Interleukin-8 (IL-8/CXCL8) drives tumor progression via CXCR1/2 signaling, promoting proliferation, invasion, angiogenesis, and recruitment of pro-tumoral immune and stromal cells. Accumulating clinical evidence indicates that elevated circulating or intratumoral IL-8 levels are consistently associated with adverse prognosis and reduced therapeutic benefit across principal solid tumors. In particular, IL-8 has emerged as a promising prognostic and predictive biomarker of resistance to immune checkpoint inhibitors. This review highlights its prognostic and predictive value across gastrointestinal, genitourinary, lung, melanoma, breast, ovarian, and head and neck cancers, and discusses strategies targeting IL-8 and the need for standardized, clinically actionable assays.

Prostate cancer (PCa) is among the most diagnosed malignancies and is a leading cause of cancer-related mortality worldwide, with clinical management complicated by important biological heterogeneity. Epigenetic alterations (including DNA methylation, histone modifications, chromatin remodeling, and non-coding RNA regulation) are increasingly recognized as key drivers of PCa initiation, progression, and therapeutic resistance. In early-stage disease, hypermethylation of promoter regions silencing tumor suppressor genes represents one of the earliest oncogenic events, offering opportunities for early detection. During progression to castration-resistance, epigenetic mechanisms modulate androgen receptor signaling through chromatin remodeling complexes, DNA demethylation regulators, and histone-modifying enzymes, all contribute to therapy resistance. In therapy-induced neuroendocrine prostate cancer (t-NEPC), an even more aggressive form of PCa, dynamic epigenetic reprogramming, driven by chromatin-modifying enzymes and metabolic-epigenetic crosstalk, underlies lineage plasticity and transdifferentiation from adenocarcinoma. Pharmacological targeting of epigenetic regulators has been explored across multiple drug classes and clinical settings, though development remains limited compared to other malignancies; certain inhibitor classes are more clinically advanced than others, while dedicated trials in particularly NEPC remain scarce. Epigenetic biomarkers, detectable in tissue, blood, and urine, show promise for diagnosis, prognosis, and risk stratification, with multi-marker signatures outperforming individual markers. Translational advances (including bisulfite-based methylation assays, liquid biopsy platforms, single-cell/multi-region sequencing, and transcriptomic classifiers) are progressively enabling clinical application. Despite this progress, intratumoral heterogeneity, lack of standardization, and insufficient prospective validation continue to hinder routine implementation, underscoring the need for integrated multi-omic approaches in future PCa precision medicine

BACKGROUND AND OBJECTIVE:Interleukin-8 (IL-8) is a chemokine involved in inflammation and primary immune response, playing a key role in recruiting neutrophils. IL-8 is produced by several cell types, including immune cells and certain cancer cells. Elevated levels of IL-8 have been associated with a poorer outcome in several tumors and have been related to advanced diseases, treatment resistance, and possibly promoting neo angiogenesis and immune cell recruitment. In the renal cell carcinoma (RCC), the prognostic role of IL-8 has not been settled. METHODS:From January 1, 2008 to June 18, 2024, PubMed, Embase, and Scopus databases were searched for all studies investigating the potential prognostic role of IL-8 in RCC. All studies were rated according to the Newcastle-Ottawa Scale. Progression-free survival (PFS) and overall survival (OS) were analyzed as clinical outcomes, and a meta-analysis was performed for both. KEY FINDINGS AND LIMITATIONS:Overall, six papers met the predefined inclusion criteria, with final analyses demonstrating that high IL-8 levels significantly correlate with worse prognosis in RCC, with a statistically shorter PFS (hazard ratio [HR]: 1.27, 95% confidence interval [CI]: 1.01-1.59; P = 0.037) and statistically shorter OS (HR: 1.85, 95% CI: 1.21-2.84; P = .001). Prospective randomized clinical trials are also necessary to investigate the predictive role of IL-8 in the contemporary treatment scenario of RCC to improve clinical decision-making. CONCLUSIONS:This meta-analysis demonstrates the significant prognostic role of IL-8 in RCC, suggesting that IL-8 could be used to refine the prognostic RCC assessment.

Prostate cancer (PCa) remains a major cause of cancer-related mortality in men, particularly in its advanced and metastatic stages. While various systemic therapies have improved clinical outcomes, therapy resistance and disease progression remain significant challenges. One critical, yet underappreciated, mechanism influencing treatment response is therapy-induced senescence (TIS), a stable form of cell cycle arrest triggered by anticancer treatments. In PCa, TIS can be elicited by chemotherapy, radiotherapy, hormonal therapies, and targeted agents, and is characterized by a complex interplay of tumor-suppressive and tumor-promoting effects, largely mediated through the senescence-associated secretory phenotype (SASP). This review explores the molecular mechanisms of senescence, the diverse therapeutic strategies that induce it, and the dual roles it plays in PCa progression and treatment resistance. We further discuss emerging approaches that combine senescence-inducing therapies with senescence-targeting strategies, such as senolytics and senomorphics, to mitigate the adverse consequences of persistent senescent PCa cells. Finally, we highlight ongoing clinical trials, translational barriers, and future directions in integrating senotherapy into the clinical management of PCa.

Evidence of the feasibility of physical exercise for patients with bone metastases is still scarce. This study assessed the feasibility of in‐person or home‐based exercise programs and explored their efficacy in patients with bone lesions. Twenty‐one patients with bone metastases were invited to participate in an exercise intervention consisting of 12 weeks of in-person or home‐based aerobic and resistance training twice a week. The primary study endpoint was the feasibility of the program, including recruitment, completion, attendance, adherence, tolerance rates, and safety. Secondary outcomes were physical fitness and patient‐reported parameters. To analyze data descriptive statistics, Student’s t test and Wilcoxon signed‐rank test were applied. The recruitment rate was 84%, and only one patient withdrew (5%). The median program attendance was 93%, and adherence was 85%, with the home‐based program showing a higher adherence rate compared to the in-person delivery. Tolerability was 98%, and 13 mild (Grade 1 or 2) adverse events were registered. At postintervention, an increase in functional capacity was observed, while no significant changes in muscle strength, flexibility, or anthropometric parameters were detected. Enhancements in quality of life domains, including physical, role, and emotional functioning, as well as reductions in fatigue and appetite loss, were also reported. Our exercise intervention, whether delivered in person or through a home‐based program, was highly feasible and safe. Trial Registration: ClinicalTrials.gov identifier: NCT04226508

Therapeutic cancer vaccines represent a promising frontier in precision oncology, aiming to elicit durable and tumor-specific immune responses. Recent advances in nucleic acid-based platforms, particularly mRNA and DNA vaccines, have accelerated clinical translation, especially following the success of mRNA vaccines against SARS-CoV-2. These innovations have enabled improved antigen delivery, immunogenicity, and flexibility through structural modifications such as self-amplifying or chemically modified mRNAs. In parallel, peptide-based vaccines have evolved through the incorporation of long synthetic peptides and the identification of tumor-specific neoantigens. Other strategies include dendritic cell-based vaccines and whole tumor cell approaches. Neoantigen vaccines have demonstrated a favorable safety profile and the ability to elicit robust CD4⁺ and CD8⁺ T cell responses across various cancer types and disease stages. Optimal efficacy, however, depends on careful antigen selection, favoring clonal, driver mutations, and timely administration, ideally in early-stage or minimal residual disease settings to circumvent immune evasion and systemic immunosuppression. The tumor microenvironment (TME) critically shapes vaccine responsiveness, influenced by both tumor-intrinsic factors (e.g., antigen presentation defects, HLA loss) and extrinsic immunosuppressive cells. High tumor mutational burden and inflamed TMEs correlate with stronger responses, but encouraging outcomes have also been observed in “cold” tumors. Combining vaccines with ICIs, chemotherapy, or cytokine therapies can enhance efficacy by overcoming immune resistance. Optimizing clinical trial design and ensuring cost-effectiveness will be essential for translating personalized cancer vaccines into routine clinical practice.

Zoledronic acid (ZA) in combination with androgen deprivation therapy (ADT) has never proved additional activity in patients with advanced prostate cancer. However, conventional imaging is poorly reliable in monitoring disease response of metastatic bone lesions. BonEnza is a randomized phase II multicenter clinical trial designed to compare activity of ADT plus Enzalutamide (E) plus/minus ZA in term of bone response rate by Whole-Body Diffusion-Weighted Magnetic Resonance Imaging (WB-DW-MRI). From February 2018 to June 2021, 126 patients with metastatic hormone-sensitive prostate cancer (mHSPC) and bone metastasis at bone scan were enrolled. Patients were randomized in a 1:1 to receive E 160 mg OD orally alone (E arm) or in combination with ZA 4 mg intravenously every 4 weeks (EZ arm). Primary endpoint of the study was overall response rate (ORR) in bone metastases, secondary endpoints were ORR with conventional imaging, progression free survival (PFS) and overall survival (OS). A logistic model was used to evaluate the association between treatment arm and ORR. After a median follow-up of 31.9 months, according to an intent to treat analysis, the ORR was superimposable in both arms: 69.8

BACKGROUND AND OBJECTIVE:Apalutamide (APA) is a treatment for metastatic castration-sensitive prostate cancer (mCSPC). In the ARON-3 study we investigated real-world experiences with APA treatment for mCSPC. METHODS:We retrospectively assessed real-world clinical outcomes for patients with mCSPC treated with APA in the ARON-3 study. Overall survival (OS) was calculated from APA initiation to death from any cause. PSA90 was defined as a prostate-specific antigen decline of ≥90% from baseline, and PSA0.2 as achievement of a PSA level ≤0.2 ng/ml. Data for adverse events were retrospectively collected from electronic and paper charts and categorized according to Common Terminology Criteria for Adverse Events v5.0. KEY FINDINGS AND LIMITATIONS:We included 531 patients with mCSPC treated with APA. High-volume disease was reported for 214 patients (40%), and 56 (11%) had visceral metastases. Median OS was not reached. PSA90 was experienced by 461 patients (87%) and PSA0.2 by 368 (69%). Median OS was significantly longer for patients with PSA90 or PSA0.2 than for subjects without these responses (p < 0.001). The incidence of grade 3-4 fatigue was higher among elderly patients (≥80 yr) than among younger patients (19% vs 5%), but the incidence of other adverse events was comparable between the age groups. CONCLUSIONS AND CLINICAL IMPLICATIONS:APA is an effective and tolerable treatment for mCSPC in the real-world setting. PATIENT SUMMARY:The ARON-3 project collects data for patients with prostate cancer treated in multiple centers worldwide to assess outcomes in the real-world setting. We analyzed data for patients with metastatic hormone-sensitive prostate cancer receiving apalutamide. Our results show that apalutamide is a safe and effective drug in the real-world setting as well as in clinical trials.

Epigenetic dysregulation has long been recognized as a significant contributor to tumorigenesis and tumor maintenance, impacting all recognized cancer hallmarks. Although some epigenetic drugs have received regulatory approval for certain hematological malignancies, their efficacy in treating solid tumors has so far been largely disappointing. However, recent advancements in developing new compounds and a deeper understanding of cancer biology have led to success in specific solid tumor subtypes through precision medicine approaches. Moreover, epigenetic drugs may play a crucial role in synergizing with other anticancer treatments, enhancing the sensitivity of cancer cells to various anticancer therapies, including chemotherapy, radiation therapy, hormone therapy, targeted therapy, and immunotherapy. In this review, we critically evaluate the evolution of epigenetic drugs, tracing their development from initial use as monotherapies to their current application in combination therapies. We explore the preclinical rationale, completed clinical studies, and ongoing clinical trials. Finally, we discuss trial design strategies and drug scheduling to optimize the development of possible combination therapies.

Despite the development of new therapies in the last few years, metastatic prostate cancer (PCa) is still a lethal disease. Radium-223 (Ra-223) is approved for patients with advanced castration-resistant prostate cancer (CRPC) with bone metastases and no visceral disease. However, patients’ outcomes are heterogenous, and there is lack of validated predictive biomarkers of response, while biomarkers for early identification of patients who benefit from treatment are limited. This case report describes a remarkable and durable response to Ra-223 in a CRPC patient with bone metastases who had rapidly progressed to many previous therapies; this response is now lasting for 5 years even after having stopped backbone androgen deprivation therapy (ADT). Here, we present the clinical course of this exceptional response, as well as comprehensive genomic and histopathology analyses on sequential biopsies acquired before and after therapy. Additionally, we review current knowledge on predictive and response biomarkers to Ra-223 in metastatic prostate cancer.

Metastatic hormone-naïve prostate cancer (mHNPC) is often the initial form of presentation for metastatic prostate cancer and encompasses a heterogeneous patient population with high inter-patient heterogeneity in prognosis and response to therapy. A more precise treatment of mHNPC, guided by evidence-based biomarkers, remains an unmet medical need. In addition, the limited number of representative laboratory models of mHNPC hampers the translation of basic research into clinical applications. We provide a comprehensive overview of the clinical and biological features that characterize mHNPC, highlight molecular data that could explain the unique prognostic characteristics of mHNPC, and identify key open questions.

Background and objective Advanced prostate cancer (PCa) is enriched for alterations in DNA damage repair genes; poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) are a class of drugs that have demonstrated effectiveness in PCa, particularly in tumors with alterations in BRCA1/2 and other homologous recombination repair (HRR) genes, acting through a synthetic lethal mechanism. To prevent or delay drug resistance, and to expand the patient population that can benefit from this class of drug, combination treatment strategies have been developed in preclinical and clinical studies. Methods This review examines the latest developments in clinical trials testing PARPi for advanced PCa and their emerging role in earlier disease settings. Furthermore, it discusses the critical role of careful patient selection and identification of additional biomarkers to enhance treatment efficacy. Key findings and limitations Two PARPi (olaparib and rucaparib) have been approved as monotherapy in metastatic castration-resistant PCa, thereby establishing the first biomarker-guided drug indications in PCa. Several combinations of PARPi with androgen receptor pathway inhibitors have now also been approved. Anemia and fatigue are the main adverse events associated with this drug class in clinical trials; gastrointestinal toxicities are common but usually manageble. Conclusions and clinical implications PARPi are active against PCa with HRR mutations, especially in those with germline or somatic BRCA1/2 mutations.  There is still a need to further optimize patient stratification strategies, particularly for combination approaches. Future research should focus on refining predictive biomarkers, improving treatment delivery strategies, and exploring the potential benefits of PARPi in earlier stages of the disease. Patient summary Here, we summarize the results from clinical trials testing different poly (ADP-ribose) polymerase inhibitors (PARPi), a novel targeted drug class, in prostate cancer. Overall, the data from these trials confirm the efficacy of this drug class in those metastatic prostate cancers that show specific gene alterations, such as mutations in the BRCA1/2 genes. Several studies combining PARPi with other standard drugs for prostate cancer suggest that there may be efficacy in larger patient populations, but some of these data still need validation in longer follow-up analyses.

705 Background: mRCC prognostic stratification is currently based on the IMDC score. However, some patients experience outcomes markedly different from those predicted by the median outcome of their risk class. Moreover, risk scores are prognostic, rather than predictive, and developing reproducible, affordable, biology-based predictive biomarkers to tailor treatment choices in individual pts remains an unmet clinical need. Methods: A retrospective cohort of 113 mRCC pts treated at the Verona University Hospital Trust between 2013 and 2021 was explored to identify additional clinical prognostic factors for OS to complement IMDC score. Outlier pts (i.e. individual pts whose clinical outcome differed significantly from the median of the IMDC group they belonged to) were further explored to find putative molecular signatures, using FISH and IHC assays. Results: At a median follow-up of 69 months (range 18-136m), novel variables impacting on OS in addition to IMDC risk group were identified: bone, central nervous system (CNS) and pancreatic mets and high neutrophil/lymphocyte ratio (N/L) with a cut-off of 3.2. We also analyzed outliers: 3 good-risk pts with lower than expected OS, 4 poor-risk pts with longer than expected OS, and two intermediate-risk pts with long treatment response. Two putative signatures were found predictive of disease behavior: a cold signature (9p loss, poor of TILs) and a hot signature (rich in CD56+, CD15+ and CD8+ infiltrating cells). The cold and hot signatures were found in good risk pts with bad OS and poor-risk pts good OS, respectively; both intermediate-risk pts had a hot signature, consistent with their disease course. Conclusions: Additional clinical and molecular factors have been identified to possibly improve IMDC prognostic performance; multivariable models including them along with standard IMDC are being developed. Molecular analysis suggests potential signatures to be applied in routine clinical practice, whose predictive performance could be validated in prospective multicentric trials. [Table: see text]

e13651 Background: In Italy, patient (pt) access to oncological drugs is almost exclusively provided by the NHS, following authorization by the European Medicines Agency (EMA) and negotiation with the Italian Medicines Agency (AIFA) for specific indications. However, regulatory delays (with respect to the availability of scientific evidence) and the need for rapid access to innovative drugs, particularly in the context of orphan and rare diseases, have prompted the utilization of atypical drug access pathways. In addition to enrollment in clinical trials, atypical drug access pathways are expected to be increasingly used in the context of a Precision Oncology practice. Methods: We explored trends in atypical drug access at the Oncology Section of the Verona University and Hospital Trust, by interrogating Oncology and Pharmacy databases and regional registries of rare diseases and reviewing AIFA registries records. Data on atypical drug access were also correlated with the use of NGS-based molecular profiling. Results: Between January 2016 and December 2022, a total of 355 atypical drug access requests for the treatment of cancer pts were recorded, with a peak in 2017 and no discernible temporal trend. Over this period, the two most common atypical access schemes were compassionate (including named patient and early access programs, 61%) and off-label (21%) use. The latter steadily increased over time (from 8% in 2017 to 39% in 2021). Overall, the type of drugs requested through atypical access were almost equally distributed between classical cytotoxic agents (CHT, 36%), immuno-oncology drugs (IO, 29%) and molecularly targeted agents (TT, 35%). Temporal trends in the usage of different classes of drugs are shown. Interestingly, TT requests decreased between 2016 and 2018 and stabilized at approximately 50% of total requests since 2019. Between 2019 and 2021, atypical drug access requests triggered by NGS-based extended molecular profiling significantly increased from 2.8% to 23.1% (p=0.0007). Conclusions: Although atypical drug access did not increase overall during the observation period, a trend towards increased off-label use of TT was identified, especially from 2019 onwards; figures for 2022 are being analyzed and will be presented at the Meeting. Since 2019, NGS-informed requests have significantly increased to constitute almost 1/4 of all atypical drug access requests, clearly identifying a trend towards implementation of Precision Oncology in routine clinical practice and evolving towards the implementation of Molecular Tumor Board case discussions. [Table: see text]

Leptomeningeal carcinomatosis is a rare but serious consequence of pre-existing tumors, such as breast, lung, and gastrointestinal carcinomas. Further, leptomeningeal carcinomatosis is more frequently diagnosed with breast cancers, if only because breast cancers are diagnosed far more often than any other carcinomas. In this paper, we present the case of a leptomeningeal carcinomatosis patient who experienced complete remission following therapy targeted at the Her-2 (human epidermal growth factor receptor 2-positive) receptor. This patient's diagnosis was complicated by the fact that brain and column MRI imaging were clear, but analysis of the cerebrospinal fluid led to the conclusion of leptomeningeal carcinomatosis. The tests were requested because the patient, under chemotherapy for advanced breast cancer at the time, reported some neurological symptoms. Following the diagnosis of leptomeningeal carcinomatosis and subsequent T-DM1 Her-2 receptor therapy, the patient showed a complete response to leptomeningeal carcinomatosis within 30 days and survived for another 16 months. This case offers compelling evidence that the effect TDM1 Her-2 receptor therapy has on a patient's remission and long-term survivability is considerably better than other therapies for similar pre-existing conditions diagnosed with leptomeningeal carcinomatosis. Further prospective studies should confirm these findings.

Therapeutic alternatives in advanced urothelial carcinoma are limited, especially in advanced lines, with only a few drugs having demonstrated relevant clinical benefit. This article discusses about a young patient with significant cardiovascular comorbidities, already treated with recommended first- and second-line drugs, and suffering from liver metastases. Despite the known poor prognosis of this disease and the few supporting data, given his peculiar clinical history, we opted to treat him with a third-line gemcitabine rechallenge with a notable response on his liver lesions. We present an intriguing case, both in terms of the therapeutic sequence and the disease course.

Bone health is often threatened in cancer patients. Bone metastasis and osteoporosis frequently occur in patients with cancer and may lead to different skeletal-related events, which may negatively affect patients' quality of life and are associated with high mortality risk. Physical exercise has been recognized as a potential adjunctive strategy in the cancer setting to improve physical function as well as treatment-related side effects. Nevertheless, exercise is often not recommended to patients with bone health impairments due to safety concerns. In the current review, we aimed, through a comprehensive review of the evidence, to explore the impact of exercise in terms of safety profile, bone outcomes, and the effects on other outcomes in patients with cancer affected by bone metastasis or at high risk of losing bone. Additionally, we explored the potential mechanisms by which exercise may act on bone, particularly the impact of mechanical load on bone remodeling. Finally, considerations about exercise prescription and programming in these populations are also discussed.

Background: On February 23rd, the 1st case of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was diagnosed at the University Hospital Trust of Verona, Italy. On March 13th, the Oncology Section was converted into a 22-inpatient bed coronavirus disease (COVID) Unit, and we reshaped our organisation to face the SARS-CoV-2 epidemic, while maintaining oncological activities. Methods: We tracked down (i) volumes of oncological activities (January 1st - March 31st, 2020 versus the same period of 2019), (ii) patients' and caregivers' perception and (iii) SARS-CoV-2 infection rate in oncology health professionals and SARS-CoV-2 infection -related hospital admissions of "active"' oncological patients. Results: As compared with the same trimester in 2019, the overall reduction in total numbers of inpatient admissions, chemotherapy administrations and specialist visits in January-March 2020 was 8%, 6% and 3%, respectively; based on the weekly average of daily accesses, reduction in some of the oncological activities became statistically significant from week 11. The overall acceptance of adopted measures, as measured by targeted questionnaires administered to a sample of 241 outpatients, was high (>70%). Overall, 8 of 85 oncology health professionals tested positive for SARS-CoV-2 infection (all but one employed in the COVID Unit, no hospital admissions and no treatment required); among 471 patients admitted for SARSCoV-2 infection, 7 had an "active"' oncological disease (2 died of infection-related complications). Conclusions: A slight, but statistically significant reduction in oncology activity was registered during the SARS-CoV-2 epidemic peak in Verona, Italy. Organisational and protective measures adopted appear to have contributed to keep infections in both oncological patients and health professionals to a minimum. (C) 2020 The Authors. Published by Elsevier Ltd.