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Simple Summary: Around 30% of patients with stage III non-small cell lung cancer (NSCLC) receiving radical chemoradiotherapy will develop symptomatic brain metastases (BM) during the disease course. Identifying risk factors for BM can help improve the management of these patients. The aim of this current study was to identify clinical risk factors, including gross tumor volume (GTV) radiomics features, for developing BM in patients with radically treated stage III NSCLC. We found that age, NSCLC subtype, and GTV of lymph nodes (GTVn) were significant factors for BM. GTVn radiomics features provided higher predictive value than GTV of primary tumor (GTVp) and GTV. Therefore, GTVp and GTVn should be separated in clinical and research practice. Purpose: To identify clinical risk factors, including gross tumor volume (GTV) and radiomics features, for developing brain metastases (BM) in patients with radically treated stage III non-small cell lung cancer (NSCLC). Methods: Clinical data and planning CT scans for thoracic radiotherapy were retrieved from patients with radically treated stage III NSCLC. Radiomics features were extracted from the GTV, primary lung tumor (GTVp), and involved lymph nodes (GTVn), separately. Competing risk analysis was used to develop models (clinical, radiomics, and combined model). LASSO regression was performed to select radiomics features and train models. Area under the receiver operating characteristic curves (AUC-ROC) and calibration were performed to assess the models' performance. Results: Three-hundred-ten patients were eligible and 52 (16.8%) developed BM. Three clinical variables (age, NSCLC subtype, and GTVn) and five radiomics features from each radiomics model were significantly associated with BM. Radiomic features measuring tumor heterogeneity were the most relevant. The AUCs and calibration curves of the models showed that the GTVn radiomics model had the best performance (AUC: 0.74; 95% CI: 0.71–0.86; sensitivity: 84%; specificity: 61%; positive predictive value [PPV]: 29%; negative predictive value [NPV]: 95%; accuracy: 65%). Conclusion: Age, NSCLC subtype, and GTVn were significant risk factors for BM. GTVn radiomics features provided higher predictive value than GTVp and GTV for BM development. GTVp and GTVn should be separated in clinical and research practice. [ABSTRACT FROM AUTHOR]

Simple Summary: In recent years, mounting evidence has recognized the key role of the crosstalk between immune system and cancer cells. Several data have suggested that gender-related immune system composition could impact on both immune response, efficacy of chemotherapy, and immunotherapy and risk of immune-related adverse events. Based on these premises, the present study aimed to evaluate the role of monocyte-to-lymphocyte ratio (MLR), representing the immune suppression cells, in the first place, and immune activating cells, in the second. The analysis, conducted on 490 patients with metastatic colorectal cancer, showed that males and females have a different profile of immune response. Of note, high MLR, both in males and females, is an unfavorable independent prognostic factor. Background: Emerging data suggest that gender-related immune system composition affects both immune response and efficacy of immunotherapy in cancer patients (pts). This study aimed to investigate the sex-related prognostic role of MLR in metastatic colorectal cancer (mCRC) pts. Methods: We analyzed a retrospective consecutive cohort of 490 mCRC patients treated from 2009 to 2018 at the Oncology Departments of Aviano and Pordenone (training set) and Udine (validation set), Italy. The prognostic impact of MLR on overall survival (OS) was evaluated with uni- and multivariable Cox regression models. The best cut-off value to predict survival was defined through ROC analyses. Results: Overall, we identified 288 males (59%) and 202 females (41%); 161 patients (33%) had a right-sided, 202 (42%) a left-sided primary, and 122 (25%) a rectal tumor. Interestingly, gender was associated with MLR (p = 0.004) and sidedness (p = 0.006). The obtained cut-off value for MLR in females and males was 0.27 and 0.49, respectively. According to univariate analysis of the training set, MLR (HR 9.07, p ≤ 0.001), MLR > 0.27 in females (HR 1.95, p = 0.003), and MLR > 0.49 in males (HR 2.65, p = 0.010) were associated with poorer OS, which was also confirmed in the validation set. In multivariate analysis, MLR > 0.27 in females (HR 2.77, p = 0.002), MLR > 0.49 in males (HR 5.39, p ≤ 0.001), BRAF mutation (HR 3.38, p ≤ 0.001), and peritoneal metastases (HR 2.50, p = 0.003) were still independently associated with worse OS. Conclusions: Males and females have a different immune response. Our study showed that high MLR, both in males and females, is an unfavorable Independent prognostic factor. Further prospective studies are needed to confirm these data. [ABSTRACT FROM AUTHOR]

Background: V600EBRAF mutated metastatic colorectal cancer (mCRC) is a subtype (10%) with overall poor prognosis, but the clinical experience suggests a great heterogeneity in survival. It is still unexplored the real distribution of traditional and innovative biomarkers among V600EBRAF mutated mCRC and which is their role in the improvement of clinical prediction of survival outcomes.Methods: Data and tissue specimens from 155 V600EBRAF mutated mCRC patients treated at eight Italian Units of Oncology were collected. Specimens were analysed by means of immunohistochemistry profiling performed on tissue microarrays. Primary endpoint was overall survival (OS).Results: CDX2 loss conferred worse OS (HR = 1.72, 95%CI 1.03-2.86, p = 0.036), as well as high CK7 expression (HR = 2.17, 95%CI 1.10-4.29, p = 0.026). According to Consensus Molecular Subtypes (CMS), CMS1 patients had better OS compared to CMS2-3/CMS4 (HR = 0.37, 95%CI 0.19-0.71, p = 0.003). Samples showing less TILs had worse OS (HR = 1.72, 95%CI 1.16-2.56, p = 0.007). Progression-free survival analyses led to similar results. At multivariate analysis, CK7 and CMS subgrouping retained their significant correlation with OS.Conclusion: The present study provides new evidence on how several well-established biomarkers perform in a homogenousV600EBRAF mutated mCRC population, with important and independent information added to standard clinical prognosticators. These data could be useful to inform further translational research, for patients' stratification in clinical trials and in routine clinical practice to better estimate patients' prognosis. [ABSTRACT FROM AUTHOR]

Background: Neuroendocrine differentiation has been extensively associated with worse prognosis and to mechanisms of therapy resistance in several epithelial cancers. A high prevalence of neuroendocrine differentiation was recently described in V600EBRAF- mutated (BRAFmt) metastatic colorectal cancers (mCRCs) but no data are available about its prognostic impact in this setting., Methods: We assessed synaptophysin immunohistochemical expression in a multi-institutional series of 159 BRAFmt mCRCs with matched clinical and pathological information. Tumours were dichotomized as synaptophysin high and low. Overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan-Meier and log-rank tests., Results: Thirty-five tumours (22.0%) showed any level of positivity for synaptophysin, and 18 (11.3%) were characterized by positivity in at least 20% of tumour cells. Four cases resulted 100% synaptophysin positive. The histotype of synaptophysin-positive tumours (i.e. ≥20%) was not otherwise specified in 11 cases (61.1%) and mucinous adenocarcinoma in 4 cases (22.2%). Four cases were DNA mismatch repair deficient (22.2%) and 7 (38.9%) were characterized by a high number of tumour-infiltrating lymphocytes. At multivariate analysis, high synaptophysin expression was a negative independent prognostic factor for both PFS (HR = 2.00, 95% confidence interval [CI] 1.21-3.33, p = 0.006) and OS (HR = 2.27, 95% CI 1.35-3.85, p = 0.001)., Conclusions: Among BRAFmt mCRCs, synaptophysin-positive tumours are characterized by worse PFS and OS. Further studies should investigate the molecular mechanisms involved in the acquisition of the neuroendocrine phenotype to identify novel-targeted treatment strategies., Competing Interests: Conflict of interest statement The authors declare no conflict of interest regarding the publication of this article. Matteo Fassan received research grant from Astellas Pharma and QED Therapeutics and is a consultant/advisory board member for Astellas Pharma, Diaceutics, Tesaro and GSK. Fotios Loupakis received lecture fees from Amgen and F. Hoffmann-La Roche and advisory fees from Bayer and Genentech. Sara Lonardi received advisory board fees from Amgen, Bayer, Eli Lilly, and Merck Serono, received research grant from Amgen and Merck Serono and is part of the speakers' bureau of Lilly and BMS. Angelo Paolo Dei Tos declares personal fees for advisory boards/speaker's bureau from PharaMar, Lilly, Roche, Bayer and Pfizer. Filippo Pietrantonio declared honoraria/speaker's bureau from Roche, Amgen, Merck-Serono, Lilly, Sanofi, Bayer and Servier and research grant from BMS. Chiara Cremolini is a consultant/advisory board member for Roche, Amgen, Bayer, Merck Serono and Servier. Massimo Di Maio received honoraria, had roles as a consultant or advisor for AstraZeneca, Bristol Myears Squibb, MSD, Takeda and Janssen and received a research grant from Tesaro. Vittorina Zagonel received honoraria and had roles as a consultant or advisor for Bristol-Myears Squibb, Bayer, Roche, Pfizer, Janssen, Novartis, Astellas and Servier and had roles as a consultant or advisor for Celgene and Merck. Lorenza Rimassa reports personal fees from Amgen, ArQule, AstraZeneca, Basilea, Bayer, Celgene, Eisai, Eli Lilly, Exelixis, Hengrui, Incyte, Ipsen, Merck Sharp & Dohme, Nerviano Medical Sciences, Roches Sanofi, AbbViem Gilead and reearch grants from Agios, ARMO BioSciences, AstraZeneca, BeiGene, Eisai, Eli Lilly, Exelixis, FibroGen, Incyte, Ipsen, Merck Sharp & Dohme and Roche. Giuseppe Aprile reports receiving personal fees and has been a consultant for Merck Serono, Amgen, Roche and Servier., (Copyright © 2021 Elsevier Ltd. All rights reserved.)