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PURPOSE Ziftomenib—a potent, highly selective, oral menin inhibitor—was well tolerated and demonstrated encouraging clinical activity as monotherapy for relapsed/refractory NPM1 -mutated ( NPM1 -m) and KMT2A -rearranged AML in the KOMET-001 phase I trial. METHODS In the registration-enabling phase II part of KOMET-001, patients with relapsed/refractory NPM1 -m AML received ziftomenib 600 mg once daily. The primary end point was the rate of complete remission with full hematologic recovery (CR)/CR with partial hematologic recovery (CRh). RESULTS From January 26, 2023, to May 13, 2024, 92 patients (median age, 69 years [range, 33-84]) were treated. The primary end point was met, with a CR/CRh rate of 22% (95% CI, 14 to 32; P = .0058); 61% were negative for measurable residual disease. Overall response rate was 33% (95% CI, 23 to 43), with a median duration of 4.6 months (95% CI, 2.8 to 7.4). Prespecified subgroup analyses showed comparable CR/CRh regardless of previous therapy, including venetoclax, or type of comutations. Median overall survival was 6.6 months (95% CI, 3.6 to 8.6). Common grade ≥3 treatment-emergent adverse events were febrile neutropenia (26%), anemia (20%), and thrombocytopenia (20%). Differentiation syndrome occurred in 25% of patients (15% grade 3; no grade 4-5) and was manageable with protocol-defined mitigation. Three patients (3%) discontinued treatment because of ziftomenib-related adverse events. CONCLUSION Ziftomenib demonstrated significant clinical benefit and deep responses in patients with heavily pretreated, relapsed/refractory NPM1 -m AML. Ziftomenib was well tolerated with a safety profile consistent with previous studies, including manageable differentiation syndrome, lack of clinically significant QTc prolongation, and low rates of myelosuppression.

Abstract Matrix-producing tumors of the sinonasal region are diagnostically challenging, with a large number of similar-appearing neoplasms having different prognoses, treatment strategies, and genetic syndrome associations. Osteochondromyxoma (OCM) is a very rare tumor known to be associated with Carney complex. Since its initial description in 2001, fewer than 20 cases have been reported, with the sinonasal tract being an apparently favored site. Herein we describe 6 new cases of sinonasal OCM.OCM cases with available slides were retrieved from the surgical pathology files of the authors’ practices. The tumors arose in 4 boys and 2 girls, ranging from 4 to 17 years (mean, 9.5 years). All presented with nasal obstruction and a mass. Radiologically the tumors presented as indolent-appearing, heterogeneous, calcified, expansile masses. Histologically the tumors all consisted of bland, normochromatic spindled to stellate cells in a myxoid to collagenized stroma, with variable amounts of cartilage and bone formation. Mitotic activity was very low and necrosis was absent. All demonstrated complete loss of PRKAR1A expression by immunohistochemistry. Of these 6 cases, 3 had been originally diagnosed as nasal chondromesenchymal hamartomas, and one as osteosarcoma. Treatment and follow up information were available for 5 patients: all were treated with surgery, with one also receiving chemotherapy after an initial osteosarcoma diagnosis. At the time of last clinical follow-up, all 5 patients were alive, one with residual disease. No patient was known to have other stigmata of Carney complex.Although rare, OCM preferentially occurs in the sinonasal tract, and therefore may be encountered by head and neck pathologists. Given their predilection for young patients and overlapping morphologic features, OCM are easily misdiagnosed as other matrix-forming sinonasal tumors, especially nasal chondromesenchymal hamartoma. Immunohistochemical demonstration of PRKAR1A loss is valuable for confirming an OCM diagnosis, which should prompt clinical investigation for the possibility of Carney complex.

Background Intracranial occlusions in embolic stroke of undetermined source are histopathologically similar to cardiac sources of embolism. Whether patients with embolic stroke of undetermined source and intracranial occlusion benefit from anticoagulation is unknown. Methods A multicenter retrospective cohort of adults with cryptogenic stroke was queried for patients with proximal or medium/distal vessel occlusion. The primary outcome was recurrent ischemic stroke, which was assessed in unadjusted and adjusted Cox proportional hazards models and repeated following 1:1 propensity score matching and biweight kernel density matching. Results Of the 2328 patients who were followed over a median of 1.31 years (interquartile range, 0.34–2.85), 999 (42.6%) had an intracranial occlusion. When compared with patients without an intracranial occlusion, those with an occlusion had fewer atherosclerotic vascular risk factors, more severe symptoms, and less severe cerebral microvascular disease. The rate of recurrent stroke was similar between patients with versus without an intracranial occlusion (6.8%/year [95% CI, 5.7–8.2] versus 7.0%/year [95% CI 6.0–8.1]; adjusted hazard ratio [HR], 1.09 [95% CI, 0.77–1.55]). There was no association between occlusion and recurrent stroke in the adjusted propensity score matching (HR, 1.01 [95% CI, 0.64–1.59]) or kernel density models (HR, 0.95 [95% CI, 0.62–1.45]). There was no interaction between occlusion and treatment with anticoagulation, sex, age, or high‐risk sources of embolism for the primary outcome in the unmatched and matched analyses. Conclusions Intracranial occlusion in patients with embolic stroke of undetermined source is not associated with a greater risk of recurrence when compared with patients without an intracranial occlusion. There was no difference in rate of recurrent stroke with anticoagulation when stratified by presence or absence of occlusion.

Introduction Male circumcision (MC) has been shown to decrease transmission of HIV and is a critical strategy to decrease its incidence in countries with high rates of heterosexually transmitted HIV. Early infant MC (EIMC), with single-use MC devices, could increase rates of MC in Sub-Saharan Africa. Our objective was to determine the safety, efficacy and satisfaction of ShangRing EIMC in resource-constrained environments. Methods Healthy male infants aged 1–60 days underwent ShangRing EIMC performed by non-physician clinicians in 14 sites in Kenya, Tanzania and Uganda. The primary outcomes were the safety and efficacy of ShangRing EIMC. Secondary outcomes were pain related to the procedure, wound healing and parental satisfaction. Male infants were assessed at discharge and on postoperative days 7 and 28 for wound healing and complications. This trial is registered with Clinical.Trials.gov, NCT03338699 , and is complete. Results From the 1697 participants enrolled from February to November 2020, 1691 (99.6%) underwent ShangRing EIMC. Median duration of the procedure was 10 min (IQR 6–13). The mean Neonatal Infant Pain Scale 20 min postprocedure was 0.3 (SD 0.8), indicating no pain. At the time of discharge, 1679 (99.0%) participants had a normal-appearing wound and 1574 (93.1%) demonstrated complete wound healing at 28 days. A total of 17 (1.0%) AEs were reported, most related to bleeding. A total of 1635 (99.1%) of parents were satisfied with the appearance of the circumcised penis at 28 days. Conclusion ShangRing EIMC is a simple and successful MC method that non-physician clinicians can perform safely, with low AE rate, satisfactory wound healing and high satisfaction rate among parents. This indicates that the ShangRing EIMC can be considered a long-term strategic approach to accelerate the scale-up of MC in Sub-Saharan Africa. Trial registration number NCT03338699 .

Objectives: Electronic health records (EHR)-based triggers (eTriggers) have been used to study diagnostic errors in the emergency department (ED), often with suboptimal performance. Our objective was to investigate incremental value of multi-factor machine learning (ML) approaches to improve eTrigger performance. Methods: Patients presenting to an academic ED were categorized into trigger-positive and trigger-negative using standard trigger (T) definitions: (T1) ED return visits resulting in admission within 10 days; (T2) care escalation from the inpatient unit to the ICU within 24 hours; and (T3) deaths within 24 hours of admission. We trained and evaluated 6 supervised ML models. Results: A total of 124,053 consecutive encounters (5791 T-positive and 118,262 T-negative) were included. Among the T-positive, 4159 (72%) were associated with T1, 1415 (24%) with T2, and 217 (4%) with T3. The T-based positive predictive values (PPV) were 5.2% for T1, 8.2% for T2, and 6.5% for T3. ML models trained and evaluated on balanced training dataset and imbalanced test set had low classification performances (accuracy: 0.72–0.95; PPV: 0.00–0.16; F1-score: 0.00–0.23). Higher performances were observed in balanced test sets (accuracy: 0.80–0.97; PPV: 0.82–1.00; F1-score: 0.79–0.97). Comparing models trained on clinically annotated data with models trained on T-based labels identified other important factors. Conclusions: Utilizing machine learning to refine e-triggers slightly improves the identification of diagnostic errors, as evidenced by an increase in PPV values. We identified new potential factors contributing to ED diagnostic errors. These findings open new avenues to construct or modify more accurate e-triggers for diagnostic error identification.

Background: Spasticity is common in spinal cord injury (SCI) and multiple sclerosis (MS), and it can manifest as repeated, rhythmic muscle contractions called clonus. The spontaneous nature of clonus can disrupt independent performance of activities of daily living and negatively impact overall health and quality of life. Objectives: To quantify biomarkers of clonus and explore management of clonus in individuals with SCI or progressive MS using epidural spinal cord stimulation (ES) or dorsal root stimulation (DRS). Methods: Four male participants were included in this case series study: 3 with SCI and 1 with MS. All participants underwent temporary percutaneous ES lead placement over the dorsolateral thoracolumbar region of the spinal cord. Participants with SCI were also implanted with DRS leads at the L4 dorsal root. Clonus was elicited mechanically at the ankle while recording electromyography of the soleus muscle synchronized to direct spinal cord field potential recordings from ES and DRS percutaneous leads. Results: Clonus was evident as a prominent band (5-8 Hz) in recordings from ES leads, DRS leads, soleus muscle, and accelerometry. In 4 participants, percutaneous spinal stimulation reduced median clonus duration and cycle count. Clonus was immediately suppressed upon activation of spinal cord stimulation, and the suppression persisted even when clonus was reinitiated after turning off the stimulation. Conclusion: The use of objective biomarkers, including spinal cord potentials, to quantify clonus in real time combined with the immediate and reversible effects of stimulation highlight the potential of neuromodulation as a therapeutic tool for managing clonus. These data demonstrate preliminary efficacy of ES and DRS for clonus monitoring and treatment in 4 participants.

ABSTRACT Objectives To characterize practice patterns and outcomes in the management of low‐ and intermediate‐grade salivary gland carcinoma prior to the existence of treatment guidelines. Methods Analysis of a registry of patients who underwent parotid and submandibular gland resections for low‐and intermediate‐grade carcinomas between 2010 and 2019. Results Of all 786 patients included in the study, 726 (92%) had preoperative imaging and 653 (83%) had preoperative biopsy. Of the 729 patients with parotid gland cancer, the majority underwent superficial ( n = 384, 53%) or total ( n = 254, 35%) parotidectomy. In patients with facial nerve preservation, total parotidectomy was associated with a significant increase in transient facial weakness (72/177 (41%) vs. 82/311 (26%), RR 0.65, 95% CI 0.50–0.84, p < 0.05) and permanent facial nerve weakness (23/176 (13%) vs. 16/301 (5%), RR 0.41, 95% CI 0.22–0.75, p < 0.05) compared to superficial parotidectomy. Adjuvant radiation therapy ( RT ) was delivered to 285 (36%) patients. The proportion of patients receiving adjuvant RT declined significantly over the time period from 2015 to 2019 compared to 2010 to 2014 at 162/504 (32%) and 123/282 (44%), respectively ( RR 0.74, 95% CI 0.61–0.89, p < 0.05). When comparing the time periods from 2015 to 2019 and 2010 to 2014, there was no significant difference in local control rates ( RR 0.52, 95% CI 0.26–1.04, p = 0.06) or regional control rates ( RR 0.75, 95% CI 0.26–2.13, p = 0.58). Conclusions Management of low‐ and intermediate‐grade salivary cancer from 2010 to 2019 was variable, which is expected given the rarity and heterogeneity of the disease and the lack of treatment guidelines prior to 2021. Most patients with parotid malignancies underwent superficial or total parotidectomy. The extent of parotidectomy had an impact on facial nerve function outcomes. Delivery of adjuvant radiation trended down with time. The data presented here will support dissemination of the guidelines and provide data that could inform future trials. Level of Evidence 2b.

Summary We investigated the outcomes of patients with advanced systemic mastocytosis (AdvSM) undergoing allogeneic haematopoietic cell therapy (alloHCT) in the US. Twenty‐seven adult (median age, 58 years) patients with AdvSM received alloHCT from 2014 to 2021. Most patients were white (93%), male (63%) and had systemic mastocytosis (SM) with associated haematological neoplasm (SM‐AHN, 70%), received peripheral blood grafts (89%) and non‐myeloablative regimens. KIT mutation was detected in 14 of the reported 16 patients (87.5%). Post‐transplantation cyclophosphamide (PTCy) was used in approximately 50% of the cohort. Approximately 1 year after alloHCT, median bone marrow mast cell burden decreased from 15% pre‐alloHCT to 1.5% (range 0–8) at 1 year post‐alloHCT. The median serum tryptase decreased from 55 ng/mL (range 3–400 ng/mL) pre‐alloHCT to 18 ng/mL (range 0–481 ng/mL) at 1 year post‐alloHCT. At 1 year, progression‐free survival (PFS) and overall survival (OS) were 59% (95% confidence interval [CI], 41%–77%) and 74% (95% CI, 56%–89%) respectively. In the subset of patients with SM‐AHN, 1‐year PFS and OS were 74% (52%–91%) and 79% (95% CI, 58%–94%) respectively. The cumulative incidence of relapse/progression for the entire population of patients with SM ( n = 27) was 4% (95% CI, 0–14) at 100 days and 15% (95% CI, 4–31) at 1 year. For the subset of patients with AHN, the cumulative incidence was 11% (95% CI, 1–28) at 100 days and 21% (95% CI, 6–42) at 1 year. Relapse/progression was the cause of death in six of 12 patients (5 died of AHN and 1 died of SM progression). Eighteen and nine patients received a KIT inhibitor before alloHCT and after alloHCT respectively. In addition, six patients received a KIT inhibitor for the treatment of relapse/progression of SM after alloHCT. Although it is difficult to delineate the exact effect of alloHCT and KIT inhibitors because of the size of the study in this era, the use of alloHCT and KIT inhibitors pre‐ and post‐ alloHCT is increasing. In the near future, larger studies are required to provide further insights into this subject.

Background: Patellofemoral instability (PFI) is a condition that leads to recurrent dislocation events and is typically secondary to extensor mechanism malalignment and rotational deformities. To correct malalignment, a tibial tubercle osteotomy (TTO) can be performed; however, an understanding of the associated complications, recurrence rates, and potential for reoperation is necessary. Purpose: To systematically review the literature to determine the incidence of postoperative complications, rate of recurrent instability, and all-cause reoperation rate after TTO for PFI. Study Design: Systematic review; Level of evidence 4. Methods: The Cochrane Database of Systematic Reviews, PubMed, Embase, MEDLINE, and CINAHL were queried for studies that reported complications after TTO. No date limits were applied. A total of 1050 studies were identified. Complications were categorized into “minor” and “major” groups using a modified Clavien-Dindo Classification. A meta-analysis was conducted to examine complication rates, recurrent instability, and all-cause reoperation, utilizing a DerSimonian and Laird random-effects model. A meta-analysis for recurrent instability was subgrouped according to follow-up periods of ≤2 years and >2 years. Results: A total of 38 studies were included, comprising 1546 patients, representing 1733 knees. The study dates ranged from 1989 to 2024, and the level of evidence ranged from 2 to 4. The weighted mean age at surgery was 24.1 years (range, 20-54 years), and 67% of patients were women. The weighted mean follow-up of all studies was 4.2 years. Overall, 197 minor complications, 39 major complications, 90 recurrent instability events, and 275 reoperations were identified. The minor complication rate was 9% (range, 0%-65% [95% CI, 6%-13%]). The major complication rate was 3% (range, 0%-10% [95% CI, 3%-4%]). Seven studies had a ≤2-year follow-up, and the remaining 31 studies had a >2-year follow-up. The recurrent instability rate was 3% in studies with ≤2 years of follow-ups (range, 0%-26% [95% CI, 1%-13%]). In studies with >2 years of follow-up, the recurrent instability rate was 8% (range, 0%-31% [95% CI, 6%-12%]). The all-cause reoperation rate was 16% (range, 0%-54% [95% CI, 11%-21%]). Conclusion: This systematic review and meta-analysis identified the incidence of complications (17%), the rate of recurrent instability (3%-8%), and the all-cause reoperation rate (16%) after TTO. TTO, performed alone or in combination with medial patellofemoral ligament reconstruction for the treatment of PFI, reliably improved clinical outcome scores in the setting of variable complication rates. Interestingly, rates of recurrent instability increased over time, and most reoperations were undertaken for hardware removal rather than revision patellar stabilization surgery.

Abstract Background Unresectable hepatocellular carcinoma (uHCC) is a leading cause of cancer death. FDA-approved first-line systemic therapies include atezolizumab/bevacizumab (atezo/bev) and durvalumab/tremelimumab (durva/treme); however, there is a lack of comparative data. Methods We reviewed outcomes of patients with uHCC who initiated atezo/bev or durva/treme between 2017 and 2024, across six institutions. Overall survival (OS) and time to treatment discontinuation (TTD) were analyzed using the Kaplan–Meier and Cox models, adjusting for baseline characteristics. Results Four hundred fifty-two uHCC pts were included. Median age: 68 years; 77% male; 81% white. Most common etiologies were viral hepatitis (38.9%) and metabolic dysfunction-associated steatohepatitis (19.5%). Disease progression was the primary reason for treatment discontinuation, atezo/bev (56%) and durva/treme (42%). Outcomes were not statistically significant (median OS [month, m]: 14.0 vs 14.6 [P = .66]; median TTD [m]: 4.9 vs 3.9 [P = .42] for atezo/bev vs durva/treme). Outcomes were significantly different between Child-Pugh classes (CP: A, B7, B8/9, C) respectively, median OS(m): 19.0, 6.1, 5.1, 2.0 (P &lt; .001); median TTD(m): 6.1, 2.3, 3.0, 1.3 (P &lt; .001). Conclusions In this real-world study of uHCC, no significant difference in clinical outcomes was observed between atezo/bev and durva/treme in the first-line setting. CP scores were a key prognostic variable with both regimens.