Mast cells are the major effector cells that mediate IgE-dependent allergic reactions. We sought to use integrated network analysis to identify genomic biomarkers associated with high response in IgE-mediated activation of primary human mast cells. Primary human mast cell cultures derived from 262 normal donors were categorized into High, Average and Low responder groups according to their activation response profiles. Transcriptome analysis was used to identify genes that were differentially expressed in different responder cultures in their baseline conditions, and the data were analyzed by constructing a personalized perturbed profile (PEEP). For upregulated genes, the construction of PEEP for each individual sample of all three responder groups revealed that High responders exhibited a higher percentage of \"perturbed\" samples whose PEEP values lay outside the normal range of expression. Moreover, the integration of PEEP of four selected upregulated genes into distinct sets of combinatorial profiles demonstrated that the specific pattern of upregulated expression of these four genes, in a tandem combination, was observed exclusively among the High responders. In conclusion, this combinatorial approach was useful in identifying a set of genomic biomarkers that are associated with high degranulation response in human mast cell cultures derived from the blood of a cohort of normal donors.

We previously reported that tumors harboring any one of four gene mutations (ATM, RB1, FANCC, or ERCC2) were likely to respond to neoadjuvant cisplatin-based chemotherapy (NAC), resulting in cancer-free surgical specimens at the time of cystectomy (pT0). Here, we report our validation of this finding. Using the CARIS 592 Gene Panel (Caris Life Sciences, Phoenix, AZ, USA), we analyzed 105 pre-NAC tumor specimens from a large multicenter trial (S1314) of either neoadjuvant gemcitabine and cisplatin (GC), or dose-dense methotrexate, vinblastine, Adriamycin, and cisplatin (DDMVAC). We found that a mutation in any one of these four genes predicted for pT0 at surgery (odds ratio = 5.36; 95% confidence interval [CI] 2.05, 14.02; two-sided p = 0.0006). The biomarker was better at predicting the presence of disease (negative predictive value for pT0 86%; 95% CI 73%, 94%) than the absence of disease (positive predictive value for pT0 48%; 95% CI 35%, 62%). There was no evidence of an interaction between the treatment arm (DDMVAC vs GC) and the genetic variant in terms of pT0. When combined with clinical assessment, these findings help inform patient selection for bladder preservation after cisplatin-based chemotherapy. PATIENT SUMMARY: A common standard of care for patients with muscle-invasive bladder cancer is neoadjuvant chemotherapy (NAC) followed by cystectomy to achieve cure. We previously discovered that specific DNA mutations in tumor samples collected at initial biopsy (transurethral resection of a bladder tumor) were predictive of a complete response to NAC. In other words, patients with these mutations were more likely to have a bladder found to be cancer free after surgery. In this study, we analyzed a larger set of tumor samples from a national clinical trial of chemotherapy followed by cystectomy to validate these earlier findings. We conclude that this biomarker test, when combined with careful clinical assessment, can be used to allocate patients to careful bladder surveillance instead of surgery. This hypothesis has been tested in the RETAIN trial presented previously (NCT02710734).

Large-scale tumor molecular profiling has revealed that diverse cancer histologies are driven by common pathways with unifying biomarkers that can be exploited therapeutically. Disease-agnostic basket trials have been increasingly utilized to test biomarker-driven therapies across cancer types. These trials have led to drug approvals and improved the lives of patients while simultaneously advancing our understanding of cancer biology. This review focuses on the practicalities of implementing basket trials, with an emphasis on molecularly targeted trials. We examine the biologic subtleties of genomic biomarker and patient selection, discuss previous successes in drug development facilitated by basket trials, describe certain novel targets and drugs, and emphasize practical considerations for participant recruitment and study design. This review also highlights strategies for aiding patient access to basket trials. As basket trials become more common, steps to ensure equitable implementation of these studies will be critical for molecularly targeted drug development.

OBJECTIVE: In contemporary urological practice, managing rare genitourinary (GU) malignancies presents significant challenges, necessitating a comprehensive understanding of their unique characteristics and tailored treatment approaches.
RESULTS: Rare GU malignancies, whether per se, variants of common histologies, or common tumors in uncommon locations, often lack widely available clinical guidelines. Consequently, treatment decisions are frequently based on empirical evidence, risking suboptimal outcomes. However, recent advances in molecular profiling, targeted therapies, and immunotherapy offer promising avenues for improving management strategies and patient outcomes. This review provides a comprehensive overview of some rare GU malignancies encountered in clinical practice, including their distinct pathological features, current management approaches, and ongoing research directions. Understanding the complexities of these rare tumors and implementing multidisciplinary treatment strategies are essential for optimizing patient care and improving survival outcomes.

UNASSIGNED: It is well-known that circulating microRNAs (miRNAs) play a relevant role in many kinds of diseases by regulating the expression of genes involved in various pathophysiologic processes, including erectile dysfunction (ED) and cardiovascular diseases (CVD).
UNASSIGNED: This study aimed to identify the miRNA-21 profile in the blood samples of patients with ED, CVD, and the combination of both pathologies to elucidate the potential function of miRNA-21.
UNASSIGNED: A total of 45 patients with CVD and/or who underwent the erectile function test were included and divided into the following categories: CVD with ED (cases, n = 29) and controls (n = 16) with either ED or CVD. Real-time polymerase chain reaction analysis verified the results. miRNA-21 expression was quantified, and informatics analysis was applied to predict the functions of this differentially expressed miRNA-21.
UNASSIGNED: A total of 64% of cases (63 ± 9 years, 66% with severe ED, 56% with CV ejection fraction) first presented ED as the sentinel clinical manifestation. Serum miRNA-21 levels in the control ED were significant, up to 10-fold higher than in the CVD controls and cases. A significant inverse (p = 0.0368, β = -2.046) correlation was found between erectile function and miRNA-21 levels.
UNASSIGNED: Our study provides comprehensive insights into the functional interaction between miRNA-21 and ED in CVD patients. Its relevance lies in the potential of miRNA as a biomarker to be applied in the cardiovascular predictive medicine field.

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The current therapeutic algorithm for Advanced Stage Melanoma comprises of alternating lines of Targeted and Immuno-therapy, mostly via Immune-Checkpoint blockade. While Comprehensive Genomic Profiling of solid tumours has been approved as a companion diagnostic, still no approved predictive biomarkers are available for Melanoma aside from BRAF mutations and the controversial Tumor Mutational Burden. This study presents the results of a Multi-Centre Observational Clinical Trial of Comprehensive Genomic Profiling on Target and Immuno-therapy treated advanced Melanoma.
82 samples, collected from 7 Italian Cancer Centres of FFPE-archived Metastatic Melanoma and matched blood were sequenced via a custom-made 184-gene amplicon-based NGS panel. Sequencing and bioinformatics analysis was performed at a central hub. Primary analysis was carried out via the Ion Reporter framework. Secondary analysis and Machine Learning modelling comprising of uni and multivariate, COX/Lasso combination, and Random Forest, was implemented via custom R/Python scripting.
The genomics landscape of the ACC-mela cohort is comparable at the somatic level for Single Nucleotide Variants and INDELs aside a few gene targets. All the clinically relevant targets such as BRAF and NRAS have a comparable distribution thus suggesting the value of larger scale sequencing in melanoma. No comparability is reached at the CNV level due to biotechnological biases and cohort numerosity. Tumour Mutational Burden is slightly higher in median for Complete Responders but fails to achieve statistical significance in Kaplan-Meier survival analysis via several thresholding strategies. Mutations on PDGFRB, NOTCH3 and RET were shown to have a positive effect on Immune-checkpoint treatment Overall and Disease-Free Survival, while variants in NOTCH4 were found to be detrimental for both endpoints.
The results presented in this study show the value and the challenge of a genomics-driven network trial. The data can be also a valuable resource as a validation cohort for Immunotherapy and Target therapy genomic biomarker research.

Genome-based testing in oncology is a rapidly expanding area of health care that is the basis of the emerging area of precision medicine. The efficient and considered adoption of novel genomic medicine testing is hampered in Canada by the fragmented nature of health care oversight as well as by lack of clear and transparent processes to support rapid evaluation, assessment, and implementation of genomic tests. This article provides an overview of some key barriers and proposes approaches to addressing these challenges as a potential pathway to developing a national approach to genomic medicine in oncology.

OBJECTIVE: Method: This research presents a model combining machine learning (ML) techniques and eXplainable artificial intelligence (XAI) to predict breast cancer (BC) metastasis and reveal important genomic biomarkers in metastasis patients.
METHODS: A total of 98 primary BC samples was analyzed, comprising 34 samples from patients who developed distant metastases within a 5-year follow-up period and 44 samples from patients who remained disease-free for at least 5 years after diagnosis. Genomic data were then subjected to biostatistical analysis, followed by the application of the elastic net feature selection method. This technique identified a restricted number of genomic biomarkers associated with BC metastasis. A light gradient boosting machine (LightGBM), categorical boosting (CatBoost), Extreme Gradient Boosting (XGBoost), Gradient Boosting Trees (GBT), and Ada boosting (AdaBoost) algorithms were utilized for prediction. To assess the models\' predictive abilities, the accuracy, F1 score, precision, recall, area under the ROC curve (AUC), and Brier score were calculated as performance evaluation metrics. To promote interpretability and overcome the \"black box\" problem of ML models, a SHapley Additive exPlanations (SHAP) method was employed.
RESULTS: The LightGBM model outperformed other models, yielding remarkable accuracy of 96% and an AUC of 99.3%. In addition to biostatistical evaluation, in XAI-based SHAP results, increased expression levels of TSPYL5, ATP5E, CA9, NUP210, SLC37A1, ARIH1, PSMD7, UBQLN1, PRAME, and UBE2T (p ≤ 0.05) were found to be associated with an increased incidence of BC metastasis. Finally, decreased levels of expression of CACTIN, TGFB3, SCUBE2, ARL4D, OR1F1, ALDH4A1, PHF1, and CROCC (p ≤ 0.05) genes were also determined to increase the risk of metastasis in BC.
CONCLUSIONS: The findings of this study may prevent disease progression and metastases and potentially improve clinical outcomes by recommending customized treatment approaches for BC patients.

The management of anal squamous cell carcinoma (ASCC) has yet to experience the transformative impact of precision medicine. Conducting genomic analyses may uncover novel prognostic biomarkers and offer potential directions for the development of targeted therapies. To that end, we assessed the prognostic and theragnostic implications of pathogenic variants identified in 571 cancer-related genes from surgical samples collected from a homogeneous, multicentric French cohort of 158 ASCC patients who underwent abdominoperineal resection treatment. Alterations in PI3K/AKT/mTOR, chromatin remodeling, and Notch pathways were frequent in HPV-positive tumors, while HPV-negative tumors often harbored variants in cell cycle regulation and genome integrity maintenance genes (e.g., frequent TP53 and TERT promoter mutations). In patients with HPV-positive tumors, KMT2C and PIK3CA exon 9/20 pathogenic variants were associated with worse overall survival in multivariate analysis (Hazard ratio (HR)KMT2C  = 2.54, 95%CI = [1.25,5.17], P value = .010; HRPIK3CA  = 2.43, 95%CI = [1.3,4.56], P value = .006). Alterations with theragnostic value in another cancer type was detected in 43% of patients. These results suggest that PIK3CA and KMT2C pathogenic variants are independent prognostic factors in patients with ASCC with HPV-positive tumors treated by abdominoperineal resection. And, importantly, the high prevalence of alterations bearing potential theragnostic value strongly supports the use of genomic profiling to allow patient enrollment in precision medicine clinical trials.