Adjuvant therapy of biliary tract cancers

Biliary tract cancers (BTCs) are rare and heterogeneous malignant tumours including cholangiocarcinoma and gallbladder cancer. They are very aggressive, often refractory to chemotherapy and associated with an overall poor prognosis. Surgical resection remains the only potentially curative treatment option but less than 35% present with resectable disease. Adjuvant treatments have been widely used but until recently, supportive data were limited to non-randomised, non-controlled retrospective studies. Recent evidence from the BILCAP trial has established adjuvant capecitabine as the standard of care. But there are still unanswered questions as to the role of adjuvant therapy. Further prospective data and translational research with reproducible evidence of clinical benefit are needed. In this review of adjuvant therapy in resectable BTCs, we will summarise the latest evidence setting current treatment standards and highlight future prospects

BRAF testing in metastatic colorectal carcinoma and novel, chemotherapy-free therapeutic options

In the past 25 years, treatment of metastatic colorectal cancer (mCRC) has undergone profound changes. The approval of newer chemotherapeutics such as irinotecan and oxaliplatin was followed in 2005 by the first targeted therapies, for example, monoclonal antibodies directed against the epidermal growth factor receptor (EGFR), as cetuximab and panitumumab, or the angiogenesis inhibitors bevacizumab, ramucirumab, and aflibercept. With the rapidly progressing molecular characterization of mCRC in the last 10 years and the classification of the disease in four consensus subtypes, further changes are emerging, which will promote, among other things, the introduction of protein-kinase inhibitors developed for specific molecular aberrations as well as immune checkpoint inhibitors into the treatment algorithm. Thorough molecular pathologic testing is indispensable today for guideline-compliant treatment of mCRC patients. In addition to RAS testing as a precondition for the therapy decision with regard to cetuximab and panitumumab, BRAF testing is of considerable relevance to allow decision making with regard to the newly approved chemotherapy-free combination of the BRAF inhibitor encorafenib and cetuximab in cases where a BRAF-V600E mutation is detected. Additional diagnostic tests should also include genome instability (microsatellite instability). Overall, more and more molecular alterations need to be investigated simultaneously, so that the use of focused next-generation sequencing is increasingly recommended. This overview describes the prognostic relevance of BRAF testing in the context of molecular pathologic diagnostics of mCRC, presents new treatment options for BRAF-mutated mCRC patients, and explains which modern DNA analytical and immunohistochemical methods are available to detect BRAF mutations in mCRC patients

Biomarker analyses of clinical outcomes in patients with advanced hepatocellular carcinoma treated with Sorafenib with or without Erlotinib in the SEARCH Trial

Purpose: Sorafenib is the current standard therapy for advanced HCC, but validated biomarkers predicting clinical outcomes are lacking. This study aimed to identify biomarkers predicting prognosis and/or response to sorafenib, with or without erlotinib, in HCC patients from the phase 3 SEARCH trial. Experimental Design: 720 patients were randomized to receive oral sorafenib 400 mg BID plus erlotinib 150 mg QD or placebo. Fifteen growth factors relevant to the treatment regimen and/or to HCC were measured in baseline plasma samples. Results: Baseline plasma biomarkers were measured in 494 (69%) patients (sorafenib plus erlotinib, n=243; sorafenib plus placebo, n=251). Treatment arm–independent analyses showed that elevated HGF (HR, 1.687 [high vs low expression]; endpoint multiplicity adjusted [e-adj] P=0.0001) and elevated plasma VEGF-A (HR, 1.386; e-adj P=0..0377) were significantly associated with poor OS in multivariate analyses, and low plasma KIT (HR, 0.75 [high vs low]; P=0.0233; e-adj P=0.2793) tended to correlate with poorer OS. High plasma VEGF-C independently correlated with longer TTP (HR, 0.633; e-adj P=0.0010) and trended toward associating with improved disease control rate (univariate:OR, 2.047; P=0.030; e-adj P=0.420). In 67% of evaluable patients (339/494), a multimarker signature of HGF, VEGF-A, KIT, epigen, and VEGF-C correlated with improved median OS in multivariate analysis (HR, 0.150; P<0.00001). No biomarker predicted efficacy from erlotinib. Conclusions: Baseline plasma HGF, VEGF-A, KIT, and VEGF-C correlated with clinical outcomes in HCC patients treated with sorafenib with or without erlotinib. These biomarkers plus epigen constituted a multimarker signature for improved OS

Predictive and prognostic potential of liver function assessment in patients with advanced hepatocellular carcinoma: a systematic literature review

INTRODUCTION: We conducted a systematic literature review to assess the utility of liver function assessments for predicting disease prognosis and response to systemic anticancer therapy in patients with advanced hepatocellular carcinoma (aHCC). METHODS: This was a PRISMA-standard review and was registered with PROSPERO (CRD42021244588). MEDLINE and Embase were systematically searched (March 24, 2021) to identify publications reporting the efficacy and/or safety of systemic anticancer therapy (vs any/no comparator) in liver-function-defined subgroups in phase 2 or 3 aHCC trials. Screening was completed by a single reviewer, with uncertainties resolved by a second reviewer and/or the authors. English-language full-text articles and congress abstracts were eligible for inclusion. Included publications were described and assessed for risk of bias using the GRADE methodology. RESULTS: Twenty (of 2579) screened publications were eligible; seven categorised liver function using the albumin–bilirubin system, nine using the Child–Pugh system, four using both. GRADE assessment classified ten, nine, and one publication(s) as reporting moderate-quality, low-quality, and very-low-quality evidence, respectively. Analyses of cross-trial trends of within-exposure arm analyses (active and control) reported a positive relationship between baseline liver function and overall survival and progression-free survival, supporting liver function as a prognostic marker in aHCC. There were also signals for a modest relationship between more preserved baseline liver function and extent of systemic treatment benefit, and with more preserved liver function and lower incidence of safety events. CONCLUSION: This review supports liver function as a prognostic variable in aHCC, and highlights the value of a priori stratification of patients by baseline liver function in aHCC trials. The predictive value of liver function warrants further study. Findings were limited by the quality of available data

BRAF-V600E-Testung beim metastasierten kolorektalen Karzinom und neue, chemotherapiefreie Therapieoptionen

In the past 25 years, treatment of metastatic colorectal cancer (mCRC) has undergone profound changes. The approval of newer chemotherapeutics such as irinotecan and oxaliplatin was followed in 2005 by the first targeted therapies, for example, monoclonal antibodies directed against the epidermal growth factor receptor (EGFR), as cetuximab and panitumumab, or the angiogenesis inhibitors bevacizumab, ramucirumab, and aflibercept. With the rapidly progressing molecular characterization of mCRC in the last 10 years and the classification of the disease in four consensus subtypes, further changes are emerging, which will promote, among other things, the introduction of protein-kinase inhibitors developed for specific molecular aberrations as well as immune checkpoint inhibitors into the treatment algorithm. Thorough molecular pathologic testing is indispensable today for guideline-compliant treatment of mCRC patients. In addition to RAS testing as a precondition for the therapy decision with regard to cetuximab and panitumumab, BRAF testing is of considerable relevance to allow decision making with regard to the newly approved chemotherapy-free combination of the BRAF inhibitor encorafenib and cetuximab in cases where a BRAF-V600E mutation is detected. Additional diagnostic tests should also include genome instability (microsatellite instability). Overall, more and more molecular alterations need to be investigated simultaneously, so that the use of focused next-generation sequencing is increasingly recommended. This overview describes the prognostic relevance of BRAF testing in the context of molecular pathologic diagnostics of mCRC, presents new treatment options for BRAF-mutated mCRC patients, and explains which modern DNA analytical and immunohistochemical methods are available to detect BRAF mutations in mCRC patients.Die Therapie des metastasierten kolorektalen Karzinoms (mKRK) hat in den letzten 25 Jahren tief greifende Veränderungen erfahren. Auf die Zulassung neuerer Chemotherapeutika folgten ab 2005 die ersten zielgerichteten Therapien, die sich gegen den epidermalen Wachstumsfaktorrezeptor (EGFR) bzw. gegen Rezeptoren vaskulärer endothelialer Wachstumsfaktoren (VEGFR) richteten. Mit der fortschreitenden molekularen Charakterisierung des mKRK in den letzten 10 Jahren und der Einteilung der Erkrankung in 4 Konsensus-Subtypen zeichnet sich weitererWandel ab, unter anderem durch Einführung speziell entwickelter Proteinkinaseinhibitoren wie auch Immuncheckpoint-Inhibitoren in den Therapiealgorithmus. Eine angepasste molekularpathologische Testung ist heute für eine leitliniengerechte Behandlung von mKRK-Patienten unabdingbar. Neben der RAS-Testung als Voraussetzung für die Therapieentscheidung bezüglich Cetuximab und Panitumumab ist die BRAFTestung äußerst relevant, um – im Falle des Nachweises einer BRAF-V600E-Mutation– eine Therapieentscheidung zugunsten der neu zugelassenen, chemotherapiefreien Kombination aus dem BRAF-Inhibitor Encorafenib und Cetuximab treffen zu können. Eine erweiterte Diagnostik sollte auch die Genominstabilität (Mikrosatelliten-Instabilität) einbeziehen. Insgesamt müssen immermehr molekulare Alterationen simultan untersucht werden, sodass sich zunehmend die Verwendung des fokussierten Next Generation Sequencing empfiehlt. Diese Übersichtsarbeit beschreibt die prognostische Relevanz der BRAF-Testung im Rahmen der molekularpathologischen Diagnostik des mKRK, stellt neue Therapieoptionen zur Behandlung BRAF-mutiertermKRKPatienten vor und erläutert,welchemodernen DNA-analytischen und immunohistochemischen Verfahren zur BRAF-Diagnostik von mKRK-Patienten zur Verfügung stehen

Therapy preferences of patients with lung and colon cancer: A discrete choice experiment

Objectives: There is increasing interest in studies that examine patient preferences to measure health-related outcomes. Understanding patients’ preferences can improve the treatment process and is particularly relevant for oncology. In this study, we aimed to identify the subgroup-specific treatment preferences of German patients with lung cancer (LC) or colorectal cancer (CRC). Methods: Six discrete choice experiment (DCE) attributes were established on the basis of a systematic literature review and qualitative interviews. The DCE analyses comprised generalized linear mixed-effects model and latent class mixed logit model. Results: The study cohort comprised 310 patients (194 with LC, 108 with CRC, 8 with both types of cancer) with a median age of 63 (SD =10.66) years. The generalized linear mixed-effects model showed a significant (P<0.05) degree of association for all of the tested attributes. “Strongly increased life expectancy” was the attribute given the greatest weight by all patient groups. Using latent class mixed logit model analysis, we identified three classes of patients. Patients who were better informed tended to prefer a more balanced relationship between length and health-related quality of life (HRQoL) than those who were less informed. Class 2 (LC patients with low HRQoL who had undergone surgery) gave a very strong weighting to increased length of life. We deduced from Class 3 patients that those with a relatively good life expectancy (CRC compared with LC) gave a greater weight to moderate effects on HRQoL than to a longer life. Conclusion: Overall survival was the most important attribute of therapy for patients with LC or CRC. Differences in treatment preferences between subgroups should be considered in regard to treatment and development of guidelines. Patients’ preferences were not affected by sex or age, but were affected by the cancer type, HRQoL, surgery status, and the main source of information on the disease

System architectures for Industrie 4.0 applications

Industrie 4.0 principles demand increasing flexibility and modularity for automated production systems. Current system architectures provide an isolated view of specific applications and use cases, but lack a global, more generic approach. Based on the specific architectures of two EU projects and one German Industrie 4.0 project, a generic system architecture is proposed. This system architecture features the strengths of the three isolated proposals, such as cross-enterprise data sharing, service orchestration, and real-time capabilities, and can be applied to a wide field of applications. Future research should be directed towards considering the applicability of the architecture to other equal applications.info:eu-repo/semantics/publishedVersio