Mechanistic and topological explanations in medicine: the case of medical genetics and network medicine.

Medical explanations have often been thought on the model of biological ones and are frequently defined as mechanistic explanations of a biological dysfunction. In this paper, I argue that topological explanations, which have been described in ecology or in cognitive sciences, can also be found in medicine and I discuss the relationships between mechanistic and topological explanations in medicine, through the example of network medicine and medical genetics. Network medicine is a recent discipline that relies on the analysis of various disease networks (including disease-gene networks) in order to find organizing principles in disease explanation. My aim is to show how topological explanations in network medicine can help solving the conceptual issues that pure mechanistic explanations of the genetics of disease are currently facing, namely the crisis of the concept of genetic disease, the progressive geneticization of diseases and the dissolution of the distinction between monogenic and polygenic diseases. However, I will also argue that topological explanations should not be considered as independent and radically different from mechanistic explanations for at least two reasons. First, in network medicine, topological explanations depend on and use mechanistic information. Second, they leave out some missing gaps in disease explanation that require, in turn, the development of new mechanistic explanations. Finally, I will insist on the specific contribution of topological explanations in medicine: they push us to develop an explanation of disease in general, instead of focusing on single explanations of individual diseases. This last point may have major consequences for biomedical research.

Eligibility to lung cancer screening among staffs of a university hospital: A large cross-sectional survey.

INTRODUCTION: Implementation of Lung cancer screening (LCS) programs is challenging. The ILYAD study objectives is to evaluate communication methods to improve participation rate among the Lyon University Hospital employees. In this first part of the study, we aimed to determinate the number of eligible individuals among our population of employees. METHOD: In November 2020, we conducted a questionnaire based cross sectional survey among the Lyon University Hospital employees (N = 26,954). We evaluated the PLCO m2012 risk prediction model and the eligibility criteria recommended by French guidelines. We assessed the proportion of eligible individuals among the responders and calculated the total eligible individuals in our hospital. RESULTS: Overall, 4,526 questionnaires were available for analysis. 16.0% were current smokers, and 28.2% were former smokers. Among the 50-75yo ever-smoker employees, 27% were eligible according to the French guidelines, 2.7% of all eversmokers according to a PLCO m2012 score ≥ 1.51%, and thus, 3.8% of the surveyed population were eligible to the combined criteria. The factors associated with higher eligibility among 50-75yo ever-smokers were educational level, feeling symptoms related to tobacco smoking, personal history of COPD and family history of lung cancer. Using the French guidelines criteria only, we estimated the total number of eligible individuals in the hospital at 838. CONCLUSION: In this study, we determined a theoretical number of eligible employees to LCS in our institution and the factors associated to eligibility. Secondly, we will propose LCS to all eligible employees of Lyon University Hospital with incremented information actions.

Brief Report: Severe Sotorasib-Related Hepatotoxicity and Non-Liver Adverse Events Associated With Sequential Anti-Programmed Cell Death (Ligand)1 and Sotorasib Therapy in KRASG12C-Mutant Lung Cancer.

INTRODUCTION: Sequential anti-programmed cell death protein 1 (PD-1) or anti-programmed death-ligand 1 (PD-L1) followed by small targeted therapy use is associated with increased prevalence of adverse events (AEs) in NSCLC. KRASG12C inhibitor sotorasib may trigger severe immune-mediated hepatotoxicity when used in sequence or in combination with anti-PD-(L)1. This study was designed to address whether sequential anti-PD-(L)1 and sotorasib therapy increases the risk of hepatotoxicity and other AEs. METHODS: This is a multicenter, retrospective study of consecutive advanced KRASG12C-mutant NSCLC treated with sotorasib outside clinical trials in 16 French medical centers. Patient records were reviewed to identify sotorasib-related AEs (National Cancer Institute Common Classification Criteria for Adverse Events-Version 5.0). Grade 3 and higher AE was considered as severe. Sequence group was defined as patients who received an anti-PD-(L)1 as last line of treatment before sotorasib initiation and control group as patients who did not receive an anti-PD-(L)1 as last line of treatment before sotorasib initiation. RESULTS: We identified 102 patients who received sotorasib, including 48 (47%) in the sequence group and 54 (53%) in the control group. Patients in the control group received an anti-PD-(L)1 followed by at least one treatment regimen before sotorasib in 87% of the cases or did not receive an anti-PD-(L)1 at any time before sotorasib in 13% of the cases. Severe sotorasib-related AEs were significantly more frequent in the sequence group compared with those in the control group (50% versus 13%, p < 0.001). Severe sotorasib-related AEs occurred in 24 patients (24 of 48, 50%) in the sequence group, and among them 16 (67%) experienced a severe sotorasib-related hepatotoxicity. Severe sotorasib-related hepatotoxicity was threefold more frequent in the sequence group compared with that in the control group (33% versus 11%, p = 0.006). No fatal sotorasib-related hepatotoxicity was reported. Non-liver severe sotorasib-related AEs were significantly more frequent in the sequence group (27% versus 4%, p < 0.001). Severe sotorasib-related AEs typically occurred in patients who received last anti-PD-(L)1 infusion within 30 days before sotorasib initiation. CONCLUSIONS: Sequential anti-PD-(L)1 and sotorasib therapy are associated with a significantly increased risk of severe sotorasib-related hepatotoxicity and severe non-liver AEs. We suggest avoiding starting sotorasib within 30 days from the last anti-PD-(L)1 infusion.

Long-term effectiveness and treatment sequences in patients with extensive stage small cell lung cancer receiving atezolizumab plus chemotherapy: Results of the IFCT-1905 CLINATEZO real-world study.

BACKGROUND: Small cell lung cancer (SCLC) has a tendency towards recurrence and limited survival. Standard-of-care in 1st-line is platinum-etoposide chemotherapy plus atezolizumab or durvalumab,based on landmarkclinical trials. METHODS: IFCT-1905 CLINATEZO is a nationwide, non-interventional, retrospectivestudy of patients with extensive-SCLC receivingatezolizumab plus chemotherapy as part of French Early Access Program. Objectives were to analyse effectiveness,safetyand subsequent treatments. RESULTS: The population analyzed included 518 patients who received atezolizumabin 65 participating centers. There were 66.2% male,mean age was 65.7 years; 89.1% had a performance status (PS) 0/1 and 26.6% brain metastases. Almost all(95.9%) were smokers. Fifty-five (10.6%) received at least 1 previous treatment. Median number of atezolizumab injections was 7.0 (range [1.0-48.0]) for a median duration of 4.9 months (95% CI 4.5-5.1). Atezolizumab was continued beyond progression in 122 patients (23.6%) for a median duration of 1.9 months (95% CI: [1.4-2.3]). Best objective response was complete and partialin 19 (3.9%) and 378 (77.1%)patients. Stable diseasewas observed in 50 patients (10.2%). Median follow-up was30.8 months (95% CI: [29.9-31.5]). Median overall survival (OS), 12-, 24-month OS rates were 11.3 months (95% CI: [10.1-12.4]), 46.7% (95% CI [42.3-50.9]) and 21.2% (95% CI [17.7-24.8]). Median real-world progression-free survival, 6-, 12-month rates were 5.2 months (95% CI [5.0-5.4]), 37.5% (95% CI [33.3-41.7]) and 15.2% (95% CI [12.2-18.6]). For patients with PS 0/1, median OS was 12.2 months (95% CI [11.0-13.5]). For patients with previous treatment, median OS was 14.9 months (95% CI [10.1-21.5]). Three-hundred-and-twenty-six patients(66.4%) received subsequent treatment and27 (5.2%) were still underatezolizumabat date of last news. CONCLUSIONS: IFCT-1905 CLINATEZO shows reproductibility, in real-life,ofIMpower-133survival outcomes, possibly attributed to selection of patients fit for this regimen, adoption of pragmatic approaches,including concurrent radiotherapy and treatment beyond progression.

Reuniting philosophy and science to advance cancer research.

Cancers rely on multiple, heterogeneous processes at different scales, pertaining to many biomedical fields. Therefore, understanding cancer is necessarily an interdisciplinary task that requires placing specialised experimental and clinical research into a broader conceptual, theoretical, and methodological framework. Without such a framework, oncology will collect piecemeal results, with scant dialogue between the different scientific communities studying cancer. We argue that one important way forward in service of a more successful dialogue is through greater integration of applied sciences (experimental and clinical) with conceptual and theoretical approaches, informed by philosophical methods. By way of illustration, we explore six central themes: (i) the role of mutations in cancer; (ii) the clonal evolution of cancer cells; (iii) the relationship between cancer and multicellularity; (iv) the tumour microenvironment; (v) the immune system; and (vi) stem cells. In each case, we examine open questions in the scientific literature through a philosophical methodology and show the benefit of such a synergy for the scientific and medical understanding of cancer.

[Oncology and psychiatry: Towards mutual connections/relationships]. / Oncologie et psychiatrie - Pour une relation réciproque féconde.

Oncology has been proposed as a model of scientificity, in order to promote scientific approaches to psychiatry. In this article, another type of relation between oncology and psychiatry is explored, which promotes the idea of a mutually enriching dialogue and underlines the contributions of psychiatry to oncology. The ways in which both fields address epistemological and ethical issues in their respective approaches to disease is also examined. We argue that these two disciplines can learn from one another in the common context of chronic conditions, thanks to the potential of big data collection and their biostatistics treatment for the identification of markers - sources of individualization -, as well as thanks to the renewed attention given to the temporal and processual dimension of these diseases, in particular within the framework of "staging" models.

Title: Oncologie et psychiatrie - Pour une relation réciproque féconde. Abstract: L'oncologie est souvent considérée par les défenseurs d'une psychiatrie scientifique comme un modèle médical à imiter. Psychiatres, oncologues et philosophes, nous proposons dans cet article une autre manière d'envisager les relations entre oncologie et psychiatrie, en promouvant l'intérêt d'un dialogue entre ces disciplines, convaincus de leur potentiel enrichissement réciproque et, en particulier, des apports possibles de la psychiatrie à l'oncologie. Nous proposons d'étudier chacune des manières de faire face aux difficultés épistémologiques et éthiques rencontrées dans l'approche des maladies. Nous pensons que psychiatrie et oncologie peuvent apprendre l'une de l'autre, dans le contexte commun de maladies chroniques qu'il s'agit de gérer plutôt que de guérir, grâce au potentiel qu'offrent le recueil de données massives et leur traitement biostatistique pour l'identification de marqueurs permettant d'individualiser les traitements, ainsi que grâce à l'attention renouvelée accordée à la dimension temporelle et processuelle de ces maladies, notamment dans le cadre de modèles de « stadification ¼ (ou staging).

Paclitaxel-bevacizumab combination in advanced non-squamous non-small-cell lung cancer (NSCLC): AVATAX, a retrospective multicentric study.

Introduction: Compared with docetaxel, the phase-III trial, ULTIMATE, showed a significant improvement of progression-free survival (PFS) with paclitaxel-bevacizumab combination (PB) as second- or third-line treatment in advanced non-small cell lung cancer (NSCLC). With the increase of immunotherapy treatment in first-line settings, the optimal treatment after first-line failure must be redefined. Methods: This multicentric retrospective study identified all advanced NSCLC patients treated with PB as second-line therapy and beyond. The main efficacy outcomes assessed were objective response rate (ORR), disease control rate (DCR), PFS, and overall survival (OS). The adverse events were reported according to Common Terminology Criteria for Adverse Events (CTCAE). Results: From January 2010 to February 2020, 314 patients in 16 centers received the PB combination. Most patients were male (55%), with a median age of 60 years (19-82), 95% had adenocarcinoma, 27% had a performance status ⩾2, 45% had brain metastases at the time of inclusion. They mostly received the PB combination either in second (20%) or in third-line (39%), and 28% were treated just after ICI failure. ORR and DCR were 40% and 77%, respectively; median PFS and OS were 5.7 [interquartile range (IQR): 3.2-9.6] and 10.8 [IQR: 5.3-19.6] months, respectively. All grade adverse events concerned 82% of patients, including 53% asthenia and 39% neurotoxicity, and 25% of patients continued monotherapy (mostly with bevacizumab) alone due to toxicity. Median PFS for patients treated after ICI failure (ICI+) was significantly superior compared with those not previously treated with ICI (ICI-): 7.0 [IQR: 4.2-11.0] versus 5.2 [IQR: 2.9-8.8] months, p = 0.01, without statistically significant difference for OS between these two groups. In multivariate analysis, factors associated with superior PFS were previous ICI treatment and performance status of 0-1. Only a performance status of 0-1 was associated with superior OS. Conclusion: PB combination as second-line treatment or beyond for advanced non-squamous NSCLC had acceptable toxicity and a clinically relevant efficacy and is an option as salvage treatment for these patients, more particularly after ICI progression.

Standardized vs peer-played patients for learning how to break bad news in lung cancer: A prospective crossover study.

CONTEXT: Residents in respiratory medicine are often confronted with breaking bad news to patients. In communication skill training, a recurring question is whether to use standardized or peer-played patients for simulation METHODS: In this prospective single-center crossover study in pulmonology residents, a range of scenarios were performed during training sessions using standardized or peer-played patients. The aim was to assess whether patient type did alter the quality of the role-play. The residents completed post-scenario questionnaires about the role-play of each scenario, but also pre- and post-session questionnaires about their perception of the effectiveness of both modalities, and pre- and post-testing questionnaires about the psychological impact of the training. RESULTS: Collectively, 4 scenarios were performed 52 times and evaluated 208 times by 52 residents. The use of standardized patients appeared to improve the quality of the patient role (8.8 ± 1.0 vs. 8.3 ± 1.1; p = 0.001) and the general quality of role-play (8.8 ± 1.0 vs. 8.2 ± 0.9; p = 0.008), without affecting the quality of the physician role played by the resident. There were no significant differences between standardized and peer-played patients regarding learning interest or psychological impact. Regardless of the modality, the training sessions did appear to significantly affect the residents' evaluations of their ability to break bad news to patients (5.7 ± 1.1 vs. 7.4 ± 1.1; p < 10-4). CONCLUSION: Our results did not point to a superiority of either of these modalities for learning how to break bad news. Both may be used, depending on the local resources.

Tobacco use and related behaviors among staff and students in a university hospital: A large cross-sectional survey.

INTRODUCTION: Smoking prevalence in the overall population in France was 27% in 2017. There are few data about smoking prevalence in hospital workers. The aim of this study was to assess prevalence of current smoking in student and staff populations at Lyon University Hospital. Secondary objectives were to identify main variables associated with current smoking and willingness to quit. METHODS: We designed a single center, cross-sectional survey, using printed questionnaires. During one day, all registered staff and students were surveyed. We used optical reading to extract information from questionnaires. We performed univariate and multivariate analysis adjusted on most relevant factors. RESULTS: We analyzed 9712 questionnaires. The participating rates were high: 40.6% in the student cohort and 51.5% in the staff cohort. The proportion of current cigarette users was 26% in students and 25% in staff. In multivariate analysis, current smoking was significantly associated with: younger age, male sex, occupation type (e.g. logistical staff, and paramedical students), overnight work, and e-cigarette use. Among smokers, 53% reported a willingness to quit. In multivariate analysis, number of quit attempts, and feeling symptoms from tobacco were associated with willingness to quit. CONCLUSIONS: Current smoking is less frequent in our cohorts of hospital staff and students than in the general French population. However, there are deep disparities in current smoking prevalence underlining a heterogeneous population. Among smokers, the majority reported a willingness to quit and some predictive factors may help to target this audience.

Impact of the First Wave of the COVID-19 Pandemic on the Lyon University Hospital Cancer Institute (IC-HCL).

This article presents the protective measures put in place at the "Institut de Cancérologie des Hospices de Lyon" (IC-HCL) during the first wave of the COVID-19 pandemic in France (spring 2020) and how they impacted IC-HCL clinical activity. Spring 2020 activities were compared to winter 2019-2020. Results showed a decrease of activity of 9% for treatment dispensations, 17% for multidisciplinary team meetings, 20% for head and neck and thoracic surgeries, and 58% for new patient enrolment in clinical trials. Characteristics of patients treated for solid cancer and hospitalized for COVID-19 during spring 2020 were collected in a retrospective study. Mortality was attributed to COVID-19 for half of the cases, 82% being patients above 70 and 73% being stage IV. This is in concordance with current findings concluding that the risk of developing severe or critical symptoms of COVID-19 is correlated with factors co-occurring in cancer patients and not to the cancer condition per se. While a number of routines and treatment regimens were changed, there was no major decline in numbers of treatments conducted at the IC-HCL during the first wave of the COVID-19 pandemic that hit France between March and May 2020, except for clinical trials and some surgery activities.

Pulmonary complications of immune checkpoint inhibitors in patients with nonsmall cell lung cancer.

Immune checkpoint inhibitor-related pneumonitis (ICI-P) during cancer treatment is rarely observed (<5%). ICI-P is more often observed in patients with nonsmall cell lung cancer (NSCLC) than in those with other cancers. Likewise, it is more common in those receiving programmed cell death (PD)-1/PD-1 ligand inhibitors rather than cytotoxic T-lymphocyte antigen (CTLA)-4 inhibitors alone. The frequency of ICI-P is higher when anti-PD-1 and anti-CTLA-4 are administered concomitantly. Despite the low fatality rate (≈13%), ICI-P is the leading cause of ICI-related deaths. This narrative review focuses on the epidemiology, clinical and radiological presentation and prognosis of ICI-P occurring in patients, especially those with advanced NSCLC. Emphasis is placed on the differences in terms of frequency or clinical picture observed depending on whether the ICI is used as monotherapy or in combination with another ICI or chemotherapy. Other pulmonary complications observed in cancer patients, yet not necessarily immune-related, are reviewed, such as sarcoid-like granulomatosis, tuberculosis or other infections. A proposal for pragmatic management, including differential diagnosis and therapeutic strategies, is presented, based on the ICI-P series reported in the literature and published guidelines.

Immunotherapy for LELC: Case Report and a Focused Review.

Lymphoepithelioma-like carcinoma of the lung (LELC) is a rare, Epstein-Barr virus-associated tumor. LELC occurs mostly in young, Asian nonsmokers. A few hundred cases have been reported, mostly from retrospective Asian studies. Optimal treatment has not been clearly established. Treatment options are based on surgery for early stage and on cisplatin-based chemotherapy as first-line therapy for metastatic disease. Prognosis may seem better than for other types of non-small-cell lung cancer, but it remains poor in advanced disease, with a median survival of 24 months, and new treatments options are still warranted. Immunotherapies are now key players in the treatment of non-small-cell lung cancer. However, few data are available for this rare histologic subgroup. We have reviewed the available data on LELC with a focus on the first few cases reported with a response to a programmed cell death 1 inhibitor.

Unifying diseases from a genetic point of view: the example of the genetic theory of infectious diseases.

In the contemporary biomedical literature, every disease is considered genetic. This extension of the concept of genetic disease is usually interpreted either in a trivial or genocentrist sense, but it is never taken seriously as the expression of a genetic theory of disease. However, a group of French researchers defend the idea of a genetic theory of infectious diseases. By identifying four common genetic mechanisms (Mendelian predisposition to multiple infections, Mendelian predisposition to one infection, and major gene and polygenic predispositions), they attempt to unify infectious diseases from a genetic point of view. In this article, I analyze this explicit example of a genetic theory, which relies on mechanisms and is applied only to a specific category of diseases, what we call "a regional genetic theory." I have three aims: to prove that a genetic theory of disease can be devoid of genocentrism, to consider the possibility of a genetic theory applied to every disease, and to introduce two hypotheses about the form that such a genetic theory could take by distinguishing between a genetic theory of diseases and a genetic theory of Disease. Finally, I suggest that network medicine could be an interesting framework for a genetic theory of Disease.