[Results of Endoscopic Screening and Therapy of the Duodenum in MUTYH-associated Polyposis]. / Ergebnisse der endoskopischen Vorsorge und Therapie des Duodenums bei MUTYH-assoziierter Polyposis.

MUTYH-associated polyposis (MAP) is a very rare autosomal recessive polyposis syndrome. It is caused by a homozygous or compound heterozygous germline mutation in the MUTYH gene. MAP is characterised by numerous colorectal adenomas; furthermore there is an increased risk for colorectal cancer (CRC). However, the phenotype can be highly variable; for example, affected individuals also have an increased risk of polyps of the upper gastrointestinal tract and development of duodenal carcinomas.This study included 15 patients with evidence of a pathogenic MUTYH variant, who were screened at the National Center for Hereditary Tumor Syndromes. Oesophagogastroduodenoscopy (EGD) results were prospectively recorded in a database from 2012 to 2023.At least one EGD (median 4, range 1-15) was performed in 15 patients, seven of whom carried a homozygous and 8 a compound heterozygous pathogenic MUTYH variant. The median surveillance period was 115 months (range, 3-215 months). The median age at baseline was 44 (range 17-65) years. A total of 72 EGDs were performed (median 4; range 1-15). Five patients had duodenal adenomas; histology showed tubular adenomas with low grade intraepithelial dysplasia (LGIEN) in all of these cases. The total number of duodenal adenomas detected was 48, and the median number was 3 (range, 1-37). Neither high grade intraepithelial neoplasia (HGIEN) nor duodenal cancer was detected during the surveillance period.Patients with MUTYH-associated polyposis should be managed in a multidisciplinary centre for hereditary tumour disease. Our cohort showed more patients with duodenal adenomas than in previously published data. However, no progression to HGIEN or duodenal carcinomas was observed as a result of the endoscopic therapy performed.

IL-6-Dependent STAT3 Activation and Induction of Proinflammatory Cytokines in Primary Sclerosing Cholangitis.

INTRODUCTION: Primary sclerosing cholangitis (PSC) is a rare cholestatic liver disease with periductal inflammation and fibrosis. Genetic studies suggest inflammatory cytokines and IL-6-dependent activation of transcription factor STAT3 as pivotal steps in PSC pathogenesis. However, details of inflammatory regulation remain unclear. METHODS: We recruited 50 patients with PSC (36 with inflammatory bowel disease, 14 without inflammatory bowel disease), 12 patients with autoimmune hepatitis, and 36 healthy controls to measure cytokines in the serum, bile, and immune cell supernatant using bead-based immunoassays and flow cytometry and immunohistochemistry to analyze phosphorylation of STATs in immune cells. Finally, we analyzed cytokines and STAT3 phosphorylation of T cells in the presence of JAK1/2 inhibitors. RESULTS: In PSC, IL-6 specifically triggered phosphorylation of STAT3 in CD4 + T cells and lead to enhanced production of interferon (IFN) gamma and interleukin (IL)-17A. Phospho-STAT3-positive CD4 + T cells correlated with systemic inflammation (C-reactive protein serum levels). Combination of immunohistology and flow cytometry indicated that phospho-STAT3-positive cells were enriched in the peribiliary liver stroma and represented CD4 + T cells with prominent production of IFN gamma and IL-17A. JAK1/2 inhibitors blocked STAT3 phosphorylation and production of IFN gamma and IL-6, whereas IL-17A was apparently resistant to this inhibition. DISCUSSION: Our results demonstrate systemic and local activation of the IL-6/STAT3 pathway in PSC. Resistance of IL-17A to STAT3-targeted inhibition points to a more complex immune dysregulation beyond STAT3 activation.

Identification and characterization of a hepatic IL-13-producing ILC3-like population potentially involved in liver fibrosis.

BACKGROUND AND AIMS: Human innate lymphoid cells (ILCs) are critically involved in the modulation of homeostatic and inflammatory processes in various tissues. However, only little is known about the composition of the intrahepatic ILC pool and its potential role in chronic liver disease. Here, we performed a detailed characterization of intrahepatic ILCs in both healthy and fibrotic livers. APPROACH AND RESULTS: A total of 50 livers (nonfibrotic = 22, and fibrotic = 29) were analyzed and compared with colon and tonsil tissue (each N = 14) and peripheral blood (N = 32). Human intrahepatic ILCs were characterized ex vivo and on stimulation using flow cytometry and single-cell RNA sequencing. ILC differentiation and plasticity were analyzed by both bulk and clonal expansion experiments. Finally, the effects of ILC-derived cytokines on primary human HSteCs were studied. Unexpectedly, we found that an "unconventional" ILC3-like cell represented the major IL-13-producing liver ILC subset. IL-13 + ILC3-like cells were specifically enriched in the human liver, and increased frequencies of this cell type were found in fibrotic livers. ILC3-derived IL-13 production induced upregulation of proinflammatory genes in HSteCs, indicating a potential role in the regulation of hepatic fibrogenesis. Finally, we identified KLRG1-expressing ILC precursors as the potential progenitor of hepatic IL-13 + ILC3-like cells. CONCLUSIONS: We identified a formerly undescribed subset of IL-13-producing ILC3-like cells that is enriched in the human liver and may be involved in the modulation of chronic liver disease.

People living with HIV, HCV and HIV/HCV coinfection in intensive care in a German tertiary referral center 2014-2019.

PURPOSE: The epidemiology of HIV-infected individuals on the Medical Intensive Care Units (MICU) has changed after profound progress in treatment of AIDS-defining illnesses and anti-retroviral therapy (ART). Changes of MICU utilization of Hepatitis C (HCV) patients following roll-out of direct-acting antivirals (DAA) are yet to evaluate. METHODS: We performed a retrospective study on all patients with HIV, HIV/HCV and HCV admitted to the MICU of University Hospital Bonn 2014-2019. We assessed sociodemographic data, available clinical data from HIV patients (CDC stage, CD4 + lymphocyte cell count, HIV-1-RNA, ART) and HCV patients (HCV-RNA, stage of liver cirrhosis, treatment history) and outcome. RESULTS: 237 patients (46 HIV, 22 HIV/HCV, 169 HCV; 168 male, median age 51.3 years) with 325 MICU admissions were included. Admission criteria for HIV patients were infections (39.7% AIDS-associated, 23.8% with controlled HIV-infection) and cardiopulmonary diseases (14.3%). HIV/HCV coinfected patients had infections in controlled/uncontrolled HIV-infection (46.4%), cardiopulmonary diseases and intoxication/drug abuse (17.9% each). Reasons for HCV-mono-infected patients were infections (24.4%), sequelae of liver disease (20.9%), intoxication/drug abuse (18.4%) and cardiopulmonary diseases (15%). 60 patients deceased; most important risk factor was need for mechanical ventilation. The number of HCV-patients admitted to MICU with chronic active disease and sequelae of liver disease decreased while the proportion of patients with completed DAA-treatment increased. CONCLUSION: Infections remain the most important reason for MICU admission in patients with HIV and/or HCV infection while non-AIDS related conditions increased. DAA roll-out has a beneficial effect on liver-associated morbidity in HCV patients admitted to MICU.

High producer variant of lipoprotein lipase may protect from hepatocellular carcinoma in alcohol-associated cirrhosis.

Background & Aims: Progression of alcohol-associated liver disease (ALD) is driven by genetic predisposition. The rs13702 variant in the lipoprotein lipase (LPL) gene is linked to non-alcoholic fatty liver disease. We aimed at clarifying its role in ALD. Methods: Patients with alcohol-associated cirrhosis, with (n = 385) and without hepatocellular carcinoma (HCC) (n = 656), with HCC attributable to viral hepatitis C (n = 280), controls with alcohol abuse without liver damage (n = 366), and healthy controls (n = 277) were genotyped regarding the LPL rs13702 polymorphism. Furthermore, the UK Biobank cohort was analysed. LPL expression was investigated in human liver specimens and in liver cell lines. Results: Frequency of the LPL rs13702 CC genotype was lower in ALD with HCC in comparison to ALD without HCC both in the initial (3.9% vs. 9.3%) and the validation cohort (4.7% vs. 9.5%; p <0.05 each) and compared with patients with viral HCC (11.4%), alcohol misuse without cirrhosis (8.7%), or healthy controls (9.0%). This protective effect (odds ratio [OR] = 0.5) was confirmed in multivariate analysis including age (OR = 1.1/year), male sex (OR = 3.0), diabetes (OR = 1.8), and carriage of the PNPLA3 I148M risk variant (OR = 2.0). In the UK Biobank cohort, the LPL rs13702 C allele was replicated as a risk factor for HCC. Liver expression of LPL mRNA was dependent on LPL rs13702 genotype and significantly higher in patients with ALD cirrhosis compared with controls and alcohol-associated HCC. Although hepatocyte cell lines showed negligible LPL protein expression, hepatic stellate cells and liver sinusoidal endothelial cells expressed LPL. Conclusions: LPL is upregulated in the liver of patients with alcohol-associated cirrhosis. The LPL rs13702 high producer variant confers protection against HCC in ALD, which might help to stratify people for HCC risk. Impact and implications: Hepatocellular carcinoma is a severe complication of liver cirrhosis influenced by genetic predisposition. We found that a genetic variant in the gene encoding lipoprotein lipase reduces the risk for hepatocellular carcinoma in alcohol-associated cirrhosis. This genetic variation may directly affect the liver, because, unlike in healthy adult liver, lipoprotein lipase is produced from liver cells in alcohol-associated cirrhosis.

Single-cell RNA sequencing identifies a population of human liver-type ILC1s.

Group 1 innate lymphoid cells (ILCs) comprise a heterogeneous family of cytotoxic natural killer (NK) cells and ILC1s. We identify a population of "liver-type" ILC1s with transcriptional, phenotypic, and functional features distinct from those of conventional and liver-resident NK cells as well as from other previously described human ILC1 subsets. LT-ILC1s are CD49a+CD94+CD200R1+, express the transcription factor T-BET, and do not express the activating receptor NKp80 or the transcription factor EOMES. Similar to NK cells, liver-type ILC1s produce IFN-γ, TNF-α, and GM-CSF; however, liver-type ILC1s also produce IL-2 and lack perforin and granzyme-B. Liver-type ILC1s are expanded in cirrhotic liver tissues, and they can be produced from blood-derived ILC precursors in vitro in the presence of TGF-ß1 and liver sinusoidal endothelial cells. Cells with similar signature and function can also be found in tonsil and intestinal tissues. Collectively, our study identifies and classifies a population of human cross-tissue ILC1s.

Real-time use of artificial intelligence (CADEYE) in colorectal cancer surveillance of patients with Lynch syndrome-A randomized controlled pilot trial (CADLY).

BACKGROUND: Lynch syndrome (LS), an autosomal dominant disorder caused by pathogenic germline variants in DNA mismatch repair (MMR) genes, represents the most common hereditary colorectal cancer (CRC) syndrome. Lynch syndrome patients are at high risk of CRC despite regular endoscopic surveillance. OBJECTIVE: Our aim was to investigate the diagnostic performance of artificial intelligence (AI)-assisted colonoscopy in comparison to High-Definition white-light endoscopy (HD-WLE) for the first time. METHODS: Patients ≥18 years with LS, with a pathogenic germline variant (MLH1, MHS2, MSH6), and at least one previous colonoscopy (interval 10-36 months) were eligible. Patients were stratified by previous CRC and affected MMR gene with a 1:1 allocation ratio (AI-assisted vs. HD white-light endoscopy) in this exploratory pilot trial. RESULTS: Between Dec-2021 and Dec-2022, 101 LS patients were randomised and 96 patients were finally analyzed after exclusion of 5 patients due to insufficient bowel preparation. In the HD-WLE arm, adenomas were detected in 12/46 patients compared to 18/50 in the AI arm (26.1% [95% CI 14.3-41.1] vs. 36.0% [22.9-50.8]; p = 0.379). The use of AI-assisted colonoscopy especially increased detection of flat adenomas (Paris classification 0-IIb) (examinations with detected flat adenomas: 3/46 [6.5%] vs. 10/50 [20%]; p = 0.07; numbers of detected flat adenomas: 4/20 vs. 17/30, p = 0.018). The median withdrawal time did not differ significantly between HD-WLE and AI (14 vs. 15 min; p = 0.170). CONCLUSION: We here present first data suggesting that real-time AI-assisted colonoscopy is a promising approach to optimize endoscopic surveillance in LS patients, in particular to improve the detection of flat adenomas.

Is HLA type a possible cancer risk modifier in Lynch syndrome?

Lynch syndrome (LS) is the most common inherited cancer syndrome. It is inherited via a monoallelic germline variant in one of the DNA mismatch repair (MMR) genes. LS carriers have a broad 30% to 80% risk of developing various malignancies, and more precise, individual risk estimations would be of high clinical value, allowing tailored cancer prevention and surveillance. Due to MMR deficiency, LS cancers are characterized by the accumulation of frameshift mutations leading to highly immunogenic frameshift peptides (FSPs). Thus, immune surveillance is proposed to inhibit the outgrowth of MMR-deficient cell clones. Recent studies have shown that immunoediting during the evolution of MMR-deficient cancers leads to a counter-selection of highly immunogenic antigens. The immunogenicity of FSPs is dependent on the antigen presentation. One crucial factor determining antigen presentation is the HLA genotype. Hence, a LS carrier's HLA genotype plays an important role in the presentation of FSP antigens to the immune system, and may influence the likelihood of progression from precancerous lesions to cancer. To address the challenge of clarifying this possibility including diverse populations with different HLA types, we have established the INDICATE initiative (Individual cancer risk by HLA type, http://indicate-lynch.org/), an international network aiming at a systematic evaluation of the HLA genotype as a possible cancer risk modifier in LS. Here we summarize the current knowledge on the role of HLA type in cancer risk and outline future research directions to delineate possible association in the scenario of LS with genetically defined risk population and highly immunogenic tumors.

A simple approach for detecting HLA-A*02 alleles in archival formalin-fixed paraffin-embedded tissue samples and an application example for studying cancer immunoediting.

The HLA system represents a central component of the antigen presentation machinery. As every patient possesses a defined set of HLA molecules, only certain antigens can be presented on the cell surface. Thus, studying HLA type-dependent antigen presentation can improve the understanding of variation in susceptibility to various diseases, including infectious diseases and cancer. In archival formalin-fixed paraffin-embedded (FFPE) tissue, the HLA type is difficult to analyze because of fragmentation of DNA, hindering the application of commonly used assays that rely on long DNA stretches. Addressing these difficulties, we present a refined approach for characterizing presence or absence of HLA-A*02, the most common HLA-A allele in the Caucasian population, in archival samples. We validated our genotyping strategy in a cohort of 90 samples with HLA status obtained by an NGS-based method. 90% (n = 81) of the samples could be analyzed with the approach. For all of them, the presence or absence of HLA-A*02 alleles was correctly determined with the method, demonstrating 100% sensitivity and specificity (95% CI: 91.40%-100% and 91.19%-100%). Furthermore, we provide an example of application in an independent cohort of 73 FFPE microsatellite-unstable (MSI) colorectal cancer samples. As MSI cancer cells encompass a high number of mutations in coding microsatellites, leading to the generation of highly immunogenic frameshift peptide antigens, they are ideally suited for studying relations between the mutational landscape of tumor cells and interindividual differences in the immune system, including the HLA genotype. Overall, our method can help to promote studying HLA type-dependency during the pathogenesis of a wide range of diseases, making archival and historic tissue samples accessible for identifying HLA-A*02 alleles.

Persisting dental foci increase the risk for bacterial infections before and after liver transplant.

BACKGROUND: Patients awaiting liver transplant are usually assessed for presence of dental foci to prevent bacterial infection post-transplant, but evidence to support dental examination and treatment is limited. We investigated if treatment of dental foci decreased bacterial infections before and after transplant. METHODS: Patients transplanted at the university hospital of Bonn were retrospectively assessed for occurrence of bacterial infections before and after transplant according to presence and treatment of dental foci. RESULTS: 35/110 patients showed good oral health, 39/110 patients received dental care and 36/110 patients did not receive dental care despite poor oral health. Patients with alcohol-associated liver disease presented with the highest rate of dental foci. Bleeding complications due to oral care occurred in five patients with poor coagulation. After transplant, the number of infections per patient was higher in patients with poor oral health (2.9) compared to patients after dental care (1.9) or with good oral health (1.8) (p = .02), with streptococcal infections being more frequent in patients with poor oral health. Before transplant, bacterial infections, in particular bacteraemia and spontaneous bacterial peritonitis, were also more common in patients with untreated dental foci. Streptococci and Staphylococci were more often detected in patients with dental foci. Dental treatment was associated with a reduction in bacterial infections. CONCLUSION: Presence of dental foci is associated with an increased risk for bacterial infections not only after but also before liver transplant. Dental treatment might be a safe and effective procedure to mitigate this risk.

HIV-Associated Microbial Translocation May Affect Cytokine Production of CD56bright NK Cells via Stimulation of Monocytes.

The mechanisms involved in HIV-associated natural killer (NK) cell impairment are still incompletely understood. We observed HIV infection to be associated with increased plasma levels of IFABP, a marker for gut epithelial barrier dysfunction, and LBP, a marker for microbial translocation. Both IFABP and LBP plasma concentrations were inversely correlated with NK cell interferon-γ production, suggesting microbial translocation to modulate NK cell functions. Accordingly, we found lipopolysaccharide to have an indirect inhibitory effect on NK cells via triggering monocytes' transforming growth factor-ß production. Taken together, our data suggest increased microbial translocation to be involved in HIV-associated NK cell dysfunction.

Genetic variation in TERT modifies the risk of hepatocellular carcinoma in alcohol-related cirrhosis: results from a genome-wide case-control study.

OBJECTIVE: Hepatocellular carcinoma (HCC) often develops in patients with alcohol-related cirrhosis at an annual risk of up to 2.5%. Some host genetic risk factors have been identified but do not account for the majority of the variance in occurrence. This study aimed to identify novel susceptibility loci for the development of HCC in people with alcohol related cirrhosis. DESIGN: Patients with alcohol-related cirrhosis and HCC (cases: n=1214) and controls without HCC (n=1866), recruited from Germany, Austria, Switzerland, Italy and the UK, were included in a two-stage genome-wide association study using a case-control design. A validation cohort of 1520 people misusing alcohol but with no evidence of liver disease was included to control for possible association effects with alcohol misuse. Genotyping was performed using the InfiniumGlobal Screening Array (V.24v2, Illumina) and the OmniExpress Array (V.24v1-0a, Illumina). RESULTS: Associations with variants rs738409 in PNPLA3 and rs58542926 in TM6SF2 previously associated with an increased risk of HCC in patients with alcohol-related cirrhosis were confirmed at genome-wide significance. A novel locus rs2242652(A) in TERT (telomerase reverse transcriptase) was also associated with a decreased risk of HCC, in the combined meta-analysis, at genome-wide significance (p=6.41×10-9, OR=0.61 (95% CI 0.52 to 0.70). This protective association remained significant after correction for sex, age, body mass index and type 2 diabetes (p=7.94×10-5, OR=0.63 (95% CI 0.50 to 0.79). Carriage of rs2242652(A) in TERT was associated with an increased leucocyte telomere length (p=2.12×10-44). CONCLUSION: This study identifies rs2242652 in TERT as a novel protective factor for HCC in patients with alcohol-related cirrhosis.

Genetic Variation of SAMM50 Is Not an Independent Risk Factor for Alcoholic Hepatocellular Carcinoma in Caucasian Patients.

Hepatocellular carcinoma (HCC) is a severe complication of advanced alcoholic liver disease, which is modulated by genetic predisposition. Identifying new genetic loci might improve screening. Genetic variation of SAMM50 was linked to HCC. We aimed to validate this finding in a large cohort of patients with advanced alcoholic liver disease (ALD). A large, well-characterised cohort of patients with alcoholic cirrhosis without (n = 674) and with (n = 386) HCC, as well as controls with HCC due to viral hepatitis (n = 134), controls with heavy alcohol abuse without liver disease (n = 266) and healthy subjects (n = 237), were genotyped for SAMM50 rs3827385 and rs3761472 and for PNPLA3 rs738409. Genotype frequencies were compared between patients with alcohol-associated cirrhosis with and without HCC by uni- and multivariate analysis. Minor variants in both SAMM50 rs3827385 and rs3761472 were significantly more frequent in patients with alcoholic HCC versus alcoholic cirrhosis and versus the control cohorts. An even stronger association was noted for PNPLA3 rs738409. The univariate analysis resulted in an odds ratio (OR) of 1.8 for carriers of at least one minor variant of SAMM50 rs3827385 and rs3761472 (each p < 0.001), but this association was lost in multivariate analysis with age (OR 1.1/year), male sex (OR 3.2), diabetes (OR 1.9) and carriage of PNPLA3 148M (OR 2.1) remaining in the final model. Although minor variants of both SAMM50 loci are strongly associated with alcoholic HCC, this association is not independent of carriage of the well-known risk variant PNPLA3 148M.

No serological evidence for neuronal damage or reactive gliosis in neuro-COVID-19 patients with long-term persistent headache.

Recent studies have indicated that long-term neurological sequelae after COVID-19 are not accompanied by an increase of canonical biomarkers of central nervous system injury in blood, but subgroup stratifications are lacking. This is a particular concern in chronic headache, which can be a leading symptom of Post-COVID diseases associated with neuronal damage such as vasculitis or autoimmune encephalitis. We here compared patients with mild Post-COVID-19 syndrome and persistent headache (persistent Post-COVID-19 headache) lasting longer than 12 weeks after the initial serological diagnosis, to patients with mild and severe COVID-19 and COVID-19-negative controls. Levels of neurofilament light chain and glial fibrillary astrocytic protein, i.e. markers of neuronal damage and reactive astrogliosis, were lower in blood from patients with persistent Post-COVID-19 headache compared to patients with severe COVID-19. Hence, our pilot serological study indicates that long-term Post-COVID-19 headache may not be a sign of underlying neuronal damage or neuroinflammation.

COVID-19 mortality in cirrhosis is determined by cirrhosis-associated comorbidities and extrahepatic organ failure: Results from the multinational LEOSS registry.

BACKGROUND AND OBJECTIVE: International registries have reported high mortality rates in patients with liver disease and COVID-19. However, the extent to which comorbidities contribute to excess COVID-19 mortality in cirrhosis is controversial. METHODS: We used the multinational Lean European Open Survey on SARS-CoV-2-infected patients (LEOSS) to identify patients with cirrhosis documented between March 2020 and March 2021, when the wild-type and alpha variant were predominant. We compared symptoms, disease progression and mortality after propensity score matching (PSM) for age, sex, obesity, smoking status, and concomitant diseases. Mortality was also compared with that of patients with spontaneous bacterial peritonitis (SBP) without SARS-CoV-2 infection, a common bacterial infection and well-described precipitator of acute-on-chronic liver failure. RESULTS: Among 7096 patients with SARS-CoV-2 infection eligible for analysis, 70 (0.99%) had cirrhosis, and all were hospitalized. Risk factors for severe COVID-19, such as diabetes, renal disease, and cardiovascular disease were more frequent in patients with cirrhosis. Case fatality rate in patients with cirrhosis was 31.4% with the highest odds of death in patients older than 65 years (43.6% mortality; odds ratio [OR] 4.02; p = 0.018), Child-Pugh class C (57.1%; OR 4.00; p = 0.026), and failure of two or more organs (81.8%; OR 19.93; p = 0.001). After PSM for demographics and comorbidity, the COVID-19 case fatality of patients with cirrhosis did not significantly differ from that of matched patients without cirrhosis (28.8% vs. 26.1%; p = 0.644) and was similar to the 28-day mortality in a comparison group of patients with cirrhosis and SBP (33.3% vs. 31.5%; p = 1.000). CONCLUSIONS: In immunologically naïve patients with cirrhosis, mortality from wild-type SARS-CoV-2 and the alpha variant is high and is largely determined by cirrhosis-associated comorbidities and extrahepatic organ failure.

Natural Killer Cell-Mediated Antibody-Dependent Cellular Cytotoxicity Against SARS-CoV-2 After Natural Infection Is More Potent Than After Vaccination.

We compared the ability of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike-specific antibodies to induce natural killer cell-mediated antibody-dependent cellular cytotoxicity (ADCC) in patients with natural infection and vaccinated persons. Analyzing plasma samples from 39 coronavirus disease 2019 (COVID-19) patients and 11 vaccinated individuals, significant induction of ADCC could be observed over a period of more than 3 months in both vaccinated and recovered individuals. Although plasma antibody concentrations were lower in recovered patients, we found antibodies elicited by natural infection induced a significantly stronger ADCC response compared to those induced by vaccination, which may affect protection conferred by vaccination.

Mitochondrial Dysfunction Contributes to Impaired Cytokine Production of CD56bright Natural Killer Cells From Human Immunodeficiency Virus-Infected Individuals Under Effective Antiretroviral Therapy.

Human immunodeficiency virus (HIV) infection is associated with impaired natural killer (NK) cell activity, which is only incompletely restored under antiretroviral therapy. Analyzing the bioenergetics profiles of oxygen consumption, we observed that several parameters were significantly reduced in HIV+ NK cells, indicating a mitochondrial defect. Accordingly, we found HIV+ CD56bright NK cells to display a decreased mitochondrial membrane potential and mitochondrial mass. Both parameters were positively correlated with interferon gamma (IFN-γ) production of NK cells. Finally, we demonstrated that stimulation of HIV+ NK cells with MitoTEMPO, a mitochondria-targeting antioxidant, significantly improved IFN-γ production. We identified mitochondrial dysfunction as a mechanism that contributes to impaired NK cell function.

Impact of regular additional endobiliary radiofrequency ablation on survival of patients with advanced extrahepatic cholangiocarcinoma under systemic chemotherapy.

Prognosis of patients with advanced extrahepatic cholangiocarcinoma (eCCA) is poor. The current standard first-line treatment is systemic chemotherapy (CT) with gemcitabine and a platinum derivate. Additionally, endobiliary radiofrequency ablation (eRFA) can be applied to treat biliary obstructions. This study aimed to evaluate the additional benefit of scheduled regular eRFA in a real-life patient cohort with advanced extrahepatic cholangiocarcinoma under standard systemic CT. All patients with irresectable eCCA treated at University Hospital Bonn between 2010 and 2020 were eligible for inclusion. Patients were stratified according to treatment: standard CT (n = 26) vs. combination of eRFA with standard CT (n = 40). Overall survival (OS), progression free survival (PFS), feasibility and toxicity were retrospectively analyzed using univariate and multivariate approaches. Combined eRFA and CT resulted in significantly longer median OS (17.3 vs. 8.6 months, p = 0.004) and PFS (12.9 vs. 5.7 months, p = 0.045) compared to the CT only group. While groups did not differ regarding age, sex, tumor stage and chemotherapy treatment regimen, mean MELD was even higher (10.1 vs. 6.7, p = 0.015) in the eRFA + CT group. The survival benefit of concomitant eRFA was more evident in the subgroup with locally advanced tumors. Severe hematological toxicities (CTCAE grades 3 - 5) did not differ significantly between the groups. However, therapy-related cholangitis occurred more often in the combined treatment group (p = 0.031). Combination of eRFA and systemic CT was feasible, well-tolerated and could significantly prolong survival compared to standard CT alone. Thus, eRFA should be considered during therapeutic decision making in advanced eCCA.