Fixed-Duration Pirtobrutinib plus Venetoclax with or without Rituximab in Relapsed/Refractory CLL: Phase 1b BRUIN Trial.

Pirtobrutinib is a highly selective, non-covalent (reversible) Bruton tyrosine kinase inhibitor (BTKi). Patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) were treated with fixed-duration pirtobrutinib plus venetoclax (PV) or pirtobrutinib plus venetoclax and rituximab (PVR) in this phase 1b trial (NCT03740529). Prior covalent BTKi therapy was allowed, but not prior venetoclax. Patients were assigned to receive PV (n=15) or PVR (n=10) for 25 cycles. Median age was 66 years (range, 39-78). Median prior lines of therapy was 2 (range, 1-4), and 17 (68%) patients had received prior covalent BTKi. At the data-cutoff date (May 5, 2023), median time on study was 27.0 months for PV and 23.3 months for PVR. Overall response rates were 93.3% (95% CI:68.1-99.8%) for PV and 100% (95% CI:69.2-100.0%) for PVR, with 10 complete responses (PV:7; PVR:3). After 12 cycles of treatment, 85.7% (95% CI:57.2-98.2%) of PV and 90.0% (95% CI:55.5-99.7%) of PVR patients achieved undetectable minimal residual disease assessed in peripheral blood by clonoSEQ® assay at a sensitivity of <1x10-4. Progression-free survival at 18 months was 92.9% (95% CI: 59.1-99.0) for PV patients and 80.0% (95% CI: 40.9-94.6) for PVR patients. No DLTs were observed in either treatment combination during the 5-week assessment period. The most common grade ≥3 adverse events for all patients included neutropenia (52%) and anemia (16%). Adverse events led to dose reduction in 3 patients and discontinuation in 2. In conclusion, fixed-duration PV or PVR was well tolerated and had promising efficacy in patients with R/R CLL, including patients previously treated with a covalent BTKi.

Community-Based Cluster-Randomized Trial to Reduce Opioid Overdose Deaths.

BACKGROUND: Evidence-based practices for reducing opioid-related overdose deaths include overdose education and naloxone distribution, the use of medications for the treatment of opioid use disorder, and prescription opioid safety. Data are needed on the effectiveness of a community-engaged intervention to reduce opioid-related overdose deaths through enhanced uptake of these practices. METHODS: In this community-level, cluster-randomized trial, we randomly assigned 67 communities in Kentucky, Massachusetts, New York, and Ohio to receive the intervention (34 communities) or a wait-list control (33 communities), stratified according to state. The trial was conducted within the context of both the coronavirus disease 2019 (Covid-19) pandemic and a national surge in the number of fentanyl-related overdose deaths. The trial groups were balanced within states according to urban or rural classification, previous overdose rate, and community population. The primary outcome was the number of opioid-related overdose deaths among community adults. RESULTS: During the comparison period from July 2021 through June 2022, the population-averaged rates of opioid-related overdose deaths were similar in the intervention group and the control group (47.2 deaths per 100,000 population vs. 51.7 per 100,000 population), for an adjusted rate ratio of 0.91 (95% confidence interval, 0.76 to 1.09; P = 0.30). The effect of the intervention on the rate of opioid-related overdose deaths did not differ appreciably according to state, urban or rural category, age, sex, or race or ethnic group. Intervention communities implemented 615 evidence-based practice strategies from the 806 strategies selected by communities (254 involving overdose education and naloxone distribution, 256 involving the use of medications for opioid use disorder, and 105 involving prescription opioid safety). Of these evidence-based practice strategies, only 235 (38%) had been initiated by the start of the comparison year. CONCLUSIONS: In this 12-month multimodal intervention trial involving community coalitions in the deployment of evidence-based practices to reduce opioid overdose deaths, death rates were similar in the intervention group and the control group in the context of the Covid-19 pandemic and the fentanyl-related overdose epidemic. (Funded by the National Institutes of Health; HCS ClinicalTrials.gov number, NCT04111939.).

A superior approach? The role of robotic sleeve gastrectomy in patients with super super obesity using the 2019-2022 MBSAQIP database.

BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) in patients with BMI ≥ 60 presents technical challenges, that might be overcome by robotic surgery, but its effectiveness has not been rigorously evaluated. We compared the 30-day outcomes of LSG and robotic sleeve gastrectomy (RSG) in patients with BMI < 60 versus ≥ 60 and between LSG and RSG in patients with BMI ≥ 60. METHODS: Patients aged 18-65 years who underwent sleeve gastrectomy were included using the 2019-2022 MBSAQIP database. We performed a Propensity Score Matching analysis, with 21 preoperative characteristics. We compared 30-day postoperative outcomes for patients with BMI < 60 versus ≥ 60 using either a laparoscopic (Analysis 1) or robotic approach (Analysis 2) and compared LSG versus RSG in patients with BMI ≥ 60 (Analysis 3). RESULTS: 297,250 patients underwent LSG and 81,008 RSG. Propensity-matched¸ outcomes in analysis 1 (13,503 matched cases), showed that patients with BMI ≥ 60 had higher rates of mortality (0.1% vs. 0.0%, p = 0.014), staple line leak (0.3% vs. 0.2%, p = 0.035), postoperative bleeding (0.2% vs 0.1%, p = 0.028), readmissions (3.5% vs. 2.4%, p < 0.001), and interventions (0.7% vs. 0.5%, p = 0.028) when compared to patients with BMI < 60. In analysis 2 (4350 matched cases), patients with BMI ≥ 60 demonstrated longer operative times, length of stay, and higher rates of unplanned ICU when compared to patients with BMI < 60. In analysis 3 (4370 matched cases), patients who underwent RSG had fewer readmissions (2.9% vs. 3.7%, p = 0.037), staple line leaks (0.1% vs. 0.3%, p = 0.029), and postoperative bleeding (0.1% vs. 0.3%, p = 0.045), compared to LSG. Conversely, a longer operative time (92.74 ± 38.65 vs. 71.69 ± 37.45 min, p < 0.001) was reported. CONCLUSION: LSG patients with BMI ≥ 60 have higher rates of complications compared to patients with a BMI < 60. Moreover, some outcomes may be improved with the robotic approach in patients with BMI ≥ 60. These results underscore the importance of considering a robotic approach in this super super obese population.

Metagenomics analysis yields assembled genomes from prokaryotic anaerobes with polymer-degrading potential.

Anaerobic microbial communities are often highly degradative, such as those found in the herbivore rumen and large-scale anaerobic digesters. Since the microbial communities in these systems degrade recalcitrant organic polymers, we hypothesize that some microbes in anaerobic environments may be involved in man-made plastic association, deformation, or even breakdown. While efforts have been put toward characterizing microbial communities, many microbes remain unidentified until they can be sufficiently cultivated to generate enough genetic material to assemble high-quality metagenome assemblies and reference genomes. In this study, microbial consortia from goat fecal pellets and anaerobic digester sludge were cultivated for over 6 weeks to assemble metagenomes from novel anaerobic taxa with potential degradative activity. To select for microbes with potential plastic-degrading abilities, plastic strips were included in culture, though the presence of plastic did not appear to enrich for particularly degradative consortia, yet it did select for novel species that otherwise may not have been characterized. Whole-genome shotgun sequencing enabled assembly of 72 prokaryotic metagenome-assembled genomes (MAGs) with >90% completion, <5% contamination, and an N50 >10,000 bp; 17 of these MAGs are classified as novel species given their lack of similarity to publicly available genomes and MAGs. These 72 MAGs vary in predicted carbohydrate-degrading abilities, with genes predicted to encode fewer than 10 or up to nearly 400 carbohydrate-active enzymes. Overall, this enrichment strategy enables characterization of less abundant MAGs in a community, and the MAGs identified here can be further mined to advance understanding of degradative anaerobic microbial consortia.

Shaping Perceptions and Inspiring Future Neurosurgeons: The Value of a Hands-On Simulated Aneurysm Clipping Workshops at a Student-Organized Neurosurgical Conference.

Objective Early exposure to niche specialities, like neurosurgery, is essential to inform decisions about future training in these specialities. This study assesses the impact of a hands-on simulated aneurysm clipping workshop on medical students' and junior doctors' perceptions of neurosurgery at a student-organized neurosurgical conference. Methods Ninety-six delegates were sampled from a hands-on workshop involving hydrogel three-dimensional printed aneurysms clipping using surgical microscopes. Consultant neurosurgeons facilitated the workshop. Changes in delegates' perceptions of neurosurgery were collected using Likert scale and free-text responses postconference. Results Postworkshop, 82% of participants reported a positive impact on their perception of neurosurgery. Thematic analysis revealed that delegates valued the hands-on experience, exposure to microsurgery, and interactions with consultant neurosurgeons. Thirty-six of the 96 delegates (37.5%) expressed that the workshop dispelled preconceived fears surrounding neurosurgery and improved understanding of a neurosurgeon's day-to-day tasks. Several delegates initially apprehensive about neurosurgery were now considering it as a career. Conclusion Hands-on simulated workshops can effectively influence medical students' and junior doctors' perceptions of neurosurgery, providing valuable exposure to the specialty. By providing a valuable and immersive introduction to the specialty, these workshops can help to dispel misconceptions, fears, and apprehensions associated with neurosurgery, allowing them to consider the specialty to a greater degree than before. This study of a one-time workshop cannot effectively establish its long-term impact on said perceptions, however.

The phase III DUO trial of PI3K inhibitor duvelisib versus ofatumumab in relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma: final analysis including overall survival.

Not available.

Transitions of care: An aerodigestive provider assessment survey.

OBJECTIVE: To create, validate, and apply an aerodigestive provider assessment survey. METHODS: A survey assessing provider knowledge and current practice in the transition of patients with chronic aerodigestive disorders from pediatric to adult care was drafted by a multidisciplinary expert panel. Once agreement of the initial survey items was obtained, the survey was distributed to a national multidisciplinary panel of aerodigestive experts for review. Responses from the national panel were systematically quantified and a content validity index (CVI) was calculated. A final survey was developed and distributed to pediatric and adult aerodigestive providers. RESULTS: From the initial 22 items presented to the national panel, 20 of the initial questions were included in the final instrument. Two additional questions were developed as a result of feedback from the expert panel. All items included in the survey had an Item Content Validity Index (I-CVI) of >0.85. The average Scale CVI in proportion to the average proportion of relevance (S-CVI/Ave) for the tool was 0.88. The average Scale CVI in proportion to universal agreement (S-CVI/UA) was 0.52. The survey was then administered to pediatric and adult specialty providers at our institution. Twenty-two providers completed the final survey. CONCLUSION: The content validity index measurements from this newly developed survey suggest that it is a valid tool for assessing current knowledge and practice in care transitions among patients with complex aerodigestive needs. The survey developed in this project has been used to identify knowledge gaps and process issues that can be addressed to ease the transition of adolescents from pediatric specialty care into adult specialty care.

Evaluating zanubrutinib for the treatment of adults with chronic lymphocytic leukemia or small lymphocytic lymphoma.

INTRODUCTION: This review evaluates zanubrutinib as a treatment option for adults with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Zanubrutinib, a covalent BTK (Bruton's tyrosine kinase) inhibitor, was recently approved by the US FDA based in part on head-to-head data demonstrating improved efficacy and safety compared to ibrutinib. AREAS COVERED: The review discusses the efficacy, safety, and comparative advantages of zanubrutinib, highlighting its safety profile compared to other BTK inhibitors. It also addresses the unmet needs of current therapies in CLL/SLL and provides an overview of competitor compounds and ongoing research in BTK inhibition. EXPERT OPINION: Zanubrutinib, the first BTK inhibitor to demonstrate superior efficacy and safety compared to another BTK inhibitor in CLL, is likely to be widely adopted due to its high-quality data and ease of use. Looking ahead, pirtobrutinib, a novel non-covalent BTK inhibitor, has shown promise in heavily pretreated CLL patients, including those unresponsive to covalent inhibitors, with ongoing phase 3 trials comparing it against ibrutinib. The field is also exploring time-limited therapies like the combination of ibrutinib and venetoclax, with ongoing trials evaluating different combinations to optimize efficacy and minimize toxicity, indicating a promising future for combination therapies in CLL treatment.

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are essentially different manifestations of the same disease that are similarly managed. A number of molecular and cytogenetic variables with prognostic implications have been identified. Undetectable minimal residual disease at the end of treatment with chemoimmunotherapy or venetoclax-based combination regimens is an independent predictor of improved survival among patients with previously untreated or relapsed/refractory CLL/SLL. The selection of treatment is based on the disease stage, presence or absence of del(17p) or TP53 mutation, immunoglobulin heavy chain variable region mutation status, patient age, performance status, comorbid conditions, and the agent's toxicity profile. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with CLL/SLL.

Changes in Compliance with Bans on Tobacco Product Display and Advertising at Traditional and Modern Point-of-Sale Retailers in Depok, Indonesia, 2019-2021.

INTRODUCTION: Banning Point-of-Sale (POS) advertising and product display is an important tobacco control strategy. Depok, Indonesia enacted some regional tobacco control policies regulating the POS environment in 2021. This study examined changes in compliance before and after the implementation of these policies as of 2021. METHODS: Data collectors visited 180 modern retailers (hyper/supermarkets/convenience stores) and 147 traditional retailers (warungs) in 2019. The same retailers were re-visited in 2021. Data collectors assessed compliance with tobacco product display, and advertising regulations at POS, including if products were displayed in spaces to target minors (near candy or at a child's eye-level). Data were analyzed using McNemar and Mann-Whitney U tests. RESULTS: From 2019 to 2021, in modern retailers, tobacco product display (95.6% vs 52.2%) and product advertising (36.1% vs 3.9%) were significantly reduced (p<0.001). In traditional retailers, tobacco product display (94.6% in 2019, 91.2% in 2021, p>0.05) and product advertising (87.1% in 2019, 87.8% in 2021, p>0.05) remained common during both data collection periods. Tobacco products were commonly displayed in spaces to target minors in both modern retailers (43.3% in 2019, 34.4% in 2021, p>0.05) and traditional retailers (90.5% in 2019, 83.0% in 2021, p>0.05). CONCLUSIONS: Compliance with bans on tobacco product advertising and display at modern retailers improved significantly from 2019 to 2021; however, most modern retailers continue to display tobacco products in 2021. Traditional retailers remain largely non-compliant. Tobacco products are commonly displayed in areas that target minors. The enforcement of regional regulations should be strengthened, particularly among traditional retailers. IMPLICATIONS: In Depok, Indonesia, tobacco advertising and product display bans have been implemented; however, more work is needed to support compliance. Enforcement efforts, such as those carried out by civil police, can focus on tobacco product display bans in traditional and modern retailers, and traditional retailers need additional support to remove tobacco product advertising. Retailers may receive money from the tobacco industry for these advertisements. Creative solutions may include supporting retailers in finding alternative advertising revenue.

Clinical Risks for Chronic Lymphocytic Leukemia.

Our understanding of risk factors for the development of chronic lymphocytic leukemia (CLL) is still incomplete and includes genetic and environmental factors. CLL is one of the most familial of all cancers, yet common high-penetrance risk alleles have not been identified. Genome-wide association studies have identified many common variants with low relative risks, whereas exome-wide rare variant analysis has implicated ATM in CLL causation. Environmental factors have also been challenging to identify given the limited understanding of the relevant time period of exposure relative to diagnosis, and the inability to quantify past exposures. Agent Orange and glyphosate herbicides have perhaps the most data to support their role. CLL is preceded by a precursor condition called monoclonal B-cell lymphocytosis (MBL), which could therefore be considered a risk factor, but which itself is likely caused by the same risk factors that ultimately give rise to CLL. Although virtually all people with CLL have a preceding MBL phase, most people with MBL will not develop CLL.

Emergence of acquired dolutegravir resistance in treatment-experienced people with HIV in Lesotho.

BACKGROUND: Since 2019, the World Health Organization has recommended dolutegravir-based antiretroviral therapy (ART) as the preferred regimen for HIV management. Large-scale programmatic transitioning to dolutegravir-based ART was subsequently implemented across Africa, often in the absence of recent viral load testing and without access to genotypic resistance testing (GRT) in case of viremia. METHODS: This study assessed for emerging dolutegravir resistance in the routine care Viral Load Cohort North-East Lesotho (VICONEL). We included pediatric and adult participants who changed from non-nucleoside transcriptase inhibitor- (NNRTI-) to dolutegravir-based ART and had at least one viral load assessment before and after the change. We sequenced available samples of participants fulfilling the additional virological criteria of having two viraemic episodes while taking dolutegravir, thereof at least one viral load ≥500 copies/mL taken ≥18 months after changing to dolutegravir. RESULTS: Among 15'349 participants, 157 (1.0%) met the virological criteria and GRT was successful for 85 (0.6%). Among these 85, eight (9.4%) had dolutegravir resistance, with two (2.4%) and six (7.1%) predicted to have intermediate and high-level dolutegravir resistance, respectively. One participant had two, two had one, and five had zero active drugs in their regimen. A GRT from before the change to dolutegravir is available for five of these eight participants: four had zero and one had one active drug in their NNRTI-based regimen. CONCLUSIONS: Nine percent of people with persistent or recurring HIV viremia ≥18 months after changing to dolutegravir-based ART had dolutegravir resistance. Detection and management of emerging dolutegravir resistance must be addressed across Africa.

Final 3-Year Study Outcomes from the Evaluation of the Zilver Vena Venous Stent for the Treatment of Symptomatic Iliofemoral Venous Outflow Obstruction (The VIVO Clinical Study).

PURPOSE: To report 3-year outcomes from a prospective, multicenter, nonrandomized, single-arm study designed to assess the safety and effectiveness of the Zilver Vena Venous Stent for the treatment of symptomatic iliofemoral venous outflow obstruction. MATERIALS AND METHODS: The VIVO study included patients with symptomatic obstruction of 1 iliofemoral venous segment (ie, 1 limb), characterized by a Clinical, Etiological, Anatomic, Pathophysiology (CEAP) clinical classification of ≥3 or a Venous Clinical Severity Score (VCSS) for pain of ≥2. Patients were retrospectively grouped based on baseline clinical presentation as postthrombotic syndrome (PTS), nonthrombotic iliac vein (NIVL) obstruction, or acute deep vein thrombosis (aDVT). Clinical improvement was assessed by change in VCSS, Venous Disability Score, Chronic Venous Disease Quality of Life Questionnaire (CIVIQ-20) scores, and CEAP C classification. Stent performance was evaluated by rates of patency by ultrasound (US), freedom from clinically driven reintervention, and freedom from stent fracture. RESULTS: The 3-year results for the 243 patients in the VIVO cohort included a 90.3% rate of patency by US and a 92.6% rate of freedom from clinically driven reintervention. The 3-year rates of patency by US for the NIVL, aDVT, and PTS groups were 100%, 84.0%, and 86.1%, respectively. Sustained clinical improvement through 3 years was demonstrated by changes in VCSS, Venous Disability Score, CIVIQ-20, and CEAP C classification. No stent fractures were observed. CONCLUSIONS: The VIVO study demonstrated sustained high rates of patency and freedom from clinically driven reintervention and improvements in venous clinical symptoms through 3 years. Each patient group (NIVL, aDVT, and PTS) showed clinical improvement and sustained patency through 3 years; some variation existed among groups (eg, only the NIVL group had a 100% patency rate).

Efforts in Organized Medicine to Eliminate Harmful Race-Based Clinical Algorithms.

This survey study describes efforts to eliminate harmful race-based clinical algorithms among state or territorial medical associations and specialty societies in the US.