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Background: The results of the Grupo Español Multidisciplinar en Cáncer Digestivo (GEMCAD)-1402 phase II randomized trial suggested that adding aflibercept to modified fluorouracil, oxaliplatin, and leucovorin (mFOLFOX6) induction, followed by chemoradiation and surgery, could increase the pathological complete response (pCR) rate in patients with high-risk, locally advanced rectal cancer. Here we update results up to 3 years of follow-up and evaluate the predictive value of consensus molecular subtypes identified with immunohistochemistry (IHC)., Methods: Patients with magnetic resonance imaging-defined T3c-d and/or T4 and/or N2 rectal adenocarcinoma in the middle or distal third were randomly assigned to mFOLFOX6 induction, with aflibercept (mF+A; n = 115) or without aflibercept (mF; n = 65), followed by capecitabine plus radiotherapy and surgery. The risk local relapse, distant metastases, disease-free survival (DFS), and overall survival (OS) were estimated at 3 years. Selected samples were classified via IHC into immune-infiltrate, epithelial, or mesenchymal subtypes., Results: mF+A and mF had 3-year DFS of 75.2% (95% confidence interval [CI] = 66.1% to 82.2%) and 81.5% (95% CI = 69.8% to 89.1%), respectively; 3-year OS of 89.3% (95% CI = 82.0% to 93.8%) and 90.7% (95% CI = 80.6% to 95.7%), respectively; 3-year cumulative local relapse incidences of 5.2% (95% CI = 1.9% to 11.0%) and 6.1% (95% CI = 1.7% to 15.0%), respectively; and 3-year cumulative distant metastases rates of 17.3% (95% CI = 10.9% to 25.5%) and 16.9% (95% CI = 8.7% to 28.2%), respectively. pCRs were achieved in 27.5% (n = 22 of 80) and 0% (n = 0 of 10) of patients with epithelial and mesenchymal subtypes, respectively., Conclusion: Adding aflibercept to mFOLFOX6 induction was not associated with improved DFS or OS. Our findings suggested that consensus molecular subtypes identified with IHC subtypes could be predictive of pCR with this treatment., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Soft tissue sarcomas (STSs) are an uncommon and heterogeneous group of tumours. Several drugs and combinations have been used in clinical practice as second-line (2L) and third-line (3L) treatment. The growth modulation index (GMI) has previously been used as an exploratory efficacy endpoint of drug activity and represents an intra-patient comparison., Methods: We performed a real-world retrospective study including all patients with advanced STS who had received at least 2 different lines of treatment for advanced disease between 2010 and 2020 at a single institution. The objective was to study the efficacy of both 2L and 3L treatments, analysing the time to progression (TTP) and the GMI (defined as the ratio of TTP between 2 consecutive lines of therapy)., Results: Eighty-one patients were included. The median TTP after 2L and 3L treatment was 3.16 and 3.06 months, and the median GMI was 0.81 and 0.74, respectively. The regimens most frequently used in both treatments were trabectedin, gemcitabine-dacarbazine, gemcitabine-docetaxel, pazopanib and ifosfamide. The median TTP by each of these regimens was 2.80, 2.23, 2.83, 4.10, and 5.00 months, and the median GMI was 0.78, 0.73, 0.67, 1.08, and 0.94, respectively. In terms of histotype, we highlight the activity (GMI > 1.33) of gemcitabine-dacarbazine in undifferentiated pleomorphic sarcoma (UPS) and in leiomyosarcoma, pazopanib in UPS, and ifosfamide in synovial sarcoma., Conclusions: In our cohort, regimens commonly used after first-line STS treatment showed only slight differences in efficacy, although we found significant activity of specific regimens by histotype., (© 2023. The Author(s), under exclusive licence to Federación de Sociedades Españolas de Oncología (FESEO).)

Background: The rising incidence of colorectal cancer (CRC) among young patients is alarming. We aim to characterize the clinico-pathological features and outcomes of patients with early-onset CRC (EOCRC), as well as the impacts of COVID-19 pandemic., Methods: We included all patients with pathologically confirmed diagnoses of CRC at Hospital Universitario La Paz from October 2016 to December 2021. The EOCRC cut-off age was 50 years old., Results: A total of 1475 patients diagnosed with CRC were included, eighty (5.4%) of whom had EOCRC. Significant differences were found between EOCRC and later-onset patients regarding T, N stage and metastatic presentation at diagnosis; perineural invasion; tumor budding; high-grade tumors; and signet ring cell histology, with all issues having higher prevalence in the early-onset group. More EOCRC patients had the RAS/ BRAF wild type. Chemotherapy was administered more frequently to patients with EOCRC. In the metastatic setting, the EOCRC group presented a significantly longer median OS. Regarding the COVID-19 pandemic, more patients with COVID-19 were diagnosed with metastatic disease (61%) in the year after the lockdown (14 March 2020) than in the pre-pandemic EOCRC group (29%)., Conclusions: EOCRC is diagnosed at a more advanced stage and with worse survival features in localized patients. More patients with EOCRC were diagnosed with metastatic disease in the year after the COVID-19 pandemic lockdown. The long-term consequences of COVID-19 are yet to be determined.

CD19-directed chimeric antigen receptor (CAR) T cell (CAR-T) therapy with axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) are approved for the treatment of relapsed or refractory large B cell lymphoma (LBCL), including de novo diffuse LBCL (DLBCL), primary mediastinal B cell lymphoma (PMBCL), and transformed follicular lymphoma (tFL). Transformed nonfollicular lymphomas (tNFLs), including transformed marginal zone lymphoma (tMZL) and transformed chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) were not included in their respective pivotal studies. This study was conducted to evaluate the outcomes of axi-cel and tisa-cel in tNFL patients, including those who received ibrutinib concomitantly through apheresis, lymphodepletion, and CAR-T infusion. This single-center retrospective study included all patients with tCLL/SLL, tMZL, tFL, and DLBCL/PMBCL treated with CAR-T therapy outside of a clinical trial setting from November 2017 to May 2021 at Moffitt Cancer Center, Tampa, Florida. We analyzed and compared outcomes in patients with tCLL/SLL or tMZL and patients with DLBCL/tFL. The study included 134 patients who received a total of 136 CAR-T treatments (111 with axi-cel and 25 with tisa-cel). Ninety patients had de novo DLBCL/PMBCL, 23 had tFL, and 21 had tNFL (12 with tMZL and 9 with tCLL/SLL). The overall response and complete response rates were 66.7% and 55.6%, respectively, for tCLL/SLL and 92.9% and 71.4% for tMZL. The overall response and complete response rates were not different between tNFL and DLBCL/tFL (P = .92 and .81, respectively). At a median follow-up of 21.3 months, the median progression-free survival (PFS) for tCLL/SLL was 5.4 months (95% confidence interval [CI], .8 month to not assessable [NA]); for tMZL, the median PFS was not reached (NR) (95% CI, 2.3 months to NA); and for DLBCL/tFL, the median PFS was 14.3 months (95% CI, 5.6 months to NA) (P = .58). The estimated 1-year PFS rate was 29.6% (95% CI, 5.2% to 60.7%) for tCLL/SLL, 50.0% (95% CI, 22.9% to 72.2%) for tMZL, 42.7% (95% CI, 22.4% to 61.6%) for tNFL, and 53.0% (95% CI, 42.3% to 62.5%) for DLBCL/tFL. The median overall survival was NR (95% CI, 9.2 months to NA) for tCLL/SLL, 27.1 months (95% CI, 8.5 months to NA) for tMZL, and NR (95% CI, 17.4 months to NA) for DLBCL/tFL (P = .79). Compared to the DLBCL/tFL cohort, tNFL patients were more likely to develop immune effector cell-associated neurologic syndrome (ICANS) and to receive tocilizumab (P = .04 and .01, respectively, after controlling for CAR-T product) and with a possibly higher incidence of grade ≥3 cytokine release syndrome (CRS) (P = .07). Two patients in the tNFL cohort died of treatment-related toxicity after receiving axi-cel. Six tNFL patients received ibrutinib concurrently with tisa-cel, with 1 case of grade ≥3 CRS/ICANS that rapidly resolved and no other severe toxicities. Our case series supports the use of CD19 CAR-T therapy in relapsed/refractory tCLL/SLL and tMZL. The concurrent use of ibrutinib and tisa-cel in tNFL was associated with manageable toxicity in tNFL., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Background: Peritoneal metastasis from colorectal cancer (CRC) has limited therapeutic options and poor prognosis. Systemic chemotherapy combined with cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) or pressurized intraperitoneal aerosol chemotherapy (PIPAC) have yielded initial promising results. However, standard local therapies with oxaliplatin and mitomycin are not optimal and a better individualized management of these patients remains as an unmet clinical need. Patient-derived organoid (PDO) technology allows to culture in three dimensions normal and cancer stem cells (CSC) that self-organize in multicellular structures that recapitulates some of the features of the particular organ or tumor of origin, emerging as a promising tool for drug-testing and precision medicine. This technology could improve the efficacy of systemic and intraperitoneal chemotherapy and avoid unnecessary treatments and side effects to the patient., Case Description: Here we report a case of a 45-year-old man with a rectal adenocarcinoma with liver, lymph node and peritoneal metastases. The patient was treated with systemic chemotherapy (FOLFOXIRI plus Bevacizumab) and was subjected to mitomycin-based PIPAC. We generated patient-derived peritoneal carcinomatosis organoids in order to screen the activity of drugs for a personalized treatment. Both 5-FU and SN-38, the active irinotecan derivative, displayed strong cytotoxicity, while the response to oxaliplatin was much lower. Although the development of a colo-cutaneous fistulae prevented from further PIPAC, the patient continued with fluoropirimidine maintenance treatment based on standard clinical practice and the drug-screening test performed on organoids., Conclusions: Our results suggest that the peritoneal implant shows chemoresistance to oxaliplatin, while it might still be sensitive to irinotecan and 5-FU, which supports a potential benefit of these two drugs in the local and/or systemic treatment of our patient. This study shows the strength of the utility of the establishment of organoids for drug response assays and thus, for the personalized treatment of colorectal carcinomatosis patients., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-22-599/coif). IP has received a grant from ISCIII-FEDER (Spain; No. ICI20/00057). AB, AM and AFB report that they have received grants from Agencia Estatal de Investigación (Spain; No. PID2019-104867RB100/AEI/10.13039/501100011033), Instituto de Salud Carlos III (ISCIII)-Fondo Europeo de Desarrollo Regional (FEDER) (Spain; No. ICI20/00057) and ISCIII-CIBERONC (Spain; No. CIBERONC/CB16/12/00273). NRS has received two grants from ISCIII-FEDER (Spain; No. ICI20/00057) and ISCIII-CIBERONC (Spain; No. CIBERONC/CB16/12/00398). DV has been awarded with a Río Hortega contract from Sociedad Española de Oncología Médica (SEOM) (Spain) and received a grant from ISCIII-FEDER (Spain; No. ICI20/00057). DCG participates on the Board of Directors of the European Society of Surgical Oncology (ESSO) and the Board of Directors of the Spanish Society of Surgical Oncology (SEOQ). The authors have no other conflicts of interest to declare., (2023 Journal of Gastrointestinal Oncology. All rights reserved.)

GATA4 and GATA6 are transcription factors involved in the differentiation and development of PDAC. GATA6 expression is related to the classic molecular subtype, while its absence is related to the basal-like molecular subtype. The aim was to determine the clinical utility of IHC determination of GATA4 and GATA6 in a series of patients with resected PDAC. GATA4 and GATA6 expression was studied by IHC in TMA samples of normal tissue, PanIN, tumor tissue and lymph node metastases from a series of 89 patients with resected PDAC. Its relationship with clinicopathologic variables and the outcome was investigated. Seventy-two (81%) tumors were GATA6+ and 37 (42%) were GATA4+. While GATA4 expression was reduced during tumor progression, GATA6 expression remained highly conserved, except in lymph node metastases. All patients with early stages and well-differentiated tumors were GATA6+. The absence of GATA4 expression was related to smoking. Patients with GATA4+ or GATA6+ tumors had significantly lower Ca 19.9 levels. The expression of GATA4 and GATA6 was related to DFS, being more favorable in the GATA4+/GATA6+ group. The determination of the expression of GATA4 and GATA6 by IHC is feasible and provides complementary clinical and prognostic information that can help improve the stratification of patients with PDAC.

Background: The prognosis of patients with stage II and stage III colon cancer is heterogeneous. Clinical and pathological characteristics, such as tumor budding, may help to further refine the recurrence risk. Methods: We included all the patients with localized colon cancer at Hospital Universitario La Paz from October 2016 to October 2021. We built a prognostic score for recurrence in the training cohort based on multivariate cox regression analysis and categorized the patients into two risk groups. Results: A total of 440 patients were included in the training cohort. After a median follow-up of 45 months, 81 (18%) patients had a first tumor recurrence. T4, N2, and high tumor budding remained with a p value <0.05 at the last step of the multivariate cox regression model for time to recurrence (TTR). We assigned 2 points to T4 and 1 point to N2 and high tumor budding. Forty-five percent of the patients were assigned to the low-risk group (score = 0). Compared to the high-risk group (score 1−4), patients in the low-risk group had a significantly longer TTR (hazard ratio for disease recurrence of 0.14 (95%CI: 0.00 to 0.90; p < 0.045)). The results were confirmed in the validation cohort. Conclusions: In our study, we built a simple score to predict tumor recurrence based on T4, N2, and high tumor budding. Patients in the low-risk group, that comprised 44% of the cohort, had an excellent prognosis.

Background: As management and prevention strategies against COVID-19 evolve, it is still uncertain whether prior exposure to immune checkpoint inhibitors (ICIs) affects COVID-19 severity in patients with cancer., Methods: In a joint analysis of ICI recipients from OnCovid (NCT04393974) and European Society for Medical Oncology (ESMO) CoCARE registries, we assessed severity and mortality from SARS-CoV-2 in vaccinated and unvaccinated patients with cancer and explored whether prior immune-related adverse events (irAEs) influenced outcome from COVID-19., Findings: The study population consisted of 240 patients diagnosed with COVID-19 between January 2020 and February 2022 exposed to ICI within 3 months prior to COVID-19 diagnosis, with a 30-day case fatality rate (CFR 30 ) of 23.6% (95% CI 17.8 to 30.7%). Overall, 42 (17.5%) were fully vaccinated prior to COVID-19 and experienced decreased CFR 30 (4.8% vs 28.1%, p=0.0009), hospitalization rate (27.5% vs 63.2%, p<0.0001), requirement of oxygen therapy (15.8% vs 41.5%, p=0.0030), COVID-19 complication rate (11.9% vs 34.6%, p=0.0040), with a reduced need for COVID-19-specific therapy (26.3% vs 57.9%, p=0.0004) compared with unvaccinated patients. Inverse probability of treatment weighting (IPTW)-fitted multivariable analysis, following a clustered-robust correction for the data source (OnCovid vs ESMO CoCARE), confirmed that vaccinated patients experienced a decreased risk of death at 30 days (adjusted OR, aOR 0.08, 95% CI 0.01 to 0.69).Overall, 38 patients (15.8%) experienced at least one irAE of any grade at any time prior to COVID-19, at a median time of 3.2 months (range 0.13-48.7) from COVID-19 diagnosis. IrAEs occurred independently of baseline characteristics except for primary tumor (p=0.0373) and were associated with a significantly decreased CFR 30 (10.8% vs 26.0%, p=0.0462) additionally confirmed by the IPTW-fitted multivariable analysis (aOR 0.47, 95% CI 0.33 to 0.67). Patients who experienced irAEs also presented a higher median absolute lymphocyte count at COVID-19 (1.4 vs 0.8 10 9  cells/L, p=0.0098)., Conclusion: Anti-SARS-CoV-2 vaccination reduces morbidity and mortality from COVID-19 in ICI recipients. History of irAEs might identify patients with pre-existing protection from COVID-19, warranting further investigation of adaptive immune determinants of protection from SARS-CoV-2., Competing Interests: Competing interests: KJH declares research funding from AstraZeneca, Boehringer-Ingelheim, MSD, Replimune and advisory board fees/honoraria from Arch Oncology, AstraZeneca, BMS, Boehringer-Ingelheim, Codiak Biosciences, Inzen Therapeutics, Merck-Serono, MSD, Pfizer, Replimune. DA reports consultation/advisory role for AstraZeneca, Bristol Myers Squibb, Merck Sharp reports speaker’s engagement from AstraZeneca, Bristol Myers Squibb, Merck Sharp reports serving as local PI for Bristol Myers Squibb, Pierre Fabre Pharma and coordinating PI for OncoLytics; reports grant funding from AbbVie; reports being/been DSMB chair of Sanofi (Genzyme); reports being/been a steering committee member of Roche. Olivier Michielin reports personal fees from Bristol-Myers Squibb, MSD, Novartis, Roche, Amgen, NeraCare, outside the submitted work. JR received speaker or advisory fees from Roche, Astra Zeneca, Merck, Ferrer, Persan Farma, Teva Pharma, Leo Pharma, Fresenius kabi, MSD, BMS. Travel expenses support from BMS, MSD, RocheUrania Dafni reports honorarium as Member of the Tumor Agnostic Evidence Generation Working Group of Roche, outside the submitted work. GP reports grants from Amgen, Lilly; grants, personal fees and nonfinancial support from Merck; grants and non-financial support from AstraZeneca; grants and personal fees from Roche, Bristol Myers Squibb, MSD, Novartis, outside the submitted work. Solange Peters reports consultation/advisory role for AbbVie, Amgen, AstraZeneca, Bayer, BeiGene, Biocartis, Bio Invent, Blueprint Medicines, Boehringer Ingelheim, Bristol- Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, Elsevier, F Hoffmann-La Roche/Genentech, Foundation Medicine, Illumina, Incyte, IQVIA, Janssen, Medscape, Merck Sharp and Dohme, Merck Serono, Merrimack, Mirati, Novartis, Pharma Mar, Phosplatin Therapeutics, Pfizer, Regeneron, Sanofi, Seattle Genetics, Takeda, Vaccibody; talk in a company’s organized public event for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, e-cancer, Eli Lilly, F. Hoffmann-La Roche/Genentech, Illumina, Medscape, Merck Sharp and Dohme, Novartis, PER, Pfizer, Prime, RTP, Sanofi, Takeda; receipt of grants/research supports from being a (sub)investigator in trials (institutional financial support for clinical trials) sponsored by Amgen, AstraZeneca, Biodesix, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, F Hoffmann-La Roche/Genentech, GSK, Illumina, Lilly, Merck Sharp and Dohme, Merck Serono, Mirati, Novartis, and Pfizer, Phosplatin Therapeutics. Emanuela Rromano reports investigator-initiated trial (funds paid to the institution) supported by Astra-Zeneca, BMS; serves on the consultancy/advisory board for Astra-Zeneca, Merck, Roche, Pierre Fabre. ML acted as consultant for Roche, Novartis, Lilly, AstraZeneca, Exact Sciences, MSD, Pfizer, Seagen and received speaker honoraria from Roche, Novartis, Lilly, Pfizer, Takeda, Ipsen and Sandoz outside the submitted work.Alessandra Gennari has declared consulting/advisory role for Roche, MSD, Eli Lilly, Pierre Fabre, EISAI, and Daichii Sankyo; speakers bureau for Eisai, Novartis, Eli Lilly, Roche, Teva, Gentili, Pfizer, Astra Zeneca, Celgene, and Daichii Sankyo; research funds: EISAI, Eli Lilly, and Roche. CMV has received travel grants and other honoraria from BMS, MSD, Novartis and Roche. Joan Brunet has declared consulting/advisory role for MSD and Astra Zeneca. Aleix Prat has declared personal honoraria from Pfizer, Roche, MSD Oncology, Eli Lilly, and Daiichi Sankyo; travel, accommodations, and expenses paid by Daiichi Sankyo; research funding from Roche and Novartis; and consulting/advisory role for NanoString Technologies, Amgen, Roche, Novartis, Pfizer and Bristol-Myers Squibb. Mark Bower received speakers’ fee from EISAI pharma, Gilead Sciences, Merck and ViiV. JT reports consulting fees from Array Biopharma, AstraZeneca, Avvinity, Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, F Hoffmann-La Roche, Genentech, HalioDX SAS, Hutchison MediPharma International, Ikena Oncology, Inspirna, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Ona Therapeutics, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Seattle Genetics, Scandion Oncology, Servier, Sotio Biotech, Taiho, Tessa Therapeutics, and TheraMyc; speaker’s fees from Imedex, Medscape Education, MJH Life Sciences, PeerView Institute for Medical Education, and Physicians Education Resource; and institutional research support from Amgen, Array Biopharma, AstraZeneca Pharmaceuticals, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Debiopharm International, F Hoffmann-La Roche, Genentech, HalioDX, Hutchison MediPharma International, Janssen-Cilag, MedImmune, Menarini, Merck Health, Merck Sharp and has had leadership roles in the European AIDS Clinical Society, UNAIDS, WHO, and The European Hematology Association/ European Society of Medical Oncology. DJP received lecture fees from ViiV Healthcare, Bayer Healthcare, BMS, Roche, EISAI, Falk Foundation, travel expenses from BMS and Bayer Healthcare; consulting fees for Mina Therapeutics, EISAI, Roche, DaVolterra and Astra Zeneca; research funding (to institution) from MSD and BMS. AC received consulting fees from MSD, BMS, AstraZeneca, Roche; speakers’ fee from AstraZeneca, MSD, Novartis and Eisai. All remaining authors have declared no conflicts of interest., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Patients with cancer have been shown to have increased risk of COVID-19 severity. We previously built and validated the COVID-19 Risk in Oncology Evaluation Tool (CORONET) to predict the likely severity of COVID-19 in patients with active cancer who present to hospital. We assessed the differences in presentation and outcomes of patients with cancer and COVID-19, depending on the wave of the pandemic. We examined differences in features at presentation and outcomes in patients worldwide, depending on the waves of the pandemic: wave 1 D614G (n = 1430), wave 2 Alpha (n = 475), and wave 4 Omicron variant (n = 63, UK and Spain only). The performance of CORONET was evaluated on 258, 48, and 54 patients for each wave, respectively. We found that mortality rates were reduced in subsequent waves. The majority of patients were vaccinated in wave 4, and 94% were treated with steroids if they required oxygen. The stages of cancer and the median ages of patients significantly differed, but features associated with worse COVID-19 outcomes remained predictive and did not differ between waves. The CORONET tool performed well in all waves, with scores in an area under the curve (AUC) of >0.72. We concluded that patients with cancer who present to hospital with COVID-19 have similar features of severity, which remain discriminatory despite differences in variants and vaccination status. Survival improved following the first wave of the pandemic, which may be associated with vaccination and the increased steroid use in those patients requiring oxygen. The CORONET model demonstrated good performance, independent of the SARS-CoV-2 variants.

Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related death worldwide. Alterations in proteins of the p53-family are a common event in CRC. ΔNp73, a p53-family member, shows oncogenic properties and its effectors are largely unknown. We performed an in-depth proteomics characterization of transcriptional control by ∆Np73 of the secretome of human colon cancer cells and validated its clinical potential. The secretome was analyzed using high-density antibody microarrays and stable isotopic metabolic labeling. Validation was performed by semiquantitative PCR, ELISA, dot-blot and western blot analysis. Evaluation of selected effectors was carried out using 60 plasma samples from CRC patients, individuals carrying premalignant colorectal lesions and colonoscopy-negative controls. In total, 51 dysregulated proteins were observed showing at least 1.5-foldchange in expression. We found an important association between the overexpression of ∆Np73 and effectors related to lymphangiogenesis, vasculogenesis and metastasis, such as brain-derived neurotrophic factor (BDNF) and the putative aminoacyl tRNA synthase complex-interacting multifunctional protein 1 (EMAP-II)-vascular endothelial growth factor C-vascular endothelial growth factor receptor 3 axis. We further demonstrated the usefulness of BDNF as a potential CRC biomarker able to discriminate between CRC patients and premalignant individuals from controls with high sensitivity and specificity., (© 2022 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Purpose: Patients with cancer are at increased risk of severe COVID-19 disease, but have heterogeneous presentations and outcomes. Decision-making tools for hospital admission, severity prediction, and increased monitoring for early intervention are critical. We sought to identify features of COVID-19 disease in patients with cancer predicting severe disease and build a decision support online tool, COVID-19 Risk in Oncology Evaluation Tool (CORONET)., Methods: Patients with active cancer (stage I-IV) and laboratory-confirmed COVID-19 disease presenting to hospitals worldwide were included. Discharge (within 24 hours), admission (≥ 24 hours inpatient), oxygen (O 2 ) requirement, and death were combined in a 0-3 point severity scale. Association of features with outcomes were investigated using Lasso regression and Random Forest combined with Shapley Additive Explanations. The CORONET model was then examined in the entire cohort to build an online CORONET decision support tool. Admission and severe disease thresholds were established through pragmatically defined cost functions. Finally, the CORONET model was validated on an external cohort., Results: The model development data set comprised 920 patients, with median age 70 (range 5-99) years, 56% males, 44% females, and 81% solid versus 19% hematologic cancers. In derivation, Random Forest demonstrated superior performance over Lasso with lower mean squared error (0.801 v 0.807) and was selected for development. During validation (n = 282 patients), the performance of CORONET varied depending on the country cohort. CORONET cutoffs for admission and mortality of 1.0 and 2.3 were established. The CORONET decision support tool recommended admission for 95% of patients eventually requiring oxygen and 97% of those who died (94% and 98% in validation, respectively). The specificity for mortality prediction was 92% and 83% in derivation and validation, respectively. Shapley Additive Explanations revealed that National Early Warning Score 2, C-reactive protein, and albumin were the most important features contributing to COVID-19 severity prediction in patients with cancer at time of hospital presentation., Conclusion: CORONET, a decision support tool validated in health care systems worldwide, can aid admission decisions and predict COVID-19 severity in patients with cancer., Competing Interests: Rebecca J. LeeSpeakers' Bureau: AstraZenecaResearch Funding: Bristol Myers Squibb (Inst), AstraZeneca/MedImmune (Inst) Rohan ShottonHonoraria: ServierTravel, Accommodations, Expenses: Servier Laurence AlbigesConsulting or Advisory Role: Bristol Myers Squibb (Inst), Ipsen (Inst), Roche (Inst), Novartis (Inst), Pfizer (Inst), Astellas Pharma (Inst), Merck (Inst), MSD (Inst), AstraZeneca (Inst), Janssen (Inst), Eisai (Inst), Corvus Pharmaceuticals (Inst), Bellerophon Therapeutics (Inst)Research Funding: Bristol Myers Squibb (Inst)Travel, Accommodations, Expenses: BMS, MSD Dirk ArnoldEmployment: Asklepios KlinikenHonoraria: Bayer, Merck Serono, Roche/Genentech, Servier, Bristol Myers Squibb, Merck Sharp and Dome, AstraZeneca, Amgen, Boston Scientific, Pierre Fabre, IpsenConsulting or Advisory Role: Bayer, Merck Serono, Biocompatibles, Terumo, Bristol Myers Squibb, MSD Oncology, AstraZenecaResearch Funding: Roche/Genentech (Inst), Sanofi (Inst), Oncolytics (Inst)Travel, Accommodations, Expenses: Boston ScientificUncompensated Relationships: ESMO Council, ESMO Journals (Ann Oncol, ESMO Open), German Society for Hematology and Medical Oncology, German Cancer Society, European Organisation for Research and Treatment of Cancer (EORTC) Kathryn BanfillStock and Other Ownership Interests: Roche (I)Honoraria: AstraZeneca Mark BaxterHonoraria: IpsenTravel, Accommodations, Expenses: Ipsen Fabrice BarlesiHonoraria: Genentech/Roche, Pfizer, Pierre Fabre, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Lilly, Novartis, Merck Serono, MSD Oncology, Takeda, Bayer, Seattle Genetics, Mirati TherapeuticsConsulting or Advisory Role: Roche/Genentech, Pfizer, Novartis, Pierre Fabre, Bristol Myers Squibb, AstraZeneca/MedImmune, Boehringer Ingelheim, Lilly, Merck Serono, MSD Oncology, Takeda, Bayer, Mirati TherapeuticsResearch Funding: Roche/Genentech (Inst), AstraZeneca/MedImmune (Inst), Bristol Myers Squibb (Inst), Pierre Fabre (Inst), AbbVie (Inst), Amgen (Inst), Bayer (Inst), Boehringer Ingelheim (Inst), Eisai (Inst), Lilly (Inst), Ipsen (Inst), Innate Pharma (Inst), Novartis (Inst), Merck Serono (Inst), MSD Oncology (Inst), Pfizer (Inst), Sanofi/Aventis (Inst), Takeda (Inst)Travel, Accommodations, Expenses: Roche/Genentech, Bristol Myers Squibb, AstraZeneca/MedImmune, MSD Oncology Benjamin BesseResearch Funding: AstraZeneca (Inst), Pfizer (Inst), Lilly (Inst), Onxeo (Inst), Inivata (Inst), AbbVie (Inst), Amgen (Inst), Blueprint Medicines (Inst), Celgene (Inst), GlaxoSmithKline (Inst), Sanofi (Inst), Takeda (Inst), Cristal Therapeutics (Inst), Daiichi Sankyo (Inst), Janssen Oncology (Inst), OSE Immunotherapeutics (Inst), BeiGene (Inst), Boehringer Ingelheim (Inst), Roche/Genentech (Inst), Tolero Pharmaceuticals (Inst), 4D Pharma (Inst), Aptitude Health (Inst), Cergentis (Inst), Chugai Pharma (Inst), Genzyme (Inst), Ipsen (Inst), Turning Point Therapeutics (Inst), Eisai (Inst) Antonio CallesHonoraria: AstraZeneca, Boehringer Ingelheim, Pfizer, Roche/Genentech, Lilly, Novartis, Merck Sharp & Dohme, Bristol Myers Squibb, Amgen, Bayer, Takeda, Sanofi/RegeneronConsulting or Advisory Role: Boehringer Ingelheim, Roche/Genentech, Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Bristol Myers Squibb, Takeda, Igen Biotech, Sanofi/RegeneronResearch Funding: MSD Oncology Ellen CopsonHonoraria: Roche, Pfizer, AstraZeneca, Lilly, NovartisConsulting or Advisory Role: Lilly, NanoString Technologies, Pfizer, Sanofi/Aventis, RocheSpeakers' Bureau: Roche, Pfizer, AstraZeneca, Sanofi/AventisResearch Funding: SECA, AstraZeneca (Inst)Travel, Accommodations, Expenses: Roche, AstraZeneca Adina E. CroitoruConsulting or Advisory Role: Ipsen, Pfizer, MSD OncologyResearch Funding: Bristol Myers Squibb (Inst), Amgen (Inst), Astellas Pharma (Inst), Exelixis (Inst), Merck (Inst), Merck KGaA (Inst)Travel, Accommodations, Expenses: Merck, ServierUncompensated Relationships: Lilly, Roche, Bayer, Pfizer, Sanofi Leonie EastlakeTravel, Accommodations, Expenses: Servier Paul FitzpatrickStock and Other Ownership Interests: AstraZeneca/MedImmuneResearch Funding: AstraZeneca/MedImmune (Inst)Other Relationship: Pistoia Alliance, EHDEN IMI project Henrik FrederiksenResearch Funding: AbbVie (Inst), Gilead Sciences (Inst), Sanofi (Inst) Hannah FrostResearch Funding: AstraZeneca (Inst) Sarju GanatraExpert Testimony: Haymarket Medical EducationTravel, Accommodations, Expenses: Haymarket Medical Education Andreas GlenthøjHonoraria: Novo NordiskConsulting or Advisory Role: Novartis, Celgene/Bristol Myers Squibb, Bluebird Bio, Sanofi, Novo Nordisk, AgiosResearch Funding: Sanofi, Saniona A/STravel, Accommodations, Expenses: Agios Fabio GomesHonoraria: AstraZeneca, Merck Serono, Roche Donna M. GrahamConsulting or Advisory Role: Clinigen GroupSpeakers' Bureau: Cancer Drug Development ForumResearch Funding: Pfizer (Inst) Kevin HarringtonHonoraria: Arch Oncology (Inst), AstraZeneca (Inst), BMS (Inst), Boehringer Ingelheim (Inst), Merck Serono (Inst), MSD (Inst), Oncolys BioPharma (Inst), Pfizer (Inst), Replimune (Inst), Inzen Therapeutics (Inst), Codiak Biosciences (Inst)Consulting or Advisory Role: Arch Oncology (Inst), AstraZeneca (Inst), BMS (Inst), Boehringer Ingelheim (Inst), Merck Serono (Inst), MSD (Inst), Oncolys BioPharma (Inst), Replimune (Inst), Inzen Therapeutics (Inst)Speakers' Bureau: BMS (Inst), Merck Serono (Inst), MSD (Inst)Research Funding: AstraZeneca (Inst), Merck Sharp & Dohme (Inst), Replimune (Inst), Boehringer Ingelheim (Inst) Lasse H. JakobsenHonoraria: Takeda, Roche Khurum KhanHonoraria: ServierConsulting or Advisory Role: Bayer Health Christophe MassardConsulting or Advisory Role: Amgen, Astellas Pharma, AstraZeneca, Bayer, BeiGene, BMS, Celgene, Debiopharm Group, Genentech/Roche, Ipsen, Janssen, Lilly, MSD, Novartis, Pfizer, Sanofi, ORION, Taiho Pharmaceutical, Blueprint Medicines, Innate Pharma, PharmaMar, Faron Pharmaceuticals Olivier MichielinConsulting or Advisory Role: Bristol Myers Squibb, MSD, Novartis, Roche, Amgen, Pierre FabreResearch Funding: MSD, Bristol Myers Squibb, NeraCare GmbHExpert Testimony: Bristol Myers SquibbTravel, Accommodations, Expenses: Bristol Myers Squibb, MSD Anne C. MosenthalHonoraria: Springer Nature Berta ObispoHonoraria: Sanofi, Lilly, Angelini, LEO Pharma, RoviConsulting or Advisory Role: Rovi George PentheroudakisHonoraria: Roche, Amgen, Bristol Myers Squibb, MSD, MerckConsulting or Advisory Role: Roche, AmgenResearch Funding: Roche (Inst), Amgen (Inst), Bristol Myers Squibb (Inst), Merck (Inst), AstraZeneca (Inst), Novartis (Inst), Pfizer (Inst)Travel, Accommodations, Expenses: Sanofi, MSD, Roche, Amgen, BMS Solange PetersHonoraria: Roche (Inst), Bristol Myers Squibb (Inst), Novartis (Inst), Pfizer (Inst), MSD (Inst), AstraZeneca (Inst), Takeda (Inst), Illumina (Inst), Medscape (Inst), Prime Oncology (Inst), RMEI Medical Education (Inst), Research to Practice (Inst), PER (Inst), Imedex (Inst), ecancer (Inst)Consulting or Advisory Role: Roche/Genentech (Inst), Novartis (Inst), Bristol Myers Squibb (Inst), Pfizer (Inst), MSD (Inst), Amgen (Inst), AstraZeneca (Inst), Janssen (Inst), Regeneron (Inst), Merck Serono (Inst), Boehringer Ingelheim (Inst), Takeda (Inst), Lilly (Inst), AbbVie (Inst), Bayer (Inst), Biocartis (Inst), Debiopharm Group (Inst), Illumina (Inst), PharmaMar (Inst), Sanofi (Inst), Seattle Genetics (Inst), Blueprint Medicines (Inst), Daiichi Sankyo (Inst), Incyte (Inst), Bioinvent (Inst), Clovis Oncology (Inst), Vaccibody (Inst), Phosplatin Therapeutics (Inst), Foundation Medicine (Inst)Research Funding: Roche (Inst), BMS (Inst), MSD (Inst), Amgen (Inst), Lilly (Inst), AstraZeneca (Inst), Pfizer (Inst), Illumina (Inst), Merck Serono (Inst), Novartis (Inst), Biodesix (Inst), Boehringer Ingelheim (Inst), Iovance Biotherapeutics (Inst), Phosplatin Therapeutics (Inst)Travel, Accommodations, Expenses: Roche, Bristol Myers Squibb, MSD, Sanofi, IncyteUncompensated Relationships: Journal of Thoracic Oncology, ESMO, European Thoracic Oncology Platform (ETOP), Annals of Oncology (I) Kimberly Rieger-ChristResearch Funding: Veracyte, Ravel, Grail, Exact Sciences, Nucleix Timothy RobinsonTravel, Accommodations, Expenses: Daiichi Sankyo/Lilly Emanuela RomanoConsulting or Advisory Role: AstraZeneca/MedImmune (Inst), Bristol Myers Squibb (Inst), Roche/Genentech (Inst)Research Funding: Bristol Myers Squibb, AmgenTravel, Accommodations, Expenses: AstraZeneca/MedImmune, Bristol Myers Squibb, Roche Michael RoweHonoraria: MSDSpeakers' Bureau: ServierTravel, Accommodations, Expenses: Astellas Pharma Anne ThomasConsulting or Advisory Role: BMSSpeakers' Bureau: Bristol Myers SquibbExpert Testimony: BMS Lance TurtleSpeakers' Bureau: Eisai (Inst) David ViñalSpeakers' Bureau: ServierTravel, Accommodations, Expenses: Merck Caroline WilsonConsulting or Advisory Role: Roche, Pfizer Carlo PalmieriHonoraria: PfizerConsulting or Advisory Role: Pfizer, Daiichi-Sankyo, Lilly, Novartis, Seattle GeneticsResearch Funding: Pfizer, Daiichi-SankyoTravel, Accommodations, Expenses: Roche Donal LandersEmployment: AstraZeneca, AthenexLeadership: DeLondra OncologyStock and Other Ownership Interests: DeLondra OncologyResearch Funding: AstraZeneca (Inst) Timothy CooksleyHonoraria: Bristol Myers Squibb Foundation Caroline DiveConsulting or Advisory Role: Biocartis, Merck, AstraZeneca, GRAIL, Boehringer IngelheimResearch Funding: AstraZeneca, Astex Pharmaceuticals, Bioven, Amgen, Carrick Therapeutics, Merck, Taiho Oncology, GlaxoSmithKline, Bayer, Boehringer Ingelheim, Roche, BMS, Novartis, Celgene, Epigene Therapeutics, Angle, Menarini, Clearbridge Biomedics, Thermo Fisher Scientific, NeoMed André FreitasResearch Funding: AstraZeneca (Inst) Anne C. ArmstrongStock and Other Ownership Interests: AstraZeneca (I)Consulting or Advisory Role: Gilead Sciences, MSDResearch Funding: AstraZeneca/MedImmune (Inst)Travel, Accommodations, Expenses: Gilead Sciences, MSD OncologyNo other potential conflicts of interest were reported.

Uveal melanoma is a rare neoplasm with poor prognosis in the metastatic setting. Unlike cutaneous melanoma, treatment with kinase inhibitors or immune checkpoint inhibitors is not effective. Glycoprotein 100 (Gp-100) is a protein highly expressed in melanocytes and melanoma that has recently been effectively targeted by tebentafusp, a first-in-class bispecific protein of the immune-mobilizing monoclonal T cell receptors against cancer (ImmTACs) family. Tebentafusp targets tumor cells that express a peptide of Gp-100 presented by HLA*A0201, creating an immune synapse that kills targeted tumor cells. Recently, a randomized phase III trial reported an overall survival benefit for tebentafusp in patients with untreated metastatic uveal melanoma. The aim of this comprehensive review is to summarize evidence of Gp-100 as a therapeutic target in melanoma, and the preclinical and clinical development of tebentafusp as a novel therapeutic strategy for patients with uveal melanoma.

The early diagnosis of colorectal cancer is a key factor in the overall survival of the patients. The actual screening programs include different approaches with significant limitations such as unspecificity, high invasiveness, and detection at late stages of the disease. The specific content of extracellular vesicles derived from malignant cells may represent a non-invasive technique for the early detection of colorectal cancer. Here, we studied the mRNA levels of ΔNp73, TAp73, and Δ133p53 in plasma-derived extracellular vesicles from healthy subjects ( n = 29), individuals with premalignant lesions ( n = 49), and colorectal cancer patients ( n = 42). Extracellular vesicles' ΔNp73 levels were already significantly high in subjects with premalignant lesions. Δ133p53 levels were statistically increased in colorectal cancer patients compared to the other two groups and were associated with patients' survival. Remarkably, TAp73 mRNA was not detected in any of the individuals. The evaluation of ΔNp73, Δ133p53 and CEA sensitivity, specificity and AUC values supports ΔNp73 as a better early diagnosis biomarker and CEA as the best to identify advanced stages. Thus, low levels of CEA and a high content of ΔNp73 may identify in screening programs those individuals at higher risk of presenting a premalignant lesion. In addition, Δ133p53 emerges as a potential prognosis biomarker in colorectal cancer.

The treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) has evolved dramatically in the recent years with the approval of several new drugs. Together with other treatment modalities including chemotherapy, hormonal therapy and immunotherapy, radiopharmaceuticals have recently been incorporated to the therapeutic scenario of prostate cancer with the approval of Radium 223 dichloride (Ra-223) for the treatment of mCRPC patients with symptomatic bone metastasis and no visceral metastases. Radiopharmaceuticals have long been used for pain palliation in patients with bone metastases. However, the bone seeking properties and the favourable physical characteristic of alpha emitter radium 223 encouraged the clinical development of the drug, leading to survival advantage in the phase III trial ALSYMPCA. Now the efforts are directed to define the optimal patient selection and drug sequence. In this review, we will provide the best available evidence of mechanism of action, clinical data and future directions of Ra-223 in mCRPC.

Objectives: Liver metastases appear in 20-30% of patients diagnosed with non-small cell lung cancer (NSCLC) and represent a poor prognosis feature of NSCLC and a possibly more treatment-resistant condition. Potential clinical outcome differences in NSCLC patients with liver metastases harboring molecular alterations in EGFR, KRAS and EML4-ALK genes are still to be determined. This study aims to evaluate the incidence of liver metastasis in a single population and look for potential correlations between EGFR mutations, liver infiltration and clinical outcomes., Methods: A total of 236 consecutive stage IV NSCLC patients treated at the Clínica Universidad de Navarra were analyzed., Results: At onset, liver metastases were present in 16.9% of patients conferring them a shorter overall survival (OS) compared to those with different metastatic locations excluding liver infiltration (10 vs. 21 months; p = 0.001). Patients with EGFR wild-type tumors receiving standard chemotherapy and showing no liver involvement presented a superior median OS compared to those with liver metastases (23 vs. 13 months; p = 0.001). Conversely, patients with EGFR-mutated tumors treated with EGFR tyrosin-kinase inhibitors (TKI's) presented no significant differences in OS regardless of liver involvement (median OS not reached vs. 25 months; p = 0.81)., Conclusion: Overall, liver metastases at onset negatively impact OS of NSCLC patients. EGFR TKIs however, may reverse the effects of an initial negative prognosis of liver metastasis in first-line treatment of EGFR mutated NSCLC patients.