Custom scoring based on ecological topology of gut microbiota associated with cancer immunotherapy outcome.

The gut microbiota influences the clinical responses of cancer patients to immunecheckpoint inhibitors (ICIs). However, there is no consensus definition of detrimental dysbiosis. Based on metagenomics (MG) sequencing of 245 non-small cell lung cancer (NSCLC) patient feces, we constructed species-level co-abundance networks that were clustered into species-interacting groups (SIGs) correlating with overall survival. Thirty-seven and forty-five MG species (MGSs) were associated with resistance (SIG1) and response (SIG2) to ICIs, respectively. When combined with the quantification of Akkermansia species, this procedure allowed a person-based calculation of a topological score (TOPOSCORE) that was validated in an additional 254 NSCLC patients and in 216 genitourinary cancer patients. Finally, this TOPOSCORE was translated into a 21-bacterial probe set-based qPCR scoring that was validated in a prospective cohort of NSCLC patients as well as in colorectal and melanoma patients. This approach could represent a dynamic diagnosis tool for intestinal dysbiosis to guide personalized microbiota-centered interventions.

Concerted and multidisciplinary management of COVID-19 drug therapies during the first two epidemic waves in a tertiary hospital in Marseille, France: Results of the PHARMA-COVID study.

OBJECTIVES: To evaluate the impact of local therapeutic recommendation updates made by the COVID multidisciplinary consultation meeting (RCP) at the Hôpital Européen Marseille (HEM) through the description of the drug prescriptions for COVID-19 during the first two waves of the epidemic. METHODS: This retrospective observational study analysed data from the hospital's pharmaceutical file. We included all patients hospitalized for COVID-19 between February 1, 2020 and January 21, 2021 and extracted specific anti-COVID-19 therapies (ST) from computerized patient record, as well as patients' demographic characteristics, comorbidities and outcome. The evolution of ST prescriptions during the study period was described and put into perspective with the updates of local recommendations made during the first (V1, from 2/24/2020 to 7/27/2020), and second (V2, from 7/28/2020 to 1/21/2021) epidemic waves. RESULTS: A total of 607 COVID-19 hospitalized patients, 197 during V1 and 410 during V2. Their mean age was 65 years-old, and they presented frequent comorbidities. In total, 93% of hospitalized patients received ST: anticoagulants (90%), glucocorticoids (39%) mainly during V2 (49% vs 17%, P<0.001), and azithromycin (30%) mainly during V1 (71% vs 10%, P<0.001). Lopinavir/ritonavir and hydroxychloroquine were prescribed to 17 and 7 inpatients, respectively, and only during V1. Remdesivir was never administered. A total of 22 inpatients were enrolled into clinical trials. CONCLUSIONS: The effective dissemination of evidence-based and concerted recommendations seems to have allowed an optimized management of COVID-19 drug therapies in the context of this emerging infection with rapidly evolving therapeutic questions.

Intestinal Akkermansia muciniphila predicts clinical response to PD-1 blockade in patients with advanced non-small-cell lung cancer.

Aside from PD-L1 expression, biomarkers of response to immune checkpoint inhibitors (ICIs) in non-small-cell lung cancer (NSCLC) are needed. In a previous retrospective analysis, we documented that fecal Akkermansia muciniphila (Akk) was associated with clinical benefit of ICI in patients with NSCLC or kidney cancer. In the current study, we performed shotgun-metagenomics-based microbiome profiling in a large cohort of patients with advanced NSCLC (n = 338) treated with first- or second-line ICIs to prospectively validate the predictive value of fecal Akk. Baseline stool Akk was associated with increased objective response rates and overall survival in multivariate analyses, independent of PD-L1 expression, antibiotics, and performance status. Intestinal Akk was accompanied by a richer commensalism, including Eubacterium hallii and Bifidobacterium adolescentis, and a more inflamed tumor microenvironment in a subset of patients. However, antibiotic use (20% of cases) coincided with a relative dominance of Akk above 4.8% accompanied with the genus Clostridium, both associated with resistance to ICI. Our study shows significant differences in relative abundance of Akk that may represent potential biomarkers to refine patient stratification in future studies.

An optimized stepwise algorithm combining rapid antigen and RT-qPCR for screening of COVID-19 patients.

BACKGROUND & AIM: We investigated the combination of rapid antigen detection (RAD) and RT-qPCR assays in a stepwise procedure to optimize the detection of COVID-19. METHODS: From August 2020 to November 2020, 43,399 patients were screened in our laboratory for COVID-19 diagnostic by RT-qPCR using nasopharyngeal swab. Overall, 4,691 of the 43,399 were found to be positive, and 200 were retrieved for RAD testing allowing comparison of diagnostic accuracy between RAD and RT-qPCR. Cycle threshold (Ct) and time from symptoms onset (TSO) were included as covariates. RESULTS: The overall sensitivity, specificity, PPV, NPV, LR-, and LR+ of RAD compared with RT-qPCR were 72% (95%CI 62%-81%), 99% (95% CI95%-100%), 99% (95%CI 93%-100%), and 78% (95%CI 70%-85%), 0.28 (95%CI 0.21-0.39), and 72 (95%CI 10-208) respectively. Sensitivity was higher for patients with Ct ≤ 25 regardless of TSO: TSO ≤ 4 days 92% (95%CI 75%-99%), TSO > 4 days 100% (95%CI 54%-100%), and asymptomatic 100% (95%CI 78-100%). Overall, combining RAD and RT-qPCR would allow reducing from only 4% the number of RT-qPCR needed. CONCLUSIONS: This study highlights the risk of misdiagnosing COVID-19 in 28% of patients if RAD is used alone. A stepwise analysis that combines RAD and RT-qPCR would be an efficient screening procedure for COVID-19 detection and may facilitate the control of the outbreak.

Adverse Events Induced by PD-1/PD-L1 Inhibitors: A Real-World Single-Centre Experience with a Management-Based Approach.

AIM: To assess the efficacy and tolerance of programmed death-1 (PD-1) and PD-ligand 1 (PD-L1) inhibitors and the impact of a standardised management-based protocol in a real-world setting. PATIENTS AND METHODS: Data from patients who had received anti-PD-(L)1 were collected from our pharmacy database. Clinical response and toxicity were assessed using RECIST criteria and CTCAE version 5.0, respectively. Overall survival (OS) and progression-free survival (PFS) were estimated with the Kaplan-Meier method. Potential prognostic factors were identified using Cox's model. RESULTS: A total of 196 patients and 201 lines of treatment were included (median age: 66 (range: 38-89) years). Types of cancer included non-small cell lung cancer (73%), transitional cell carcinoma (10%), renal cell carcinoma (6%), small cell lung cancer (5%), head and neck squamous cell carcinoma (4%) and classical Hodgkin's lymphoma (1%). Twenty-five (12%) patients had pre-existing autoimmune conditions. Our standardised management-based protocol included 129 (64%) patients. Objective response rate was 29%, median OS was 10 months (IQR: 7-15) and median PFS was 5 months (IQR: 1-22). Patients with an abnormal baseline complete blood count had a worse OS (HR=2.48 [95% CI: 1.24-4.96]; p=0.0103). Thirty-three (16%) patients experienced severe (grade 3 or 4) immune-related adverse event (irAE). There were three (1%) irAE-related deaths. AEs resolved faster when patients were assessed by an internist before anti-PD-(L)1 initiation (p=0.0205). CONCLUSION: PD-1 and PD-L1 inhibitors are effective and safe in a real-world setting. Implementation of a standardised management-based protocol with internal medicine specialists is an effective way to optimise irAE management.

Impact of a Multimodal Telemonitoring Intervention on CPAP Adherence in Symptomatic OSA and Low Cardiovascular Risk: A Randomized Controlled Trial.

BACKGROUND: One of the major challenges in treating OSA is to achieve adequate CPAP adherence. Telemonitoring has the potential to provide individualized management and early recognition of problems during treatment. RESEARCH QUESTION: What is the effect of a multimodal telemonitoring intervention on treatment adherence, quality of life, and functional status in symptomatic patients with OSA and low cardiovascular risk? STUDY DESIGN AND METHODS: In a multicenter, randomized controlled trial, patients newly diagnosed with OSA were randomly assigned to multimodal telemonitoring for 6 months vs usual care (UC). Telemonitoring consisted of built-in electronic alert algorithms for early adjustment of CPAP treatment in case of side effects, leaks, or persistent residual events. The primary outcome was CPAP adherence (in hours per night). Secondary outcomes included daily symptoms such as fatigue and sleepiness, and quality of life measured by using self-reported questionnaires. RESULTS: A total of 206 patients with OSA and a median age of 50.6 years (interquartile range [IQR], 42.1; 58.1 years) were included in the study; they were predominantly male (63%) with a median BMI of 30.6 kg/m2 (IQR, 26.8; 35.1 kg/m2) and a median apnea-hypopnea index of 45.2 events/h (IQR, 34.0; 60.0 events/h). Of these, 102 received UC and 104 received telemonitoring. After 6 months of treatment, CPAP adherence was similar in the two groups when assessed either by mean duration of usage (4.73 ± 2.48 h per night in the telemonitoring group and 5.08 ± 2.44 h per night in the UC group; P = .30) or in percentage of patients adherent to treatment (> 4 h usage per night, > 70% nights; 64% in the telemonitoring group vs 72% in the UC group; P = .24). There was no significant difference between the groups in effect size of improvement in fatigue and sleepiness. INTERPRETATION: In patients with severe OSA and low cardiovascular risk, multimodal telemonitoring did not increase CPAP adherence. For both the telemonitoring and UC groups, similar improvements in daytime symptoms were achieved. TRIAL REGISTRY: ClinicalTrials.gov; No.: 01796769; URL: www.clinicaltrials.gov.

Dual versus triple therapy in patients hospitalized for COPD in France: a claims data study.

Purposes: Following a hospitalization for COPD, dual and triple therapies were compared in terms of persistence and relations with outcomes (exacerbations, health care resource use and costs). Methods: This was a historical observational database study. All patients aged ≥45 hospitalized for COPD between 2007 and 2015 were identified in a 1/97th random sample of French claims data. Patients receiving dual therapy within 60 days after hospitalization were compared to patients receiving triple therapy, after propensity score matching on disease severity. Results: Of the 3,089 patients hospitalized for COPD, 1,538 (49.8%) received either dual or triple therapy in the 2 months following inclusion, and 1,500 (48.6%) had at least 30 days of follow-up available; 846 (27.4%) received dual therapy, and 654 (21.2%) received triple therapy. After matching, the number of exacerbations was 2.4 per year in the dual vs 2.3 in the triple group (p=0.45). Among newly treated patients (n=206), persistence at 12 months was similar in the dual and triple groups (48% vs 41%, respectively, p=0.37). As compared to patients on dual therapy, more patients on triple therapy received oral corticosteroids (49.1 vs 40.4%, p=0.003) or were hospitalized for any reason (67% vs 55.8%, p=0.0001) or for COPD (35.3 vs 25.1%, p=0.0002) during follow-up. Cost of care was higher for patients on triple than for those on dual therapy (€11,877.1 vs €9,825.1, p=0.01). Conclusion: Following hospitalizations for COPD, patients on dual and triple therapy experienced recurrent exacerbations, limited adherence to therapies and high cost of care. Patients on triple therapy appeared more severe than those on dual therapy, as reflected by exacerbations and health care resource use.

Multidimensional analyses to assess the relations between treatment choices by physicians and patients' characteristics: the example of COPD.

BACKGROUND: In some situations, practice guidelines do not provide firm evidence-based guidance regarding COPD treatment choices, especially when large trials have failed to identify subgroups of particularly good or poor responders to available medications. METHODS: This observational cross-sectional study explored the yield of four types of multidimensional analyses to assess the associations between the clinical characteristics of COPD patients and pharmacological and non-pharmacological treatments prescribed by lung specialists in a real-life context. RESULTS: Altogether, 2494 patients were recruited by 515 respiratory physicians. Multiple correspondence analysis and hierarchical clustering identified 6 clinical subtypes and 6 treatment subgroups. Strong bi-directional associations were found between clinical subtypes and treatment subgroups in multivariate logistic regression. However, although the overall frequency of prescriptions varied from one clinical subtype to the other for all types of pharmacological treatments, clinical subtypes were not associated with specific prescription profiles. When canonical analysis of redundancy was used, the proportion of variation in pharmacological treatments that was explained by clinical characteristics remained modest: 6.23%. This proportion was greater (14.29%) for non-pharmacological components of care. CONCLUSION: This study shows that, although pharmacological treatments of COPD are quantitatively very well related to patients' clinical characteristics, there is no particular patient profile that could be qualitatively associated to prescriptions. This underlines uncertainties perceived by physicians for differentiating the respective effects of available pharmacological treatments. The methodology applied here is useful to identify areas of uncertainty requiring further research and/or guideline clarification.

Virus-Associated Hemophagocytic Syndrome related to acute CMV and HBV sexual co-infection: a case report.

BACKGROUND: Secondary or reactive hemophagocytic syndrome is frequently related to viral infections and is named Virus-Associated Hemophagocytic Syndrome (VAHS). Cytomegalovirus (CMV) has been associated with hemophagocytic syndrome in healthy subjects, patients with inflammatory bowel diseases rheumatologic diseases, and transplant recipients. CMV and hepatitis B virus (HBV) can be sexually transmitted. However, co-infection with these viruses has never been reported and the clinical follow-up after acute HBV-CMV infection is not known. OBJECTIVES: To report on the first case of a VAHS related to acute CMV and HBV co-infection probably acquired after sexual contact. STUDY DESIGN: A 47-year-old woman, with no past medical history, complaining of severe asthenia, pneumonia, myalgia, and high fever, was hospitalized for the first time on July 5, 2008. During 20 days, her CMV viral load and HBV DNA were monitored. RESULTS: Ten days after her hospitalization, all signs and symptoms worsened. Twenty days after hospitalization, the patient had a natural recovery from acute HBV infection and a rapid clearance of CMV infection. Three weeks later, the patient was discharged without any complaints. CONCLUSION: This report points out the etiological role of CMV and HBV co-infection in VAHS due to probable sexual transmission.

Morphine prescription to terminally ill patients with lung cancer and dyspnea: French physicians' attitudes.

This study aimed to investigate factors associated with analgesic use of morphine in end-of-life care. French general practitioners (GPs) and oncologists (N = 719) were asked whether they would prescribe morphine as first-line therapy to patients with terminal lung cancer suffering from dyspnea associated with cough and great anxiety. Overall, 54 percent of oncologists and 40 percent of GPs stated that they would prescribe morphine in the presented case. This prescriptive attitude correlated with physicians' age, professional background, communication skills, and attitude toward terminally ill patients. The findings of this study indicate that improving analgesic use of opioids in end-of-life care is not only a matter of enhancing technical skills acquired through training or experience but also a matter of improving communication and empathy between physicians and patients.

[Opinion of general and specialized physicians toward euthanasia. Results from the French survey on attitudes and practices against palliative care, 2002]. / Opinion des médecins généralistes et spécialistes sur l'euthanasie. Résultats de l'enquête française << Attitudes et pratiques face aux soins palliatifs--2002 >>.

OBJECTIVES: To evaluate opinion of physicians about the legalization of euthanasia according to their professional characteristics, their attitudes toward morphine, their attitudes toward communication with end-of-life patients, and their perception of specific types of terminal care. METHOD: Univariate and multivariate analyses were carried out from data collected among 1.000 general practitioners, oncologists, neurologists and HIV specialists (French cross-sectional survey on palliative care, 2002). RESULTS: 42.5% of physicians agreed with the statement that euthanasia should be legalized as it is already the case in the Netherlands. Inadequate prescription of morphine and calling terminal sedation as active euthanasia were associated with a favorable opinion toward legalization of euthanasia. CONCLUSION: Specific training on pain management and terminal sedation would help physicians to have a better view of the problem of euthanasia.

French physicians' attitudes toward legalisation of euthanasia and the ambiguous relationship between euthanasia and palliative care.

In 1999, the French Parliament established a "right to palliative care", which reactivated public debate about euthanasia. In order to investigate jointly physicians' attitude toward palliative care and euthanasia, we conducted a cross-sectional survey of a national sample of French GPs, oncologists, and neurologists. Overall, 917 physicians participated in the survey. Significant proportions of respondents, especially among GPs and neurologists, considered that palliative sedation and withdrawing life-sustaining treatments (WLST) were euthanasia. Multivariate analysis showed that the physicians who had special medical training in palliative care, and those who distinguish palliative sedation and WLST from euthanasia were more likely to oppose legalisation of euthanasia. Thus, French physicians' attitude to the legalisation of euthanasia is strongly influenced by whether or not they distinguish palliative care from euthanasia. Improved palliative care requires better training of the entire medical profession, and clearer guidelines about which end-of-life care practices are legally and ethically acceptable.