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Levels of mineral oil hydrocarbons were measured in a large range of green and roasted coffee beans or ground powder. To better understand the consumer exposure to mineral oil hydrocarbons, the transfer to the brewed coffee was assessed under three different preparations. As a result, less than 5% of mineral oil hydrocarbons were transferred to the cup. With this low transfer rate, the coffee contribution to the mineral oils daily intake can be assessed to be very low, below 0.8% of the total exposure.

Small-cell lung cancer (SCLC), accounting for 10-20 % of all lung tumors, represents the most aggressive high-grade neuroendocrine carcinoma. Most patients are diagnosed with extensive-stage SCLC (ES-SCLC), with brian metastases identified in ∼ 80 % of cases during the disease cours, and the prognosis is dismal, with a 5-year survival rate of less than 5 %. Current available treatments in the second-line setting are limited, and topotecan has long been the only FDA-approved drug in relapsed or refractory ES-SCLC, until the recent approval of lurbinectedin, a selective inhibitor of RNA polymerase II. Temozolomide (TMZ) is an oral alkylating agent, which showed single-agent activity in SCLC, particularly among patients with O 6 -methylguanine-DNA methyltransferase (MGMT) promoter methylation. Several studies have revealed the synergistic activity of temozolomide with poly-ADP-ribose polymerase (PARP) inhibitors, that prevent repair of TMZ-induced DNA damage. This review focuses on the rationale for the use of TMZ in ES-SCLC and provides an overview of the main trials that have evaluated and are currently investigating its role, both as a single-agent and in combinations, in relapse or refractory disease., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Activating point mutations in the MET tyrosine kinase domain (TKD) are oncogenic in a subset of papillary renal cell carcinomas. Here, using comprehensive genomic profiling among >600,000 patients, we identify activating MET TKD point mutations as putative oncogenic driver across diverse cancers, with a frequency of ∼0.5%. The most common mutations in the MET TKD defined as oncogenic or likely oncogenic according to OncoKB resulted in amino acid substitutions at positions H1094, L1195, F1200, D1228, Y1230, M1250, and others. Preclinical modeling of these alterations confirmed their oncogenic potential and also demonstrated differential patterns of sensitivity to type I and type II MET inhibitors. Two patients with metastatic lung adenocarcinoma harboring MET TKD mutations (H1094Y, F1200I) and no other known oncogenic drivers achieved confirmed partial responses to a type I MET inhibitor. Activating MET TKD mutations occur in multiple malignancies and may confer clinical sensitivity to currently available MET inhibitors. Significance: The identification of targetable genomic subsets of cancer has revolutionized precision oncology and offers patients treatments with more selective and effective agents. Here, we demonstrate that activating, oncogenic MET tyrosine kinase domain mutations are found across a diversity of cancer types and are responsive to MET tyrosine kinase inhibitors., (©2024 The Authors; Published by the American Association for Cancer Research.)

Older patients have similar immune checkpoint inhibitor efficacy and rates of adverse events as younger patients, but appear to have decreased tolerability, particularly in the oldest patient cohort (>80 years), often leading to early cessation of therapy. We aimed to determine whether early discontinuation impacts efficacy of anti-PD-1 therapy in patients ≥80 years old. In this retrospective, multicenter, international cohort study, we examined 773 patients with 4 tumor types who were at least 80 years old and treated with anti-PD-1 therapy. We determined response rate, overall survival (OS), and progression-free survival (PFS) in patients who discontinued therapy early (<12 months) for reasons other than progression or death. We used descriptive statistics for demographics, response, and toxicity rates. Survival statistics were described using Kaplan Meier curves. Median (range) age at anti-PD-1 initiation was 83.0 (75.8-97.0) years. The cancer types included were melanoma (n = 286), non-small cell lung cancer (NSCLC) (n = 345), urothelial cell carcinoma (UCC) (n = 108), and renal cell carcinoma (RCC) (n = 34). Of these, 102 met the primary endpoint of <12 months to discontinuation for reasons other than death or progression. Median PFS and OS, respectively, for these patients were 34.4 months and 46.6 months for melanoma, 15.8 months and 23.4 months for NSCLC, and 10.4 months and 15.8 months for UCC. This study suggests geriatric patients who have demonstrated therapeutic benefit and discontinued anti-PD-1 therapy at less than 12 months of duration for reasons other than progression may have durable clinical benefit without additional therapy., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Alessio Cortellini declares grants for consultancies/advisory boards from MSD, OncoC4, IQVIA, AstraZeneca, Access Infinity, Ardelis-Health, Alpha Sight, Roche, REGENERON; speaker fees from AstraZeneca, Eisai, Pierre-Fabre, MSD, Sanofi/REGENERON; writing/editorial activity from BMS, MSD; travel support from Sanofi, MSD. Anwaar Saaed reports research grants (to institution) from AstraZeneca, Bristol-Myers Squibb, Merck, Clovis, Exelixis, Actuate therapeutics, Incyte Corporation, Daiichi Sankyo, Five prime therapeutics, Amgen, Innovent biologics, Dragonfly therapeutics, Oxford biotherapeutics, KAHR medical, Biontech, and advisory board/consulting fees from AstraZeneca, Bristol-Myers Squibb, Merck, Xilio therapeutics, Arcus therapeutics, Exelixis, Pfizer, and Daiichi Sankyo. Akiva Diamond served on an Advisory Board for Incyte. Christopher Hoimes has served on advisory boards or as a consultant for BMS, Merck, Seagen. Amin H. Nassar receives honoraria from OncLive, TEMPUS, and Korean Society for Medical Oncology and received consulting fees from Guidepoint Global. Dwight Owen discloses research funding (to institution) from BMS, Merck, Genentech, Palobiofarma, and Onc.AI. Toni Choueiri reports institutional and/or personal, paid and/or unpaid support for research, advisory boards, consultancy, and/or honoraria past 5 years, ongoing or not, from: Alkermes, AstraZeneca, Aravive, Aveo, Bayer, Bristol Myers-Squibb, Calithera, Circle Pharma, Deciphera Pharmaceuticals, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, Gilead, HiberCell, IQVA, Infinity, Ipsen, Jansen, Kanaph, Lilly, Merck, Nikang, Nuscan, Novartis, Oncohost, Pfizer, Roche, Sanofi/Aventis, Scholar Rock, Surface Oncology, Takeda, Tempest, Up-To-Date, CME events (Peerview, OncLive, MJH, CCO and others), outside the submitted work. TC also reports institutional patents filed on molecular alterations and immunotherapy response/toxicity, and ctDNA; equity: Tempest, Pionyr, Osel, Precede Bio, CureResponse, InnDura Therapeutics, Primium; committees: NCCN, GU Steering Committee, ASCO/ESMO, ACCRU, KidneyCan; medical writing and editorial assistance support may have been funded by Communications companies in part; no speaker's bureau. TC entored several non-US citizens on research projects with potential funding (in part) from non-US sources/Foreign Components. The institution of TC (Dana-Farber Cancer Institute) may have received additional independent funding of drug companies or/and royalties potentially involved in research around the subject matter. David J Pinato declares the following competing interests: Lecture fees: Bayer Healthcare, Astra Zeneca, EISAI, Bristol Myers-Squibb, Roche, Ipsen; Travel expenses: Bristol Myers-Squibb, Roche, Bayer Healthcare; Consulting fees: Mina Therapeutics, Boeringer Ingelheim, Ewopharma, EISAI, Ipsen, Roche, H3B, Astra Zeneca, DaVolterra, Mursla, Starpharma, Avammune Therapeutics, LiFT Biosciences, Exact Sciences; Research funding (to institution): MSD, BMS, GSK. Thomas Marron currently or has previously served on Advisory and/or Data Safety Monitoring Boards for Rockefeller University, Regeneron, AbbVie, Merck, Bristol-Meyers Squibb, Boehringer Ingelheim, Atara, AstraZeneca, Genentech, Celldex, Chimeric, DrenBio, Glenmark, Simcere, Surface, G1 Therapeutics, NGMbio, DBV Technologies, Arcus, Fate, Ono, Larkspur, and Astellas. Abdul Rafeh Naqash receives funding for trials he is PI on: Loxo@Lilly, Surface Oncology, ADC Therapeutics, IGM Biosciences, EMD Serono, Aravive, Nikang Therapeutics, Inspirna, Exelexis, Revolution Medicine, Jacobio, Pionyr, Jazz Pharmaceuticals, and NGM Biopharmaceuticals. ARN also received Consultant Editor Compensation from JCO Precision Oncology, Travel Compensation from: SITC/AACR/Conquer Cancer Foundation/BinayTara Foundation and Foundation Med, Caris Life Sciences, and serves on the Advisory Board for Foundation Med. Douglas Johnson has served on advisory boards or as a consultant for BMS, Mallinckrodt, Merck, Mosaic ImmunoEngineering, Novartis, Oncosec, Pfizer, Targovax, and Teiko, and has received research funding from BMS and Incyte., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Image reconstruction is crucial for improving overall image quality and diagnostic accuracy. Q.Clear is a novel reconstruction algorithm that reduces image noise. The aim of the present study is to assess the preferred Q.Clear β-level for digital [ 68 Ga]Ga-DOTANOC PET/CT reconstruction vs. standard reconstruction (STD) for both overall scan and single-lesion visualization. Methods: Inclusion criteria: (1) patients with/suspected neuroendocrine tumors included in a prospective observational monocentric study between September 2019 and January 2022; (2) [ 68 Ga]Ga-DOTANOC digital PET/CT and contrast-enhanced-CT (ceCT) performed at our center at the same time. Images were reconstructed with STD and with Q.Clear β-levels 800, 1000, and 1600. Scans were blindly reviewed by three nuclear-medicine experts: the preferred β-level reconstruction was independently chosen for the visual quality of both the overall scan and the most avid target lesion < 1 cm (t) and >1 cm (T). PET/CT results were compared to ceCT. Semiquantitative analysis was performed (STD vs. β1600) in T and t concordant at both PET/CT and ceCT. Subgroup analysis was also performed in patients presenting discordant t. Results : Overall, 52 patients were included. β1600 reconstruction was considered superior over the others for both overall scan quality and single-lesion detection in all cases. The only significantly different ( p < 0.001) parameters between β1600 and STD were signal-to-noise liver ratio and standard deviation of the liver background. Lesion-dependent parameters were not significantly different in concordant T ( n = 37) and t ( n = 10). Among 26 discordant t, when PET was positive, all findings were confirmed as malignant. Conclusions : β1600 Q.Clear reconstruction for [ 68 Ga]Ga-DOTANOC imaging is feasible and improves image quality for both overall and small-lesion assessment.

Introduction: Cancer is a leading cause of morbidity and mortality worldwide, and coordinated research efforts are vital to improve global outcomes. Clinical or translational research is usually planned, coordinated and executed by clinical researchers. With this survey we aimed to identify the main hurdles in front of young clinical investigators in oncology., Methods and Materials: An anonymized survey was distributed using social media between April and November 2022. Target population were health-care professionals in the field of oncology - physicians, nurses and researchers. We divided participants according to working experience (<40 vs. >40 years of age) and country of practice (Europeans vs. non-Europeans)., Results: We received 121 responses from participants practicing in 36 countries. Eighty-seven (72%) of the participants were under 40 years. Eighty-nine (74%) were from European countries and thirty-two (26%) were from non-European. Experienced and European professionals were more likely to be involved in all different aspects of clinical trials. The main source of funding - independently of geographic location - were industry grants. Investigators out of Europe have less participation in international grants. Over 50% of participants dedicate time for clinical research from their personal time and are not paid for it. Almost 50% of investigators don't have access to an experienced mentor in their institution., Conclusion: The majority of respondents to our survey are active clinical researchers. Our data indicate that access to education and training as well as possibilities for appropriate networking, and specifically lack of mentorship, are key limiting factors in developing clinical research by healthcare professionals., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 Published by Elsevier Ltd.)

Introduction: Although antibiotic prophylaxis (AB) demonstrated a statistically significant reduction in bacteriuria after invasive urodynamics (UDS), no significant decrease in the incidence of urinary tract infections (UTI) has been confirmed. No absolute recommendations on the use of AB in case of relevant potential risk of UTI have been reported, though some categories of patients at increased infective probability after UDS have been recognized. The aim of this study is to report the experts' consensus on the best practice for the use of AB before UDS in the main categories of patients at potential risk of developing UTI., Materials and Methods: A systematic literature review was performed on AB before UDS in males and females. A panel of experts from the Italian Society of Urodynamics, Continence, Neuro-Urology, and Pelvic Floor (SIUD) assessed the review data and decided by a modified Delphi method on 16 statements proposed and discussed by the panel. The cut-off percentage for the consensus was a ≥70% of positive responses to the survey. The study was a Delphi consensus with experts' opinions, not a clinical trial involving directly patients., Results: The panel group was composed of 57 experts in functional urology and UDS, mainly urologists, likewise gynaecologists, physiatrists, infectivologists, pediatric urologists, and nurses. A positive consensus was achieved on 9/16 (56.25%) of the statements, especially on the need for performing AB before UD in patients with neurogenic bladder and immunosuppression. Urine analysis and urine culture before UDS are mandatory, and in the event of their positivity, UDS should be postponed. A consensus was reached on avoiding AB in menopausal status, diabetes, age, gender, bladder outlet obstruction, high postvoid residual, chronic catheterization, previous urological surgery, lack of urological abnormalities, pelvic organ prolapse, and negative urine analysis., Conclusions: Antibiotic prophylaxis is not recommended for patients without notable risk factors and with a negative urine test due to the potential morbidities that may result from antibiotic administration. However, AB can be used for risk categories such as neurogenic bladder and immunosuppression. The evaluation of urine analysis and urine culture and postponing UDS in cases of positive tests were considered good practices, as well as performing AB in the neurogenic bladder and immunosuppression., (© 2024 Wiley Periodicals LLC.)

Introduction: Responses to first-line programmed cell death protein 1 inhibition vary among patients with metastatic NSCLC and a programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) greater than or equal to 50%. We previously reported improved clinical outcomes to first-line programmed cell death protein 1 inhibition in patients with metastatic NSCLC with a PD-L1 TPS of greater than or equal to 90% versus 50% to 89% in a pilot study. Here, we report the three-year survival with first-line pembrolizumab and cemiplimab in two large independent cohorts of patients with PD-L1 TPS greater than or equal to 90% versus 50% to 89% and characterize genomic and immunophenotypic differences between these PD-L1 expression groups, which were largely unknown., Methods: We analyzed three-year outcomes of the following two independent cohorts: (1) a multicenter cohort of patients from four academic centers in the United States treated with pembrolizumab and (2) EMPOWER-Lung 1, randomized, phase III trial comparing first-line cemiplimab with chemotherapy. Tumor genomic profiling and multiplexed immunofluorescence were performed to evaluate genomic and immunophenotypic correlates of very high PD-L1 expression., Results: At three years of follow-up, progression-free survival (hazard ratio [HR], 0.69; p < 0.001) and overall survival (HR, 0.70; p < 0.01) to first-line commercial pembrolizumab were significantly improved in patients with a PD-L1 TPS greater than or equal to 90% versus 50% to 89%. In the EMPOWER-Lung 1, patients assigned to the cemiplimab arm with a PD-L1 TPS greater than or equal to 90% also had significant improvements in progression-free survival (HR, 0.53; p < 0.0001) and overall survival (HR, 0.63; p  = 0.007) compared with those with a PD-L1 of 50% to 89%. Tumor genomic profiling of 553 NSCLC samples revealed that mutations in STK11 and SMARCA4 were significantly more frequent in tumors with a PD-L1 TPS of 50% to 89% compared with those with a PD-L1 TPS greater than or equal to 90% (Q < 0.15), whereas BRCA2 was enriched in NSCLC samples with a PD-L1 TPS greater than or equal to 90% (Q < 0.15). Multiplexed immunofluorescence on 93 NSCLC samples identified higher intratumoral CD8 + PD1 + T cells ( p  = 0.02) in tumors with PD-L1 TPS greater than or equal to 90% versus 50% to 89%., Conclusion: Pembrolizumab and cemiplimab were found to have long-term survival benefit and favorable genomic and immunophenotypic profile in patients with advanced NSCLC with PD-L1 TPS greater than or equal to 90% compared with TPS 50% to 89%., Competing Interests: Dr. Ricciuti reports serving on the consulting/advisory board of AstraZeneca, Amgen, and Regeneron; receiving honoraria from Targeted Oncology; and receiving speaker fees from AstraZeneca. Dr. Lin reports receiving consulting from Genentech, C4 Therapeutics, Blueprint Medicines, Nuvalent, Bayer, Elevation Oncology, Novartis, Mirati Therapeutics, Regeneron, Pfizer, Takeda, Ellipses Pharma, Hyku BioSciences, AnHeart Therapeutics, Claim Therapeutics, Turning Point Therapeutics, Bristol-Myers Squibb, and Daiichi Sankyo; receiving institutional research funding from Hengrui Therapeutics, Turning Point Therapeutics, Neon Therapeutics, 10.13039/100019393Relay Therapeutics, 10.13039/100004326Bayer, Elevation Oncology, 10.13039/100004337Roche, Linnaeus Therapeutics, Nuvalent, and 10.13039/100004336Novartis. Dr. Altan reports receiving research funding (to institution) from Genentech, Nektar Therapeutics, Merck, GlaxoSmithKline, Novartis, Jounce Therapeutics, Bristol-Myers Squibb, Eli Lilly, Adaptimmune, Shattuck Lab, and Gilead; serving on the advisory board of GlaxoSmithKline, Shattuck Lab, Bristol-Myers Squibb, AstraZeneca, and Insightec; receiving speaker fees from AstraZeneca, Nektar Therapeutics, and SITC; and having participation of safety review committee for Nanobiotix-MDA Alliance and Hengenix. Dr. Zhang reports receiving grants from 10.13039/100004334Merck; grants and personal fees from Johnson and Johnson and Novartis; and personal fees from Bristol-Myers Squibb, AstraZeneca, GenePlus, Innovent, Varian, Catalyst, and Hengrui, outside the submitted work. Dr. Gainor has served as a compensated consultant or received honoraria from Bristol-Myers Squibb, Genentech/Roche, Takeda, Loxo/Lilly, Blueprint Medicine, Gilead, Moderna, AstraZeneca, Mariana Therapeutics, Mirati, Jounce, Merus Pharmaceuticals, Nuvalent, Pfizer, Novocure, AI Proteins, Novartis, Merck, iTeos, Karyopharm, and Silverback Therapeutics; has received research support from 10.13039/100004336Novartis, Genentech/Roche, and Takeda; has received institutional research support from 10.13039/100002491Bristol-Myers Squibb, Palleon, Tesaro, 10.13039/100019533Moderna, Blueprint, Jounce, 10.13039/100007174Array Biopharma, Merck, Adaptimmune, Novartis, and Alexo; has equity in AI Proteins; and has an immediate family member who is an employee with equity at Ironwood Pharmaceuticals. Dr. Heymach reports serving on the advisory committees of Genentech, Mirati Therapeutics, Eli Lilly & Co., Janssen Pharmaceuticals, Boehringer-Ingelheim Pharmaceuticals, Regeneron, Takeda Pharmaceuticals, BerGenBio, Jazz Pharmaceuticals, Curio Science, Novartis, AstraZeneca Pharmaceuticals, BioAlta, Sanofi, Spectrum Pharmaceuticals, GlaxoSmithKline, EMD Serono, BluePrint Medicine, and Chugai Pharmaceutical; receiving research support from 10.13039/100004325AstraZeneca, Boehringer-Ingelheim, 10.13039/100006399Spectrum, Mirati, Bristol-Myers Squibb, and Takeda; and receiving licensing/royalties from Spectrum. Dr. Pouliot reports being an employee at Regeneron and a Regeneron shareholder. Dr. McIntyre reports being an employee at Regeneron. Dr. Awad reports receiving research funding from Bristol-Myers Squibb, Lilly, 10.13039/100004328Genentech, AstraZeneca, and Elva J. and Clayton L. McLaughlin Fund for Lung Cancer Research; receiving consulting fees from/serving on the advisory board of Merck, Bristol-Myers Squibb, Genentech, AstraZeneca, Nektar, Maverick, Blueprint Medicine, Syndax, AbbVie, Gritstone, ArcherDX, Mirati, NextCure, and EMD Serono. Dr. Rietschel reports being an employee at Regeneron and a Regeneron shareholder with patent issued PCT/US2018/018747. Dr. Nishino reports receiving research funding from Merck, Canon Medical Systems, AstraZeneca, and 10.13039/501100022274Daiichi Sankyo; receiving consulting fees from Daiichi Sankyo and AstraZeneca; and receiving honoraria from Roche. Dr. Sholl reports receiving consulting fee from Genentech, Lilly, and GV20 Therapeutics. The remaining authors have no conflict of interests to disclose., (© 2024 The Authors.)

Gastric neuroendocrine neoplasms (gNENs) display peculiar site-specific features among all NENs. Their incidence and prevalence have been rising in the past few decades. gNENs comprise gastric neuroendocrine carcinomas (gNECs) and gastric neuroendocrine tumours (gNETs), the latter further classified into three types. Type I anatype II gNETs are gastrin-dependent and develop in chronic atrophic gastritis and as part of Zollinger-Ellison syndrome within a multiple endocrine neoplasia type 1 syndrome (MEN1), respectively. Type III or sporadic gNETs develop in the absence of hypergastrinaemia and in the context of a near-normal or inflamed gastric mucosa. gNECs can also develop in the context of variable atrophic, relatively normal or inflamed gastric mucosa. Each gNEN type has different clinical characteristics and requires a different multidisciplinary approach in expert dedicated centres. Type I gNETs are managed mainly by endoscopy or surgery, whereas the treatment of type II gNETs largely depends on the management of the concomitant MEN1. Type III gNETs may require both locoregional approaches and systemic treatments; NECs are often metastatic and therefore require systemic treatment. Specific data regarding the systemic treatment of gNENs are lacking and are derived from the treatment of intestinal NETs and NECs. An enhanced understanding of molecular and clinical pathophysiology is needed to improve the management and outcomes of patients' gNETs., (© 2024. Springer Nature Limited.)

Purpose: Although immune checkpoint inhibitors (ICI) have extended survival in patients with non-small-cell lung cancer (NSCLC), acquired resistance (AR) to ICI frequently develops after an initial benefit. However, the mechanisms of AR to ICI in NSCLC are largely unknown., Methods: Comprehensive tumor genomic profiling, machine learning-based assessment of tumor-infiltrating lymphocytes, multiplexed immunofluorescence, and/or HLA-I immunohistochemistry (IHC) were performed on matched pre- and post-ICI tumor biopsies from patients with NSCLC treated with ICI at the Dana-Farber Cancer Institute who developed AR to ICI. Two additional cohorts of patients with intervening chemotherapy or targeted therapies between biopsies were included as controls., Results: We performed comprehensive genomic profiling and immunophenotypic characterization on samples from 82 patients with NSCLC and matched pre- and post-ICI biopsies and compared findings with a control cohort of patients with non-ICI intervening therapies between biopsies (chemotherapy, N = 32; targeted therapies, N = 89; both, N = 17). Putative resistance mutations were identified in 27.8% of immunotherapy-treated cases and included acquired loss-of-function mutations in STK11 , B2M , APC , MTOR , KEAP1 , and JAK1 / 2 ; these acquired alterations were not observed in the control groups. Immunophenotyping of matched pre- and post-ICI samples demonstrated significant decreases in intratumoral lymphocytes, CD3e + and CD8a + T cells, and PD-L1-PD1 engagement, as well as increased distance between tumor cells and CD8 + PD-1 + T cells. There was a significant decrease in HLA class I expression in the immunotherapy cohort at the time of AR compared with the chemotherapy ( P = .005) and the targeted therapy ( P = .01) cohorts., Conclusion: These findings highlight the genomic and immunophenotypic heterogeneity of ICI resistance in NSCLC, which will need to be considered when developing novel therapeutic strategies aimed at overcoming resistance.

Background: The optimal treatment sequencing for advanced, well-differentiated pancreatic neuroendocrine tumors (pNETs) is unknown. We performed a multicenter, retrospective study to evaluate the best treatment sequence in terms of progression-free survival to first-line (PFS1) and to second-line (PFS2), and overall survival among patients with advanced, well-differentiated pNETs. Methods : This multicenter study retrospectively analyzed the prospectively collected data of patients with sporadic well-differentiated pNETs who received at least two consecutive therapeutic lines, with evidence of radiological disease progression before change of treatment lines. Results : Among 201 patients, 40 (19.9%) had a grade 1 and 149 (74.1%) a grade 2 pNET. Primary tumor resection was performed in 98 patients (48.8%). First-line therapy was performed in 128 patients with somatostatin analogs (SSA), 35 received SSA + radioligand therapy (RLT), 21 temozolomide-based chemotherapy, and 17 SSA + targeted therapy. PFS was significantly longer in patients with grade 1 pNETs compared to those with grade 2, in patients who received primary tumor surgery, and in patients treated with RLT compared to other treatments. At multivariate analysis, the use of upfront RLT was independently associated with improved PFS compared to SSA. Second-line therapy was performed in 94 patients with SSA + targeted therapy, 35 received chemotherapy, 45 SSA + RLT, and 27 nonconventional-dose SSA or SSA switch. PFS was significantly longer in patients treated with RLT compared to other treatments. At multivariate analysis, the type of second-line therapy was independently associated with the risk for progression. OS was significantly longer in patients who received primary tumor surgery, with Ki67 < 10%, without extrahepatic disease, and in patients who received SSA-RLT sequence compared to other sequences. Conclusions : In this large, multicenter study, RLT was associated with better PFS compared to other treatments, and the SSA-RLT sequence was associated with the best survival outcomes in patients with pNETs with Ki67 < 10%. Primary tumor surgery was also associated with improved survival.

Neuroendocrine neoplasms (NENs) are rare tumors with diverse clinical behaviors. Large databases like the Surveillance, Epidemiology, and End Results (SEER) program and national NEN registries have provided significant epidemiological knowledge, but they have limitations given the recent advancements in NEN diagnostics and treatments. For instance, newer imaging techniques and therapies have revolutionized NEN management, rendering older data less representative. Additionally, crucial parameters, like the Ki67 index, are missing from many databases. Acknowledging these gaps, the Italian Association for Neuroendocrine Tumors (Itanet) initiated a national multicenter prospective database in 2019, aiming to gather data on newly-diagnosed gastroenteropancreatic neuroendocrine (GEP) NENs. This observational study, coordinated by Itanet, includes patients from 37 Italian centers. The database, which is rigorously maintained and updated, focuses on diverse parameters including age, diagnostic techniques, tumor stage, treatments, and survival metrics. As of October 2023, data from 1,600 patients have been recorded, with an anticipation of reaching 3600 by the end of 2025. This study aims at understanding the epidemiology, clinical attributes, and treatment strategies for GEP-NENs in Italy, and to introduce the Itanet database project. Once comprehensive follow-up data will be acquired, the goal will be to discern predictors of treatment outcomes and disease prognosis. The Itanet database will offer an unparalleled, updated perspective on GEP-NENs, addressing the limitations of older databases and aiding in optimizing patient care. STUDY REGISTRATION: This protocol was registered in clinicaltriasl.gov (NCT04282083)., (© 2024. The Author(s).)

Functional precision oncology-a strategy based on perturbing primary tumor cells from cancer patients-could provide a road forward for personalized treatment. Here, we present a comprehensive protocol covering generation and culture of patient-derived colorectal organoids, isolation and expansion of tumor-infiltrating lymphocytes (TILs), and isolation and culture of peripheral blood mononuclear cells (PBMCs). With this protocol, samples fulfilling the demands for performing multi-omics analysis, e.g., RNA sequencing (RNA-seq), whole-exome sequencing (WES), single-cell RNA sequencing (scRNA-seq), and (phospho-)proteomics, can be generated. For complete details on the use and execution of this protocol, please refer to Plattner et al. (2023). 1 ., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The recent introduction of novel treatments for advanced neuroendocrine tumors (NETs) and the well-established impact of clinical case discussion within dedicated multidisciplinary teams indicates the need to promote the centralization of rare diseases, such as NENs (neuroendocrine neoplasms). Data on the real-life use of and indications for [68Ga]Ga-DOTANOC PET/CT were collected from a prospective monocentric 5-year electronic archive including consecutive patients with confirmed and suspected NETs (September 2017 to May 2022). Overall, 2082 [68Ga]Ga-DOTANOC PET/CT scans (1685 confirmed NETs, 397 suspected NETs) were performed in 1537 patients. A high positivity rate was observed across different clinical settings (approximately 70%). Approximately 910/2082 scans were requested by the local oncology ward (851 confirmed NETs, 59 suspected NETs). The following observations were found: (i) the detection rate across all indications was 73.2% (higher for staging, peptide receptor radioligand therapy (PRRT) selection, and treatment response assessment); (ii) in suspected NETs, PET was more often positive when based on radiological findings. This systematic data collection in a high-volume diagnostic center represents a reliable cohort reflecting the global trends in the use of [68Ga]Ga-DOTANOC PET/CT for different clinical indications and primary tumor sites, but prompts the need for further multicenter data sharing in such a rare and slowly progressive disease setting.