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Introduction: Understanding the mutational landscape of colon cancer (CC) is crucial for targeted therapy development. Microsatellite instability (MSI-H), rat sarcoma (RAS), and B-Raf proto-oncogene, serine/threonine kinase (BRAF) mutations (MT) are pivotal markers. Further investigation into clinicopathological features of RAS and BRAF MT in microsatellite stable (MSS) and MSI-H tumors is warranted. Methods: A retrospective analysis of 4883 localized CC patients (pts.) was conducted. Molecular profiling assessed MSI, KRAS, NRAS, and BRAF MT. Correlation with clinicopathological data employed ANOVA and Chi-square tests. Disease-free survival (DFS) and overall survival (OS) were analyzed adjusting for age, gender, sidedness, UICC stage, Charlson Comorbidity Index (CCI). A Cox model incorporated all variables as covariates. Results: This analysis included 4883 pts. (2302 female/2572 male, 3865 (79.2%) MSS, 1018 (20.8%) MSI-H). MSS pts. had more All-Wild Type (WT), KRAS MT, and NRAS MT tumors vs. MSI-H pts. (42.1% vs. 21.1%; 39.8% vs. 15.4%; 3.6% vs. 0.7%; p<0.001 for each). BRAF MT tumors (95.5% BRAF V600E MT) were more prevalent in MSI-H individuals (62.8% vs. 8.1%, p<0.001). KRAS and BRAF MT tumors were more frequently right-sided, while BRAF MT tumors were associated with female gender, advanced disease stage, lymph node positivity, and poorer differentiation in the MSS subset (p<0.001). Common KRAS mutations included p.G12D (30.44%) and p.G12V (21.3%) in MSS and p.G13D (28.9%) and p.G12D (22.37%) in MSI-H. NRAS MT tumors were dominated by codon 61 mutations (51.7%). Survival analysis revealed worst prognosis in BRAF MT MSS tumors (DFS: HR 1.74 (95% CI 1.15-2.62, p=0.009; OS: HR 1.61 (95% CI 0.99-2.6), p=0.055). The 3-years DFS and 5-years OS rates were lowest in this subset (61.6% and 57.7% respectively). Discussion: These findings highlight the complex interplay between molecular subtypes, clinicopathological features, and survival outcomes in early CC. Further research is needed to elucidate underlying mechanisms and develop personalized treatment strategies. [ABSTRACT FROM AUTHOR] more...

Introduction Inflammation is an essential mechanism for restoring tissue integrity after myocardial infarction (MI). After restriction of blood supply, the inflammatory response is characterized by a multistep cascade at both [...], The inflammatory response after myocardial infarction (MI) is a precisely regulated process that greatly affects subsequent remodeling. Here, we show that basophil granulocytes infiltrated infarcted murine hearts, with a peak occurring between days 3 and 7 Antibody-mediated and genetic depletion of basophils deteriorated cardiac function and resulted in enhanced scar thinning after MI. Mechanistically, we found that basophil depletion was associated with a shift from reparative [Ly6C.sup.lo] macrophages toward increased numbers of inflammatory [Ly6C.sup.hi] monocytes in the infarcted myocardium. Restoration of basophils in basophil-deficient mice by adoptive transfer reversed this proinflammatory phenotype. Cellular alterations in the absence of basophils were accompanied by lower cardiac levels of IL-4 and IL-13, two major cytokines secreted by basophils. Mice with basophil-specific IL-4/IL-13 deficiency exhibited a similarly altered myeloid response with an increased fraction of [Ly6C.sup.hi] monocytes and aggravated cardiac function after MI. In contrast, IL-4 induction in basophils via administration of the glycoprotein IPSE/[alpha]-1 led to improved post-MI healing. These results in mice were corroborated by the finding that initially low counts of blood basophils in patients with acute MI were associated with a worse cardiac outcome after 1 year, characterized by a larger scar size. In conclusion, we show that basophils promoted tissue repair after MI by increasing cardiac IL-4 and IL-13 levels. more...

Objectives: The German‐speaking Myeloma Multicenter Group (GMMG) conducted this trial to investigate efficacy and safety of the three‐drug combination bendamustine/prednisone/bortezomib (BPV) as first‐line therapy for elderly patients with multiple myeloma (MM). Methods: Elderly MM patients requiring first‐line therapy and not eligible for intensive treatment were enrolled in this phase IIb multicenter study. Patients were treated with BPV regimen for a maximum of nine cycles. Results: Forty‐six patients were included in the trial with a median age of 76 years. Nineteen patients had renal impairment at baseline. The ORR was 78.8% for patients treated with 3 and more BPV cycles and 71.1% for all evaluable patients. The median progression‐free survival was 25 months, and overall survival at 24 months was 83.3%. The clinical benefit rate including MR was 91.2%. In patients with renal impairment at baseline, a renal response was observed in 11 pts. with complete recovery of the renal function in six patients. The most frequent CTC grade 3/4 AEs experienced by patients were hematological (17.5%) and infectious (9.8%) complications. No new safety signals were observed for the study drugs under investigation. Conclusions: Bendamustine/prednisone/bortezomib may serve as a first‐line regimen for transplant‐ineligible elderly MM patients in particular for patients with renal impairment requiring a fast and durable renal response. [ABSTRACT FROM AUTHOR] more...

The progression-free-survival ratio is a popular endpoint in oncology trials, which is frequently applied to evaluate the efficacy of molecularly targeted treatments in late-stage patients. Using elementary calculations and simulations, numerous shortcomings of the current methodology are pointed out. As a remedy to these shortcomings, an alternative methodology is proposed, using a marginal Cox model or a marginal accelerated failure time model for clustered time-to-event data. Using comprehensive simulations, it is shown that this methodology outperforms existing methods in settings where the intrapatient correlation is low to moderate. The performance of the model is further demonstrated in a real data example from a molecularly aided tumor trial. Sample size considerations are discussed., (© 2024 The Author(s). Biometrical Journal published by Wiley‐VCH GmbH.) more...

Background: Colorectal cancer (CRC) remains a leading cause of death despite notable advancements through guideline-based management. We present data on changes of CRC care during the COVID-19 pandemic in Germany., Methods: Retrospective data from 22 AIO CCs and an academic Institute of Pathology compared the first (fw, 03-05.2020) and second wave (sw, 11-12.2020) of the pandemic with corresponding 2019 periods. Parameters were: number of cases diagnosed, age, sex, tumor stage, surgical procedures, quality criteria of CRC care (presentation in multidisciplinary tumor boards (MTB), psychological or social consultation), number of precancerous and malignant colorectal lesions (CRL). Data points were compared as mean values with confidence intervals estimated according to Clopper and Pearson (1934). Hypothesis tests were conducted using Poisson regression models that included interaction terms (year*sex or year*age over70). Statistical significance was considered at P < .05., Results: A total of 4316 cases diagnosed (AIO CC) revealed a substantial reduction (fw -20.58%; sw -23.48%). Hypothesis test showed a significant decline in incidence due to the fw and sw of the pandemic. Quality criteria of cancer care remained stable except for trial participation. Analysis from 60,695 CRL detected a decrease in precancerous (fw: -16 %/sw: -4 %) and malignant (fw: -18 %) lesions while malignant CRL increased in the sw (+8 %). Hypothesis test revealed a significant decline only for the fw 2020 and detected age > 70 as independent risk factor in both waves., Conclusion: We detected substantial alterations in cancer care during the pandemic, including detected precancerous CRL. CCs showed high resilience in quality criteria for CRC care., Competing Interests: Disclosure There are no conflicts of interest concerning this work., (Copyright © 2025 Elsevier Inc. All rights reserved.) more...

Existing methods concerning the assessment of long-term survival outcomes in one-armed trials are commonly restricted to one primary endpoint. Corresponding adaptive designs suffer from limitations regarding the use of information from other endpoints in interim design changes. Here we provide adaptive group sequential one-sample tests for testing hypotheses on the multivariate survival distribution derived from multi-state models, while making provision for data-dependent design modifications based on all involved time-to-event endpoints. We explicitly elaborate application of the methodology to one-sample tests for the joint distribution of (i) progression-free survival (PFS) and overall survival (OS) in the context of an illness-death model, and (ii) time to toxicity and time to progression while accounting for death as a competing event. Large sample distributions are derived using a counting process approach. Small sample properties are studied by simulation. An already established multi-state model for non-small cell lung cancer is used to illustrate the adaptive procedure., (© 2021 The Authors. Biometrical Journal published by Wiley-VCH GmbH.) more...

No biomarker panel is established for prediction of sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD), a major complication of allogeneic stem cell transplantation (alloSCT). We compared the potential of the Endothelial Activation and Stress Index (EASIX), based on lactate dehydrogenase, creatinine, and thrombocytes, with that of the SOS/VOD CIBMTR clinical risk score to predict SOS/VOD in two independent cohorts. In a third cohort, we studied the impact of endothelium-active prophylaxis with pravastatin and ursodeoxycholic acid (UDA) on SOS/VOD risk. The cumulative incidence of SOS/VOD within 28 days after alloSCT in the training cohort (Berlin, 2013-2015, n=446) and in the validation cohort (Heidelberg, 2002-2009, n=380) was 9.6% and 8.4%, respectively. In both cohorts, EASIX assessed at the day of alloSCT (EASIX-d0) was significantly associated with SOS/VOD incidence (p<0.0001), overall survival (OS) and non-relapse mortality (NRM). In contrast, the CIBMTR score showed no statistically significant association with SOS/VOD incidence, and did not predict OS and NRM. In patients receiving pravastatin/UDA, the cumulative incidence of SOS/VOD was significantly lower at 1.7% (p<0.0001, Heidelberg, 2010-2015, n=359) than in the two cohorts not receiving pravastatin/UDA. The protective effect was most pronounced in patients with high EASIX-d0. The cumulative SOS/VOD incidence in the highest EASIX-d0 quartiles were 18.1% and 16.8% in both cohorts without endothelial prophylaxis as compared to 2.2% in patients with pravastatin/UDA prophylaxis (p<0.0001). EASIX-d0 is the first validated biomarker for defining a subpopulation of alloSCT recipients at high risk for SOS/VOD. Statin/UDA endothelial prophylaxis could constitute a prophylactic measure for patients at increased SOS/VOD risk. more...