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Abstract Background Stroke is a leading cause of mortality and disability globally. However, information about stroke burden in the Philippines is limited. We sought to analyze stroke burden in the Philippines from 1990 to 2023. Methods Incidence, prevalence, mortality, and disability-adjusted life-years (DALYs) estimates from the Global Burden of Disease Study 2023 data were used as indicators to analyze the burden of stroke by sex and age. Temporal trends in both crude and age-standardized rates were analyzed using joinpoint regression analysis. Results In 2023, stroke incidence was estimated at 156.2 (95% uncertainty interval [UI]: 140.8–175.4) thousand, prevalence at 1.2 (95% UI: 1.2–1.4) million, mortality at 72.2 (95% UI: 63.2–83.0) thousand, and DALYs at 2.1 (95% UI: 1.8–2.3) million. High systolic blood pressure was the leading contributor to risk-attributable stroke mortality and DALYs. Since 1990, age-standardized rates declined significantly, whereas crude rates increased markedly. Compared with women, men had a higher fatal burden and consistently exhibited a higher age-standardized burden. Although older adults (≥ 55 years) had the highest stroke burden and achieved reductions in stroke incidence and fatal outcomes, both fatal and non-fatal burdens consistently increased among young adults (35–54 years). Conclusion While age-standardized rates have improved, the rising crude burden and shift towards younger adults present significant public health challenges. These trends highlight the pressing need for aggressive and targeted risk factor control, sustained risk monitoring, and strengthened acute and post-stroke care to mitigate the growing health burden of stroke in the Philippines.

Abstract Castleman disease (CD) is a heterogeneous group of lymphoproliferative disorders anatomically classified by distribution (unicentric CD [UCD], oligocentric CD [oligoCD], or multicentric CD [MCD]). Human herpes virus 8–negative MCD is called idiopathic MCD (iMCD), which includes clinical subtypes with varying phenotypes and responses: TAFRO (thrombocytopenia, anasarca, fever, renal dysfunction and/or reticulin fibrosis, and organomegaly), IPL (idiopathic plasmacytic lymphadenopathy), and not otherwise specified. OligoCD has recently emerged as an intermediate form between UCD and MCD, with unclear clinical behavior, and IPL has not been validated in a Western cohort. We retrospectively analyzed 217 patients with CD evaluated at our institution between January 2004 and August 2024. Survival probabilities were compared using log-rank tests. Overall, 57% had UCD, 20% had oligoCD, and 23% had iMCD. Patients with oligoCD and iMCD more frequently exhibited systemic symptoms than those with UCD. Patients with oligoCD and iMCD had significantly shorter event-free survival (EFS) of 8.9 and 2.3 years, respectively, than those with UCD (not reached; P< .001 and P< .02). Among iMCD subtypes, iMCD-IPL demonstrated a longer EFS than iMCD-TAFRO (P = .02), with no deaths during the follow-up periods. The results validate oligoCD and iMCD-IPL as new subtypes in this Western cohort. The survival outcome in oligoCD was intermediate between UCD and iMCD, with only a subset of patients with oligoCD requiring systemic therapy. iMCD-IPL had a favorable survival outcome in this US cohort, similar to what has been reported in non-Western countries. Tailoring treatment strategies to disease subtypes and vigilant monitoring of oligoCD for progression may improve survival outcomes in CD.

Abstract Introduction: Patients with multiple myeloma (MM) have an increased risk of infection secondary to hypogammaglobulinemia, due to myeloma itself and anti-myeloma therapies. Prophylactic immunoglobulin (Ig) supplementation has been considered a potential strategy to reduce the risk of infections. A randomized controlled trial (Chapel, Lancet, 1994) demonstrated a reduction in both overall and major infections with the use of Ig. However, its real-world benefit remains unclear and prophylactic Ig is not routinely given as part of standard therapies. Furthermore, little is known regarding the routine use of Ig in the context of modern therapeutic agents such as chimeric antigen receptor T-cell (CAR-T) therapy or bispecific antibody therapies. To address this gap, we conducted an updated systematic review and meta-analysis (SRMA) to elucidate the efficacy of prophylactic immunoglobulin in patients with MM. Methods: We performed a SRMA of observational and randomized controlled trials comparing the outcomes in patients with MM who received prophylactic immunoglobulin versus those who did not. A comprehensive search of PubMed, Scopus, and Cochrane CENTRAL databases was conducted up to July 2025, along with a manual review of the reference lists from relevant articles. This review adheres to the recommendations from the Cochrane Collaboration and the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement guidelines. R software version 4.5.1 was used for statistical analyses. Results: A total of 18 studies were included in the systematic review. Among them, 11 studies compared patients who received immunoglobulin prophylaxis with those who did not (“Ig” versus “no Ig” groups). The remaining seven studies analyzed the same group of patients, comparing periods when they were receiving Ig (“on-Ig”) with periods when they were not (“off-Ig”). Among 18 studies, 13 studies were included in meta-analysis due to data availability (eight from the former group and five from the latter group). First, we conducted a meta-analysis of 1,234 patients from the eight studies that preceded this analysis, comparing Ig and no-Ig. Three studies included MM patients treated with bispecific antibodies, two focused on those treated with autologous stem cell transplantation (ASCT), and one on those treated with anti-CD38 antibodies. The dose of Ig was 0.4 g/kg every four weeks in most studies, and the timing of initiation of Ig varied across studies. The majority of Ig was delivered through an intravenous route. Most studies defined severe infections as those greater than grade 3 according to the Common Terminology Criteria for Adverse Events, while one study defined them as infections requiring intravenous or oral antibiotic treatment. The incidence of severe infection was significantly lower in patients who received prophylactic Ig compared with those who did not (odds ratio [OR] 0.22; 95% CI 0.08-0.63; p = 0.005). There was no significant difference in the overall infection rate between the two groups (OR 0.97; 95% CI 0.68-1.37; p = 0.85). A subgroup analysis by treatment type (chemotherapy, bispecific antibody, and ASCT) showed no significant differences in the overall infection rate among the subgroups (ASCT: OR 0.97; 95% CI 0.64-1.45; Bispecific antibody: OR 0.74; 95% CI 0.49-1.11). However, a significant reduction in the rate of severe infections was observed in patients treated with bispecific antibodies (OR 0.33; 95% CI 0.13-0.85; p = 0.021). Next, we analyzed 460 patients from the latter five studies comparing on-Ig and off-Ig. The incidence rate ratio (IRR) of overall infection was significantly lower during on-Ig periods compared with off-Ig periods (IRR 0.62; 95% CI 0.43-0.88; p = 0.0082). Conclusions: In patients with MM, prophylactic Ig use was associated with a low incidence of severe infections. Furthermore, the incidence rate ratio of overall infection was lower during periods of Ig prophylaxis compared to periods without Ig. These findings underscore the potential efficacy of a routine Ig prophylaxis in patients with MM to mitigate the risk of infections. Since this meta-analysis does not include studies involving patients treated with CAR-T therapy, further studies are warranted to evaluate the effectiveness of Ig in patients receiving novel therapies such as CAR-T therapy, while also considering the cost and time associated with Ig administration in real-world clinical practice.

Abstract Introduction: Castleman disease (CD) is a heterogeneous group of lymphoproliferative disorders classified anatomically as unicentric (UCD), oligocentric (OligoCD), or multicentric (MCD). Human herpesvirus 8 (HHV-8)-negative MCD is referred to as idiopathic MCD (iMCD), which includes clinical subtypes with distinct phenotypes and treatment responses: TAFRO (thrombocytopenia, anasarca, fever, renal dysfunction and/or reticulin fibrosis, and organomegaly), idiopathic plasmacytic lymphadenopathy (IPL), and not otherwise specified (NOS). While UCD and iMCD, including TAFRO, have been more clearly defined, OligoCD and iMCD-IPL remain under-characterized, particularly in Western cohorts. This study aimed to validate the updated clinical classification of CD using a large institutional cohort by retrospectively reclassifying patients based on lymph node distribution and clinicopathologic criteria. We further examined whether OligoCD and IPL represent clinically and prognostically distinct entities compared to UCD or iMCD, and other iMCD subtypes. Methods: This study included 217 patients evaluated for CD at our institution between January 2004 and August 2024. All cases were reclassified based on the extent of lymph node involvement and iMCD subtype. UCD was defined as the involvement of a single lymph node region. OligoCD was defined as involvement of ≥2 contiguous lymph node stations without sufficient systemic symptoms to meet iMCD criteria. Patients with POEMS syndrome or HIV/HHV-8–associated CD, or lacking pathologic confirmation, were excluded. We evaluated clinical presentation, laboratory data, histopathology, treatment regimens, and outcomes. The primary endpoint was overall survival (OS), and the secondary endpoint was event-free survival (EFS), defined as time from first-line treatment to progression, change in therapy, or death. Survival outcomes were assessed using the log-rank test. Results: Among 217 CD patients, 123 (57%) had UCD, 43 (20%) had OligoCD, and 51 (23%) had iMCD. iMCD-defining symptoms were more common in iMCD compared to UCD and OligoCD. Among all, only fatigue and organomegaly were more common in OligoCD than in UCD. Laboratory values related to CD disease activities, including hemoglobin, serum creatinine, albumin, CRP, and plasma IL-6, showed significant differences in iMCD compared to UCD and OligoCD. No significant difference in the laboratory findings was observed between UCD and OligoCD, although patients with OligoCD had intermediate values between UCD and iMCD. With median follow-up of 4.0, 7.6, and 4.6 years for UCD, OligoCD, and iMCD, respectively, the 5-year OS was 99.0%, 97.7%, and 89.5% without differences among groups. Corresponding 2-year EFS rates were 95.2% for UCD, 68.0% for OligoCD, and 53.8% for iMCD. With OligoCD being the reference, UCD had a significantly lower hazard ratio (HR) of 0.20 (95% CI 0.10–0.41), and iMCD had a significantly higher HR of 2.0 (95% CI 1.1–3.6). Among OligoCD patients initially treated with surgery (40%), none required systemic therapy thereafter. Those treated with rituximab or glucocorticoid monotherapy required subsequent therapy in 50% and 43%, respectively. Within iMCD subtypes (TAFRO (n=16), IPL (n=9), and NOS (n=26)), the 5-year OS was 80.4%, 100%, and 91.0%, respectively, without significant differences among the subtypes. However, 1-year EFS rates were 40.2%, 100%, and 65.6%, respectively, with an HR of 4.3 (95% CI 1.2–15.2; p = 0.02) in TAFRO and 1.6 (95% CI 0.77–3.5) in NOS compared to IPL. Patients with IPL had a high rate of symptomatic improvement assessed by a physician of 89% with a longer time-to-next treatment. Conclusions: This extensive, retrospective cohort study supports the clinical relevance of updated CD subtype classification. As the present study spans two decades, it reflects evolving diagnostic criteria and therapeutic standards, including the 2014 FDA approval of siltuximab, the iMCD consensus criteria in 2017, with the addition of OligoCD and iIPL. The findings confirm the aggressive clinical nature of iMCD and suggest that OligoCD demonstrated intermediate features between UCD and iMCD, though closer to UCD in outcome. Also, the results reconfirmed that TAFRO is associated with severe symptomatic diseases, and validated that patients with IPL, even in the Western cohort, likely have favorable responses to treatment. Continued prospective efforts are warranted to confirm the clinical distinctions.

Abstract Introduction: Idiopathic multicentric Castleman disease (iMCD) is a rare lymphoproliferative disorder characterized by systemic inflammation of unknown etiology. Clinically, iMCD is classified into idiopathic plasmacytic lymphadenopathy (IPL), thrombocytopenia, anasarca, fever, renal dysfunction/reticulin fibrosis, and organomegaly (TAFRO), and not otherwise specified (NOS) subtypes. Among these, TAFRO and a subset of NOS cases share overlapping clinicopathological features and often follow a fatal clinical course. However, the pathogenesis remains largely undefined. This study combines a comprehensive transcriptomic analysis with histological assessment, focusing on vascular proliferation to elucidate the molecular mechanisms of the TAFRO subtype. Methods: We conducted a pathological analysis of nine IPL, nine TAFRO, and eight NOS cases, and performed transcriptome analysis from frozen lymph node specimens from 12, two, and four IPL, TAFRO, and NOS cases, respectively. Differentially expressed genes (DEGs) and KEGG pathway analysis were performed to identify significant pathways in TAFRO and NOS, with IPL cases as controls. Results: Histologically, TAFRO and NOS exhibited a significantly higher degree of vascularization than IPL (IPL vs TAFRO: p < 0.001, IPL vs NOS: p = 0.002). In addition, “whirlpool vessels” in GCs were seen in most cases in TAFRO and NOS (TAFRO: 9/9, 100%, NOS: 6/8, 75%), but not in IPL (IPL vs TAFRO: p < 0.001, IPL vs NOS: p = 0.007). Immunostaining for Ets-related gene revealed that the number of endothelial cells of TAFRO and NOS was significantly larger than that in IPL (TAFRO vs IPL: p < 0.001, NOS vs IPL: p = 0.002). KEGG pathway analysis revealed the PI3K–Akt signaling pathway was significantly enriched in the TAFRO/NOS groups. Immunohistochemistry of phosphorylated Akt and phosphorylated p38, both upstream and downstream effectors of the PI3K–Akt signaling pathway, were positive in vascular endothelial cells of TAFRO and NOS. Discussion: TAFRO and NOS exhibit marked angiogenesis and are histologically distinct from IPL. Furthermore, this angiogenesis is thought to be driven by upregulation of the PI3K–Akt signaling pathway, which may also contribute to extravascular fluid leakage, potentially leading to pleural and ascitic effusion or systemic edema observed in the TAFRO subtype. Conclusion: The present results suggest the crucial role of PI3K–Akt signaling pathway in TAFRO pathogenesis from transcriptomic and histopathological findings. This mechanistic insight may help elucidate the distinct pathogenesis of iMCD subtypes.

Abstract Introduction: The epidemiology and clinical characteristics of familial myelodysplastic syndromes/acute myeloid leukemia (MDS/AML) remain poorly understood, particularly among Native Hawaiians and Other Pacific Islanders (NHOPI). Methods: To investigate the real-world evidence in this area, we conducted a retrospective study at the Queen's Medical Center (QMC), Hawaii's largest tertiary referral hospital. The data was gathered from QMC's electronic medical record. Familial MDS or familial AML patients in this study were defined as MDS or AML occurring in a patient with a family history of MDS and/or AML. Patients with acute promyelocytic leukemia (APL), as well as those with a family history of APL, were excluded given the differences in disease characteristics and its genetic phenotype from other AML subtypes. Unspecified leukemia was defined when a patient had a family history of leukemia but the specific subtype was unavailable. Some patients underwent comprehensive panel testing, while others had targeted next-generation sequencing (NGS) assays ordered at the discretion of their treating physicians. NGS was performed at Clinical Laboratory Improvement Amendments (CLIA)-certified commercial laboratories. NGS panels typically included the following genes: ASXL1, BCOR, BRAF, CEBPA, CSF3R, DNMT3A, ETV6, EZH2, FLT3, HRAS, IDH1, IDH2, JAK2, KIT, KRAS, MLL, NPM1, NRAS, PDGFRA, PHF6, PML, PTPN11, RUNX1, SETBP1, STAG2, TET2, TP53, and WT1. Results: Among 1,686 MDS/AML patients presented between January 2012 and July 2023, 12 (0.71 %) had familial MDS/AML and 25 (1.48%) had a family history of unspecified leukemia. While no NHOPI were identified among familial MDS/AML cases, 20% of patients with a family history of unspecified leukemia were NHOPI. The median age at diagnosis of familial MDS/AML was 70 years, and 50% of familial MDS patients had MDS with low blasts based on the World Health Organization 2022 classification. Based on International Consensus Classification 2022 criteria, 25% had MDS, not otherwise specified (NOS) with multilineage dysplasia, and 25% had MDS, NOS with single lineage dysplasia. Among the eight patients with familial MDS, the median overall survival (OS) was 12.7 years, with an estimated 5-year OS rate of 75.0% (95% CI: 12.8–96.1), based on Kaplan–Meier analysis. In contrast, the three patients with familial AML had a median survival of 10.2 months and a 3-year OS estimate of 33.3% (95% CI: 0.90–77.4). For patients with a family history of unspecified leukemia, the median survival was not reached during the follow-up period. The estimated 5-year OS rate was 53.3% (95% CI: 12.5–82.7) for the 10 familial MDS cases and 53.3% (95% CI: 20.9–77.3) for the 13 familial AML cases. When combining all familial cases, the median OS for familial MDS (n = 18) was 12.7 years with a 5-year OS rate of 61.9% (95% CI: 26.8–84.0). The median OS for familial AML (n = 16) was 0.90 years, and the estimated 5-year OS rate was 48.2% (95% CI: 20.8–71.3). When all cases were combined, there was no statistically significant difference in overall survival between patients with familial AML (n = 16) and those with familial MDS (n = 18), based on the log-rank test (p = 0.22). Regarding NGS, ASXL1 mutations were the most frequent in the cohort, detected in six of the 32 NGS tests performed (18.8%). Among patients with familial MDS, recurrent somatic mutations were observed in several genes. ASXL1 mutations were identified in two patients; one had a brother with MDS, and the other had a maternal uncle with unspecified leukemia. DNMT3A mutations were also found in two patients with familial MDS; one had a brother with MDS, and the other had a paternal uncle with MDS. SRSF2 mutations were detected in two patients; one had a brother with MDS, and the other had a granddaughter with leukemia. Additionally, SF3B1 mutations were found in two patients; one had a mother with MDS, and the other had a paternal uncle with MDS. Two patients with familial AML were found to have ASXL1 mutation, both with fathers who had unspecified leukemia. Otherwise, no other repeated mutations were found. None of the cases involved NHOPI patients. Conclusion: Our study offers new insights into familial MDS/AML within Hawaii's multiethnic population. Although no NHOPI patients were identified among the familial cases, our findings underscore the genetic heterogeneity and clinical variability of these disorders.

Abstract Background: Immune checkpoint inhibitors (ICIs) have been established as standard of care for patients with classical Hodgkin lymphoma (cHL), including relapsed or refractory (r/r) disease. However, ICIs discontinued in some patients due to treatment-related toxicities or disease progression may later be re-initiated. The outcomes of this common clinical practice of ICI re-initiation, or ‘rechallenge,‘ have not been evaluated. Here, we present real-world efficacy and safety data of ICI rechallenge in patients with cHL. Methods: We conducted a retrospective cohort study of patients with cHL treated with ICIs between 2015 and 2024 at Mayo Clinic sites. Patients were identified via institutional records using diagnostic and treatment codes. Included patients were adults ≥18 years with histologically confirmed diagnosis of cHL receiving ≥1 cycle of ICI therapy. Patients in the rechallenge cohort received a second course of ICI therapy following discontinuation of the initial ICI for any reason. The control cohort included patients with ICI discontinuation without subsequent rechallenge. Primary outcomes included progression-free survival (PFS), event-free survival (EFS), and duration of response (DOR), defined respectively as time from first ICI initiation to disease progression, time from first ICI initiation to disease progression, adverse events, treatment change, or death, and time from first recorded response per positron emission tomography–computed tomography until the occurrence of disease progression. Secondary outcomes included overall survival (OS), and incidence and severity of irAEs following ICI rechallenge. Survival outcomes were compared using propensity-score-matched (PSM) cohorts with a proportional Cox model. Results: A total of 145 patients were included. Of these, 30 (21%) underwent ICI rechallenge, while 115 (79%) received no subsequent ICI treatments. The median age was 40 years (interquartile range [IQR] 26-66). Most were male (59%), predominantly nodular sclerosis subtype (71%), Ann Arbor stage III-IV disease (65%), and ECOG ≤ 1 (96%). ICIs were utilized for r/r disease in 66%, with median 6 (IQR 4-13) cycles and follow up of 40.8 months (IQR 21.1–78.1). Patients received median 1 prior line of therapy (IQR 0-2.5). During initial ICI treatment, 34/145 patients (23%) experienced irAEs, including 17 patients (57%) in the rechallenge group and 17 (15%) in the non-rechallenge group. Most irAEs were of grade 1–2 severity, though 10 (30%) experienced grades ≥3 irAEs. irAE severity did not differ between groups. Among patients who underwent ICI rechallenge, the majority (53%) discontinued due to irAEs. The decision to pursue ICI rechallenge was driven predominantly by disease progression (63%). Among the 1:1 PSM cohorts using bone marrow transplant status and the International Prognostic Score, PFS did not significantly differ between rechallenged vs. non-rechallenged groups (HR 1.7, 95% CI 0.60–4.5, p=0.32). Similarly, no difference was noted among the groups in EFS and DOR using 1:3 PSM cohorts using the number of ICI cycles (HR 1.6, 95% CI 0.83–3.0, p = 0.16 and HR 1.6, 95% CI 0.37–7.0, p = 0.53, respectively). In the 1:1 matched cohort, ICI rechallenge was not associated with inferior OS compared to those without rechallenge (HR 1.6, 95% CI 0.48–5.4, p=0.43). irAE occurred in 20%, including pneumonitis (n=2), hepatitis (n=1), and pancreatitis (n = 1). Of the patients who had experienced irAEs during their initial ICI course, only two developed recurrent irAEs of the same type upon rechallenge, both at reduced severity. Overall, 80% of rechallenged patients did not experience any irAE with their second ICI course. Conclusions: ICI rechallenge was not associated with inferior PFS, EFS, DOR or OS compared patients without rechallenge. Among patients receiving ICI rechallenge after irAE, recurrence of same irAE was rare. ICI rechallenge may be a feasible and potentially effective strategy in selected patients with cHL.