Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori

Background Complete mesocolic excision refers to a radical right hemicolectomy for cancer following embryologically defined anatomical planes. However, heterogeneity in definitions and techniques is a barrier to research. The aim of the Radical Right Colectomy—Surgical Technique Approved Report (RRoC-STAR) collaborative is to provide international expert consensus-based definitions and standardized terminology and surgical steps for right hemicolectomy for locally advanced colon cancer. Methods Authors of publications reporting on radical right hemicolectomy techniques were invited to complete an ACCORD-compliant Delphi questionnaire (two rounds). A standardized name (for the procedure) and a data sheet for reporting the procedure were proposed, along with 21 items, including terminology and surgical steps. The assembled panel was asked to vote for each item, with consensus considered to have been reached for items that achieved at least 80% agreement. Results Of 162 invited authors, 67 completed both Delphi rounds. All but 1 of the 21 items received consensus after 2 rounds. Consensus was reached on the use of the proposed data sheet for reporting, the term radical right colectomy (RRC), and the surgical steps deemed necessary for RRC, namely preservation of mesocolic integrity, sharp dissection of the anterolateral surface of the superior mesenteric vein up to the middle colic vein, ligation at the origin of vessels, and dissection of lymphoadipose tissue around the gastrocolic trunk of Henle. Conclusion This study provides an international expert consensus-based definition and standardization of terminology and the surgical steps required to perform RRC. A comprehensive data sheet for reporting RRC is introduced to enable data homogenization from current and future studies.

This study investigates the chemopreventive potential of a grape pomace extract (GPE) derived from Verdicchio grapes, aligning with circular economy principles to repurpose winery waste into a nutraceutical targeting gastric cancer prevention. Soxhlet extraction yielded a bioactive‐rich extract. Comprehensive chemical characterization via HPLC/ESI/Q‐TOF identified 39 metabolites spanning key chemical classes. Anthocyanins were predominant, with malvidin glucoside (12,546 mg/kg DM; 36.3%), malvidin coumaroyl glucoside (9941 mg/kg DM; 28.8%), and malvidin acetylglucoside (7189 mg/kg DM; 20.8%) as the most abundant compounds. Carboxylic acids included tartaric, malic, isocitric, aconitic, and succinic acids, while lipid molecules, such as phytosphingosine and stearic acid, and amino acids like proline, valine, leucine, and phenylalanine further enriched the extract's chemical heterogeneity. Biological evaluations revealed GPE's selective cytotoxicity against AGS (IC50: 13.64 μg/mL) and KATO III (IC50: 7.11 μg/mL) gastric cancer cells, sparing GES‐1 cells. Mechanistically, GPE‐induced apoptosis through caspase‐3 activation and mitochondrial dysfunction, as evidenced by inner membrane disruption and cardiolipin peroxidation. TEM and CLSM morphological analyses revealed hallmark apoptotic features, including chromatin condensation, micronuclei formation, and apoptotic bodies. Additionally, GPE impaired autophagy, marked by Beclin‐1 downregulation and LC3B‐II upregulation. The accumulation of degradative vacuoles indicated disrupted autophagosome clearance, shifting autophagy from a survival mechanism to a cell death‐promoting pathway. These findings highlight GPE's dual impact on apoptosis and autophagy in gastric cancer cells, underscoring its potential as a dietary intervention for gastric cancer prevention.

Background The optimal first-line therapy for metastatic renal cell carcinoma (mRCC) remains uncertain, despite recent advancements in immune-based combinations. This retrospective study compares the effectiveness of pembrolizumab plus axitinib (PA) and nivolumab plus cabozantinib (NC) as first-line treatments for mRCC in a real-world setting. Methods Patient data were collected from 55 centers across 16 countries, encompassing individuals diagnosed with mRCC receiving first-line treatment with PA or NC between January 2016 and October 2023. Clinical and tumor features and treatment responses were recorded. The primary endpoints were overall response rate (ORR), overall survival (OS), progression-free survival (PFS), and time to second progression. Statistical analyses included Kaplan–Meier survival estimates, Cox proportional hazard models, and chi-square tests. Results A total of 760 patients with a median age of 64 years (range, 29–88) were included. Of them, 607 received PA, and only 153 NC. In the overall study population, ORR was 59% for and 49% for PA. Median OS was 55.7 months and not reached (NR) for PA and NC, respectively (P = .51), while median PFS was longer with NC (27.6 months) than for PA (16.2 months, P = .003). Subgroup analysis suggested a PFS benefits for NC in male, younger patients, intermediate risk group, clear cell histology, and lung involvement, as well as ORR favored NC in good risk patients. Multivariate analysis identified first-line therapy as a significant factor associated with PFS. Conclusions In this certainly biased retrospective comparison, NC demonstrated superior ORR and longer PFS compared to PA in mRCC. These findings underscore the importance of considering individual patient characteristics and risk profiles when selecting first-line therapy for mRCC.

Background Durvalumab after concurrent chemoradiotherapy (cCRT) is the standard of care for patients with unresectable, stage III non-small-cell lung cancer (NSCLC). However, patients often receive sequential chemoradiotherapy (sCRT) due to factors including advanced age or frailty, comorbidities, or disease- or access-related concerns. The phase II PACIFIC-6 trial (NCT03693300) evaluated the safety of durvalumab after sCRT in this setting. Interim results indicated a similar safety profile to that observed with durvalumab after cCRT, with encouraging preliminary efficacy. We report outcomes from the final analysis. Patients and methods Adults with unresectable, stage III NSCLC, Eastern Cooperative Oncology Group performance status ≤2, and no disease progression following platinum-based sCRT were enrolled to receive durvalumab 1500 mg intravenously once every 4 weeks for up to 24 months. The primary endpoint was the incidence of grade 3/4 adverse events (AEs) possibly related to treatment (PRAEs) occurring within 6 months. Secondary endpoints included overall survival (OS) and progression-free survival (PFS; investigator assessed as per RECIST v1.1). Results As of 20 March 2023, 117 patients (65.8% aged ≥65 years; 98.3% with past or present comorbidities) were enrolled. Overall, 27.4% of patients had grade 3/4 AEs and 6.0% had grade 3/4 PRAEs, including two patients (1.7%) with pneumonitis. Three patients (2.6%) had fatal AEs, with one (0.9%) having a fatal PRAE (pneumonitis). Overall, 27.4% discontinued durvalumab due to AEs. Median follow-up was 32.6 and 30.2 months among patients censored for OS and PFS, respectively. Median OS was 39.0 months [95% confidence interval (CI) 30.6 months-not calculable]; 3-year OS rate was 56.5% (95% CI 46.4% to 65.5%). Median PFS was 13.1 months (95% CI 7.4-19.9 months); 2-year PFS rate was 35.3% (95% CI 26.5% to 44.3%). Conclusions Durvalumab after sCRT was well tolerated and could be an alternative treatment strategy when cCRT is not feasible. Confirmatory randomized phase III data are awaited.

PET/CT (positron emission tomography and computed tomography) is an advanced imaging technique that combines the benefits of computed tomography (CT) and positron emission tomography (PET). CT provides detailed images of anatomical structure, while PET allows visualization of metabolic and functional activity in tissues, offering crucial information about the biochemical behavior of cells. This combination provides high-resolution images that integrate anatomical and functional data, making PET/CT particularly useful in the diagnosis and monitoring of oncological, cardiovascular, and neurological diseases. In oncology, for example, PET/CT is used to identify tumors, assess metastatic spread, monitor treatment response, and plan targeted therapies. PET uses radioisotopes that emit positrons through β+ decay. These positrons annihilate with electrons in the surrounding medium, producing two γ-rays of 511 keV emitted simultaneously in opposite directions. A series of time-coincident detectors around the patient determines their flight path. The process involves four key phases: positron emission, annihilation, γ-ray interaction with tissue, and detection. The PET acquisition system consists of ring detectors surrounding the patient, capturing γ-ray pairs emitted at a 180° angle. Modern PET systems use multiring detector arrays arranged in full rings with diameters of 80–90 cm. Tomographic imaging is achieved by recording lines of response (LORs) at various angles.

Purpose There is an urgent need of biomarkers to personalize metastatic castration-resistant prostate cancer (mCRPC) treatment. A new prognostic model described by our group combines molecular characteristics (ptDNA levels), metabolic features from PET-scans (metabolic tumor volume), clinical parameters (visceral metastases), and lab tests (lactate-dehydrogenase levels) in abiraterone or enzalutamide-treated patients. This study aims to validate the score on mCRPC patients undergoing taxane treatment. Patients and Methods Twenty-eight patients affected by mCRPC, pre-treated with abiraterone or enzalutamide, candidate for taxane-based treatments, have been prospectively evaluated. All patients underwent a basal PET/CT scan with F-choline and blood samples. The prognostic model previously described was applied to this population; based on the partial results of the parameters, we assigned the patients into three risk groups. Results In the 28 patients evaluated, we observed a different median OS among the three risk groups (risk group I, 18.1 months [95% CI: 15.2–33.1 months]; risk group II, 12.7 months [4.9–18.6 months]; and risk group III, 10.1 months [3.4–15.4 months]; p = 0.012). Statistically significant differences were also observed for PFS. Conclusion The prognostic score has confirmed to be a good prognostic tool also in a more advanced cohort of patients treated with taxanes. This tool may represent a valid method to refine prognostication and treatment selection in a cohort of patients where biomarkers are scarce.

Background Melanoma of the sole is an aggressive rare form, often diagnosed late. Plantar atypical nevi (pAN) are frequently misdiagnosed as plantar early melanomas (pEM) and therefore excised. Our aim was to develop a clinical‐dermoscopic risk‐scoring model to help discriminate these plantar atypical melanocytic lesions (pAMLs). Materials and Methods We collected 490 pAMLs (98 pEM, 392 pAN) paired with histopathological diagnosis, dermoscopic and clinical image, maximum lesion diameter, plantar location and age and sex of the patient from 17 European centres. This plantar dataset was grouped into training (261), validation (174) and testing (55 pAMLs) subsets. European participants (104 dermatologists, 56 residents) performed a blinded tele‐dermoscopic test, including intuitive diagnosis, pattern analysis, rating of case difficulty, diagnostic confidence assessment and management decision. Results A total of 2887 dermoscopic evaluations were obtained. The iDScore_plantar model gave an average area under the receiver operating characteristic curve of 0.95 (against 0.77 for pattern analysis). It was composed of the sum of five scores ( S ) for the following items: maximum diameter 8–12 ( S = 1)/>12 mm ( S = 5); age 40–50 ( S = 2 )/>50 years ( S = 5); location on heel ( S 4) or on toes/plantar eminence ( S = 2); asymmetry of colours ( S = 2) and/or asymmetry of structures ( S = 1). ‘Long/short follow‐up, biopsy, excision’ decisions were matched with four risk ranges: no risk ( S = 0–3), low‐medium risk ( S = 4–8), medium‐high risk ( S = 9–12) and very high risk ( S = 13–17). By applying the model, participants would have reduced the number of misdiagnosed pAN and the number of pAN excised by −25.5% and −27.7%, respectively, and would have increased the number of correctly diagnosed pEM by +18.5%, the number of pEM recommended for surgical excision by +8.5% and the number of pEM recommended directly for surgical excision instead of biopsy by +16.15%. Conclusion The iDScore_plantar model proved to be a simple scoring tool to help clinicians in assigning a progressive risk of malignancy to pAMLs.

Standard of care first‐line systemic treatment for advanced biliary tract cancer includes chemo‐immunotherapy with gemcitabine, cisplatin, and durvalumab, followed by maintenance durvalumab monotherapy. The present work aims to investigate the differences in baseline clinical and molecular characteristics between patients with early progression during chemo‐immunotherapy and those who reach durvalumab maintenance therapy. The study population included patients with unresectable, locally advanced, or metastatic BTC who received treatment at 38 clinical Institutions in 12 countries from July 2021 to December 2023. The primary objective of the study was to investigate whether baseline clinical and molecular characteristics differed between patients with early progression during chemo‐immunotherapy versus those reaching durvalumab maintenance therapy. Four hundred forty‐eight patients were included in this study. Two hundred twenty‐seven patients (50.7%) received maintenance with durvalumab monotherapy, whereas 221 (49.3%) did not receive maintenance therapy due to PD during first‐line chemo‐immunotherapy before completing 8 cycles. Results show that patients who received maintenance were more likely to be older (≥70 years), have an ECOG = 0, locally advanced disease, and a neutrophil‐to‐lymphocyte ratio (NLR) <3. A higher proportion of patients with BAP1 mutations received maintenance, while TP53 mutations were more common in those who progressed early. According to the present analysis, a substantial proportion of patients (50.7%) with advanced BTC who were treated with chemotherapy plus durvalumab proceeded to receive maintenance therapy with durvalumab monotherapy, with a median treatment duration of 4.4 cycles. Patients ≥70 years, with ECOG PS 0, with locally advanced disease, and with NLR <3 had a higher likelihood of receiving maintenance therapy.

Background Strict adherence to GMP guidelines and regulatory compliance is crucial when transitioning from research to clinical-grade production of ATMPs like CAR T cells. The success of CAR T cell therapy in treating hematological malignancies highlights the need for closed or automated systems to ensure quality and efficacy. Recent evidence also suggests that ex vivo culture conditions can significantly impact CAR T cell functionality. Methods We present our optimized methodology for expanding Sleeping Beauty transposon-engineered Chimeric Antigen Receptor-Cytokine-Induced Killer (CARCIK) cells using G-Rex devices and evaluate its impact on CARCIK cell phenotype and T cell fitness. Results Building on our previously validated protocol, we introduced key simplifications to optimize the CARCIK differentiation process. Delaying the nucleofection step eliminated the need for feeder cells while maintaining efficient CAR expression and high cell viability. Transitioning from T-flasks to G-Rex bioreactors reduced operator hands-on time from 21 to 28 days to 14–17 days and resulted in a less differentiated CARCIK cell product. Metabolic and transcriptional analyses showed that the novel protocol improves CARCIK cell fitness and in vivo efficacy against B-cell lymphoma. The novel method was validated in Good Manufacturing Practices (GMP) conditions at our two Cell Factories and yielded enough numbers of CARCIK-CD19 cells for clinical use. Conclusions Optimizing non-viral CARCIK cell production using G-Rex bioreactors and refined timing adjustments has streamlined the workflow, enhanced cell fitness, and resulted in a highly effective therapeutic product with demonstrated in vivo efficacy in mice. These improvements reduced manipulation and contamination risks, while optimizing logistics and space efficiency, facilitating allogeneic CARCIK generation for a current phase I/II clinical trial (NCT05869279) in patients with R/R CD19 + non-Hodgkin Lymphoma (B-cell NHL) and Chronic Lymphocytic Leukemia (CLL), confirming the approach’s scalability and clinical potential.

Background Circulating tumor DNA (ctDNA) acts as an early biomarker of the efficacy of androgen receptor signaling inhibitor (ARSI) therapy. In this study, we aimed to reveal if ctDNA can supplement imaging to better predict metastasis burden and radiographic progression disease (PD) in metastatic castration-resistant prostate cancer (mCRPC). Methods Targeted next-generation sequencing was performed to assess ctDNA fraction. Radiographic evidence was documented by conventional imaging according to Prostate Cancer Working Group 3 criteria. Results We prospectively collected plasma samples from 112 mCRPC with bone (n = 77), lymph nodal (n = 31), and visceral (n = 4) metastases. Only bone metastatic patterns were significantly associated with median ctDNA at baseline, during treatment and at PD (P <.0001). At first radiographic restaging, 24 (31.2%) men with a progressive worsening of bone disease had early ctDNA rise with a % ctDNA variation of 150.6% (interquartile range [IQR] = 104.9-210.7] compared with 11.1% (IQR = 0-36.6), P <.0001, in men with no change in bone disease. Univariate analysis showed that early ctDNA rise was significantly associated with progression free/overall survival (PFS/OS). In multivariable analysis including ctDNA change from baseline to 3-month treatment, variation of bone metastatic patterns (from oligometastatic to polymetastatic and/or to widespread disease), presence of visceral metastasis, age, PSA, performance status and prior docetaxel therapy, the transition from low- to high-ctDNA within 3 months of starting ARSI therapy was a significant predictor of OS (HR = 2.50, 90% CI, 1.06-5.88, P =.035) and persistent high level of ctDNA was a predictor of PFS (HR = 2.53, 95% CI, 1.10-5.81, P =.028). Metastatic involvement demonstrated that the transition from bone polymetastatic to widespread disease and the presence of visceral metastases were both associated with worse OS (HR = 2.43, 95% CI, 1.10-5.35, P =.028, and HR = 3.40, 95% CI, 1.50-7.66, P =.003, respectively). Prior therapy with docetaxel represented an independent predictor of both PFS and OS (HR = 2.47, 95% CI, 1.40-4.35, P =.002, and HR = 1.78, 95% CI, 1.00-3.15, P =.049, respectively). Conclusions Early ctDNA variation might reflect changes in metastatic burden and, likely, in bone metastatic patterns on ARSI therapy allowing to track pattern of disease progression and to predict outcome.

(1) Background: NRAS mutations affect fewer than 1% of lung adenocarcinomas. The aim of this study was to describe the clinicopathological features of lung carcinomas with NRAS mutations. (2) Methods: A series of NRAS-mutated lung carcinomas was collected from a molecular diagnostic unit (from four hospitals). The cases were analyzed with next-generation sequencing. A log-rank test for overall survival (OS) was calculated. (3) Results: NRAS mutations were detected in 14/1948 samples (0.72%) of non-small-cell lung carcinomas from 13 patients (8 males, 5 females). NRAS mutations involved codon 61 in the majority (9/13, 69.2%) of cases. The other NRAS mutations affected codon 12 (2/13, 15.4%), codon 13 (1/13, 7.7%), and codon 142 (1/13, 7.7%). In 7/13 cases, co-alterations in additional genes were also present. Pleomorphic/sarcomatoid features were identified in 3/13 (23.1%) cases, in 2/8 (25.0%) histological specimens, and in 2/5 (40.0%) surgical specimens, respectively. Follow-up data were available in 11/13 cases, with 6 patients deceased. By a log-rank test, patients with NRAS mutations in codon 61 had a better outcome (estimated mean of 32.6 ± 7.1 months) compared to those with other NRAS mutations (estimated mean of 8.7 ± 4.4 months), with a significant difference (p = 0.048 for OS). (4) Conclusions: Lung carcinomas with NRAS mutation may display pleomorphic or sarcomatoid features. Mutations in codon 61 showed a more favorable prognosis than those in other codons.

The advent of next-generation antibody-drug conjugates (ADCs), particularly trastuzumab deruxtecan (T-DXd), has transformed our understanding of human epidermal growth factor receptor 2 (HER2) targetability for breast cancer (BC) treatment. Historically categorized as HER2-positive or HER2-negative on the basis of trastuzumab eligibility, this classification has evolved significantly over the past 5 years. The DESTINY-Breast04 trial marked the entry of anti-HER2 therapies for patients with HER2-low BC, while DESTINY-Breast06 demonstrated the potential for earlier and broader use of T-DXd. The latter trial revealed that even minimal HER2 expression in tumors previously classified as HER2-0 might be clinically relevant and targetable with T-DXd. This has led to further refinement of HER2 classification, introducing the concepts of HER2-ultralow (HER2-0 with staining) and HER2-null BC (HER2-0 without staining). With these findings, most patients with metastatic BC are currently considered eligible for T-DXd. Accurately identifying candidates for these therapies has highlighted the limitations of current HER2 diagnostic practices, on the basis of immunohistochemistry (IHC)/in situ hybridization assessment. IHC assay, optimized to detect high levels of HER2 protein, faces limitations in discriminating finer variations at the lower end of the HER2 expression spectrum. This is further complicated by the heterogeneity of HER2 expression. To overcome these barriers, new approaches may be required. Quantitative methods for HER2 membrane assessment, genomic and transcriptomic evaluations of HER2, and the integration of artificial intelligence into tissue analysis hold promise and are currently under investigation. Additionally, noninvasive strategies, such as analysis of circulating tumor DNA or circulating tumor cells, may enable real-time HER2 status assessment and better patient selection for ADC. However, these techniques require rigorous validation to ensure their clinical utility. This evolving landscape underscores the need for improvement of diagnostic approaches to support the expanding role of ADCs in BC treatment.