BCR::ABL1 Kinase N-lobe Mutants Confer Moderate to High Degrees of Resistance to Asciminib.

Secondary kinase domain mutations in BCR::ABL1 represent the most common cause of resistance to tyrosine kinase inhibitor (TKI) therapy in chronic myeloid leukemia patients. The first five approved BCR::ABL1 TKIs target the ATP-binding pocket. Mutations confer resistance to these ATP-competitive TKIs and those approved for other malignancies by decreasing TKI affinity and/or increasing ATP affinity. Asciminib, the first highly active allosteric TKI approved for any malignancy, targets an allosteric regulatory pocket in the BCR::ABL1 kinase C-lobe. As a non-ATP-competitive inhibitor, the activity of asciminib is predicted to be impervious to increases in ATP affinity. Here we report several known mutations that confer resistance to ATP-competitive TKIs in the BCR::ABL1 kinase N-lobe that are distant from the asciminib binding pocket yet unexpectedly confer in vitro resistance to asciminib. Among these is BCR::ABL1 M244V, which confers clinical resistance even to escalated asciminib doses. We demonstrate that BCR::ABL1 M244V does not impair asciminib binding, thereby invoking a novel mechanism of resistance. Molecular dynamics simulations of the M244V substitution implicate stabilization of an active kinase conformation through impact on the -C helix as a mechanism of resistance. These N-lobe mutations may compromise the clinical activity of ongoing combination studies of asciminib with ATP-competitive TKIs.

Genomic ancestry in kidney cancer: Correlations with clinical and molecular features.

INTRODUCTION: Genetic ancestry (GA) refers to population hereditary patterns that contribute to phenotypic differences seen among race/ethnicity groups, and differences among GA groups may highlight unique biological determinants that add to our understanding of health care disparities. METHODS: A retrospective review of patients with renal cell carcinoma (RCC) was performed and correlated GA with clinicopathologic, somatic, and germline molecular data. All patients underwent next-generation sequencing of normal and tumor DNA using Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets, and contribution of African (AFR), East Asian (EAS), European (EUR), Native American, and South Asian (SAS) ancestry was inferred through supervised ADMIXTURE. Molecular data was compared across GA groups by Fisher exact test and Kruskal-Wallis test. RESULTS: In 953 patients with RCC, the GA distribution was: EUR (78%), AFR (4.9%), EAS (2.5%), SAS (2%), Native American (0.2%), and Admixed (12.2%). GA distribution varied by tumor histology and international metastatic RCC database consortium disease risk status (intermediate-poor: EUR 58%, AFR 88%, EAS 74%, and SAS 73%). Pathogenic/likely pathogenic germline variants in cancer-predisposition genes varied (16% EUR, 23% AFR, 8% EAS, and 0% SAS), and most occurred in CHEK2 in EUR (3.1%) and FH in AFR (15.4%). In patients with clear cell RCC, somatic alteration incidence varied with significant enrichment in BAP1 alterations (EUR 17%, AFR 50%, SAS 29%; p = .01). Comparing AFR and EUR groups within The Cancer Genome Atlas, significant differences were identified in angiogenesis and inflammatory pathways. CONCLUSION: Differences in clinical and molecular data by GA highlight population-specific variations in patients with RCC. Exploration of both genetic and nongenetic variables remains critical to optimize efforts to overcome health-related disparities.

Implementation of a National Liver Review Board for exception requests in the United States: A 2-year monitoring report.

The exception point system for liver allocation in the United States allows for additional waitlist priority for candidates where the Model for End-Stage Liver Disease or Pediatric End-stage Liver Disease does not effectively represent their urgency or need for a transplant. In May 2019, the review process for liver exception cases transitioned from 11 Regional Review Boards (RRBs) to 1 National Liver Review Board (NLRB), intended to increase consistency nationwide, improve efficiency, and balance transplant access for candidates with and without exception scores. This report provides a review of liver exception request and review practices, waitlist outcomes, and transplant activity in the first 2 years after implementation of the NLRB and acuity circle-based distribution in the United States. We compared initial and extension exception request forms submitted from May 13, 2017 to May 13, 2019 (prepolicy or RRB era) to the period from February 4, 2020 to February 3, 2022 (postpolicy or NLRB era). During this time, the NLRB reviewed 10,083 initial exception requests and 12,686 extension requests. Notable postpolicy highlights include (1) an increase in the proportion of initial and extension requests that were automatically approved instead of manually reviewed; (2) a decrease in the overall approval rates of initial exception requests (87.8% for adult HCC, 64.3% for adult other diagnoses, and 71.5% for pediatric); and (3) reduction in the time from exception request submission to adjudication to a median of 3.73 days. The proportions of waitlist registration and deceased donor liver transplants for patients with exception scores decreased, and waitlist outcomes between patients with and without exception scores are now comparable. Implementation of the NLRB improved efficiency, reduced case workloads, and standardized criteria for exception cases, with similar waitlist outcomes between patients with and without exception scores and improved equity in terms of access to liver transplants.

Chronic Myeloid Leukemia, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology.

Chronic myeloid leukemia (CML) is defined by the presence of Philadelphia chromosome resulting from a reciprocal translocation between chromosomes 9 and 22 [t9;22] that gives rise to a BCR::ABL1 fusion gene. CML occurs in 3 different phases (chronic, accelerated, and blast phase) and is usually diagnosed in the chronic phase in developed countries. Tyrosine kinase inhibitor (TKI) therapy is a highly effective treatment option for patients with chronic phase-CML. The primary goal of TKI therapy in patients with chronic phase-CML is to prevent disease progression to accelerated phase-CML or blast phase-CML. Discontinuation of TKI therapy with careful monitoring is feasible in selected patients. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with chronic phase-CML.

N-(3-Methoxyphenyl)-6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)pyridin-2-amine is an inhibitor of the FLT3-ITD and BCR-ABL pathways, and potently inhibits FLT3-ITD/D835Y and FLT3-ITD/F691L secondary mutants.

Activating mutations within FLT3 make up 30 % of all newly diagnosed acute myeloid leukemia (AML) cases, with the most common mutation being an internal tandem duplication (FLT3-ITD) in the juxtamembrane region (25 %). Currently, two generations of FLT3 kinase inhibitors have been developed, with three inhibitors clinically approved. However, treatment of FLT3-ITD mutated AML is limited due to the emergence of secondary clinical resistance, caused by multiple mechanism including on-target FLT3 secondary mutations - FLT3-ITD/D835Y and FLT3-ITD/F691L being the most common, as well as the off-target activation of alternative pathways including the BCR-ABL pathway. Through the screening of imidazo[1,2-a]pyridine derivatives, N-(3-methoxyphenyl)-6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)pyridin-2-amine (compound 1) was identified as an inhibitor of both the FLT3-ITD and BCR-ABL pathways. Compound 1 potently inhibits clinically related leukemia cell lines driven by FLT3-ITD, FLT3-ITD/D835Y, FLT3-ITD/F691L, or BCR-ABL. Studies indicate that it mediates proapoptotic effects on cells by inhibiting FLT3 and BCR-ABL pathways, and other possible targets. Compound 1 is more potent against FLT3-ITD than BCR-ABL, and it may have other possible targets; however, compound 1 is first step for further optimization for the development of a balanced FLT3-ITD/BCR-ABL dual inhibitor for the treatment of relapsed FLT3-ITD mutated AML with multiple secondary clinical resistant subtypes such as FLT3-ITD/D835Y, FLT3-ITD/F691L, and cells co-expressing FLT3-ITD and BCR-ABL.

The impact of asymptomatic human immunodeficiency virus (HIV)-positive disease status on inpatient complications following total joint arthroplasty: a propensity score-matched analysis.

PURPOSE: The number of patients with asymptomatic human immunodeficiency virus (AHIV) is increasing as the efficacy of antiretroviral therapy improves. While there is research on operative risks associated with having HIV, there is a lack of literature describing the impact of well-controlled HIV on postoperative complications. This study seeks to elucidate the impact of AHIV on postoperative outcomes after total hip (THA) and knee (TKA) arthroplasty. METHODS: The Nationwide Inpatient Sample was retrospectively reviewed for patients undergoing TKA and THA from 2005 to 2013. Subjects were subdivided into those with AHIV and those without HIV (non-HIV). Patient demographics, hospital-related parameters, and postoperative complications were all collected. One-to-one propensity score-matching, Chi-square analysis, and multivariate logistical regressions were performed to compare both cohorts. RESULTS: There were no significant differences between AHIV and non-HIV patients undergoing TKA or THA in terms of sex, age, insurance status, or total costs (all, p ≥ 0.081). AHIV patients had longer lengths of stay (4.0 days) than non-HIV patients after both TKA (3.3 days) and THA (3.1 days) (p ≤ 0.011). Both TKA groups had similar postoperative complication rates (p > 0.081). AHIV patients undergoing THA exhibited an increased rate of overall surgical complications compared non-HIV patients (0 vs. 4.5%, p = 0.043). AHIV was not associated with increased complications following both procedures. CONCLUSION: Despite lengthier hospital stays among AHIV patients, baseline AHIV was not associated with adverse outcomes following TKA and THA. This adds to the literature and warrants further research into the impact of asymptomatic, well-controlled HIV infection on postoperative outcomes following total joint arthroplasty.

The impact of immunosuppressive agents on immune checkpoint inhibitor efficacy in patients with advanced melanoma: A real-world, multicenter, retrospective study.

BACKGROUND: Immune-related adverse events (irAEs) associated with immune checkpoint inhibitors (ICIs) are often managed via immunosuppressive agents (ISAs); however, their impact on ICI efficacy is not well studied. The impact of the use of ISAs on ICI efficacy in patients with advanced melanoma was therefore investigated. METHODS: This is a real-world, multicenter, retrospective cohort study of patients with advanced melanoma who received ICIs (n = 370). Overall survival (OS) and time to treatment failure (TTF) from the time of ICI initiation were compared among patients in subgroups of interest by unadjusted and 12-week landmark sensitivity-adjusted analyses. The association of irAEs and their management with OS and TTF were evaluated using univariate and multivariable Cox proportional hazards regression models. RESULTS: Overall, irAEs of any grade and of grade ≥3 occurred in 57% and 23% of patients, respectively. Thirty-seven percent of patients received steroids, and 3% received other ISAs. Median OS was longest among patients receiving both (not reached [NR]), shorter among those receiving only systemic steroids (SSs) (84.2 months; 95% CI, 40.2 months to NR), and shortest among those who did not experience irAEs (10.3 months; 95% CI, 6-20.1 months) (p < .001). Longer OS was significantly associated with the occurrence of irAEs and the use of SSs with or without ISAs upon multivariable-adjusted analysis (p < .001). Similar results were noted with anti-programmed death 1 (PD-1) monotherapy and combination anti-PD-1 plus anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) therapy, and with 12-week landmark sensitivity analysis (p = .01). CONCLUSIONS: These findings in patients with melanoma who were treated with ICIs suggest that the use of SSs or ISAs for the management of irAEs is not associated with inferior disease outcomes, which supports the use of these agents when necessary.

Treatment-free remission after dasatinib in patients with chronic myeloid leukaemia in chronic phase with deep molecular response: Final 5-year analysis of DASFREE.

Patients with chronic myeloid leukaemia in chronic phase (CML-CP) who have a sustained deep molecular response (DMR) are eligible to discontinue treatment and attempt treatment-free remission (TFR). In the DASFREE study (ClinicalTrials.gov; NCT01850004), the 2-year TFR rate after dasatinib discontinuation was 46%; here we present the 5-year update. Patients with a stable DMR after ≥2 years of dasatinib therapy discontinued treatment and were followed for 5 years. At a minimum follow-up of 60 months, in 84 patients discontinuing dasatinib, the 5-year TFR rate was 44% (n = 37). No relapses occurred after month 39 and all evaluable patients who relapsed and restarted dasatinib (n = 46) regained a major molecular response in a median of 1.9 months. The most common adverse event during the off-treatment period was arthralgia (18%, 15/84); a total of 15 withdrawal events were reported in nine patients (11%). At the 5-year final follow-up, almost half of the patients who discontinued dasatinib after a sustained DMR maintained TFR. All evaluable patients who experienced a relapse quickly regained a DMR after restarting dasatinib, demonstrating that dasatinib discontinuation is a viable and potentially long-term option in patients with CML-CP. The safety profile is consistent with the previous report.

Drawing: A Dialogue across Disciplines.

There are many examples of a cross pollination between those involved in the arts and in the field of health care. This fruitful dialogue has resulted in the production of impressive artwork across many genres and given opportunities for the development of collaborative projects. Although advanced technologies have become more prevalent in clinics, wards and operating theatres, drawing activities continue to be a significant means of recording observations, communication and planning as well as a methodology for teaching and learning. Interdisciplinary creative projects reveal the continued importance of drawing as a central, primal activity both as part of a purposeful dialogue and also as a useful tool to encourage active participation in teaching and learning. Other studies continue to show drawing activities to be an excellent tool for developing skills in observation and communication, useful for improving the physical and psychological support for individual patients.

The impact of surgical trainee involvement in total knee arthroplasty: a systematic review of surgical efficacy, patient safety, and outcomes.

PURPOSE: Trainee involvement in patient care has raised concerns about the potential risk of adverse outcomes and harming patients. We sought to analyze the impact and potential consequence of surgical trainee involvement in total knee arthroplasty (TKA) procedures in terms of surgical efficacy, patient safety, and functional outcomes. METHODS: We systematically reviewed Medline/PubMed, EMBASE, the Cochrane library, and Scopus databases in April 2021. Eligible studies reported on the impact of trainee participation in TKA procedures performed with and without such involvement. RESULTS: Twenty-three publications met our eligibility criteria and were included in our study. These studies reported on 132,624 surgeries completed on 132,416 patients. Specifically, 23,988 and 108,636 TKAs were performed with and without trainee involvement, respectively. The mean operative times for procedures with (n = 19,573) and without (n = 94,581) trainee involvement were 99.77 and 85.05 min, respectively. Both studies that reported data on cost of TKAs indicated a significant increase (p < 0.001) associated with procedures completed by teaching hospitals compared to private practices. Mean overall complication rates were 7.20% and 7.36% for TKAs performed with (n = 9,386) and without (n = 31,406) trainees. Lastly, the mean Knee Society Scale (KSS) knee scores for TKAs with (n = 478) and without (n = 806) trainee involvement were similar; 82.81 and 82.71, respectively. CONCLUSION: Our systematic review concurred with previous studies that reported trainee involvement during TKAs increases the mean operative time. However, the overall complication rates and functional outcomes were similar. Larger studies with a better methodology and higher level of evidence are still needed for a resolute conclusion.

The impact of surgical trainee involvement in total hip arthroplasty: a systematic review of surgical efficacy, patient safety, and outcomes.

PURPOSE: Concerns persist that trainee participation in surgical procedures may compromise patient care and potentiate adverse events and costs. We aimed to analyse the potential impact and consequences of surgical trainee involvement in total hip arthroplasty (THA) procedures in terms of surgical efficacy, patient safety, and functional outcomes. METHODS: We systematically reviewed Medline/PubMed, EMBASE, the Cochrane library, and Scopus databases in October 2021. Eligible studies reported a direct comparison between THA cases performed with and without trainee involvement. RESULTS: Eighteen publications met our eligibility criteria and were included in our study. The included studies reported on 142,450 THAs completed on 142,417 patients. Specifically, 48,155 and 94,295 surgeries were completed with and without trainee involvement, respectively. The mean operative times for procedures with (n = 5,662) and without (n = 14,763) trainee involvement were 106.20 and 91.41 min, respectively. Mean overall complication rates were 6.43% and 5.93% for THAs performed with (n = 4842) and without (n = 12,731) trainees. Lastly, the mean Harris Hip Scores (HHS) for THAs performed with (n = 442) and without (n = 750) trainee participation were 89.61 and 86.97, respectively. CONCLUSION: Our systematic review confirmed previous studies' reports of increased operative time for THA cases with trainee involvement. However, based on the overall similar complication rates and functional hip scores obtained, patients should be reassured concerning the relative safety of trainee involvement in THA. Future prospective studies with higher levels of evidence are still needed to reinforce the existing evidence.

A call to "own the bone": osteoporosis is a predictor for adverse two-year outcomes following total hip and knee arthroplasty.

PURPOSE: While bone health is instrumental in orthopedic surgery, few studies have described the long-term outcomes of osteoporosis (OP) in patients undergoing total hip (THA) or knee (TKA) arthroplasties. METHODS: Using the New York State statewide planning and research cooperative system database, all patients who underwent primary TKA or THA for osteoarthritis from 2009 to 2011 with minimum 2-year follow-up were identified. They were divided based on their OP status (OP and non-OP) and 1:1 propensity score matched for age, sex, race, and Charlson/Deyo index. Cohorts were compared for demographics, hospital-related parameters, and 2-year postoperative complications and reoperations. Multivariate binary logistic regression was utilized to identify significant independent associations with 2-year medical and surgical complications and revisions. RESULTS: A total of 11,288 TKA and 8248 THA patients were identified. OP and non-OP TKA patients incurred comparable overall hospital charges for their surgical visit and hospital length of stay (LOS) (both, p ≥ 0.125). Though OP and non-OP THA patients incurred similar mean hospital charges for their surgical visit, they experienced longer hospital LOS (4.3 vs. 4.1 days, p = 0.035). For both TKA and THA, OP patients had higher rates of overall and individual medical and surgical complications (all, p < 0.05). OP was independently associated with the 2-year occurrence of any overall, surgical, and medical complications, and any revision in TKA and THA patients (all, OR ≥ 1.42, p < 0.001). CONCLUSION: Our study found OP was associated with a greater risk of 2-year adverse outcomes following TKA or THA, including medical, surgical, and overall complications as well as revision operations compared to non-OP patients.

Patient- and physician-reported pain after tyrosine kinase inhibitor discontinuation among patients with chronic myeloid leukemia.

For patients with optimally treated chronic myeloid leukemia (CML), discontinuation of tyrosine kinase inhibitor (TKI) therapy can lead to treatment-free remission. In previous trials, TKI discontinuation has been associated with increased musculoskeletal pain in some patients ("withdrawal syndrome"), based on physician-reported adverse events (AE). Patient-reported pain has not been described. The Life After Stopping TKI study was a 14-site prospective, non-randomized clinical trial of TKI discontinuation. We defined increased pain after discontinuation as: (i) a physician-reported pain AE, (ii) a 2-level increase in self-reported musculoskeletal pain (4-level single item), or (iii) initiation of a medication for pain. We plotted the trajectory of patient-reported pain over time using a piecewise mixed-effects ordinal logistic model. Within 3 months of discontinuation, 35 of 172 patients (20.3%) had a physician-reported pain AE, 22 of 172 (12.8%) had an increase in self-reported pain, and 18 of 154 (11.7%) initiated a pain medication. Agreement among these measures was limited; overall, 60 of 172 patients (34.9%) had increased pain. Three patients (1.7%) restarted a TKI because of pain. The modelpredicted trajectory showed an increase in pain in the first 3 months followed by a decrease, returning to baseline levels by 6 months and further decreasing after that. This trajectory was similar among patients who did and did not restart TKI, suggesting that resuming a TKI for withdrawal syndrome may be necessary for some, but other approaches to manage pain should be tried so that patients can remain in treatment-free remission when possible.

The Risk of Opportunistic Infections and the Role of Antibiotic Prophylaxis in Patients on Checkpoint Inhibitors Requiring Steroids.

BACKGROUND: Immune-related adverse events (irAEs) often require treatment with high-dose systemic steroids (SS) and other immunosuppressive agents (ISAs). NCCN Guidelines recommend prophylactic antibiotics for Pneumocystis jirovecii pneumonia (PJP) for patients receiving prolonged SS/ISAs. However, there is a paucity of evidence regarding the incidence of opportunistic infections (OIs) and non-OIs and the role of prophylactic antibiotics in patients on SS/ISAs for irAEs. METHODS: A retrospective analysis was conducted of patients treated using immune checkpoint inhibitor (ICI) therapy at 5 MedStar Health hospitals from January 2011 to April 2018. OIs were defined per the Infectious Diseases Society of America guidelines for the prevention and treatment of OIs in patients with HIV. The study cohort included patients who received ≥20 mg daily of a prednisone equivalent for ≥4 weeks to manage irAEs. RESULTS: The study cohort identified 112 (15%) of 758 total patients treated using ICIs. Baseline characteristics included the following: median age was 64 years, 74% (n=82) of patients were White, 89% (n=100) had an ECOG performance status ≤1, 61% (n=68) had melanoma, 19% (n=21) had non-small cell lung cancer, 45% (n=50) were treated using an anti-PD-(L)1 ICI, and 33% (n=37) were treated using an anti-PD-1/anti-CTLA-4 combination. The median starting SS dose was 100 mg of a prednisone equivalent, and 25% of patients required additional ISAs, with infliximab (n=15) and mycophenolate mofetil (n=9) being the most common. We found that 20% (n=22) of patients developed any infection, including 7% (n=8) with OIs (oral candidiasis [n=4], nondisseminated varicella zoster infection [n=2], PJP [n=1], and Listeria monocytogenes endophthalmitis [n=1]) and 13% (n=14) with non-OIs (most common: Clostridium difficile and pneumonia [n=5 each]). PJP prophylaxis with sulfamethoxazole/trimethoprim was given to 13% (n=14) patients, of whom 43% (n=6) developed OIs/non-OIs. CONCLUSIONS: Our study highlights the fundamental issues for patients on ICI therapy who require SS/ISAs for irAEs: the degree of immunosuppression and the relative risk of OI. We noted a low incidence of OIs overall and breakthrough infections despite PJP prophylaxis. We question whether PJP prophylaxis is efficacious or necessary. Prospective trials are required to answer these questions.

A randomized study of a best practice alert for platelet transfusions.

BACKGROUND AND OBJECTIVES: Inappropriate platelet transfusions represent an opportunity for improvements in patient care. Use of a best practice alert (BPA) as clinical decision support (CDS) for red cell transfusions has successfully reduced unnecessary red blood cell (RBC) transfusions in prior studies. We studied the impact of a platelet transfusion BPA with visibility randomized by patient chart. MATERIALS AND METHODS: A BPA was built to introduce CDS at the time of platelet ordering in the electronic health record. Alert visibility was randomized at the patient encounter level. BPA eligible platelet transfusions for patients with both visible and non-visible alerts were recorded along with reasons given for override of the BPA. Focused interviews were performed with providers who interacted with the BPA to assess its impact on their decision making. RESULTS: Over a 9-month study period, 446 patient charts were randomized. The visible alert group used 25.3% fewer BPA eligible platelets. Mean monthly usage of platelets eligible for BPA display was 65.7 for the control group and 49.1 for the visible alert group (p = 0.07). BPA-eligible platelets used per inpatient day at risk per month were not significantly different between groups (2.4 vs. 2.1, p = 0.53). CONCLUSION: It is feasible to study CDS via chart-based randomization. A platelet BPA reduced total platelets used over the study period and may have resulted in $151,069 in yearly savings, although there were no differences when adjusted for inpatient days at risk. During interviews, providers offered additional workflow insights allowing further improvement of CDS for platelet transfusions.

Ponatinib after failure of second-generation tyrosine kinase inhibitor in resistant chronic-phase chronic myeloid leukemia.

Ponatinib, the only third-generation pan-BCR::ABL1 inhibitor with activity against all known BCR::ABL1 mutations including T315I, has demonstrated deep and durable responses in patients with chronic-phase chronic myeloid leukemia (CP-CML) resistant to prior second-generation (2G) TKI treatment. We present efficacy and safety outcomes from the Ponatinib Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) and CML Evaluation (PACE) and Optimizing Ponatinib Treatment in CP-CML (OPTIC) trials for this patient population. PACE (NCT01207440) evaluated ponatinib 45 mg/day in CML patients with resistance to prior TKI or T315I. In OPTIC (NCT02467270), patients with CP-CML and resistance to ≥2 prior TKIs or T315I receiving 45 or 30 mg/day reduced their doses to 15 mg/day upon achieving ≤1% BCR::ABL1IS or received 15 mg/day continuously. Efficacy and safety outcomes from patients with CP-CML treated with ≥1 2G TKI (PACE, n = 257) and OPTIC (n = 93), 45-mg starting dose cohort, were analyzed for BCR::ABL1IS response rates, overall survival (OS), progression-free survival (PFS), and safety. By 24 months, the percentages of patients with ≤1% BCR::ABL1IS response, PFS, and OS were 46%, 68%, and 85%, respectively, in PACE and 57%, 80%, and 91%, respectively, in OPTIC. Serious treatment-emergent adverse events and serious treatment-emergent arterial occlusive event rates were 63% and 18% in PACE and 34% and 4% in OPTIC. Ponatinib shows high response rates and robust survival outcomes in patients whose disease failed prior to 2G TKIs, including patients with T315I mutation. The response-based dosing in OPTIC led to improved safety and similar efficacy outcomes compared with PACE.

Male Youth Ice Hockey Concussion Incidence in a USA Hockey Membership-Adjusted Population: A Peak in 2011 and the Impact of Major Rule Changes.

OBJECTIVE: To investigate the incidence of youth ice hockey-related concussions preceding and following the implementation of new body-checking and head contact rules by USA hockey in 2011. We hypothesized a decrease in concussions after the rule change. DESIGN: Retrospective analysis. SETTING: United States emergency department (ED) data queried in the National Electronic InjurySurveillance System (NEISS). PATIENTS: National Electronic Injury Surveillance System reported male youth (≤18 years) ice hockey concussion cases from January 1, 2002, to December 31, 2016. In total, 848 players were diagnosed with concussion, representing a national estimate of 17 374 cases. INDEPENDENT VARIABLES: Time, specifically years. MAIN OUTCOME MEASURES: Incidences and incidence rates (measured per 10 000 person-years) of male youth ice hockey concussions. Annual trends were analyzed using descriptive and linear or polynomial regression analysis. RESULTS: The national estimate of youth ice hockey-related concussions seen in US emergency departments (EDs) increased significantly from 656 in 2007 to 2042 in 2011 (P < 0.01). During the same period, their respective incidence increased significantly from 21.8 to 66.8 per 10 000, before dropping through 2016 (P < 0.05). After 2011, concussions decreased from 1965 in 2012 to 1292 in 2016 (P = 0.055). The gap in concussion incidence between the 11 to 12 and 13 to 14 divisions widened after 2011 (before 2011: 41 vs 49 per 10 000 person-years [P = 0.80]; after 2011: 45 and 89, respectively [P < 0.01]). CONCLUSIONS: US EDs experienced a significant increase in youth ice hockey concussion visits from 2007 to 2011. After the 2011 rule changes, concussion visits decreased significantly from 2012 to 2016.

Evaluating program planning using an equity framework.

To plan for an expansion of healthcare services in newly developed neighbourhoods, a planning initiative was conducted to better understand the needs of the population. Ensuring equity of care was identified as a priority for this initiative. To evaluate how closely the planning adhered to the principles of health equity, we applied Ontario Health's Equity, Inclusion, Diversity, and Anti-Racism Framework to determine which areas of action were successfully addressed, and which areas of action require further focus. The framework contains 11 components, each delineating a key area of action. Using this framework helped identify areas where the principles of equity were well addressed, as well as pointing to additional areas where further efforts are required. Healthcare organizations must take a leadership role in advancing health equity by planning, delivering, improving, and advocating for the services and systematic changes that will allow its local community members to realize their highest attainable standard of health. Using such a framework can help develop strategic approaches to advancing equity.

Trends and epidemiology of radial head subluxation in the United States from 2004 to 2018.

BACKGROUND: Increased body mass may predispose children to a greater risk for radial head subluxation (RHS). Recent studies in the literature have reported a plateau in obesity prevalence among infants and toddlers. This study sought to examine recent epidemiological trends in RHS incidence from 2004 to 2018 using the National Electronic Injury Surveillance System database to determine how obesity patterns may affect RHS incidence. METHODS: The National Electronic Injury Surveillance System (NEISS) database was queried for patients 6 years of age or younger presenting with radial head subluxation between January 1, 2004 and December 31, 2018. Patient demographics, mechanisms of injury, and location of injury were recorded. RESULTS: An estimated total 253,578 children 6 years or younger were treated for RHS with 14,204 (95% CI = 8124-20,284) in 2004 to 21,408 (95% CI = 12,882-29,934) in 2018. The overall annual rate of RHS per 10,000 children ≤ 6 years was 6.03 (95% CI = 4.85-7.58). The annual rate of RHS per 10,000 children ≤ 6 years increased (m = 0.200, ß = 0.802, p < 0.001) from 5.18 (95% CI 2.96-7.39) in 2004 to 7.69 (95% CI = 4.63-10.75) in 2018. The most common mechanism associated with RHS was falls (39.4%) with 103,466 (95% CI 74,806-132,125) cases. Pulls accounted for the second most common mechanism of injury, accounting for 90,146 (95% CI 68,274-112,018) cases or 36.2%. Yearly RHS incidence was compared to obesity prevalence for ages 2-5 children provided by the National Health and Nutritional Examination Survey (NHANES) surveys. Changes in obesity prevalence may visually reflect RHS incidence trends, but no causality between obesity prevalence and RHS incidence could be confirmed. CONCLUSION: This study corroborated previous findings that falls and arm pulling contribute to the vast majority of RHS cases. The nonsignificant rise in RHS cases may reflect a possible plateau in obesity prevalence of children aged 2-5 years in recent years. LEVEL OF EVIDENCE: III.

Venetoclax combines synergistically with FLT3 inhibition to effectively target leukemic cells in FLT3-ITD+ acute myeloid leukemia models.

FLT3 internal tandem duplication (FLT3-ITD) mutations account for ~25% of adult acute myeloid leukemia cases and are associated with poor prognosis. Venetoclax, a selective BCL-2 inhibitor, has limited monotherapy activity in relapsed/refractory acute myeloid leukemia with no responses observed in a small subset of FLT3-ITD+ patients. Further, FLT3-ITD mutations emerged at relapse following venetoclax monotherapy and combination therapy suggesting a potential mechanism of resistance. Therefore, we investigated the convergence of FLT3-ITD signaling on the BCL-2 family proteins and determined combination activity of venetoclax and FLT3-ITD inhibition in preclinical models. In vivo, venetoclax combined with quizartinib, a potent FLT3 inhibitor, showed greater anti-tumor efficacy and prolonged survival compared to monotherapies. In a patient-derived FLT3-ITD+ xenograft model, cotreatment with venetoclax and quizartinib at clinically relevant doses had greater anti-tumor activity in the tumor microenvironment compared to quizartinib or venetoclax alone. Use of selective BCL-2 family inhibitors further identified a role for BCL-2, BCL-XL and MCL-1 in mediating survival in FLT3-ITD+ cells in vivo and highlighted the need to target all three proteins for greatest anti-tumor activity. Assessment of these combinations in vitro revealed synergistic combination activity for quizartinib and venetoclax but not for quizartinib combined with BCL-XL or MCL-1 inhibition. FLT3-ITD inhibition was shown to indirectly target both BCL-XL and MCL-1 through modulation of protein expression, thereby priming cells toward BCL-2 dependence for survival. These data demonstrate that FLT3-ITD inhibition combined with venetoclax has impressive anti-tumor activity in FLT3-ITD+ acute myeloid leukemia preclinical models and provides strong mechanistic rational for clinical studies.