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Background: In the last years, a dramatic increase in colorectal cancer (CRC) diagnoses in early-onset (EO) patients has been observed. The prognosis of EO-CRC compared to late-onset (LO) patients is still unclear. This meta-analysis aims to clarify whether there is any difference in the prognosis between the two groups., Methods: A systematic review was conducted on EMBASE-Medline, Pubmed and Cochrane Library in March 2024 to identify studies comparing overall survival (OS), cancer-specific survival (CSS), disease-free survival (DFS), local recurrence (LR) and distant recurrence (DR) risk outcomes between EO-CRC (<50 years old) and LO-CRC (>50 years old) with at least 50 patients per group and one year of follow-up. The risk of bias was assessed with the ROBINS-E tool. Data from stage prevalence and survival were extracted and meta-analysed. Meta-regression was used to identify impacting effect modifiers. The PROSPERO registration number was CRD42024573264., Results: Twenty-six studies were identified; 1,062,037 patients (13.4% EO-CRC and 86.6% LO-CRC) were included in the stage prevalence and 567,689 in the prognostic meta-analysis. Overall, 60% of the EO-CRC and 49% of the LO-CRC were diagnosed with an advanced stage (III-IV) of disease (RR 1.26, 95%CI 1.19-1.35, I 2 =87%). EO-CRC had a better OS than LO-CRC (HR 0.89, 95%CI 0.81-0.99, I 2 =89%) but equal CSS (HR 0.94, 95%CI 0.83-1.06, I 2 =82%), DFS (HR 1.05 95%CI 0.94-1.16, I 2 =76%), LR (HR 1.41, 95%CI 0.62-3.18, I 2 =49%) and DR (HR 1.51, 95%CI 0.79-2.89) risk. Meta-regression analysis identified a worse DFS in the EO-CRC rectal cancer subgroup (HR 1.14, 95%CI 1.00-1.30, I 2 =0%)., Conclusions: Despite the high heterogeneity of existing studies, EO-CRC patients are diagnosed with significantly more advanced stages than LO-CRC, although this is not reflected in any difference in cancer-related survival. There is an urgent need for increased vigilance in the early detection of CRC in young patients., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Davide Ciardiello receives travel support from Sanofi, MBS, and Merck KgA; the other authors do not have any conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Based on the Khorana score, guidelines recommend anticoagulation for primary prophylaxis (PP) in outpatients with cancer with an intermediate-to-high risk of venous thromboembolism (VTE). ONKOTEV score has been prospectively externally validated as novel risk assessment model (RAM) with good discriminatory performances but no direct comparisons with Khorana Score are available., Methods: Using the ONKOTEV validation dataset (n = 425), we applied generalized decision curve analysis (gDCA) which integrates the principles of evidence-based medicine with treatment effects, model accuracy and patient preferences (weighted as the relative value [RV] of avoiding VTE versus major bleeding [MB]). The aim is to select the most optimal treatment strategy among multiple options: "no treatment", "treat all patients with DOAC/LMVH", or "use ONKOTEV/KHORANA scores to guide PP with DOAC/LMWH"., Results: Results showed that ONKOTEV-guided PP (using DOAC or LMWH) remained the most optimal strategy for wide range assumption of treatment efficacy and patient's preference. For those patients, who value avoiding VTE more than MB, then offering DOAC to all patients represents the best strategy. When MBs are feared more than the morbidity of VTE, ONKOTEV-guided PP (DOAC) represents the best management strategy. In all cases, ONKOTEV outperformed Khorana for individualized VTE prevention., Conclusions: When the two predictive models are integrated within a decision analysis framework, ONKOTEV appears superior to Khorana Score in guiding individualized prevention of cancer-related VTE in outpatients with cancer. The findings herein reported provide cutting edge insights in cancer care and support the spread of ONKOTEV score in the ambulatory cancer setting., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: CAC reports personal fees from BMS and Leo Pharma; and a research grant from IPSEN (institutional). BD has no conflict of interest to declare. IH has no conflict of interest to declare. FL received fees for lectures, expert appraisal or consulting services from Amgen GmbH, Astellas Pharma GmbH, AstraZeneca GmbH, Bayer AG, BioNTech SE, Bristol-Myers Squibb GmbH & Co. KGaA, Daiichi Sankyo Deutschland GmbH, Lilly Deutschland GmbH, Elsevier GmbH, Falk Foundation e.V., Incyte Inc, Merck KGaA, MSD Sharp & Dohme GmbH, Novartis Pharma GmbH, Roche Deutschland Holding GbmH, Servier Deutschland GmbH, Springer Nature AG & Co. KGaA, StreamedUp! GmbH; research projects are supported by Bristol-Myers Squibb GmbH und Co. KGaA and Gilead Science GmbH. VB has no conflict of interest to declare. SF has no conflict of interest to declare. LG has no conflict of interest to declare. NF received personal fees from AAA, Hutchinson MediPharma, Merck, Novartis; has financial interest with 4SC, Astellas, Beigene, FIBROGEN, Incyte, IPSEN, MSD and NUCANA; and has received research grant form IPSEN (institutional)., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Purpose: There is an increasing interest in the role of sex and gender in cancer patients. The impact of sex differences in oncological systemic therapies is still unknown, and there is a lack of evidence specially in uncommon neoplasms like neuroendocrine tumours (NET). In the present study, we combine the differential toxicities by sex in five published clinical trials with multikinase inhibitors (MKI) in gastroenteropancreatic (GEP) NET., Methods: We performed a pooled univariate analysis of reported toxicity in patients treated in five phase 2 and phase 3 clinical trials with MKI in the GEP NET setting: sunitinib (SU11248, SUN1111), Pazopanib (PAZONET), sorafenib-bevacizumab (GETNE0801) and Lenvatinib (TALENT). Differential toxicities between male and female patients were evaluated considering relationship with study drug and different weights of each trial by random effect adjustment., Results: We found nine toxicities which were more frequent in female patients (leukopenia, alopecia, vomiting, headache, bleeding, nausea, dysgeusia, neutrophil count decreased and dry mouth) and two toxicities being more frequent in male patients (Anal Symptoms and Insomnia). Asthenia and diarrhoea were the only severe (Grade 3-4) toxicities more frequent in female patients., Conclusions: Sex-related differences in toxicity with the MKI treatment require targeted information and individualised management of patients with NET. Differential reporting of toxicity should be promoted when clinical trials are published., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jorge Hernando: Speakers Bureau: Angelini, Leo, Eisai, Adacap, Novartis, Pfizer, Advanz, Ipsen. Alejandro García-Alvarez: Speakers Bureau: Angelini. Travel/Accommodation, Expenses: Pfizer, Ipsen, EISAI, Advanz, AAA. Toni Ibrahim: Advisory board (Amgen, Galxosmithkline and Pharmamar). Cover Participation at scientific meeting (Istituto gentili and Pharmamar). Enrique Grande: EG has received honoraria for speaker engagements, advisory roles or funding of continuous medical education from Adacap, AMGEN, Angelini, Astellas, AstraZeneca, Bayer, Blueprint, Bristol Myers Squibb, Caris Life Sciences, Celgene, Clovis-Oncology, Eisai, Eusa Pharma, Genetracer, Guardant Health, HRA-Pharma, IPSEN, ITM-Radiopharma, Janssen, Lexicon, Lilly, Merck KGaA, MSD, Nanostring Technologies, Natera, Novartis, ONCODNA (Biosequence), Palex, Pharmamar, Pierre Fabre, Pfizer, Roche, Sanofi Genzyme, Servier, Taiho, and Thermo Fisher Scientific. EG has received research grants from Pfizer, AstraZeneca, Astellas, and Lexicon Pharmaceuticals. Eric Raymond: Consulting and Share holder for Genoscience Pharma, StromaCare, SCOR life science. Share Holder at Neuronax. Scientific and steering committee at Onward Therapeutics and BeiGen. Received travel grant for data presentation from BeiGen. Rocio Garcia-Carbonero: RGC has provided scientific advice and/or received honoraria or funding for continuous medical education from AAA-Novartis, Advanz Pharma, Amgen, Bayer, BMS, Boerhinger, Esteve, Hutchmed, Ipsen, Merck, Midatech Pharma, MSD, PharmaMar, Pierre Fabre, Roche, Servier and Sanofi, and has received research support from Pfizer, BMS and MSD. Ramon Salazar: Invited speaker: Advanced Accelerator Applications, Amgen, Astellas, Bayer, BMS, Eisai, GSK, Janssen Oncology, Lilly, Pierre Fabre, Roche, Sanofi Genzyme. Expert testimony: AstraZeneca, Celgene, Merck, MSD, Novartis, Pfizer. Advisory Board: Agendia, Amgen, Ferrer, Guardant Health, Ipsen, Lilly, Merck, MSD, Novartis, Pfizer, Roche Diagnostic, Roche Farma, Tayhoo, VCN-BCN. Alex Teule: Speakers Bureau: AAA, Pfizer, Ipsen, Novartis, AstraZeneca. Travel, Accommodation, Expenses: AAA, Pfizer, Ipsen, Novartis, AstraZeneca. Salvatore Tafuto: S.Tafuto has provided scientific advice and/or received honoraria or funding for continuous medical education from AAA-Novartis, Boerhinger, Ipsen, Merck, PharmaMar and has received research support from NOVARTIS, IPSEN. Vicente Alonso: VA has provided scientific advice and/or received honoraria or funding for continuous medical education from AAA-Novartis, Amgen, Ipsen, Merck, Pierre Fabre, Roche, Servier and Sanofi. Daniel Castellano: Advisory role Lilly, Pierre Fabre, Boehringer Ingelheim, Roche/Genentech, AstraZeneca, Ipsen, Bayer, Sanofi, Janssen Oncology, Pfizer, Bristol Myers Squibb, Astellas Pharma, Novartis, MSD Oncology, Sanofi. The rest of the authors declare no conflict of interest for this publication., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Specific data regarding coronavirus disease 2019 (COVID-19) in patients with neuroendocrine neoplasms (NENs) are lacking. The aim of this study is to describe the characteristics of patients with NENs who tested severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive., Material and Methods: This is a worldwide study collecting cases of patients with NENs along with a positive nasopharyngeal swab reverse transcriptase-polymerase chain reaction (RT-PCR) test for SARS-CoV-2 between June 1, 2020, and March 31, 2021. Centres treating patients with NENs were directly contacted by the principal investigator. Patients with NENs of any primary site, grade and stage were included, excluding small-cell lung carcinoma and mixed adenoneuroendocrine carcinoma., Results: Among 81 centres directly contacted, 88.8% responded and 48.6% of them declined due to lack of cases or interest. On March 31 st , 2021, eight recruiting centres enrolled 89 patients. The median age was 64 years at the time of COVID-19 diagnosis. Most patients had metastatic, non-functioning, low-/intermediate-grade gastroenteropancreatic NENs on treatment with somatostatin analogues and radioligand therapy. Most of them had comorbidities. Only 8% of patients had high-grade NENs and 12% were receiving chemotherapy. Most patients had symptoms or signs of COVID-19, mainly fever and cough. Only 3 patients underwent sub-intensive treatment, whereas most of them received medical therapies, mostly antibiotics. In two third of cases, no changes occurred for the anti-NEN therapy. More than 80% of patients completely recovered without sequelae, whereas 7.8% patients died due to COVID-19., Conclusions: Patients included in this study reflect the typical NEN population regardless of SARS-CoV-2. In most cases, they overcome COVID-19 without need of intensive care, short-term sequelae and discontinuation of systemic oncological therapy., Competing Interests: Conflict of interest statement 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 article., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background and Purpose: Combined mTORC1 inhibition with everolimus (EVE) and phosphatidylinositol 3-kinase catalytic subunit p110α blockade with alpelisib (ALP) has demonstrated synergistic efficacy in preclinical models and supports testing the combination of ALP and EVE in the clinical setting. The primary objective was to determine the maximum tolerated dose (MTD)/recommended dose for expansion (RDE) of ALP in combination with EVE and in combination with EVE and exemestane (EXE) and subsequently assess safety, preliminary efficacy and effect of ALP on the pharmacokinetics of EVE and determine the magnitude of the drug-drug interaction., Patients and Methods: Dose escalation phases were conducted in patients with advanced solid tumours and in postmenopausal women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC). The dose expansion phase was conducted in patients with pancreatic neuroendocrine tumour and renal cell carcinoma (RCC) (both mechanistic target of rapamycin inhibitor [mTORi]-naive), in patients with mTORi-pretreated solid tumours and in postmenopausal women with HR+, HER2- ABC., Results: During the doublet escalation phase, dose-limiting toxicities (DLTs) were reported in 5 of 10 (50%) patients: one patient had grade (Gr) 2 hyperglycemia and one patient had Gr 3 diarrhoea in the 300 mg dose group, one patient had Gr 2 hyperglycemia and one patient had Gr 4 hypocalcaemia in the 250 mg dose group, and one patient in the 200 mg dose group had Gr 3 diarrhoea and Gr 3 stomatitis. The combination of ALP 250 mg + EVE 2.5 mg was declared as the MTD/RDE in subjects with advanced solid tumours. In the triplet escalation phase, one patient who received ALP 200 mg + EVE 2.5 mg + EXE 25 mg had a DLT of Gr 3 acute kidney injury. This dose combination was declared as the MTD and RDE in subjects with advanced HR-positive HER2-negative BC. The common adverse events (≥30% patients), occurring across all phases, were hyperglycaemia, stomatitis, diarrhoea, nausea, asthenia, decreased appetite and fatigue. The sixteen-week progression-free survival rate was 52.4% (90% confidence interval [CI]: 32.8, 71.4) in the RCC cohort, 35.3% (90% CI: 16.6, 58.0) in the prior pNET cohort and 30.0% (90% CI: 8.7, 60.7) in the prior mTORi cohort. The pharmacokinetics of 2.5 mg of EVE was largely unchanged in the presence of ALP, independent of the dose (250 mg or 300 mg). There were no clinically relevant drug-drug interactions observed between ALP and EVE., Conclusion: The overall safety profile of ALP with EVE and EXE is manageable and reversible; no unexpected safety signals were noted compared with the individual safety profiles. Pharmacokinetics of ALP, EVE and EXE was largely unchanged in combination with each other., Competing Interests: Conflict of interest statement G.C. reports personal fees from Pfizer, personal fees from Novartis, personal fees from Lilly, personal fees from Seagen, personal fees from Amgen, personal fees from Roche, personal fees from AstraZeneca and personal fees from Daiichi Sankyo, outside the submitted work. M.M. reports personal fees from AstraZeneca, grants and personal fees from Roche, personal fees from Lilly, grants and personal fees from Puma, grants and personal fees from Novartis, personal fees from Taiho Oncology, personal fees from Pfizer, personal fees from PharmaMar and personal fees from Daiichi Sankyo, outside the submitted work. K.J. reports grants and personal fees from Novartis, personal fees from Spectrum Pharmaceuticals, grants and personal fees from ADC Therapeutics, grants and personal fees from Pfizer, personal fees from Bristol Myers Squibb, personal fees from Jounce Therapeutics, personal fees from Taiho Oncology, grants and personal fees from Genentech, personal fees from Synthon, personal fees from AbbVie, personal fees from Eisai, grants from Clovis Oncology, grants from AstraZeneca, grants from Novita Pharmaceuticals, grants from Debiopharm, grants from Lilly, grants from Zymeworks, grants from Immunomedics and grants from Puma Biotechnology, outside the submitted work. J.T.B. reports grants from AbbVie, grants from Alliance, grants from Amgen, grants from Ascentage Pharma Group, grants from AstraZeneca, grants from Bayer, grants from Boston Biomedical, grants from Bristol Myers Squibb, grants from Celgene, grants from Eli Lilly, grants from Genentech-Roche, grants from Hutchison, grants from Immunomedics, grants from Janssen, grants from MT Group, grants from Nektar, grants from Pfizer, grants from Polynoma, grants from Seattle Genetics, grants from EMD Serono, grants from Tesaro, grants from TG Therapeutics, grants from Biodesix and grants from Exact Sciences, during the conduct of the study. G.T. declared no conflict of interest. N.F. reports honoraria from Novartis, Ipsen, Merck, Sanofi-Aventis and Advanced Accelerator Applications; consulting or advisory role in Novartis/Ipsen, Advanced Accelerator Applications, Pfizer, Ipsen, Merck Serono, MSD Oncology and Wren Laboratories, Europe; research funding from Novartis (Inst), Merck Serono (Inst), Ipsen (Inst) and MSD (Inst) and other relationship with Springer and II Pensiero Scientifico Editore. M.M. and R.A.H. declared no conflict of interest. H.L. reports grants, personal fees and non-financial support from Novartis, personal fees and non-financial support from Ipsen and personal fees and non-financial support from Pfizer, during the conduct of the study. V.D. is a Novartis employee and declared no conflict of interest. O.A. is a Novartis employee and declared no conflict of interest. Z.L. is a Novartis employee and declared no conflict of interest. L.B. is a Novartis employee and declared no conflict of interest. F.A. reports grants from Novartis, during the conduct of the study, grants from Pfizer, grants from Roche, grants from Daiichi, grants from Eli Lilly and grants from Astra Zeneca, outside the submitted work., (Copyright © 2021 Elsevier Ltd. All rights reserved.)