Citations

Abstract BACKGROUND Selinexor (SEL) is a first-in-class XPO1 inhibitor with potent antitumor activity via tumor suppressor protein nuclear localization and reactivation, oncoprotein translation suppression, and DNA repair inhibition. As a single agent, SEL has demonstrated adequate brain penetration and clinically relevant responses in glioblastoma. We seek to enhance the effect and benefit of SEL by priming with temozolomide (TMZ). METHODS We developed in vitro and in vivo studies to rationally design a phase I/II trial to evaluate the safety and efficacy of the sequential combination of SEL+TMZ. Sequential treatment of U87 cells and intracranial mouse xenografts demonstrated superior DNA damage (ɣH2A.X, cleaved PARP) and overall survival compared to combination or single-agent therapy (HR 0.25 [95% CI, 0.07-0.84]; p = 0.01, log-rank). We used the top-scoring pair method to identify a 6 gene-pair RNAseq signature associated with response to SEL. RESULTS Based on preclinical findings, we developed and opened a multi-institutional phase I/II clinical trial in October 2022. Eligibility includes histologically confirmed 1st recurrent MGMT promoter methylated glioblastoma. Primary objectives are safety and preliminary efficacy. Secondary objectives are overall response rate, efficacy, and prospective validation of a molecular signature of response. Phase I dose finding by IQ 3 + 3 (n = 12) involves TMZ 150mg/m2 on days 1-5 of a 28-day cycle plus SEL on days 8 and 15. Phase II will involve randomization (n = 72) to the RP2D of SEL+TMZ versus monotherapy TMZ. Using proportional hazards regression, RHR 0.5 with p < 0.1 will demonstrate sufficient efficacy. We have enrolled 3 participants in dose level 1 (SEL 60mg) with no dose-limiting toxicities (DLTs) observed. Additional preliminary results will be presented. CONCLUSION Preliminary results suggest that a sequential dosing regimen of SEL+TMZ is feasible and initial dose is well-tolerated and may minimize the cumulative toxicity of SEL. The trial is currently enrolling nationwide (NCI #10505, NCT05432804).

Abstract Background Inotrope-dependent heart failure (HF) carries a poor prognosis. Advanced mechanical supports have been viewed as primary treatment modalities for these patients, but cardiac resynchronization therapy (CRT) is an emerging alternative. Whether CRT is viable in HF patients who require inotropic support is uncertain. Purpose To assess outcomes of CRT in end-stage inotrope-dependent HF. Methods Following PRISMA guidelines, we searched Medline, EMBASE, Scopus, and Cochrane Library until December 31st 2022, with the following terms: "end-stage heart failure," "catecholamine-dependent overt heart failure," "inotrope-dependent heart failure," "advanced heart failure," "New York Heart Association class IV," "NYHA class IV." These terms were combined with "cardiac resynchronization therapy" OR "CRT" OR "biventricular device". Studies were included if: 1) HF patients required on inotropic support at CRT implantation; 2) patients were at least 18 years old; and 3) provided a clear definition of "inotrope dependence" or "inability to wean." A meta-analysis with random effects was performed in R (Version 3.5.1) with data presented as mean ± standard error. Results 19 studies comprised of 386 inotrope-dependent HF patients (mean age 64.4 ± 1.2 years, 76.9% male, 54.6% non-ischemic cardiomyopathy, mean QRS duration 168.0 ± 4.6 ms, mean follow-up 778 ± 110.7 days) were included for meta-analysis. A large majority of patients survived until discharge at 90% (95% CI: 81.0%-96.8%, I2=51%, p=0.04, Figure 1A), 88.6% were weaned off inotropes (95% CI: 77.5%-96.8%, I2=64%, p<0.01), and mean time to discharge post-CRT was 7.8 days (95% CI: 3.9-11.7, I2= 84%, p<0.01). After one year of follow-up 69.5% survived (95% CI: 59.2%-78.9%, I2=53%, p=0.02, Figure 1B) and 59.1% (95% CI: 50.1%-67.8%, I2=58%, p<0.01, Figure 1C) were alive at the end of follow-up. During follow-up the mean number of hospital admission for HF was reduced by 1.87 (95% CI: 2.70-1.04, I2=77%, p=0.04). Post-CRT mean QRS duration was reduced by 29.0 ms (95% CI: 41.33-16.68, I2=69%, p=0.006, Fig) and mean left ventricular ejection fraction increased by 4.83% (95% CI: 3.09%-6.57%, I2=16%, p=0.31, Fig). The mean NYHA class post-CRT was 2.7 (95% CI: 2.5-3.0, I2=56%, p=0.03, Figure 2A), 39.6% (95% CI: 18,.7%-62.3%, I2=83%, p<0.01, Figure 2C) improved to NYHA class III and 34.6% (95% CI: 16.4%-55.2%, I2=79%, p<0.01, Figure 2D) improved to NYHA class II. Responders to CRT tended be male (85.7% vs. 40%, p=0.015), have a history of left bundle branch block (71.4% vs. 30%, p=0.036) or an increased left ventricular end-diastolic volume (274.3 mL vs. 225.9 mL, p=0.038). Conclusion(s) Our results suggest that CRT is an alternative option for end-stage inotrope-dependent HF, improving survival, NYHA status, and HF readmission. CRT responders appear to be male with evidence of preserved diastolic function or a history of a left bundle branch block.

Abstract Background and Aims This post hoc analysis assessed the efficacy and safety of upadacitinib in patients with moderately to severely active ulcerative colitis stratified by corticosteroid use from the ulcerative colitis Phase 3 clinical trial programme. Methods Patients were randomised [1:2] to 8 weeks’ placebo or upadacitinib 45 mg once daily; Week 8 responders were re-randomised [1:1:1] to 52 weeks’ placebo or upadacitinib 15 or 30 mg daily. Corticosteroid dose was kept stable during induction but tapered according to a protocol-defined schedule [or investigator discretion] during maintenance Weeks 0–8. Efficacy outcomes and exposure-adjusted, treatment-emergent adverse event [TEAE] rates were assessed for induction and maintenance stratified by corticosteroid use at induction baseline. Results Overall, 377/988 [38%] patients were receiving corticosteroids at induction baseline [placebo, n = 133; upadacitinib 45 mg, n = 244] and 252 [37%] of the 681 clinical responders who entered maintenance were on corticosteroids at induction baseline [n = 84 for each treatment]. Similar proportions of patients receiving upadacitinib achieved clinical remission per Adapted Mayo Score with and without baseline corticosteroids at Weeks 8 and 52. The total proportion of patients re-initiating corticosteroids was higher with placebo [24/84;29%] vs upadacitinib 15 mg [16/81; 20%)] and 30 mg [11/81; 14%]. During induction, patients receiving corticosteroids at baseline had higher rates of TEAEs, serious TEAEs, and serious infections vs those not receiving corticosteroids; however, TEAE rates were similar during maintenance after corticosteroid withdrawal. Conclusions Upadacitinib is an effective steroid-sparing treatment in patients with moderately to severely active ulcerative colitis. Clinicaltrials.gov identifiers: NCT02819635; NCT03653026

Comprehensive resources exist on how to plan a systematic review and meta-analysis. The objective of this article is to provide guidance to authors preparing their systematic review protocol in the fields of regional anesthesia and pain medicine. The focus is on systematic reviews of healthcare interventions, with or without an aggregate data meta-analysis. We describe and discuss elements of the systematic review methodology that review authors should prespecify, plan, and document in their protocol before commencing the review. Importantly, authors should explain their rationale for planning their systematic review and describe the PICO framework—participants (P), interventions (I),comparators (C), outcomes (O)—and related elements central to constructing their clinical question, framing an informative review title, determining the scope of the review, designing the search strategy, specifying the eligibility criteria, and identifying potential sources of heterogeneity. We highlight the importance of authors defining and prioritizing the primary outcome, defining eligibility criteria for selecting studies, and documenting sources of information and search strategies. The review protocol should also document methods used to evaluate risk of bias, quality (certainty) of the evidence, and heterogeneity of results. Furthermore, the authors should describe their plans for managing key data elements, the statistical construct used to estimate the intervention effect, methods of evidence synthesis and meta-analysis, and conditions when meta-analysis may not be possible, including the provision of practical solutions. Authors should provide enough detail in their protocol so that the readers could conduct the study themselves.

In Part I of this series, we provide guidance for preparing a systematic review protocol. In this article, we highlight important steps and supplement with exemplars on conducting and reporting the results of a systematic review. We suggest how authors can manage protocol violations, multiplicity of outcomes and analyses, and heterogeneity. The quality (certainty) of the evidence and strength of recommendations should follow the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. It is our goal that Part II of this series provides valid guidance to authors and peer reviewers who conduct systematic reviews to adhere to important constructs of transparency, structure, reproducibility, and accountability. This will likely result in more rigorous systematic reviews being submitted for publication to the journals like Regional Anesthesia & Pain Medicine and Anesthesia & Analgesia.

In Part I of this series, we provide guidance for preparing a systematic review protocol. In this article, we highlight important steps and supplement with exemplars on conducting and reporting the results of a systematic review. We suggest how authors can manage protocol violations, multiplicity of outcomes and analyses, and heterogeneity. The quality (certainty) of the evidence and strength of recommendations should follow the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. It is our goal that Part II of this series provides valid guidance to authors and peer reviewers who conduct systematic reviews to adhere to important constructs of transparency, structure, reproducibility, and accountability. This will likely result in more rigorous systematic reviews being submitted for publication to the journals like Regional Anesthesia & Pain Medicine and Anesthesia & Analgesia .

Comprehensive resources exist on how to plan a systematic review and meta-analysis. The objective of this article is to provide guidance to authors preparing their systematic review protocol in the fields of regional anesthesia and pain medicine. The focus is on systematic reviews of health care interventions, with or without an aggregate data meta-analysis. We describe and discuss elements of the systematic review methodology that review authors should prespecify, plan, and document in their protocol before commencing the review. Importantly, authors should explain their rationale for planning their systematic review and describe the PICO framework—participants (P), interventions (I), comparators (C), outcomes (O)—and related elements central to constructing their clinical question, framing an informative review title, determining the scope of the review, designing the search strategy, specifying the eligibility criteria, and identifying potential sources of heterogeneity. We highlight the importance of authors defining and prioritizing the primary outcome, defining eligibility criteria for selecting studies, and documenting sources of information and search strategies. The review protocol should also document methods used to evaluate risk of bias, quality (certainty) of the evidence, and heterogeneity of results. Furthermore, the authors should describe their plans for managing key data elements, the statistical construct used to estimate the intervention effect, methods of evidence synthesis and meta-analysis, and conditions when meta-analysis may not be possible, including the provision of practical solutions. Authors should provide enough detail in their protocol so that the readers could conduct the study themselves.

Introduction and importance: Edward syndrome is a severe chromosomal defect that occurs as a result of non-disjunction through meiosis. It presents with cardiac septal defects, horseshoe kidneys, patent ductus arteriosus, central nervous system dysgenesis, distinctive craniofacial deformities, and overriding or overlapping fingers. Klinefelter syndrome (47, XXY) is found in 1 in 660 newborn males. It is considered to be one of the most common genetic causes of infertility. It manifests with small firm testes, androgen insufficiency, and azoospermia. Case presentation: A 2-month-old male infant with a history of weakness in feeding, frequent convulsions, and an increase in cyanosis two days ago. There were multiple skeletal deformities and a tendency to spasm in the extremities, left ventricular atrophy, mitral atresia, atrial septal defect, ventricular septal defect with dilated right cavities, tricuspid valve regurgitation, pulmonary valve stenosis; and the aorta exits in the right ventricle. There is a widening of the subdural space, which was observed in the left frontal-parietal side with cortical atrophy in that area and a widening of the Sylvian fissure. A karyotype test confirmed the presence of Edward and Klinefelter syndromes. Clinical discussion: Aneuploidy is a chromosomal issue characterized by an abnormal number of a chromosome copies. The coexistence of two aneuploidies is called “double aneuploidy” which is a rare occurrence. Herein, we report a case of a 2-month-old male with Edward syndrome and Klinefelter syndrome. Conclusion: This publication aims to highlight the challenges in diagnosing and treating a complicated genetic disease.