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Gastric cancer (GC) remains a public health problem, being the fifth most common cancer worldwide. In the western countries, the majority of patients present with advanced disease. Additionally, 65 to 75% of patients treated with curative intent will relapse and develop systemic disease. In metastatic disease, systemic treatment still represents the state of the art, with less than a year of median overall survival. The new molecular classification of GC was published in 2014, identifying four distinct major subtypes of gastric cancer, and has encouraged the investigation of new and more personalized treatment strategies. This paper will review the current evidence of immunotherapy in advanced gastric cancer.

Abstract Although upper tract urothelial carcinoma (UTUC) and bladder urothelial carcinoma (BUC) share histological features, they differ in clinical behavior and management. Valid adjuvant options include surveillance, platinum-based chemotherapy, and immune checkpoint inhibitors (ICIs). To assess real-world practice, we conducted a survey among Portuguese medical oncologists dedicated to genitourinary malignancies, exploring their preferences for adjuvant therapy in high-risk UTUC (illustrated as pT2N1M0) across three clinical scenarios that differed by PD-L1 status and renal function. Among 34 respondents, cisplatin plus gemcitabine was the preferred regimen in cisplatin-eligible patients, regardless of PD-L1 status (94% in PD-L1-negative and 85% in PD-L1-positive tumors). In PD-L1-positive, cisplatin-ineligible patients, carboplatin plus gemcitabine was preferred (47%), followed by ICIs (44%). These findings suggest a consistent preference for platinum-based chemotherapy, likely reflecting UTUC-specific evidence from the POUT trial and apparent limited ICI benefit in this subgroup, underscoring the need for dedicated prospective trials.

Background: Real-world safety profiles of immune checkpoint inhibitors (ICIs) in older adults remain insufficiently characterized. Although ICIs are widely used across tumor types, older patients, particularly those with frailty, multimorbidity, or polypharmacy, are consistently under-represented in clinical trials, limiting the external validity of trial-derived toxicity estimates. Robust real-world data are therefore essential to clarify the incidence, seriousness, and age-related patterns of immune-related adverse events (irAEs) in routine practice. Methods: This is a nationwide retrospective study of spontaneous ICI-related ADRs reported in INFARMED’s Portal RAM (2011–2024). We evaluated the frequency, seriousness, fatality, and organ-specific patterns of ICI-related adverse drug reactions (ADRs) reported to the Portuguese National Pharmacovigilance System. The analytic unit was the ADR case. Endpoints included seriousness (primary), fatality, hospitalization, time-to-onset, and System Organ Class. Multivariable logistic regression adjusted for age, sex, regimen, tumor type, polypharmacy, and calendar period; sensitivity analyses using first ADR per patient were concordant. Results: We identified 2300 eligible ICI-related ADRs (corresponding to 925 patients). Median age at the time of ADR was 65 years (IQR not reported); 33.7% occurred in adults aged ≥70 years, and 62.8% of reports involved male patients. PD-1 inhibitors accounted for 77.5% of ADRs, and monotherapy for 72.9%. Overall, 85.8% of ADRs were classified as serious; 17.9% led to hospitalization and 19.1% were fatal. Serious-event reporting was similar in older and younger adults (≥70 vs. <70 years: 84.5% vs. 86.5%, p = 0.22), and the proportion explicitly labeled immune-related did not differ (9.3% vs. 8.7%, p = 0.56). In contrast, fatal outcomes were significantly more common in older adults (25.3% vs. 16.0%; p < 0.001). Age was associated with distinct organ-specific patterns. Adults ≥ 70 years had higher odds of nervous system disorders (aOR 1.75, 95% CI 1.23–2.48) and immune system disorders (aOR 1.42, 95% CI 1.02–1.98), but lower odds of hepatobiliary (aOR 0.52, 95% CI 0.36–0.76; p = 0.001) and blood/lymphatic disorders (aOR 0.50, 95% CI 0.32–0.79). In multivariable models, age ≥ 70 years did not predict seriousness (aOR 0.98, 95% CI 0.76–1.27), whereas combination therapy remained independently associated with increased seriousness (aOR 1.57, 95% CI 1.13–2.18). Conversely, age ≥ 70 years independently predicted fatal outcomes (aOR 1.66, 95% CI 1.31–2.09). Later calendar periods (2017–2024) were associated with substantially lower fatality (aOR 0.16; 95% CI 0.10–0.27). CTLA-4-containing regimens demonstrated a tendency toward higher fatality (aOR 1.50; 95% CI 0.94–2.37). Conclusions: Chronological age does not seem to increase the likelihood of reporting a serious ICI-related ADR, but, once toxicity occurs, older adults experience higher fatality rates. Age-related phenotypic differences and regimen-specific risks highlight the need for early recognition systems and tailored toxicity management in older populations.

Background: Androgen deprivation therapy (ADT) is a primary treatment for prostate cancer (PCa) that effectively reduces androgen levels to suppress tumor progression. However, growing evidence suggests potential cognitive side effects, raising concerns about the long-term neurological consequences of this treatment. Objective: This scoping review aims to synthesize the existing evidence linking ADT to cognitive changes in men with PCa, identifying the key cognitive domains affected and outlining gaps in the existing literature. Methods: A systematic literature search was conducted according to the PRISMA-ScR guidelines in CINAHL, PubMed, Scopus, and Web of Science. Studies investigating cognitive function in ADT-treated PCa patients were included, covering randomized controlled trials (RCTs) and cohort, case–control, and cross-sectional studies. The extracted data included the study design, evaluated cognitive characteristics, measurement tools, and overall findings. Results: A total of 22 studies met the inclusion and exclusion criteria. Cognitive assessments varied across studies. While some studies reported cognitive impairments in ADT-treated patients—particularly in working, verbal, and visual memory and executive function—others found no significant effects. The variability in prostate cancer staging, epidemiological study designs, and treatment regimens; the exclusion of comorbid conditions; and the differences in assessment tools, sample sizes, and study durations hinder definitive conclusions about the cognitive effects of ADT. Conclusions: This scoping review highlights the heterogeneous and often contradictory evidence regarding ADT-associated cognitive dysfunction. While certain cognitive domains may be affected, methodological inconsistencies limit robust conclusions. Standardized cognitive assessments and longer longitudinal studies are required to clarify ADT’s role in cognitive decline. As the PCa survival rate increases with extended ADT use, integrating routine cognitive monitoring into clinical practice should be considered for PCa patients.

Background Inflammation is a crucial component in carcinogenesis. The neutrophil-to-eosinophil ratio (NER) has been studied as a biomarker of prognosis and predictive of response in metastatic renal cell carcinoma (mRCC). In the present study, we evaluated the relevance of baseline NER on the progression-free survival (PFS) and overall survival (OS) outcomes in real-world patients with mRCC treated with nivolumab in second or subsequent lines. We also assessed the association of baseline NER with objective response, as well as with toxicity and histology. Methods In this multicenter retrospective analysis of patients with mRCC treated with nivolumab, the last systemic absolute neutrophil and eosinophil count before treatment with nivolumab was used to calculate the NER. An additive Cox proportional hazards model was used to identify the cut-off point for NER considering PFS and the patients were allocated into low and high NER groups. Median OS and median PFS were estimated using the Kaplan-Meier estimator, and survival curves of groups were compared using the log-rank test. Univariable and multivariable Cox regression models were used to study OS and PFS and Fisher's exact test was performed to evaluate the association of NER with the response, toxicity, and histology. Results The 49 analyzed patients had a median follow-up of nine months. The NER cut-off was established at 48, locating 29 patients in the low NER group (NER < 48) and 20 in the high NER group (NER ≥ 48). Median PFS and median OS were significantly shorter in patients with high NER versus low NER (3 vs. 30 months (p < 0.001) and 6 vs. 24 months (p = 0.002), respectively). Multivariable analyses showed that NER (HR 3.92 (95% CI: 1.66-9.23), p = 0.002) was an independent factor for PFS and that NER (HR 3.85 (95% CI: 1.33-11.17), p = 0.013) and progressive disease (HR 5.62 (95% CI: 1.88-16.83), p = 0.002) were independent factors for OS. NER was significantly associated with objective response rate (ORR) (NER ≥ 48-12.5% vs. NER < 48-87.5%, p = 0.003), immune-related adverse events (irAEs) (NER ≥ 48-10.0% vs. NER < 48-42.9%, p = 0.014), and tumor's histology as patients of high NER group had more non-clear cell carcinoma than low NER group (35.0% vs. 7.4%, p = 0.017). Conclusion Our real-world data analysis of NER in patients with mRCC confirmed the prognostic value of this biomarker, supporting clinical utility in predicting survival. Results also suggested an association between lower NER and better ORR, and that irAEs occur more frequently in patients with a lower NER. However, further large-scale prospective studies are needed to confirm these findings and to validate this biomarker.

The prognosis in the setting of metastatic castration-resistant prostate cancer patients (mCRPC) remains limited. Therefore, novel treatment strategies remain an unmet need. Antibody-drug conjugates (ADC) emerged as a new drug concept with the potential to deliver a cytotoxic payload with limited off-target toxicity and potentially bystander effect. Following the success of ADCs in breast cancer and urothelial tumours, their activity in prostate cancer is now under investigation. Thus, the aim of this systematic review was to identify published and ongoing prospective clinical trials regarding ADC treatment in prostate cancer. A systematic search of PubMed, MEDLINE, and Web of Science was conducted as per PRISMA guidelines to identify prospective clinical trials of ADCin prostate cancer. Trials are currently ongoing on ClinicalTrials.gov and in the EU. The Clinical Trials Register was also identified. Abstracts, publications in languages other than English, review articles, retrospective analyses, and phase I trials were excluded. A total of six phase I/II prospective clinical trials already published were included. Seven ongoing trials were also identified. All studies were in the refractory/advanced tumour setting, and two included only mCRPC patients. The ADC targets were prostate-specific membrane antigen (PSMA), trophoblast cell surface antigen-2 (TROP-2), six-transmembrane epithelial antigen of prostate-1 (STEAP-1), tissue factor (TF), delta-like protein 3 (DLL-3), B7-H3 family of proteins (B7-H3), and human epidermal growth factor receptor 2 (HER2). Regarding the efficacy of PSMA ADC treatment in the second-line or beyond mCRPC setting, a PSA ≥ 50% decline rate in 14% of all treated patients was reported. One patient achieved a complete response with TROP-2 ADC. Overall, a wide range of safety issues were raised, particularly in connection with neuropathy and hematologic toxicity. Novel therapies have been changing the scope of treatment in mCRPC. ADCs seem to provide efficacy benefits, even with potential toxicity. The results of most prospective ongoing studies are still awaited, and a longer follow-up time is warranted to evaluate the real impact of ADCs in PCa.

Introduction In clinical practice, there is a binary distinction between human epidermal growth factor receptor 2 (HER2)-positive and HER2-negative (HER2-) breast cancer (BC). However, within HER2- disease, there is significant heterogeneity. Particularly, HER2- tumors that express some level of HER2 by immunohistochemistry (IHC) score 1+ or 2+/in situ hybridization (ISH) non-amplified are currently defined as HER2-low. This subgroup has shown distinct biological features compared to HER2-zero (HER2-0) BC and additionally novel antibody-drug conjugate therapies have demonstrated a potential and promising activity in HER2-low BC population. This study aims to evaluate the impact of HER2-low status in response to neoadjuvant chemotherapy (NACT) in HER2- BC being HER2-low and HER2-0 status. Materials and methods In a single institution, we retrospectively reviewed clinical and pathological data of HER2 early-stage BC patients treated with NACT following definitive surgery from January 2015 to December 2020. Tumors with HER2 IHC 0 were classified as HER2-0 and IHC score 1+ and 2+/ISH non-amplified as HER2-low. The primary objective was to evaluate the rate of pathological complete response (pCR) using the definition of ypT0/Tis ypN0 according to HER2-low and HER2-0 subgroups. Secondary objectives were to evaluate biological features between the two subgroups, disease-free survival (DFS), and overall survival (OS). Pearson chi-square, Fisher's exact, and Mann-Whitney tests were performed. The Kaplan-Meier method was used to plot DFS and OS curves. A p-value of <0.05 was considered statistically significant. Results A total of 72 patients with HER2 BC were included with a median age at diagnosis of 52.5 years and a median follow-up time of 35.5 months. Of patients, 56.9% had HER2-low disease and 43.1% had HER2-0 disease. Significant differences between the two subgroups were detected regarding hormonal receptor status and proliferation grade (Ki67). In the HER2-low subgroup, 70% of tumors were luminal-like and 64.5% of HER2-0 patients had triple-negative BC (p = 0.03). There were statistically significant differences regarding estrogen (p = 0.00) and progesterone (p = 0.02) receptors. The median Ki67 rate was higher in the HER2-0 subset (mean rank = 43.9) compared to HER2-low (mean rank = 30.9) and this difference was statistically significant (p = 0.00). HER2-low patients presented more stage III tumors (65.9%) and HER2-0 patients were mainly stage II (61.3%), and this was statistically relevant (p = 0.03). The prevalence of other clinical and pathological features was comparable between both groups. HER2-low subgroup achieved lower pCR rates (14.6% vs. 29.0%) but this difference was not statistically significant (p = 0.15). Similarly, there was no difference between the two subgroups regarding DFS (p = 0.97) and OS (p = 0.35), although the data were immature. Conclusion As in prior studies, this study did not support a significant impact of HER2-low status on response to NACT in HER2- patients with early-stage BC. HER2-low patients had a lower pCR, which may suggest a worse response to classic chemotherapy regimen and may have clinical implications that should be further exploited. The prevalence of hormonal receptors in HER2-low tumors was consistent with previous data in the literature. Although retrospective, the data suggest that HER2-low tumors should be regarded as a distinct biological subtype and more research is warranted.

Notwithstanding the marked progress in breast cancer (BC) management, it still constitutes the most common malignancy in women and a major cause of morbidity and mortality, thus remaining a major health issue worldwide. Most BC cases are hormone receptor (HR) positive (luminal A or B molecular subtypes) and endocrine treatment (ET) is an important therapeutic modality at all disease stages. Nevertheless, despite substantial improvements in BC patient outcome, effectiveness of ET is limited, as up to 40% of patients eventually relapse or progress and endocrine resistant BC has a less favorable prognosis and constitutes a therapeutic challenge. The biological mechanisms underlying endocrine resistance are, however, still poorly understood. In this review, we focused on data regarding the main epigenetic mechanisms associated with the development of endocrine treated-resistant BC described so far, including alterations in DNA methylation, non-coding RNAs, chromatin remodeling, post-translational histone modifications and histone variants. Notably, specific epigenetic alterations have been characterized in this subset of breast tumors and may be of clinical value for individualized patient management in the future.

Background Breast cancer (BC) is a major health concern and better understanding of its biology might improve treatment decisions and patient outcomes. Histone3 Lysine27 tri-methylation (H3K27me3) is a post-translational histone modification frequently associated with altered gene expression. In BC patients, lower H3K27me3 expression has been associated with worse prognosis. We assessed H3K27me3 immunoexpression with digital imaging software assistance, in a cohort of luminal-like BC patients with long-term follow-up time and evaluated its association with clinically relevant endpoints and its clinical usefulness. Methods H3K27me3 immunoexpression was assessed, by means of digital-imaging system, in archival tissue samples of 160 luminal A/B-like HER2-negative invasive BC, stages I-III. Survival analysis was performed using Kaplan-Meier and Cox regression. Cases were categorized as ‘low’ or ‘high’ expression based on cut-off defined by receiver operating characteristic (ROC) curve analysis. Results The patient cohort showed a median age of 61-years, with a median follow-up time of 11.7 years. Low H3K27me3 expression (below 85% cut-off) was significantly associated with recurrence, both in univariable (HR = 1.99, 95%CI 1.066–3.724) and multivariable analysis when adjusting for grade and age (HR = 1.89, 95%CI 1.004–3.559). A trend for higher risk of death in low H3K27me3 expression BC was observed ( p  = 0.069), reaching statistical significance in younger patients ( p  = 0.021). Conclusions H3K27me3 immunoexpression assessed by digital imaging scoring software is an independent prognosis biomarker in luminal-like BC patients and may assist in more individualized adjuvant treatment decisions, thus potentially reducing recurrences after curative-intent treatment, while sparing unnecessary toxicity.

Drug-induced interstitial lung disease (DI-ILD) is a significant complication in patients undergoing treatment with certain anti-cancer therapies, with incidence rates rising, particularly with newer drugs such as trastuzumab-deruxtecan, which may impact their safe and effective use. Although the exact pathophysiological mechanisms remain unknown, and different drugs may induce lung damage through different pathways, the most recognized mechanisms are cytotoxic- and immune-mediated effects. Multidisciplinary teams play a crucial role in the diagnosis, management, and prevention of DI-ILD. Given the wide variability in the onset of DI-ILD, which may occur within the first few days of treatment or months after, patient education and clinician training are essential for early detection and improved outcomes. Moreover, the diagnostic confirmation requires the exclusion of alternative causes through clinical, imaging and bronchoscopy evaluation. Treatment strategies largely depend on the grade of severity of the clinical manifestations of DI-ILD, ranging from interruption or discontinuation of the offending drug to corticosteroid therapy and hospitalization for appropriate monitoring. Nonetheless, further research is needed to better understand the impact of emerging anti-cancer drugs on DI-ILD and to establish standardized management protocols.