[Gender-specific differences in the development of colorectal cancer in Lynch syndrome patients-A systematic review]. / Geschlechtsspezifische Unterschiede in der Entwicklung kolorektaler Karzinome bei Lynch-Syndrom-Betroffenen ­ ein systematisches Review.

BACKGROUND: Lynch syndrome (LS) is the most frequent hereditary tumor syndrome and is associated with an increased risk of colorectal cancer (CRC). While gene-specific and age-specific differences are considered in patient surveillance, gender-specific risks in the development of CRC have been reported in many studies but are not consistently documented. OBJECTIVE: This systematic review aims to investigate gender-specific differences in CRC development among LS patients. MATERIAL AND METHODS: A systematic literature search following PRISMA 2020 guidelines was conducted in the PubMed, Ovid, The Cochrane Library and Web of Science databases. A total of 688 studies were screened, and 41 met the inclusion criteria. RESULTS: Men have a higher risk of CRC and develop CRC earlier compared to women. CONCLUSION: These findings indicate gender-specific differences in the risk of CRC among LS patients, although they do not currently justify separate surveillance strategies.

An artificial intelligence-assisted system versus white light endoscopy alone for adenoma detection in individuals with Lynch syndrome (TIMELY): an international, multicentre, randomised controlled trial.

BACKGROUND: Computer-aided detection (CADe) systems for colonoscopy have been shown to increase small polyp detection during colonoscopy in the general population. People with Lynch syndrome represent an ideal target population for CADe-assisted colonoscopy because adenomas, the primary cancer precursor lesions, are characterised by their small size and higher likelihood of showing advanced histology. We aimed to evaluate the performance of CADe-assisted colonoscopy in detecting adenomas in individuals with Lynch syndrome. METHODS: TIMELY was an international, multicentre, parallel, randomised controlled trial done in 11 academic centres and six community centres in Belgium, Germany, Italy, and Spain. We enrolled individuals aged 18 years or older with pathogenic or likely pathogenic MLH1, MSH2, MSH6, or EPCAM variants. Participants were consecutively randomly assigned (1:1) to either CADe (GI Genius) assisted white light endoscopy (WLE) or WLE alone. A centre-stratified randomisation sequence was generated through a computer-generated system with a separate randomisation list for each centre according to block-permuted randomisation (block size 26 patients per centre). Allocation was automatically provided by the online AEG-REDCap database. Participants were masked to the random assignment but endoscopists were not. The primary outcome was the mean number of adenomas per colonoscopy, calculated by dividing the total number of adenomas detected by the total number of colonoscopies and assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT04909671. FINDINGS: Between Sept 13, 2021, and April 6, 2023, 456 participants were screened for eligibility, 430 of whom were randomly assigned to receive CADe-assisted colonoscopy (n=214) or WLE (n=216). 256 (60%) participants were female and 174 (40%) were male. In the intention-to-treat analysis, the mean number of adenomas per colonoscopy was 0·64 (SD 1·57) in the CADe group and 0·64 (1·17) in the WLE group (adjusted rate ratio 1·03 [95% CI 0·72-1·47); p=0·87). No adverse events were reported during the trial. INTERPRETATION: In this multicentre international trial, CADe did not improve the detection of adenomas in individuals with Lynch syndrome. High-quality procedures and thorough inspection and exposure of the colonic mucosa remain the cornerstone in surveillance of Lynch syndrome. FUNDING: Spanish Gastroenterology Association, Spanish Society of Digestive Endoscopy, European Society of Gastrointestinal Endoscopy, Societat Catalana de Digestologia, Instituto Carlos III, Beca de la Marato de TV3 2020. Co-funded by the European Union.

[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.

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.

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.

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.

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.

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.

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.

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.

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.

Complement activation induces excessive T cell cytotoxicity in severe COVID-19.

Severe COVID-19 is linked to both dysfunctional immune response and unrestrained immunopathology, and it remains unclear whether T cells contribute to disease pathology. Here, we combined single-cell transcriptomics and single-cell proteomics with mechanistic studies to assess pathogenic T cell functions and inducing signals. We identified highly activated CD16+ T cells with increased cytotoxic functions in severe COVID-19. CD16 expression enabled immune-complex-mediated, T cell receptor-independent degranulation and cytotoxicity not found in other diseases. CD16+ T cells from COVID-19 patients promoted microvascular endothelial cell injury and release of neutrophil and monocyte chemoattractants. CD16+ T cell clones persisted beyond acute disease maintaining their cytotoxic phenotype. Increased generation of C3a in severe COVID-19 induced activated CD16+ cytotoxic T cells. Proportions of activated CD16+ T cells and plasma levels of complement proteins upstream of C3a were associated with fatal outcome of COVID-19, supporting a pathological role of exacerbated cytotoxicity and complement activation in COVID-19.

The Different Immune Profiles of Normal Colonic Mucosa in Cancer-Free Lynch Syndrome Carriers and Lynch Syndrome Colorectal Cancer Patients.

BACKGROUND & AIMS: Owing to the high load of immunogenic frameshift neoantigens, tumors arising in individuals with Lynch syndrome (LS), the most common inherited colorectal cancer (CRC) syndrome, are characterized by a pronounced immune infiltration. However, the immune status of normal colorectal mucosa in LS is not well characterized. We assessed the immune infiltrate in tumor-distant normal colorectal mucosa from LS CRC patients, sporadic microsatellite-unstable (MSI) and microsatellite-stable (MSS) CRC patients, and cancer-free LS carriers. METHODS: CD3-positive, FOXP3-positive, and CD8-positive T cells were quantified in, respectively, 219, 233, and 201 formalin-fixed paraffin-embedded (FFPE) normal colonic mucosa tissue sections from CRC patients and cancer-free LS carriers and 26, 22, and 19 LS CRCs. CD3-positive T cells were also quantified in an independent cohort of 97 FFPE normal rectal mucosa tissue sections from LS carriers enrolled in the CAPP2 clinical trial. The expression of 770 immune-relevant genes was analyzed in a subset of samples with the use of the NanoString nCounter platform. RESULTS: LS normal mucosa specimens showed significantly elevated CD3-, FOXP3-, and CD8-positive T-cell densities compared with non-LS control specimens. Gene expression profiling and cluster analysis revealed distinct immune profiles in LS carrier mucosa with and without cancer manifestation. Long-term follow-up of LS carriers within the CAPP2 trial found a correlation between mucosal T-cell infiltrate and time to subsequent tumor occurrence. CONCLUSIONS: LS carriers show elevated mucosal T-cell infiltration even in the absence of cancer. The normal mucosa immune profile may be a temporary or permanent tumor risk modifier in LS carriers.

Adenoma and colorectal cancer risks in Lynch syndrome, Lynch-like syndrome and familial colorectal cancer type X.

Lynch syndrome (LS), Lynch-like syndrome (LLS) and familial colorectal cancer type X (FCCX) are different entities of familial cancer predisposition leading to an increased risk of colorectal cancer (CRC). The aim of this prospective study was to characterise and to compare the risks for adenoma and CRC in these three risk groups. Data was taken from the registry of the German Consortium for Familial Intestinal Cancer. Patients were prospectively followed up in an intensified colonoscopic surveillance programme that included annual examinations. Cumulative risks for adenoma and CRC were calculated separately for LS, LLS and FCCX, and then for males and females. Multivariate Cox regression was used to analyse the independent contributions of risk group, mismatch repair gene (within LS), sex and previous adenoma. The study population comprised 1448 individuals (103 FCCX, 481 LLS and 864 LS). The risks were similar for colorectal adenomas, but different for first and metachronous CRC between the three risk groups. CRC risk was highest in LS, followed by LLS and lowest in FCCX. Male sex and a prevalent adenoma in the index colonoscopy were associated with a higher risk for incident adenoma and CRC. In patients with LS, CRC risks were particularly higher in female MSH2 than MLH1 carriers. Our study may support the development of risk-adapted surveillance policies in LS, LLS and FCCX.

Early IFN-α signatures and persistent dysfunction are distinguishing features of NK cells in severe COVID-19.

Longitudinal analyses of the innate immune system, including the earliest time points, are essential to understand the immunopathogenesis and clinical course of coronavirus disease (COVID-19). Here, we performed a detailed characterization of natural killer (NK) cells in 205 patients (403 samples; days 2 to 41 after symptom onset) from four independent cohorts using single-cell transcriptomics and proteomics together with functional studies. We found elevated interferon (IFN)-α plasma levels in early severe COVD-19 alongside increased NK cell expression of IFN-stimulated genes (ISGs) and genes involved in IFN-α signaling, while upregulation of tumor necrosis factor (TNF)-induced genes was observed in moderate diseases. NK cells exert anti-SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) activity but are functionally impaired in severe COVID-19. Further, NK cell dysfunction may be relevant for the development of fibrotic lung disease in severe COVID-19, as NK cells exhibited impaired anti-fibrotic activity. Our study indicates preferential IFN-α and TNF responses in severe and moderate COVID-19, respectively, and associates a prolonged IFN-α-induced NK cell response with poorer disease outcome.

Early detection of duodenal cancer by upper gastrointestinal-endoscopy in Lynch syndrome.

Small bowel cancer (SBC) is the malignancy with the highest standardized incidence ratio in Lynch syndrome (LS) patients. Of all SBCs, about 50% are duodenal cancers (DCs), therefore being accessible by esophago-gastro-duodenoscopy (EGD) for surveillance. We asked whether early detection of DC is possible for LS patients undergoing surveillance by EGD and if surveillance should be limited to specific subgroups. Data for LS patients with DC were retrieved from the registry of the German Consortium for Familial Intestinal Cancer. Patients undergoing active surveillance by EGDs (surveillance group) were compared to those who did not (nonsurveillance group) regarding tumor stage at diagnosis. Union for International Cancer Control stages I-IIA were defined as early stage disease and IIB-IV as advanced stage disease. Statistical analysis was performed using Fisher's exact test. Among 2015 patients with pathogenic variants in any mismatch-repair-gene, 47 patients with 49 DCs were identified. In 10% of cases, patients were under 35 years at diagnosis; family and personal tumor history did not correlate with DC diagnosis. Pathogenic germline variants in MSH6, PMS2 or EPCAM were present in 10% of patients. Statistical analysis could be performed on 13 DC patients in the surveillance group and 14 in the nonsurveillance group. Early detection was possible for 71% of patients in the surveillance group and 29% of patients in the nonsurveillance group (P = .021). Early detection of DC by EGD in LS patients is feasible regardless of family history, mutational status and should start no later than 25 years of age.

Swarm Learning for decentralized and confidential clinical machine learning.

Fast and reliable detection of patients with severe and heterogeneous illnesses is a major goal of precision medicine1,2. Patients with leukaemia can be identified using machine learning on the basis of their blood transcriptomes3. However, there is an increasing divide between what is technically possible and what is allowed, because of privacy legislation4,5. Here, to facilitate the integration of any medical data from any data owner worldwide without violating privacy laws, we introduce Swarm Learning-a decentralized machine-learning approach that unites edge computing, blockchain-based peer-to-peer networking and coordination while maintaining confidentiality without the need for a central coordinator, thereby going beyond federated learning. To illustrate the feasibility of using Swarm Learning to develop disease classifiers using distributed data, we chose four use cases of heterogeneous diseases (COVID-19, tuberculosis, leukaemia and lung pathologies). With more than 16,400 blood transcriptomes derived from 127 clinical studies with non-uniform distributions of cases and controls and substantial study biases, as well as more than 95,000 chest X-ray images, we show that Swarm Learning classifiers outperform those developed at individual sites. In addition, Swarm Learning completely fulfils local confidentiality regulations by design. We believe that this approach will notably accelerate the introduction of precision medicine.