Search Results (671)

Background: Muscle-invasive bladder cancer (MIBC) is associated with high recurrence and mortality rates. While cisplatin-based neoadjuvant chemotherapy followed by radical cystectomy remains the standard of care, many patients are ineligible for cisplatin. Recent advances in immunotherapy and biomarker research are reshaping perioperative strategies, aiming to personalize treatment and improve outcomes. Methods: We conducted a comprehensive narrative review of the recent literature and clinical trials on the perioperative treatment of MIBC. We focused on published phase II and III trials assessing neoadjuvant and adjuvant strategies, including immunotherapy, antibody-drug conjugates (ADCs), combination regimens, and circulating tumor DNA (ctDNA)-based approaches. Results: Numerous trials (e.g., PURE-01, ABACUS, NABUCCO, AURA, NIAGARA) have demonstrated the feasibility and efficacy of immune checkpoint inhibitors (ICIs) in both cisplatin-eligible and -ineligible populations. Combination strategies, including ICIs plus chemotherapy or ADCs, have shown promising pathological complete response rates and event-free survival. In the adjuvant setting, nivolumab improved disease-free survival and received regulatory approval. Biomarkers such as PD-L1 and ctDNA are emerging tools for predicting treatment response and recurrence risk, although prospective validation is ongoing. Conclusions: The treatment paradigm for MIBC is shifting toward multimodal and biomarker-driven approaches. Integration of ICIs into perioperative management, especially in combination with chemotherapy or ADCs, may enhance outcomes. ctDNA shows potential as a predictive and prognostic biomarker, guiding therapeutic decisions and surveillance. Future research should focus on refining patient selection, optimizing treatment sequencing, and validating ctDNA-guided strategies to personalize care while minimizing overtreatment. Full article

Background: Growth Differentiation Factor 15 (GDF15) has emerged as a key biomarker and therapeutic target in oncology, with roles extending beyond cancer cachexia. Elevated GDF15 levels correlate with poor prognosis across several solid tumors, including colorectal, gastric, pancreatic, breast, lung, prostate, and head and neck cancers. GDF15 modulates tumor progression through PI3K/AKT, MAPK/ERK, and SMAD2/3 signaling, thereby promoting epithelial-to-mesenchymal transition, metastasis, immune evasion, and chemoresistance via Nrf2 stabilization and oxidative stress regulation. Methods: We performed a narrative review of the literature focusing on the role of GDF15 in solid tumors, with a particular emphasis on head and neck cancers. Results: In head and neck squamous cell carcinoma (HNSCC), GDF15 overexpression is linked to aggressive phenotypes, radioresistance, poor response to induction chemotherapy, and failure of immune checkpoint inhibitors (ICIs). Similar associations are observed in colorectal, pancreatic, and prostate cancer, where GDF15 contributes to metastasis and therapy resistance. Targeting the GDF15-GFRAL axis appears therapeutically promising: the monoclonal antibody ponsegromab improved cachexia-related outcomes in the PROACC-1 trial, while visugromab combined with nivolumab enhanced immune response in ICI-refractory tumors. Conclusions: Further investigation is warranted to delineate the role of GDF15 across malignancies, refine patient selection, and evaluate combinatorial approaches with existing treatments. Full article

Hodgkin’s Lymphoma (HL) affects approximately 8500 individuals annually in the United States. The 5-year relative survival rate has improved to 88.5%, driven by transformative advances in immunotherapy and precision oncology. The integration of Brentuximab vedotin (BV) and immune checkpoint inhibitors (ICIs) has redefined treatment paradigms. The phase III SWOG S1826 trial established nivolumab plus doxorubicin, vinblastine, and dacarbazine (N + AVD) as an emerging new standard for advanced-stage HL, achieving a 2-year progression-free survival (PFS) of 92% compared to 83% for BV plus AVD (HR 0.48, 95% CI: 0.33–0.70), with superior safety, particularly in patients over 60. In relapsed/refractory HL, pembrolizumab outperforms BV, with a median PFS of 13.2 versus 8.3 months (HR 0.65, 95% CI: 0.48–0.88), as demonstrated in the KEYNOTE-204 trial. Emerging strategies, including novel ICI combinations, minimal residual disease (MRD) monitoring via circulating tumor DNA (ctDNA), and artificial intelligence (AI)-driven diagnostics, promise to further personalize therapy. This review synthesizes HL’s epidemiology, pathogenesis, diagnostic innovations, and therapeutic advances, highlighting the role of precision medicine in addressing unmet needs and disparities in HL care. Full article

Background: Renal cell carcinoma (RCC) is a common malignancy with a rising global incidence. While cytoreductive nephrectomy (CRN) was historically a cornerstone in the management of metastatic RCC (mRCC), its role has been questioned following pivotal trials such as CARMENA and SURTIME. With the advent of immune checkpoint inhibitors (ICIs) and targeted therapies, the contemporary relevance of CRN coupled with first-line immunotherapy and targeted therapy combination regimens warrants re-evaluation. Methods: This retrospective cohort study utilized the TriNetX research network to identify patients aged 18–90 years diagnosed with mRCC between 2005 and 2024 who received first-line systemic therapies. Patients were stratified into two cohorts based on receipt of CRN status within one year of diagnosis. Propensity score matching (1:1) was done to adjust baseline characteristics. Kaplan–Meier survival analysis and Cox proportional hazards modeling were used to compare five-year overall survival between the groups. Results: Among 5960 eligible patients, 1776 (888 CRN matched to 888 who did not) formed the cohort of analysis. The CRN group demonstrated significantly higher five-year survival (57.7% vs. 45.0%, p < 0.0001) with a hazard ratio of 1.56 (95% CI: 1.33–1.83). Subgroup analyses showed consistent survival benefits across all four NCCN-recommended first-line regimens—Axitinib + Pembrolizumab: 64.0% (CRN) vs. 53.3% (no CRN), p = 0.01; Cabozantinib + Nivolumab: 50.1% vs. 40.4%, p = 0.004; Lenvatinib + Pembrolizumab: 37.4% vs. 22.8%, p = 0.012; Nivolumab + Ipilimumab: 56.4% vs. 46.1%, p = 0.005. Conclusions: In the era of modern immunotherapy and targeted agents, CRN remains associated with improved survival in patients with mRCC receiving NCCN-recommended first-line regimens. These findings support the continued evaluation of CRN as a component of multimodal therapy, particularly in patients with favorable risk profiles. Full article

Background: Patients with resected stage IIB and IIC melanoma are at high risk of recurrence and distant metastasis, despite surgical treatment. The recent emergence of immune checkpoint inhibitors (ICIs) has led to their evaluation in the adjuvant setting for early-stage disease. This review aims to synthesize current evidence regarding adjuvant immunotherapy for stage IIB/IIC melanoma, explore emerging strategies, and highlight key challenges and future directions. Methods: We conducted a comprehensive literature review of randomized clinical trials, observational studies, and relevant mechanistic and biomarker research on adjuvant therapy in stage IIB/IIC melanoma. Particular focus was placed on pivotal trials evaluating PD-1 inhibitors (KEYNOTE-716 and CheckMate 76K), novel vaccine and targeted therapy trials, mechanisms of resistance, immune-related toxicity, and biomarker development. Results: KEYNOTE-716 and CheckMate 76K demonstrated significant improvements in recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) with pembrolizumab and nivolumab, respectively, compared to placebo. However, no definitive overall survival benefit has yet been shown. Adjuvant immunotherapy is linked to immune-related adverse events, including permanent endocrinopathies. Emerging personalized approaches, such as circulating tumor DNA monitoring and gene expression profiling, may enhance patient selection, but remain investigational. Conclusions: Adjuvant PD-1 blockade offers clear RFS benefits in high-risk stage II melanoma, but optimal patient selection remains challenging, due to uncertain overall survival benefit and toxicity concerns. Future trials should integrate biomarker-driven approaches to refine therapeutic decisions and minimize overtreatment. Full article

Background: Lung cancer remains the leading cause of cancer-related mortality worldwide. Advances in screening, diagnosis, and management have transformed clinical practice, particularly with the integration of immunotherapy and target therapies. Methods: A systematic literature search was carried out for the period between October 2016 to September 2024. Phase II and III randomized trials evaluating ICI monotherapy, ICI–chemotherapy combinations, and dual ICI regimens in patients with advanced NSCLC were included. Outcomes of interest included overall survival (OS), progression-free survival (PFS), and treatment-related adverse events (AEs). Results: PD-1-targeted therapies demonstrated superior OS compared to PD-L1-based regimens, with cemiplimab monotherapyranking highest for OS benefit (posterior probability: 90%), followed by sintilimab plus platinum-based chemotherapy (PBC) and pemetrexed—PBC. PFS atezolizumab plus bevacizumab and PBC, and camrelizumab plus PBC were the most effective regimens. ICI–chemotherapy combinations achieved higher ORRs but were associated with greater toxicity. The most favorable safety profiles were observed with cemiplimab, nivolumab, and avelumab monotherapy, while atezolizumab plus PBC and sugemalimab plus PBC carried the highest toxicity burdens. Conclusions: In PD-L1-unselected advanced NSCLC, PD-1 blockade—particularly cemiplimab monotherapy—and rationally designed ICI–chemotherapy combinations represent the most efficacious treatment strategies. Balancing efficacy with safety remains critical, especially in the absence of predictive biomarkers. These findings support a patient-tailored approach to immunotherapy and highlight the need for further biomarker-driven and real-world investigations to optimize treatment selection. Full article

Background/Objectives: Upper tract urothelial carcinoma (UTUC) is a rare and biologically distinct subset of urothelial malignancies, comprising approximately 5–10% of urothelial cancers. UTUC presents unique diagnostic and therapeutic challenges, with both a higher likelihood of invasive disease at presentation and a less favorable prognosis compared to urothelial carcinoma of the bladder. Current treatment strategies for UTUC are largely derived from bladder cancer studies, underscoring the need for UTUC-directed research. This review provides a comprehensive overview of UTUC, encompassing diagnostic approaches, systemic and intraluminal therapies, surgical management, and future directions. Methods: A narrative review was conducted synthesizing evidence from guideline-based recommendations, retrospective and prospective clinical studies, and ongoing trials focused on UTUC. Results: Neoadjuvant cisplatin-based chemotherapy is increasingly preferred in UTUC due to the risk of postoperative renal impairment that may preclude adjuvant cisplatin use. Surgical management includes kidney-sparing approaches and radical nephroureterectomy (RNU), with selection guided by tumor risk and patient comorbidities. While endoscopic management (EM) preserves renal function, it carries a higher recurrence and surveillance burden; RNU remains standard for high-risk cases. Systemic therapy for advanced and metastatic UTUC mirrors that of bladder urothelial carcinoma. Enfortumab vedotin (EV) plus pembrolizumab showed superior efficacy over chemotherapy in the EV-302 trial, with improved response rate, progression-free survival, and overall survival across subgroups, including UTUC. For patients ineligible for EV, the CheckMate-901 study supported first-line chemoimmunotherapy with gemcitabine, cisplatin, and nivolumab. Further systemic therapy strategies include maintenance avelumab post-chemotherapy (JAVELIN Bladder 100), targeted therapies such as erdafitinib (THOR trial), and trastuzumab deruxtecan (DESTINY-PanTumor02) in FGFR2/3-altered and HER2-positive disease, respectively. Conclusions: Historically, the therapeutic landscape of UTUC has been extrapolated from bladder cancer; however, ongoing research specific to UTUC is deriving more precise regimens involving the use of immune checkpoint inhibitors, antibody–drug conjugates, and biomarker-driven therapies. Full article

Background: Despite recent advances in the management of metastatic renal cell carcinoma (mRCC), real-world outcomes remain heterogeneous, and early treatment failure is common. Predictive biomarkers for time to treatment failure (TTF) outside clinical trials are poorly characterized. Objective: To identify clinical and laboratory predictors associated with early treatment failure in a real-world cohort of mRCC patients treated with immune checkpoint inhibitors (ICIs), tyrosine kinase inhibitors (TKIs), or combination regimens. Methods: We conducted a retrospective, single-center analysis of patients with metastatic non-urothelial RCC treated between 2018 and 2023. Cox proportional hazards regression was used to evaluate the association between baseline biological parameters and TTF for each treatment regimen. Results: Among 137 patients receiving first-line therapy, 50 received Ipilimumab + Nivolumab, 49 Sunitinib, and 17 Avelumab + Axitinib. For Ipilimumab + Nivolumab, elevated AST was significantly associated with shorter TTF. For Avelumab + Axitinib, shorter TTF was associated with lymph node metastases, low lymphocyte count, low creatinine, low BMI, and low hemoglobin. For Cabozantinib in subsequent lines, a higher platelet count, ALT, and presence of liver metastases were associated with shorter TTF. No statistically significant predictors were found for Nivolumab used in the second-line setting. Conclusions: Routine, accessible biomarkers such as AST, hemoglobin, lymphocyte count, and creatinine may serve as predictors of treatment failure in specific therapeutic contexts. These findings support risk-adapted strategies and individualized monitoring in real-world clinical practice, though further validation in larger cohorts is warranted. Full article

The tumor microenvironment (TME) in advanced solid tumors is determined by immune checkpoints (PD-1, CTLA-4, and CD95) and cytokine networks (IL-2, IL-10, and TNF-α) that drive CD8+ T cell exhaustion, metabolic reprogramming, and apoptosis resistance, enabling immune evasion. Some studies revealed PD-1/CD95 co-expression is a marker of T cell dysfunction, while CTLA-4 upregulation correlates with suppressed early T cell activation. IL-10 has emerged as a potential biomarker for chemoresistance and tumor aggressivity, consistent with its role in promoting anti-apoptotic signaling in cancer stem cells (CSCs). Engineered IL-2 variants and TNF-α modulation are highlighted as promising strategies to revitalize exhausted CD8+ T cells and disrupt CSC niches. This prospective single-center study investigated the dynamic TME alterations in 16 patients with immunotherapy-naïve stage IV non-small-cell lung cancer (NSCLC) and metastatic melanoma treated with anti-PD-1 nivolumab. The longitudinal immunophenotyping of peripheral blood lymphocytes (via flow cytometry) and serum cytokine analysis (via ELISA) were performed at the baseline, >3, and >6 months post-treatment to evaluate immune checkpoint co-expression (PD-1/CD95 and CTLA-4/CD8+) and the cytokine profiles (IL-2, IL-10, and TNF-α). Full article

TP (tumor protein) 53 mutation status plays a critical role in cancer progression and may influence survival outcomes in non-small cell lung cancer (NSCLC) patients receiving immunotherapy. This study investigates the impact of TP53 mutation status and immunotherapy treatment on survival in NSCLC patients. This retrospective study analyzed NSCLC patients treated with pembrolizumab or ipilimumab plus nivolumab, stratified by TP53 mutation status and PD-L1 (programmed death-ligand 1) expression (<1%, 1–49%, >50%). Survival outcomes (overall survival (OS) and progression free survival (PFS) were assessed using Kaplan–Meier curves and log-rank tests, with subgroup analysis by histological subtype. In squamous cell cancer (SCC) patients, no significant differences in OS or PFS were found based on TP53 mutation status or treatment type. A trend toward improved survival was observed with pembrolizumab (p = 0.088). In adenocarcinoma patients, significant differences in OS and PFS were observed based on TP53 mutation status. Pembrolizumab showed superior survival outcomes compared to ipilimumab plus nivolumab in TP53 wild-type patients (p < 0.001). PD-L1 ≥ 1% also predicted better outcomes, especially in adenocarcinoma patients. TP53 mutation status and immunotherapy type significantly influence survival outcomes in NSCLC, particularly in adenocarcinoma patients. Pembrolizumab demonstrated superior efficacy in TP53 wild-type patients, with PD-L1 expression further refining survival predictions. These findings underscore the importance of personalized treatment strategies based on TP53 status and PD-L1 expression in NSCLC. Further studies are needed to validate these results and optimize treatment approaches. Full article

Background/Objectives: Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy; however, reliable biomarkers of therapeutic efficacy remain limited. We investigated the clinical utility of plasma WFDC2 levels in patients receiving anti-PD-1 antibody treatment. Methods: Twenty-one patients with non-small cell lung, gastric, or bladder cancer received nivolumab or pembrolizumab. Plasma WFDC2 concentrations were measured by ELISA before ICI treatment (pre-ICI) and after two and four treatment cycles. Associations between WFDC2 expression changes and overall survival (OS), progression-free survival (PFS), and tumor progression were assessed. ROC curve analyses compared the predictive performance of WFDC2, soluble PD-L1 (sPD-L1), soluble PD-1 (sPD-1), and their combinations, with the area under the curve (AUC) evaluating predictive accuracy. Results: Levels of WFDC2 pre-ICI and those after two cycles were significantly higher than levels in healthy donors. However, no significant differences in WFDC2 levels were found between the time points during treatment. Greater increases in WFDC2 levels were significantly correlated with shorter OS (p = 0.002), shorter PFS (p = 0.037), and tumor progression (p = 0.003). ROC analysis revealed that WFDC2 achieved a higher AUC (0.700) than sPD-L1 (0.538) or sPD-1 (0.650). Combining biomarkers improved the predictive accuracy, with sPD-L1 plus WFDC2 showing the highest AUC (0.825). Conclusions: Serial increases in plasma WFDC2 are associated with poor clinical outcomes, highlighting its potential as a biomarker. Baseline plasma WFDC2 outperformed sPD-L1 and sPD-1 diagnostically. These findings should be interpreted as exploratory and hypothesis-generating, requiring confirmation in larger, tumor-specific cohorts with multivariate adjustment. WFDC2 represents a promising minimally invasive biomarker for the early identification of patients unlikely to benefit from ICI therapy. Full article

Background: Immune checkpoint inhibitors (ICIs) have reshaped the treatment landscape of metastatic melanoma. While combination regimens often demonstrate improved response and survival compared to monotherapy, they are also associated with a higher incidence of immune-related adverse events (irAEs). Understanding the balance between benefit and risk is essential for making informed treatment decisions, especially given the variability in reported outcomes across clinical trials. Methods: We conducted a systematic review and meta-analysis of 14 clinical trials (comprising 22 treatment arms and >5000 patients) comparing ICI monotherapy (nivolumab, ipilimumab, or pembrolizumab) and combination therapy (nivolumab + ipilimumab) in advanced melanoma. Treatment-related outcomes were synthesized using fixed-effects, random-effects, or generalized linear mixed models (GLMMs), depending on study variability. Survival data were extracted from published Kaplan–Meier curves and analyzed using longitudinal GLMMs to capture trends over time. Results: Compared to monotherapy, combination immunotherapy achieved higher clinical benefit, with an overall response of 52.2% (vs. 31.6%), a five-year overall survival of 55.7% (vs. 34.3%), and a five-year progression-free survival of 39.0% (vs. 17.2%). However, this benefit came with a higher risk of toxicity: immune-related adverse events occurred in 93.2% of patients receiving combination therapy versus in 81.9% receiving monotherapy. Differences were consistent across all individual severe toxicities. Conclusions: Combination immunotherapy offers greater long-term clinical benefit than monotherapy in metastatic melanoma but at the cost of increased toxicity. By applying models adapted to study variability, we provide more reliable estimates of treatment efficacy and risk. GLMMs provide the most robust estimates and enable the modeling of survival dynamics over time. These findings support evidence-based decision-making and highlight the value of model-informed meta-analysis in oncology. Full article

Background/Objectives: Nivolumab is a key therapy for advanced-stage melanoma; however, limited data are available from Asian populations comparing the efficacy and side effects of four dosing regimens: 3 mg/kg every 2 weeks (3mg/kgQ2W), 2 mg/kg every 3 weeks (2mg/kgQ3W), 240 mg every 2 weeks (240mgQ2W), and 480 mg every 4 weeks (480mgQ4W). This retrospective study evaluated Japanese patients with advanced melanoma treated with various nivolumab regimens to assess the impact of dosing interval and dosage on treatment efficacy and immune-related adverse events (irAEs). Methods: We reviewed the records of 153 participants with stage IV melanoma who received nivolumab monotherapy between February 2012 and December 2024 at Shizuoka Cancer Center. Patients were categorized by nivolumab regimen, dosing interval, and dose per body weight. We then compared treatment efficacy and incidence of irAEs across groups. Results: No significant differences were observed in objective response rate (ORR), progression-free survival (PFS), overall survival (OS), or irAE incidence between the 240mgQ2W and 480mgQ4W groups. Similar results were observed in the 3mg/kgQ2W and 2mg/kgQ3W groups. However, participants who received nivolumab within 3 weeks exhibited a significantly higher ORR than those who received nivolumab more than 3 weeks. No significant differences were found in PFS or OS. Conclusions: The administration of nivolumab at shorter intervals may provide short-term benefits in Japanese patients with advanced melanoma. However, long-term efficacy and side effects did not differ significantly across the studied nivolumab regimens. Full article

Background: Melanoma management has been revolutionized by the use of immune checkpoint inhibitors (ICIs). However, ICIs are associated with immune-related adverse events (irAEs), including rhinosinusitis, which remains underexplored. This study evaluated the incidence, characteristics, management, and prognostic implications of rhinosinusitis in patients with melanoma under ICIs. Methods: A retrospective analysis was conducted on adult patients with melanoma treated with ICIs. Demographic, clinical, laboratory, treatment, and survival data were collected. Rhinosinusitis was defined radiographically and graded using the Harvard scoring system. Associations between rhinosinusitis and survival outcomes were analyzed. Results: Among 304 patients, 64 (21.1%) developed imaging-confirmed rhinosinusitis during ICI treatment, with 9.4% symptomatic cases. Rhinosinusitis was the sole irAE in 11.8% of patients, and 9.2% experienced it alongside other irAEs. A significant correlation with eosinophilia was observed: 39.6% of eosinophilic patients developed rhinosinusitis versus 17.1% without eosinophilia (p < 0.001). Most cases occurred during the first ICI line (86.4%), particularly with nivolumab monotherapy (32.8%). Importantly, in metastatic melanoma, rhinosinusitis was associated with significantly longer overall survival since ICI initiation (OS_ICI) compared to patients without rhinosinusitis (33.3 vs. 15.4 months, p = 0.025). No survival benefit was observed in the adjuvant setting. The condition was predominantly aseptic, and corticosteroids were used in 7.8%. Conclusions: This study highlights rhinosinusitis as an irAE associated with improved OS in metastatic melanoma. Further research is required to elucidate the underlying mechanisms and assess the resolution of rhinosinusitis after ICI discontinuation. Additionally, rhinosinusitis may serve as a marker of favorable prognosis in metastatic melanoma patients receiving ICIs. Full article

Resectable non-small cell lung cancer (NSCLC) continues to pose significant challenges with high recurrence and mortality rates, despite traditional platinum-based chemotherapy yielding only an approximate 5% improvement in 5-year overall survival when administered preoperatively or postoperatively. In recent years, the integration of immune checkpoint inhibitors (ICIs), such as nivolumab, durvalumab and pembrolizumab, with platinum-based regimens in the perioperative setting has emerged as a transformative strategy. Our comprehensive review, based on a systematic bibliographic search of PubMed, Google Scholar, EMBASE, Cochrane Library, and clinicaltrials.gov, targeting pivotal clinical trials from the past two decades, examines the impact of these neoadjuvant and adjuvant chemoimmunotherapy approaches on major pathological response rates and overall survival in early-stage NSCLC. Although these perioperative strategies represent a paradigm shift in treatment, promising durable responses are offset by persistent recurrence, emphasizing the necessity for optimized treatment sequencing, duration, and the identification of predictive biomarkers. Collectively, our findings underscore the critical role of the perioperative schema, particularly the neoadjuvant component, which enables the evaluation of novel biomarkers as surrogates for overall survival, in improving patient outcomes and delineating future research directions aimed at reducing mortality and enhancing the quality of life for patients with resectable NSCLC. Full article