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The functional signal of bone internal structure has been widely studied. Isolated form-function relationships have often been assumed from the observation of presumed morphofunctional relationships, but have never been truly tested. Indeed, distinct bone microanatomical feature co-evolve in response to various constraints that are difficult to detangle. This study tested for the first time the impact of various microanatomical parameters taken one by one, plus some in pairs, on bone strength under compression using biomechanical modelling. We carried out finite element analyses on humerus models, obtained from a white rhinoceros, with different heterogeneous internal structures, and analysed the magnitude and distribution of von Mises stresses. These tests validated earlier hypotheses of form-function relationships about the greater resistance to compression provided by the thickening of the cortex and the filling of the medullary area by trabecular bone and highlighted the stronger impact of increasing trabecular bone compactness than of avoiding an open medullary cavity. By making it possible to estimate the relative impact of each parameter and of combinations of microanatomical features, they also showed the more limited impact of the trabecular bone compactness in the epiphyses to resist compression, and the fact that microanatomical changes of opposite but of similar amplitude impact can compensate each other, but that the impact of the sum of two negative microanatomical changes far exceeds the sum of the impacts of each of the two changes taken separately. These results contribute to a better understanding of bone adaptation and form-function relationships so that they later can be used with confidence for palaeobiological inferences on fossil specimens, contributing to a better understanding of skeletal evolution during the evolutionary history of vertebrates. They also highlight the potential of taking internal structure into account in the bone biomechanical analyses. In addition, they can be used in bioinspiration to design resistant structures subjected to compression., (© 2024 Anatomical Society.)

Background: Although the benefit of supportive care in the postcancer period is now well demonstrated, its implementation in the patient journey remains challenging. This article describes the development, since 2015 and in routine care, of supportive postcancer care comprising a multidisciplinary rehabilitation programme (MRP) based on exercise for patients with early breast cancer., Methods: As part of quality control, we reviewed all patient files since the programme was implemented. Patient data regarding the type of cancer, clinical and pathological factors, and treatment were recorded in a computerised database., Results: From April 2015 to January 2024, 655 patients participated in the MRP. The programme lasts for 14 weeks, totalling 126 hours of face-to-face programme, with a maximum of 8 patients per group, in 5 different centres. A multidisciplinary professional team provide supportive care. The MRP is mainly based on supervised physical exercise and patients also participate in social, psychological, dietary support and educational sessions. Supervised physical exercise includes cardiorespiratory endurance work through specific sessions on ergometers or outdoor walking and adapted physical activity sessions to improve muscular capacities (endurance, strength and flexibility)., Conclusion: We describe here the practical implementation of a routine multidisciplinary supportive care programme, based mainly on physical activity, for post-treatment breast cancer patients. We report almost 9 years of experience with the programme. We show that offering this programme in the postcancer setting and in clinical routine practice is feasible and can be maintained in the long term., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Introduction: Immune checkpoint inhibitors (ICIs) are a key component of standard anticancer systemic therapy. While their immune-related adverse effects (irAEs) have been widely described, there are few data on grade≥3 irAEs. The primary aim of our descriptive study was to evaluate their incidence and characteristics., Methods: An observational, retrospective, monocentric study was conducted. It included patients with locally advanced or metastatic melanoma, non-small cell lung cancer or renal cell carcinoma who initiated ICI therapy between 2016-2021 and experienced at least one grade≥3 irAEs coded according to the MedDRA® system., Results: All cancer types and ICIs combined, the incidence of grade≥3 irAEs was estimated at 11.7% [9.6-13.9]. These were mainly hepatobiliary (22%), gastrointestinal (17%), musculoskeletal (16%) and respiratory (16%) disorders. They occurred on average 6.2±6.2 months after the start of treatment, resulting in hospitalization or prolonged hospitalization in over 40 and 20% of cases, respectively. Resolution without sequelae was observed in 56% of cases, but four patients died., Discussion: This real-world study investigated three cancers and several ICIs, unlike previously published studies that focused on a single cancer and/or one ICI. It provides a better understanding of grade≥3 irAEs, most of which are reversible, which an aim to optimize patient care., (Copyright © 2024 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Background: Colorectal cancer is a public health issue and was the third leading cause of cancer-related death worldwide in 2022. Early diagnosis can improve prognosis, making screening a central part of colorectal cancer management. Blood-based screening, diagnosis and follow-up of colorectal cancer patients are possible with the study of cell-free circulating tumor DNA. This study aimed to identify novel DNA methylation biomarkers of colorectal cancer that can be used for the follow-up of patients with colorectal cancer., Methods: A DNA methylation profile was established in the Gene Expression Omnibus (GEO) database (n = 507) using bioinformatics analysis and subsequently confirmed using The Cancer Genome Atlas (TCGA) database (n = 348). The in silico profile was then validated on local tissue and cell-free DNA samples using methylation-specific digital PCR in colorectal cancer patients (n = 35) and healthy donors (n = 35)., Results: The DNA methylation of COL25A1 and METAP1D was predicted to be a colorectal cancer biomarker by bioinformatics analysis (ROC AUC = 1, 95% CI [0.999-1]). The two biomarkers were confirmed with tissue samples, and the combination of COL25A1 and METAP1D yielded 49% sensitivity and 100% specificity for cell-free DNA., Conclusion: Bioinformatics analysis of public databases revealed COL25A1 and METAP1D DNA methylation as clinically applicable liquid biopsies DNA methylation biomarkers. The specificity implies an excellent positive predictive value for follow-up, and the high sensitivity and relative noninvasiveness of a blood-based test make these biomarkers compatible with colorectal cancer screening. However, the clinical impact of these biomarkers in colorectal cancer screening and follow-up needs to be established in further prospective studies., (© 2024. The Author(s).)

Indexing techniques relying on k-mers have proven effective in searching for RNA sequences across thousands of RNA-seq libraries, but without enabling direct RNA quantification. We show here that arbitrary RNA sequences can be quantified in seconds through their decomposition into k-mers, with a precision akin to that of conventional RNA quantification methods. Using an index of the Cancer Cell Line Encyclopedia (CCLE) collection consisting of 1019 RNA-seq samples, we show that k-mer indexing offers a powerful means to reveal non-reference sequences, and variant RNAs induced by specific gene alterations, for instance in splicing factors., (© 2024. The Author(s).)

Context and Aims: Eribulin is used in taxane and anthracycline refractory HER2-negative metastatic breast cancers (MBC). Patients treated in pivotal clinical trials achieved low survival rates, therefore, the identification of prognostic criteria for long progression-free survival (PFS) is still an unmet medical need. In this study, we sought to determine potential prognostic criteria for long-term eribulin response in HER2-negative MBC., Methods: Our retrospective cohort includes female patients with HER2-negative MBC treated with eribulin in Franche-Comté, France. We defined a long-term response as at least 6 months of eribulin treatment. The primary endpoint was the analysis of criteria that differ according to the progression-free survival. Secondary outcomes concerned overall survival and response rate., Results: From January 2011 to April 2020, 431 patients treated with eribulin were screened. Of them, 374 patients were included. Median PFS was 3.2 months (2.8-3.7). Eighty-eight patients (23.5%) had a long-term response to eribulin. Four discriminant criteria allowed to separate PFS in 2 arms (PFS < 3 months or > 6 months) with a 78% positive predictive value: histological grade, absence of meningeal metastasis, response to prior chemotherapy, and OMS status. We have developed a nomogram combining these 4 criteria. Median overall survival was 8.5 months (7.0-9.5)., Conclusion: Eribulin response in MBC can be driven by clinical and biological factors. Application of our nomogram could assist in the prescription of eribulin., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Up to 70% of breast cancer patients report symptoms of insomnia during and after treatment. Despite the ubiquity of insomnia symptoms, they are under-screened, under-diagnosed and poorly managed in breast cancer patients. Sleep medications treat symptoms but are ineffective to cure insomnia. Other approaches such as cognitive behavioral therapy for insomnia, relaxation through yoga and mindfulness are often not available for patients and are complex to implement. An aerobic exercise program could be a promising treatment and a feasible option for insomnia management in breast cancer patients, but few studies have investigated the effects of such a program on insomnia., Methods: This multicenter, randomized clinical trial evaluate the effectiveness of a moderate to high intensity physical activity program (45 min, 3 times per week), lasting 12 weeks, in minimizing insomnia, sleep disturbances, anxiety/depression, fatigue, and pain, and in enhancing cardiorespiratory fitness. Patients with breast cancer be recruited from six hospitals in France and randomly allocated to either the "training" or the "control" group. Baseline assessments include questionnaires [Insomnia Severity Index (ISI), Pittsburgh Sleep Quality Index questionnaire (PSQI), Hospital Anxiety Depression Scale (HADS), Epworth Sleepiness Scale (ESS)], home polysomnography (PSG), and 7-day actigraphy coupled with completion of a sleep diary. Assessments are repeated at the end of training program and at six-month follow-up., Discussion: This clinical trial will provide additional evidence regarding the effectiveness of physical exercise in minimizing insomnia during and after chemotherapy. If shown to be effective, exercise intervention programs will be welcome addition to the standard program of care offered to patients with breast cancer receiving chemotherapy., Trial Registration: National Clinical Trials Number (NCT04867096)., (© 2023. The Author(s).)

Metastatic relapse after treatment is the leading cause of cancer mortality, and known resistance mechanisms are missing for most treatments administered to patients. To bridge this gap, we analyze a pan-cancer cohort (META-PRISM) of 1,031 refractory metastatic tumors profiled via whole-exome and transcriptome sequencing. META-PRISM tumors, particularly prostate, bladder, and pancreatic types, displayed the most transformed genomes compared with primary untreated tumors. Standard-of-care resistance biomarkers were identified only in lung and colon cancers-9.6% of META-PRISM tumors, indicating that too few resistance mechanisms have received clinical validation. In contrast, we verified the enrichment of multiple investigational and hypothetical resistance mechanisms in treated compared with nontreated patients, thereby confirming their putative role in treatment resistance. Additionally, we demonstrated that molecular markers improve 6-month survival prediction, particularly in patients with advanced breast cancer. Our analysis establishes the utility of the META-PRISM cohort for investigating resistance mechanisms and performing predictive analyses in cancer., Significance: This study highlights the paucity of standard-of-care markers that explain treatment resistance and the promise of investigational and hypothetical markers awaiting further validation. It also demonstrates the utility of molecular profiling in advanced-stage cancers, particularly breast cancer, to improve the survival prediction and assess eligibility to phase I clinical trials. This article is highlighted in the In This Issue feature, p. 1027., (©2023 The Authors; Published by the American Association for Cancer Research.)

CD226 has been reported to participate in the rescue of CD8 + T cell dysfunction. In this study, we aimed to assess the prognostic value of CD226 in tumor-infiltrating lymphocytes (TILs) derived from colorectal cancer (CRC) liver metastases treated with chemotherapy and radical surgery. TILs from 43 metastases were isolated and analyzed ex vivo using flow cytometry. CD155 and CD3 levels in the tumor microenvironment were assessed by immunohistochemistry. Exploration and validation of biological processes highlighted in this study were performed by bioinformatics analysis of bulk RNA-seq results for 28 CRC liver metastases pretreated with chemotherapy as well as public gene expression datasets. CD226 expression contributes to the definition of the immune context in CRC liver metastases and primary tumors. CD226 on CD8 + T cells was not specifically coexpressed with other immune checkpoints, such as PD1, TIGIT, and TIM3, in liver metastases. Multivariate Cox regression analysis revealed CD226 expression on CD8 + T cells to be an independent prognostic factor (p = 0.003), along with CD3 density at invasion margins (p = 0.003) and TIGIT expression on CD4 +  T cells (p = 0.019). CD155 was not associated with the prognostic value of CD226. Gene expression analysis in a validation dataset confirmed the prognostic value of CD226 in CRC liver metastases but not in primary tumors. Downregulation of CD226 on CD8 + TILs in the liver microenvironment was restored by IL15 treatment. Overall, CD226 expression on liver metastasis-infiltrating CD8 + T cells selectively contributes to immune surveillance of CRC liver metastases and has prognostic value for patients undergoing radical surgery., (© 2023. The Author(s).)

Combining immunogenic cell death-inducing chemotherapies and PD-1 blockade can generate remarkable tumor responses. It is now well established that TGF-β1 signaling is a major component of treatment resistance and contributes to the cancer-related immunosuppressive microenvironment. However, whether TGF-β1 remains an obstacle to immune checkpoint inhibitor efficacy when immunotherapy is combined with chemotherapy is still to be determined. Several syngeneic murine models were used to investigate the role of TGF-β1 neutralization on the combinations of immunogenic chemotherapy (FOLFOX: 5-fluorouracil and oxaliplatin) and anti-PD-1. Cancer-associated fibroblasts (CAF) and immune cells were isolated from CT26 and PancOH7 tumor-bearing mice treated with FOLFOX, anti-PD-1 ± anti-TGF-β1 for bulk and single cell RNA sequencing and characterization. We showed that TGF-β1 neutralization promotes the therapeutic efficacy of FOLFOX and anti-PD-1 combination and induces the recruitment of antigen-specific CD8 +  T cells into the tumor. TGF-β1 neutralization is required in addition to chemo-immunotherapy to promote inflammatory CAF infiltration, a chemokine production switch in CAF leading to decreased CXCL14 and increased CXCL9/10 production and subsequent antigen-specific T cell recruitment. The immune-suppressive effect of TGF-β1 involves an epigenetic mechanism with chromatin remodeling of CXCL9 and CXCL10 promoters within CAF DNA in a G9a and EZH2-dependent fashion. Our results strengthen the role of TGF-β1 in the organization of a tumor microenvironment enriched in myofibroblasts where chromatin remodeling prevents CXCL9/10 production and limits the efficacy of chemo-immunotherapy., Competing Interests: CB declares research grant from Roche, Bayer and advisory board for MSD, Sanofi, Bayer. All other authors report no conflict of interest., (© 2022 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Breast cancers expressing high levels of Ki67 are associated with poor outcomes. Oncotype DX test was designed for ER+/HER2- early-stage breast cancers to help adjuvant chemotherapy decision by providing a Recurrent Score (RS). RS measures the expression of 21 specific genes from tumor tissue, including Ki67. The primary aim of this study was to assess the agreement between Ki67 RNA obtained with Oncotype DX RS and Ki67 IHC . Other objectives were to analyze the association between the event free survival (EFS) and the expression level of Ki67 RNA ; and association between RS and Ki67 RNA . Herein, we report a low agreement of 0.288 by Pearson correlation coefficient test between Ki67 IHC and Ki67 RNA in a cohort of 98 patients with early ER+/HER2- breast cancers. Moreover, Ki67 RNA high tumors were significantly associated with the occurrence of events (p = 0.03). On the other hand, we did not find any association between Ki67 IHC and EFS (p = 0.26). We observed a low agreement between expression level of Ki67 RNA and Ki67 protein labelling by IHC. Unlike Ki67 IHC and independently of the RS, Ki67 RNA could have a prognostic value. It would be interesting to better assess the prognosis and predictive value of Ki67 RNA measured by qRT-PCR. The Ki67 RNA in medical routine could be a good support in countries where Oncotype DX is not accessible., (© 2022. The Author(s).)

Background: The positive role of CD8+ tumor-infiltrating lymphocytes (TIL) in patients with colorectal cancer (CRC) has been well described but the prognostic value of CD4 T cell subsets remained to be investigated. In this study, we expanded TIL from surgically resected liver metastases of patients with CRC and characterized the phenotype and the prognostic value of expanded-CD4 T cells., Methods: Liver metastases were surgically resected from 23 patients with CRC. Tumors were enzymatically digested and cultured in high dose of interleukin-2 for up to 5 weeks. T cell phenotype and reactivity of cultured-T cells were measured by flow cytometry and correlated with patients' clinical outcomes., Results: We successfully expanded 21 over 23 TIL from liver metastases of patients with CRC. Interestingly, we distinguished two subsets of expanded T cells based on T cell immunoglobulin mucin domain-containing protein 3 (TIM-3) expression. Medians fold expansion of expanded T cells after rapid expansion protocol was higher in CD3 + TIM-3 low cultures. In an attempt to investigate the correlation between the phenotype of expanded CD4 T cells and clinical outcomes, we observed on one hand that the level of Tregs in culture as well as the expression of both PD1 and TIM-3 by expanded T cells was not correlated to the clinical outcomes. Interestingly, on the other hand, cultures containing high levels of Th17 cells were associated with a poor prognosis (p=0.0007)., Conclusions: Our data confirmed the presence of Th17 cells in expanded T cells from liver metastases. Among CD4 T cell characteristics investigated, TIM-3 but not programmed cell death protein 1 predicted the expansion capacity of TIL while only the Th17 phenotype showed correlation with patients' survival, suggesting a particular role of this T cell subset in CRC immune contexture., Trial Registration Number: NCT02817178., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Angiopoietin-2 (ANGPT2) is a prognostic factor in metastatic colorectal cancer (CRC). Nevertheless, it remains to be elucidated which molecular characteristics make up the ANGPT2-related poor-prognosis CRC subset. Public transcriptomic datasets were collected from Gene Expression Omnibus GEO and with the TCGAbiolinks R-package for the TCGA. After appropriate normalization, differential expression analysis was performed using Benjamini and Hochberg method for false discovery rate. Plasma from two prospective clinical trials were used to investigate the clinical impact of ANGPT2-related biomarkers. In the 935 samples included in four annotated platforms (GPL) and derived from localized CRC, ANGPT2 hi expression conferred a worst overall survival (HR = 1.20; p = 0.02). CRC stage, ANGPT2 hi expression but not Consortium Molecular Subtype (CMS) predict overall survival in multivariate analysis. ANGPT2 expression was not correlated with a specific CMS nor to RAS, RAF, MSI, p53, CIN, CIMP genomic alterations. Gene expression analysis revealed that ANGPT2 hi CRC subset is characterized by angiogenesis-related gene expression, presence of myeloid cells, stromal organization and resistance to chemotherapy. A prognostic model was proposed using seric levels of ANGPT2, STC1 and CD138 in 97 mCRC patients. Our results provide evidence that ANGPT2 is a prognostic factor in localized CRC and defined a specific CRC subset with potential clinical implementation., (© 2020 UICC.)

Germ-cell tumors are the most common solid tumors in young men. The follow-up of these patients is very important in their management. In stage I testicular cancer, surveillance is the standard for low-risk disease. In addition to the early detection of relapse, follow-up should be directed towards prevention, detection and treatment of late toxicity, and secondary malignancies. Follow up consists in physical examination, laboratory analysis and radiological imaging. Recently, guidelines recommend risk-adapted surveillance strategy, with a reduction of CT scans numbers, due to the recognition of the risk of ionizing radiation exposure. However, efforts to maintain adequate compliance with follow up are required., (Copyright © 2019. Published by Elsevier Masson SAS.)

We conducted a retrospective study to assess the follow-up of patients with localized breast cancer and the first indicators of advanced breast cancer recurrence. All patients with advanced breast cancer recurrence treated between January 2010 and June 2016 in our institution were registered. Among these patients, 303 patients initially treated for early breast cancer with curative intent were identified. After initial curative treatment, follow-up involved the oncologist, the general practitioner and the gynecologist in 68.0%, 48.9% and 19.1% of cases, respectively. The median DFI was 4 years for luminal A, 3.8 years for luminal B, 3.7 years for HER2-positive and 1.5 years for TNBC (p = 0.07). Breast cancer tumor marker was prescribed for 164 patients (54.1%). No difference in terms of follow-up was observed according to the molecular subtype. Symptoms were the primary indicator of relapse for 143 patients (47.2%). Breast cancer recurrence was discovered by CA 15.3 elevation in 57 patients (18.8%) and by CAE elevation in 3 patients (1%). The rate of relapse diagnosed by elevation of CA 15.3 or CAE was not statistically associated with the molecular subtype (p = 0.65). Luminal A cases showed a significantly higher rate of bone metastases (p = 0.0003). TNBC cases showed a significantly higher rate of local recurrence (p = 0.002) and a borderline statistical significant higher rate of lung/pleural metastases (p = 0.07). Follow-up recommendations could be adapted in clinical practice according to the molecular subtype. General practitioners should be more involved by the specialists in breast cancer follow-up., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Unlabelled: In France, HIV-infected (HIV+) patients are frequently coinfected with hepatitis B virus (HBV) or at risk for this infection. Physicians and their patients should be more committed to HBV prevention than the average population., Aims: To gain insight into the attitude towards HBV and its vaccination in HIV+ patients from the Aquitaine Cohort and their attending physicians in France., Methods: A cross-sectional survey based on self-administered questionnaires was performed from November 2002 to June 2003. It targeted 198 physicians from the clinical group on AIDS epidemiology (Groupe d'Epidémiologie Clinique du SIDA en Aquitaine, GECSA) or participating in medical HIV networks in southwestern France; and 512 patients from the cohort. Questions concerned the following items for the physicians: HBV status, prescription of HBV serology and vaccination (frequency, type, schedule), risk factors assessed, reasons for non-vaccination; and for the patients: HBV status, information received, risk factors, attitude towards vaccination., Results: 93% of physicians and 22% of patients stated they were vaccinated against HBV. HBV serological status was reported to be systematically ascertained by 75% of physicians, but post-vaccinal testing was only prescribed by 23% of them. The main reasons for not prescribing more often HBV vaccine were forgetting (79%), difficulty to identify subjects at risk (44%) and being afraid of post-vaccinal complications (32%). Thirty percent of patients reported not to have received any information on HBV vaccination. Overall, 44% considered not to be at risk of infection but 82% of them had been confronted with at least one risk. The main reasons for not having been vaccinated were mostly worry about AIDS (70%), not having been asked by physician (65%) or afraid of complications (58%); nonetheless, 42% of patients were willing to be vaccinated., Conclusions: Results from this survey underline the need for specific health actions to be undertaken concerning hepatitis B vaccination in HIV+ patients as well as their health care providers.

Collagenous colitis and microscopic colitis are histologic entities which do not have corresponding endoscopic features. Their precise incidence and role in the development of intestinal symptoms are poorly known. The aim of this study was to determine the frequency of these histologic abnormalities in patients with endoscopically normal colon and to correlate these findings with abdominal symptoms. Total colonoscopy was performed in 132 consecutive patients, 81 females and 51 males, aged 19 to 83 years (mean: 47.8 years). Patients complained of abdominal pain and/or diarrhea (66 cases), normal bowel transit or constipation (66 cases). Subjects were prepared for colonoscopy with polyethylene glycol 4,000. Three to 8 biopsies were taken from the rectum and the different parts of the colon. Histologic abnormalities were found in 36 patients (27.2 p. 100): collagenous colitis (7 cases), microscopic colitis (21 cases), and melanosis coli (8 cases). The frequency of diarrhea was significantly higher in patients with collagenous colitis and microscopic colitis than in those with melanosis coli or normal colonic mucosa. These results clearly demonstrate that routine biopsies of the rectum and colon are useful in patients with abdominal symptoms, particularly diarrhea, and normal endoscopy.