Citations

Background/Objective: Although most melanocytic lesions are diagnosed as benign or malignant by histopathologic evaluation, with or without the aid of immunohistochemistry, diagnosis may remain uncertain in a minority of cases. Assessment of copy number abnormalities (CNAs) may provide sufficient additional evidence to favor either a benign or malignant diagnosis in both pediatric and adult cases and in melanocytic lesions of various subtypes, including Spitzoid, mucosal, and acral. CNAs are common in melanomas, while they are rare, with few exceptions, in benign lesions. Detection of CNAs by fluorescence in situ hybridization (FISH) and chromosomal microarray (CMA) has been well established for melanocytic lesions, with advantages and disadvantages for each. The objective of this meta-analysis was to evaluate the utility of CNA testing for the diagnosis of melanoma, across subtypes, when a lesion remains ambiguous after histopathologic and immunohistochemical assessment. In addition, the utility of CNAs to determine prognosis in established diagnoses of melanoma was also evaluated. Methods: The Cancer Genomics Consortium Working Group for Melanocytic Lesions reviewed published data from January 1998 through September 2022 of CNAs in melanocytic lesions detected by either FISH or CMA and conducted a meta-analysis of the findings. Results: Specific abnormalities common in primary cutaneous melanomas of various subtypes and uveal melanomas were enumerated. Differences in CNAs found in primary versus metastatic lesions were also determined, and published evidence for prognosis was summarized. Conclusions: The working group established evidence-based recommendations for the use of CNA testing for evaluation of ambiguous melanocytic lesions.

ABSTRACT The HLA‐C*03:31 allele is characterised by a nucleotide substitution at genomic DNA position 400 in exon 2.

Introduction: Many patients with prostate cancer have an indication for anticoagulation. This presents a pharmacokinetic dilemma as enzalutamide and apalutamide have significant effects on the metabolism of direct oral anticoagulants. To date, data on coadministration of these agents is limited to pharmacokinetic studies and post-hoc analysis, which suggest no deleterious effects. Our study seeks to elucidate whether the concomitant administration of enzalutamide or apalutamide with apixaban or rivaroxaban results in a clinically meaningful change in thromboembolic events. Methods: We conducted a retrospective, observational cohort study of adult prostate cancer patients on concomitant apalutamide or enzalutamide and apixaban or rivaroxaban for ≥ 3 months from January 1, 2018 to August 9, 2024 at all 3 tertiary sites of our care network. The primary outcome was incidence of deep vein thrombosis, pulmonary embolism, or ischemic stroke. The secondary outcomes included the incidence of switching of anticoagulant therapy or prostate-directed therapy due to concern for drug-drug interaction. The secondary outcomes were assessed in the entire cohort without exclusion. Results: A total of 500 patients were assessed for eligibility, of which 94 were included in the final analysis of primary outcome. The primary outcome occurred in 4 patients (4.3%). The switching of anticoagulant therapy occurred in 32 patients (6.4%). The switching of prostate-directed therapy occurred in 5 patients (1%). Conclusion: This study suggests that there is not an increased incidence of VTE or stroke when compared to historical controls. This study may help clinicians make risk benefit decisions regarding concurrent therapies.

Measurable residual disease (MRD) has established prognostic significance in patients with myeloid disorders; however, there is limited data regarding its prognostic and predictive value and the optimal technique for measurement in the setting of post allogeneic hematopoietic cell transplantation (allo-HCT). A multi-gene next generation sequencing (NGS) panel can overcome the limitations of conventional techniques for measurement of MRD and can shed light onto the longitudinal evolution and genomic complexity of patients undergoing allo-HCT for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). In this study, patients with AML or MDS who underwent their first allo-HCT and completed NGS testing at day +100 and were in a state of morphological remission were identified from the transplant registry of Mayo Clinic in Florida. The primary aim was to evaluate the prognostic impact of somatic variants detected via NGS at day +100 post allo-HCT on long-term outcomes. In total, 105 patients who underwent allo-HCT for AML and MDS and completed NGS testing on day +100 were included in the study population. Seventeen patients were found to have detectable variants, and 88 patients were without a detectable variant. At a median follow up of 1.4 years (0.1–5.5), presence of any variant at day +100 was associated with inferior 4-year overall survival (OS) (32% vs. 69%, P < 0.001), decreased progression free survival (PFS) (34% vs. 61%, P < 0.001), and a higher incidence of relapse (64% vs. 23%, P < 0.001). In univariate models, a lower Karnofsky performance score and presence of variants post allo-HCT remained significantly associated with inferior OS, higher relapse incidence, and a decreased PFS. The presence of variants at day +100 post allo-HCT remained significant in multivariate models for relapse ( P = 0.002) but not for OS ( P = 0.06) and PFS ( P = 0.08). These results indicate that the presence of detectable somatic variants at day +100 is associated with poor long-term outcomes and are predictive of a higher incidence of relapse.

ABSTRACT Myelofibrosis is characterized by perturbation of the JAK/STAT pathway and upregulation of anti‐apoptotic factors leading to myeloproliferation, bone marrow fibrosis (BMF), extramedullary hematopoiesis, splenomegaly, and cytopenias. Navitoclax, a potent oral B‐cell lymphoma (BCL)‐X L /BCL‐2 inhibitor, promotes apoptosis of malignant myelofibrosis cells. Herein, we present results of Cohort 3 of the Phase 2 REFINE study (NCT03222609), which evaluated efficacy and safety of navitoclax plus ruxolitinib in JAKi‐naïve patients with myelofibrosis. JAKi‐naïve patients with primary or secondary myelofibrosis (≥ 18 years with splenomegaly, DIPSS intermediate‐2 and high‐risk myelofibrosis, and ECOG 0–2) and platelet count > 100 × 10 9 /L were enrolled and treated with navitoclax 100 mg once daily (QD) or 200 mg QD according to platelet count (≤ 150 × 10 9 /L or > 150 × 10 9 /L, respectively). Ruxolitinib was given twice daily (dose per label). Primary endpoint: spleen volume reduction of ≥ 35% (SVR 35 ) at week 24. Secondary endpoints: ≥ 50% reduction in total symptom score (TSS 50 ) at week 24, change in grade of BMF, anemia response, and safety. Thirty‐two patients received ≥ 1 dose of navitoclax plus ruxolitinib. Median (range) duration of follow‐up was 44 months (5–58). 63% (20/32) of patients achieved SVR 35 at week 24; median (range) time to first SVR 35 was 12 weeks (11─48). Of 24 evaluable patients, 21% achieved ≥ 50% reduction in driver gene variant allele frequency (VAF). Of 27 evaluable patients, 11 (41%) achieved TSS 50 at week 24; median (range) time to first TSS 50 of 3 weeks (0─16). BMF improved from baseline by ≥ 1 grade in 13/27 patients (48%) at any time on study. Anemia response rates were 38% (5/13) for transfusion‐independent and 100% (2/2) for transfusion‐dependent patients. No bleeding events or deaths were attributed to navitoclax. These findings suggest navitoclax plus ruxolitinib has a tolerable safety profile and provides clinically meaningful improvements for JAKi‐naïve patients with myelofibrosis. Trial Registration NCT03222609.

ABSTRACT Background There is limited data regarding the surgical outcomes of urosymphyseal fistula (USF) repair with primary repair or autologous tissue transfer. We performed a study to compare outcomes of USF repair with primary repair, VRAM flap, and omental flap. Methods We retrospectively identified patients with a diagnosis of USF who underwent fistula decompression and urinary tract reconstruction. The minimal follow‐up was 3 months. Patients with distal urethral obstruction, radiation cystitis, or a non‐viable sphincter underwent anterior exenteration and flap transfer. Results Fifty‐six patients were included. Eleven patients underwent surgical management for USF using primary repair (19.6%), 34 had omental flap‐based reconstruction (60.8%), and a VRAM flap was used in 11 patients (19.6%). The 90‐day rate of sepsis was lower with omentum flap transposition (3%) compared with VRAM flap (27%) or primary repair (18%, p = 0.041). The rate of fistula recurrence was lower in the omentum flap group compared with USF primary repair (30%) or VRAM flap repair group (27.3%, p = 0.04). On multivariable analysis, USF repair with the omentum flap decreased the odds of fistula recurrence 90 days after surgery compared with primary repair (OR 0.012, p = 0.011) but not when compared with VRAM. Conclusion The omentum flap may offer a better safety profile in terms of decreasing the rate of early sepsis and rate of fistula recurrence for USF repair in comparison to primary repair. There is limited evidence regarding the superiority of the omentum flap to decrease the rate of late fistula recurrence when compared with the VRAM flap.

Purpose Two-dimensional (2D) X-ray imaging is routinely used in radiotherapy for patient alignment but offers limited tumor visibility due to anatomical overlap. We propose a novel technique, prior information-based subtraction (PIBS) radiography, to enhance tumor visualization on 2D X-ray and facilitate more accurate patient alignment. Materials and methods PIBS X-ray improves tumor visualization on 2D X-ray by subtracting signal contributions from non-essential (NE) tissues, which can be obtained from the planning CT (prior information). To demonstrate the feasibility, we acquired four CT scans using a thorax phantom with a spherical lung target, representing the planning CT and three treatment-day CTs capturing the patient’s positions with the lung tumor at three different locations, respectively. NE tissues, defined as structures outside the thoracic cavity, were segmented from the planning CT. On treatment days, we aligned NE tissues based on bony structures via 3D/3D or 2D/2D registration and applied the calculated shifts so the patient’s position matched that in the planning CT. To simulate 2D X-rays, digitally reconstructed radiographs (DRRs) were generated from the planning CT of NE tissues and aligned with treatment-day CTs. Subtracting NE tissue contributions from conventional 2D X-ray yielded PIBS X-ray. PIBS X-ray images were compared with conventional X-ray images to assess tumor visibility. Results PIBS X-ray provided better tumor visualization across all projection angles and all tumor locations compared to conventional X-ray, even for certain cases where the tumor was completely indistinguishable on conventional X-ray. Both 3D/3D and 2D/2D registrations produced acceptable alignment of NE tissues because of the clear visibility of bony structures. Conclusion PIBS X-ray is a promising technique to enhance tumor visualization on 2D X-ray. In this study, we demonstrated its potential in improving radiotherapy on-board imaging using a thorax phantom. In the future, we will explore strategies for integrating this technology into clinical workflows and evaluate its clinical benefits in radiotherapy patients.

ABSTRACT Introduction Cardiac myosin inhibitors (CMIs) improve hemodynamics and symptoms in hypertrophic cardiomyopathy (HCM), but recent real‐world data have raised concerns regarding an increased risk of atrial fibrillation (AF). We sought to reassess AF risk using randomized controlled trial (RCT) evidence and to contextualize discrepancies with observational reports. Methods and Results We performed a systematic review and random‐effects meta‐analysis of RCTs evaluating the effect of CMIs on incident AF in HCM. MEDLINE, Scopus, and CENTRAL were searched through November 25, 2025. Eight RCTs ( n = 1581) comparing mavacamten or aficamten with placebo or active control were included. Event counts were pooled as risk ratios (RRs) with 95% confidence intervals (CIs). CMIs were not associated with increased AF risk (RR 1.11, 95% CI 0.62–1.98; heterogeneity I 2 = 0%). No differences were observed between mavacamten and aficamten, with consistent findings across HCM subtypes (obstructive and non‐obstructive). Importantly, most trials (7/8) excluded patients with uncontrolled, persistent, or permanent AF, five excluded paroxysmal AF at screening, and one excluded any AF history. Baseline left atrial enlargement was generally in the mild to moderate range across trials, suggesting limited representation of high‐risk AF phenotypes. Conclusion Randomized evidence to date does not demonstrate an increased AF risk with CMIs. Differences between RCT populations and real‐world cohorts, including restrictive AF eligibility criteria, lower baseline atrial remodeling, and limited rhythm surveillance may explain discordant observational findings and highlight the need for longitudinal monitoring in clinical practice.

ABSTRACT Purpose To simultaneously measure skeletal muscle energetics and blood flow (BF) before, during, and after dynamic plantar flexion exercise (PFE). Methods Non‐localized pulse‐acquire phosphorus‐31 magnetic resonance spectroscopy ( 31 P MRS) and phase contrast flow magnetic resonance imaging ( 1 H MRI) using golden‐angle rotated spiral readouts were acquired in an interleaved fashion. Data were collected at rest, during PFE to volitional fatigue, and post‐exercise recovery in 10 healthy adults. Interleaved popliteal artery BF was validated against conventional cine phase‐contrast measures at rest and post‐exercise recovery, while calf muscle energetics were validated by comparing to conventional 31 P MRS‐only measures at rest. To minimize motion artifacts during dynamic PFE, flow data were resolved in 3 dimensions (cardiac phase, pedal position, and exercise stage). Results Resting phosphocreatine (PCr) and inorganic phosphate concentrations were similar between both techniques (both p > 0.05). During PFE, PCr declined to 46% ± 10% of rest. PCr recovery time was 43 ± 15 s. Resting BF was 132 ± 43 mL/min and increased up to four‐fold during PFE depending on exercise stage and pedal position. Notably, there was excellent agreement between the interleaved and conventional BF measures ( r 2 = 0.95, slope = 0.977, p < 0.0001) with minimal bias (12.62 mL/min) over a wide range of physiologically relevant BF values (from ∼60 to 600 mL/min). Conclusion The feasibility of simultaneous assessment of skeletal muscle energetics and BF during dynamic exercise by interleaved 31 P MRS/ 1 H flow MRI was demonstrated along with good agreement between interleaved and conventional techniques during rest and recovery. One can now simultaneously quantify critical BF‐metabolism relationships and use this to probe disease‐related adaptations.

ABSTRACT We report a case of fulminant Clostridium perfringens septicemia complicated by massive intravascular hemolysis in a 19‐year‐old male with acute myelogenous leukemia. The patient presented with severe anemia and laboratory evidence of profound hemolysis. Despite the high mortality associated with this condition, the patient was successfully treated with broad‐spectrum antibiotics, including clindamycin, and three consecutive sessions of therapeutic plasma exchange (TPE). TPE was employed to remove circulating α‐toxin and cell‐free hemoglobin, thereby mitigating ongoing hemolysis and organ injury. This case highlights the potential role of TPE, in conjunction with appropriate antimicrobial therapy, as an intervention in C. perfringens septicemia with hemolysis.