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Purpose: AIO KRK-0104 investigated first-line therapy of metastatic colorectal cancer (mCRC) with cetuximab, capecitabine and irinotecan versus cetuximab, capecitabine and oxaliplatin. This analysis investigated the impact of primary tumor location on outcome of patients. Patients and methods: Left-sided primary tumors were defined as tumors from rectum to left flexure, while tumors in the remaining colon were regarded right sided. Overall survival (OS), progression-free survival (PFS) and response rate were correlated with primary tumor location. A Cox regression model was used to evaluate interaction between primary tumor location and KRAS mutation. Results: Of 146 patients of the AIO KRK-0104 trial, 100 patients presented left-sided (of those 68 KRAS codon 12/13 wild-type) and 46 patients right-sided primary tumors (of those 27 KRAS codon 12/13 wild-type). Left-sided tumors were associated with significantly longer OS ( p = 0.016, HR = 0.63) and PFS ( p = 0.02, HR = 0.67) as compared to right-sided tumors. These effects were present in the KRAS codon 12/13 wild-type population (HR OS: 0.42; HR PFS: 0.54), while no impact of primary tumor location was evident in patients with KRAS codon 12/13 mutant tumors (HR OS: 1.3; HR PFS: 1.01). A significant interaction of KRAS status and primary tumor location concerning OS and PFS was observed. Conclusion: Our findings suggest that primary tumor location and KRAS codon 12/13 mutational status interact on the outcome of patients with mCRC receiving cetuximab-based first-line therapy. Left-sided primary tumor location might be a predictor of cetuximab efficacy. [ABSTRACT FROM AUTHOR]

Proteome profiling of formalin-fixed paraffin-embedded (FFPE) specimens has gained traction for the analysis of cancer tissue for the discovery of molecular biomarkers. However, reports so far focused on single cancer entities, comprised relatively few cases and did not assess the long-term performance of experimental workflows. In this study, we analyze 1220 tumors from six cancer entities processed over the course of three years. Key findings include the need for a new normalization method ensuring equal and reproducible sample loading for LC-MS/MS analysis across cohorts, showing that tumors can, on average, be profiled to a depth of >4000 proteins and discovering that current software fails to process such large ion mobility-based online fractionated datasets. We report the first comprehensive pan-cancer proteome expression resource for FFPE material comprising 11,000 proteins which is of immediate utility to the scientific community, and can be explored via a web resource. It enables a range of analyses including quantitative comparisons of proteins between patients and cohorts, the discovery of protein fingerprints representing the tissue of origin or proteins enriched in certain cancer entities., Competing Interests: Disclosure and competing interests statement BK is the founder and shareholder of OmicScouts and MSAID. He has no operational role in either company. The remaining authors declare no competing interests., (© 2024. The Author(s).)

Purpose: In 2016, the University of Munich Molecular Tumor Board (MTB) was implemented to initiate a precision oncology program. This review of cases was conducted to assess clinical implications and functionality of the program, to identify current limitations and to inform future directions of these efforts., Methods: Charts, molecular profiles, and tumor board decisions of the first 1000 consecutive cases (01/2016-03/2020) were reviewed. Descriptive statistics were applied to describe relevant findings., Results: Of the first 1000 patients presented to the MTB; 914 patients received comprehensive genomic profiling. Median age of patients was 56 years and 58% were female. The most prevalent diagnoses were breast (16%) and colorectal cancer (10%). Different types of targeted or genome-wide sequencing assays were used; most of them offered by the local department of pathology. Testing was technically successful in 88%. In 41% of cases, a genomic alteration triggered a therapeutic recommendation. The fraction of patients receiving a tumor board recommendation differed significantly between malignancies ranging from over 50% in breast or biliary tract to less than 30% in pancreatic cancers. Based on a retrospective chart review, 17% of patients with an MTB recommendation received appropriate treatment., Conclusion: Based on these retrospective analyses, patients with certain malignancies (breast and biliary tract cancer) tend to be more likely to have actionable variants. The low rate of therapeutic implementation (17% of patients receiving a tumor board recommendation) underscores the importance of meticulous follow-up for these patients and ensuring broad access to innovative therapies for patients receiving molecular tumor profiling., (© 2022. The Author(s).)

Objective: To identify a prognostic significant gene signature for predicting colorectal cancer (CRC) recurrence., Background: Traditional prognostic risk assessment in stage II/III CRC patients remains controversial. Epithelial-mesenchymal transition is thought to be closely related to the malignant progression of tumors. Thus, it is promising to establish a prognostic model based on epithelial-mesenchymal transition-related gene (ERG) signature., Materials and Methods: We retrospectively analyzed transcriptome profiles and clinical information of 1780 stage II/III CRC patients from 15 public datasets. Coefficient variant analysis was used to select reference genes for normalizing gene expression levels. Univariate, LASSO, and multivariate Cox regression analyses were combined to develop the ERG signature predicting disease-free survival (DFS). The patients were divided into high-risk and low-risk based on the ERG signature recurrence risk score. The survival analysis was performed in different CRC cohorts., Results: The proposed ERG signature contained 7 cancer-related ERGs and 3 reference genes. The ERG signature recurrence risk score was prognostically relevant in all cohorts ( P <0.05) and proved as an independent prognostic factor in the training cohort. In the pooled cohort, high-risk CRC patients exhibited worse DFS ( P <0.0001) and overall survival ( P =0.0058) than low-risk patients. The predictive performance of the ERG signature was superior to Oncotype DX colon cancer. An integrated decision tree and nomogram were developed to improve prognosis evaluation., Conclusions: The identified ERG signature is a promising and powerful biomarker predicting recurrence in CRC patients. Moreover, the presented ERG signature might help to stratify patients according to their tumor biology and contribute to personalized treatment., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

The goal of radiomics is to convert medical images into a minable data space by extraction of quantitative imaging features for clinically relevant analyses, e.g. survival time prediction of a patient. One problem of radiomics from computed tomography is the impact of technical variation such as reconstruction kernel variation within a study. Additionally, what is often neglected is the impact of inter-patient technical variation, resulting from patient characteristics, even when scan and reconstruction parameters are constant. In our approach, measurements within 3D regions-of-interests (ROI) are calibrated by further ROIs such as air, adipose tissue, liver, etc. that are used as control regions (CR). Our goal is to derive general rules for an automated internal calibration that enhance prediction, based on the analysed features and a set of CRs. We define qualification criteria motivated by status-quo radiomics stability analysis techniques to only collect information from the CRs which is relevant given a respective task. These criteria are used in an optimisation to automatically derive a suitable internal calibration for prediction tasks based on the CRs. Our calibration enhanced the performance for centrilobular emphysema prediction in a COPD study and prediction of patients' one-year-survival in an oncological study.

Background: Cetuximab-induced skin toxicity (Cet-ST) is positively associated with outcome in metastatic colorectal cancer (mCRC). Besides its predictive relevance for targeted therapy, we investigated its prognostic impact with early tumor shrinkage (ETS) ≥20%, another on-treatment surrogate for clinical outcome in FIRE-3., Patients and Methods: FIRE-3 evaluated first-line FOLFIRI (folinic acid, fluorouracil and irinotecan) plus cetuximab (FOLFIRI/Cet) versus FOLFIRI plus bevacizumab (FOLFIRI/Bev) in mCRC patients with RAS-WT tumors (i.e. wild-type in KRAS and NRAS exons 2-4). Retrospective data on Cet-ST that occurred during cycles 1-3 of treatment were correlated with efficacy endpoints, including ETS. To control for guarantee-time bias, only patients who had completed three or more treatment cycles were considered., Results: Of 199 patients treated with FOLFIRI/Cet, 181 (91.0%) completed three or more treatment cycles. A significant survival benefit of FOLFIRI/Cet over FOLFIRI/Bev was only evident in patients developing Cet-ST grade 2-3 [41.0 versus 26.6 months; hazard ratio (HR) = 0.73; 95% confidence interval (CI): 0.61-0.87; P < 0.001] compared with Cet-ST grade 0-1 (HR = 0.90; 95% CI: 0.67-1.20; P = 0.48). Regarding prognosis, Cet-ST grade 2-3 (n = 75; 41.4%), compared with Cet-ST grade 0-1 (n = 106; 58.6%), was associated with prolonged overall survival (OS; HR = 0.62; 95% CI: 0.42-0.91; P = 0.01). In multivariate analysis, both Cet-ST (HR = 0.66; 95% CI: 0.50-0.87; P = 0.003) and ETS (HR = 0.55; 95% CI: 0.41-0.74; P < 0.0001) were independently prognostic for OS. Absence of both Cet-ST grade ≥2 and ETS identified a subgroup of patients with very poor prognosis (median OS 15.1 months)., Conclusions: In FIRE-3, the addition of cetuximab to FOLFIRI was associated with superior OS compared with FOLFIRI/Bev only in patients developing Cet-ST grade ≥2. Regarding prognostic relevance, both Cet-ST and ETS were independent and early predictors of survival. The present analysis supports that a combined evaluation of on-treatment parameters such as Cet-ST and ETS may help to guide treatment of mCRC., (Copyright © 2019 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Introduction: To increase the rate of bystander resuscitation, basic life support (BLS) training for schoolchildren is now recommended on a broad level. However, debate continues about the optimal teaching methods. In this study, we investigated the effects of a 90 min BLS training on female pupils' BLS knowledge and self-confidence and whether learning outcomes were influenced by the instructors' professional backgrounds or test-enhanced learning., Methods: We conducted a cluster randomised, longitudinal trial in a girls' grammar school in Germany from 2013 to 2014. Pupils aged 10-17 years were randomised to receive BLS training conducted by either emergency physicians or medical students. Using a multiple-choice questionnaire and a Likert-type scale, BLS knowledge and self-confidence were investigated before training (t 0 ), 1 week (t 1 ) and 9 months after training (t 2 ). To investigate whether test-enhanced learning influenced learning outcomes, the questionnaire was administered 6 months after the training in half of the classrooms. The data were analysed using linear mixed-effects models., Results: The study included 460 schoolchildren. BLS knowledge (mean number of correct answers) increased from 5.86 at t 0 to 9.24 at t 1 (p<0.001) and self-confidence (mean score on the Likert-type scale) increased from 8.70 at t 0 to 11.29 at t 1 (p<0.001). After 9 months, knowledge retention was good (8.94 at t 2 ; p=0.080 vs t 1 ), but self-confidence significantly declined from t 1 to 9.73 at t 2 (p<0.001). Pupils trained by medical students showed a slight but statistically significant greater increase in the knowledge at both t 1 and t 2 , whereas instructors' background did not influence gain or retention of self-confidence. Retesting resulted in a marginally, non-significantly better retention of knowledge., Conclusions: BLS training led to short-term gains in knowledge and self-confidence. Although knowledge was retained at 9 months after the training session, self-confidence significantly decreased. Interim testing did not appear to impact retention of knowledge or self-confidence. Medical students should be considered as instructors for these courses given their favourable learning outcomes and greater availability., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Increased baseline carcinoembryonic antigen (CEA) serum level is associated with inferior overall survival (OS) in metastatic colorectal cancer (mCRC). However, limited data exist on its predictive relevance for targeted therapies. Therefore, we analysed its relevance in FIRE-3, a randomised phase III study., Experimental Design: FIRE-3 evaluated first-line FOLFIRI plus cetuximab (FOLFIRI/Cet) versus FOLFIRI plus bevacizumab (FOLFIRI/Bev) in mCRC patients with RAS-WT tumour (i.e. wild-type in KRAS and NRAS exons 2-4). Herein, the impact of CEA on patient outcome was investigated., Results: Of 400 patients, 356 (89.0%) were evaluable for CEA. High CEA (>10 ng/ml; N = 237) compared to low CEA (≤10 ng/ml; N = 119) was associated with shorter OS in the FOLFIRI/Bev arm (hazard ratio [HR] = 1.50; P = 0.036), while no significant OS difference was observed in the FOLFIRI/Cet arm (HR = 1.07; P = 0.74). In patients with high CEA, FOLFIRI/Cet compared to FOLFIRI/Bev showed a greater OS benefit (HR = 0.56; P < 0.001) than in patients with low CEA (HR = 0.78; P = 0.30). Furthermore, FOLFIRI/Cet exhibited significantly superior objective response rate in patients with high CEA (odds ratio = 2.21; P = 0.006) in contrast to patients with low CEA (odds ratio = 0.90; P = 0.85)., Conclusion: In patients with RAS-WT mCRC receiving first-line chemotherapy with FOLFIRI/Cet versus FOLFIRI/Bev, elevated CEA was associated with inferior survival in the bevacizumab arm, while this was not the case when cetuximab was applied. Comparison of OS and objective response rate according to treatment arms indicated that cetuximab was greatly superior to bevacizumab in patients with elevated CEA, while this effect was markedly lower and lost statistical significance in patients with low CEA., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: We explored the impacts of sequential application of various treatment lines on survival kinetics. Therefore, differences in overall survival (OS) observed in FIRE-3 were investigated in the context of time and exposure to applied treatment., Patients and Methods: OS analyses (stratified by treatment with FOLFIRI plus either cetuximab or bevacizumab) were performed according to time intervals as well as using a Cox model to define changes of hazard ratio (HR) over time., Results: The fraction of patients with systemic treatment and time on treatment markedly decreases over treatment lines and time. OS evaluation by a Cox model indicated a trend towards a non-proportional hazard between treatment arms (P = 0.12/P = 0.09 for KRAS-intention-to-treat (ITT)/all-RAS wild-type populations, respectively). To improve the fit of the model, a change-point (point of curve separation) was estimated at 22.6 months (day 687) after randomisation. The HR between the two arms before 22.6 months was not significantly different from one. However, markedly different survival kinetics in favour of the cetuximab arm were apparent after the change-point (KRAS-ITT: P = 0.0018; HR, 0.60 [95% confidence interval [CI], 0.44-0.83] and RAS: P = 0.0006; HR, 0.51 [95% CI, 0.35-0.75])., Conclusion: The differences in OS favouring the cetuximab arm become apparent about 22.6 months after randomisation, indicating that only those patients who survive 22.6 months after randomisation benefit from the superiority of the cetuximab arm. When OS curves separate, only few patients receive active systemic treatment in short courses, suggesting that earlier treatment effects are responsible for later kinetics of survival curves., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Palliative chemotherapy for metastatic colorectal cancer has undergone substantial changes in recent years. The implementation of modern biologicals in the treatment has substantially improved overall survival up to 30 months. With the increasing number of therapeutic options, the question of optimal treatment sequence arises, which is addressed in current studies like FIRE 4 or STRATEGIC-1. Furthermore, clinical and molecular biomarkers to predict efficacy and tolerability are urgently needed. Today, the detection of activating RAS mutations is the only validated biomarker which precludes patients from anti-EGFR treatment. The detection of BRAF mutation V600E is associated with a very poor prognosis corresponding to a survival of 9-12 months. Prospective trials evaluating an optimal approach to this subgroup are still missing. First results from strategies targeting the aberrant signal transduction are promising and require further validation. Despite the advances so far, life expectancy unfortunately continues to be limited in the majority of patients with metastatic colorectal cancer. New strategies are needed to improve the prognosis. To this end, the identification of Her2/neu as a potential target and first experiences with checkpoint inhibition in patients with mismatch repair-deficient tumors are promising and also require further validation.

Background and Aim: In metastatic colorectal cancer (mCRC) available systemic treatment options substantially increased in the last decades. Nowadays, overall survival in mCRC patients ranges from 25 to 35 months as recent studies report. We compared treatment modalities and survival in mCRC patients who were treated at our center in two different periods., Patients and Methods: Within two sequential monocentric analyses patients with mCRC treated at our Comprehensive Cancer Center (CCC) between 07/1994 and 10/2007 (cohort 1) and from 11/2007 to 05/2010 (cohort 2) were evaluated for applied treatment, for best response to treatment and for survival (OS). For statistical analysis the Kaplan-Meier estimator was used., Results: Both patient cohorts showed comparable characteristics regarding median age (63 vs. 64 yrs), localization of primary tumor (colon 60% vs. rectum 40%) and number and site of distant metastasis (1 site [75%] vs. ≥ 2 site [25%]; liver-only metastasis [55%]). About half of all patients in each cohort received at least three consecutive chemotherapy regimens. In cohort 1, treatment mainly consisted of chemotherapy alone (>80%), whereas in cohort 2 chemotherapy was combined with a monoclonal antibody in nearly 70%. Rate of surgical resection of metastasis increased over time (8% vs. 17%). Median OS was 27.3 months (cohort 1) vs. 39.4 months (cohort 2)., Conclusion: The increasing availability of effective substances including monoclonal antibodies and individual approaches including secondary surgery of distant metastasis might explain that survival in pts with mCRC has substantially improved over the last decades., (© Georg Thieme Verlag KG Stuttgart · New York.)

The development of hematopoietic neoplasms is often associated with mutations, altered gene expression or chromosomal translocations. Recently, the t(5, 9)(q33;q22) translocation was found in a subset of peripheral T cell lymphomas and was shown to result in an IL-2-inducible kinase-spleen tyrosine kinase (ITK-Syk) fusion transcript. In this study, we show that T cell-specific expression of the ITK-Syk oncogene in mice leads to an early onset and aggressive polyclonal T cell lymphoproliferation with concomitant B cell expansion and systemic inflammation by 7-9 wk of age. Because this phenotype is strikingly different from previous work showing that ITK-Syk expression causes clonal T cell lymphoma by 20-27 wk of age, we investigated the underlying molecular mechanism in more detail. We show that the reason for the severe phenotype is the lack of B-lymphocyte-induced maturation protein-1 (Blimp-1) induction by low ITK-Syk expression. In contrast, high ITK-Syk oncogene expression induces terminal T cell differentiation in the thymus by activating Blimp-1, thereby leading to elimination of oncogene-expressing cells early in development. Our data suggest that terminal differentiation is an important mechanism to prevent oncogene-expressing cells from malignant transformation, as high ITK-Syk oncogene activity induces cell elimination. Accordingly, for transformation, a specific amount of oncogene is required, or alternatively, the induction of terminal differentiation is defective.

Peripheral T cell lymphomas (PTCLs) are highly aggressive malignancies with poor prognosis. Their molecular pathogenesis is not well understood and small animal models for the disease are lacking. Recently, the chromosomal translocation t(5;9)(q33;q22) generating the interleukin-2 (IL-2)-inducible T cell kinase (ITK)-spleen tyrosine kinase (SYK) fusion tyrosine kinase was identified as a recurrent event in PTCL. We show that ITK-SYK associates constitutively with lipid rafts in T cells and triggers antigen-independent phosphorylation of T cell receptor (TCR)-proximal proteins. These events lead to activation of downstream pathways and acute cellular outcomes that correspond to regular TCR ligation, including up-regulation of CD69 or production of IL-2 in vitro or deletion of thymocytes and activation of peripheral T cells in vivo. Ultimately, conditional expression of patient-derived ITK-SYK in mice induces highly malignant PTCLs with 100% penetrance that resemble the human disease. Our work demonstrates that constitutively enforced antigen receptor signaling can, in principle, act as a powerful oncogenic driver. Moreover, we establish a robust clinically relevant and genetically tractable model of human PTCL.