Citations

Introduction This case describes the application of spinal cord stimulation for the treatment of phantom limb pain in a patient with a left transhumeral amputation. Treatment of pain involving a high frequency spinal cord stimulator allowed the patient to utilize his myoelectric prosthesis and improve his overall function. Clinical findings Severe, phantom limb pain with associated involuntary muscle contractions prevented the patient from wearing a prosthesis for more than three hours per day. He also had difficulty using his myoelectric prosthesis to use his left upper extremity for functional tasks. Therapeutic intervention A high frequency spinal cord stimulator was placed at the level of the cervical spine. The patient had improvement in pain and overall function. He was also able to tolerate wearing his prosthesis longer each day. Conclusion High frequency spinal cord stimulation may be an effective treatment option for individuals with phantom limb pain. Treatment of phantom limb pain may decrease barriers to prosthesis use and improve overall function.

While most cases of human muscle-invasive bladder cancer (MIBC) are diagnosed as conventional urothelial carcinoma (UC), there is growing recognition of histologic subtypes and divergent differentiation within conventional UC. In this study, 31 dogs with UC (33 slides) were evaluated for histologic subtypes and divergent differentiation, as specified by the recent World Health Organization update on the classification of urinary bladder cancers. Slides were reviewed by a medical uropathologist and 3 board-certified veterinary pathologists and assessed for expression of uroplakin III, vimentin, and E-cadherin. All tumors were classified as UC. Fifteen cases were identified as conventional UC. Among the remainder, 8 displayed glandular differentiation, 4 were classified as sarcomatoid UC, 2 showed squamous differentiation, 1 case was classified as a large nested subtype, and 1 case was classified as a tubular/microcystic subtype. This study found a higher frequency of certain histologic subtypes and divergent differentiation in canine UC, particularly sarcomatoid UC and UC with glandular differentiation, compared to previous reports of both canine UC and human MIBC. The relatively high prevalence of the sarcomatoid UC and UC with glandular differentiation in dogs observed in this study suggests that canine UC may serve as a valuable translational model for evaluating novel therapeutic agents, particularly for these rare and aggressive subtypes in humans.

Objective This study evaluates the impact of international observerships organized by Help Ukraine Group (HUG) on professional development, knowledge transfer, and clinical practice improvement in radiation oncology in Ukraine. Methods A total of 50 observerships were facilitated for Ukrainian medical professionals at 14 institutions across the USA, Canada, Europe, and Australia from 2022 to 2024, including 31 radiation oncologists and medical physicists. A survey assessed their impact on oncology care, focusing on knowledge gained, lessons learned, and challenges in implementing new techniques. The primary outcome was the success score, defined as a composite score of implementing new procedures, initiating improvement projects, and knowledge dissemination efforts. Descriptive and comparative analyses examined satisfaction and success outcomes. Results A total of 43 respondents participated in the survey (response rate 86.0%). Twenty-eight of the responders were radiation oncology professionals (67.8% radiation oncologists, 32.1% medical physicists). The median observership duration for radiation oncology professionals was four weeks, with 96.4% also attending a professional conference. Overall satisfaction was high (mean 9.5 out of 10, median 10.0, IQR 9.0-10.0) while the success score was substantial (mean 6.1 out of 10, median 7.0, IQR 5.0-8.0). Time since certification influenced success, with ≥10 years’ experience associated with higher success scores (7.4 vs. 4.7, p=0.01). Importantly, 100% of respondents learned new procedures, 89.3% reported shifts in their clinical perspective, and 60.7% successfully implemented new techniques. Subsequent knowledge dissemination in Ukraine was substantial: 82.1% provided informal training, 60.7% delivered institutional or national presentations, 39.3% incorporated materials into lectures, and 10.7% engaged in all activities. Continued mentorship with host institutions was reported by 82.1%. Conclusions Amid the war, international observerships advanced clinical practice, education, and procedures in Ukraine, demonstrating the resilience of its medical community and providing a model that other LMICs/UMICs can follow.

Summary Evidence for an association between insulin‐like growth factors (IGF) and multiple myeloma (MM) is inconsistent. We examined total IGF‐I concentrations and risk of MM by combining baseline serological data among UK Biobank participants ( n = 444 187; 732 incident MM) with a two‐sample Mendelian randomisation (MR) analysis using identified genetic variants associated with circulating total IGF‐I and IGF‐binding protein 3 (IGFBP‐3) in the InterLymph consortium (2434 MM and their 2567 controls). Finally, additional lymphoid neoplasm (LN) subtypes were included for comparison with the main hypothesis. Circulating IGF‐I level was positively associated with MM risk Hazard ratio‐HR‐per one standard deviation‐SD‐increase (HR 1‐SD = 1.11, 95% confidence interval [CI]: 1.01–1.22; p ‐value = 0.03), especially closer to diagnosis. Genetically inferred IGF‐I levels were associated with increased MM risk (odds ratio [OR] = 1.27, 95% CI: 1.05–1.54) but not with any other LNs. Genetically inferred IGFBP‐3 levels showed no associations with any LN evaluated. Corroborating previous findings, in a secondary analysis, IGF‐I levels were associated with the risk of chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) in males with higher body mass index (HR 1‐SD in obese male = 1.36, 95% CI: 1.14–1.61). Our serological and MR analyses suggest a contributing role of IGF‐I in the susceptibility of MM; the CLL/SLL findings warrant further investigation considering sex‐specific adiposity.

Abstract Background Surrogate endpoints are increasingly used as the basis of cancer drug approvals. A strong association between treatment effects on the surrogate and true endpoint is essential for their validation as reliable endpoints. We assess the current evidence of trial-level surrogacy for colorectal cancer (CRC) endpoints through a novel framework. Methods We developed a framework to grade the quality of oncology surrogate endpoints in 7 domains of the surrogate relationship: data source quality (A-B); disease setting homogeneity (0-3); uniformness of surrogate and true endpoint definitions (0-3); number of trials evaluated (0-4); and individual- (0-2) and trial-level associations (0-8). We screened PubMed using keywords and medical subject headings terms for meta-analyses published before July 6, 2024, validating surrogate endpoint associations across CRC trials. Two reviewers blindly assessed each article before reaching a consensus score. The main outcomes were framework-derived evidence scores and reported trial-level associations (R2) with overall survival. Results A total of 18 articles were identified, containing 39 evaluations of 12 unique surrogate endpoints for overall survival. Evidence scores ranged from B6 to A23. Only disease-free survival consistently demonstrated high-quality evidence of trial-level surrogacy (≥A18, median R2 = 0.92). Progression-free survival and objective response rate were low-quality surrogates in metastatic CRC (progression-free survival: B6-A15, median R2 = 0.55; objective response rate: B6-A13, median R2 = 0.33). Other evaluated endpoints were demonstrated to be unreliable surrogates. Conclusion Disease-free survival shows high-quality surrogacy in stage II-III colon cancer. Endpoints identified in the metastatic setting demonstrate inconsistent surrogacy evidence. Reassessment and identification of new endpoints are warranted, particularly with immunotherapy.

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 Hereditary hemorrhagic telangiectasia (HHT), an autosomal dominant vasculopathy affecting 1 in 5000 individuals, is the second most common inherited bleeding disorder worldwide. Despite this prevalence, comprehensive data on disease manifestations and complications remain limited. To address this gap, the US Congress allocated funding leading to the Comprehensive HHT Outcomes Registry of the United States (CHORUS), a prospective, 15-center longitudinal registry enrolling unselected patients with confirmed HHT. In this initial report, we describe findings from the first 600 participants, with a median age of 53 (range, 0-88) years and 60% female. Despite most participants developing typical HHT manifestations by age 13 years, the majority (63%) were not diagnosed until mid-to-late adulthood. Recurrent spontaneous epistaxis occurred in 95% of participants, chronic gastrointestinal bleeding in 30%, and heavy menstrual bleeding in 35% of postmenarche females, together resulting in moderate-to-severe mucosal bleeding in 76%. Iron deficiency and/or anemia were diagnosed in 68%, with 41% requiring IV iron and 25% requiring red cell transfusions. Serious complications of solid-organ arteriovenous malformations were frequent, including intracranial hemorrhage (3%), pulmonary hemorrhage (2%), venous thromboembolism (7%), arterial thromboembolism (11%), heart failure (7%), and pulmonary hypertension (7%). These data from CHORUS, the first national US registry of its kind, provide reliable, real-world estimates of the incidence, prevalence, and severity of numerous HHT manifestations and complications. HHT has a high burden of moderate-to-severe bleeding, anemia, thrombosis, and major neurologic and cardiopulmonary complications. There is a mean interval between first symptoms and diagnosis of >2 decades, during which substantial, serious, and preventable HHT morbidity, including early intracranial hemorrhage, may occur. This trial was registered at clinicaltrials.gov as NCT06259292.

ABSTRACT The local treatment of bladder and prostate rhabdomyosarcoma is a multidisciplinary decision, incorporating elements of patient age, tumor size and location, nodal involvement, and access to local expertise and technology. The relative absence of long‐term bladder and bowel function outcome data complicates discussions, particularly given improved survival rates and development of new surgical and radiotherapy techniques. These INSTRuCT guidelines, a collaboration of the Children's Oncology Group, Soft Tissue Sarcoma Committee, European Pediatric Soft Tissue Sarcoma Study Group, and the Cooperative Weichteilsarkom Studiengruppe, reflect international expert consensus and are intended to inform practice, generate discussion, and highlight areas of future inquiry.

Abstract Diffuse leptomeningeal glioneuronal tumors (DLGNT) are rare central nervous system tumors. Our understanding of the clinical course, prognostic factors, and optimal treatment strategies remains limited. Histologic, molecular, and clinical data were collected and analyzed for 25 patients with DLGNT reviewed at St. Jude Children’s Research Hospital. The median age at diagnosis was 6 years (11 months-20 years). Nineteen (72%) patients were male. The disease was localized at diagnosis in 12 (48.0%) patients, with most tumors localized in the spinal cord. BRAF fusion was present in 22 (95.6%) of 23 patients who had material for testing. Of 18 patients who had tissue for DNA methylation profiling, 3 (16.7%) matched to DLGNT MC-1, 3 (16.7%) to DLGNT MC-2, and 12 (66.7%) did not match to a DLGNT subclass. Median follow-up was 63 months. Twenty-four (96.0%) patients received adjuvant therapy after initial diagnosis or at progression. Thirty-five cytotoxic chemotherapy and 24 single-agent targeted therapy regimens were used in 22 and 13 patients, respectively. With targeted therapy, 3 (12%) patients had partial responses. Eleven (44.0%) received radiotherapy. Median progression-free survival (PFS) after a patient’s first chemotherapy, targeted therapy, or radiotherapy regimen was 44 months (1-77), 11 months (4-39), and 16.5 months (9-23), respectively. The 5-year PFS was 18.7%±9.2, while the 5-year overall survival (OS) was 82.4%±9.2. The 5-year OS was lower in patients older than 9 years at diagnosis (60.0%±21.9 vs 91.7%±8.0, p = 0.02). Ki67 >4% was associated with worse PFS (0%±0 vs 24.6%±11.9 at 5 years, p = 0.03). Initial disease dissemination (localized vs. disseminated) and 1q gain status do not influence PFS or OS. PFS for DLGNT remains poor across all treatment modalities, including targeted therapies, despite the high frequency of BRAF fusions. Due to its rarity, establishing optimal therapeutic strategies for DLGNT requires additional treatment and outcome data and prospective multi-institutional trials.