e18028 Background: POINT trial treated platinum-resistant, recurrent/metastatic (RM) Nasopharyngeal Carcinoma (NPC) patients (pts) with pembrolizumab and olaparib combination. To explore mechanisms of treatment sensitivity/resistance, we performed a translational analysis on selected pts who got opposite treatment response as excellent or poor. Methods: We retrieved baseline FFPE samples of 4 good responders -R- (pts obtaining clinical benefit with partial response or long-lasting stable disease), and 4 non-responders -NR- (progression within 4 months since treatment start), matched-paired for age, ECOG performance status, baseline plasma EBV DNA load, and disease burden/subsites. Samples were processed through Chromium X and libraries were sequenced on NextSeq 2000 platform (Illumina). Single cell data analysis was performed using Seurat (v5.3.1). Results: Patient’s characteristics are reported in Table 1. Immune and stromal cell types, identified based on transcriptomic profile, exhibited distinct proportional differences between R and NR. In R, T cells were enriched for gene signatures associated with migration, cytotoxicity, and active metabolic states; tumor epithelial cells’ phenotype, expressing IDO1 , PROX1 and CXCL14 , was consistent with a microenvironment actively supporting immune response. In contrast, NR T cells showed increased expression of chronic activation state genes, MAP4K1 , ZAP70 , and PIK3CD ; tumor epithelial cells displayed a more aggressive transcriptional profile, marked by signatures of invasion, epithelial–mesenchymal transition, extracellular matrix remodeling and immune suppression. Furthermore, B cells from responders to the treatment express tertiary lymphoid structure’s markers, such as CXCR5. Validation of these findings is ongoing through spatial transcriptomics. Conclusions: We highlighted clear differences in both cellular composition and gene expression profiles between R and NR baseline samples from platinum-resistant NPC pts treated with an immunotherapy-based approach. These preliminary findings provide novel insights on treatment selection of NPC pts and on future improvements in therapeutic strategies for resistant pts. Clinical trial information: NCT04825990 . Patients 1-R 1-NR 2-R 2-NR 3-R 3-NR 4-R 4-NR Plasma EBV DNA (copies/ml) 732 441 181 24 6341 7020 1258 1429 Disease sites Local Local, bone Hepatic Hepatic, bone Local, hepatic Hepatic, bone, nodal Pleural Distant nodal Sex M M F F M M F M Age (years) 51 62 55 51 40 42 69 40 ECOG PS 0 0 0 0 0 0 0 0 PFS (months) 9 4 17 2 15 2 20 4

Systemic inflammatory indices have been proposed as prognostic biomarkers in several malignancies; however, their role in patients receiving avelumab maintenance for advanced urothelial carcinoma (aUC) remains poorly defined. This study aimed to evaluate the prognostic impact of inflammatory markers in this context and to develop a composite score for outcome stratification. We retrospectively analyzed patients with aUC who were treated with avelumab maintenance therapy. Systemic inflammatory markers - including the neutrophil-to-lymphocyte ratio (NLR), neutrophil-to-eosinophil ratio (NER), lymphocyte-to-monocyte ratio (LMR), platelet-to-lymphocyte ratio (PLR), and the systemic immune-inflammation index (SII) - were collected at baseline and after treatment initiation (cycle 3), and changes from baseline to cycle three were analyzed (increase versus stability/decrease). Overall survival (OS), the primary endpoint, was evaluated using Kaplan-Meier and Cox models. A prognostic score was created from the multivariable analysis. Time-dependent Receiver operating characteristics (ROC) analysis was employed to evaluate model discrimination at 6, 12, and 24 months. The prognostic impact on disease control rate (DCR - secondary endpoint) was assessed using logistic regression and ROC curves. A total of 358 patients were included in the study. In the multivariable analysis, high NLR, high NER, low LMR, increasing NLR trend, bone and liver metastases were independently associated with worse OS. These variables were incorporated into a 0-6 point prognostic score, which demonstrated good discrimination (C-index 0.76; AUC at 6, 12, and 24 months: 0.87, 0.75, and 0.73, respectively). The score remained prognostic across subgroups and following sensitivity analyses. High LMR, low NER, the absence of liver metastases, and the absence of bone metastases were independently associated with higher DCR. A response-associated score combining these variables showed a decreasing DCR from 69% (score 0) to 25% (score 4). Baseline and dynamic inflammatory markers may serve as prognostic factors for OS in patients with aUC undergoing avelumab maintenance therapy. A composite score that integrates laboratory and clinical features could allow for clinically meaningful stratification of survival and response outcomes, with potential applications in clinical practice. However, a prospective evaluation is necessary.

Prostate cancer (PC) is the second most common cancer among males, following lung cancer, more frequently occurring at an advanced age. Even nowadays, early diagnosis represents a challenge and validated screening methods are still missing. To date, multiple therapeutic strategies are available and a tailored approach is possible. The backbone of PC therapy is represented by the inhibition of the androgen signaling pathway, which mediates tumor cells growth. In this current therapeutic scenario, androgen-receptors signaling inhibitors (ARSIs) play a role in improving cancer treatment. This paper provides an overview of the currently available treatment options, focusing on the new drugs (ARSIs), their actual implications and future developments. METHODS: We conducted a research from Pubmed and Embase database regarding the terms 'prostate cancer', 'ARSI', 'androgen receptor inhibitors', ''enzalutamide", "apalutamide", and "Darolutamide". Original full-text articles published in English were reviewed. Based on this research 185 potentially relevant articles were found, limiting our research to the period 2019-2025 of publication. 75 articles were excluded on the basis of abstract, title or the content.

e16572 Background: Avelumab maintenance after first-line platinum-based chemotherapy represents a cornerstone for the treatment of metastatic urothelial carcinoma (mUC). However, identifying prognostic biomarkers is paramount for optimizing patients’ benefits while minimizing toxicity. Systemic inflammatory indexes have been studied as prognostic biomarkers for immune checkpoint inhibitors in many tumor types, but their role in mUC is still debatable. We hypothesized that systemic inflammatory indexes could be correlated with survival in mUC patients treated with maintenance avelumab. Methods: Meet-URO25 is a multicenter Italian prospective/retrospective registry of mUC patients treated with first-line avelumab maintenance from 01/2021 to 12/2024. In the SAILOR/Meet-URO25a sub-analysis, we investigated the correlation with overall survival (OS) of five inflammatory indexes (neutrophil-to-lymphocyte ratio [NLR], lymphocyte-to-monocyte ratio [LMR], platelet-to-lymphocyte ratio [PLR], neutrophil-to-eosinophil ratio [NLR], and systemic-inflammation-index [SII]) at baseline and after 3 cycles of avelumab. ROC curves with Youden’s test, the Kaplan-Meier method with log-rank test, and Cox regression analyses were used. Results: 258 patients (106 female; median age: 63yrs) were included in the analysis. Low baseline NLR (Hazard ratio [HR] 0.37; 95% confidence interval [CI] 0.19-0.73; p: 0.016) and SII (HR 0.75; 95%CI 0.52-0.98; p: 0.033) were associated with better OS. After 3 cycles of therapy, decreasing NLR (HR 0.64; 95%CI 0.43-0.94; p: 0.02), NER (HR 0.67; 95%CI 0.46-0.99; p: 0.006) and SII (HR 0.55; 95%CI 0.37-0.81; p: 0.002) were significantly associated with longer OS. In the multivariate analysis, the presence of liver metastases, response both to first-line chemotherapy and avelumab, baseline NLR, early NLR and NER reduction were independent predictors of OS. Conclusions: Our results suggest that baseline levels of NLR and systemic inflammatory indexes and their kinetics after avelumab initiation may be prognostic in pts with mUC. The combined evaluation of systemic inflammatory indexes and their early changes should be further investigated to obtain additional prognostic or predictive value.

Italy remains one of the lowest-ranking Western European countries in terms of rights and protections for transgender and gender-diverse (TGD) individuals, with serious consequences for equitable healthcare access. In response to these disparities, and thanks to the initiative and support of the advocacy group Salute Donna Odv Salute Uomo, a multidisciplinary team organised a series of public conferences in Pavia and Milan in 2024. These events brought together healthcare professionals, researchers, LGBTQIA+ organisations, and patient advocates to define practical strategies for more inclusive cancer care. The outcome is a shared framework presented in this manuscript, aimed at enhancing cultural competence and institutional responsiveness in oncology services for TGD patients.

BACKGROUND:Primary mediastinal germ-cell tumors (PMGCTs) account for 1%-3% of all germ-cell tumors (GCTs). Non-seminoma have a poorer prognosis compared to their gonadal counterpart and, according to the International Germ Cell Cancer Collaborative Group, they are considered 'poor risk' disease. Medical treatment is the same, with overall survival (OS) being ∼40%, declining to 10%-15% at 3 years in case of lung and non-visceral metastases. Patients failing first-line chemotherapy have a dismal prognosis, with only 5%-10% of cases being cured in the salvage setting. High-dose chemotherapy (HDC) with autologous stem cell transplantation (ASCT) has been successfully used to treat patients with relapsed or refractory gonadal GCTs. PATIENTS AND METHODS:This retrospective study aimed to investigate the value of HDC with ASCT in the whole population and define primary mediastinal non seminoma germ cell tumor (PMNSGCT) patient subgroups, who were registered in the European Society for Blood and Marrow Transplantation database from January 2000 to January 2018. Sixty-nine adult male patients with PMNSGCT were included. HDC consisted mainly of carboplatin/etoposide doublet, and most patients received HDC as part of a multiple sequential HDC program. RESULTS:OS was 43.3% at 2 years, and 34.7% at 5 and 10 years for the entire cohort. Analysis of outcomes showed that patients undergoing HDC as upfront therapy had a better progression-free survival (PFS) and OS compared to those treated in subsequent relapses (5-year PFS 51.8% versus 26.8% and 5-year OS 51.3% versus 25.9%). Better remission status before transplantation was predictive of the benefit of HDC. Three treatment-related deaths were recorded. CONCLUSIONS:To our knowledge, this is the most extensive retrospective study of HDC in PMNSGCTs patients and the first to thoroughly investigate potential predictors of benefit from this treatment. HDC with ASCT may well represent a therapeutic option in patients with PMNSGCTs after the first relapse or even as a front-line program.

Introduction: In the multidisciplinary management of oligometastatic, persistent, or recurrent (MPR) ovarian cancer, radiotherapy (RT) is becoming a more and more worthwhile treatment to potentially improve the chronicity of the disease. Particle beam RT has proved to be effective in several gynecological malignancies, but so far no data are available for ovarian cancer. Material and Methods: This is a real-world, retrospective, bi-institutional, single-arm study aimed to assess the effectiveness and the safety of carbon ion RT (CIRT) in this setting. The co-first endpoints are 1-year and 2-year actuarial local control (LC) rates and the objective response rate (ORR) defined on a "per lesion" basis. The secondary endpoint was toxicity. Actuarial outcomes were evaluated using the Kaplan-Meier method while potential predictors were explored using the Log-rank test. Bi-variable logistic regression was employed in the analysis of factors predicting the complete response on a per-lesion basis. Results: 26 patients accounting for a total of 36 lesions underwent CIRT with a total median dose of 52.8 Gy[RBE] (range: 39-64 Gy[RBE]). Five patients received CIRT for re-irradiation. No concomitant systemic therapies were administered during CIRT. Within 12 months after the treatment, 17 lesions (47 %) achieved complete response while 18 (50 %) obtained a partial response with an ORR of 97 %. The achievement of a complete response is related to the dose per fraction (>4.2 Gy[RBE], p = 0.04) and total dose (>52,8 Gy[RBE], p = 0.05). The 1-year LC was 92 % and the 2-year LC was 83 %, according to the achievement of a CR (p = 0.007) and GTV <= 14 cm3 (p = 0.024). No grade > 3 toxicities were recorded both in na & iuml;ve and re-irradiated patients. PARP-i and antiVEGF seemed not to exacerbate the risk of severe toxicities. Conclusions: CIRT was effective and safe in MPR ovarian cancers, even in the case of re-irradiation. Largest cohort studies and longer follow-up are needed to confirm these data.

Primitive Retroperitoneal Germinal Cell Tumors (pR-GCT) corresponds to the clinical case of retroperitoneal ascertained GCT without evidence of primary testicular tumor and accounts for up to 40 % of extragonadal GCTs. An occult primary testicular tumor is often missed at diagnosis. Treatment modalities and outcomes have not been specifically addressed, preventing robust recommendations. We performed an international call to assess prognosis of treatment outcomes of these pts. Clinical, pathological and treatment data pts with pR-GCT between April 1988 and January 2022 were retrospectively collected across four referral centers. Kaplan Meier methods, univariable and multivariable Cox regression models (MCRMs) were used. Ninety-nine pts (median age 37 years - IQR: 29-45) were collected. Ninety-three (94%) had histological diagnosis by biopsy or primary retroperitoneal lymph-node dissection: 60 (62.5%) had non-seminomatous (pR-NSGCTs) and 33 (34.4%) had seminomatous (pR-SGCTs). IGCCCG prognostic allocation was possible in 91 pts: 34 (35.8%) were good, 23 (24.2%) intermediate and 34 (35.8%) poor-risk, respectively. All pts underwent cisplatin-based chemotherapy, usually BEP (94.9%). After chemotherapy, 25 (25.3%) pts underwent orchiectomy: viable tumor was present in 8 (32%), burn-out lesions in 6 (24%) and no lesion in 11 (44%). After a median FUP of 45 m (IQR:15-90), the 5-yrs OS was 58%, being 85% in case of pR-SGCT and 46% in case of pR-NSGCT. According to IGCCCG classification 5-yrs OS was 83.3% for good, 57% for intermediate, 42% for poor-risk pts, respectively. No difference in term of OS (60% vs 56%, p-value 0.81) was observed between patient who had or not radical orchiectomy. At MCRMs only IGCCCG poor risk category (HR 3.2, CI: 1.18-8.84, p-value 0.02) was independent predictor of a worse OS. Eventually, a significant proportion of patients with pR-GCT had a misclassified primary testicular tumor. 5 years-OS according to IGCCCG-classification is worse than expected. The role of a surgical exploration of the suspected primary tumor remains controversial and the existence of a real category of p-RGCT cannot be excluded.

510 Background: pR-GCT corresponds to the clinical case of retroperitoneal ascertained GCT without radiological evidence of primary testicular tumor and accounts for up to 40% of extragonadal GCTs. An occult primary testicular tumor is often missed at diagnosis. Treatment modalities and outcomes have not been specifically addressed, preventing robust recommendations. We performed an international call to assess prognosis of treatment outcomes of these patients. Methods: Clinical, pathological and treatment data pts with pR-GCT between 04/1988 and 01/2022 were retrospectively collected across 4 referral centers. Kaplan Meier methods, univariable and multivariable Cox regression models (MCRMs) were used. Results: Ninety-nine patients (median age 37 yrs - IQR: 29-45) were collected. Ninety-three (94%) had histological diagnosis by biopsy or primary retroperitoneal lymph-node dissection (RPLND): 60 (62.5%) had non-seminomatous pR-GCTs (pR-NSGCTs) and 33 (34.4%) had seminomatous pR-GCTs (pR-SGCTs). IGCCCG prognostic allocation was possible in 91 pts: 34 (35.8%) were good, 23 (24.2%) intermediate and 34 (35.8%) poor risk, respectively. All pts underwent cisplatin-based chemotherapy, usually BEP regimen (94.9%). After chemotherapy, 25 (25.3%) pts underwent orchiectomy: viable tumor was present in 8 (32%), burn-out lesions in 6 (24%) and no lesion in 11 (44%) cases. After a median follow-up of 45 mos (IQR:15-90), the 5-years OS was 58%, being 85% in case of pR-SGCT and 46% in case of pR-NSGCT. According to IGCCCG classification 5-years OS was 83.3% for good, 57% for intermediate and 42% for poor risk patients, respectively. No difference in term of OS (60% vs 56%, p-value 0.81) was observed between patient who had or not radical orchiectomy. At MCRMs only IGCCCG poor risk category (HR 3.2, CI: 1.18-8.84, p-value 0.02) was independent predictors of a worse OS. Conclusions: Eventually, a significant proportion of pts with a pR-GCT had a misclassified primary testicular tumor. 5 yrs-OS according to IGCCCG classification is worse than expected. The role of a surgical exploration of the suspected primary tumor remains controversial and the existence of a real category of p-GCT cannot be excluded.

Radiotherapy has been increasingly considered as an active treatment to combine with other approaches (i.e., surgery, chemotherapy, and novel target-based drugs) in ovarian cancers to palliate symptoms and/or to prolong chemotherapy-free intervals. This narrative review aimed to summarize the current knowledge of the radiosensitivity/radioresistance of ovarian cancer which remains the most lethal gynecological cancer worldwide. Indeed, considering the high rate of recurrence in and out of the radiotherapy fields, in the era of patient-tailored oncology, elucidating the mechanisms of radiosensitivity and identifying potential radioresistance biomarkers could be crucial in guiding clinical decision-making.

Background Refractory or metastatic nasopharyngeal carcinoma (NPC) patients have a poor prognosis due to the lack of effective salvage treatments and prolonged survival by means of combination chemotherapy being described only for a minority of younger patients with oligometastatic disease. Targeting the Epstein - Barr virus (EBV) proteins expressed in NPC cells has been shown to be a feasible strategy that could help control systemic disease. Patients and Methods Between 2011 and 2014, 16 patients with recurrent/metastatic EBV-NPC received first-line chemotherapy (CT) followed by 2 doses of autologous cytotoxic EBV specific T-lymphocytes (15-25 x 10 7 total cells/dose, 2 weeks apart), based on our previous studies showing the feasibility and efficacy of this infusion regimen. Cumulative overall survival (OS) and median OS were analysed in the whole population and according to specific clinical and biological parameters. Results All patients received the planned T-cell therapy schedule, 9 after reaching partial (n=5) or complete (n=4) disease remission with CT, and 7 after failing to obtain benefit from chemotherapy. No severe adverse events were recorded. Patients who received cytotoxic T-lymphocytes (CTLs) had a cumulative 10-year OS of 44%, with a median OS of 60 months (95% CI 42-62). Patients responding to CT, with oligometastatic disease (<3 disease sites), and plasma EBV-DNA <1000 copies/mL had a better outcome. Conclusions Autologous EBV-specific CTLs transplanted following conventional first-line CT demonstrated promising efficacy with several patients obtaining long-lasting disease control. The rationale provided by this study, with the crucial role likely played by the timing of CTL administration when trying to induce synergy with conventional treatment needs to be confirmed in a prospective controlled trial.

Spermatocytic tumor (ST) is a very rare disease, accounting for approximately 1% of testicular cancers. Previously classified as spermatocytic seminoma, it is currently classified within the non-germ neoplasia in-situ-derived tumors and has different clinical-pathologic features when compared with other forms of germ cell tumors (GCTs). A web-based search of MEDLINE/PubMed library data was performed in order to identify pertinent articles. In the vast majority of cases, STs are diagnosed at stage I and carry a very good prognosis. The treatment of choice is orchiectomy alone. Nevertheless, there are two rare variants of STs having very aggressive behavior, namely anaplastic ST and ST with sarcomatous transformation, that are resistant to systemic treatments and their prognosis is very poor. We have summarized all the epidemiological, pathological and clinical features available in the literature regarding STs that have to be considered as a specific entity compared to other germ GCTs, including seminoma. With the aim of improving the knowledge of this rare disease, an international registry is required.

In the past years cancer treatments have drastically changed, mainly due to the development of immune checkpoint inhibitors capable of immune modulation in vivo, thus providing major clinical benefit in a number of malignancies. Simultaneously, considerable technical refinements have opened new prospects for the development of immune cell-based medicinal products and unprecedented success with chimeric antigen receptor (CAR)-T cells targeting B-cell hematologic malignancies has been obtained. However, T cell therapies introduced and performed in the field of solid tumors have produced so far only limited responses in selected patient populations. This standstill is attributable to the difficulty in identifying target antigens which are homogeneously expressed by all tumor cells while absent from normal tissues, and the limited T cell persistence and proliferation in a hostile tumor microenvironment that favors immune escape. Replicating the results observed in hematology is a major scientific challenge in solid tumors, and ongoing translational and clinical research is focused on obtaining insight into the mechanisms of tumor recognition and evasion, and how to improve the efficacy of cellular therapies, also combining them with immune checkpoint inhibitors or other agents targeting either the cancer cell or the tumor environment. This paper provides an overview of current adaptive T cell therapy approaches in solid tumors, the research performed to increase their efficacy and safety, and results from ongoing clinical trials.

Risk-reducing surgery (RRS) is recommended in BRCA-mutated carriers because of their increased risk of developing ovarian cancer, while its role is still discussed for women harboring mutations in non-BRCA homologous repair genes. The aim of this study was to retrospectively evaluate the occurrence of pathological findings in a high-risk population undergoing RRS in San Matteo Hospital, Pavia between 2012 and 2022, and correlate their genetic and clinical outcomes, comparing them with a control group. The final cohort of 190 patients included 85 BRCA1, 63 BRCA2, 11 CHEK2, 7 PALB2, 4 ATM, 1 ERCC5, 1 RAD51C, 1 CDH1, 1 MEN1, 1 MLH1 gene mutation carriers and 15 patients with no known mutation but with strong familial risk. Occult invasive serous carcinoma (HGSC) and serous tubal intraepithelial carcinoma (STIC) were diagnosed in 12 (6.3%) women, all of them BRCA carriers. No neoplastic lesion was diagnosed in the non-BRCA group, in women with familial risk, or in the control group. Oral contraceptive use and age ≤45 at surgery were both found to be favorable factors. While p53 signature and serous tubal intraepithelial lesion (STIL) were also seen in the control group and in non-BRCA carriers, STIC and HGSC were only found in BRCA1/2 mutation carriers.