Aparna Sharma

Thymic epithelial tumors (TETs), comprising thymomas and thymic carcinomas, are rare, biologically heterogeneous thoracic malignancies with limited therapeutic advances since platinum-based regimens were adopted decades ago. Recent genomic and immunophenotypic profiling has uncovered recurrent genomic alterations and high programmed death-ligand 1 (PD-L1) expression, particularly in thymic carcinoma, yet few targeted or immunotherapies have achieved regulatory approval. This mini-review synthesizes current knowledge on TET heterogeneity and the genomic landscape, evaluates the clinical evidence supporting targeted agents and immune checkpoint inhibitors, and examines emerging biomarkers, including circulating tumor DNA. We also address practical barriers to precision oncology in TETs: challenges of next-generation sequencing implementation and cost in resource-limited settings; scarcity of large, biomarker-driven trials; and safety concerns unique to TETs (immune-related toxicity). Finally, we discuss the translational hurdles for antibody–drug conjugates and cellular therapies, limited validated cell surface targets, antigen heterogeneity, and preclinical model gaps and outline strategic paths forward to enable rational, safe, and equitable precision therapeutics for TET patients.

Follicular lymphoma (FL) is an indolent disease with a prolonged clinical course, however, a subset of patients with histological transformation (HT) has a poor prognosis. HT affects 10–15% of all follicular lymphoma patients, typically presenting as an early relapse after chemo-immunotherapy (CIT). However, given the diverse clinical presentations, histological confirmation (ideally with metabolic biopsy) is mandatory. The molecular basis of HT is multifaceted, involving genetic and epigenetic alterations, dysregulated signaling pathways, and immune dysregulation. Genetic aberrations, such as mutations in genes like TP53 and MYC, play a pivotal role in driving HT, with recent evidence suggesting baseline differences in the genomic characteristics of FL patients destined to develop HT. Management of HT is a challenge, given the aggressive nature of disease, coupled with paucity of high-quality evidence. Treatment-strategies depend upon patient characteristics, as well as prior therapy directed (or not) at the initial FL. Most patients with HT responding to CIT are consolidated with autologous stem-cell transplantation. Patients with multiply relapsed or refractory disease may be offered cellular therapy (chimeric antigen receptor T cell therapy or allogenic stem-cell transplantation) or bispecific T cell engagers, antibody drug conjugates or immunomodulators like lenalidomide as per fitness and availability. The choice of therapy should be individualized, with a focus on balancing treatment efficacy and toxicity. Elderly/ unfit patients may be offered lenalidomide based therapy. Prognosis remains poor for the vast majority of patients. In this article, we are reporting three cases of follicular lymphoma with HT along with a narrative review of the relevant literature.

PURPOSE: Genetic predisposition plays an important role in the pathogenesis of renal cell carcinoma. The prevalence of pathogenic/likely pathogenic (P/LP) in patients with renal cell cancer (RCC) is highly variable, and close to 40% of these can be missed with the current testing guidelines. METHODS: This is a prospective study of all patients with metastatic RCC unselected for high-risk features, registered at our center between September 2023 and August 2024. Baseline clinicopathologic details were collected, and germline whole-exome sequencing was done on blood samples. Our aim was to determine the frequency of germline mutations in an unselected cohort of patients with metastatic RCC. Germline P/LP variants were visualized using cBioPortal, and chi-square and Mann-Whitney U tests were used to identify differences in patients with/without these variants. RESULTS: Out of 140 participants, P/LP variants in cancer-predisposition genes were detected in 20%, and 4.2% were in RCC-associated genes. Fumarate hydratase was the most common RCC-associated variant (2.8%), while WT1 , BRCA1 , BRIP1, and ATM (1.4% each) were the commonest non–RCC-associated variants. RCC-associated genes were more frequent in non–clear cell histology ( P = .02); there was no difference in cancer predisposition genes on the basis of age, histology, or sex. CONCLUSION: Patients with advanced RCC have a high prevalence of germline variants in both RCC-associated and non-RCC cancer-specific genes irrespective of the high-risk genetic features, signifying the importance of a baseline genetic evaluation in all patients with advanced RCC as it has implications for family screening and, in future, selection of therapy.

PURPOSE: Mediastinal germ cell tumors (GCTs) are rare malignancies, predominantly affecting young males, with limited real-world data on treatment outcomes in India. This study aimed to evaluate the clinical characteristics, treatment patterns, and survival outcomes of patients with mediastinal GCTs, emphasizing the effectiveness of first-line chemotherapy regimens. METHODS: A retrospective analysis was conducted on 81 patients diagnosed with mediastinal GCTs at two tertiary cancer centers in India from 2005 to 2023. Data on demographics, histological subtypes, presenting symptoms, treatment regimens, and outcomes were collected. Kaplan-Meier analysis was used to calculate progression-free survival (PFS) and overall survival (OS). RESULTS: The median age at diagnosis was 26 years, with a male predominance (96.3%). Common histological subtypes included seminoma (34.3%) and yolk sac tumor (31.3%). First-line chemotherapy comprised bleomycin, etoposide, and cisplatin (BEP; 60.5%) and etoposide, ifosfamide, and cisplatin (VIP; 27.8%). Response rates included complete response (25.3%) and partial response (54.4%). After a median follow-up of 15 months, the median PFS and OS were not reached, with 2-year PFS and OS rates of 92.7% and 93.3%, respectively. Seminomas demonstrated better PFS compared with nonseminomatous GCTs ( P = .004). Severe toxicities were observed in 48.1% of patients, with febrile neutropenia being the most common. CONCLUSION: This study highlights the effectiveness of BEP and VIP chemotherapy in achieving high response rates and favorable survival outcomes in mediastinal GCTs. Early diagnosis, appropriate histological classification, and aggressive multimodal treatment strategies are essential for improving long-term outcomes in this predominantly young patient population. Further research is warranted to validate these findings and optimize therapeutic approaches.

PURPOSE: Prevention of chemotherapy-induced nausea and vomiting with currently recommended NK1 receptor antagonist–based triplet during carboplatin (AUC ≥4) chemotherapy appears inadequate. A comparative study between olanzapine and NK1 receptor antagonist–based combination is lacking. METHODS: This was a single-center, phase III, prospective randomized, double-blind, placebo-controlled superiority study comparing olanzapine (olanzapine, ondansetron, dexamethasone [OOD]-experimental arm) with fosaprepitant (fosaprepitant, ondansetron, dexamethasone [FOD]-standard arm) in combination with ondansetron and dexamethasone among chemotherapy-naïve patients (age ≥18 years) receiving carboplatin (AUC ≥4) during the first cycle of single-day chemotherapy. The OOD arm received olanzapine 5 mg per oral once daily (day 1-4), ondansetron 8 mg with dexametahsone 12 mg intravenous (IV) once daily (20 mg with paclitaxel; day 1), and matching placebo for fosaprepitant (day 1). The FOD arm received fosaprepitant 150 mg IV once daily, with the combination (day 1) and matching placebo for olanzapine (days 1-4). The primary outcome was no nausea during the overall period (0-120 hours). RESULTS: Between April 2021 and August 2022, a total of 195 patients were evaluable. The proportion of patients without nausea (0 as per Edmonton Symptom Assessment System scale) in OOD versus FOD arms was 44.1% versus 34.4% ( P = .19) in the overall period (0-120 hours). Complete response rates and total control rates were also similar in both arms. One patient had grade 3 sedation in the olanzapine arm. CONCLUSION: Olanzapine, in comparison with NK1 antagonist, is not superior for nausea control during carboplatin-induced emesis. It may act as an effective oral alternative for prevention.

PURPOSE: To explore the perceived utility and effect of simplified radiology reports on oncology patients' knowledge and feasibility of large language models (LLMs) to generate such reports. MATERIALS AND METHODS: This study was approved by the Institute Ethics Committee. In phase I, five state-of-the-art LLMs (Generative Pre-Trained Transformer-4o [GPT-4o], Google Gemini, Claude Opus, Llama-3.1-8B, and Phi-3.5-mini) were tested to simplify 50 oncology computed tomography (CT) report impressions using five distinct prompts with each LLM. The outputs were evaluated quantitatively using readability indices. Five LLM-prompt combinations with best average readability scores were also assessed qualitatively, and the best LLM-prompt combination was selected. In phase II, 100 consecutive oncology patients were randomly assigned into two groups: original report (received original report impression) and simplified report (received LLM-generated simplified versions of their CT report impressions under the supervision of a radiologist). A questionnaire assessed the impact of these reports on patients' knowledge and perceived utility. RESULTS: In phase I, Claude Opus-Prompt 3 (explain to a 15-year-old) performed slightly better than other LLMs, although scores for GPT-4o, Gemini, Claude Opus, and Llama-3.1 were not significantly different ( P > .0033 on Wilcoxon signed-rank test with Bonferroni correction). In phase II, simplified report group patients demonstrated significantly better knowledge of primary site and extent of their disease as well as showed significantly higher confidence and understanding of the report ( P < .05 for all). Only three (of 50) simplified reports required corrections by the radiologist. CONCLUSION: Simplified radiology reports significantly enhanced patients’ understanding and confidence in comprehending their medical condition. LLMs performed very well at this simplification task; therefore, they can be potentially used for this purpose, although there remains a need for human oversight.

Background: Approximately 20%-25% of patients with metastatic castration-resistant prostate cancer (mCRPC) harbor a deleterious germline or somatic mutation in the homologous recombination repair (HRR) pathway genes, which is involved in the repair of double-stranded DNA damage. Half of these mutations are germline, while the remaining are exclusively somatic. While polyadenosine 5’diphosphoribose [poly (ADP-ribose)] polymerase inhibitors, such as olaparib and rucaparib, are effective in this subgroup, their widespread use is limited due to the associated high cost, especially in resource-constrained settings. Notably, platinum agents like carboplatin have exquisite sensitivity to cells with defective DNA repair machinery. Carboplatin, a conventional, inexpensive chemotherapeutic agent, offers a potential alternative treatment in such patients. Several retrospective small case series support this hypothesis. However, there are no prospective clinical trials of carboplatin in patients with mCRPC with HRR mutations. Objective: The primary objective is to assess the objective response rate of 3 weekly carboplatin treatments in patients with mCRPC harboring deleterious mutations in the HRR pathway genes and previously treated with a taxane or a novel antiandrogen agent. The secondary objectives include progression-free survival, health-related quality of life, and safety profile of carboplatin. Methods: Patients diagnosed with mCRPC harboring HRR pathway mutations previously treated with docetaxel or novel antiandrogen agents (abiraterone, enzalutamide, apalutamide, or darolutamide) or both will be eligible. Genes involved directly or indirectly in the HRR pathway will be tested. In this single-arm phase II study, we will screen approximately 200 patients to enroll 49 patients, and carboplatin (dosing at the area under curve=5) will be administered every 3 weeks until progression or intolerable side effects. The primary end point will be assessed as the proportion of patients with a reduction of serum prostate-specific antigen by more than 50% from enrollment. Secondary outcomes include progression-free survival—soft-tissue disease progression (by response evaluation criteria in solid tumors, version 1.1, and bone lesion progression using Prostate Cancer Clinical Trials Working Group 3 criteria), health-related quality of life during carboplatin treatment using the Functional Assessment of Cancer Therapy—Prostate questionnaire and the European Organisation for Research and Treatment of Cancer questionnaire and safety profile of carboplatin (National Cancer Institute’s Common Terminology Criteria for Adverse Events version 5.0). Results: The trial started enrollment in September 2023. This trial is ongoing, and 12 patients have been recruited to date. All 49 participants will be enrolled according to plan. Conclusions: This prospective phase II trial represents a critical step toward addressing the therapeutic gap in patients with mCRPC harboring HRR pathway mutations, particularly in demographic regions with limited access to poly (ADP-ribose) polymerase inhibitors. Outcomes from this study will inform clinical practice and guide future phase III randomized trials, ultimately improving patient outcomes globally. Trial Registration: Clinical Trials Registry of India CTRI/2023/04/051507; https://ctri.nic.in/Clinicaltrials/pmaindet2.php?EncHid=Njc0NjU=&Enc=&userName= International Registered Report Identifier (IRRID): DERR1-10.2196/54086