Database Closure Research Articles

Negative Pressure Dressings to Prevent Surgical Site Infection After Emergency Laparotomy: The SUNRRISE Randomized Clinical Trial.

Patients undergoing unplanned abdominal surgical procedures are at increased risk of surgical site infection (SSI). It is not known if incisional negative pressure wound therapy (iNPWT) can reduce SSI rates in this setting. To evaluate the effectiveness of iNPWT in reducing the rate of SSI in adults undergoing emergency laparotomy with primary skin closure. SUNRRISE was an assessor-masked, pragmatic, phase 3, individual-participant, randomized clinical trial. Adult patients undergoing emergency laparotomy in 22 hospitals in the UK and 12 hospitals in Australia between December 18, 2018, and May 25, 2021, were recruited. Patients were followed up for 30 days postprocedure; database closure was on August 25, 2021. Participants were randomized 1:1 to receive iNPWT (n = 411), which involved a specialized dressing used to create negative pressure over the closed wound vs the surgeon's choice of wound dressing (n = 410). Randomization and dressing application occurred in the operating room at the end of the surgical procedure. The primary outcome measure was SSI up to 30 days postprocedure, evaluated by an assessor masked to the randomized allocation and using criteria from the US Centers for Disease Control and Prevention. There were 7 secondary outcomes, including length of hospital stay, postoperative complications up to 30 days, hospital readmission for wound-related complications within 30 days, wound pain, and quality of life. A total of 840 patients were randomized (536 from the UK; 304 from Australia). Overall, 52% were female; the mean age was 63.8 (range, 18.8 to 95.3) years. After postrandomization exclusions (N = 52), 394 participants per group were included in the primary analysis. The number of participants who had an SSI in the iNPWT group was 112 of 394 (28.4%), compared with 108 of 394 (27.4%) in the surgeon's preference group (relative risk, 1.03 [95% CI, 0.83-1.28]; P = .78). This finding was consistent across the preplanned subgroup analyses, including degree of contamination, presence of a stoma, participant body mass index, and skin preparation used, and across all preplanned sensitivity analyses. Of 7 secondary outcomes, 6 showed no significant difference, including hospital readmission, quality of life, and hospital stay (median [IQR], 8 [6-14] days in the iNPWT group and 9 [6-14.5] days in the surgeon's preference group [ratio of geometric means, 0.96 (95% CI, 0.88-1.06); P = .21]). Routine application of iNPWT to the closed surgical wound after emergency laparotomy did not prevent SSI more than other dressings. isrctn.com Identifier: ISRCTN17599457; anzctr.org.au Identifier: ACTRN12619000496112.

CTNI-65. DETERMINANTS OF LONG-TERM SURVIVAL IN PATIENTS WITH IDH-MUTANT GLIOMAS

Abstract BACKGROUND Survival times of patients with IDH-mutant gliomas is variable and can extend to decades. Many studies only provide progression-free rather than overall survival times and prognostic factors remain ill-defined. Here we explored clinical disease characteristics of long-term survivors within a large cohort of patients with extended follow-up. METHODS This single-center, retrospective analysis included 114 patients with IDH-mutant glioma that either died due to tumor-related causes or survived at least 15 years after first diagnosis. Patient characteristics, outcomes, and prognostic factors were stratified by short- (< 15 years) versus long-term (≥ 15 years) survival. Initial diagnosis was (re-)classified according to the WHO 2016 classification. Uni- and multivariate analyses were performed. RESULTS Overall, 66 patients (58%) were diagnosed with astrocytoma and 48 patients (42%) with oligodendroglioma. Median follow-up of the survivors was 16.6 years (range 15-28.9). 62 tumor-related deaths (54%) had been reported at database closure. Patients that died before reaching 15 years survival time had been diagnosed with astrocytoma in 41 (72%) and oligodendroglioma in 16 cases (28%). The long-term survivor cohort comprised 25 patients (44%) with astrocytoma and 32 patients (56%) with oligodendroglioma. Long-term survival was associated with grade 2 histology (p < 0.01), smaller tumor volumes (p < 0.01), and lack of contrast enhancement (p = 0.02). 41 long-term survivors (72%) were initially monitored by a wait-and-scan strategy as opposed to 16 patients (28%) in the cohort of short-term survival (p<0.01). In patients with oligodendroglioma, a higher KPS was associated with longer survival (HR 0.25; 95% CI 0.02-0.67; p = 0.05). Tumor resection (HR 0.43; 95% CI 0.22-0.86; p = 0.02) and wait-and-scan strategies (HR 0.34; 95% CI 0.14-0.79; p = 0.01) were associated with longer survival in patients with astrocytoma. CONCLUSION Tumor resection followed by a wait-and-scan strategy may yield excellent survival times, especially in patients with IDH-mutant grade 2 astrocytoma. Age appears not be an important predictor for survival in patients with IDH-mutant gliomas.

Recurrence patterns in differentiated thyroid cancer (DTC) following adjuvant radioiodine therapy.

With an increasing incidence of differentiated thyroid cancer (DTC) diagnosis, questions emerge about the optimal duration of follow-up for detecting recurrent disease and its outcomes. The objective of this retrospective research was to assess the clinical course of differentiated thyroid cancer after radioiodine adjuvant treatment in patients monitored over an extended period. Special attention was paid to the analysis of the time from treatment to recurrence. We also assessed patient outcomes after recurrence. A total of 650 patients with DTC after total/near-total thyroidectomy and adjuvant radioiodine post-recombinant human thyrotropin (post-rhTSH) stimulation were evaluated. All patients were followed up with neck ultrasound, serum thyroid-stimulating hormone (TSH), thyroglobulin (Tg), and antithyroglobulin antibody (anti-Tg) measurements at intervals of 6 to 18 months. Only structural recurrences were considered. They were defined as locoregional recurrence confirmed by biopsy or distant metastases [confirmed by computed tomography (CT) or magnetic resonance imaging (MRI), or abnormal foci on radioiodine scintigraphy or 18F-gluorodeoxyglucose positron emission tomography [18 F] FDG-PET scan], regardless of thyroglobulin (Tg) or anti-Tg levels. The median follow-up was 12 years (5-15.5). Structural recurrence was observed in 47 out of 650 patients (7%). All but 3 locoregional recurrences were suitable for surgery. The median time to structural recurrence was 16 months, with only 9 (1.4%) patients presenting with recurrence after more than 60 months. At the time of the database closure, 601 patients (92%) had an excellent response, including 20 out of 47 (42%) patients with structural recurrence. Eighty-one out of 650 patients had died (12.5%) before the database closure. The median age at the last follow-up of the patients who died was 72 years (range 20-88). A second recurrence was diagnosed in 10 out of 650 patients (1.5%), corresponding to 21% (10 out of 47) of patients who had already experienced a recurrence. The median time from radioiodine (RAI) therapy to the second structural recurrence was 108 months. Structural recurrences in DTC are uncommon, with most patients showing a favourable response to treatment. Improved understanding of recurrence timing may define the duration of patient surveillance at reference centres that can be safely discontinued after 5 years in low- and intermediate-risk groups, as indicated in our study.

BRIVA-ONE study: 12-month outcomes of brivaracetam monotherapy in clinical practice.

This study investigated the effectiveness and tolerability of brivaracetam (BRV) monotherapy in a large series of patients with epilepsy. This was a multicenter, retrospective, observational, non-interventional study in 24 hospitals across Spain. Patients aged ≥18 years who started on BRV monotherapy, either as first-line or following conversion, at least 1 year before database closure were included. Patients were evaluated at baseline and at 3, 6 and 12 months after initiation of BRV monotherapy, in accordance with usual clinical practice at these centers. Data were collected retrospectively from patients' individual charts by participating physicians. The primary effectiveness and safety endpoints were the percentage of seizure-free patients 1 year after initiation of BRV monotherapy and the proportion of patients reporting adverse events (AEs) over the complete follow-up period. Retention rates and subpopulation analysis (levetiracetam switchers, elderly and different etiologies) were also investigated. A total of 276 patients were included (48 with BRV as first-line monotherapy and 228 who converted to BRV monotherapy). The overall retention rate in monotherapy at 12 months was 89.9% (87.5% for first-line monotherapy group; 90.4% for conversion-to-monotherapy group). Seizure-freedom rates at 12 months were 77.8% (75% for first-line monotherapy group; 78.4% for conversion-to-monotherapy group). AEs occurred in 39.5% of patients at 12 months (35.4% for first-line monotherapy group; 40.4% for conversion-to-monotherapy group). Most AEs were mild-to-moderate. The most frequent AEs were irritability (12.3%) and dizziness (10.1%). The most frequent AEs leading to BRV withdrawal were dizziness (1.8%) and memory problems (1.4%). Similar outcomes in terms of effectiveness and tolerability of BRV monotherapy were observed in patients switching from levetiracetam, those with different epilepsy etiologies, and elderly patients. BRV was effective and well tolerated both as first-line monotherapy and following conversion to monotherapy in a real-world setting of patients with epilepsy. The goal of the medical treatment of epilepsy is to ensure best possible patient quality of life, by maximizing seizure control and minimizing medication toxicity. Brivaracetam (BRV) is a new-generation epilepsy treatment that is well tolerated by patients. In our study, monotherapy with BRV reduced seizures in patients who had not received other treatments and in patients who switched from a previous treatment to BRV monotherapy. BRV was well tolerated and also effective in sensitive patients (i.e., the elderly and those who had epilepsy caused by a brain tumor or a brain injury).

Phase II clinical trial assessing the efficacy of enzalutamide in advanced non-resectable granulosa cell ovarian tumors: The GREKO III study (GETHI2016–01)

BackgroundGranulosa cell ovarian tumors (GCT) are orphan disease with limited treatments. Hormone therapy is a potential treatment, due to the overexpression of hormone receptors in most tumors. This study explores the activity of the antiandrogen, enzalutamide, in metastatic cases. MethodsWe designed a phase II clinical trial under the Spanish Collaborative Group for Transversal Oncology and Rare and Orphan Tumors (GETTHI). Eligible participants were adult women with advanced GCT. Primary endpoint was objective response rate. Secondary endpoints included clinical benefit rate, progression-free survival, overall survival, and safety profile. Patients received enzalutamide 160 mg once daily. ResultsFrom April 2018 to March 2020, eighteen patients were screened, and sixteen were included across nine institutions. Median age was 56.4 years (range 45–71), and most were Caucasian (14 cases), one Arabian and one Latin. ECOG performance status was zero in 13 cases (81 %) and one in three (19 %). Six patients (38 %) had previously received hormone therapy as adjuvant treatment or for advanced disease, and 15 (94 %) chemotherapy. Median time from metastasis to study entry was 96 months (range 4.5–198).No objective response was observed, but the clinical benefit rate reached 68.8 % (95 % CI [46 %–91.5 %]). Median progression-free survival was 3.8 months (95 % CI [1.36–6.14]). Median overall survival was not reached, with a median follow-up of 6 months (range 2.2–19).At the time of database closure, 14 patients had discontinued treatment, 13 due to disease progression and one by personal choice. Two deaths attributed to disease progression were recorded.Five grade 3 adverse events were reported, with only one (asthenia) deemed related to the therapy. ConclusionsAlthough enzalutamide demonstrated modest activity in GCT, durable stabilization was observed in some cases.Trial Registration:ClinicalTrials.gov Identifier: NCT03464201

Determinants of long-term survival in patients with IDH-mutant gliomas

BackgroundSurvival times of patients with IDH-mutant gliomas are variable and can extend to decades. Many studies provide progression-free rather than overall survival times and prognostic factors remain ill-defined. Here we explored characteristics of short- and long-term survivors within a cohort of patients with extended follow-up.MethodsThis single-center, case-control study included 86 patients diagnosed between 1998 and 2023 who either died within 6 years after diagnosis or survived at least 15 years. Patient characteristics and prognostic factors were stratified by short- (< 6 years) versus long-term (≥ 15 years) survival.ResultsForty-seven patients (55%) diagnosed with astrocytoma and 39 patients (45%) with oligodendroglioma were included retrospectively. Median follow-up of the survivors was 16.6 years (range 15-28.9). Thirty-four deaths (40%) had been reported at database closure. Long-term survival was associated with CNS WHO grade 2 (p < 0.01), smaller tumor volumes (p = 0.01), lack of contrast enhancement (p < 0.01), wait-and-scan strategies (p < 0.01) and female sex (p = 0.04). In multivariate analyses for oligodendroglioma, larger T2 tumor volumes were associated with shorter survival (HR 1.02; 95% CI 1.01–1.05; p = 0.04). In patients with astrocytoma, lack of contrast enhancement (HR 0.38; 95% CI 0.15–0.94; p = 0.04) and wait-and-scan strategies (HR 5.75; 95% CI 1.66–26.61; p = 0.01) were associated with longer survival.ConclusionLarge T2 tumor volume and contrast enhancement may be important risk factors for shorter survival, while age might be of lesser importance. Wait-and-scan strategies may yield excellent long-term survival in some patients with astrocytoma.

Self-transfers, Hospital Admissions and Mortality Among Children and Adolescents Lost to Follow-up From Antiretroviral Therapy Programs in the Western Cape, South Africa Between 2004 and 2019: Linkage to Provincial Records.

Pediatric programs face a high rate of loss to follow-up (LTFU) among children and adolescents living with HIV (CAHIV). We assessed true outcomes and predictors of these among CAHIV who were LTFU using linkage to the Western Cape Provincial Health Data Centre at Western Cape sites of the International epidemiology Databases to Evaluate AIDS-Southern Africa collaboration. We examined factors associated with self-transfer, hospital admission and mortality using competing risks regression in a retrospective cohort of CAHIV initiating antiretroviral therapy <15 years old between 2004 and 2019 and deemed LTFU (no recorded visit at the original facility for ≥180 days from the last visit date before database closure and not known to have officially transferred out or deceased). Of the 1720 CAHIV deemed LTFU, 802 (46.6%) had self-transferred and were receiving care elsewhere within the Western Cape, 463 (26.9%) had been hospitalized and 45 (2.6%) CAHIV had died. The overall rates of self-transfer, hospitalization, mortality and LTFU were 9.4 [95% confidence interval (CI): 8.8-10.1], 5.4 (95% CI: 5.0-6.0), 0.5 (95% CI: 0.4-0.7) and 4.8 (95% CI: 4.4-5.3) per 100 person-years respectively. Increasing duration on antiretroviral therapy before LTFU was associated with self-transfers while male sex, older age at last visit (≥10 years vs. younger) were associated with hospital admission and immune suppression at last visit was associated with 5 times higher mortality. Nearly half of CAHIV classified as LTFU had self-transferred to another health facility, a quarter had been hospitalized and a small proportion had died.

Clinical responses and relapses in omalizumab-assisted desensitization to food in children: long-term evolution in real life

Desensitization (DSZ) or oral tolerance induction is increasingly used in children who do not outgrow their food allergies. Off-label omalizumab (OMZ) is used as adjuvant therapy for those with severe reactions, but there is little information on outcomes when OMZ is withdrawn. The long-term outcome in a group of children with severe milk or egg allergy who had undergone an OMZ-assisted DSZ procedure is here described. Clinical data from 21 children from the time they started DSZ until database closure were retrospectively collected, to assess the appearance of symptoms and response to clinical decisions under real-life conditions. Patients received OMZ before, during, and after the DSZ procedure itself and OMZ was subsequently discontinued. The scheduled treatment protocol had to be changed in almost all patients due to reactions or individual needs. Three of 21 patients had to prematurely abandon the procedure due to DSZ failure. The other 18 patients were able to tolerate the target dose of food, but nine of them developed symptoms when eating the food 1.5 to 6 months after stopping OMZ. These patients underwent a second course of OMZ-assisted DSZ, which was successful in six, but three had a second relapse 3 to 8 months after stopping OMZ and decided to quit. OMZ-assisted DSZ failed in almost a third of patients with severe allergy even after a second course of OMZ, almost 40% had a successful outcome with one course of OMZ, while almost a third required a second course. Relapses of symptoms occurred up to six months after stopping OMZ.

The prognostic role of variations in tumour markers (CEA, CA15.3) in patients with metastatic breast cancer treated with CDK4/6 inhibitors.

Tumour markers have no established role in the monitoring of the course of metastatic breast cancer during antineoplastic therapy, yet cancer antigen 15.3 (CA15.3) and carcinoembryonic antigen (CEA) are commonly used in clinical practice to aid in the early detection of progression of disease (PD). In our multicentre, prospective, real-life study, we enrolled 142 consecutive patients with advanced breast cancer receiving endocrine therapy in combination with a CDK4/6 inhibitor from January 2017 to October 2020; 75 patients had PD at the time of database closure. We measured serum marker concentrations at regular 4-month intervals together with radiological tumour response assessments and in cases of clinical suspicion of PD. Appropriate descriptive and inferential statistical methods were used to analyse serum marker level trends amongst prespecified subgroups and at specific time points (baseline, best radiologically documented tumour response and first detection of PD) in the subpopulation of patients with PD at the time of database closure. Notably, the median time from treatment initiation to best tumour response was 4.4 months. We evaluated the presence of an association between baseline CA15.3 and CEA levels and prespecified clinical characteristics but found no clinically meaningful correlation. We assessed marker level variations at the time of best radiologically documented disease response and PD: in the subgroup of patients who responded to treatment before progressing, we detected a statistically significant correlation with tumour marker variation between the time of best response and progression; this finding was not confirmed in the subgroup of patients that did not benefit from treatment. In conclusion, serum tumour marker flares can be useful in the early diagnosis of PD but should not be used as the sole factor prompting a change in treatment strategy without radiological confirmation.

Evaluation of patient STress level caused by radiological Investigations in early Postoperative phase After CRANIOtomy (IPAST-CRANIO): protocol of a Swiss prospective cohort study

IntroductionPostoperative imaging after neurosurgical interventions is usually performed in the first 72 hours after surgery to provide an accurate assessment of postoperative resection status. Patient frequently report that early postoperative...

First Demonstration Project of Long-Acting Injectable Antiretroviral Therapy for Persons With and Without Detectable Human Immunodeficiency Virus (HIV) Viremia in an Urban HIV Clinic.

Long-acting injectable antiretroviral therapy (LAI-ART) is approved for treatment-naive or experienced people with human immunodeficiency virus (HIV; PWH) based on trials that only included participants with viral suppression. We performed the first LAI-ART demonstration project to include PWH unable to achieve or maintain viral suppression due to challenges adhering to oral ART. Ward 86 is a large HIV clinic in San Francisco that serves publicly insured and underinsured patients. We started patients on LAI-ART via a structured process of provider referral, multidisciplinary review (MD, RN, pharmacist), and monitoring for on-time injections. Inclusion criteria were willingness to receive monthly injections and a reliable contact method. Between June 2021 and April 2022, 51 patients initiated LAI-ART, with 39 receiving at least 2 follow-up injections by database closure (median age, 46 years; 90% cisgender men, 61% non-White, 41% marginally housed, 54% currently using stimulants). Of 24 patients who initiated injections with viral suppression (median CD4 cell count, 706 cells/mm3), 100% (95% confidence interval [CI], 86%-100%) maintained viral suppression. Of 15 patients who initiated injections with detectable viremia (median CD4 cell count, 99 cells/mm3; mean log10 viral load, 4.67; standard deviation, 1.16), 12 (80%; 95% CI, 55%-93%) achieved viral suppression, and the other 3 had a 2-log viral load decline by a median of 22 days. This small demonstration project of LAI-ART in a diverse group of patients with high levels of substance use and marginal housing demonstrated promising early treatment outcomes, including in those with detectable viremia due to adherence challenges. More data on LAI-ART in hard-to-reach populations are needed.

P1611: INSIGHTS INTO FACILITATED IMMUNOGLOBULIN (FSCIG) USE IN PATIENTS WITH SECONDARY IMMUNODEFICIENCY DISEASES: FINAL RESULTS FROM THE FIGARO STUDY

Background: Secondary immunodeficiency diseases (SID) are common among patients with hematological malignancies such as chronic lymphocytic leukemia (CLL) and multiple myeloma, putting patients at increased risk of severe, recurrent/persistent infections and contributing to morbidity and mortality. Pharmacotherapeutic options available to patients with SID include antimicrobial treatment and immunoglobulin replacement therapy (IGRT). Facilitated subcutaneous immunoglobulin (fSCIG) is a dual-vial unit of immunoglobulin G 10% and recombinant human hyaluronidase (rHuPH20) approved in the European Union for patients with SID. rHuPH20 depolymerizes hyaluronan in the extracellular matrix to transiently increase local subcutaneous tissue permeability, allowing for fSCIG infusion at rates, volumes, and frequencies comparable to intravenous immunoglobulin with better systemic tolerability. Aims: To provide insights on the real-world utilization and tolerability of fSCIG for up to 3 years in a broad population of patients with SID and assess any impact of older age on use. Methods: FIGARO (NCT03054181) was a European prospective, observational study in 14 sites. Patients (n=156) who received ≥1 fSCIG infusion for primary immunodeficiency diseases or SID and provided informed consent were included and followed for up to 3 years. Study initiation was December 2016; database closure was May 2021. Here we report final data for the overall cohort of patients with SID, together with further subgroup analysis for patients aged 18–64 years [adult] and ≥65 years [older adult]. Results: The SID cohort included 31 patients; 1 pediatric (not reported as age subgroup), 15 adult, and 15 older adult patients. At study close, 1-, 2-, and 3-year follow-up data were available for 25, 13, and 11 patients, respectively. The most common indications for IGRT were CLL (n=20) and non-Hodgkin lymphoma (n=6); the most common supportive therapies included Pneumocystis jirovecii pneumonia prophylaxis, virostatics, and antibiotics. In the year prior to inclusion, 10 (32%) patients had experienced ≥1 acute severe bacterial infection. At the inclusion visit, fSCIG was most recently infused at home (61%) or a medical facility (39%) by the patient (58%) or a nurse (42%), with a tendency of adult patients to more self-application than older adults. Most patients received fSCIG every 4 weeks (71%), infused into a single site (most commonly upper abdomen in adults, and lower abdomen in older adults). Over the 3-year observation period, the median monthly dose of fSCIG, and median monthly infusion volume per patient remained consistent at 30 g and 300 mL, respectively, in both the adult and older adult groups. All patients received the full dose as planned, except for 1 patient at the 36-month follow-up visit who experienced infusion/technical problems. Two patients (in the adult group) each reported 1 adverse drug reaction (ADR; infusion site inflammation and headache) at the inclusion visit, with no ADRs reported at any of the follow-up visits. No acute severe bacterial infections were reported during the study. Summary/Conclusion: These data provide insights into the long-term feasibility and tolerability of fSCIG administration at home or in a medical facility in patients with SID primarily due to hematologic malignancies, including in older patients aged ≥65 years.

Maturation of overall survival (OS) in TIVO-3 with long-term follow-up.

4557 Background: Maturity of survival data is a consideration in the value assessment and confident clinical application of oncology drugs based on trial evidence. TIVO-3 supported FDA-approval of tivozanib (TIVO) in relapsed/refractory (R/R) advanced RCC, meeting the primary endpoint of significantly improved PFS over sorafenib (SOR) (HR: 0.73, 95% CI, 0.56-0.95). Long-term follow-up analyses demonstrate that the PFS rate at 3-years with TIVO is &gt;5x higher than with SOR (12% vs 2%, respectively), yet a significant OS benefit for TIVO has not been observed to date. Here we report the contribution of event accumulation and data maturation on the stability of KM survival estimates. Methods: Intent-to-treat analyses of Cox proportional hazards and log-rank statistics were used to estimate the HR and 95% CI for OS in the TIVO-3 trial at prespecified (2-years after last-patient-in [LPI]; ≥251 events) and exploratory extended follow-up timepoints (≥270 events; database closure). Patients were followed for survival until death, consent withdrawal, or loss to follow-up. Results: 350 patients were randomized 1:1 to TIVO (n=175) or SOR (n=175). 2-years post LPI and a mean follow-up of 17.9 months (data cut-off August 2019), 65% of patients experienced an event (HR: 0.99, 95% CI, 0.76-1.29). Subsequent analyses are reported at 20.3 (May 2020), 21.9 (January 2021), and 22.8 (May 2021) months follow-up. Accumulation of events and HR over time is shown in the Table. After almost 23 months of follow-up and realization of 80% of events, OS HR has decreased to below 0.90, in favor of TIVO. Conclusions: Serial OS analyses using KM estimates are subject to increased curve reliability with decreased censoring and limited residual patients at risk for death. Long-term follow-up of TIVO-3 suggests early and consistent PFS benefit with TIVO over SOR is associated with an OS HR decline over-time with more events. Clinical trial information: NCT02627963. [Table: see text]

In Revision THA, Is the Re-revision Risk for Dislocation and Aseptic Causes Greater in Dual-mobility Constructs or Large Femoral Head Bearings? A Study from the Australian Orthopaedic Association National Joint Replacement Registry.

Dislocation is one of the most common causes of a re-revision after a revision THA. Dual-mobility constructs and large femoral head bearings (≥ 36 mm) are known options for mitigating this risk. However, it is unknown which of these choices is better for reducing the risk of dislocation and all-cause re-revision surgery. It is also unknown whether there is a difference between dual-mobility constructs and large femoral head bearings according to the size of the acetabular component. We used data from a large national registry to ask: In patients undergoing revision THA for aseptic causes after a primary THA performed for osteoarthritis, (1) Does the proportion of re-revision surgery for prosthesis dislocation differ between revision THAs performed with dual-mobility constructs and those performed with large femoral head bearings? (2) Does the proportion of re-revision surgery for all aseptic causes differ between revision THAs performed with dual-mobility constructs and those performed with large femoral head bearings? (3) Is there a difference when the results are stratified by acetabular component size? Data from the Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR) were analyzed for 1295 first-revision THAs for aseptic causes after a primary THA performed for osteoarthritis. The study period was from January 2008-when the first dual-mobility prosthesis was recorded-to December 2019. There were 502 dual-mobility constructs and 793 large femoral head bearings. There was a larger percentage of women in the dual-mobility construct group (67% [334 of 502]) compared with the large femoral head bearing group (51% [402 of 793]), but this was adjusted for in the statistical analysis. Patient ages were similar for the dual-mobility construct group (67 ± 11 years) and the large femoral head group (65 ± 12 years). American Society of Anesthesiologists (ASA) class and BMI distributions were similar. The mean follow-up was shorter for dual-mobility constructs at 2 ± 1.8 years compared with 4 ± 2.9 years for large femoral head bearings. The cumulative percent revision (CPR) was determined for a diagnosis of prosthesis dislocation as well as for all aseptic causes (excluding infection). Procedures using metal-on-metal bearings were excluded. The time to the re-revision was described using Kaplan-Meier estimates of survivorship, with right censoring for death or database closure at the time of analysis. The unadjusted CPR was estimated each year of the first 5 years for dual-mobility constructs and for each of the first 9 years for large femoral head bearings, with 95% confidence intervals using unadjusted pointwise Greenwood estimates. The apparent shorter follow-up of the dual-mobility construct group relates to the more recent increase in dual-mobility numbers recorded in the registry. The results were adjusted for age, gender, and femoral fixation. Results were subanalyzed for acetabular component sizes < 58 mm and ≥ 58 mm, set a priori on the basis of biomechanical and other registry data. There was no difference in the proportion of re-revision for prosthesis dislocation between dual-mobility constructs and large femoral head bearings (hazard ratio 1.22 [95% CI 0.70 to 2.12]; p = 0.49). At 5 years, the CPR of the re-revision for prosthesis dislocation was 4.0% for dual mobility constructs (95% CI 2.3% to 6.8%) and 4.1% for large femoral head bearings (95% CI 2.7% to 6.1%). There was no difference in the proportion of all aseptic-cause second revisions between dual-mobility constructs and large femoral head bearings (HR 1.02 [95% CI 0.76 to 1.37]; p = 0.89). At 5 years, the CPR of dual-mobility constructs was 17.6% for all aseptic-cause second revision (95% CI 12.6% to 24.3%) and 17.8% for large femoral head bearings (95% CI 14.9% to 21.2%). When stratified by acetabular component sizes less than 58 mm and at least 58 mm, there was no difference in the re-revision CPR for dislocation or for all aseptic causes between dual-mobility constructs and large femoral head bearings. Either dual-mobility constructs or large femoral head bearings can be used in revision THA, regardless of acetabular component size, as they did not differ in terms of re-revision rates for dislocation and all aseptic causes in this registry study. Longer term follow-up is required to assess whether complications develop with either implant or whether a difference in revision rates becomes apparent. Ongoing follow-up and comparison in a registry format would seem the best way to compare long-term complications and revision rates. Future studies should also compare surgeon factors and whether they influence decision-making between prosthesis options and second revision rates. Nested randomized controlled trials in national registries would seem a viable option for future research. Level III, therapeutic study.

Effectiveness of expiratory technique and induced sputum in obtaining good quality sputum from patients acutely hospitalized with suspected lower respiratory tract infection: a statistical analysis plan for a randomized controlled trial

BackgroundTargeted antimicrobial treatment is essential to avoid unnecessary use of broad-spectrum antibiotics and antimicrobial resistance. Targeted treatment relies on a precise microbiological diagnosis — in pneumonia, this poses a challenge as the usefulness of Gram stains and cultures is highly dependent on the quality of the sputum sample.This study aims to examine adverse effects and quality of sputum samples obtained by expiratory techniques (forced expiratory technique and sputum induction) compared with tracheal suction. The hypothesis is that expiratory techniques are non-inferior to tracheal suction in obtaining samples from the lower respiratory tract. This statistical analysis plan (SAP) describes the study design, method, and data analysis of the trial to increase transparency, avoid reporting bias or data-driven analysis and increase the study’s reproducibility.MethodThe design is a pragmatic, non-inferiority, parallel-arm randomized controlled trial including 280 patients admitted with suspected lower respiratory infection to two emergency departments. Patients are randomized to a usual care group, where sputum samples are collected by tracheal suction or to an intervention group where sputum samples are collected by forced expiratory technique and sputum induction. The statistical analysis will follow an intention-to-treat protocol. This SAP is developed and submitted before the end of recruitment, database closure, and statistical analyses.DiscussionThe results of this study will provide valuable knowledge to clinical practice by comparing adverse effects and sputum sample quality associated with different sample methods.Trial registrationClinicaltrials.gov, NCT04595526. Submitted on October 19, 2020

Oral immunotherapy in severe cow's milk allergic patients treated with omalizumab: Real life survey from a Spanish registry.

Oral immunotherapy is a frequent treatment for the management of food allergies, but adverse events (AE) are common. This study assessed the outcome of cow's milk oral immunotherapy (MOIT) in severe cow`s milk-allergic patients treated with omalizumab in a real-life setting. OmaBASE was a national, multicenter, open, and observational registry that collected clinical, immunologic, and treatment from patients with food allergy receiving omalizumab. Data derived from 58 patients aged 10.3years (IQR 6.3-13.2) and median milk-specific IgE 100kUA /L at the start of omalizumab treatment. Most had experienced anaphylaxis by accidental exposures (70.7%) and had asthma (81.0%). Omalizumab in monotherapy induced tolerance to ≥6000mg of cow's milk protein (CMP) to 34.8% of patients tested by oral food challenge. Omalizumab combined with MOIT conferred desensitization to ≥6000mg of CMP to 83.0% of patients. Omalizumab withdrawal triggered more AE (P=.013) and anaphylaxis (P=.001) than no discontinuation. Anaphylaxis was observed in 36.4% of patients who discontinued omalizumab, and more in those with sudden (50.0%) rather than progressive (12.5%) discontinuation. At database closure, 40.5% of patients who had completed follow-up tolerated CMP without omalizumab (7.2% 1500-4500mg; 33.3% ≥6000mg). Milk oral immunotherapy initiated under omalizumab allows the desensitization of subjects with severe cow's milk allergy even after omalizumab discontinuation. However, discontinuation of omalizumab can lead to severe AE and should be carefully monitored.

Estimated life expectancy gains with antiretroviral therapy among adults with HIV in Latin America and the Caribbean: a multisite retrospective cohort study

There are few data on life expectancy gains among people living with HIV in low-income and middle-income settings where antiretroviral therapy (ART) is increasingly available. We aimed to analyse life expectancy trends from 2003 to 2017 among people with HIV beginning treatment with ART within the Caribbean, central America, and South America. We did a multisite retrospective cohort study and included people with HIV who had started treatment with ART and were aged 16 years or older between Jan 1, 2003, and Dec 31, 2017, from Caribbean, Central and South America network for HIV epidemiology (CCASAnet) sites in Argentina, Brazil, Chile, Haiti, Honduras, Mexico, and Peru, who contributed person-time data from the age of 20 years until date of death, last contact, database closure, or Dec 31, 2017. We used the Chiang method of abridged life tables to estimate life expectancy at age 20 years for three eras (2003-08, 2009-12, and 2013-17) overall and by demographic and clinical characteristics at ART initiation. We used Poisson regression models to weight mortality rates to account for informative censoring. 30 688 people with HIV were included in the study; 17 491 (57·0%) were from the Haiti site and 13 197 (43·0%) were from all other sites. There were 2637 deaths during the study period: 1470 in Haiti and 1167 in other sites. Crude and weighted mortality rates decreased among all age groups over calendar eras. From 2003-08 to 2013-17, overall life expectancy for people with HIV at age 20 years increased from 13·9 years (95% CI 12·5-15·2) to 61·2 years (59·0-63·4) in Haiti and from 31·0 years (29·3-32·8) to 69·5 years (67·2-71·8) in other sites. Life expectancies at the end of the study period were within 10 years of those of the general population (69·9 years in Haiti and 78·0 years in all other sites in 2018). Disparities in life expectancy among people with HIV by sex or HIV transmission risk factor, CD4 cell count, level of education, and history of tuberculosis at or before ART initiation persisted across calendar eras. Life expectancy among people with HIV receiving ART has significantly improved in Latin America and the Caribbean. Persistent disparities in life expectancy among people with HIV by demographic and clinical factors at ART initiation highlight vulnerable populations in the region. National Institutes of Health. For the Spanish translation of the abstract see Supplementary Materials section.

Pirfenidone in patients with progressive fibrotic interstitial lung diseases other than idiopathic pulmonary fibrosis (RELIEF): a double-blind, randomised, placebo-controlled, phase 2b trial

Pirfenidone has been shown to slow disease progression in patients with idiopathic pulmonary fibrosis (IPF). However, there are few treatment options for progressive fibrotic interstitial lung diseases (ILDs)) other than IPF. In view of the pathomechanistic and clinical similarities between IPF and other progressive fibrotic ILDs, we aimed to assess the efficacy and safety of pirfenidone in patients with four non-IPF progressive fibrotic ILDs. We did a multicentre, double-blind, randomised, placebo-controlled, parallel phase 2b trial (RELIEF) in 17 centres with expertise in ILD in Germany. Eligible participants were patients aged 18-80 years with progressive fibrotic ILD due to four diagnoses: collagen or vascular diseases (ie, connective tissue disease-associated ILDs), fibrotic non-specific interstitial pneumonia, chronic hypersensitivity pneumonitis, or asbestos-induced lung fibrosis. Other eligibility criteria included a forced vital capacity (FVC) of 40-90% predicted, a diffusing capacity of the lung for carbon monoxide of 10-90% predicted, and an annual decline of FVC of at least 5% predicted despite conventional therapy, based on at least three measurements within 6-24 months before enrolment. Patients who had received any previous antifibrotic therapy were excluded. We randomly assigned patients (1:1) to either oral pirfenidone (267 mg three times per day in week 1, 534 mg three times per day in week 2, and 801 mg three times per day thereafter) or matched placebo, added to their ongoing medication. Randomisation was done centrally using permuted block randomisation with varying block sizes stratified by the four diagnostic groups. Patients, investigators, statisticians, monitors, and the study coordinator were masked to treatment assignment until database closure. The placebo-controlled study period was 48 weeks (including up-titration). The primary endpoint was absolute change in percentage of predicted FVC (FVC % predicted) from baseline to week 48 in the intention-to-treat population, with imputation of missing data by the smallest sum of squared differences and attribution of deceased patients to the lowest rank in a rank ANCOVA model. Additionally, we did linear mixed-model repeated measures slope analyses of FVC % predicted longitudinal data over the course of the study as a prespecified sensitivity analysis and post-hoc sensitivity analyses of the primary endpoint in the intention-to-treat population using imputation methods of last observation carried forward [LOCF] and a regression-based multiple imputation procedure. Safety was assessed in all patients who received at least one dose of study medication. This trial is registered with EudraCT 2014-000861-32; DRKS00009822 and is no longer recruiting. Between April 5, 2016, and Oct 4, 2018, we randomly assigned 127 patients to treatment: 64 to pirfenidone, 63 to placebo. After 127 patients had been randomised, the study was prematurely terminated on the basis of an interim analysis for futility triggered by slow recruitment. After 48 weeks and in the overall population of 127 patients, rank ANCOVA with diagnostic group included as a factor showed a significantly lower decline in FVC % predicted in the pirfenidone group compared with placebo (p=0·043); the result was similar when the model was stratified by diagnostic group (p=0·042). A significant treatment effect was also observed when applying the LOCF and multiple imputation methods to analyses of the primary endpoint. The median difference (Hodges-Lehmann estimate) between pirfenidone and placebo groups for the primary endpoint was 1·69 FVC % predicted (95% CI -0·65 to 4·03). In the linear mixed-model repeated measures slope analysis of FVC % predicted, the estimated difference between treatment and placebo groups from baseline to week 48 was 3·53 FVC % predicted (95% CI 0·21 to 6·86) with imputation of deaths as prespecified, or 2·79 FVC % predicted (95% CI 0·03 to 5·54) without imputation. One death (non-respiratory) occurred in the pirfenidone group (2%) and five deaths (three of which were respiratory) occurred in the placebo group (8%). The most frequent serious adverse events in both groups were infections and infestations (five [8%] in the pirfenidone group, ten [16%] in the placebo group); general disorders including disease worsening (two [3%] in the pirfenidone group, seven [11%] in the placebo group); and cardiac disorders (one ([2%] in the pirfenidone group, 5 [8%] in the placebo group). Adverse events (grade 3-4) of nausea (two patients on pirfenidone, two on placebo), dyspnoea (one patient on pirfenidone, one on placebo), and diarrhoea (one patient on pirfenidone) were also observed. In view of the premature study termination, results should be interpreted with care. Nevertheless, our data suggest that in patients with fibrotic ILDs other than IPF who deteriorate despite conventional therapy, adding pirfenidone to existing treatment might attenuate disease progression as measured by decline in FVC. German Center for Lung Research, Roche Pharma.

Neurotoxicities associated with immune checkpoint inhibitor therapy.

Immune checkpoint inhibitors (ICIs) have emerged as a promising class of cancer immunotherapies. Neurotoxicities are uncommon, but often severe, and potentially fatal complications of ICIs, and clinical experience is limited. The aim of this study is to further define the clinical spectrum and outcome of ICI-mediated neurotoxicities. Patients with ICI-associated neurotoxicities were identified from retrospective review of the quality control database at a single institution. Data regarding demographics, medical history, clinical presentation, diagnosis, management and outcome were recorded. We identified 18 patients with neurotoxicity following ICI therapy with pembrolizumab, nivolumab, atezolizumab, or ipilimumab for a diverse set of malignancies. Neurotoxicities comprised central demyelinating disorder (28%), autoimmune encephalitis predominantly affecting the grey matter (17%), aseptic meningitis (6%), myasthenia gravis (MG) (17%) with concurrent myositis (6%), sensorimotor polyneuropathy (11%) and hypophysitis (17%). Median time to onset of neurotoxicities was 5weeks (range 1-72). All patients discontinued ICIs and received steroids with additional immunomodulation required in 9 patients, resulting in improvement for 16 of 18 patients. Grade 3-4 neurotoxicity developed in 14 patients, of whom 6 had died at database closure. Grade 3-4 severity negatively impacted overall survival (OS) (p = 0.046). ICI-mediated neurotoxicities present early, are rapidly progressive and include a diverse phenotype affecting the CNS, PNS and neuroendocrine system. A high level of vigilance is warranted, as early diagnosis and targeted treatment can substantially prevent morbidity and mortality. Prospective clinical trials are warranted to assess optimized management of ICI-induced neurotoxicities.

Treatment options for progression or recurrence of glioblastoma: a network meta-analysis.

Treatment options for progression or recurrence of glioblastoma: a network meta-analysis.