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The reporting of adverse events (AEs) is fundamental to characterize safety profiles of novel therapeutic drug classes, however, conventional analysis strategies are suboptimal tools for this task. We therefore attempted to contribute to the modernization of AE analysis by encompassing the dimension of time, the duration and the recurrent nature of AEs induced by these extended treatment durations. This paper presents and highlights the benefits of alternative approaches to modernize AE analysis based on the MOTIVATE prospective study modeling immune-related AEs (irAEs) in patients with solid tumors (regardless of the primary site) treated with immune checkpoint inhibitor irrespective of disease stage. The probability of presenting an irAE over time was estimated using the prevalence function. The time-to-onset (TTO) and the mean number of recurrent irAEs were also assessed. Among the 147 patients analyzed, 39.7% had a melanoma, 37.7% a non-small cell lung cancer (NSCLC) and 74.8% were treated for metastatic disease. Despite a higher proportion of melanoma patients presenting at least one irAE, the prevalence of irAEs was lower in melanoma than in NSCLC patients over time. TTO analysis showed that irAEs occurred earlier in NSCLC patients whereas melanoma patients experienced more recurrent irAEs over the long-term. The prevalence function of non-metastatic and metastatic patients revealed different long-term toxicity profiles. These alternative methodologies capture different toxicity patterns (time-to-onset, recurrent, acute episodic or long-term moderate AEs) and provide a more consistent safety assessment for new therapeutics, thereby assisting clinicians and health authorities in their therapeutic decision-making processes., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Aims: The cerebellum is a key structure in working and procedural memory. The aim of the present prospective exploratory study was to investigate, the metabolic characteristics of the cerebellum in posterior fossa tumor (PFT) survivors using 3D proton magnetic resonance spectroscopy imaging (3D MRSI), to determine whether metabolites could be useful biomarkers of memory impairment., Materials and Methods: Sixty participants were included in the IMPALA study, divided into three groups: 22 irradiated PFT, 17 nonirradiated PFT, and 21 healthy controls matched with irradiated PFT for age, sex, and handedness. PFT survivors were treated at least 5 years ago, either by surgery or a combination of surgery, chemotherapy, and radiotherapy. All participants underwent working and procedural memory tests and multimodal MRI including a 3D MRSI sequence. N-acetylaspartate (NAA), choline (Cho), creatine (Cr), and lactate (Lac) metabolite values were extracted from the cerebellum for comparisons between groups, correlations with neurocognitive test scores, and radiotherapy doses., Results: Median (range) age at neurocognitive tests was 18 (7-26) years. Median Cho, Cr, NAA, and Lac values, and the ratio of NAA to the sum of metabolites were significantly lower for PFT survivors than for healthy controls (p < 0.05). Scores on working and procedural memory tests were significantly lower for PFT survivors (p < 0.004) and correlated with median and maximum Cho and NAA values (0.28

Background and Aims: Transarterial chemoembolization is the most common treatment used for HCC patients on liver transplant waiting list. The aims of this study are to evaluate the radio-histological correlation of the post-chemoembolization HCC response and its influence on overall survival (OS) and recurrence-free survival (RFS)., Methods: Monocentric, retrospective study, including liver transplant patients with HCC who received chemoembolization from 2007 to 2018. The response of the hypervascular nodules was evaluated according to mRECIST, EASL., Results: A total of 70 patients with 122 hypervascular and 28 hypovascular HCCs were included. A complete radiological response concerned 34.3% patients. Concordance rates of hypervascular nodules (mRECIST, EASL and lipiodol uptake) with tumor necrosis ranged from 49% to 57%, with a specificity of 35% and a positive predictive value of 54%. Bilobar involvement was a predictive factor for incomplete radiological response. Major tumor necrosis was significantly correlated with the decrease in αFP level between the first CEL and liver transplantation. OS and RFS at 5 years were 64% and 60%, respectively, and 69% and 66% at complete radiological response., Conclusion: Radiological response is significantly related to histological tumor necrosis, but with poor prediction. In case of complete radiological response, OS and RFS seem to be improved., Competing Interests: Declaration of competing interest There was no financial support. None of the authors have any conflicts of interest related to this manuscript., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The effects of postoperative pancreatic fistula on survival rates remain controversial. The aim of the present study was to evaluate the influence of postoperative pancreatic fistula on overall survival and recurrence-free survival after upfront pancreatoduodenectomy for pancreatic ductal adenocarcinoma., Methods: Patients operated on between January 2007 and December 2017 at seven tertiary pancreatic centres for pancreatic ductal adenocarcinoma were included in the study. Postoperative pancreatic fistula was defined using the 2016 International Study Group on Pancreatic Surgery grading system. The impact of postoperative pancreatic fistula on overall survival, recurrence-free survival (excluding 90-day postoperative deaths) and corresponding risk factors were investigated by univariable and multivariable analyses. Comparisons between groups were made using the chi-squared or Fisher's exact test for categorical variables and the Mann-Whitney U test for continuous variables. Odds ratios were estimated with their 95% confidence intervals. Survival rates were calculated using the Kaplan-Meier method with their 95% confidence intervals., Results: A total of 819 patients were included between 2007 and 2017. Postoperative pancreatic fistula occurred in 14.4% (n = 118) of patients; of those, 7.8% (n = 64) and 6.6% (n = 54) accounted for grade B and grade C postoperative pancreatic fistula respectively. The 5-year overall survival was 37.0% in the non-postoperative pancreatic fistula group and 45.3% in the postoperative pancreatic fistula cohort (P = 0.127). Grade C postoperative pancreatic fistula (excluding 90-day postoperative deaths) was not a prognostic factor for overall survival. The 5-year recurrence-free survival was 26.0% for patients without postoperative pancreatic fistula and 43.7% for patients with postoperative pancreatic fistula (P = 0.003). Eight independent prognostic factors for recurrence-free survival were identified: age over 70 years, diabetes, moderate or poor tumour differentiation, T3/T4 tumour stage, lymph node positive status, resection margins R1, vascular emboli and perineural invasion., Conclusion: This high-volume cohort showed that grade C postoperative pancreatic fistula, based on the 2016 International Study Group on Pancreatic Surgery grading system, does not impact overall or recurrence-free survival (excluding 90-day postoperative deaths)., (© The Author(s) 2024. Published by Oxford University Press on behalf of BJS Foundation Ltd.)

Introduction: In France, 40% of patients diagnosed with lung cancer are ≥70 years old, but these are under-represented in clinical trials. Using data from the French Epidemiological Strategy and Medical Economics (ESME) platform on Lung Cancer (LC), the objective is to provide an overview of the management and the prognosis of older patients with advanced or metastatic non-small cell lung cancer (AM-NSCLC) in a real-world context., Materials and Methods: From the ESME-LC database, we selected patients with AM-NSCLC (stage IIIB, IIIC, and IV), diagnosed between 2015 and 2019, and who received first-line systemic treatment. Demographics, tumour characteristics, and treatment received were described in patients ≥70, and compared to younger ones. Real-world progression-free survival (rwPFS) and overall survival (OS) were evaluated using the multivariable Cox model., Results: Among 10,002 patients with AM-NSCLC, the median age was 64 years, with 2,754 (27.5%) aged ≥70. In comparison with patients <70, older patients were more often male, with worse performance status and more comorbidities, but they were less underweight and more often non-smokers. The proportion of EGFR mutated non-squamous NSCLC was higher in older patients (25.0% vs 12.8%, p < 0.001), particularly among smokers and former smokers (12.7% vs 7.3%, p < 0.001). Among patients ≥70, 76.6% received first-line chemotherapy (including 67.0% treated with a platinum-based doublet), 15.0% received only targeted therapy, and 11.0% received immunotherapy (alone or in combination). Median first-line rwPFS was 5.1 months (95% confidence interval [CI] = [4.8;5.4]) for patients ≥70 and 4.6 months (95%CI = [4.4;4.8]) for patients <70, but age was not associated with rwPFS in multivariable analysis. Median OS was 14.8 months (95%CI = [13.9;16.1]) for patients ≥70 and 16.7 months (95%CI = [15.9;17.5]) for patients <70, with a significant effect of age in multivariable analysis for patients treated with chemotherapy and/or with targeted therapy, but not for patients treated with immunotherapy (alone or in combination with chemotherapy)., Discussion: In this real-world cohort of patients with AM-NSCLC, age was not associated with first-line rwPFS regardless of treatment received, nor with OS for patients receiving immunotherapy. However, OS was significantly shorter for patients aged ≥70 treated with chemotherapy or with targeted therapy alone., Competing Interests: Declaration of Competing Interest Mathilde Cabart reports non-financial support from Janssen, non-financial support from Pfizer, outside the submitted work. Loïc Mourey reports personal fees and non-financial support from Sanofi, personal fees from Astellas, personal fees and non-financial support from Janssen, personal fees and non-financial support from MSD, personal fees and non-financial support from BMS, personal fees and non-financial support from Ipsen, personal fees and non-financial support from Astra-Zeneca, personal fees and non-financial support from Pfizer, personal fees from Merck, outside the submitted work. David Pasquier has nothing to disclose. Sophie Schneider has nothing to disclose. Hervé Léna reports personal fees and non-financial support from Roche, personal fees from Astrazeneca, personal fees and non-financial support from MSD, personal fees and non-financial support from Novartis, personal fees and non-financial support from Takeda, personal fees from BMS, personal fees and non-financial support from Pfizer, non-financial support from Lilly, personal fees and non-financial support from Amgen, outside the submitted work. Nicolas Girard reports grants and personal fees from AstraZeneca, personal fees from Daiichi, grants and personal fees from Roche, grants and personal fees from MSD, grants and personal fees from BMS, grants and personal fees from Pfizer, grants and personal fees from Janssen, grants and personal fees from Boehringer Ingelheim, grants and personal fees from Takeda, grants and personal fees from Novartis, grants and personal fees from Sanofi, outside the submitted work; and Family Member employee of AstraZeneca. Christos Chouaid reports grants, personal fees and non-financial support from AstraZeneca, grants, personal fees and non-financial support from Boehringer Ingelheim, grants, personal fees and non-financial support from GSK, grants, personal fees and non-financial support from Roche, grants, personal fees and non-financial support from Sanofi Aventis, grants, personal fees and non-financial support from BMS, grants, personal fees and non-financial support from MSD, grants, personal fees and non-financial support from Lilly, grants, personal fees and non-financial support from Novartis, grants, personal fees and non-financial support from Pfizer, grants, personal fees and non-financial support from Takeda, grants, personal fees and non-financial support from Bayer, grants, personal fees and non-financial support from Janssen, grants, personal fees and non-financial support from Viatris, grants, personal fees and non-financial support from Chugai, grants, personal fees and non-financial support from Pierre Fabre, grants, personal fees and non-financial support from Amgen, outside the submitted work. Roland Schott reports personal fees and non-financial support from Roche, non-financial support from Takeda, personal fees and non-financial support from AstraZeneca, personal fees and non-financial support from Pfizer, non-financial support from IPSEN, personal fees and non-financial support from BMS, outside the submitted work. Sandrine Hiret reports non-financial support from Roche, non-financial support from Novartis, other from Sanofi, other from Astra Zeneca, other from Takeda, other from BMS, outside the submitted work. Didier Debieuvre has nothing to disclose. Xavier Quantin has nothing to disclose. Anne Madroszyk has nothing to disclose. Pascale Dubray-Longeras reports personal fees from MSD, personal fees from AstraZeneca, personal fees and non-financial support from Takeda, non-financial support from Pfizer, outside the submitted work. Eric Pichon reports personal fees and non-financial support from Takeda, personal fees from AstraZeneca, personal fees from MSD, outside the submitted work. Anne Baranzelli has nothing to disclose. Grégoire Justeau has nothing to disclose. Maurice Pérol reports personal fees and non-financial support from Takeda, personal fees from Janssen, personal fees and non-financial support from AstraZeneca, outside the submitted work. Lise Bosquet has nothing to disclose. Bastien Cabarrou has nothing to disclose., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Current guidelines recommend that patients with HER2-low metastatic breast cancer (MBC) receive sequentially two antibody-drug conjugates (ADCs): Sacituzumab Govitecan (SG) and Trastuzumab Deruxtecan (T-DXd), despite a similar payload. However, the effectiveness of one after another is unknown., Methods: ADC-Low is a multicentre, retrospective study evaluating the efficacy of SG and T-DXd, one after another, with or without intermediary lines of chemotherapy, in patients with HER2-low MBC., Results: One hundred and seventy-nine patients were included: the majority with HR-negative tumours received SG first (ADC1) (n = 100/108) while most with HR-positive tumours received T-DXd first (n = 56/71). Median progression-free survival 2 was short: 2.7 months (95% CI: 2.4-3.3) in the whole population, respectively, 3.1 (95% CI: 2.6-3.6) and 2.2 months (95% CI: 1.9-2.7) for patients receiving T-DXd or SG second (ADC2). Intermediary lines of chemotherapy between ADC1 and ADC2 had no impact. Primary resistance to ADC2 occurred in 54.4% of patients. Certain patients showed initial response to ADC2., Conclusions: Clinical benefit of sequentially administered SG and T-DXd is limited for most patients. Nevertheless, a subset of patients might benefit-on the short term-from a second ADC. Additional studies are needed to identify patients who could benefit from two ADCs with similar payloads., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Objective: The aim of this study was to compare surgical complexity, post-operative complications, and survival outcomes between patients with minimal residual disease (completeness of cytoreduction (CC) score) CC-1 at the time of primary debulking surgery and those with complete cytoreduction (CC-0) at the time of interval debulking surgery., Methods: A retrospective multicenter study was conducted of patients with advanced ovarian cancer (International Federation of Gynecology and Obstetrics stage IIIC-IV) who underwent cytoreductive surgery achieving either minimal or no residual disease between January 2008 and December 2015. Patients underwent either primary or interval debulking surgery after receiving ≥3 cycles of neoadjuvant chemotherapy. The sub-group of patients with primary debulking surgery/CC-1 was compared with those with interval debulking surgery/CC-0. Overall survival and disease-free survival were estimated using the Kaplan-Meier method., Results: A total of 549 patients were included, with upfront surgery performed in 175 patients (31.9%) and 374 patients (68.1%) undergoing interval debulking surgery. After primary debulking surgery, 157/175 (89.7%) had complete cytoreduction and 18/175 (10.3%) had minimal residual disease (primary debulking surgery/CC-1 group), while after interval debulking surgery, 324/374 (86.6%) had complete cytoreduction (interval debulking surgery/CC-0 group) and 50/374 (13.4%) had minimal residual disease. The rate of patients with peritoneal cancer index >10 was 14/17 (82.4%) for the primary debulking surgery/CC-1 group and 129/322 (40.1%) for the interval debulking surgery/CC-0 (p<0.001). The rate of patients with an Aletti score of ≥8 was 11/18 (61.1%) and 132/324 (40.7%), respectively (p=0.09) and the rate of major post-operative complications was 5/18 (27.8%) and 64/324 (19.8%), respectively (p=0.38). Overall median disease-free and overall survival were 19.4 months (95% CI 18.0 to 20.6) and 56.7 months (95%CI 50.2 to 65.8), respectively. Median disease-free survival for the primary debulking surgery/CC-1 group was 16.7 months (95% CI 13.6 to 20.0) versus 18.2 months (95% CI 16.4 to 20.0) for the interval debulking surgery/CC-0 group (p=0.56). Median overall survival for the primary debulking surgery/CC-1 group was 44.7 months (95% CI 34.3 to not reached) and 49.4 months (95% CI 46.2 to 57.3) for the interval debulking surgery/CC-0 group (p=0.97)., Conclusions: Patients with primary debulking surgery with minimal residual disease and those with interval debulking surgery with no residual disease had similar survival outcomes. Interval surgery should be considered when achieving absence of residual disease is challenging at upfront surgery, given the lower tumor burden found during surgery., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: High-risk prostate cancer (PCa) patients frequently experience recurrence and progression after radical prostatectomy (RP). Neoadjuvant androgen deprivation therapy (ADT) has not demonstrated a clear oncological benefit and is not currently recommended., Objective: The SUGAR trial is the first phase 2, randomised, controlled, multicentre, noncommercial, open-label study investigating single-agent perioperative darolutamide compared with the standard of care (ie, upfront RP, without neoadjuvant ADT)., Design, Setting, and Participants: SUGAR aims to randomise 240 men affected by nonmetastatic PCa, with the major eligibility criteria being International Society of Urological Pathology grade group ≥4, seminal vesicle invasion at magnetic resonance imaging and/or clinically node-positive disease. Patients in the experimental arm will undergo neoadjuvant darolutamide monotherapy, RP, and adjuvant darolutamide, completing 9 mo of treatment., Outcome Measurements and Statistical Analysis: The primary endpoint is noncurable recurrence-free survival, an innovative and clinically meaningful measure; the secondary endpoints encompass safety; recurrence-free, metastasis-free, and overall survival; pathological response; and quality of life. A predictive biomarker analysis will also be performed., Results and Limitations: Initial data suggest that intensified neoadjuvant treatment with androgen receptor signalling inhibitors (ARSIs) is associated with a sustained pathological response and may improve outcomes, via tumour downstaging and micrometastasis eradication. ARSI monotherapy could further enhance tolerability., Conclusions: SUGAR will provide efficacy and safety information on perioperative darolutamide monotherapy compared with upfront RP, in a contemporary high-risk PCa population undergoing surgery., Patient Summary: The on-going SUGAR clinical trial evaluates 9 mo of darolutamide treatment in addition to radical prostatectomy, in men affected by prostate cancer with specific high-risk characteristics. It investigates whether this hormonal treatment can lower the rates of noncurable recurrences, maintaining a favourable tolerability profile., (Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Objective: As craniospinal irradiation (CSI) is delivered more frequently by helical tomotherapy (HT) with few reports about late effects, we analysed all patients treated in our centre over an 11-year period., Methods and Materials: Our study included all patients that underwent CSI by HT, between September 2009 and January 2020, in the Department of Radiation Oncology of the Toulouse Cancer Institute. Acute radiotherapy toxicities were reported and medium- to long-term outcomes analysed., Results: Among the 79 patients included, 70.9 % were younger than 18 years at diagnosis, the median age was 13 (range: 1-52) at the time of radiation therapy, 67.1 % of patients had medulloblastoma. Half of them (49.4 %) had a metastatic disease at diagnosis. The median dose of CSI was 36 Gy (range, 18-36). Seventy-seven patients received a radiation boost to the original location of the primary tumour (97.5 %), 32 patients also received a boost to their metastatic sites (40.5 %). Median follow-up was 55.5 months (95 %CI = [41.2; 71.8]). The 3-year event-free survival rate was 66.3 % (95 %CI = [54.2; 75.9]). Most patients presented with acute haematological toxicities during CSI (85.9 %), predominantly severe thrombocytopenia (39.7 %). Among the 64 patients assessed for medium- and long-term outcomes, 52 survived and 47 were alive and disease-free at the latest follow-up visit on record. There were 3.8 % secondary tumours: two meningiomas and one diffuse intrinsic pontine glioma. Adult and paediatric patients respectively presented with secondary cataract (4.3 % vs 22.0 %), persistent hearing disorders (26.1 % vs 29.3 %), pulmonary or cardiac late effects (4.3 % vs 2.4 %), hormonal pituitary gland deficiencies (30.0 % vs 56.8 %) and psycho-cognitive disorders (56.5 % vs 53.7 %)., Conclusion: CSI dispensed by HT, did not result in any additional acute or late toxicities when compared to 3D-CSI. There was no increase in the secondary tumour rate compared to that reported in the literature., Competing Interests: 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 The Authors.)

Aims: Posterior fossa tumours (PFTs), which account for two-thirds of paediatric brain tumours, are successfully treated in about 70% of patients, but most survivors experience long-term cognitive impairment. We evaluated arterial spin labelling (ASL), a common, non-invasive magnetic resonance imaging (MRI) technique, as a biomarker of cognitive impairment in a paediatric PFT survivor population., Materials and Methods: Sixty participants were prospectively analysed. PFT survivors were at least 5 years post-treatment and had been treated as appropriate for their age and type of tumour. Group 1 had received radiotherapy and Group 2 had not. Group 3 were healthy controls matched to Group 1 for age, sex and handedness. All participants underwent cognitive assessment and multimodal MRI, including an ASL perfusion sequence. We used semi-quantitative ASL methods to assess differences in mean perfusion in the thalamus, caudate, putamen and hippocampus., Results: Statistically, no significant associations between cognitive data and radiation doses were identified. Compared with healthy controls, Group 1 patients had significantly lower overall mean perfusion values (20-30% lower, depending on the cerebral structure) and Group 2 had slightly lower mean perfusion values (5-10% lower). Perfusion values did not correlate with total prescribed irradiation doses nor with doses received by different cerebral structures. Episodic and semantic memory test scores were significantly lower in Group 1 and correlated with lower mean absolute perfusion values in the hippocampus (P < 0.04)., Conclusions: These preliminary results indicate that radiotherapy affects the perfusion of specific cerebral structures and identify perfusion as a potential biomarker of hippocampus-dependent memory deficit., (Copyright © 2023. Published by Elsevier Ltd.)

Even though male breast cancer (MBC) risk encompasses both genetic and environmental aetiologies, the primary risk factor is a germline pathogenic variant (PV) or likely pathogenic variant (LPV) in BRCA2, BRCA1 and/or PALB2 genes. To identify new potential MBC-specific predisposition genes, we sequenced a panel of 585 carcinogenesis genes in an MBC cohort without BRCA1/BRCA2/PALB2 PV/LPV. We identified 14 genes carrying rare PVs/LPVs in the MBC population versus noncancer non-Finnish European men, predominantly coding for DNA repair and maintenance of genomic stability proteins. We identified for the first time PVs/LPVs in PRCC (pre-mRNA processing), HOXA9 (transcription regulation), RECQL4 and WRN (maintenance of genomic stability) as well as in genes involved in other cellular processes. To study the specificity of this MBC PV/LPV profile, we examined whether variants in the same genes could be detected in a female breast cancer (FBC) cohort without BRCA1/BRCA2/PALB2 PV/LPV. Only 5/109 women (4.6%) carried a PV/LPV versus 18/85 men (21.2%) on these genes. FBC did not carry any PV/LPV on 11 of these genes. Although 5.9% of the MBC cohort carried PVs/LPVs in PALLD and ERCC2, neither of these genes were altered in our FBC cohort. Our data suggest that in addition to BRCA1/BRCA2/PALB2 , other genes involved in DNA repair/maintenance or genomic stability as well as cell adhesion may form a specific MBC PV/LPV signature.

Background: Hypofractionated stereotactic radiotherapy (hFSRT) is a salvage option for recurrent glioblastoma (GB) which may synergize anti-PDL1 treatment. This phase I study evaluated the safety and the recommended phase II dose of anti-PDL1 durvalumab combined with hFSRT in patients with recurrent GB., Methods: Patients were treated with 24 Gy, 8 Gy per fraction on days 1, 3, and 5 combined with the first 1500 mg Durvalumab dose on day 5, followed by infusions q4weeks until progression or for a maximum of 12 months. A standard 3 + 3 Durvalumab dose de-escalation design was used. Longitudinal lymphocytes count, cytokines analyses on plasma samples, and magnetic resonance imaging (MRI) were collected., Results: Six patients were included. One dose limiting toxicity, an immune-related grade 3 vestibular neuritis related to Durvalumab, was reported. Median progression-free interval (PFI) and overall survival (OS) were 2.3 and 16.7 months, respectively. Multi-modal deep 
learning-based analysis including MRI, cytokines, and lymphocytes/neutrophil ratio isolated the patients presenting pseudoprogression, the longest PFI and those with the longest OS, but statistical significance cannot be established considering phase I data only., Conclusion: Combination of hFSRT and Durvalumab in recurrent GB was well tolerated in this phase I study. These encouraging results led to an ongoing randomized phase II. (ClinicalTrials.gov Identifier: NCT02866747)., (© The Author(s) 2023. Published by Oxford University Press.)

Background: IDH mutant and 1p/19q codeleted oligodendrogliomas are the gliomas associated with the best prognosis. However, despite their sensitivity to treatment, patient survival remains heterogeneous. We aimed to identify gene expressions associated with response to treatment from a national cohort of patients with oligodendrogliomas, all treated with radiotherapy +/- chemotherapy., Methods: We extracted total RNA from frozen tumor samples and investigated enriched pathways using KEGG and Reactome databases. We applied a stability selection approach based on subsampling combined with the lasso-pcvl algorithm to identify genes associated with progression-free survival and calculate a risk score., Results: We included 68 patients with oligodendrogliomas treated with radiotherapy +/- chemotherapy. After filtering, 1697 genes were obtained, including 134 associated with progression-free survival: 35 with a better prognosis and 99 with a poorer one. Eight genes (ST3GAL6, QPCT, NQO1, EPHX1, CST3, S100A8, CHI3L1, and OSBPL3) whose risk score remained statistically significant after adjustment for prognostic factors in multivariate analysis were selected in more than 60% of cases were associated with shorter progression-free survival., Conclusions: We found an eight-gene signature associated with a higher risk of rapid relapse after treatment in patients with oligodendrogliomas. This finding could help clinicians identify patients who need more intensive treatment.

Background: Interstitial lung disease is a heterogeneous group of diseases, some of which are known to present an independent risk factor for lung cancer. Its pathophysiological mechanism has not been fully elucidated and therapeutic management is also complex. We aim to both describe a cohort of patients with lung cancer associated with pre-existing fibrosing interstitial lung disease and to characterize their molecular profile., Methods: We conducted a retrospective, single centre cohort study, at Toulouse University Hospital. Immuno-histochemical (PD-L1, CD8) and molecular analysis was performed on archived tumour sample. Molecular signalling pathways involved were analysed with the Reactome Pathway Database., Results: Forty-nine patients were analysed. Most common histology was adenocarcinoma (65,3%), followed by squamous cell carcinoma (30.6%). Idiopathic pulmonary fibrosis (30,6%) and interstitial lung disease associated with connective tissue disease (22,4%) were mostly diagnosed. Usual interstitial pneumonia dominated the scans patterns. A high proportion of early tumour stages was observed and overall survival was 34,5 months. In metastatic stages response rate to first line chemotherapy was 38% and overall survival was 11,2 months. Main cause of death was complex cancer progression. PD-L1 expression (n=23) was low (0%) to intermediate (1-49%). Tumour mutational burden was low in 69,2% of analysed cases (n=12) and microsatellite status was stable in all cases (n=13). Sample genotyping (n=14) showed frequent involvement of the TP53 gene and the implication of signalling pathways common to fibrotic processes such as TGFβ and PI3K/AKT., Conclusions: We suggest a particular phenotype of lung cancer associated with fibrosing interstitial lung disease that could provide the basis for specific therapeutic strategies., Competing Interests: Declaration of Competing Interest All authors have completed the disclosure form. Julien Mazières benefits from funding Roche FMI tests. The other authors have no conflicts of interest to declare, (Copyright © 2022 SPLF and Elsevier Masson SAS. All rights reserved.)

Purpose: Data about incidence, biological, and clinical characteristics of oligometastatic breast cancer (OMBC) are scarce. However, these data are essential in determining optimal treatment strategy. Gaining knowledge of these elements means observing and describing large, recent, and consecutive series of OMBC in their natural history., Methods: We collected data retrospectively at our institution from 998 consecutive patients diagnosed and treated with synchronous or metachronous metastatic breast cancer (MBC) between January 2014 and December 2018. The only criterion used to define OMBC was the presence of one to five metastases at diagnosis., Results: Of 998 MBC, 15.8% were classified OMBC. Among these, 88% had one to three metastases, and 86.7% had only one organ involved. Bone metastases were present in 52.5% of cases, 20.9% had progression to lymph nodes, 14.6% to the liver, 13.3% to the brain, 8.2% to the lungs, and 3.8% had other metastases. 55.7% had HR+/HER2- OMBC, 25.3% had HER2+OMBC, and 19% had HR-/HER2- OMBC. The HR+/HER2- subtype statistically correlated with bone metastases (p = 0.001), the HER2+subtype with brain lesions (p = 0.001), and the HR-/HER2- subtype with lymph node metastases (p = 0.008). Visceral metastases were not statistically associated with any OMBC subtypes (p = 0.186). OMBC-SBR grade III was proportionally higher than in the ESME series of 22,109 MBC (49.4% vs. 35.1%, p < 0.001)., Conclusion: OMBC is a heterogeneous entity whose incidence is higher than has commonly been published. Not an indolent disease, each subgroup, with its biological and anatomical characteristics, merits specific management., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background and Purpose: To investigate the feasibility of using a multiapproach analysis combining clinical data, diffusion- and perfusion-weighted imaging, and 3D magnetic resonance spectroscopic imaging to distinguish true tumor progression (TP) from pseudoprogression (PSP) in patients with glioblastoma., Materials and Methods: Progression was suspected within 6 months of radiotherapy in 46 of the 180 patients included in the Phase-III SpectroGlio trial (NCT01507506). Choline/creatine (Cho/Cr), choline/N-acetyl aspartate (Cho/NAA) and lactate/N-acetyl aspartate (Lac/NAA) ratios were extracted. Apparent diffusion coefficient (ADC) and cerebral blood volume (CBV) maps were calculated. ADC, relative CBV values and tumor volume (TV) were collected at relapse. Differences between TP and PSP were evaluated using Mann-Whitney tests, and p values were adjusted with Bonferroni correction., Results: Patients with suspected progression underwent a new MRI scan 1 month after the first one. Of these, 28 were classified as PSP, and 18 as TP. After a median follow-up of 41 months, median overall survival was higher in PSP than in TP (25.2 vs 20.3 months; p = 0.0092). Lac/NAA and Cho/Cr ratios were higher in TP than in PSP (1.2 vs 0.5; p = 0.006; and 3 vs 2.2; p = 0.021). After multivariate regression analysis, TV was the most significant predictor of TP vs PSP, and the only one retained in the model (p = 0.028)., Conclusion: Three spectroscopic ratios could be used to differentiate PSP from TP. TV at relapse was the most predictive factor in the multivariate analysis, and overall survival was higher in PSP than in TP., (Copyright © 2023. Published by Elsevier B.V.)

Purpose: Local ablative treatment (LAT) is increasingly combined with systemic therapy in oligometastatic breast cancer (OMBC), without a high-level evidence to support this strategy. We evaluated the addition of LAT to systemic treatment in terms of progression-free survival (PFS) and overall survival (OS). Secondary endpoints were local control (LC) and toxicity. We sought to identify prognostic factors associated with longer OS and PFS., Methods and Materials: We identified consecutive patients treated between 2014 and 2018 for synchronous or metachronous OMBC (defined as ≤ 5 metastases). LAT included stereotactic body radiation therapy (SBRT) and volumetric modulated arc therapy (VMAT), surgery, cryotherapy and percutaneous radiofrequency ablation (PRA). PFS and OS were calculated, and Cox regression models analyzed for potential predictors of survival., Results: One hundred two patients were included (no-LAT, n = 62; LAT, n = 40). Sixty-four metastases received LAT. Median follow-up was 50.4 months (95% CI [44.4; 53.4]). One patient experienced grade 3 toxicity in the LAT group. Five-year PFS and OS were 34.75% (95% CI [24.42-45.26]) and 63.21% (95% CI [50.69-73.37]) respectively. Patients receiving both LAT and systemic therapy had longer PFS and OS than those with no-LAT ([HR 0.39, p = 0.002]) and ([HR 0.31, p = 0.01]). The use of LAT, HER2-positive status and hormone-receptor positivity were associated with longer PFS and OS whereas liver metastases led to worse PFS., Conclusions: LAT was associated with improved outcomes in OMBC when added to systemic treatment, without significantly increasing toxicity. The prognostic factors identified to extend PFS and OS may help guide clinicians in selecting patients for LAT., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Our study aimed to evaluate the association between timing of cytoreductive surgery and pattern of presentation of the first recurrence in patients with advanced ovarian cancer. We also aimed to assess the impact of the pattern of recurrence on post-relapse overall survival according to surgical timing., Methods: This retrospective multicenter study evaluated patients with International Federation of Gynecology and Obstetrics (FIGO) stage IIIC-IV ovarian cancer. Patients had undergone either primary debulking surgery, early interval debulking surgery after 3-4 cycles of neoadjuvant chemotherapy, or delayed debulking surgery after 6 cycles, with minimal or no residual disease, between January 2008 and December 2015. Survival analyses were conducted using the Log-rank test and the Cox model. Cumulative incidences of the different patterns of recurrence were estimated using a competing risks methodology., Results: A total of 549 patients were included: 175 (31.9%) patients had primary, 224 (40.8%) early interval, and 150 (27.3%) delayed debulking surgery. The cumulative incidence of peritoneal recurrences at 2 years was higher with increasing neoadjuvant cycles (24.4%, 30.9% and 39.2%; p=0.019). For pleural or pulmonary recurrences, it was higher after early interval surgery (9.9%, 13.0% and 4.1%; p=0.022). Median post-relapse overall survival was 33.5 months (95% confidence interval (CI) (24.3 to 44.2)), 26.8 months (95% CI (22.8 to 32.6)), and 24.5 months (95% CI (18.6 to 29.4)) for primary, early interval, and delayed debulking surgery groups, respectively (p=0.025). The pattern of recurrence in a lymph node (hazard ratio (HR) 0.42, 95% CI (0.27 to 0.64)), delayed surgery (HR 1.53, 95% CI (1.11 to 2.13)) and time to first recurrence (HR 0.95, 95% CI (0.93 to 0.96)) were associated with post-relapse overall survival. For primary and early interval surgery, lymph node recurrences were associated with significantly longer post-relapse overall survival., Conclusions: The pattern of first recurrence was associated with timing of surgery, with peritoneal recurrences being more frequent with the increasing number of cycles of neoadjuvant chemotherapy. Lymph node recurrences were associated with better prognosis, having higher post-relapse overall survival. This improved prognosis of lymphatic recurrences was not observed in patients who underwent delayed surgery., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

According to expert guidelines, lymph node surgical excision is the standard of care for lymphoma diagnosis. However, core needle biopsy (CNB) has become widely accepted as part of the lymphoma diagnostic workup over the past decades. The aim of this study was to present the largest multicenter inventory of lymph nodes sampled either by CNB or surgical excision in patients with suspected lymphoma and to compare their diagnostic performance in routine pathologic practice. We reviewed 32 285 cases registered in the French Lymphopath network, which provides a systematic expert review of all lymphoma diagnoses in France, and evaluated the percentage of CNB and surgical excision cases accurately diagnosed according to the World Health Organization classification. Although CNB provided a definitive diagnosis in 92.3% and seemed to be a reliable method of investigation for most patients with suspected lymphoma, it remained less conclusive than surgical excision, which provided a definitive diagnosis in 98.1%. Discordance rates between referral and expert diagnoses were higher on CNB (23.1%) than on surgical excision (21.2%; P = .004), and referral pathologists provided more cases with unclassified lymphoma or equivocal lesion through CNB. In such cases, expert review improved the diagnostic workup by classifying ∼90% of cases, with higher efficacy on surgical excision (93.3%) than CNB (81.4%; P < 10-6). Moreover, diagnostic concordance for reactive lesions was higher on surgical excision than CNB (P = .009). Overall, although CNB accurately diagnoses lymphoma in most instances, it increases the risk of erroneous or nondefinitive conclusions. This large-scale survey also emphasizes the need for systematic expert review in cases of lymphoma suspicion, especially in those sampled by using CNB., (© 2022 by The American Society of Hematology.)

Background: Given the inherent challenges of conducting randomized phase III trials in older cancer patients, single-arm phase II trials which assess the feasibility of a treatment that has already been shown to be effective in a younger population may provide a compelling alternative. Such an approach would need to evaluate treatment feasibility based on a composite endpoint that combines multiple clinical dimensions and to stratify older patients as fit or frail to account for the heterogeneity of the study population to recommend an appropriate treatment approach. In this context, stratified adaptive two-stage designs for binary or composite endpoints, initially developed for biomarker studies, allow to include two subgroups whilst maintaining competitive statistical performances. In practice, heterogeneity may indeed affect more than one dimension and incorporating co-primary endpoints, which independently assess each individual clinical dimension, would therefore appear quite pertinent. The current paper presents a novel phase II design for co-primary endpoints which takes into account the heterogeneity of a population.  METHODS: We developed a stratified adaptive Bryant & Day design based on the Jones et al. and Parashar et al. algorithm. This two-stage design allows to jointly assess two dimensions (e.g. activity and toxicity) in two different subgroups. The operating characteristics of this new design were evaluated using examples and simulation comparisons with the Bryant & Day design in the context where the study population is stratified according to a pre-defined criterion., Results: Simulation results demonstrated that the new design minimized the expected and maximum sample sizes as compared to parallel Bryant & Day designs (one in each subgroup), whilst controlling type I error rates and maintaining a competitive statistical power as well as a high probability of detecting heterogeneity., Conclusions: In a heterogeneous population, this two-stage stratified adaptive phase II design provides a useful alternative to classical one and allows to identify a subgroup of interest without dramatically increasing sample size. As heterogeneity is not limited to older populations, this new design may also be relevant to other study populations such as children or adolescents and young adults or the development of targeted therapies based on a biomarker., (© 2022. The Author(s).)

Objective: We sought to evaluate the impact of chemotherapy response score according to the number of cycles of neoadjuvant chemotherapy, on disease-free survival and overall survival, in patients with advanced epithelial ovarian cancer ineligible for primary debulking surgery., Methods: This multicenter retrospective study included patients with International Federation of Gynecology and Obstetrics (FIGO) stage IIIC-IV epithelial ovarian cancer who underwent 3-4 or 6 cycles of a platinum and taxane-based neoadjuvant chemotherapy, followed by complete cytoreduction surgery (CC-0) or cytoreduction to minimal residual disease (CC-1), between January 2008 and December 2015, in four institutions. Disease-free survival and overall survival were assessed according to the histological response to chemotherapy defined by the validated chemotherapy response score., Results: A total of 365 patients were included: 219 (60.0%) received 3-4 cycles of neoadjuvant chemotherapy, and 146 (40.0%) had 6 cycles of neoadjuvant chemotherapy before cytoreductive surgery. There were no significant differences in early relapses, disease-free survival, and overall survival according to the number of neoadjuvant chemotherapy cycles. However, regardless of the number cycles of neoadjuvant chemotherapy, persistent extensive histological disease (chemotherapy response score 1-2) was significantly associated with a higher peritoneal cancer index, minimal residual disease (CC-1), and early relapses. Median disease-free survival in patients with complete or near-complete response (score 3) was 28.3 months (95% CI 21.6 to 36.8), whereas it was 16.3 months in patients with chemotherapy response score 1-2 (95% CI 14.7 to 18.0, p<0.001)., Conclusion: In our cohort, the number of neoadjuvant chemotherapy cycles was not associated with disease-free survival or overall survival. Chemotherapy response score 3 improved oncological outcome regardless of the number of neoadjuvant chemotherapy cycles., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To assess the impact on survival of major postoperative complications and to identify the factors associated with these complications in patients with advanced ovarian cancer after cytoreductive surgery., Methods: We designed a retrospective multicenter study collecting data from patients with IIIC-IV FIGO Stage ovarian cancer who had undergone either primary debulking surgery (PDS), early interval debulking surgery (IDS) after 3-4 cycles of neoadjuvant chemotherapy, or delayed debulking surgery (DDS) after 6 cycles, with minimal or no residual disease, from January 2008 to December 2015. Univariable and multivariable analyses were conducted to identify factors associated with major surgical complications (≥Grade 3). We assessed disease-free survival (DFS) and overall survival (OS) rates according to the occurrence of major postoperative complications., Results: 549 women were included. The overall rate of major surgical complications was 22.4%. Patients who underwent PDS had a higher rate of major complications (28.6%) than patients who underwent either early IDS (23.2%) or DDS (14.0%). Multivariable analysis revealed that extensive peritonectomy and surgical timing were associated with the occurrence of major complications. Median DFS and OS were 16.9 months (95%CI = [13.7-18.4]) and 48.0 months (95%CI = [37.2-73.1]) for the group of patients with major complications, and 20.1 months (95%CI = [18.6-22.4]) and 56.7 months (95%CI = [51.2-70.4]) for the group without major complications. Multivariable analysis revealed that major surgical complications were significantly associated with DFS, but not with OS., Conclusions: Patients who experienced major surgical complications had reduced DFS, compared with patients without major morbidity. Extensive peritonectomy and surgical timing were predictive factors of postoperative morbidity., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: This study aims to assess the outcomes of adjuvant interstitial brachytherapy (BT) to the tumor bed for oral cavity squamous cell carcinoma (SCC), and to compare the oncological outcomes and toxicity profile of low-dose-rate (LDR) and pulsed-dose-rate (PDR) BT., Design: This retrospective single-center study included all patients who underwent postoperative LDR- or PDR-BT to the tumor bed as the sole adjuvant treatment for an oral tongue or floor of the mouth SCC between January 2000 and December 2020., Results: A total of 79 patients were eligible for this study. The cohort was divided into an LDR group (n = 38) and a PDR group (n = 41). The median time interval between surgery and brachytherapy was 55 days. Median delivered total dose was 55 Gy and median hospital stay was 5 days. Five patients (8.3%) experienced grade 3-4 early toxicity, 2 in the LDR group and 3 in the PDR group. Late toxicities were present in 28 patients (44.4%) and were dominated by grade 1-2 residual pain and dysesthesia, without a statistical difference between the groups. After a median follow-up of 65.1 months, 5‑year local control (LC), disease-free survival (DFS), and overall survival (OS) for the whole cohort were 76.3% (95% CI = 63.4-85.1), 61.6% (95% CI = 49.0-72.0), and 71.4% (95% CI = 58.6-80.8), respectively., Conclusion: Adjuvant BT after excision of oral cavity SCC provides satisfactory oncological outcomes along with good tolerance. In our study, PDR-BT showed similar oncological and functional results to LDR-BT in this indication., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)