Pirtobrutinib monotherapy in Bruton tyrosine kinase inhibitor-intolerant patients with B-cell malignancies: results of the phase I/II BRUIN trial.

Bruton tyrosine kinase inhibitors (BTKi) have transformed the treatment of B-cell malignancies, but intolerance has often led to their discontinuation. The phase 1/2 BRUIN study evaluated pirtobrutinib, a highly selective non-covalent (reversible) BTKi, in patients with R/R B-cell malignancies (NCT03740529). Pirtobrutinib was investigated in 127 patients with intolerance to at least one prior BTKi therapy in the absence of progressive disease. The most common adverse event (AE) leading to BTKi discontinuation was cardiac disorders (n=40, 31.5%), specifically atrial fibrillation (n=30, 23.6%). The median follow-up was 17.4 months and the median time on pirtobrutinib was 15.3 months. The most common reasons for pirtobrutinib discontinuation were progressive disease (26.8%), AE (10.2%), or death (5.5%). The most frequent treatment-emergent AEs were fatigue (39.4%) and neutropenia (37.0%). Among patients who discontinued a prior BTKi for a cardiac issue, 75% had no recurrence of their cardiac AE. No patient discontinued pirtobrutinib for the same AE that led to discontinuation of the prior BTKi. In 78 CLL/SLL and 21 MCL patients intolerant to prior BTKi, ORR to pirtobrutinib was 76.9% and 81.0%, respectively. Median PFS for CLL/SLL was 28.4 months and was not estimable for MCL. These results suggest that pirtobrutinib was safe, well-tolerated, and an efficacious option in patients with prior BTKi-intolerance.

Causes, Diagnostic Testing, and Treatments Related to Clinical Deterioration Events Among High-Risk Ward Patients.

IMPORTANCE: Timely intervention for clinically deteriorating ward patients requires that care teams accurately diagnose and treat their underlying medical conditions. However, the most common diagnoses leading to deterioration and the relevant therapies provided are poorly characterized. OBJECTIVES: We aimed to determine the diagnoses responsible for clinical deterioration, the relevant diagnostic tests ordered, and the treatments administered among high-risk ward patients using manual chart review. DESIGN, SETTING, AND PARTICIPANTS: This was a multicenter retrospective observational study in inpatient medical-surgical wards at four health systems from 2006 to 2020. Randomly selected patients (1000 from each health system) with clinical deterioration, defined by reaching the 95th percentile of a validated early warning score, electronic Cardiac Arrest Risk Triage, were included. MAIN OUTCOMES AND MEASURES: Clinical deterioration was confirmed by a trained reviewer or marked as a false alarm if no deterioration occurred for each patient. For true deterioration events, the condition causing deterioration, relevant diagnostic tests ordered, and treatments provided were collected. RESULTS: Of the 4000 included patients, 2484 (62%) had clinical deterioration confirmed by chart review. Sepsis was the most common cause of deterioration (41%; n = 1021), followed by arrhythmia (19%; n = 473), while liver failure had the highest in-hospital mortality (41%). The most common diagnostic tests ordered were complete blood counts (47% of events), followed by chest radiographs (42%) and cultures (40%), while the most common medication orders were antimicrobials (46%), followed by fluid boluses (34%) and antiarrhythmics (19%). CONCLUSIONS AND RELEVANCE: We found that sepsis was the most common cause of deterioration, while liver failure had the highest mortality. Complete blood counts and chest radiographs were the most common diagnostic tests ordered, and antimicrobials and fluid boluses were the most common medication interventions. These results provide important insights for clinical decision-making at the bedside, training of rapid response teams, and the development of institutional treatment pathways for clinical deterioration.

Reimagining Undergraduate Critical Care Medical Education: A Path for the Next Decade.

Foundational training in critical care medicine is an integral part of both undergraduate and graduate medical education. Yet, many medical school graduates enter residency underprepared to care for critically ill patients because of a lack of ubiquity of undergraduate critical care education and the heterogeneity of existing didactic and clinical experiences. This Perspective explores the importance of undergraduate critical care education, the current national and international landscape, innovative educational strategies and exemplar curricula, and recent advances in assessment that may better reflect learner-centered educational outcomes. As broad curricular reforms push medical education toward a more innovative, interactive, and collaborative future, now is the time to rethink and reimagine undergraduate critical care education.

Development and Validation of a Machine Learning Model for Early Detection of Untreated Infection.

BACKGROUND: Early diagnostic uncertainty for infection causes delays in antibiotic administration in infected patients and unnecessary antibiotic administration in noninfected patients. OBJECTIVE: To develop a machine learning model for the early detection of untreated infection (eDENTIFI), with the presence of infection determined by clinician chart review. DERIVATION COHORT: Three thousand three hundred fifty-seven adult patients hospitalized between 2006 and 2018 at two health systems in Illinois, United States. VALIDATION COHORT: We validated in 1632 patients in a third Illinois health system using area under the receiver operating characteristic curve (AUC). PREDICTION MODEL: Using a longitudinal discrete-time format, we trained a gradient boosted machine model to predict untreated infection in the next 6 hours using routinely available patient demographics, vital signs, and laboratory results. RESULTS: eDENTIFI had an AUC of 0.80 (95% CI, 0.79-0.81) in the validation cohort and outperformed the systemic inflammatory response syndrome criteria with an AUC of 0.64 (95% CI, 0.64-0.65; p < 0.001). The most important features were body mass index, age, temperature, and heart rate. Using a threshold with a 47.6% sensitivity, eDENTIFI detected infection a median 2.0 hours (interquartile range, 0.9-5.2 hr) before antimicrobial administration, with a negative predictive value of 93.6%. Antibiotic administration guided by eDENTIFI could have decreased unnecessary IV antibiotic administration in noninfected patients by 10.8% absolute or 46.4% relative percentage points compared with clinicians. CONCLUSION: eDENTIFI could both decrease the time to antimicrobial administration in infected patients and unnecessary antibiotic administration in noninfected patients. Further prospective validation is needed.

Culturally Adapted Lifestyle Intervention for South Asian Adults With Cardiovascular Risk Factors: The SAHELI Randomized Clinical Trial.

Importance: South Asian adults in the US experience excess cardiovascular disease (CVD) compared with other racial and ethnic groups. The effectiveness and reach of guideline-recommended lifestyle interventions have not been evaluated in this population. Objective: To evaluate whether a culturally adapted, group lifestyle intervention will improve CVD risk factors more effectively than written health education materials among US South Asian adults. Design, Setting, and Participants: This single-blind randomized clinical trial was conducted from March 6, 2018, to February 11, 2023 at community sites in the Chicago, Illinois, metropolitan area. South Asian adults aged 18 to 65 years who were overweight or obese, had no history of CVD events, and had at least 1 additional CVD risk factor (hypertension, dyslipidemia, prediabetes, or diabetes) were eligible for inclusion. Intervention: A 16-week, culturally adapted, group-based lifestyle intervention led by community health coaches. Lifestyle modification counseling was delivered in English, Gujarati, Hindi, and Urdu. Participants tracked their diet and physical activity (PA) and received 4 optional group maintenance sessions between months 5 and 11 of follow-up. The intervention was delivered in person prior to the onset of the COVID-19 pandemic and via videoconference starting in March 2020. The control group received written health education materials, delivered monthly. Main Outcomes and Measures: Primary outcomes were the between-group differences in CVD risk factor changes from baseline to 12 months, including weight, systolic blood pressure (SBP), diastolic blood pressure (DBP), glycated hemoglobin (HbA1c), and total cholesterol, estimated using multivariate mixed-effects regression models. Secondary outcomes were self-reported diet quality, PA, and self-efficacy, estimated using univariate mixed-effects regression models. Results: Among 549 randomized participants, 318 (57.9%) were women, and mean (SD) participant age was 49.2 (9.5) years. Mean differences in CVD risk factor changes from baseline to 12 months in the intervention vs control group were calculated for weight (mean difference, -0.07 kg; 95% CI, -0.55 to 0.42), SBP (mean difference, 0.47 mm Hg; 95% CI, -1.85 to 2.79), DBP (mean difference, 0.44 mm Hg; 95% CI, -1.06 to 1.95), cholesterol (mean difference, -2.47 mg/dL; 95% CI, -8.51 to 3.57), and HbA1c (mean difference, -0.07%; 95% CI -0.20% to 0.07%). Intervention participation was associated with greater improvements in dietary quality, PA, and self-efficacy than control. Conclusions and Relevance: In the SAHELI randomized clinical trial, a culturally adapted, group lifestyle intervention was not more effective than written health education materials for CVD risk factor reduction among US South Asian adults, but the intervention was associated with small improvements in self-reported health behaviors. Effective CVD prevention interventions for this elevated-risk population require further investigation. Trial Registration: ClinicalTrials.gov Identifier: NCT03336255.

Polygenic Score for the Prediction of Postoperative Nausea and Vomiting: A Retrospective Derivation and Validation Cohort Study.

BACKGROUND: Postoperative nausea and vomiting (PONV) is a key driver of unplanned admission and patient satisfaction following surgery. Because traditional risk factors do not completely explain variability in risk, we hypothesize that genetics may contribute to the overall risk for this complication. The objective of this research is to perform a genome-wide association study of PONV, derive a polygenic risk score for PONV, assess associations between the risk score and PONV in a validation cohort, and compare any genetic contributions to known clinical risks for PONV. METHODS: Surgeries with integrated genetic and perioperative data performed under general anesthesia at Michigan Medicine and Vanderbilt University Medical Center were studied. PONV was defined as nausea or emesis occurring and documented in the PACU. In the Discovery Phase, genome-wide association studies were performed on each genetic cohort and the results were meta-analyzed. Next, in the Polygenic Phase, we assessed whether a polygenic score, derived from genome-wide association study in a derivation cohort from Vanderbilt University Medical Center, improved prediction within a validation cohort from Michigan Medicine, as quantified by discrimination (C-statistic) and net reclassification index. RESULTS: Of 64,523 total patients, 5,703 developed PONV (8.8%). We identified 46 genetic variants exceeding P<1x10-5 threshold, occurring with minor allele frequency > 1%, and demonstrating concordant effects in both cohorts. Standardized polygenic score was associated with PONV in a basic model, controlling for age and sex, (aOR 1.027 per standard deviation increase in overall genetic risk, 95% CI 1.001-1.053, P=0.044), a model based on known clinical risks (aOR 1.029, 95% CI 1.003-1.055, P=0.030), and a full clinical regression, controlling for 21 demographic, surgical, and anesthetic factors, (aOR 1.029, 95% CI 1.002-1.056, P=0.033). The addition of polygenic score improved overall discrimination in models based on known clinical risk factors (c-statistic: 0.616 compared to 0.613, P=0.028) and improved net reclassification of 4.6% of cases. CONCLUSION: Standardized polygenic risk was associated with PONV in all three of our models, but the genetic influence was smaller than exerted by clinical risk factors. Specifically, a patient with a polygenic risk score > 1 standard deviation above the mean, has 2-3% greater odds of developing PONV when compared to the baseline population, which is at least an order of magnitude smaller than the increase associated with having prior PONV/motion sickness (55%), having a history of migraines (17%), or being female (83%), and is not clinically significant. Furthermore, the use of a polygenic risk score does not meaningfully improve discrimination compared to clinical risk factors and is not clinically useful.

Characterizing features affecting local ancestry inference performance in admixed populations.

In recent years, significant efforts have been made to improve methods for genomic studies of admixed populations using Local Ancestry Inference (LAI). Accurate LAI is crucial to ensure downstream analyses reflect the genetic ancestry of research participants accurately. Here, we test analytic strategies for LAI to provide guidelines for optimal accuracy, focusing on admixed populations reflective of Latin America's primary continental ancestries - African (AFR), Amerindigenous (AMR), and European (EUR). Simulating LD-informed admixed haplotypes under a variety of 2 and 3-way admixture models, we implemented a standard LAI pipeline, testing three reference panel compositions to quantify their overall and ancestry-specific accuracy. We examined LAI miscall frequencies and true positive rates (TPR) across simulation models and continental ancestries. AMR tracts have notably reduced LAI accuracy as compared to EUR and AFR tracts in all comparisons, with TPR means for AMR ranging from 88-94%, EUR from 96-99% and AFR 98-99%. When LAI miscalls occurred, they most frequently erroneously called European ancestry in true Amerindigenous sites. Using a reference panel well-matched to the target population, even with a lower sample size, LAI produced true-positive estimates that were not statistically different from a high sample size but mismatched reference, while being more computationally efficient. While directly responsive to admixed Latin American cohort compositions, these trends are broadly useful for informing best practices for LAI across other admixed populations. Our findings reinforce the need for inclusion of more underrepresented populations in sequencing efforts to improve reference panels.

Comparison of Thiotepa-based Conditioning Regimens for Older Adults with Primary Diffuse Large B-cell Lymphoma of the Central Nervous System Undergoing Autologous Hematopoietic Cell Transplantation.

In this study, we compare outcomes of older patients with primary diffuse large B-cell lymphoma of the central nervous system (PCNSL) undergoing autologous hematopoietic cell transplantation (autoHCT) with either thiotepa/carmustine (BCNU/Thio) or thiotepa/busulfan/cyclophosphamide (TBC) conditioning. We used a postpublication dataset made available by the Center for International Blood and Marrow Transplantation Research including patients who were ≥65 years in age with PCNSL and underwent autoHCT as consolidation with TBC or BCNU/Thio conditioning. Out of 147 patients; n = 84 received BCNU/Thio and n = 63 received TBC. The 1-year NRM in the BCNU/Thio group was 10% versus 22% in the TBC group (P = .05) and the 2-year relapse rate was 5% versus 5%, respectively (P = 1.00). The 2-year progression-free survival (PFS) in the BCNU/Thio group was 85% versus 71% in the TBC group (P = .05) and 2-year overall survival (OS) was 86% versus 74% (P = .08). In a multivariable regression model, BCNU/Thio was associated with a lower risk for NRM (hazard ratio [HR], 0.33, P = .009), improved PFS (HR, 0.41, P = .008) and OS (HR, 0.37, P = .007), but there was no association with relapse risk. We found that in older adults with PCNSL undergoing consolidation with autoHCT, BCNU/Thio conditioning is associated with lower NRM and improved OS compared to TBC.

Industry Perspective on First-in-Human and Clinical Pharmacology Strategies to Support Clinical Development of T-Cell Engaging Bispecific Antibodies for Cancer Therapy.

T-cell-engaging bispecific antibodies (TCEs) that target tumor antigens and T cells have shown great promise in treating cancer, particularly in hematological indications. The clinical development of TCEs often involves a lengthy first-in-human (FIH) trial with many dose-escalation cohorts leading up to an early proof of concept (POC), enabling either a no-go decision or dose selection for further clinical development. Multiple factors related to the target, product, disease, and patient population influence the efficacy and safety of TCEs. The intricate mechanism of action limits the translatability of preclinical models to the clinic, thereby posing challenges to streamline clinical development. In addition, unlike traditional chemotherapy, the top dose and recommended phase II doses (RP2Ds) for TCEs in the clinic are often not guided by the maximum tolerated dose (MTD), but rather based on the integrated dose-response assessment of the benefit/risk profile. These uncertainties pose complex challenges for translational and clinical pharmacologists (PK/PD scientists), as well as clinicians, to design an efficient clinical study that guides development. To that end, experts in the field, under the umbrella of the American Association of Pharmaceutical Scientists, have reviewed learnings from published literature and currently marketed products to share perspectives on the FIH and clinical pharmacology strategies to support early clinical development of TCEs.

Outcomes of a hydroxyapatite ceramic-coated femoral stem in primary total hip arthroplasty: a report of excellent survivorship from a single United Kingdom centre.

BACKGROUND: Hydroxyapatite (HA) coated femoral stems were introduced to enhance the biological fixation at the implant-bone interface, aiming to increase the longevity and survival of the prostheses. We aimed to assess the long-term outcomes of an HA ceramic (HAC) coated stem in primary total hip arthroplasty (THA), assess the stem survival, and clinically evaluate the patients using patient-reported outcome measures (PROMs) and radiological evaluation of stem osseointegration. PATIENTS AND METHODS: This was a prospective evaluation of a retrospective cohort of 385 patients (442 hips) who underwent primary THA between June 2008 and December 2018. The mean age was 63.83 years (range, 30-82 years). During the follow-up duration, 23 patients died, and 36 patients (38 hips) were lost to follow-up. Prospective data collected for 326 patients (381 hips) was used to evaluate stem survival with the Kaplan-Meier method using aseptic loosening or any revision as the endpoint. Clinical evaluation was done using the EuroQol five-dimension (EQ-5D) scoring system and PROMs using the Oxford Hip Score (OHS) and Merle D'Aubigne Postel (MDP) score. Radiological assessments were performed using the Engh radiological criteria for stem osteointegration. RESULTS: The mean follow-up duration was 9.39 years (range, 4-14.5 years). The survival of the HAC-coated femoral stem was 100% (95% confidence interval [CI], 96.7-100%) at 14 years with aseptic loosening as the endpoint, and 98.9% (CI, 96.7-100%) at 14 years with stem revision for any reason as the endpoint. The mean OHS was 44.5 (range, 30-48), and the mean MDP score was 15.87 (range, 10-18). Radiological evaluations showed full osseointegration of all stems. CONCLUSION: This HAC-coated femoral stem has shown excellent survivorship, functional outcomes, and full osseointegration at the final follow-up.

Intraoperative hypoglycemia among adults with intraoperative glucose measurements: a cross-sectional multicentre retrospective cohort study.

PURPOSE: Intraoperative hypoglycemia is presumed to be rare, but generalizable multicentre incidence and risk factor data for adult patients are lacking. We used a multicentre registry to characterize adults with intraoperative hypoglycemia and hypothesized that intraoperative insulin administration would be associated with hypoglycemia. METHODS: We conducted a cross-sectional retrospective multicentre cohort study. We searched the Multicenter Perioperative Outcomes Group registry to identify adult patients with intraoperative hypoglycemia (glucose < 3.3 mmol·L-1 [< 60 mg·dL-1]) from 1 January 2015 to 31 December 2019. We evaluated characteristics of patients with intraoperative glucose measurements and with intraoperative hypoglycemia. RESULTS: Of 516,045 patients with intraoperative glucose measurements, 3,900 (0.76%) had intraoperative hypoglycemia. Diabetes mellitus and chronic kidney disease were more common in the cohort with intraoperative hypoglycemia. The odds of intraoperative hypoglycemia were higher for the youngest age category (18-30 yr) compared with the odds for every age category above 40 yr (odds ratio [OR], 1.57-3.18; P < 0.001), and were higher for underweight or normal weight patients compared with patients with obesity (OR, 1.48-2.53; P < 0.001). Parenteral nutrition was associated with lower odds of hypoglycemia (OR, 0.23; 95% confidence interval [CI], 0.11 to 0.47; P < 0.001). Intraoperative insulin use was not associated with hypoglycemia (OR, 0.996; 95% CI, 0.91 to 1.09; P = 0.93). CONCLUSION: In this large cross-sectional retrospective multicentre cohort study, intraoperative hypoglycemia was a rare event. Intraoperative insulin use was not associated with hypoglycemia.

RéSUMé: OBJECTIF: L'hypoglycémie peropératoire est présumée rare, mais il n'existe pas de données généralisables sur l'incidence multicentrique et les facteurs de risque chez la patientèle adulte. Nous avons utilisé un registre multicentrique pour caractériser les personnes adultes atteintes d'hypoglycémie peropératoire et émis l'hypothèse que l'administration peropératoire d'insuline serait associée à l'hypoglycémie. MéTHODE: Nous avons réalisé une étude de cohorte multicentrique rétrospective transversale. Nous avons effectué des recherches dans le registre du Multicenter Perioperative Outcomes Group afin d'identifier les patient·es adultes atteint·es d'hypoglycémie peropératoire (glucose < 3,3 mmol· L−1 [< 60 mg·dL−1]) du 1er janvier 2015 au 31 décembre 2019. Nous avons évalué les caractéristiques des patient·es présentant des mesures de glucose et une hypoglycémie peropératoires. RéSULTATS: Sur 516 045 patient·es ayant des mesures de glucose peropératoires, 3900 (0,76 %) ont présenté une hypoglycémie peropératoire. Le diabète sucré et l'insuffisance rénale chronique étaient plus fréquents dans la cohorte présentant une hypoglycémie peropératoire. Les risques d'hypoglycémie peropératoire étaient plus élevés pour la catégorie d'âge la plus jeune (18-30 ans) par rapport aux catégories d'âge au-dessus de 40 ans (rapport des cotes [RC], 1,57-3,18; P < 0,001), et étaient plus élevés chez les patient·es de poids insuffisant ou de poids normal par rapport aux patient·es obèses (RC, 1,48-2,53; P < 0,001). La nutrition parentérale était associée à une probabilité plus faible d'hypoglycémie (RC, 0,23; intervalle de confiance [IC] à 95 %, 0,11 à 0,47; P < 0,001). L'utilisation peropératoire d'insuline n'était pas associée à l'hypoglycémie (RC, 0,996; IC 95 %, 0,91 à 1,09; P = 0,93). CONCLUSION: Dans cette vaste étude de cohorte multicentrique rétrospective transversale, l'hypoglycémie peropératoire était un événement rare. L'utilisation peropératoire d'insuline n'était pas associée à l'hypoglycémie.

Knowledge, skills, and confidence gaps impacting treatment decision making in relapsed/refractory chronic lymphocytic leukemia and mantle cell lymphoma: a quantitative survey study in France, Germany, and the United States.

BACKGROUND: With recent advancements in the treatment of chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), healthcare specialists may face challenges making treatment and management decisions based on latest evidence for the optimal care of patients with these conditions. This study aimed to identify specific knowledge, skills, and confidence gaps impacting the treatment of CLL and MCL, to inform future educational activities. METHODS: Hematologists and hemato-oncologists (HCPs, n = 224) from France (academic settings), Germany, and the United States (academic and community settings) responded to a 15-minute quantitative needs assessment survey that measured perceived knowledge, skills, and confidence levels regarding different aspects of treatment and management of CLL and MCL patients, as well as clinical case questions. Descriptive statistics (cross tabulations) and Chi-square tests were conducted. RESULTS: Four areas of educational need were identified: (1) sub-optimal knowledge of treatment guidelines; (2) sub-optimal knowledge of molecular testing to inform CLL/MCL treatment decisions; (3) sub-optimal skills when making treatment decisions according to patient profile (co-morbidities, molecular testing results); and (4) challenges balancing the risk of toxicities with benefits of treatment. Over one-third of the respondents reported skill gaps when selecting suitable treatment options and prescribing therapies and reported a lack in confidence to initiate and manage treatment. Larger gaps in knowledge of guidelines and skills in patient assessment were identified in MCL, compared to CLL. CONCLUSIONS: This study suggests the need for continuing medical education specifically to improve knowledge of treatment guidelines, and to assist clinicians in developing skills and confidence when faced with clinical decision-making scenarios of patients with specific comorbidities and/or molecular test results, for example, through case-based learning activities.

Development and Validation of a Machine Learning COVID-19 Veteran (COVet) Deterioration Risk Score.

BACKGROUND AND OBJECTIVE: To develop the COVid Veteran (COVet) score for clinical deterioration in Veterans hospitalized with COVID-19 and further validate this model in both Veteran and non-Veteran samples. No such score has been derived and validated while incorporating a Veteran sample. DERIVATION COHORT: Adults (age ≥ 18 yr) hospitalized outside the ICU with a diagnosis of COVID-19 for model development to the Veterans Health Administration (VHA) (n = 80 hospitals). VALIDATION COHORT: External validation occurred in a VHA cohort of 34 hospitals, as well as six non-Veteran health systems for further external validation (n = 21 hospitals) between 2020 and 2023. PREDICTION MODEL: eXtreme Gradient Boosting machine learning methods were used, and performance was assessed using the area under the receiver operating characteristic curve and compared with the National Early Warning Score (NEWS). The primary outcome was transfer to the ICU or death within 24 hours of each new variable observation. Model predictor variables included demographics, vital signs, structured flowsheet data, and laboratory values. RESULTS: A total of 96,908 admissions occurred during the study period, of which 59,897 were in the Veteran sample and 37,011 were in the non-Veteran sample. During external validation in the Veteran sample, the model demonstrated excellent discrimination, with an area under the receiver operating characteristic curve of 0.88. This was significantly higher than NEWS (0.79; p < 0.01). In the non-Veteran sample, the model also demonstrated excellent discrimination (0.86 vs. 0.79 for NEWS; p < 0.01). The top three variables of importance were eosinophil percentage, mean oxygen saturation in the prior 24-hour period, and worst mental status in the prior 24-hour period. CONCLUSIONS: We used machine learning methods to develop and validate a highly accurate early warning score in both Veterans and non-Veterans hospitalized with COVID-19. The model could lead to earlier identification and therapy, which may improve outcomes.

Autologous transplant vs. CAR-T therapy in patients with DLBCL treated while in complete remission.

In patients with relapsed DLBCL in complete remission (CR), autologous hematopoietic cell transplantation (auto-HCT) and CAR-T therapy are both effective, but it is unknown which modality provides superior outcomes. We compared the efficacy of auto-HCT vs. CAR-T in patients with DLBCL in a CR. A retrospective observational study comparing auto-HCT (2015-2021) vs. CAR-T (2018-2021) using the Center for International Blood & Marrow Transplant Research registry. Median follow-up was 49.7 months for the auto-HCT and 24.7 months for the CAR-T cohort. Patients ages 18 and 75 with a diagnosis of DLBCL were included if they received auto-HCT (n = 281) or commercial CAR-T (n = 79) while in a CR. Patients undergoing auto-HCT with only one prior therapy line and CAR-T patients with a previous history of auto-HCT treatment were excluded. Endpoints included Progression-free survival (PFS), relapse rate, non-relapse mortality (NRM) and overall survival (OS). In univariate analysis, treatment with auto-HCT was associated with a higher rate of 2-year PFS (66.2% vs. 47.8%; p < 0.001), a lower 2-year cumulative incidence of relapse (27.8% vs. 48% ; p < 0.001), and a superior 2-year OS (78.9% vs. 65.6%; p = 0.037). In patients with early (within 12 months) treatment failure, auto-HCT was associated with a superior 2-year PFS (70.9% vs. 48.3% ; p < 0.001), lower 2-year cumulative incidence of relapse (22.8% vs. 45.9% ; p < 0.001) and trend for higher 2-year OS (82.4% vs. 66.1% ; p = 0.076). In the multivariable analysis, treatment with auto-HCT was associated with a superior PFS (hazard ratio 1.83; p = 0.0011) and lower incidence of relapse (hazard ratio 2.18; p < 0.0001) compared to CAR-T. In patients with relapsed LBCL who achieve a CR, treatment with auto-HCT is associated with improved clinical outcomes compared to CAR-T. These data support the consideration of auto-HCT in select patients with LBCL achieving a CR in the relapsed setting.

Microneurosurgery for Ruptured Aneurysm of Distal Intracranial Vertebral Artery: A Case Report.

The International Subarachnoid Aneurysm Trial led to a shift from clipping to endovascular coiling as the primary therapy for cerebral aneurysm particularly in the management of posterior circulation aneurysm. However, endovascular therapy is often unavailable in low-resource settings, emphasizing the importance of maintaining surgical skill sets in resource-poor countries. This article presents a detailed case report on the successful microneurosurgical management of a 65-year-old female with a history of headache and weakness with past history of hypertension and a right posterior cerebral artery territory infarct who was diagnosed with a ruptured aneurysm situated within the intracranial vertebral artery. Patient was operated with the far lateral approach and clipping of the aneurysm. This case report elucidates the intricate surgical techniques employed, and the challenges neurosurgeons encountered in treating posterior circulation intracranial aneurysms, particularly those with ruptured complications. The aneurysms' intricate anatomy and increased rupture risk necessitate a meticulous microneurosurgical approach. The severity of subarachnoid hemorrhage from ruptured aneurysms increases morbidity and mortality rates.

Pirtobrutinib, a highly selective, non-covalent (reversible) BTK inhibitor in patients with B-cell malignancies: analysis of the Richter transformation subgroup from the multicentre, open-label, phase 1/2 BRUIN study.

BACKGROUND: Richter transformation usually presents as an aggressive diffuse large B-cell lymphoma, occurs in up to 10% of patients with chronic lymphocytic leukaemia, has no approved therapies, and is associated with a poor prognosis. Pirtobrutinib has shown promising efficacy and tolerability in patients with relapsed or refractory B-cell malignancies, including those who progress on covalent Bruton tyrosine kinase (BTK) inhibitors. This study aims to report the safety and activity of pirtobrutinib monotherapy in a subgroup of patients with Richter transformation from the multicentre, open-label, phase 1/2 BRUIN study. METHODS: This analysis included adult patients (aged ≥18 years) with histologically confirmed Richter transformation, an Eastern Cooperative Oncology Group performance status score of 0-2, and no limit of previous therapies, with patients receiving first-line treatment added in a protocol amendment (version 9.0, Dec 15, 2021). Pirtobrutinib 200 mg was administered orally once a day in 28-day cycles. The primary endpoint of phase 1 of the BRUIN trial as a whole, which has been previously reported, was to establish the recommended phase 2 dose for pirtobrutinib monotherapy and the phase 2 primary endpoint was overall response rate. Safety and activity were measured in all patients who received at least one dose of pirtobrutinib monotherapy. This BRUIN phase 1/2 trial was registered with ClinicalTrials.gov and is closed to enrolment (NCT03740529). FINDINGS: Between Dec 26, 2019, and July 22, 2022, 82 patients were enrolled, of whom five were enrolled during phase 1 and 77 during phase 2. All but one patient received a starting dose of 200 mg pirtobrutinib once a day as the recommended phase 2 dose. The remaining patient received 150 mg pirtobrutinib once a day, which was not escalated to 200 mg. The median age of patients was 67 years (IQR 59-72). 55 (67%) of 82 patients were male and 27 (33%) were female. Most patients were White (65 [79%] of 82). 74 (90%) of 82 patients received at least one previous Richter transformation-directed therapy. Most patients (61 [74%] of 82) had received previous covalent BTK inhibitor therapy for chronic lymphocytic leukaemia or Richter transformation. The overall response rate was 50·0% (95% CI 38·7-61·3). 11 (13%) of 82 patients had a complete response and 30 (37%) of 82 patients had a partial response. Eight patients with ongoing response electively discontinued pirtobrutinib to undergo stem-cell transplantation. The most common grade 3 or worse adverse event was neutropenia (n=19). There were no treatment-related deaths. INTERPRETATION: Pirtobrutinib shows promising safety and activity among patients with Richter transformation, most of whom received previous Richter transformation-directed therapy, including covalent BTK inhibitors. These data suggest that further investigation is warranted of pirtobrutinib as a treatment option for patients with relapsed or refractory Richter transformation after treatment with a covalent BTK inhibitor. FUNDING: Loxo Oncology.

Beyond Brick and Mortar: The Rise of Street Medicine.

In 2023, approximately 650,000 people experienced homelessness (PEH) nightly in the United States, the highest number recorded in the country's history. This alarming statistic has made homelessness a key issue in the 2024 elections, especially with the White House's goal to reduce homelessness by 25% by 2025. Despite efforts and investments, homelessness remains a persistent public health challenge. The recent inclusion of street medicine services in Center for Medicare and Medicaid Services (CMS) billing codes represents a significant step forward. Street medicine, defined by CMS as healthcare provided in non-permanent locations to unsheltered individuals, now qualifies for Medicare reimbursement. This policy change, alongside state-level initiatives, aims to improve healthcare access for the unhoused, particularly older adults. However, challenges remain in establishing adequate fee schedules and integrating care management. Despite these obstacles, the integration of healthcare and housing services is crucial for addressing homelessness effectively, promoting stability, and improving health outcomes for PEH. This manuscript explores the history, practical guidance, and potential impacts of these developments on homelessness and public health.

Comparison of Patch Testing Results of White and Black Patients.

Patch testing is the standard diagnostic test used for patients presenting with symptoms of allergic contact dermatitis. The grading of patch test results classically varies from 1 to 3. The assessment of these results begins with a visual inspection of the presence of erythema, vesiculation, and induration. This leads to a subjectivity in visual evaluation of a patch test. Positive patch testing results can present differently in patients with darker skin tones. A greater variety of images of allergic contact dermatitis in patients with darker skin phototypes can better guide the diagnosis of this condition in skin of color. People with darker phototypes are historically underrepresented in dermatologic images and texts; thus, identifying erythema in darker phototypes may be more difficult for dermatologists, whether or not they were trained in areas of decreased phototype diversity. In this article, we present positive patch testing findings on several different phototypes, with the intention of contributing to images of phototypes underrepresented in dermatology literature.