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Background and Aims In patients with acute liver failure (ALF) who suffer from massive hepatocyte loss, liver progenitor cells (LPCs) take over key hepatocyte functions, which ultimately determines survival. This study investigated how the expression of hepatocyte nuclear factor 4 alpha (HNF4 alpha), its regulators, and targets in LPCs determines clinical outcome of patients with ALF. Approach and Results Clinicopathological associations were scrutinized in 19 patients with ALF (9 recovered and 10 receiving liver transplantation). Regulatory mechanisms between follistatin, activin, HNF4 alpha, and coagulation factor expression in LPC were investigated in vitro and in metronidazole-treated zebrafish. A prospective clinical study followed up 186 patients with cirrhosis for 80 months to observe the relevance of follistatin levels in prevalence and mortality of acute-on-chronic liver failure. Recovered patients with ALF robustly express HNF4 alpha in either LPCs or remaining hepatocytes. As in hepatocytes, HNF4 alpha controls the expression of coagulation factors by binding to their promoters in LPC. HNF4 alpha expression in LPCs requires the forkhead box protein H1-Sma and Mad homolog 2/3/4 transcription factor complex, which is promoted by the TGF-beta superfamily member activin. Activin signaling in LPCs is negatively regulated by follistatin, a hepatocyte-derived hormone controlled by insulin and glucagon. In contrast to patients requiring liver transplantation, recovered patients demonstrate a normal activin/follistatin ratio, robust abundance of the activin effectors phosphorylated Sma and Mad homolog 2 and HNF4 alpha in LPCs, leading to significantly improved coagulation function. A follow-up study indicated that serum follistatin levels could predict the incidence and mortality of acute-on-chronic liver failure. Conclusions These results highlight a crucial role of the follistatin-controlled activin-HNF4 alpha-coagulation axis in determining the clinical outcome of massive hepatocyte loss-induced ALF. The effects of insulin and glucagon on follistatin suggest a key role of the systemic metabolic state in ALF.

INTRODUCTION Chronic kidney disease (CKD) is associated with significant morbidity and mortality after lung transplantation (LTX). Calcineurin inhibitor (CNI) nephrotoxicity is the leading cause of CKD. After kidney transplantation, polyomavirus-associated nephropathy (PyVAN) is a well-recognized problem. This study aims to evaluate the role of polyomavirus in patients after LTX. METHODS From January 2017 to January 2020, all lung transplant recipients who performed follow-up visits in our center were included in the study and retrospectively assessed. We measured renal function (creatinine levels before and after transplantation), JCPyV, and BKPyV load by polymerase chain reaction (PCR) in serum and urine samples after transplantation. RESULTS In total, 104 consecutive patients (59 males, 56.7%) with a mean age of 49.6 ± 11.1 years were identified. JCPyV was found in urine of 36 patients (34.6%) and serum of 3 patients (2.9%). BKPyV was found in urine of 40 patients (38.5%) and serum of 4 patients (3.8%), respectively. Urine evidence for JCPyV (p

Objective Evaluation of pulmonary function impairment after COVID-19 in persistently symptomatic and asymptomatic patients of all disease severities and characterisation of risk factors. Methods Patients with confirmed SARS-CoV-2 infection underwent prospective follow-up with pulmonary function testing and blood gas analysis during steady-state cycle exercise 4 months after acute illness. Pulmonary function impairment (PFI) was defined as reduction below 80% predicted of DLCOcSB, TLC, FVC, or FEV1. Clinical data were analyzed to identify risk factors for impaired pulmonary function. Results 76 patients were included, hereof 35 outpatients with mild disease and 41 patients hospitalized due to COVID-19. Sixteen patients had critical disease requiring mechanical ventilation, 25 patients had moderate–severe disease. After 4 months, 44 patients reported persisting respiratory symptoms. Significant PFI was prevalent in 40 patients (52.6%) occurring among all disease severities. The most common cause for PFI was reduced DLCOcSB (n = 39, 51.3%), followed by reduced TLC and FVC. The severity of PFI was significantly associated with mechanical ventilation (p p p = 0.014) and in hospitalized patients CT score. A decrease of paO2 > 3 mmHg during cycle exercise occurred in 1/5 of patients after mild disease course. Conclusion We characterized pulmonary function impairment in asymptomatic and persistently symptomatic patients of different severity groups of COVID-19 and identified further risk factors associated with persistently decreased pulmonary function. Remarkably, gas exchange abnormalities were revealed upon cycle exercise in some patients with mild disease courses and no preexisting pulmonary condition.

A fraction of COVID-19 patients progress to a severe disease manifestation with respiratory failure and the necessity of mechanical ventilation. Identifying patients at risk is critical for optimized care and early therapeutic interventions. We investigated the dynamics of SARS-CoV-2 shedding relative to disease severity. We analyzed nasopharyngeal and tracheal shedding of SARS-CoV-2 in 92 patients with diagnosed COVID-19. Upon admission, standardized nasopharyngeal swabs or sputum were collected. If patients were mechanically ventilated, tracheal aspirates were additionally obtained. Viral shedding was quantified by real-time PCR detection of SARS-CoV-2 RNA. 45% (41 of 92) of COVID-19 had a severe disease course with the need for mechanical ventilation (severe group). At week 1, the initial viral shedding determined from nasopharyngeal swabs showed no significant difference between non-severe and severe cases. At week 2, a difference could be observed as the viral shedding remained elevated in severely ill patients. A time course of C-reactive-Protein (CRP), Interleukin-6 (Il-6), and Procalcitonin (PCT) revealed an even more protracted inflammatory response following the delayed drop of virus shedding load in severely ill patients. A significant proportion (47.8%) of patients showed evidence of prolonged viral shedding (>17 days), which was associated with severe disease courses (73.2%). We report that viral shedding does not differ significantly between severe and non-severe cases upon admission to the hospital. Elevated SARS-CoV-2 shedding in the second week of hospitalisation, a systemic inflammatory reaction peaking between second and third week and prolonged viral shedding are associated with a more severe disease course., We report that elevated SARS-CoV-2 shedding in the second week of hospitalisation, a systemic inflammatory reaction peaking between second and third week and prolonged viral shedding are associated with a more severe disease course.

High-grade neuroendocrine neoplasms (NEN) comprise a rare entity. Due to the lack of randomized controlled trials, therapy recommendations were mainly extrapolated from its pulmonary analogue, small cell lung cancer and mostly validated in small retrospective case series. The multicentric Nordic NEC Study of gastro-entero-pancreatic (GEP) and cancer of unknown primary (CUP) high-grade neuroendocrine neoplasms showed a significant disease control upon treatment with etoposide and platinum-based chemotherapies 1. Such a combination with etoposide and a platinum (CE) compound is currently considered standard first-line treatment for high-grade GEP/CUP NEN. High-grade mixed-neuroendocrine-non-neuroendocrine neoplasms (MiNEN) formerly termed mixed adeno-neuroendocrine carcinomas (MANEC) also have a poor prognosis and are generally treated like other high-grade NEN. The CE protocol has significant activity in high-grade NEN and MiNEN, but the response is short-lived in most cases with response rates around 50-60 %. Second-line treatment alternatives are not established so far. The need for additional treatment options is evident.Combination chemotherapy with doxorubicin, cyclophosphamide and vincristine (CAV) showed efficacy in small cell lung carcinoma (SCLC) and was considered standard first-line therapy before the era of etoposide and platinum combinations. Due to a better toxicity profile, doxorubicin was replaced by epirubicin, resulting in the combination of epirubicin, cyclophosphamide and vincristine (abbreviated as EpiCO or CEV).In analogy to SCLC, selected patients with high-grade NEN were treated with the EpiCO regimen in second line (or in one patient first line) at our center. In this report we present the retrospective series of 5 cases with metastatic high-grade GEP/CUP NEN/MiNEN who received chemotherapy according to this protocol.High-grade neuroendokrine Neoplasien (NEN) sind eine seltene Entität. Bisher sind keine randomisierten kontrollierten Studien durchgeführt worden. Therapieempfehlungen sind hauptsächlich von dem pulmonalen Analog, dem kleinzelligen Bronchialkarzinom (SCLC), extrapoliert und in retrospektiven Fallserien validiert. Die multizentrische Nordic-NEC-Studie von gastroenteropathischen (GEP) und „cancer of unknown primary“ (CUP) high-grade neuroendokrinen Neoplasien zeigte ein signifikantes Therapieansprechen auf etoposid- und platinhaltige Kombinationen 1. Diese Kombination ist Standard-Erstlinientherapie für high-grade GEP/CUP NEN. High-grade gemischtzellige neuroendokrine/nicht-neuroendokrine Neoplasien (MiNEN), früher auch als gemischtzellige adenoneuroendokrine Karzinome (MANEC) bezeichnet, zeigen ebenfalls eine schlechte Prognose und werden wie andere high-grade NEN behandelt. Das Carboplatin/Etoposide(CE)-Protokoll zeigt ein Ansprechen von 50–60 % in high-grade NEN und MiNEN, aber Remissionen sind häufig von kurzer Dauer 1. Zweitlinientherapien sind nicht allgemein etabliert.Eine Therapie mit Doxorubicin, Cyclophosphamid und Vincristine (CAV) zeigte Effektivität beim SCLC und galt als Standardchemotherapie vor der Ära von etoposid- und platinhaltigen Zytostatikakombinationen. Aufgrund eines besseren Toxizitätsprofils wurde Doxorubicin durch Epirubicin ersetzt, das daraus resultierende Regime mit Epirubicin, Cyclophosphamid und Vincristin wurde EpiCO oder CEV abgekürzt 4 5 6.In Analogie zum SCLC wurden ausgewählte Patienten mit high-grade NEN mit EpiCO in einem Zweitliniensetting am Universitätsklinikum Regensburg behandelt. In dieser retrospektiven Arbeit berichten wir von 5 Patienten mit metastasiertem high-grade GEP/CUP NEN/MiNEN, die eine Chemotherapie nach diesem Schema erhielten.

In spite of their major impact in cancer therapy, immune checkpoint inhibitors are considered to be contraindicated in liver transplant recipients due to fear of rejection and fatal liver failure. Nevertheless, an increasing number of instances of liver transplant recipients treated with checkpoint inhibitors is being published. We reviewed the reports on 14 known cases of liver transplant recipients who underwent treatment with checkpoint inhibitors and discuss factors likely to determine susceptibility to organ rejection including the choice of the agent and the immunosuppression employed, the assessment of Programmed cell death 1 ligand 1 (PD-L1) status in liver graft biopsies, and the time of treatment initiation.

Background: The clinicopathological significance of the mucinous subtype of colorectal cancer (CRC) remains controversial. As of today, none of the current guidelines differentiate treatment with respect to mucinous or nonmucinous cancer. Due to the lack of substantiated data, best treatment remains unclear and the mucinous subtype of CRC is usually treated along the lines of recommendations for adenocarcinoma of the colon. Methods: We investigated an East-Bavarian cohort of 8,758 patients with CRC. These included 613 (7.0%) patients with a mucinous subtype, who were analyzed for assessing their characteristics in clinical course and for evaluating the efficacy of common chemotherapy protocols. Results and Conclusion: Mucinous CRC was predominantly located in the right hemicolon; it was diagnosed at more advanced stages and occurred with preponderance in women. A higher rate of G3/4 grading was observed at diagnosis (all p < 0.001). An association of mucinous CRC with younger age at initial diagnosis, previously reported by other groups, could not be confirmed. Patients with mucinous stage IV colon cancer demonstrated poorer survival (p = 0.006). In contrast, no differences in survival were observed for specific stages I–III colon cancer. Stage-dependent analysis of rectal cancer stages I–IV also showed no differences in survival. However, univariable overall analysis resulted in significant poorer survival of mucinous compared to nonmucinous rectal cancer (p = 0.029). Also, combined analysis of all patients with mucinous CRC revealed poorer overall survival (OS) of these patients compared to nonmucinous CRC patients (median 48.4 vs. 60.2 months, p = 0.049) but not in multivariable analysis (p = 0.089). Chemotherapeutic treatment showed comparable efficacy regarding OS for mucinous and nonmucinous cancers in both an adjuvant and palliative setting for colon cancer patients (p values comparing mucinous and nonmucinous cancers < 0.001–0.005).

761 Background: 5-Fluorouracil (5FU), Folinic acid (FA), and Oxaliplatin (FOLFOX) or 5FU, FA, and Irinotecan (FOLFIRI) are standard regimens for palliative chemotherapy of metastatic colon cancer. Since data showing the influence of dose reduction in palliative treatment are rare, the objective of this single center, retrospective study was to further characterize the influence of dose reduction on efficacy of these therapeutic regimens. Methods: 109 patients, diagnosed with stage IV colon cancer between 2004 and 2012 and receiving palliative first-line chemotherapy with either FOLFOX or FOLFIRI regimens in our outpatient clinic were analyzed for treatment efficacy. Patients who received dose reductions due to side effects usually received doses of 80% or lower of per protocol dose. Survival data were obtained from the Regensburg Tumor Registry. Survival analysis was performed using Kaplan-Meier statistical analysis. Results: Dose reduction was independent of age. Major reasons for dose reduction were neutropenia (30%) followed by polyneuropathy (16%) and diarrhea (14%). Dosage was more often reduced in patients receiving FOLFOX based therapy. Two-year survival of FOLFOX and FOLFIRI treated patients was comparable (35%). We observed no significant (p = 0.323) difference on two-year survival in patients receiving a reduction of chemotherapy with dose reduction (48%) compared to standard dose (31%). Further subgroup analysis did not reveal any subgroup of patients suffering from side effects with significantly worse outcome upon dose reduction. In contrast, patients who underwent dose reduction received more cycles of chemotherapy (13.7 vs. 10.8 cycles) and cumulative dosage was similar in both groups. Conclusions: A moderate reduction of chemotherapy due to side effects has no measurable effect on survival in patients with palliative colorectal cancer. This may be partially due to a longer treatment of patients with reduced chemotherapy dosage if side effects are present.

Liver fibrogenesis is a process involving the participation of several cellular components. We described a new role for hepatocytes in the process of fibrogenesis, in which TGFbeta induces expression and secretion of CTGF, another potent profibrogenic cytokine. Recently Interleukin-15 has emerged as a new player in several models of liver damage, but its precise role has not yet been determined. Real Time PCR showed that TGFbeta induces IL-15 mRNA up to 80 fold after 24h in primary hepatocytes, and up to 10 fold in AML12 cells. Using chemical inhibitors we determined that although ALK5 activity is essential, ERK and JNK pathways cooperate in this induction. Two isoforms are expressed, differing in the length of the signal peptide. By PCR we observed induction of both splice variants of IL-15. Using siRNA we determined that Smad3 but not Smad2 is partially necessary for IL-15 mRNA induction. Software analysis of a -1,8kb region of mouse IL-15 promoter revealed binding sites for Smad3, Fast-1 and AP-1 highlighting the potential cooperation between Smad3 and AP-1 complexes. By ELISA we detected IL-15 in cell pellets but not in supernatants, indicating that IL-15 and IL-15/IL-15R complex are not secreted. Immunohistochemistry analysis of mouse and human livers revealed expression of IL-15 in hepatocytes found increased in TGFbeta transgenic mice, and in patients with liver fibrosis due to HBV, Schistosoma japonicum and gallstone bladder. Our results indicate that a new potent cytokine is induced in hepatocytes by TGFbeta. We are currently investigating the biological significance of this finding with regard to TGFbeta induced hepatocyte apoptosis, EMT and fibrotic processes.