Istituto Oncologico Veneto

Background Pembrolizumab plus lenvatinib is a treatment option for metastatic Renal Cell Carcinoma (mRCC). In the ARON-1 study we investigated we the real-world experiences gained from the use of this combination for mRCC. Methods We retrospectively investigated real-world clinical outcomes of mRCC patients receiving pembrolizumab plus lenvatinib within the ARON-1 study. Overall survival (OS) was calculated from the start of pembrolizumab plus lenvatinib to death for any cause. Progression-Free Survival (PFS) was defined as the time from the start of pembrolizumab to progression or death from any cause. Duration of response (DoR) was defined as the time from the start of pembrolizumab to disease progression or death, whichever occurred first, in patients who achieved complete remission (CR) or partial response (PR). Overall Response Rate (ORR) was defined as the proportion of patients who achieve a CR or PR per RECIST criteria. Adverse events were retrospectively collected from electronic and paper charts and categorized by the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Results Overall, we included 202 mRCC patients treated with pembrolizumab plus lenvatinib. The median follow-up time was 15.1 months. The median OS was not reached (NR), with a median PFS of 25.6 months and an Overall Response Rate (ORR) of 59%. The median Duration of Response (DoR) was 26.2 months. G3-G4 adverse events (AEs) were observed in 92 patients (46%), with hypertension being the most common AE (13%). Conclusions Pembrolizumab plus lenvatinib is an effective and tolerable treatment for mRCC also in the real-world setting.

Objectives To perform a Delphi-based consensus on published evidence on image-guided injections for facet joint pain (FJP) and provide clinical indications. Methods We report the results of an evidence-based Delphi consensus of 38 experts from the European Society of Musculoskeletal Radiology and the European Society of Neuroradiology, who reviewed the published literature for evidence on image-guided injections for FJP. Experts drafted a list of statements and graded them according to the Oxford Centre for evidence-based medicine levels of evidence. Consensus was considered strong when ≥ 95% of experts agreed with the statement or broad when > 80% but < 95% agreed. The results of the consensus were used to write the paper. Results Twenty statements on image-guided FJP treatment have been drafted. Eighteen statements received strong consensus, while two received broad consensus. Three statements reached the highest level of evidence, all of them regarding the lumbar spine. All radiological methods are used for image-guided injections for FJP, and regardless of the radiological method used, all show good safety and efficacy. Facet joint injections and medial branch blocks are used in all spinal regions to treat FJP, and both show similar clinical outcomes. Advanced technological solutions have been studied in the field of lumbar FJP; however, the level of evidence for these is low. Conclusion Despite promising results reported by published papers on image-guided injections for FJP, there is still a lack of evidence on injection efficacy, appropriateness of imaging methods, and optimal medication. Key Points Question Image-guided injections to treat facet joint pain (FJP) are performed throughout the spine; however, the highest level of evidence exists for the lumbar spine. Findings Regardless of the imaging method used, image-guided injections for facet joint pain treatment are safe, with only minor adverse events in rare cases. Clinical relevance All imaging methods are used for injection guidance to treat FJP, each with advantages and disadvantages. These statements on image-guided injections for FJP provide a concise and up to date overview on the topic, serving as a list of clinical indications. Graphical Abstract

Background The impact of surgical excision margin size on the survival of patients with cutaneous melanoma (CM) is controversial. The aim of this study was to assess the impact of excision margins on patient outcomes. Methods This retrospective population-based follow-up study analysed data from patients presenting with CM without extranodal disease. The linear distance of CM from the excision margin was assessed microscopically. Regarding overall and melanoma-specific survival estimates, Kaplan–Meier analysis, the Cox proportional hazards model, and the subdistribution hazard ratio of the Fine–Gray model were applied. Results Of 3262 patients, a total of 2698 (82.7%) with pathological (p) T1–2 and 564 (17.3%) with pT3–4 CM underwent wide local excision. Multivariable analyses, adjusting for melanoma incidence cohort, age, sex, anatomical site, ulceration, histotype, mitotic count, and tumour-infiltrating lymphocytes, demonstrated that, in pT1–2 CM, surgical excision > 1.1 cm resulted in significant CM-specific survival benefit. In pT4 disease, a CM distance to the surgical margins of < 1.6 cm significantly lowered CM-specific survival. Conclusion This population-based study conducted in real-world clinical practice found that the prognosis of patients with pT1–2 CM may benefit from excision margins > 1.1 cm. In pT3–4 CM, margins < 1.6 cm were significantly associated with lower CM-specific survival rates. These findings highlight the need for further prospective studies to evaluate the safety of surgical excision margins in managing primary CM.

Background The addition of a programmed death-ligand 1 (PD-L1) inhibitor, either atezolizumab or durvalumab, to platinum-etoposide prolonged survival in a limited subset of patients with extensive-stage small-cell lung cancer (ES-SCLC). Preclinical studies demonstrated synergistic antitumor activity of combined vascular endothelial growth factor receptor and PD-L1 inhibition in SCLC. Since bevacizumab added to platinum-etoposide was safe and active in ES-SCLC, we investigated the efficacy of atezolizumab, bevacizumab, carboplatin, and etoposide as first-line treatment of ES-SCLC. Methods The CeLEBrATE study is an Italian multicentric single-arm phase II trial of carboplatin (area under the curve 5 ml/min), etoposide (100 mg/sqm), bevacizumab (7.5 mg/kg), and atezolizumab (1,200 mg) every 3 weeks (q3w) for four to six courses, followed by bevacizumab and atezolizumab maintenance q3w in patients with ES-SCLC and no contraindications to immunotherapy or antiangiogenic therapy. Patients with asymptomatic brain metastases were eligible. Prophylactic cranial irradiation and consolidation thoracic external radiotherapy were not permitted while on study treatment. Primary endpoint was overall survival (OS) rate at 1 year. Results 53 patients were enrolled (45.3% women, median age 65 years) and received at least one dose of study treatment. At a median follow-up time of 23.4 months (95% CI: 21.1 to 26.0), the 1-year OS rate was 61.8% (90% CI: 50.7% to 72.8%; p=0.04), with a median OS of 12.9 months (95% CI: 11.6 to 17.5). Median progression-free survival was 6.2 months (95% CI: 5.4 to 6.6) and objective response rate was 83.3% (95% CI: 69.8% to 92.5%). Grade 3–4 adverse events were reported in 34 patients (64.2%) leading to dose reductions in 24 (45.3%), and dose delays in 39 (73.9%) and 32 (69.6%) during the induction and maintenance phase, respectively. 19 (35.8%) treatment-related serious adverse events were reported. Conclusion The CeLEBrATE study met its primary objective demonstrating a signal of efficacy of bevacizumab, atezolizumab, carboplatin, and etoposide in the first-line treatment of patients with ES-SCLC. Trial registration number GOIRC-01–2019 ML41241, Eudract Number: 2019-003798-2.

Primary hyperparathyroidism (pHPT) occurs as hereditary disease in approximately 10% of cases. GCM2 germline mutations have been recently described as responsible for the development of a novel variant of hereditary pHPT. This study aimed to determine the features of GCM2 -related pHPT. Demographics, laboratory, and surgical data were assessed in a series of 17 index cases carrying GCM2 mutations undergoing surgery for pHPT. The GCM2 germline pathogenic variant c.1181 A>C p.(Tyr394Ser) was detected in 59% of cases. GCM2 -related pHPT was diagnosed at a median age of 57 years (range 32–82) with a Female/Male ratio 1.8. Preoperative median calcemia was 2.89 mmol/L (range 2.69–3.8). Family history of pHPT was absent in 65% of cases. Complete clinical, surgical and follow-up data were available for 13 patients. At initial surgery, bilateral neck exploration with subtotal parathyroidectomy was performed in 46% of patients; achieving cure in all cases at a median follow-up of 51 months (range 7–60). In the remaining cases undergoing selective parathyroidectomy, a persistent pHPT occurred in 3 cases; recurrent pHPT in 1 patient (after a disease-free interval of 4 years) while 3 are disease free at a mean follow-up of 21 months. Thus, at an overall prolonged follow-up (median 48 months, range 7–216), multiglandular involvement occurred in 77% of cases. GCM2 germline mutations may cause hereditary pHPT, even if it may mimic sporadic variant due to the absence of familial history and late onset. The main feature is multiglandular involvement, needing bilateral neck exploration and subtotal parathyroidectomy to achieve long-term cure.

Purpose Schizophrenia (SCZ) is a severe psychiatric disorder marked by abnormal dopamine synthesis, measurable through [ ¹⁸ F]FDOPA PET imaging. This imaging technique has been proposed as a biomarker for treatment stratification in SCZ, where one-third of patients respond poorly to standard antipsychotics. This study explores the use of radiomics on [ ¹⁸ F]FDOPA PET data to examine dopamine synthesis in SCZ and predict antipsychotic response. Methods We analysed 273 [ ¹⁸ F]FDOPA PET scans from healthy controls ( n = 138) and SCZ patients ( n = 135) from multiple cohorts, including first-episode psychosis cases. Radiomic features from striatal regions were extracted using the MIRP Python package. Reproducibility was assessed with test–retest scans, selecting features with an intraclass correlation coefficient (ICC) > 0.80. These features were grouped via hierarchical clustering based on Spearman correlation. Regression analysis evaluated sex and age effects on radiomic features. Predictive power for treatment response was tested and compared to standard imaging analysis obtained from the Standardised Uptake Value ratio (SUVr) of striatal over cerebellar tracer activity. Results Out of 177 features, 15 met the ICC criteria (ICC: 0.81–0.99). Age and sex influenced features in patients but not in controls. The best performance were was by the GLCM joint maximum feature, which effectively differentiated responders from non-responders (AUC: 0.66–0.87), but did not reach statistical significance in classification over SUVr. Conclusion Radiomic analysis of [ ¹⁸ F]FDOPA PET supports its use as a biomarker for assessing antipsychotic efficacy in schizophrenia, highlighting differential striatal tracer uptake based on patient response. While it provides modest classification improvements over standard imaging, further validation in larger datasets and integration with multivariate classification algorithms are needed.

Background The higher rate of pathological complete response (pCR) after neoadjuvant chemoradiotherapy (NACRT) is an argument to support this treatment. However, previous studies have not demonstrated a survival benefit of NACRT for adenocarcinoma (ADC) compared with neoadjuvant chemotherapy (NACT) and the correlation between pathological tumor response (pTR) and survival is unclear. We aimed to verify whether the prognostic value of pTRis influenced by the type of neoadjuvant treatment performed. Methods Patients with ADC who underwent NACT or NACRT and surgery between 2015 and 2020 were included. The correlation between pTR and overall survival (OS) and disease-free survival (DFS) after both treatments was evaluated by using Kaplan-Meier analysis. pTR was assessed by using the Mandard tumor regression grade (TRG). Results Overall, 563 patients were included; 278 received NACT, and 285 NACRT. The incidence of pCR was significantly higher after NACRT (24.6% vs. 11.2%, p < 0.0001). The TRG of both node-negative (pN0) and node-positive (pN+) patients significantly correlated with the 5 years OS after NACT (pN0 p = 0.03, pN+ p = 0.01). The same result was not detected in NACRT patients (pN0 p = 0.98, pN+ p = 0.23). The 5-year DFS of the patients with pCR was higher in the NACT group (84% vs. 66.5%, p = 0.05). The proportion of patients showing distant recurrences was significantly higher in the NACRT group (35.4% vs. 23.8%, p = 0.009). Conclusions Tumor regression grade was significantly associated with survival after NACT, but not with NACRT. Despite a lower rate of pCR, both OS and, especially, DFS of patients with pCR improved after NACT compared with NACRT.

Circulating melanoma cells (CMCs) are responsible for the hematogenous spread of melanoma and, ultimately, metastasis. However, their study has been limited by the low abundance in patient blood and the heterogeneous expression of surface markers. The FDA-approved CellSearch platform enriches CD146-positive CMCs, whose number correlates with progression-free survival and overall survival. However, a single marker may not be sufficient to identify them all. The Parsortix system allows enrichment of CMCs based on their size and deformability, keeping them viable and suitable for downstream molecular analyses. In this study, we tested the strengths, weaknesses and potential convergences of both platforms to integrate the counting of CMCs with a protocol for their genetic analysis. Samples run on Parsortix were labeled with a customized melanoma antibody cocktail, which efficiently labeled and distinguished CMCs from endothelial cells/leukocytes. The capture rate of CellSearch and Parsortix was comparable for cell lines, but Parsortix had a higher capture rate in real-life samples. Moreover, double enrichment with both CellSearch and Parsortix succeeded in removing most of the leukocyte contamination, resulting in an almost pure CMC sample suitable for genetic analysis. In this regard, a proof-of-concept analysis of CMCs from a paradigmatic case of a metastatic uveal melanoma patient led to the identification of multiple genetic alterations. In particular, the GNAQ p.Q209L was identified as homozygous, while a deletion in BAP1 exon 9 was found hemizygous. Moreover, an isochromosome 8 and a homozygous deletion of the CDKN2A gene were detected. In conclusion, we have optimized an approach to successfully enrich and retrieve viable CMCs from metastatic melanoma patients. Moreover, this study provides proof-of-principle for the feasibility of a marker-agnostic CMC enrichment followed by CMC phenotypic identification and genetic analysis.Kindly check and confirm the processed contributed equally is correctly identify We confirm Supplementary Information The online version contains supplementary material available at 10.1038/s41598-025-99153-y.

This Policy Review summarises an expert Delphi consensus process on larynx-preservation treatments in patients affected by intermediate-to-advanced laryngeal or hypopharyngeal squamous cell carcinoma. The experts, who represented all perspectives involved in multidisciplinary management of these patients and included patient representatives, approved 137 consensus statements that cover several relevant areas in the field of larynx-preserving treatments. Statements are grouped in the following topics: granular indications for T2–T3 cancer, indications for T4a cancer, indications for salvage organ-preservation surgery after chemoradiation failure, laryngeal function at baseline, which comorbidities are contraindications and to what extent, organ preservation in older patients: selection criteria, post-treatment surveillance, prognostic and predictive factors, listening to the patient's preferences: tools and implementation, prehabilitation and rehabilitation protocols, and cost-effectiveness of different laryngeal preservation approaches. We present a high-level summary of the results of the consensus process, with detailed reference to the full list of statements and supporting literature.

Introduction Data on the dynamics of HIV‐DNA and immune profiles under treatment with long‐acting cabotegravir and rilpivirine (LACR) are limited. Methods We prospectively enrolled people living with HIV who initiated LACR in our centre and assessed changes in HIV‐DNA levels (measured by digital droplet PCR), as well as immune activated, senescent, exhausted, and regulatory T and B cells (analysed by flow cytometry), in peripheral blood mononuclear cells (PBMC) from baseline (T0) to 48 weeks of treatment (T5). Bivariate analyses, one‐way repeated measures ANOVA and mixed ANOVA were conducted to assess differences in characteristics and biomarker changes over time between individuals switching to LACR from a dual (Group A) or triple (Group B) antiretroviral regimen. Results A total of 71 persons were included (77.5% males, median age of 48 years). Overall, HIV‐DNA levels exhibited a slight non‐significant decrease, whereas activated CD8 cells decreased significantly (p < 0.001). Proportions of activated CD4 and regulatory T cells showed strong negative trends, but decreases did not reach statistical significance (p = 0.002 and 0.005). The dynamics of these markers within the two subgroups mirrored those of the entire cohort, with some differences. At baseline, Group A tended to exhibit higher levels of HIV‐DNA (96 [31–160] vs. 41 [6–93] copies/10⁶ PBMC, p = 0.088), and activated CD4 (% activated CD4 cells: 2.3 [1–2.9] vs. 1 [0.7–2], p = 0.154) and CD8 cells (% activated CD8 cells: 4.9 [2.2–5.8] vs. 2.2 [1.2–3.5], p = 0.023) than Group B. Over the 48‐week treatment period, HIV‐DNA levels decreased slightly in both groups, remaining higher in Group A. At the end of the 48‐week treatment period, the decrease of activated CD4 and CD8 cells was more pronounced in Group A than in Group B, ultimately reaching comparable levels between the two groups (% of activated CD4 cells: 0.9 [0.6–1.9] vs. 0.7 [0.6–1.1], p = 0.502): % of CD8 activated cells: (2 [1.3–2.5] vs. 1.6 [0.9–2.2], p = 0.278). Conclusion During the first year of treatment, LACR does not significantly impact the HIV reservoir. However, it may reduce immune activation, particularly in persons switching from a dual therapy regimen.

If, as widely recognized in the scientific community, adolescent and young adult cancer patients are in many ways unique, then the spaces where they receive care should be equally special. The design of hospital environments that cater to the specific needs of young patients is a crucial factor in defining the essential features that care centers should ideally include to provide the best possible support for adolescent and young adult patients. This paper explores the growing importance of hospital design in fostering continuity in patients' lives, balancing both functionality and aesthetics. While healthcare systems face logistical and financial constraints, it is essential to recognize and promote the role of architecture, culture, and the arts as integral components of a holistic approach to care. Beauty in healthcare settings should not be considered a luxury, but rather a fundamental aspect of upholding the right to health.

Objective The Clinical Trials Regulation EU 536/2014 (CTR) has presented challenges for adapting experimental centres. To address this regulatory change, in 2023, the Italian Sarcoma Group (ISG) established a Federated Trial Centre (FTC) model, including Clinical Research Coordinators (CRCs) and Research Nurses (RNs). Methods To explore the CTR’s impact, a 40-question survey was launched in April 2023, distributed among 48 FTC members from 27 Italian institutions, with 30 responding. Results 46.6% of responders reported the progress of their institutions in adapting to the regulation, 70% had good knowledge of the updates, 60% confirmed staff training on the CTIS (Clinical Trials Information System). However, 63.3% noted that administrative personnel were not aligned with new contract deadlines, and only in 26.6% of cases institutions offered CTR-specific training. Additionally, 53.4% expressed concerns that the CTR does not support academic research. Conclusion The ISG’s FTC model was assessed as promoting collaboration between clinicians, staff, and CRCs to improve the management of academic studies and raise awareness within the sarcoma research community, by defining roles for CRCs and RNs and proposing collaborative projects and meetings.

Background and purpose Anti-claudin 18.2 (anti-CLDN18.2) therapy has been approved for patients with CLDN18-positive gastric and gastroesophageal junction adenocarcinomas. The current study aims at evaluating the expression of CLDN18 in a large cohort of pathologically characterized biliary tract cancers (BTCs). Materials and methods A series of 237 BTCs were collected and reviewed under the BITCOIN protocol. All samples were assessed for CLDN18 status using immunohistochemistry (clone 43-14A). Tumor positivity for CLDN18 was determined if ≥75% of tumor cells exhibited moderate-to-strong membranous staining. Results CLDN18 expression was found in 29.5% of BTCs (70/237), with the highest rates in gallbladder carcinoma (GBC; 62.5%; 20/32) and extrahepatic cholangiocarcinoma (eCCA; 53.4%; 31/58), compared with intrahepatic cholangiocarcinoma (iCCA; 12.9%; 19/147) (P < 0.0001). CLDN18 positivity was detected in 5.5% of cases (13/237), most common in GBC (15.6%; 5/32), followed by eCCAs (8.6%; 5/58) and iCCAs (2.0%; 3/147) (P = 0.0045). Most CLDN18-positive samples (10/13) exhibited a heterogenous staining pattern. In iCCAs, large duct subtypes had higher CLDN18 expression [33.3% (10/30) versus 7.7% (9/117), P = 0.0002] and positivity [6.7% (2/30) versus 0.9% (1/117), P = 0.106] than small duct iCCAs. No significant differences were observed across GBC and eCCA histotypes, and CLDN18 was not associated with IDH1 or FGFR2 status in iCCAs. Conclusions This study demonstrates that CLDN18 expression is present in a subset of BTCs, with significantly higher positivity rates in GBCs and eCCAs compared with iCCAs. In iCCAs, CLDN18 expression was more frequent in the large duct subtype but was not associated with IDH1 or FGFR2 status. These findings suggest that CLDN18 could be a potential therapeutic target in BTCs, warranting further prospective studies to evaluate its clinical significance and impact on patient outcomes.