHODS: We used standardized hospital discharge data provided by the Federal Statistical Office of Germany to evaluate hospital mortality and current developments of AP in Germany between 2008 and 2017. RESULTS: In this analysis, 516,618 hospitalized AP cases were included. Main disease etiologies featured biliary (29.9%) and alcoholic (22.7%) AP. The annual frequency of AP increased from 48,858 (2008) to 52,611 (2017), mainly due to a rising incidence of biliary AP. Average hospital mortality was 2.85% and significantly improved over time. While uncomplicated AP had low hospital mortality (1.38%), the presence of organ complications was associated with a mortality of 12.34%. The necessity of mechanical ventilation dramatically increased hospital mortality to 44.06%. Hospital mortality was significantly higher in female patients (3.31%) than males (2.55%) and showed a stepwise increase with patient age. We further identified type 2 diabetes mellitus and obesity as factors associated with increased hospital mortality. Hospital mortality was lowest among patients treated at departments specializing in gastroenterology. Finally, high case volume centers (defined as >98 annual AP cases) had the lowest hospital mortality for patients with complicated courses of AP. CONCLUSION: With over 50,000 annual hospitalization cases, AP is one of the most important inpatient treatment indications in gastroenterology in Germany. Overall, AP mortality has improved in recent years, presumably due to improved interdisciplinary treatment concepts. In this study, we identified important clinical and epidemiological risk factors for an unfavorable course, which could help to improve risk prediction and triaging, and thus the management of AP.