The mitotic rate as a prognostic biomarker after preoperative radiotherapy for high-grade limb/trunk soft tissue sarcoma.

PURPOSE: Currently there is no generally accepted standardized approach for the pathologic evaluation of soft tissue sarcoma (STS) histology appearance after preoperative radiotherapy (PORT). This study aimed to investigate the prognostic value of pathological appearance after PORT for patients with high-grade limb/trunk STS. METHODS: A cohort of 116 patients with high-grade STS of the limb/trunk treated with PORT followed by resection were evaluated. Patient characteristics, imaging tumor morphology (size, volume), and histopathology (mitotic and necrosis rate, viable cell, hyalinization/fibrosis cytopathic effect) were reviewed and reassessed. Disease free survival (DFS) and overall survival (OS) were calculated using the Kaplan-Meier method, and the hazard ratio was derived from Cox proportional hazard models. Two predictive nomograms were calculated based on significant predictors identified. RESULTS: The 5-year DFS and OS were 52.9% and 70.3%, respectively. Tumor size before (HR:1.07, 95%CI: 1.01-1.14) and after PORT (HR:1.08, 95%CI: 1.01-1.14), tumor volume (HR:1.06, 95%CI: 1.01-1.12), mitotic rate after PORT (HR: 1.06, 95%CI: 1.02-1.11), mitotic rate change after PORT (HR:1.04, 95%CI:1.00-1.09) were independent risk factors for DFS. Tumor size before (HR:1.08, 95%CI: 1.03-1.14) and after PORT (HR:1.09, 95%CI: 1.04-1.15), tumor volume (HR:1.05, 95%CI: 1.01-1.09), mitotic rate after PORT (HR: 1.09, 95%CI: 1.04-1.13), mitotic rate change after PORT (HR:1.05, 95%CI:1.01-1.09) were independent risk factors for OS. The C-index of pathologic predictive nomogram based on mitotic rate for DFS and OS were 0.67 and 0.73, respectively. The C-index of morphology-pathology predictive nomogram for OS was 0.79. CONCLUSION: Tumor size before and after PORT, tumor volume, mitotic rate after PORT, mitotic rate change after PORT were independent risk factors for DFS and OS in high-grade STS patients treated with PORT. The mitotic rate, independent of tumor morphology, showed its potential as a prognostic biomarker for pathologic evaluation in patients treated with PORT.

Plain language summary of zanubrutinib or ibrutinib in chronic lymphocytic leukemia that is resistant to treatment or has come back after treatment.

What is this summary about? This is a plain language summary of a research study called ALPINE. The study involved people who had been diagnosed with, and previously treated at least once for, relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).Lymphocytes help to find and fight off viruses and infections in the body, but when someone has CLL or SLL, the body creates abnormal lymphocytes, leaving the patient with a weakened immune system and susceptible to illness. In CLL, these lymphocytes are in the bone marrow and bloodstream, whereas for SLL, they are mostly found in the lymph nodes, such as those in the neck.How was the research done? The ALPINE study was designed to directly compare the cancer-fighting effects and side effects of zanubrutinib and ibrutinib as treatment for patients with relapsed or refractory CLL/SLL.What were the results? After 30 months, zanubrutinib was more effective than ibrutinib at reducing and keeping the cancer from coming back. Clinical Trial Registration: NCT03734016 (ClinicalTrials.gov).

Comparing Outcomes Between Standard Mepilex and Mepilex Silver for Tracheotomy Dressings.

OBJECTIVE: The purpose of the study is to compare the incidence of early postoperative tracheotomy stoma wound complications in pediatric patients using a silver-impregnated barrier dressing (Mepilex Ag) versus a standard absorbent foam dressing (standard Mepilex). METHODS: This is a prospective, non-blinded, randomized trial of pediatric patients undergoing tracheotomy at a tertiary care children's hospital. Patients were randomized to receive Mepilex Ag versus standard Mepilex tracheostoma dressings following tracheotomy. All patients received standard postoperative wound care and daily stomal examination. Wound related complications, breakdown, granulation, and infection were recorded for the first 7 days after surgery. A non-inferiority study design was used to test the hypothesis that the Mepilex group had a non-inferior wound complication rate (within 10% margin) compared to the Mepilex Ag group. RESULTS: Eighty-two patients were enrolled; 52 received Mepilex Ag, and 30 received standard Mepilex. There was no difference between the groups with respect to age, sex, race, surgical indication, or postoperative length of stay. Non-inferiority testing demonstrated that the Mepilex standard cohort had no more than 10% greater stomal wound complication rate than that of Mepilex Ag dressing group (p = 0.0108). CONCLUSION: Standard Mepilex was found to be non-inferior to Mepilex Ag in the prevention of tracheotomy stomal wound complications. Standard Mepilex may be used effectively in the postoperative period, potentially reducing costs to caregivers and the institution. Further work is needed to analyze additional factors that could contribute to poor postoperative stoma healing such as bacterial colonization. LEVEL OF EVIDENCE: Randomized Controlled Trial, Level 2 Laryngoscope, 2024.

Standard diet and animal source influence hippocampal spatial reference learning and memory in congenic C57BL/6J mice.

Background: Assessing learning and memory has become critical to evaluate brain function in health, aging or neurological disease. The hippocampus is crucially involved in these processes as illustrated by H.M.'s remarkable case and by the well-established early symptoms of Alzheimer's disease. Numerous studies have reported the impact of gut microbiota on hippocampal structure and function using pro-, pre- and antibiotics, diet manipulations, germ-free conditions or fecal transfer. However, most diet manipulations have relied on Western diet paradigms (high fat, high energy, high carbohydrates). Here, we compared the impact of two standard diets, 5K52 and 2918 (6% fat, 18% protein, 3.1kcal/g), and how they influenced hippocampal learning and memory in adult 6-month-old congenic C57BL/6J mice from two sources. Results: Using a hippocampal-dependent task, we found that 5K52-fed mice performed consistently better than 2918-fed animals in the Barnes circular maze. These behavioral differences were accompanied with marked changes in microbiota, which correlated with spatial memory retention performance. We next tested whether 2918-induced alterations in behavior and microbiome could be rescued by 5K52 diet for 3 months. Changing the 2918 diet to 5K52 diet mid-life improved spatial learning and memory in mice. Shotgun sequencing and principal component analyses revealed significant differences at both phylum and species levels. Multivariate analyses identified Akkermansia muciniphila or Bacteroidales bacterium M11 and Faecalibaculum rodentium as the strongest correlates to spatial memory retention in mice depending on the animal source. In both settings, the observed behavioral differences only affected hippocampal-dependent performance as mice fed with either diet did similarly well on the non-spatial variant of the Y-maze. Conclusions: In summary, these findings demonstrate the diverging effects of seemingly equivalent standard diets on hippocampal memory. Based on these results, we strongly recommend the mandatory inclusion of the diet and source of animals used in rodent behavioral studies.

Resistance-informed versus empirical management of viraemia in children and adolescents with HIV in Lesotho and Tanzania (GIVE MOVE trial): a multisite, open-label randomised controlled trial.

BACKGROUND: Children and adolescents with HIV taking antiretroviral therapy (ART) have high rates of viraemia. We assessed if genotypic resistance testing (GRT) to inform onward treatment improved treatment outcomes in Lesotho and Tanzania, two countries with little access to GRT. METHODS: The Genotype-Informed Versus Empirical Management of Viremia (GIVE MOVE) open-label, parallel-group randomised controlled trial enrolled children and adolescents with HIV between the ages of 6 months and 19 years, taking ART, and with a viral load at least 400 copies per mL. Participants were recruited from ten clinical centres and hospitals in Lesotho and Tanzania. Participants were electronically randomly allocated 1:1 to receive either GRT with expert recommendation (GRT group) or repeat viral-load testing and empirical onward treatment (usual care group). Participants and study staff were not masked, but the endpoint committee and laboratory staff conducting viral-load testing were. Participants in both groups received at least three sessions of enhanced adherence counselling, and in the GRT group, blood for GRT assessed via Sanger sequencing was drawn at enrolment. The composite primary endpoint was death, hospitalisation, a new WHO HIV clinical stage 4 event, or not having documented viral suppression of less than 50 copies per mL at 36 weeks in the modified intention-to-treat population, which excluded participants who were retrospectively found to be ineligible after randomisation. Serious adverse events were analysed in the modified intention-to-treat population. The trial was registered with ClinicalTrials.gov (NCT04233242) and the trial status is completed. FINDINGS: Between March 3, 2020, and July 5, 2022, 286 participants were enrolled and 284 were included in the modified intention-to-treat analysis (144 in the GRT group and 140 in the usual care group). Of these participants, 158 (56%) were female and 126 (44%) were male. Five (3%) in the GRT group and four (3%) in the usual care group did not complete follow-up but were included in the primary analysis. The median age across both groups was 14 years (IQR 9-16). The composite primary endpoint occurred in 67 (47%) participants in the GRT group and 73 (52%) in the usual care group (adjusted odds ratio 0·79 [95% CI 0·49 to 1·27]; adjusted risk difference -0·06 [95% CI -0·17 to 0·06]; p=0·34); all participants reaching the composite primary endpoint had no documented viral suppression at 36 weeks. No deaths were recorded, and only one clinical stage 4 event requiring hospitalisation occurred (in the usual care group); this was the only serious adverse event recorded in the study. INTERPRETATION: GRT-informed management did not significantly improve treatment outcomes for children and adolescents with viraemia while taking ART. FUNDING: Fondation Botnar, Swiss National Science Foundation, and Gottfried and Julia Bangerter-Rhyner Foundation. TRANSLATIONS: For the Sesotho and Swahili translations of the abstract see Supplementary Materials section.

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.

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.

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.

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.).

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.

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.

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.

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.