It is well known how the precise localization of glioblastoma multiforme (GBM) predicts the direction of tumor spread in the surrounding neuronal structures. The aim of the present review is to reveal the lateralization of GBM by evaluating the anatomical regions where it is frequently located as well as the main molecular alterations observed in different brain regions. According to the literature, the precise or most frequent lateralization of GBM has yet to be determined. However, it can be said that GBM is more frequently observed in the frontal lobe. Tractus and fascicles involved in GBM appear to be focused on the corticospinal tract, superior longitudinal I, II and III fascicles, arcuate fascicle long segment, frontal strait tract, and inferior fronto‑occipital fasciculus. Considering the anatomical features of GBM and its brain involvement, it is logical that the main brain regions involved are the frontal‑temporal‑parietal‑occipital lobes, respectively. Although tumor volumes are higher in the right hemisphere, it has been determined that the prognosis of patients diagnosed with cancer in the left hemisphere is worse, probably reflecting the anatomical distribution of some detrimental alterations such as TP53 mutations, PTEN loss, EGFR amplification, and MGMT promoter methylation. There are theories stating that the right hemisphere is less exposed to external influences in its development as it is responsible for the functions necessary for survival while tumors in the left hemisphere may be more aggressive. To shed light on specific anatomical and molecular features of GBM in different brain regions, the present review article is aimed at describing the main lateralization pathways as well as gene mutations or epigenetic modifications associated with the development of brain tumors.

The increasing availability of genomic sequencing of tumor tissue in oncology provided valuable insights into tumor evolution and offered clinicians the unprecedented opportunity to tailor therapies on each individual patient, according to the treatment-impacting alterations identified in the tumor cells. In addition to the characterization of somatic alterations in tumor samples, the identification of germline (i.e., constitutional) pathogenic variants can provide additional information to guide informed and personalized therapeutic planning for patients and to enable risk-based screening protocols for at-risk relatives. In genitourinary malignancies, only a few associations between germline mutations and cancer risk and behavior have been thoroughly investigated (e.g., alterations in DNA repair genes in prostate cancer or mutations in Lynch syndrome genes in upper tract urothelial carcinoma). To achieve a wider use of both tumor genomic and germline genetic testing, an integrative approach led by scientific societies is necessary to involve physicians, patients and advocacy groups, to develop a shared strategy to advance the field and provide value-based and reproducible standards of care for patients and their families.

Mesothelioma (MM) is an aggressive and lethal disease with few therapeutic opportunities. Platinum-pemetrexed chemotherapy is the backbone of first-line treatment for MM. The introduction of immunotherapy (IO) has been the only novelty of the last decades, allowing an increase in survival compared to standard chemotherapy (CT). However, IO is not approved for epithelioid histology in many countries. Therefore, therapy for relapsed MM remains an unmet clinical need, and the prognosis of MM remains poor, with an average survival of only 18 months. Increasing evidence reveals MM complexity and heterogeneity, of which histological classification fails to explain. Thus, scientific focus on possibly new molecular markers or cellular targets is increasing, together with the search for target therapies directed towards them. The molecular landscape of MM is characterized by inactivating tumor suppressor alterations, the most common of which is found in CDKN2A, BAP1, MTAP, and NF2. In addition, cellular targets such as mesothelin or metabolic enzymes such as ASS1 could be potentially amenable to specific therapies. This review examines the major targets and relative attempts of therapeutic approaches to provide an overview of the potential prospects for treating this rare neoplasm.

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related death worldwide. It is commonly diagnosed in advanced stages and therapeutic interventions are typically constrained to systemic chemotherapy, which yields only modest clinical outcomes. In this review, we examine recent developments in targeted therapy tailored to address distinct molecular pathway alteration required for PDAC. Our review delineates the principal signaling pathways and molecular mechanisms implicated in the initiation and progression of PDAC. Subsequently, we provide an overview of prevailing guidelines, ongoing investigations, and prospective research trajectories related to targeted therapeutic interventions, drawing insights from randomized clinical trials and other pertinent studies. This review focus on a comprehensive examination of preclinical and clinical data substantiating the efficacy of these therapeutic modalities, emphasizing the potential of combinatorial regimens and novel therapies to enhance the quality of life for individuals afflicted with PDAC. Lastly, the review delves into the contemporary application and ongoing research endeavors concerning targeted therapy for PDAC. This synthesis serves to bridge the molecular elucidation of PDAC with its clinical implications, the evolution of innovative therapeutic strategies, and the changing landscape of treatment approaches.

Acute myeloid leukemia (AML) is an aging-related and heterogeneous hematopoietic malignancy. In this study, a total of 1,474 newly diagnosed AML patients with RNA sequencing data were enrolled, and targeted or whole exome sequencing data were obtained in 94% cases. The correlation of aging-related factors including age and clonal hematopoiesis (CH), gender, and genomic/transcriptomic profiles (gene fusions, genetic mutations, and gene expression networks or pathways) was systematically analyzed. Overall, AML patients aged 60 y and older showed an apparently dismal prognosis. Alongside age, the frequency of gene fusions defined in the World Health Organization classification decreased, while the positive rate of gene mutations, especially CH-related ones, increased. Additionally, the number of genetic mutations was higher in gene fusion-negative (GF-) patients than those with GF. Based on the status of CH- and myelodysplastic syndromes (MDS)-related mutations, three mutant subgroups were identified among the GF- AML cohort, namely, CH-AML, CH-MDS-AML, and other GF- AML. Notably, CH-MDS-AML demonstrated a predominance of elderly and male cases, cytopenia, and significantly adverse clinical outcomes. Besides, gene expression networks including HOXA/B, platelet factors, and inflammatory responses were most striking features associated with aging and poor prognosis in AML. Our work has thus unraveled the intricate regulatory circuitry of interactions among different age, gender, and molecular groups of AML.

BACKGROUND: EGFR inhibitor and immunotherapy have been approved for adjuvant treatment in resectable non-small cell lung cancer (NSCLC). Limited reports of molecular and clinical characteristics as prognostic factors in NSCLC have been published.
METHODS: Medical records of patients with resectable NSCLC stage I-III diagnosed during 2015-2020 were reviewed. Real time-PCR (RT-PCR) was performed for EGFR mutations (EGFRm). Immunohistochemistry staining was conducted for ALK and PD-L1 expression. Categorical variables were compared using chi-square test and Fisher\'s exact test. Survival analysis was done by cox-regression method.
RESULTS: Total 441 patients were included. The prevalence of EGFRm, ALK fusion, and PD-L1 expression were 57.8%, 1.9%, and 20.5% (SP263), respectively. The most common EGFRm were Del19 (43%) and L858R (41%). There was no significant difference of recurrence free survival (RFS) by EGFRm status whereas patients with PD-L1 expression (PD-L1 positive patients) had lower RFS compared to without PD-L1 expression (PD-L1 negative patients) (HR = 1.75, P = 0.036). Patients with both EGFRm and PD-L1 expression had worse RFS compared with EGFRm and PD-L1 negative patients (HR = 3.38, P = 0.001). Multivariable analysis showed higher CEA at cut-off 3.8 ng/ml, pT4, pN2, pStage II, and margin were significant poor prognostic factors for RFS in the overall population, which was similar to EGFRm population (exception of pT and pStage). Only pStage was a significant poor prognostic factor for PD-L1 positive patients. The predictive score for predicting of recurrence were 6 for all population (63% sensitivity and 86% specificity) and 5 for EGFRm population (62% sensitivity and 93% specificity).
CONCLUSIONS: The prevalence and types of EGFRm were similar between early stage and advanced stage NSCLC. While lower prevalence of PD-L1 expression was found in early stage disease. Patients with both EGFRm and PD-L1 expression had poorer outcome. Thus PD-L1 expression would be one of the prognostic factor in EGFRm patients. Validation of the predictive score should be performed in a larger cohort.

OBJECTIVE: This study aimed to describe the performance of a next-generation sequencing (NGS) panel for the detection of precise genomic alterations in cancer in Spanish clinical practice. The impact of tumor characteristics was evaluated on informative NGS and actionable mutation rates.
METHODS: A cross-sectional study was conducted at the Fundación Jiménez Díaz University Hospital (May 2021-March 2022) where molecular diagnostic of 537 Formalin-Fixed Paraffin-Embedded (FFPE) tissue samples of diverse solid tumors (lung, colorectal, melanoma, gastrointestinal stromal, among others) was performed using AVENIO Tumor Tissue Targeted Kit. A descriptive analysis of the features of all samples was carried out. Multivariable logistic analysis was conducted to assess the impact of sample characteristics on NGS performance defined by informative results rate (for all tumors and for lung tumors), and on actionable mutations rate (for lung tumors only).
RESULTS: AVENIO performance rate was 75.2% in all tumor samples and 75.3% in lung cancer samples, and the multivariable analysis showed that surgical specimens are most likely to provide informative results than diagnostic biopsies. Regarding the mutational findings, 727 pathogenic, likely pathogenic, or variant of unknown significance mutations were found in all tumor samples. Single nucleotide variant was the most common genomic alteration, both for all tumor samples (85.3% and 81.9% for all solid tumors and lung samples, respectively). In lung tumors, multivariable analysis showed that it is more likely to find actionable mutations from non-smokers and patients with adenocarcinoma, large cell, or undifferentiated histologies.
CONCLUSIONS: This is the largest cohort-level study in Spain to profile the analyses of biopsy samples of different tumors using NGS in routine clinical practice. Our findings showed that the use of NGS routinely provides good rates of informative results and can improve tumor characterization and identify a greater number of actionable mutations.

Vaibhavi VengurlekarObjectives  Malignant melanoma demonstrates frequently occurring mutations of genes in the serine/threonine kinase pathway, namely BRAF, NRAS, and neurofibromin 1. There is rare documentation of a detailed analysis of these mutations in cases of melanoma among Indian patients. We present molecular features in cases of malignant melanoma, diagnosed at a tertiary cancer referral center in India, over a period of 8 years (2011-2018). Materials and Methods  This study was performed on formalin fixed paraffin embedded tissues of 88 histologically confirmed cases of malignant melanoma. BRAF gene alterations were studied by both Sanger sequencing and real-time polymerase chain reaction techniques ( n  = 74). Molecular testing for BRAF and NRAS gene alterations was accomplished in 74/88 cases (80%). Molecular test results were correlated with clinicopathological features using IBM SPSS Statistical software 25.0. Results  The age ranged from 13 to 79 years (median = 57), with a M:F ratio of 1.4:1. BRAF mutations were observed in 12/74 (16.21%) patients, including V600E ( n  = 7), A594T ( n  = 1), T599 = ( n  = 2), V600K ( n  = 1), and Q612P ( n  = 1), while NRAS mutations were observed in 6/38 (15.7%) patients. Among various subtypes, nodular melanoma was the most frequent subtype (33%) among cutaneous malignant melanomas. Among non-cutaneous melanomas, mucosal melanomas were observed in 37.5% of cases. Conclusion  This constitutes one of the few reports on comprehensive analysis of molecular alterations underlying melanomas in Indian patients. A larger sample size, with more extensive molecular markers, would yield additional information on the disease manifestation.

The outcome of metastatic testicular germ cell tumor patients has been dramatically improved by cisplatin-based chemotherapy combinations. However, up to 30% of patients with advanced disease relapse after first-line therapy and require salvage regimens, which include treatments with conventional-dose chemotherapy or high-dose chemotherapy with autologous stem cell transplantation. For these patients, prognosis estimation represents an essential step in the choice of medical treatment but still remains a complex challenge. The available histological, clinical, and biochemical parameters attempt to define the prognosis, but they do not reflect the tumor\'s molecular and pathological features and do not predict who will exhibit resistance to the several treatments. Molecular selection of patients and validated biomarkers are highly needed in order to improve current risk stratification and identify novel therapeutic approaches for patients with recurrent disease. Biomolecular biomarkers, including microRNAs, gene expression profiles, and immune-related biomarkers are currently under investigation in testicular germ cell tumors and could potentially hold a prominent place in the future treatment selection and prognostication of these tumors. The aim of this review is to summarize current scientific data regarding prognostic and predictive biomarkers for salvage therapy in testicular germ cell tumors.

The HOXA9 transcription factor serves as a molecular orchestrator in cancer stemness, epithelial-mesenchymal transition (EMT), metastasis, and generation of the tumor microenvironment in hematological and solid malignancies. However, the multiple modes of regulation, multifaceted functions, and context-dependent interactions responsible for the dual role of HOXA9 as an oncogene or tumor suppressor in cancer remain obscure. Hence, unravelling its molecular complexities, binding partners, and interacting signaling molecules enables us to comprehend HOXA9-mediated transcriptional programs and molecular crosstalk. However, it is imperative to understand its central role in fundamental biological processes such as embryogenesis, foetus implantation, hematopoiesis, endothelial cell proliferation, and tissue homeostasis before designing targeted therapies. Indeed, it presents an enormous challenge for clinicians to selectively target its oncogenic functions or restore tumor-suppressive role without altering normal cellular functions. In addition to its implications in cancer, the present review also focuses on the clinical applications of HOXA9 in recurrence and drug resistance, which may provide a broader understanding beyond oncology, open new avenues for clinicians for accurate diagnoses, and develop personalized treatment strategies. Furthermore, we have also discussed the existing therapeutic options and accompanying challenges in HOXA9-targeted therapies in different cancer types.