[Palliative Treatment of Metastatic Rectal Cancer]. / Palliative Systemtherapie des metastasierten Rektumkarzinoms.

Palliative treatment of metastatic rectal cancer (mCRC) has developed considerably in recent years, with new therapeutic strategies such as induction and maintenance therapies, the establishment of targeted therapies and molecularly defined strategies in defined subgroups such as MSI-H-patients. The following article presents evidence based therapeutic options and algorithms.

Emerging Roles of Small Extracellular Vesicles in Gastrointestinal Cancer Research and Therapy.

Discovered in the late eighties, sEVs are small extracellular nanovesicles (30-150 nm diameter) that gained increasing attention due to their profound roles in cancer, immunology, and therapeutic approaches. They were initially described as cellular waste bins; however, in recent years, sEVs have become known as important mediators of intercellular communication. They are secreted from cells in substantial amounts and exert their influence on recipient cells by signaling through cell surface receptors or transferring cargos, such as proteins, RNAs, miRNAs, or lipids. A key role of sEVs in cancer is immune modulation, as well as pro-invasive signaling and formation of pre-metastatic niches. sEVs are ideal biomarker platforms, and can be engineered as drug carriers or anti-cancer vaccines. Thus, sEVs further provide novel avenues for cancer diagnosis and treatment. This review will focus on the role of sEVs in GI-oncology and delineate their functions in cancer progression, diagnosis, and therapeutic use.

Symptoms and Management of Aseptic Liver Abscesses.

Aseptic liver abscesses occur very rarely. Clinical guidelines on the management of the disease do not exist, and the diagnosis is challenging.We screen MEDLINE and PUBMED databases for relevant case reports from inception to November 2022. Information on patient age, sex, initial symptoms, the extent of abscess formation, further diagnoses, treatment, and course of the disease is analyzed.Thirty cases with sterile hepatic abscess formation are identified. In most patients (n=18), the spleen is affected as well. Patients typically present with fever, abdominal pain, and increased inflammatory values. Comorbidity with inflammatory bowel disease is very common (n=18) and is associated with a significantly younger age at the time of hepatic abscess development. In addition, many patients show autoimmune-mediated cutaneous, ocular, or arthritic rheumatoid manifestations. Histological examination of abscess material reveals neutrophilic infiltration. The majority of patients initially receive corticosteroid therapy. Furthermore, response to azathioprine, anti-TNF-α antibodies, and other immunomodulatory drugs is reported. Ten out of fourteen patients with a long-term follow-up (≥ 36 months) have at least one relapse of hepatic abscess formation.Aseptic hepatic abscesses should be considered in the case of sterile punctures and non-response to antibiotics. Patients with aseptic liver abscesses have a high risk of recurrence warranting immunomodulatory maintenance therapy.

Risks and benefits of TIPS in HCC and other liver malignancies: a literature review.

BACKGROUND: Transjugular intrahepatic portosystemic shunt (TIPS) is a well-validated treatment option for clinically significant portal hypertension (CSPH) in the context of liver cirrhosis. Its high efficacy and safety in the management of treatment-refractory ascites and variceal bleeding have been extensively proven. Contraindications for TIPS include severe right heart failure, hepatic encephalopathy, and sepsis. However, the role of liver malignancy in TIPS is debatable. Mostly, primary liver malignancies such as hepatocellular carcinoma (HCC) emerge from advanced liver diseases. Coexisting portal hypertension in HCC often results in limited treatment options and a poor prognosis. Previous studies have shown that TIPS implantation in patients with HCC is technically feasible and is usually not associated with major adverse events. Furthermore, TIPS may help in bridging the time to liver transplantation in early HCC and allow for locoregional treatment in advanced HCC. However, several studies suggest that seeding tumour cells to the lungs by TIPS placement might worsen the prognosis. CONCLUSIONS: TIPS placement in patients with coexisting liver malignancy remains a case-by-case decision, and there is no profound evidence allowing general recommendations. This review aims to provide a state-of-the-art overview of the potential risks and benefits of TIPS placement in patients with liver malignancies.

Protocol of the IntenSify-Trial: An open-label phase I trial of the CYP3A inhibitor cobicistat and the cytostatics gemcitabine and nab-paclitaxel in patients with advanced stage or metastatic pancreatic ductal adenocarcinoma to evaluate the combination's pharmacokinetics, safety, and efficacy.

Expression of CYP3A5 protein is a basal and acquired resistance mechanism of pancreatic ductal adenocarcinoma cells conferring protection against the CYP3A and CYP2C8 substrate paclitaxel through metabolic degradation. Inhibition of CYP3A isozymes restores the cells sensitivity to paclitaxel. The combination of gemcitabine and nab-paclitaxel is an established regimen for the treatment of metastasized or locally advanced inoperable pancreatic cancer. Cobicistat is a CYP3A inhibitor developed for the pharmacoenhancement of protease inhibitors. The addition of cobicistat to gemcitabine and nab-paclitaxel may increase the antitumor effect. We will conduct a phase I dose escalation trial with a classical 3 + 3 design to investigate the safety, tolerability, and pharmacokinetics (PKs) of gemcitabine, nab-paclitaxel, and cobicistat. Although the doses of gemcitabine (1000 mg/m2 ) and cobicistat (150 mg) are fixed, three dose levels of nab-paclitaxel (75, 100, and 125 mg/m2 ) will be explored to account for a potential PK drug interaction. After the dose escalation phase, we will set the recommended dose for expansion (RDE) and treat up to nine patients in an expansion part of the trial. The trial is registered under the following identifiers EudraCT-Nr. 2019-001439-29, drks.de: DRKS00029409, and ct.gov: NCT05494866. Overcoming resistance to paclitaxel by CYP3A5 inhibition may lead to an increased efficacy of the gemcitabine and nab-paclitaxel regimen. Safety, efficacy, PK, and RDE data need to be acquired before investigating this combination in a large-scale clinical study.

Multicentric pilot study to standardize clinical whole exome sequencing (WES) for cancer patients.

A growing number of druggable targets and national initiatives for precision oncology necessitate broad genomic profiling for many cancer patients. Whole exome sequencing (WES) offers unbiased analysis of the entire coding sequence, segmentation-based detection of copy number alterations (CNAs), and accurate determination of complex biomarkers including tumor mutational burden (TMB), homologous recombination repair deficiency (HRD), and microsatellite instability (MSI). To assess the inter-institution variability of clinical WES, we performed a comparative pilot study between German Centers of Personalized Medicine (ZPMs) from five participating institutions. Tumor and matched normal DNA from 30 patients were analyzed using custom sequencing protocols and bioinformatic pipelines. Calling of somatic variants was highly concordant with a positive percentage agreement (PPA) between 91 and 95% and a positive predictive value (PPV) between 82 and 95% compared with a three-institution consensus and full agreement for 16 of 17 druggable targets. Explanations for deviations included low VAF or coverage, differing annotations, and different filter protocols. CNAs showed overall agreement in 76% for the genomic sequence with high wet-lab variability. Complex biomarkers correlated strongly between institutions (HRD: 0.79-1, TMB: 0.97-0.99) and all institutions agreed on microsatellite instability. This study will contribute to the development of quality control frameworks for comprehensive genomic profiling and sheds light onto parameters that require stringent standardization.

Treatment sequences and prognostic/predictive factors in metastatic pancreatic ductal adenocarcinoma: univariate and multivariate analyses of a real-world study in Europe.

BACKGROUND: Real-world data on treatment patterns/outcomes for metastatic pancreatic cancer (mPAC) are limited. This study aims to assess real-world treatment patterns, survival outcomes, and prognostic/predictive factors in patients with mPAC. METHODS: Retrospective, observational, chart-review involving medical oncologists and gastroenterologists from five European countries. Physicians reported information on disease and patient characteristics, diagnosis, and treatment for patients diagnosed with mPAC from January-October 2016. Outcomes included median progression-free survival (mPFS), median overall survival (mOS), and the impact of baseline performance status on survival. Univariate/multivariate regression analyses were undertaken to identify prognostic/predictive factors. RESULTS: Three hundred four physicians and 3432 patients were included. First-line therapies included modified (m)FOLFIRINOX (28.4%), gemcitabine + nab-paclitaxel (28.0%), and gemcitabine monotherapy (23.0%). Frequent second-line therapies were gemcitabine monotherapy (25.0%), fluorouracil (5-FU) + oxaliplatin (21.8%), and gemcitabine + nab-paclitaxel (16.7%). Most frequent first- to second-line treatment sequences were gemcitabine + nab-paclitaxel followed by fluoropyrimidine combinations. Longest unadjusted estimated mOS was observed with (m)FOLFIRINOX followed by gemcitabine-based combinations (19.1 months). Multivariate analysis identified significant prognostic/predictive factors for OS and PFS including performance status and carbohydrate antigen 19-9 (CA 19-9) levels. CONCLUSIONS: Treatment and treatment sequences were generally in accordance with guidelines at the time of the study. Identification of prognostic/predictive factors for survival may help inform the individualised management of mPAC patients in the future.

A Systematic Evaluation of the SARS-CoV-2 Vaccine-Induced Anti-S-RBD-Ig Response in a Population of Health Care Workers.

In the wake of the COVID-19 pandemic, the novel class of mRNA vaccines has been granted first-time approval for active immunization against SARS-CoV-2 alongside the already established viral vector-based vaccines. In this prospective single-center study, we set out to determine the vaccine-induced humoral immune response in a population of 1512 health care employees after the second and third vaccination, respectively. Anti-SARS-CoV-2 receptor-binding domain (RBD) and nucleocapsid antigen antibody concentrations were assessed using commercially available immunoassays. We could show that, in particular, young study subjects aged below 30 years, as well as those with a prior SARS-CoV-2 infection, developed significantly higher antibody concentrations. Our data further suggest that being in physically close contact with formerly SARS-CoV-2-positive people positively affects the post-vaccination response. Surprisingly, study subjects with a BMI > 30 produced the highest anti-S-RBD Ig antibody levels if they had recently received their third vaccination. Also, heterologous dual vaccine regimens consisting of a BNT162b2 and ChAdOx1 n-CoV-19, a homologous triple combination of BNT162b2, and an application of mRNA-1273 as the third vaccine, were most efficient at eliciting a humoral immune response. Our study substantiates existing evidence, but beyond that, scrutinizes the impact of vaccine agents and their respective combinations, as well as different time intervals on humoral immunogenicity.

DNA methylation-associated allelic inactivation regulates Keratin 19 gene expression during pancreatic development and carcinogenesis.

Within the pancreas, Keratin 19 (KRT19) labels the ductal lineage and is a determinant of pancreatic ductal adenocarcinoma (PDAC). To investigate KRT19 expression dynamics, we developed a human pluripotent stem cell (PSC)-based KRT19-mCherry reporter system in different genetic backgrounds to monitor KRT19 expression from its endogenous gene locus. A differentiation protocol to generate mature pancreatic duct-like organoids was applied. While KRT19/mCherry expression became evident at the early endoderm stage, mCherry signal was present in nearly all cells at the pancreatic endoderm (PE) and pancreatic progenitor (PP) stages. Interestingly, despite homogenous KRT19 expression, mCherry positivity dropped to 50% after ductal maturation, indicating a permanent switch from biallelic to monoallelic expression. DNA methylation profiling separated the distinct differentiation intermediates, with site-specific DNA methylation patterns occurring at the KRT19 locus during ductal maturation. Accordingly, the monoallelic switch was partially reverted upon treatment with a DNA-methyltransferase inhibitor. In human PDAC cohorts, high KRT19 levels correlate with low locus methylation and decreased survival. At the same time, activation of oncogenic KRASG12D signalling in our reporter system reversed monoallelic back to biallelic KRT19 expression in pancreatic duct-like organoids. Allelic reactivation was also detected in single-cell transcriptomes of human PDACs, which further revealed a positive correlation between KRT19 and KRAS expression. Accordingly, KRAS mutant PDACs had higher KRT19 mRNA but lower KRT19 gene locus DNA methylation than wildtype counterparts. KRT19 protein was additionally detected in plasma of PDAC patients, with higher concentrations correlating with shorter progression-free survival in gemcitabine/nabPaclitaxel-treated and opposing trends in FOLFIRINOX-treated patients. Apart from being an important pancreatic ductal lineage marker, KRT19 appears tightly controlled via a switch from biallelic to monoallelic expression during ductal lineage entry and is aberrantly expressed after oncogenic KRASG12D expression, indicating a role in PDAC development and malignancy. Soluble KRT19 might serve as a relevant biomarker to stratify treatment. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

RBPJ Deficiency Sensitizes Pancreatic Acinar Cells to KRAS-Mediated Pancreatic Intraepithelial Neoplasia Initiation.

BACKGROUND AND AIMS: Development of pancreatic ductal adenocarcinoma (PDAC) is a multistep process intensively studied; however, precocious diagnosis and effective therapy still remain unsatisfactory. The role for Notch signaling in PDAC has been discussed controversially, as both cancer-promoting and cancer-antagonizing functions have been described. Thus, an improved understanding of the underlying molecular mechanisms is necessary. Here, we focused on RBPJ, the receiving transcription factor in the Notch pathway, examined its expression pattern in PDAC, and characterized its function in mouse models of pancreatic cancer development and in the regeneration process after acute pancreatitis. METHODS: Conditional transgenic mouse models were used for functional analysis of RBPJ in the adult pancreas, initiation of PDAC precursor lesions, and pancreatic regeneration. Pancreata and primary acinar cells were tested for acinar-to-ductal metaplasia together with immunohistology and comprehensive transcriptional profiling by RNA sequencing. RESULTS: We identified reduced RBPJ expression in a subset of human PDAC specimens. Ptf1α-CreERT-driven depletion of RBPJ in transgenic mice revealed that its function is dispensable for the homeostasis and maintenance of adult acinar cells. However, primary RBPJ-deficient acinar cells underwent acinar-to-ductal differentiation in ex vivo. Importantly, oncogenic KRAS expression in the context of RBPJ deficiency facilitated the development of pancreatic intraepithelial neoplasia lesions with massive fibrotic stroma formation. Interestingly, RNA-sequencing data revealed a transcriptional profile associated with the cytokine/chemokine and extracellular matrix changes. In addition, lack of RBPJ delays the course of acute pancreatitis and critically impairs it in the context of KRASG12D expression. CONCLUSIONS: Our findings imply that downregulation of RBPJ in PDAC patients derepresses Notch targets and promotes KRAS-mediated pancreatic acinar cells transformation and desmoplasia development.

AMBAR - Interactive Alteration annotations for molecular tumor boards.

MOTIVATION: Personalized decision-making for cancer therapy relies on molecular profiling from sequencing data in combination with database evidence and expert knowledge. Molecular tumor boards (MTBs) bring together clinicians and scientists with diverse expertise and are increasingly established in the clinical routine for therapeutic interventions. However, the analysis and documentation of patients data are still time-consuming and difficult to manage for MTBs, especially as few tools are available for the amount of information required. RESULTS: To overcome these limitations, we developed an interactive web application AMBAR (Alteration annotations for Molecular tumor BoARds), for therapeutic decision-making support in MTBs. AMBAR is an R shiny-based application that allows customization, interactive filtering, visualization, adding expert knowledge, and export to clinical systems of annotated mutations. AVAILABILITY: AMBAR is dockerized, open source and available at https://sysbio.uni-ulm.de/?Software:Ambar Contact:hans.kestler@uni-ulm.de.

Implementation of precision medicine in healthcare-A European perspective.

The technical development of high-throughput sequencing technologies and the parallel development of targeted therapies in the last decade have enabled a transition from traditional medicine to personalized treatment and care. In this way, by using comprehensive genomic testing, more effective treatments with fewer side effects are provided to each patient-that is, precision or personalized medicine (PM). In several European countries-such as in England, France, Denmark, and Spain-the governments have adopted national strategies and taken "top-down" decisions to invest in national infrastructure for PM. In other countries-such as Sweden, Germany, and Italy with regionally organized healthcare systems-the profession has instead taken "bottom-up" initiatives to build competence networks and infrastructure to enable equal access to PM. In this review, we summarize key learnings at the European level on the implementation process to establish sustainable governance and organization for PM at the regional, national, and EU/international levels. We also discuss critical ethical and legal aspects of implementing PM, and the importance of access to real-world data and performing clinical trials for evidence generation, as well as the need for improved reimbursement models, increased cross-disciplinary education and patient involvement. In summary, PM represents a paradigm shift, and modernization of healthcare and all relevant stakeholders-that is, healthcare, academia, policymakers, industry, and patients-must be involved in this system transformation to create a sustainable, non-siloed ecosystem for precision healthcare that benefits our patients and society at large.

Use of overactive bladder anticholinergic medications associated with falls leading to emergency department visits: results from the ADRED study.

PURPOSE: Drug intake might be a modifiable factor for the individual fall-risk of older adults, and anticholinergic properties of drugs need to be considered. This study is aimed at analyzing the association of older adults' individual anticholinergic load with particular focus on use of overactive bladder anticholinergic medications with falls in multi-medicated patients. MATERIALS AND METHODS: Cases of the prospective, observational, multi-center study on adverse drug reactions leading to emergency departments (ADRED study) between 2015 and 2018 in Germany were analyzed comparing the exposure of overactive bladder anticholinergic medications on the chance to present with a fall with patients without exposure. Logistic regression analysis was used adjusting for pre-existing conditions, drug exposure, and the individual anticholinergic burden by drug use. To this end, a combination of seven expert-based anticholinergic rating scales was used. RESULTS: The anticholinergic burden was higher in patients with overactive bladder anticholinergic medications (median 2 [1; 3]) compared to not taking drugs of interest. Presenting with a fall was associated with overactive bladder anticholinergic medications (odds ratio (OR) 2.34 [95% confidence interval 1.14-4.82]). The use of fall-risk increasing drugs was likewise associated (OR 2.30 [1.32-4.00]). The anticholinergic burden itself seemed not to be associated with falls (OR 1.01 [0.90-1.12]). CONCLUSIONS: Although falls occur multifactorial in older adults and confounding by indication cannot be ruled out, the indication for a drug treatment should be decided with caution when other, non-pharmacological treatment options have been tried. GERMAN CLINICAL TRIAL REGISTER: DRKS-ID: DRKS00008979, registration date 01/11/2017.

CD8 T cell-mediated depletion of HBV surface-antigen-expressing, bilineal-differentiated liver carcinoma cells generates highly aggressive escape variants.

The expression of viral antigens in chronic hepatitis B virus (HBV) infection drives continuous liver inflammation, one of the main risk factors to develop liver cancer. HBV developed immune-suppressive functions to escape from the host immune system, but their link to liver tumor development is not well understood. Here, we analyzed if and how HBV surface antigen (HBs) expression in combined hepatocellular-cholangiocarcinoma (cHCC/iCCA) cells influences their antigenicity for CD8 T cells. We randomly isolated liver tumor tissues from AlfpCre+-Trp53fl/fl/Alb-HBs+ tg mice and established primary carcinoma cell lines (pCCL) that showed a bilineal (CK7+/HNF4α+) cHCC/iCCA phenotype. These pCCL uniformly expressed HBs (HBshi), and low levels of MHC-I (MHC-Ilo), and were transiently convertible to a high antigenicity (MHC-Ihi) phenotype by IFN-γ treatment. HBshi/pCCL induced HBs/(Kb/S190-197)-specific CD8 T cells and developed slow-growing tumors in subcutaneously transplanted C57Bl/6J (B6) mice. Interestingly, pCCL-ex cells, established from HBshi/pCCL-induced and re-explanted tumors in B6 but not those in immune-deficient Rag1-/- mice showed major alterations, like an MHC-Ihi phenotype, a prominent growth-biased gene expression signature, a significantly decreased HBs expression (HBslo) and a switch to fast-growing tumors in re-transplanted B6 or PD-1-/- hosts with an unlocked PD-1/PD-L1 control system. CD8 T cell-mediated elimination of HBshi/pCCL, together with the attenuation of the negative restraints of HBs in the tumor cells, like ER-stress, reveals a novel mechanism to unleash highly aggressive HBslo/pCCL-ex immune-escape variants. Under certain conditions, HBs-specific CD8 T-cell responses thus potentiate tumor growth, an aspect that should be considered for therapeutic vaccination strategies against chronic HBV infection and liver tumors.

Pancreatic Cancer: BRCA Targeted Therapy and Beyond.

Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second leading cause of cancer-related death in the US by 2030, despite accounting for only 5% of all cancer diagnoses. Germline gBRCA1/2-mutated PDAC represents a key subgroup with a favorable prognosis, due at least in part to additional approved and guideline-endorsed therapeutic options compared with an unselected PDAC cohort. The relatively recent incorporation of PARP inhibition into the treatment paradigm for such patients has resulted in renewed optimism for a biomarker-based approach to the management of this disease. However, gBRCA1/2 represents a small subgroup of patients with PDAC, and efforts to extend the indication for PARPi beyond BRCA1/2 mutations to patients with PDAC and other genomic alterations associated with deficient DNA damage repair (DDR) are ongoing, with several clinical trials underway. In addition, despite an array of approved therapeutic options for patients with BRCA1/2-associated PDAC, both primary and acquired resistance to platinum-based chemotherapies and PARPi presents a significant challenge in improving long-term outcomes. Herein, we review the current treatment landscape of PDAC for patients with BRCA1/2 and other DDR gene mutations, experimental approaches under investigation or in development, and future directions.