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.
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.
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.
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.
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.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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.
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.
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.
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.
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.
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?
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.
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/m
(IQR, 26.8; 35.1 kg/m
) 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.
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.
ClinicalTrials.gov; No.: 01796769; URL: www.clinicaltrials.gov.
We investigated the combination of rapid antigen detection (RAD) and RT-qPCR assays in a stepwise procedure to optimize the detection of COVID-19. 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. 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 less than or equal to 25 regardless of TSO: TSO less than or equal to 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. 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.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
BackgroundImmune checkpoint inhibitors (ICIs) are associated with long-term survival in ~20% of advanced NSCLC patients while biological mechanisms triggering resistance are not fully elucidated. The ...PIONeeR project (NCT03493581, ANR-17-RHUS-0007) aims to predict the response/resistance to PD1/L1 ICIs in advanced NSCLC patients through comprehensive agnostic multiparametric biomarkers assessment. The immune system is crucial for tumor evolution and is composed of different subsets of immune cells that can be activating (T-, B-lymphocytes, ...) or regulating such as regulatory T-cells (Treg).MethodsTumor was sampled at diagnosis from 101 advanced pretreated NSCLC patients, ECOG PS0/1, treated with standard PD1/L1 ICIs monotherapy. Complete database of ≥2nd line PIONeeR patients was released in July 2023. Overall Response Rate was assessed by RECIST 1.1. Multiplex IHC Brightplex® T-cells exhaustion quantifies cytotoxic (Tc) (CD3+CD8+) and helper (Th) (CD3+CD8-) T-lymphocytes in both tumor parenchyma and stroma. This quantification allows stratification into 4 tumor groups: Hot, Parenchyma Hot, Cold and Stroma Tumor Infiltrating Lymphocytes (TILs).1 2 Dual staining CD4 FOXP3 quantifies Treg density in parenchyma and stroma. Correlation analyses: spearman non-parametric test. Samples’ classification: unsupervised neural-network-based machine learning algorithm Self-Organizing Maps (SOM). Statistical significance of progression-free/overall survival (PFS/OS) differences: log-rank test. Response distribution differences: Fisher’s test.ResultsPatients were mainly male (65%), current/previous smoker (92%), <70yrs (68%) with median PFS=4.4months. Across the 101 tumors, Treg were not strongly correlated to any other cell type (Tc: R=0.54, Th: R=0.59). As expected, Brightplex® TCE identified 4 patient groups based on Th/Tc infiltration revealing outcome differences: Hot (N=32), Cold (N=19), Parenchyma Hot (N=15) and Stroma TILs (N=35). Each group was stratified according to Th/Treg infiltration. The 35 Stroma TILs patients (median PFS=6.4) were split into 4 groups (SOM): low Th/Treg-infiltration (N=10); Th-only parenchyma-infiltration (N=7); intermediate Treg+Th infiltration in both compartments (N=9); Treg+Th high infiltration (N=9). The two lowest infiltrated groups had poorer outcome (median PFS=1.6/1.8; median OS=6.9/7.4 respectively) than both infiltrated groups (median PFS=17.3/14.1; median OS=17.3/not reached respectively), p=4.1e-4. 10/11 responders were part of both infiltrated groups (p=2.6e-3) regardless of PDL1 status.ConclusionsTreg infiltration evaluation improved previous lymphocyte-associated NSCLC classification regarding response to anti-PD1/L1 ICIs.1 2 Absence of Treg, regardless of Th cells infiltration, in the Stroma TILs patient subset, was associated with early progression and poor survival. These unexpected results were already described in some cancers and could be linked to Tregs’ ability to suppress general inflammation that itself triggers cell proliferation and metastasis.AcknowledgementsThis work benefited from a government grant handled by the French National Research Agency (ANR) as part of the France 2030 investment plan, under the reference ANR-17-RHUS-0007. A partnership of AMU, AP-HM, CNRS, Inserm, Centre Léon Bérard, Institut Paoli-Calmettes, AstraZeneca, Veracyte, Innate Pharma & ImCheck Therapeutics, sponsored by AP-HM and initiated by Marseille Immunopole. Drug supply is funded by AstraZeneca.Trial RegistrationNCT03493581ReferencesGhezali L, Landri M, Monville F, et al. Brightplex® TCE and Brightplex® MDSC assays combination improves NSCLC patients’ stratification under anti-PD1/L1 immunotherapy in the PIONeeR project. Journal for ImmunoTherapy of Cancer 2022;10.Leca V, Kassambara A, Ghezali L, et al. Spatial distribution of infiltrating T lymphocytes with Immunoscore® CR T Cells Exhaustion test helps stratification of NSCLC patients treated with PD1/PDL1 inhibitors in the PIONeeR project. Journal for ImmunoTherapy of Cancer 2021;9.Ethics ApprovalThe study is conducted in accordance with Good Clinical Practice and the French applicable regulatory requirements (Public Health Code, article L.1121-1/La loi n° 2012–300 du 5 mars 2012 relative aux recherches impliquant la personne humaine (dite loi Jardé), the applicable subject privacy requirements, and the ethical principles that are outlined in the Declaration of Helsinski. The study was approved by the French Ethic Committee, CPP Ouest II - Angers, ref. CPP: 2028/08, Ref ANSM (French competent authority) 2018020500208, 2018072600120, 2019083000148. Freely given written informed consent was signed and obtained from each individual participating in the study, before any study specific procedure was undertaken and after the provision of information about the study by the investigator during a physician-patient consultation and sufficient time for reflection.
Abstract 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.
BackgroundPD1/L1 Immune Checkpoint Inhibitors (ICI) have significantly improved long-term outcome in about 20% of advanced Non Small Cells Lung Cancer (NSCLC) patients (pts), but 80% present primary ...or secondary resistance. The PIONeeR project (NCT03493581) aims to predict the response/resistance to PD1/L1 ICIs in advanced NSCLC pts through a comprehensive agnostic multiparametric and longitudinal biomarkers assessment. Data presented here are a focus on the quantification of tumor infiltration by lymphocytes, their activation as potential markers of the resistance to treatment by ICI.MethodsAdvanced NSCLC pts with available archived tumor tissue at screening visit (VS), treated with standard PD1/L1 ICIs (nivolumab, pembrolizumab or atezolizumab), alone (2nd line or more) or combined with chemotherapy (1st line), were re-biopsied at 6 weeks (V2) of treatment. PD1/L1 ICIs overall response rate (ORR) was assessed by RECIST 1.1 every 6 weeks. The multiplex IHC test ”Immunoscore® CR T Cells Exhaustion” (IS TCE) quantifies cytotoxic lymphocytes expressing three checkpoints: PD1, LAG3, TIM3, extrapolating their exhaustion status, both in the stroma and parenchyma. The unsupervised neural-network-based machine learning algorithm SOM (Self-Organizing Maps) was used to classify samples based on the 27 IS TCE variables. Statistical significance of survival differences between groups was evaluated using the log-rank test.ResultsAmong the first 100 pts, (male (64%), smokers (91,8%), <70yrs (69%), with an ECOG PS0/1 (97%), treated in 2nd line setting (86%)), 79 VS + 30 V2 biopsies were tested with IS TCE. SOM clustering highlighted four distinct clusters: a group with moderate T-cells infiltration (group 1), hot tumors with high T cells infiltration in both stroma and parenchyma (group 2), cold tumors with very low T cells infiltration (group 3), and finally, a highly distinguishable group with important T-cells density in stroma only (group 4). None of the 11 responders was present in the Group 3, ”Cold” cluster. The four groups presented different Progression Free Survival (PFS) rates (p=5,2e-4) with better relapse-free survival Groups 1 and 2. Additionally, V2/VS ratios showed lymphocytes recruitment induced by the treatment in parenchyma only: no significant lymphocytes recruitment was observed in the stromal compartment. Interestingly, the most recruited lymphocyte populations expressed PD1.ConclusionsIS TCE test may help stratifying and predicting responders to anti PD1/L1 therapy through checkpoint expressing lymphocytes quantification and spatial distribution. Additional tests performed on the PIONeeR cohort to explore other aspects of the immune response to cancer should complete these results.AcknowledgementsThis work is supported by French National Research Agency (ANR-17-RHUS-0007), a partnership of AMU, APHM, AstraZeneca, Centre Léon Bérard, CNRS, HalioDx, ImCheck Therapeutics, Innate Pharma, Inserm, Institut Paoli Calmettes and sponsored by AP HM. Drug supply is funded by AstraZeneca. Special thanks to patients and families.Trial RegistrationNCT03493581Ethics ApprovalThe study is conducted in accordance with Good Clinical Practice and the French applicable regulatory requirements (Public Health Code, article L.1121-1/La loi n° 2012–300 du 5 mars 2012 relative aux recherches impliquant la personne humaine (dite loi Jardé), the applicable subject privacy requirements, and the ethical principles that are outlined in the Declaration of Helsinski. The study was approved by the French Ethic Committee, CPP Ouest II - Angers, ref. CPP: 2028/08, Ref ANSM (French competent authority) 2018020500208, 2018072600120, 2019083000148. Freely given written informed consent was signed and obtained from each individual participating in the study, before any study specific procedure was undertaken and after the provision of information about the study by the investigator during a physician-patient consultation and sufficient time for reflection.
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.
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