METΔ14ex is the driver alteration for approximately 3% of non-small cell lung cancers (NSCLC) and associated with a higher PD-L1 expression, but unclear benefit from immunotherapy (IO). Seventy-eight consecutive patients with metastatic NSCLC harboring METΔex14 who received first-line IO as monotherapy or chemoimmunotherapy (CHT+IO) in 10 German academic lung cancer centers were analyzed. The median age was 72 years (range 49-86), 34 patients (44%) were female, 47 (60%) were active or former smokers, and 23 (29%) presented with brain metastases. The Eastern Cooperative Group (ECOG) performance status was 0, 1, 2 and 3 in 27 (35%), 28 (36%), 18 (23%) and 4 (5%) cases, respectively. The most common histology was adenocarcinoma (n=61, 78%). IO was given to 43 (55%) patients as monotherapy, and to 35 (45%) combined with CHT. For patients with PD-L1 tumor proportion score (TPS) ≥50% (n=52, 67%), 1-49% (n=14, 18%) and <1% (n=12, 15%), disease control rates (DCR) were 56%, 57% and 100% (p=0.015), respectively. Other efficacy parameters including overall response rate (ORR), median progression-free survival (mPFS) and median overall survival (mOS) by PD-L1 tumor proportion score (TPS) and type of treatment are summarized in the table. Primary progressive disease/early death (before radiologic reassessment) under IO monotherapy, but not under CHT+IO, was significantly associated with never-smoker status (p=0.041). No significant correlations were found between smoking status and PD-L1 TPS (p=0.595). Table: 54PTPS≥50% / IO n=43TPS≥50% / CHT+IO n=9TPS 1-49% / CHT+IO n=14TPS 0% / CHT+IO n=12p-valueORR (%)355643500.599DCR (%)5467571000.030mPFS (mo)346150.520mOS (mo)14515160.690 Open table in a new tab Our exploratory analysis suggests an association between higher PD-L1 TPS and worse clinical outcomes under IO in patients with NSCLC harboring METΔ14ex. Although these results should be interpreted with caution, they contrast the favorable effect of PD-L1 expression for IO efficacy in other NSCLC and underline the need for alternative biomarkers for IO in this patient population.

Abstract Study question How does the gene expression profile of epithelium cells differ between deep infiltrating endometriosis (DIE) and adenomyosis (FA)? Summary answer The gene expression of epithelial cells from DIE reveals a significant upregulation of the PI3K-pathway and downregulation of the RAS-pathway compared to epithelium from FA. What is known already Both DIE and FA, are histologically considered benign but have features of malignant diseases, such as a tendency for local tissue invasion. Recent next generation sequencing studies have detected driver mutations in cancer-associated genes such as PIK3CA, ARID1A, PPP2R1A and KRAS in the epithelium of DIE, as well as in KRAS in epithelium of FA. Furthermore, identical mutations in the KRAS gene were detected in coexisting adenomyotic and endometriotic lesions, supporting the theory of a common molecular mechanism. The gene expression differences between these two entities were therefore investigated in the present study. Study design, size, duration This is an experimental analysis of 7 adenomyosis and 19 DIE samples (histologically confirmed), that were formalin-fixed and paraffin-embedded (FFPE) collected between 2003 and 2018. These were provided by the tissue bank of the National Centre for Tumour Diseases (Heidelberg, Germany), in accordance with the Ethics Committee of the University of Heidelberg (approval number S-362/2017). In addition, the medical and epidemiological data of the corresponding patients were retrospectively analyzed based on the clinical data collected. Participants/materials, setting, methods For this study, the epithelia of FFPE samples were microdissected in a laser-guided fashion. After RNA extraction, the expression of 770 genes was analyzed using the nCounter Technology with the Human PanCancer Pathways Panel (Nanostring). All genes with an adjusted false discovery rate of p < 0.05 and a fold change of < 0.66 or > 1.5 were considered differentially expressed and subjected to functional annotation and clustering using DAVID bioinformatics resources. Main results and the role of chance Our analysis revealed a total of 162 differentially expressed genes, that were either significantly increased (n = 116) or decreased (n = 46) in epithelium of DIE compared to that of FA (with log2 fold changes of < 0.66 or > 1.5 and an adjusted p-value of < 0.05). Gene ontology and KEGG pathway analysis for genes with increased expression in DIE compared with FA revealed significant upregulation of genes belonging to the PI3K-pathway and the focal adhesion pathway, as well as pathways related to viral infection, endocrine resistance, and malignancy. The upregulated pathways in adenomyosis mainly included the RAS-pathway. Limitations, reasons for caution The average age of DIE patients was lower, but many of them were hormonally inactive due to GnRH analogues, which mitigates any age-related differences. Furthermore, only relative expression was studied between the groups without comparison to normal endometrium. Overall, the sample size is relatively small and further studies are needed. Wider implications of the findings The expression of different signaling pathways in the two entities could, for example, explain the different sensitivity of the two diseases to certain therapeutic approaches. While DIE responds well to therapy with the progestogen dienogest, progesterone resistance is often described in adenomyosis patients. Trial registration number not applicable

BACKGROUND:The pathogenesis of deep infiltrating endometriosis (DIE) is poorly understood. It is considered a benign disease but has histologic features of malignancy, such as local invasion or gene mutations. Moreover, it is not clear whether its invasive potential is comparable to that of adenomyosis uteri (FA), or whether it has a different biological background. Therefore, the aim of this study was to molecularly characterize the gene expression signatures of both diseases in order to gain insight into the common or different underlying pathomechanisms and to provide clues to pathomechanisms of tumor development based on these diseases. METHODS:In this study, we analyzed formalin-fixed and paraffin-embedded tissue samples from two independent cohorts. One cohort involved 7 female patients with histologically confirmed FA, the other cohort 19 female patients with histologically confirmed DIE. The epithelium of both entities was microdissected in a laser-guided fashion and RNA was extracted. We analyzed the expression of 770 genes using the nCounter expression assay human PanCancer (Nanostring Technology). RESULTS:In total, 162 genes were identified to be significantly down-regulated (n = 46) or up-regulated (n = 116) in DIE (for log2-fold changes of < 0.66 or > 1.5 and an adjusted p-value of < 0.05) compared to FA. Gene ontology and KEGG pathway analysis of increased gene expression in DIE compared to FA revealed significant overlap with genes upregulated in the PI3K pathway and focal adhesion signaling pathway as well as other solid cancer pathways. In FA, on the other hand, genes of the RAS pathway showed significant expression compared to DIE. CONCLUSION:DIE and FA differ significantly at the RNA expression level: in DIE the most expressed genes were those belonging to the PI3K pathway, and in FA those belonging to the RAS pathway.

Homologous repair deficiency (HRD) is present in many cancer types at variable prevalence and can indicate response to platinum-based chemotherapy and PARP inhibition. We developed a tumor classification system based on the loss of function of genes in the homologous recombination repair (HRR) pathway. To this end, somatic and germline alterations in BRCA1/2 and 140 other HRR genes were included and assessed for the impact on gene function. Additionally, information on the allelic hit type and on BRCA1 promoter hypermethylation was included. The HRDsum score including LOH, LST, and TAI was calculated for 8847 tumors of the TCGA cohort starting from genotyping data and for the subcohort of ovarian cancer also starting from WES data. Pan-cancer, deleterious BRCA1/2 alterations were detected in 4% of the tumors, while 18% of the tumors were HRD-positive (HRDsum ≥ 42). Across 33 cancer types, both BRCA1/2 alterations and HRD-positivity were most prevalent in ovarian cancer (20% and 69%). Pan-cancer, tumors with biallelic deleterious alterations in BRCA1/2 were separated strongly from tumors without relevant alterations (AUC = 0.89), while separation for tumors with monoallelic deleterious BRCA1/2 alterations was weak (AUC = 0.53). Tumors with biallelic deleterious alterations in other HHR genes were separated moderately from tumors without relevant alterations (AUC = 0.63), while separation for tumors with such monoallelic alterations was weaker (AUC = 0.57). In ovarian cancer, HRDsum scores calculated from WES data correlated strongly with HRDsum scores calculated from genotyping data (R = 0.87) and were slightly (4%) higher. We comprehensively analyzed HRD scores and their association with mutations in HRR genes in common cancer types. Our study identifies important parameters influencing HRD measurement and argues for an integration of HRDsum score with specific mutational profiles.

PD-(L)1 monotherapy can be used as a second-line treatment for metastatic non-small-cell lung cancer (NSCLC) with PD-L1 expression. However, many patients do not respond, and reliable biomarkers are lacking.

Abstract Objective According to the 2019 published ASCO guidelines patients with resected biliary tract cancer should be offered adjuvant capecitabine chemotherapy based solely on the results of the BILCAP trial. Aim of this work is to analyze the quality of the BILCAP trial. Methods Design, conduct, statistics and reporting of the study were analyzed according to the Delphi list and the CONSORT checklist. The risk of bias was assessed using the Cochrane Risk of Bias Tool. Results Several shortcomings could be identified in the study regarding design, conduct, statistics and reporting. The BILCAP study is a randomized, controlled, multicenter, phase 3 study which was done across 44 specialist hepatopancreatobiliary centres in the UK. Despite the inclusion of high specialized centres, the number of included patients each year for each center is extremely low. In particular, a total of 447 patients were included by 44 centers over a period of 11 years, meaning that less than 1 patient was included in this study every year by each center. However, the analysis was not adjusted for center which was one of the stratification factors. Follow up treatment for patients who had disease recurrence was not recorded. Randomization procedure is not well described. Minimization technique was adopted for stratification but mode of application is poorly reported and the choice of variables not justified. No blinding was present. Extensive power evaluations after adjusting the number of needed events, due to lower event rates than expected, were not done. For the observed HR = 0.81 with 234 events statistical power is only around 37%. 4 out of 9 items of the Delphi list and 6 out of 35 items of the CONSORT checklist were not properly addressed. According to the Cochrane Risk of Bias Tool (RoB 2) the overall risk-of-bias judgment for the outcome overall survival of the BILCAP study was “some concerns”. Almost all authors declared to have received funds from pharmaceutical companies, so a conflict of interest cannot be excluded. Additionally, the funding agency for this study (Cancer Research UK and Roche) had an advisory role in design and the first author of the BILCAP study was also involved in the generation of the ASCO guideline. Conclusion Based on the results of this study there is not enough evidence for the administration of adjuvant chemotherapy with capecitabine in patients with resected biliary tract cancer.

Einleitung Invasive Pilzinfektionen (IFI) stellen eine schwerwiegende Komplikation mit hoher Mortalität bei Patienten mit Leberzirrhose dar, insbesondere bei intensivmedizinischer Versorgung.

Background: Targeted therapies have improved survival and quality of life for patients with non-small-cell lung cancer with actionable driver mutations. However, epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 gene (HER2, also known as ERBB2) exon 20 insertions (Ex20mut) are characterized by a poor response to currently approved tyrosine kinase inhibitors and immunotherapies. The underlying immune biology is not well understood. Materials and methods: We carried out messenger RNA expression profiling of lung adenocarcinomas (ADCs) with ERBB2 (n = 19) and EGFR exon 20-insertion mutations (n = 13) and compared these to tumors with classical EGFR mutations (n = 40, affecting EGFR exons 18, 19 or 21) and EGFR/ERBB2 mutation-negative lung ADC (EGFR/ERBB2wt, n = 26) focusing on immunologically relevant transcripts. Tumor-infiltrating immune cells were estimated from gene expression profiles. Results: Cytotoxic cells were significantly lower in EGFR-mutated tumors regardless of the affected exon, while Th1 cells were significantly lower in EGFR-Ex20mut compared to EGFR/ERBB2wt tumors. We assessed the differentially expressed genes of ERBB2-Ex20mut and EGFR-Ex20mut tumors compared to EGFR-Ex18/19/21mut and EGFR/ERBB2wt tumors. Of these, the genes GUSB, HDAC11, IFNGR2, PUM1, RASGRF1 and RBL2 were up-regulated, while a lower expression of CBLC, GBP1, GBP2, GBP4 and MYC was observed in all three comparison groups. The omnibus test revealed 185 significantly (FDR = 5%) differentially expressed genes and we found these four most significant gene expression changes in the study cohort: VHL and JAK1 were overexpressed in ERBB2-Ex20mut and EGFR-Ex20mut tumors compared to both EGFR-Ex18/19/21mut and EGFR/ERBB2wt tumors. RIPK1 and STK11IP showed the highest expression in ERBB2-Ex20mut tumors. Conclusions: Targeted gene expression profiling is a promising tool to read out the characteristics of the tumor microenvironment from routine diagnostic lung cancer biopsies. Significant immune reactivity and specific immunosuppressive characteristics in ERBB2-Ex20mut and EGFR-Ex20mut lung ADC with at least some degree of immune infiltration support further clinical evaluation of immune-modulators as partners of immune checkpoint inhibitors in such tumors.

Lebertransplantierte Patienten mit einer biliodigestiven Anastomose (BDA) erhalten bei Gallengangsstenosen regelmäßig perkutane transhepatische Cholangiographien (PTCs). Hierbei stellt die postinterventionelle Cholangitis eine der Hauptkomplikationen dar. Eine klare Empfehlung zur Dauer der periinterventionellen Antibiose liegt bislang nicht vor. Aufgrund der steigenden Resistenzraten ist ein gezielter Einsatz von Antibiotika wichtiger denn je.

OBJECTIVE:Panel-based next-generation sequencing (NGS) is increasingly used for the diagnosis of EGFR-mutated non-small-cell lung cancer (NSCLC) and could improve risk assessment in combination with clinical parameters. MATERIALS AND METHODS:To this end, we retrospectively analyzed the outcome of 400 tyrosine kinase inhibitor (TKI)-treated EGFR+ NSCLC patients with validation of results in an independent cohort (n = 130). RESULTS:EGFR alterations other than exon 19 deletions (non-del19), TP53 co-mutations, and brain metastases at baseline showed independent associations of similar strengths with progression-free (PFS hazard ratios [HR] 2.1-2.3) and overall survival (OS HR 1.7-2.2), in combination defining patient subgroups with distinct outcome (EGFR+NSCLC risk Score, "ENS", p < 0.001). Co-mutations beyond TP53 were rarely detected by our multigene panel (<5%) and not associated with clinical endpoints. Smoking did not affect outcome independently, but was associated with non-del19 EGFR mutations (p < 0.05) and comorbidities (p < 0.001). Laboratory parameters, like the blood lymphocyte-to-neutrophil ratio and serum LDH, correlated with the metastatic pattern (p < 0.01), but had no independent prognostic value. Reduced ECOG performance status (PS) was associated with comorbidities (p < 0.05) and shorter OS (p < 0.05), but preserved TKI efficacy. Non-adenocarcinoma histology was also associated with shorter OS (p < 0.05), but rare (2-3 %). The ECOG PS and non-adenocarcinoma histology could not be validated in our independent cohort, and did not increase the range of prognostication alongside the ENS. CONCLUSIONS:EGFR variant, TP53 status and brain metastases predict TKI efficacy and survival in EGFR+ NSCLC irrespective of other currently available parameters ("ENS"). Together, they constitute a practical and reproducible approach for risk stratification of newly diagnosed metastatic EGFR+ NSCLC.

Purpose: Epidermal growth factor receptor mutated (EGFR)+ non-small-cell lung cancer (NSCLC) is a model disease for the effectiveness of tyrosine kinase inhibitors (TKI) in thoracic oncology. The majority of patients present directly with metastatic tumors, however some show relapse of previous nonmetastatic disease after varying treatments including surgery, chemotherapy and/or radiotherapy. Potential clinical and biologic differences between these two patient subsets are unclear at present.

Die Präzisionsonkologie spielt eine zunehmend wichtigere Rolle in der Therapie maligner Erkrankungen. Die Indikationsstellung zielgerichteter Therapien bedarf hierbei der molekularpathologischen Aufarbeitung des Tumorgewebes. Dies geschieht derzeit üblicherweise mittels gezielter Panelsequenzierung (Next Generation Sequencing) durch die – in Abhängigkeit vom Paneldesign und der verwendeten Methode – alle für die Therapieentscheidung relevanten zugelassenen prädiktiven Biomarker oder therapeutischen Zielstrukturen untersucht werden können. Dies schließt auch Genfusionen und Kopienzahlveränderungen ein. Gleichwohl gibt es klinische Szenarien, in denen umfassendere genomische Ansätze (Ganzexom- oder Ganzgenom- sowie Transkriptomanalysen) erwogen werden können. Diese müssen in einen Studienkontext eingebunden sein. Die vorliegende Übersicht beschreibt Kernaspekte der jeweiligen Profilingverfahren und zeigt mögliche Anwendungsgebiete auf.

Drugs acting on the renin-angiotensin system (RAS) may have beneficial effects on mental health. We investigated whether use of drugs acting on the RAS, as add-on to selective serotonin reuptake inhibitors (SSRIs), was associated with a reduced risk of psychiatric hospital contacts. We identified all individuals initiating treatment with an SSRI between 1997 and 2012. Individuals using an SSRI without concomitant use of a RAS drug (SSRI-only users) were propensity score matched 1:1 to individuals using both an SSRI and a drug acting on the RAS (SSRI+RAS users). The SSRI-only and SSRI+RAS users were followed for up to three years or until December 31, 2013. We performed Cox proportional hazard regression analyses to calculate risks for psychiatric hospital contacts, hospital contacts due to depression, suicidal behavior, and all-cause mortality. We followed 30,311 SSRI-only users and 30,311 SSRI+RAS users for a total of 49,327 person-years. Compared to SSRI-only users, concomitant use of SSRI+RAS was associated with a significantly reduced risk for psychiatric hospital contacts (hazard rate ratio (HRR)=0.91; 95%-confidence intervals (95%-CI)=0.84–0.98) and lower mortality rate (HRR=0.70; 95%-CI=0.66–0.75). The associations between SSRI+RAS use and psychiatric hospital contacts for depression (HRR=0.92; 95%-CI=0.80–1.05) and suicidal behavior (HRR=1.06; 95%-CI=0.79–1.42) were not statistically significant. In this observational cohort study, concomitant use of an SSRI and a drug acting on the RAS was associated with a slightly reduced risk for psychiatric hospital contacts, when compared to use of an SSRI alone.

As in other organs, carcinogenesis of bile duct tumors today is considered a multistep process, morphologically reflected in the existence of two histologically defined precursor lesions, biliary intraepithelial neoplasia (BilIN) and intraductal papillary neoplasia of the bile duct (IPNB). However, current knowledge on the molecular alterations in cholangiocarcinogenesis is scarce and no information is available regarding the chronological sequence of the changes involved. By deciphering the course of transcriptional alterations in cholangiocarcinogenesis, this study aimed to identify early, potentially driving genetic events.