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Abstract Background Women with breast cancer face many barriers to return to work (RTW) after their cancer. The main objective of the FASTRACS-RCT is to evaluate the impact of the FASTRACS (Facilitate and Sustain Return to Work after Breast Cancer) intervention on the sustainable RTW of breast cancer patients, 12 months after the end of active treatment. Methods FASTRACS-RCT is a prospective, national, multicentre, randomized, controlled and open-label study. A total of 420 patients with early breast cancer scheduled for surgery and (neo)adjuvant chemotherapy, will be randomly assigned (1:1 ratio) to: (i) the intervention arm comprising four steps over 6 months : Handing over the intervention tools; transitional medical consultation with the general practitioner (GP); pre-RTW visit with the company’s occupational physician (OP); catch-up visit with a hospital-based RTW expert (if sick leave > 10 months) (ii) the control arm to receive usual care. The design of the FASTRACS intervention was informed by intervention mapping for complex interventions in health promotion planning, and involved patients and representatives of relevant stakeholders. Specific tools were developed to bridge the gap between the hospital, the GP, the OP and the workplace: a toolkit for breast cancer patients comprising a theory-based guide; specific checklists for the GP and the OP, respectively; and a theory-based guide for workplace actors (employer, manager, colleagues). The primary endpoint will associate sustainable RTW (full-time or part-time work at 50% or more of working time, for at least 28 consecutive days) and days off work. It will be assessed at 4, 8 and 12 months after the end of active oncological treatment. Secondary endpoints will include quality of life, anxiety, depression, RTW self-efficacy, physical activity, social support, job accommodations, work productivity, job status, and the usefulness and acceptability of the intervention’s tools. Discussion FASTRACS-RCT will be supplemented by a realist evaluation approach aimed at understanding the influence of context in activating the intervention’s mechanisms and effects. If the expected impact of the intervention is confirmed, the intervention will be adapted and scaled-up for other cancers and chronic diseases to better integrate healthcare and work disability prevention. Trial registration NCT04846972 ; April 15, 2021.

Introduction: Pleural effusions frequently signal disseminated cancer. Diagnostic markers of pleural malignancy at presentation that would assess cancer risk and would streamline diagnostic decisions remain unidentified. Methods: A consecutive cohort of 323 patients with pleural effusion (PE) from different etiologies were recruited between 2013 and 2017 and was retrospectively analyzed. Data included history, chest X-ray, and blood/pleural fluid cell counts and biochemistry. Group comparison, receiver-operator characteristics, unsupervised hierarchical clustering, binary logistic regression, and random forests were used to develop the malignant pleural effusion detection (MAPED) score. MAPED was validated in an independent retrospective UK cohort (n = 238). Results: Five variables showed significant diagnostic power and were incorporated into the 5-point MAPED score. Age > 55 years, effusion size > 50% of the most affected lung field, pleural neutrophil count 〈 2,500/mm3, effusion protein 〉 3.5 g/dL, and effusion lactate dehydrogenase > 250 U/L, each scoring one point, predicted underlying cancer with the area under curve(AUC) = 0.819 (P < 10−15) in the derivation cohort. The integrated discrimination improvement of MAPED scores showed an increase compared to cytology (p

Kirsten rat sarcoma virus (KRAS)-mutant cancers are frequent, metastatic, lethal, and largely undruggable. While interleukin (IL)-1β and nuclear factor (NF)-κB inhibition hold promise against cancer, untargeted treatments are not effective. Here, we show that human KRAS-mutant cancers are addicted to IL-1β via inflammatory versican signaling to macrophage inhibitor of NF-κB kinase (IKK) β. Human pan-cancer and experimental NF-κB reporter, transcriptome, and proteome screens reveal that KRAS-mutant tumors trigger macrophage IKKβ activation and IL-1β release via secretory versican. Tumor-specific versican silencing and macrophage-restricted IKKβ deletion prevents myeloid NF-κB activation and metastasis. Versican and IKKβ are mutually addicted and/or overexpressed in human cancers and possess diagnostic and prognostic power. Non-oncogene KRAS/IL-1β addiction is abolished by IL-1β and TLR1/2 inhibition, indicating cardinal and actionable roles for versican and IKKβ in metastasis.

Background The overall activity of general practitioners (GPs) related to cancer screening and follow-up is poorly documented. Objectives To describe cancer screening and follow-up activities carried out in general practice and analyse them according to the socio-economic characteristics of patients. Methods We used data from a French nationwide, multicentre, cross-sectional study that described the distribution of health problems managed in general practice and the associated processes of care. Analyses were adjusted on age and gender when appropriate, using a multivariate, hierarchical, linear mixed-effects model. Results Among 20,613 consultations recorded, 580 involved cancer screening (2.8%) and 475 cancer follow-ups (2.3%). The most frequent cancer screening procedures concerned colorectal cancer (38.6% of screening procedures), breast cancer (32.6%), cervical cancer (17.0%), and prostate cancer (9.3%). In consultations with female patients, the most frequent types of cancer followed up were breast (44.9%) and colorectal cancer (10.5%), and with male patients, the most frequent were prostate (37.3%) and skin cancer (10.3%). After adjustment on age and gender, consultations with cancer follow-up included a mean 1.9 health problems managed in addition to cancer. Consultations with cancer screening or follow-up issue less often involved a patient on low income than other consultations (2.4% vs. 4.2%, and 1.1% vs. 4.2%, respectively). Conclusion Around 5% of French general practice consultations include cancer screening or follow-up. Socio-economical inequalities demand further research.

Abstract Malignant pleural mesothelioma (MPM) arises from mesothelial cells lining the pleural cavity of asbestos‐exposed individuals and rapidly leads to death. MPM harbors loss‐of‐function mutations in BAP1, NF2, CDKN2A, and TP53, but isolated deletion of these genes alone in mice does not cause MPM and mouse models of the disease are sparse. Here, we show that a proportion of human MPM harbor point mutations, copy number alterations, and overexpression of KRAS with or without TP53 changes. These are likely pathogenic, since ectopic expression of mutant KRASG12D in the pleural mesothelium of conditional mice causes epithelioid MPM and cooperates with TP53 deletion to drive a more aggressive disease form with biphasic features and pleural effusions. Murine MPM cell lines derived from these tumors carry the initiating KRASG12D lesions, secondary Bap1 alterations, and human MPM‐like gene expression profiles. Moreover, they are transplantable and actionable by KRAS inhibition. Our results indicate that KRAS alterations alone or in accomplice with TP53 alterations likely play an important and underestimated role in a proportion of patients with MPM, which warrants further exploration.

OBJECTIVES: This study aimed to explore the views of breast cancer (BC) specialists as to their role in the return-to-work (RTW) process of their BC patients. METHODS: A qualitative study using semi-structured interviews was conducted in a sample of 20 BC specialists selected according to age, gender, medical specialty (medical oncology, radiation oncology, gynecological surgery), and healthcare organization (regional cancer center, university or private hospital). All interviews were audiotaped and transcribed for qualitative thematic content analysis. RESULTS: BC specialists had heterogeneous representations and practices regarding their role in their patients` RTW process, ranging from non-involvement to frequent discussion. Most BC specialists had concerns regarding the “right time and right way” to address patient`s RTW. They hardly mentioned workplace and job factors as potential barriers but rather stressed motivation. The main reported barriers to involvement in the RTW process were lack of time, lack of knowledge, lack of skills, and a professional attitude exclusively focused on cancer care issues. CONCLUSION: While our study showed varying representations and practices among BC specialists, participants consistently identified barriers in supporting BC survivors` RTW. The results will guide the development of an intervention to facilitate the role of BC specialists in the RTW process as part of a multicomponent intervention to facilitate BC survivors` RTW.

Abstract A comprehensive characterization of lung adenocarcinoma (LADC) clinical features is currently missing. We prospectively evaluated Caucasian patients with early‐stage LADC. Patients with LADC diagnosed between 2011 and 2015 were prospectively assessed for lung resection with curative intent. Fifty clinical, pathologic, radiologic, and molecular variables were recorded. Patients were followed till death/study conclusion. The main findings were compared to a separate cohort from France. Of 1943 patients evaluated, 366 were enrolled (18.8%; 181 female; 75 never‐smokers; 28% of registered Bavarian cases over the study period). Smoking and obstruction were significantly more prevalent in GLAD compared with adult Bavarians (P 7.5 and 3.6 years, respectively. Patients aged 65 years, resected >60 days postdiagnosis, with abnormal FVC/DLCOVA, N2/N3 stage, or solid histology had significantly decreased survival estimates. These were fit into a weighted locoregional LADC death risk score that outperformed pTNM7 in predicting survival in the GLAD and in our second cohort. We define the clinical gestalt of locoregional LADC and provide a new clinical tool to predict survival, findings that may aid future management and research design.

KRAS (KRAS proto-oncogene, GTPase) inhibitors perform less well than other targeted drugs in vitro and fail clinical trials. To investigate a possible reason for this, we treated human and murine tumor cells with KRAS inhibitors deltarasin (targeting phosphodiesterase-δ), cysmethynil (targeting isoprenylcysteine carboxylmethyltransferase), and AA12 (targeting KRASG12C), and silenced/overexpressed mutant KRAS using custom-designed vectors. We showed that KRAS-mutant tumor cells exclusively respond to KRAS blockade in vivo, because the oncogene co-opts host myeloid cells via a C-C-motif chemokine ligand 2 (CCL2)/interleukin-1 beta (IL-1β)-mediated signaling loop for sustained tumorigenicity. Indeed, KRAS-mutant tumors did not respond to deltarasin in C-C motif chemokine receptor 2 (Ccr2) and Il1b gene-deficient mice, but were deltarasin-sensitive in wild-type and Ccr2-deficient mice adoptively transplanted with wild-type murine bone marrow. A KRAS-dependent pro-inflammatory transcriptome was prominent in human cancers with high KRAS mutation prevalence and poor predicted survival. Our findings support that in vitro cellular systems are suboptimal for anti-KRAS drug screens, as these drugs function to suppress interleukin-1 receptor 1 (IL1R1) expression and myeloid IL-1β-delivered pro-growth effects in vivo. Moreover, the findings support that IL-1β blockade might be suitable for therapy for KRAS-mutant cancers.

Lung cancer and chronic lung diseases impose major disease burdens worldwide and are caused by inhaled noxious agents including tobacco smoke. The cellular origins of environmental-induced lung tumors and of the dysfunctional airway and alveolar epithelial turnover observed with chronic lung diseases are unknown. To address this, we combined mouse models of genetic labeling and ablation of airway (club) and alveolar cells with exposure to environmental noxious and carcinogenic agents. Club cells are shown to survive KRAS mutations and to form lung tumors after tobacco carcinogen exposure. Increasing numbers of club cells are found in the alveoli with aging and after lung injury, but go undetected since they express alveolar proteins. Ablation of club cells prevents chemical lung tumors and causes alveolar destruction in adult mice. Hence club cells are important in alveolar maintenance and carcinogenesis and may be a therapeutic target against premalignancy and chronic lung disease.

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Return to work (RTW) is an important step for breast cancer survivors (BCSs). However, they face many barriers that affect particularly women with low socioeconomic status (SES). Health care, workplace, and insurance actors lack knowledge and collaborate poorly. No intervention to date has proven effective to reduce social disparities in employment after breast cancer. The intervention mapping (IM) protocol is being used in France to develop, implement, and evaluate an intervention to facilitate and sustain RTW after breast cancer [FAciliter et Soutenir le retour au TRAvail après un Cancer du Sein (FASTRACS) project]. The research question of this study was to elicit the needs for RTW after breast cancer from various stakeholders’ point of view. The aim of this study was to describe the process and the preliminary results of the needs assessment of the FASTRACS project. Different methods were followed to (a) establish and work with a planning group and (b) conduct a needs assessment to create a logic model of the problem. A planning group was organized to gather the stakeholders with the research team. A review of the literature and indicators was conducted to identify the magnitude of the problem and the factors influencing RTW. A qualitative inquiry was conducted with 12 focus groups and 48 individual semi-structured interviews to explore the needs and experience of the stakeholders. The results of these tasks were the proposition of a charter of partnership to structure the participative process, a review of the scientific evidence and indicators, and the description by the stakeholders of their needs and experience. Many stakeholders disagreed with the concept of “early intervention.” They advocated for a better support of BCSs during their RTW, emphasized as a process. Anticipation, intersectoral collaboration, and workplace accommodation were mentioned to fit the needs of the BCS and their environment. A logic model of the problem was elaborated from these data. The ability of the model to consider specific characteristics of women with low SES is discussed, with a view to developing the FASTRACS intervention through the next steps of the IM protocol.

Cysteine cathepsin C (CatC) is a ubiquitously expressed, lysosomal aminopeptidase involved in the activation of zymogens of immune-cell-associated serine proteinases (elastase, cathepsin G, proteinase 3, neutrophil serine proteinase 4, lymphocyte granzymes, and mast cell chymases). CatC is first synthetized as an inactive zymogen containing an intramolecular chain propeptide, the dimeric form of which is processed into the mature tetrameric form by proteolytic cleavages. A molecular modeling analysis of proCatC indicated that its propeptide displayed a similar fold to those of other lysosomal cysteine cathepsins, and could be involved in dimer formation. Our in vitro experiments revealed that human proCatC was processed and activated by CatF, CatK, and CatV in two consecutive steps of maturation, as reported for CatL and CatS previously. The unique positioning of the propeptide domains in the proCatC dimer complex allows this order of cleavages to be understood. The missense mutation Leu172Pro within the propeptide region associated with the Papillon–Lefèvre and Haim–Munk syndrome altered the proform stability as well as the maturation of the recombinant Leu172Pro proform.

The glycoprotein osteopontin (OPN) possesses multiple functions in health and disease. To this end, osteopontin has beneficial roles in wound healing, bone homeostasis, and extracellular matrix (ECM) function. On the contrary, osteopontin can be deleterious for the human body during disease. Indeed, osteopontin is a cardinal mediator of tumor-associated inflammation and facilitates metastasis. The purpose of this review is to highlight the importance of osteopontin in malignant processes, focusing on lung and pleural tumors as examples.