Background: Delaying time to prone positioning (PP) may be associated with higher mortality in acute respiratory distress syndrome (ARDS) due to coronavirus disease 2019 (COVID-19). We evaluated the use and the impact of early PP on clinical outcomes in intubated patients hospitalized in intensive care units (ICUs) for COVID-19. Methods: All intubated patients with ARDS due to COVID-19 were involved in a secondary analysis from a prospective multicenter cohort study of COVID-ICU network including 149 ICUs across France, Belgium and Switzerland. Patients were followed-up until Day-90. The primary outcome was survival at Day-60. Analysis used a Cox proportional hazard model including a propensity score. Results: Among 2137 intubated patients, 1504 (70.4%) were placed in PP during their ICU stay and 491 (23%) during the first 24 h following ICU admission. One hundred and eighty-one patients (36.9%) of the early PP group had a PaO2/FiO2 ratio > 150 mmHg when prone positioning was initiated. Among non-early PP group patients, 1013 (47.4%) patients had finally been placed in PP within a median delay of 3 days after ICU admission. Day-60 mortality in non-early PP group was 34.2% versus 39.3% in the early PP group (p = 0.038). Day-28 and Day-90 mortality as well as the need for adjunctive therapies was more important in patients with early PP. After propensity score adjustment, no significant difference in survival at Day-60 was found between the two study groups (HR 1.34 [0.96-1.68], p = 0.09 and HR 1.19 [0.998-1.412], p = 0.053 in complete case analysis or in multiple imputation analysis, respectively). Conclusions: In a large multicentric international cohort of intubated ICU patients with ARDS due to COVID-19, PP has been used frequently as a main treatment. In this study, our data failed to show a survival benefit associated with early PP started within 24 h after ICU admission compared to PP after day-1 for all COVID-19 patients requiring invasive mechanical ventilation regardless of their severity.
Rationale Early corticosteroid treatment is used to treat COVID-19-related acute respiratory distress syndrome (ARDS). Infection is a well-documented adverse effect of corticosteroid therapy. Objectives To determine whether early corticosteroid therapy to treat COVID-19 ARDS was associated with ventilator-associated pneumonia (VAP). Methods We retrospectively included adults with COVID-19-ARDS requiring invasive mechanical ventilation (MV) for ≥ 48 h at any of 15 intensive care units in 2020. We divided the patients into two groups based on whether they did or did not receive corticosteroids within 24 h. The primary outcome was VAP incidence, with death and extubation as competing events. Secondary outcomes were day 90-mortality, MV duration, other organ dysfunctions, and VAP characteristics. Measurements and main results Of 670 patients (mean age, 65 years), 369 did and 301 did not receive early corticosteroids. The cumulative VAP incidence was higher with early corticosteroids (adjusted hazard ratio [aHR] 1.29; 95% confidence interval [95% CI] 1.05–1.58; P = 0.016). Antibiotic resistance of VAP bacteria was not different between the two groups (odds ratio 0.94, 95% CI 0.58–1.53; P = 0.81). 90-day mortality was 30.9% with and 24.3% without early corticosteroids, a nonsignificant difference after adjustment on age, SOFA score, and VAP occurrence (aHR 1.15; 95% CI 0.83–1.60; P = 0.411). VAP was associated with higher 90-day mortality (aHR 1.86; 95% CI 1.33–2.61; P = 0.0003). Conclusions Early corticosteroid treatment was associated with VAP in patients with COVID-19-ARDS. Although VAP was associated with higher 90-day mortality, early corticosteroid treatment was not. Longitudinal randomized controlled trials of early corticosteroids in COVID-19-ARDS requiring MV are warranted.
Objective To provide recommendations on the management of urgent obstetrical emergencies outside the maternity ward. Design A group of 24 experts from the French Society of Emergency Medicine (SFMU), the French Society of Anaesthesia and Intensive Care Medicine (SFAR) and the French College of Gynaecologists and Obstetricians (CNGOF) was convened. Potential conflicts of interest were formally declared at the outset of the guideline development process, which was conducted independently of industry funding. The authors followed the GRADE (Grading of Recommendations Assessment, Development and Evaluation) method to assess the level of evidence in the literature. The potential drawbacks of strong recommendations in the presence of low-level evidence were highlighted. Some recommendations with an insufficient level of evidence were not graded. Methods Eight areas were defined: imminent delivery, postpartum haemorrhage (prevention and management), threat of premature delivery, hypertensive disorders in pregnancy, trauma, imaging, cardiopulmonary arrest, and emergency obstetric training. For each field, the expert panel formulated questions according to the PICO model (population, intervention, comparison, outcomes) and an extensive literature search was conducted. Analysis of the literature and formulation of recommendations were conducted according to the GRADE method. Results Fifteen recommendations on the management of obstetrical emergencies were issued by the SFMU/SFAR/CNGOF panel of experts, and 4 recommendations from formalised expert recommendations (RFE) established by the same societies were taken up to answer 4 PICO questions dealing with the pre-hospital context. After two rounds of voting and several amendments, strong agreement was reached for all the recommendations. For two questions (cardiopulmonary arrest and inter-hospital transfer), no recommendation could be made. Conclusions There was significant agreement among the experts on strong recommendations to improve practice in the management of urgent obstetric complications in emergency medicine.
Background Primary Ovarian Insufficiency (POI), a public health problem, affects 1-3.7% of women under 40 yielding infertility and a shorter lifespan. Most causes are unknown. Recently, genetic causes were identified, mostly in single families. We studied an unprecedented large cohort of POI to unravel its molecular pathophysiology. Methods 375 patients with 70 families were studied using targeted (88 genes) or whole exome sequencing with pathogenic/likely-pathogenic variant selection. Mitomycin-induced chromosome breakages were studied in patients’ lymphocytes if necessary. Findings A high-yield of 29.3% supports a clinical genetic diagnosis of POI. In addition, we found strong evidence of pathogenicity for nine genes not previously related to a Mendelian phenotype or POI: ELAVL2, NLRP11, CENPE, SPATA33, CCDC150, CCDC185, including DNA repair genes: C17orf53(HROB), HELQ, SWI5 yielding high chromosomal fragility. We confirmed the causal role of BRCA2, FANCM, BNC1, ERCC6, MSH4, BMPR1A, BMPR1B, BMPR2, ESR2, CAV1, SPIDR, RCBTB1 and ATG7 previously reported in isolated patients/families. In 8.5% of cases, POI is the only symptom of a multi-organ genetic disease. New pathways were identified: NF-kB, post-translational regulation, and mitophagy (mitochondrial autophagy), providing future therapeutic targets. Three new genes have been shown to affect the age of natural menopause supporting a genetic link. Interpretation We have developed high-performance genetic diagnostic of POI, dissecting the molecular pathogenesis of POI and enabling personalized medicine to i) prevent/cure comorbidities for tumour/cancer susceptibility genes that could affect life-expectancy (37.4% of cases), or for genetically-revealed syndromic POI (8.5% of cases), ii) predict residual ovarian reserve (60.5% of cases). Genetic diagnosis could help to identify patients who may benefit from the promising in vitro activation-IVA technique in the near future, greatly improving its success in treating infertility. Funding Université Paris Saclay, Agence Nationale de Biomédecine.
Context: SC Isa delivery would optimize convenience of administration. Prior results showed SC Isa administered by syringe pump has efficacy and safety profiles comparable to IV Isa; recommended Phase 2 dose (RP2D) 1400 mg (IMW21 P-207). Objective: Evaluate safety, pharmacokinetics (PK), and efficacy of SC vs IV Isa+Pd Design: Multicenter Phase 1b study. Patients: RRMM patients after ≥2 prior treatment lines. Intervention: Patients randomized 2:1 to SC1000mg or IV10mg/kg and to SC1400mg or IV. Expansion cohort was implemented with SC Isa administered at RP2D via OBDS (wearable bolus injector applied to abdomen). Main Outcome Measure: Primary endpoints were safety, including injection site (IS) reactions (ISRs), and PK. Results: 56 patients were randomized and treated: 12 IV, 12 SC1000, 10 SC1400, 22 OBDS. At study entry, ISS stage II–III: IV 67%, SC1000 33%, SC1400 60%, OBDS 50%. On January 20th, 2022, 33% IV, 25% SC1000, 50% SC1400, 86% OBDS patients remained on treatment. Due to sequential accrual, median follow-up (FU; in mo) was longer in IV (20.6) and SC1000 (23.8) than SC1400 (18.1) and OBDS (6.5). Infusion reactions (IRs) were infrequent (≤10% in each cohort, Grade [G] 2), at first IV/SC infusion/injection, with no IRs in OBDS. Local tolerability of OBDS was very good; 5 (22.7%) patients experienced 7 ISR episodes, (G1) of 305 administrations (2.3%): 5 IS erythemas, 1 IS hemorrhage, 1 IS induration. Median duration of OBDS was 10 min. Lower percentage of ≥G3 treatment-related adverse events in OBDS (77%) vs other cohorts (≥80%) may be due to shorter FU. Overall response rate: IV and SC1000 66.7%, SC1400 80.0%, OBDS 77.3%, SC1400+OBDS 78.1%; ≥very good partial response ranged between 40%-50%, complete response 13-25%, partial response 16-40% across cohorts; longer FU is needed for OBDS. Median PFS was: IV 22 mo, SC1000 12.5 mo, SC1400 and OBDS not reached. PK and CD38 receptor occupancy in OBDS were consistent with SC1400. Conclusions: SC Isa via OBDS shows safety profile consistent with IV; with no IRs and excellent tolerability. Efficacy in SC cohorts was comparable to Phase 3 ICARIA. Isa SC administration by OBDS is well-tolerated, requires a short injection duration, and provides a handsfree option.
Context: Achieving minimal residual disease negativity (MRD–) in MM is associated with improved survival. Isatuximab (Isa) plus carfilzomib (K) and dexamethasone (d) is approved for relapsed MM patients after ≥1 prior therapy, based on IKEMA interim analysis (NCT03275285). Objective: Report updated, longer-term depth of response (DoR) results from IKEMA, including MRD–status. Design and Patients: IKEMA, a randomized, open-label, multicenter Phase 3 study, investigates Isa-Kd (n=179) versus Kd (n=123) in relapsed MM patients with 1–3 prior lines of therapy. Interventions: IV Isa 10 mg/kg was given QW for 4 weeks, followed by Q2W. Both arms received an approved schedule of K (IV) and d (oral/IV). Main Outcome Measures: This prespecified analysis evaluated PFS (primary endpoint) at 159 events; secondary endpoints were ≥CR (+stringent CR), MRD–, and ≥CR+MRD–rates, as determined by IRC based on central laboratory data and review of local radiology. MRD status was assessed by NGS (sensitivity threshold ≥10–5) in bone marrow aspirates from patients achieving ≥VGPR. HYDRASHIFT Isa immunofixation (IFE) test, removing Isa interference in IFE, was used to update ≥CR rate. Secondary endpoints were compared between treatment arms using Cochran–Mantel–Haenszel test. One-sided descriptive P-values were provided. All randomized patients not reaching MRD– or without MRD assessment were considered MRD+. Results: At cutoff (14-Jan-2022), with a median follow-up of 44 months, deeper responses were observed in Isa-Kd versus Kd, ≥CR rates 44.1% versus 28.5% (OR: 2.09; 95%CI=1.26–3.48; descriptive P=0.0021). For Isa-Kd versus Kd patients, MRD– (10–5) occurred in 33.5% versus 15.4% (OR: 2.78; 95%CI=1.55–4.99; descriptive P=0.0002), with 26.3% versus 12.2% reaching ≥CR+MRD– (10–5; OR: 2.57; 95%CI=1.35–4.88; P=0.0015); MRD– at 10–6 sensitivity occurred in 10.6% versus 3.3%. MRD– versus MRD+ patients (10–5) had longer mPFS (months); Isa-Kd: not calculable ([NC]; 95%CI=NC–NC) versus 21.7 (95%CI=16.4–27.1); Kd: NC (95%CI=29.2–NC) versus 16.2 (95%CI=13.4–19.5). Conclusions: These results demonstrate clinically meaningful improvement in DoR with Isa-Kd versus Kd. Impressive ≥CR and ≥CR+MRD– (10–5) rates in Isa-Kd versus Kd are the highest reported for proteasome inhibitor–based regimens in relapsed MM. Achieving MRD– led to better outcomes in both arms; Isa-Kd patients had >2-fold higher likelihood of achieving MRD–. Additionally, Isa improved outcomes of MRD+ patients.
Context: Anti-CD38 antibody Isa in combination with Kd is approved in various countries for relapsed multiple myeloma (MM) patients after ≥1 prior therapy based on primary interim analysis (IA) of the Phase 3 IKEMA study (NCT03275285). Objective: To report updated efficacy and safety results from IKEMA. Setting and Main Outcome Measures: This prespecified analysis (179 patients randomized to Isa-Kd, 123 to Kd) evaluated progression-free survival (PFS) (primary endpoint) at 159 PFS events, PFS2, minimal residual disease negativity (MRD–) rate, complete response (CR) rate, MRD– and CR rates in all patients, and safety. Interventions: Isa 10 mg/kg was given IV weekly for 4 weeks and then every 2 weeks; Kd (20/56 mg/m2, twice weekly, 3/4 weeks) was administered in both arms. Results: At cutoff (14-Jan-2022), with a 44-month median follow-up, 49 (27.4%) patients in Isa-Kd and 11 (8.9%) in Kd were still on treatment. Updated PFS, consistent with IA results, demonstrated significant benefit in favor of Isa-Kd (vs. Kd): HR=0.58 (95.4%CI=0.42–0.79; 35.7 vs. 19.2 months); PFS2 HR=0.68 (95%CI=0.50–0.94; 47.2 vs. 35.6 months). Primary PFS analysis, per FDA request/sensitivity analysis for other countries (censoring PFS events occurring >8 weeks after last valid assessment), was 41.7 versus 20.8 months (HR=0.59, 95%CI=0.42–0.83). With additional follow-up and using Hydrashift Isa immunofixation assay to rule out potential Isa interference in CR determination, final CR rate (Isa-Kd vs. Kd) was 44.1% versus 28.5% (OR=2.09, 95%CI=1.26–3.48); ORR was 86.6% versus 83.7%; MRD– was reached in 33.5% versus 15.4% patients (OR=2.78, 95%CI=1.55–4.99); and the rate of MRD– CR patients was 26.3% versus 12.2% (OR=2.57, 95%CI=1.35–4.88). Safety profiles in both arms remain consistent with prior IKEMA findings. Serious TEAEs were reported in 70.1% of Isa-Kd versus 59.8% Kd patients. The most common any-grade non-hematologic TEAEs in Isa-Kd were infusion reaction (45.8%), diarrhea (39.5%), hypertension (37.9%), and upper respiratory tract infection (37.3%). Conclusions: These results show unprecedented mPFS, CR, MRD–, and MRD– CR rates in non-lenalidomide containing regimens with benefits maintained through subsequent therapies and a manageable safety profile. Moreover, PFS analysis using FDA censoring rules showed consistent results with the IA. Our findings support Isa-Kd as a standard-of-care treatment for relapsed MM patients.
Combined therapies involve the use of multiple drugs to increase efficacy and reduce the toxicity of individual treatments. We evaluated the use of combinations of conventional systemic therapies and biologics in children with psoriasis in daily practice. This two‐part study used data from the 170 children in the Franco‐Italian BiPe cohorts to evaluate the use, efficacy, and safety of combined conventional systemic–biologic therapies, and from a survey carried out among French and Italian dermatologists to better understand the reasons for using or avoiding these combinations. In total, 33 children (19.4%) from 13 dermatology centres received 48 combined conventional systemic–biologic therapies (cumulative duration: 43.6 years), including three triple combination therapies (acitretin–methotrexate, with a TNF‐alpha inhibitor). Fourteen different combinations were used, most frequently etanercept–acitretin (n=10), adalimumab–acitretin (n=7), adalimumab–methotrexate (n=5), and ustekinumab–methotrexate (n=5). The combined therapies were started at biologic initiation in 41 cases (85.4%), and after a period of biologic monotherapy in the remaining 7 cases. Mean PGA and PASI scores decreased between baseline and M3 with all the combinations used. Four serious adverse events were reported, all with favourable outcomes. The survey was completed by 61 dermatologists: 39 (63.9%) had previously used or planned to use the combined therapies, most commonly TNF‐alpha inhibitors with acitretin or methotrexate. The main reason for using these treatments was to improve the outcome of biologic therapies in cases of partial efficacy or loss of efficacy. Combined therapies have been used frequently in the treatment of childhood psoriasis, in a range of clinical situations and in variable drug combinations, without significant toxicity. Although the use of these combined therapies needs to be clarified in future management guidelines, these combined therapies should be considered for the treatment of children with severe psoriasis, psoriatic arthritis, and recalcitrant disease. This article is protected by copyright. All rights reserved.
Background and purpose: MCA aneurysms are still commonly clipped surgically despite the recent development of a number of endovascular tools and techniques. We measured clinical uncertainty by studying the reliability of decisions made for patients with middle cerebral artery (MCA) aneurysms. Materials and methods: A portfolio of 60 MCA aneurysms was presented to surgical and endovascular specialists who were asked whether they considered surgery or endovascular treatment to be an option, whether they would consider recruitment of the patient in a randomized trial, and whether they would provide their final management recommendation. Agreement was studied using κ statistics. Intrarater reliability was assessed with the same, permuted portfolio of cases of MCA aneurysm sent to the same specialists 1 month later. Results: Surgical management was the preferred option for neurosurgeons (n = 844/1320; [64%] responses/22 raters), while endovascular treatment was more commonly chosen by interventional neuroradiologists (1149/1500 [76.6%] responses/25 raters). Interrater agreement was only "slight" for all cases and all judges (κ = 0.094; 95% CI, 0.068-0.130). Agreement was no better within specialties or with more experience. On delayed requestioning, 11 of 35 raters (31%) disagreed with themselves on at least 20% of cases. Surgical management and endovascular treatment were always judged to be a treatment option, for all patients. Trial participation was offered to patients 65% of the time. Conclusions: Individual clinicians did not agree regarding the best management of patients with MCA aneurysms. A randomized trial comparing endovascular with surgical management of patients with MCA aneurysms is in order.
Preservation of fertility has become a growing concern in young females with Hodgkin lymphoma (HL). However, the rate of pregnancy after the current most frequently prescribed ABVD chemotherapy for HL has rarely been studied. We aimed to determine the impact of ABVD on the fertility of women treated for HL. A non-interventional, multicentric study of female patients of child-bearing age with HL treated. Two healthy apparied women non exposed at chemotherapy (our controls) were assigned for each patient. Fertility was assessed by the number of pregnancies and births after HL treatment. Sixty-seven patients were included. The median age at diagnosis was 24.4 years (16-43). Hodgkin lymphoma was localized disease for 68.7%. 53.7% of all the patients started at least one pregnancy after treatment versus 54.5% of the controls (p=0.92). 81% of patients who desired children had at least one pregnancy. Patients treated with ABVD did not have a longer median time to pregnancy (4.8 years in the group of patients and 6.8 years for controls). Across patients, there has been 58 pregnancies and 48 births (ratio 1.2) and for control cohort, 136 pregnancies and 104 births (ratio 1.3). No increase in obstetric or neonatal complications has been reported in HL in our study. The number of pregnancies, births and the time to start a pregnancy in young women treated with ABVD for HL is not different to that of controls. Therefore, female with HL and treated by ABVD should be reassured in regards to fertility.
Molecular monitoring of tumor-derived alterations has an established role in the surveillance of leukemias, and emerging nucleic acid sequencing technologies are likely to similarly transform the clinical management of lymphomas. Lymphomas are well suited for molecular surveillance due to relatively high cell-free DNA and circulating tumor DNA concentrations, high somatic mutational burden, and the existence of stereotyped variants enabling focused interrogation of recurrently altered regions. Here, we review the clinical scenarios and key technologies applicable for the molecular monitoring of lymphomas, summarizing current evidence in the literature regarding molecular subtyping and classification, evaluation of treatment response, the surveillance of active cellular therapies, and emerging clinical trial strategies. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 18 is January 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
A three-year-old girl with a history of epilepsy seizures was diagnosed with acute lymphoblastic leukemia. A comprehensive genetic study of blast cells led to the discovery of a constitutional deletion of the PCDH19 gene. This description underlines how modern techniques of molecular investigations in hematological disorders may lead to unexpected findings.
Poster session 3, September 23, 2022, 12:30 PM - 1:30 PM Objectives Pulmonary mucormycosis (PM) is a life-threatening invasive fungal infection mostly affecting immunocompromised patients. We aimed to study the influence of underlying conditions on disease presentation and diagnostic strategy during PM. Methods All PM cases from six French teaching hospitals between 2008 and 2019 were retrospectively reviewed. Cases were defined according to EORTC/MSG 2019 criteria with the addition of diabetes and traumatism as host factors and positive serum or tissue PCR as mycological evidence. Thoracic CT scans were reviewed centrally. Results Among 114 cases of PM, 52 (46%) were proven and 62 (54%) were probable, including 12 cases with a positive serum qPCR as the sole mycological criterion. Hematological malignancy was the most common risk factor (49%), followed by allogeneic hematopoietic stem-cell transplantation (21%), and solid organ transplantation (SOT, 17%). Fever was the first symptom for 66% patients and was more frequent in patients with neutropenia than in those without (97% vs 52%, P <.01). A total of 46 (40%) patients had a disseminated infection, which was more frequently reported in neutropenic patients (50% vs 25%, P <.01). Main dissemination sites were the liver (48%), spleen (48%), brain (44%), and kidneys (37%). Sinusitis was present in 13% of cases. Chest radiological presentation included consolidation (58%), pleural effusion (52%), reversed halo sign (26%), halo sign (24%), vascular abnormalities (26%), and excavation (23%). The excavation was more frequently reported in SOT patients (64%, P <.01) compared with other groups. Vascular involvement was associated with reversed halo sign and Rhizomucor infection. Neutropenic patients presented more frequently than non-neutropenic patients with ground-glass opacities (75 vs 49%, P = .01), halo sign (32% vs 10%, P = .02), and reversed halo sign (35 vs 10%, P <.01). A total of 83 (73%) patients had a positive fungal culture from any type of respiratory sample. Serum qPCR was positive for 42/53 patients (79%) and respiratory fluid qPCR for 16/21 (76%) patients. In neutropenic patients, BAL culture was less often positive (30% vs 66%, P <.01), and serum qPCR was more frequently positive (91% vs 62%, P = .02). A transthoracic lung biopsy was contributive in 8/11 (73%) patients with negative bronchoalveolar lavage (BAL). Serum qPCR was more frequently positive in patients with the main lesion of >3 cm in diameter (91% vs 62%, P = .02). Rhizomucor spp. Was identified in 31 patients (32%), Rhizopus spp. In 29 patients (30%), Lichtheimia spp. In 24 patients (25%), Mucor spp. In 10 patients (10%) and Cunninghamella spp. In 4 patients (4%). Neutropenic patients were more frequently infected with Rhizomucor (43% vs 13%, P <.01) and less frequently with Rhizopus (17% vs 50%, P <.01). Histopathological specimens were available for 48 patients (42%) and revealed Mucorales hyphae in 85% of cases. Patients with a disseminated infection and neutropenia presented more often with angioinvasion than patients with localized disease (50% vs 9%, P <.01 and 38% vs 13%, P = .10). Overall, 90-day mortality was 59%. Conclusion Underlying conditions significantly influenced clinical and radiological presentation and diagnostic tools’ contribution. Neutropenic patients present more frequently with dissemination, fever, reversed halo sign, pathological angioinvasion, the negativity of BAL culture, the positivity of serum qPCR, and Rhizomucor infection.
Background Spread of resistant bacteria causes severe morbidity and mortality. Stringent control measures can be expensive and disrupt hospital organization. In the present study, we assessed the effectiveness and cost-effectiveness of control strategies to prevent the spread of Carbapenemase-producing Enterobacterales (CPE) in a general hospital ward (GW). Methods A dynamic, stochastic model simulated the transmission of CPE by the hands of healthcare workers (HCWs) and the environment in a hypothetical 25-bed GW. Input parameters were based on published data; we assumed the prevalence at admission of 0.1%. 12 strategies were compared to the baseline (no control) and combined different prevention and control interventions: targeted or universal screening at admission (TS or US), contact precautions (CP), isolation in a single room, dedicated nursing staff (DNS) for carriers and weekly screening of contact patients (WSC). Time horizon was one year. Outcomes were the number of CPE acquisitions, costs, and incremental cost-effectiveness ratios (ICER). A hospital perspective was adopted to estimate costs, which included laboratory costs, single room, contact precautions, staff time, i.e. infection control nurse and/or dedicated nursing staff, and lost bed-days due to prolonged hospital stay of identified carriers. The model was calibrated on actual datasets. Sensitivity analyses were performed. Results The baseline scenario resulted in 0.93 CPE acquisitions/1000 admissions and costs 32,050 €/1000 admissions. All control strategies increased costs and improved the outcome. The efficiency frontier was represented by: (1) TS with DNS at a 17,407 €/avoided CPE case, (2) TS + DNS + WSC at a 30,700 €/avoided CPE case and (3) US + DNS + WSC at 181,472 €/avoided CPE case. Other strategies were dominated. Sensitivity analyses showed that TS + CP might be cost-effective if CPE carriers are identified upon admission or if the cases have a short hospital stay. However, CP were effective only when high level of compliance with hand hygiene was obtained. Conclusions Targeted screening at admission combined with DNS for identified CPE carriers with or without weekly screening were the most cost-effective options to limit the spread of CPE. These results support current recommendations from several high-income countries.
Anti-CD19 CAR T-cells represent a major advance in the treatment of relapsed/refractory aggressive B-cell lymphomas. However, a significant number of patients experiences failure. Among 550 patients registered in the French registry DESCAR-T, 238 (43.3%) experienced progression/relapse, with a median follow-up of 7.9 months. At registration, 57.0% of patients presented an age adjusted International Prognostic Index of 2-3, 18.9% had ECOG performance status ≥2, 57.1% received >3 lines of treatment prior to receiving CAR T-cells, and 87.8% received bridging therapy. At infusion, 66% of patients presented progressive disease and 38.9% high lactate dehydrogenase (LDH). Failure after CAR T-cells occurred after a median of 2.7 months (range, 0.2-21.5). Fifty-four (22.7%) patients presented very early failure (day [D] 0-D30); 102 (42.9%) had early failure (D31-D90), and 82 (34.5%) had late (>D90) failure. After failure, 154 (64%) patients received salvage treatment: 38.3% had lenalidomide, 7.1% bispecific antibodies, 21.4% targeted treatment, 11% radiotherapy, and 20% immuno-chemotherapy with various regimens. Median progression-free survival was 2.8 months, and median overall survival (OS) was 5.2 months. Median OS for patients failing during D0-D30 versus after D30 was 1.7 vs 3.0 months respectively (p=0.0001). Overall, 47.9% of patients were alive at 6 months, but only 18.9% were alive after very early failure. In multivariate analysis, predictors of OS were high LDH at infusion, time to CAR-T failure <D30, and high C-reactive protein at infusion. This multicentric analysis confirms the poor outcome of patients relapsing after CAR T-cells, highlighting the need for further strategies dedicated to this population.
Background: Enterococcus faecalis infective endocarditis (EFIE) are characterized by a higher frequency of relapses than other infective endocarditis. The role of the treatment on their occurrence remains poorly understood. The aim of this study was to investigate whether the antibiotic regimen could impact the risk of relapse in EFIE. Materials: This was a multicenter retrospective study of patients diagnosed with definite EFIE between 2015 and 2019 in 14 French hospitals. The primary endpoint was the occurrence of relapses within the year following endocarditis diagnosis. As death was a competing risk for relapse, Fine & Gray models were used for studying risk factors and impact of treatment. Results: Of the 279 patients included, 83 (29.7%) received the amoxicillin-gentamicin (A-G) combination, 114 (40.9%) amoxicillin-ceftriaxone (A-C), 63 (22.6%) A-G and A-C (A-G/A-C) sequentially, 9 (3.2%) amoxicillin (A), and 10 received other treatments. One-year-relapse rate was 9.3% (26 patients). Relapse occurred after a median delay of 107 days from EFIE diagnosis; 6 occurred after 6 months, and 6 were diagnosed by blood cultures in asymptomatic patients. In multivariate analysis, surgery during treatment was a protective factor against one-year relapse and death.The cumulative incidence of relapse one year after endocarditis was 46.2% for patients treated with amoxicillin, 13.4% with A-G, 14.7% with A-C, and 4.3% with A-G/A-C (P≥.05 in multivariate analysis). Conclusion: Relapses after treatment of EFIE are frequent, frequently asymptomatic, and may occur more than 6 months after the initial episode.
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