Citations

Background: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare disease listed as a separate entity in the 5th edition of the World Health Organization Classification of Haematolymphoid Tumours. It is a clinically aggressive hematologic malignancy derived from precursors of plasmacytoid dendritic cells. Traditionally, therapeutic options for BPDCN consisted of conventional antineoplastic chemotherapy, adopted from regimens used to treat acute leukemia (myeloid or lymphoblastic, or lymphomas. Tagraxofusp, a CD123 directed antibody conjugate composed of human interleukin-3 (IL-3) and truncated diphtheria toxin, is also approved for treatment of BPDCN. Unfortunately, none of these are curative options of this disease. Allogeneic (Allo) hematopoietic cell transplantation (HCT) is an established treatment modality for patients with BPDCN with reported encouraging survival, whereas reported data on autologous (auto) HCT are limited. Methods: We conducted a systematic review and meta-analysis (SR/MA) to assess the totality of evidence on the role of allo- and auto-HCT in patients with BPDCN. We performed a comprehensive search of EMBASE and PUBMED/MEDLINE, on April 25, 2024. To be eligible for inclusion in this SR/MA, studies must have included ≥10 patients; be published in full manuscript or letter to editor and have evaluated the use of an allo-HCT and/or auto-HCT for treating BPDCN. Pertaining to benefits, we extracted data based on complete remission (CR), progression-free survival (PFS) (substituted with disease-free survival (DFS) if PFS missing), and overall survival (OS). For harms, we extracted data on non-relapse mortality (NRM) and relapse. Data were pooled under a random effects model. Results: Initial search identified 692 references, of which, 10 met our inclusion criteria. For allo-HCT, 10 studies were included; and for auto-HCT, there were 3 studies. For allo-HCT, pooled rates for CR, PFS/DFS and OS were 69% (2 studies, 91 patients (pts)), 49% (10 studies, 561 pts), and 55% (9 studies, 531 pts), respectively. Pooled rates for NRM and relapse were 24% (8 studies, 470 pts) and 24% (10 studies, 561 pts). Tests of heterogeneity were as follows: for CR analysis (I2=97.04%), PFS/DFS (I2=79.57%), OS (I2=33.18%), NRM (I2=0) and relapse (I2=55.55%). For auto-HCT, only one study reported CR=100%. Pooled rates of PFS/DFS and OS were 68% (3 studies, 43 pts), and 66% (3 studies, 43 pts), respectively. Pooled rates for NRM and relapse were 3% (2 studies, 27 pts) and 25% (3 studies, 43 pts). Tests of heterogeneity were as follows: for CR analysis (I2=not applicable), PFS/DFS (I2=0), OS (I2=27.90%), NRM (I2=0) and relapse (I2=0). A subgroup analysis for allo-HCT recipients in CR1 showed pooled rates of PFS and OS of 60% (5 studies, 76 pts) and 69% (5 studies, 76 pts), respectively. Tests of heterogeneity for PFS and OS for the allo-HCT in CR1 were I2=51.99% and I2=0, respectively. Conclusion: Results of this SR/MA demonstrate that both allo-HCT and auto-HCT are effective treatments for patients with BPDCN, although data supporting the latter are scarce. Allo-HCT in CR1 is associated with a higher pooled rate of OS (69%). Efforts should focus on prompt referral of BPDCN patients for an allo-HCT in CR1, whenever possible, to optimize survival outcomes.

Introduction Linvoseltamab is an investigational, BCMA×CD3 bispecific antibody designed for the treatment of RRMM. High objective response rates (ORR) to linvoseltamab 200 mg in the LINKER-MM1 trial (NCT03761108) were demonstrated across high-risk subgroups, including patients aged ≥75 years, patients with high-risk cytogenetics, and patients with penta-class refractory status. The aim of this study was to compare ORR, overall and in key subgroups, between patients in Phase 2 of the LINKER-MM1 trial and patients in an international RW SOC external control arm (ECA). Methods The ECA was derived from a chart review of 16 academic sites across 10 countries that are part of the International Myeloma Foundation (IMF)-International Myeloma Working Group (IMWG) and 2 US electronic health record databases (COTA and Guardian Research Network [GRN]). Included patients initiated ≥1 anti-MM treatment after meeting key eligibility criteria of LINKER-MM1. Weighted random sampling and inverse probability of treatment weighting (IPTW) were used to select 1 line of therapy (LOT) per patient and balance the overall ECA and trial populations on prespecified prognostic factors (Kumar S, et al. IMS 2023). For ORR assessment, LINKER-MM1 and IMF-IMWG used independent central review committees per IMWG criteria, COTA used algorithmic assessment based on IMWG criteria, and GRN used physician-assessed responses. Prior to conducting comparative analyses, an independent committee of epidemiology and oncology experts reviewed the comparability of the cohorts and endpoint assessments, and approved study continuation. ORR among patients in LINKER-MM1 and patients in the ECA was compared overall and across prespecified subgroups (≥10 patients per subgroup), including age, race, cytogenetic risk score, international Staging System (ISS), presence of extramedullary plasmacytoma (EMP), refractory class, bone marrow plasma cell (BMPC) proportion, and number of prior LOTs. Results Median duration of follow-up was 14.3 months (data cut-off: January 6, 2024) for patients receiving linvoseltamab (n=105) and 13.6 months for the ECA (n=307; n=194, n=72, and n=41 from IMF-IMWG, COTA, and GRN, respectively). Following IPTW, 13 prognostic factors with <30% missingness were balanced between cohorts, with an effective sample size in the ECA of 197. After adjustment, ORR was significantly higher in patients who received linvoseltamab compared with patients in the ECA (69.5% vs 45.7%, odds ratio [OR] 2.5 [95% confidence interval (CI) 1.6-4.1]) and in key subgroups with age 65-74 years (76.9% vs 48.3%, OR 3.6 [1.6-8.6]), age ≥75 years (72.4% vs 48.5%, OR 2.8 [1.1-7.4]), Black or African American race (82.4% vs 25.0%, OR 14.0 [3.0-85.4]), White race (68.9% vs 49.7%, OR 2.2 [1.3-4.0]), standard cytogenetic risk (72.3% vs 51.3%, OR 2.5 [1.3-4.8]), ISS stage III (58.8% vs 19.7%, OR 5.8 [1.5-25.2]), absence of EMP (71.6% vs 49.3%, OR 2.6 [1.5-4.6]), triple-class refractory status (68.2% vs 45.7%, OR 2.6 [1.5-4.4]), quadruple-class refractory status (66.7% vs 45.9%, OR 2.4 [1.3-4.3]), 4-5 prior LOTs (65.1% vs 40.4%, OR 2.8 [1.3-6.0]), and >5 prior LOTs (75.7% vs 36.1%, OR 5.5 [2.4-13.6]). Numerically higher (not statistically significant) or similar ORR was observed for patients receiving linvoseltamab compared with patients in the ECA with age <65 years (59.5% vs 46.8%, OR 1.7 [0.79-3.6]), high-risk cytogenetics (65.0% vs 63.1%, OR 1.1 [0.41-2.9]), ISS stage I (73.3% vs 64.6%, OR 1.5 [0.62-3.7]), ISS stage II (67.6% vs 53.5%, OR 1.8 [0.72-4.7]), presence of EMP (58.8% vs 56.9%, OR 1.1 [0.32-3.8]), penta-class refractory status (64.3% vs 48.5%, OR 1.9 [0.78-4.8]), BMPC <50% (77.0% vs 67.2%, OR 1.6 [0.61-4.3]), BMPC ≥50% (41.7% vs 36.0%, OR 1.3 [0.36-4.7]), and ≤3 prior LOTs (68.0% vs 66.4%, OR 1.1 [0.43-2.9]). Separate findings will be presented for IMF-IMWG and COTA/GRN data at the congress. Conclusions Linvoseltamab induced better ORR vs RW SOC treatments overall, and better or similar ORR in the key subgroups assessed, highlighting its therapeutic value across a range of patients with RRMM with heterogeneous risk profiles and levels of disease burden.

Case: This is a case of a 6-year-old patient diagnosed with Gorham-Stout disease (GSD), a rare lymphangiogenic skeletal disorder, localized to the left femur. Initial nonoperative treatment with pharmaceuticals and bracing was unsuccessful. We describe a definitive operative treatment with radical femoral resection and a modified rotationplasty technique through a tibiopelvic rotational hip arthroplasty. At 2-year follow-up, the patient was able to walk with a prosthetic device. Conclusion: The use of this modified rotationplasty technique is an effective treatment option for patients with femoral GSD to improve function and quality of life.

Abstract Senescent cells drive tissue dysfunction through the senescence-associated secretory phenotype (SASP). We uncovered a central role for mitochondria in the epigenetic regulation of the SASP, where mitochondrial-derived metabolites, specifically citrate and acetyl-CoA, fuel histone acetylation at SASP gene loci, promoting their expression. We identified the mitochondrial citrate carrier (SLC25A1) and ATP-citrate lyase (ACLY) as critical for this process. Inhibiting these pathways selectively suppresses SASP without affecting cell cycle arrest, highlighting their potential as therapeutic targets for age-related inflammation. Notably, SLC25A1 inhibition reduces systemic inflammation and extends healthspan in aged mice, establishing mitochondrial metabolism as pivotal to the epigenetic control of aging.

Abstract Up to 80% of the world's population with epilepsy lives in low and middle‐income countries. Around one‐third of these patients will have drug‐resistant epilepsy, for which epilepsy surgery is an option. Unfortunately, many of these regions, as well as some more developed nations, lack sufficient epilepsy surgery units and trained neurosurgeons. With this in mind, the International League Against Epilepsy (ILAE) formed the Epilepsy Surgery Education Taskforce to address the shortage of further educational opportunities for surgeons and neurologists and to promote the creation of more epilepsy surgery units around the world. In this article, we publish our findings from a web‐based international survey, in which we investigated the global distribution and experience of neurosurgeons who perform epilepsy surgery, their educational paths, and opinions on the further need for epilepsy surgery education, as well as the resources available to them. We report a detailed analysis of the 202 survey replies received from 35 different countries across six continents. The lack of adequate numbers of epilepsy surgery units in the Southern Hemisphere is notable, and the aim of this task force with other ILAE committees, is to improve access to epilepsy surgery for patients and to enhance training for their health care providers.

Abstract Purpose: Although the B-cell receptor (BCR) signal plays a critical role in chronic lymphocytic leukemia (CLL) cell survival and a target of current therapies (ibrutinib targets Bruton’s tyrosine kinase; idelalisib targets PI3Kδ), contribution of the cytokine-driven JAK2 pathway to the “CLL cell-survival signaling network” is largely undefined. Experimental Design: Patients with CLL were enrolled to investigate expression/activation of JAK2 and acylglycerol kinase (AGK), and their functional implication in primary CLL cell survival. A series of biochemical and molecular biology assays were employed to uncover the underlying mechanism. Results: We detected that compared with normal B cells, CLL cells aberrantly express constitutively active JAK2. Mechanistically, HSP90 forms a chaperoning complex with JAK2, resulting in its aberrant accumulation in CLL cells. We also discovered aberrant upregulation of a novel mitochondrial lipid kinase, AGK, which remains complexed with HSP90 in CLL cells activating JAK2. Although AGK is typically mitochondrial, we detected its nuclear localization in association with JAK2 in some CLL cells. Functionally, JAK2 phosphorylates its noncanonical substrate, histone H3(Y41), but not STAT3, activating transcription of diverse sets of genes in a patient-specific manner. Additionally, JAK2 activates the BCR signal in CLL cells via LYN/Bruton’s tyrosine kinase axis. Targeted inhibition of JAK2 as monotherapy, or in combination with the BCR inhibitors or venetoclax (a BCL2 inhibitor), induced apoptosis synergistically in CLL cells. Conclusions: These findings suggest that aberrantly expressed AGK activates JAK2, independent of cytokine, leading to activation of diverse sets of gene transcription in CLL cells. Combined targeting of JAK2 and BCR signals or BCL2 may be effective in some patients with CLL.

The Canadian Consortium on Neurodegeneration in Aging (CCNA) was created by the Canadian federal government through its health research funding agency, the Canadian Institutes for Health Research (CIHR), in 2014, as a response to the G7 initiative to fight dementia. Two five-year funding cycles (2014–2019; 2019–2024) have occurred following peer review, and a third cycle (Phase 3) has just begun. A unique construct was mandated, consisting of 20 national teams in Phase I and 19 teams in Phase II (with research topics spanning from basic to clinical science to health resource systems) along with cross-cutting programs to support them. Responding to the needs of researchers within the CCNA teams, a unique sample of 1173 deeply phenotyped patients with various forms of dementia was accrued and studied over eight years (COMPASS-ND). In the second phase of funding (2019–2024), a national dementia prevention program (CAN-THUMBS UP) was set up. In a short time, this prevention program became a member of the World Wide FINGERS prevention consortium. In this article, the challenges, successes, and impacts of CCNA in Canada and internationally are discussed. Short-term deliverables have occurred, along with considerable promise of impacts in the longer term. The creation of synergy, networking, capacity building, engagement of people with lived experience, and economies of scale have contributed to the considerable success of CCNA by all measures. CCNA is evidence that an organized “centrally-organized” approach to dementia research can catalyze important progress nationally and yield significant and measurable results.

Abstract Objective To study pregnancy outcomes and complications in women with congenital adrenal hyperplasia (CAH). Methods A retrospective multicenter study was conducted at tertiary reference centers in 5 countries (Austria, Germany, Italy, Sweden, USA), including 72 adult women with CAH (nonclassic [NC] n = 34, simple virilizing [SV] n = 21, salt wasting [SW] n = 17). Results A total of 133 pregnancies, 112 live births, and 25 abortions were documented. Prolonged latency to pregnancy was observed (median 11 months in SW, 24 months in SV, 8 months in NC), with a notable use of fertility-enhancing medication (25.6%) and assisted reproductive techniques (30.8%). Over half of the women in each group took more than 12 months to conceive. The average number of live births (1.4-1.6 children per woman) was similar across CAH phenotypes and comparable to the general population. Spontaneous abortion rates (18.0%) were also similar across phenotypes. Primary cesarean section rates (60.9%) were higher than in the general population, though 23.8% of women with SV and 29.4% of women with SW gave birth naturally, despite most having undergone genital surgery. Children categorized as small for gestational age were 20.5%. Pregnancy, delivery, and postpartum complications were rare for mothers and neonates. Conclusion The study indicates a prolonged latency to pregnancy and high use of fertility treatments in CAH patients, regardless of phenotype. Abortion rates were not increased, and overall pregnancy and perinatal outcomes were favorable.

AbstractAimMinimally invasive transanal platforms are now the standard of care for select low‐risk rectal tumours. However, existing platforms come with persistent technical challenges. The da Vinci SP Surgical System™ offers a new alternative designed to work effectively in narrow spaces. This technology has the potential to enhance the feasibility and proximal extent of complex transanal resections. This study aimed to describe the morbidity and technical success in patients undergoing single‐port robotic transanal minimally invasive surgery (SPR‐TAMIS). Secondary outcomes include rates of local recurrence.MethodsA retrospective analysis was conducted on all patients who underwent SPR‐TAMIS at our institution between February 2019 and December 2023.ResultsThe study included 31 patients (19 men, 12 women) with a mean age of 61 ± 13.3 years. The average tumour distance from the anal verge was 10 cm. Thirty patients completed SPR‐TAMIS, with one patient requiring conversion to robotic sigmoidectomy due to location in the mid‐sigmoid colon. The mean operating time was 106 ± 42 min. Twenty‐eight out of 30 patients underwent full‐thickness excision and all but two were successfully closed. All specimens were resected intact, and margins were negative in 93.5% of cases. The average tumour size was 13 ± 34 cm2, with 13 lesions classified as adenomas and 16 as adenocarcinomas. All patients who did not undergo associated procedures were discharged on the day of surgery. Two patients experienced 30‐day morbidity. At a mean follow‐up of 18 months (± 13), no local or systemic recurrences were identified.ConclusionSPR‐TAMIS for excision of low‐risk rectal tumours is associated with high rates of technical success and low 30‐day morbidity. Further research is needed to compare SPR‐TAMIS with other techniques to determine potential advantages over current transanal platforms.