Citations

Background: Thrombotic thrombocytopenic purpura (TTP) is a life-threatening hematologic emergency caused by ADAMTS13 deficiency, leading to microvascular thrombosis, haemolytic anaemia, thrombocytopenia, and end-organ damage. Neurological symptoms occur in up to 90% of cases and are frequently misdiagnosed as stroke. Prompt recognition and treatment reduce the mortality rate from over 90% to 10–20%. Case presentation: A 70-year-old woman with no significant medical history presented with acute aphasia and right-sided facial and upper extremity numbness. Five days prior, she had experienced fatigue, headache, and bruising. On admission, she had stable vitals with mild aphasia and purpuric ecchymoses noted on examination. Laboratory findings revealed haemolytic anaemia (haemoglobin 7.8 g/dl, lactate dehydrogenase 875 U/l, total bilirubin 2.4 mg/dl), thrombocytopenia (35 ×109/l), and unremarkable coagulation studies (partial thromboplastin time 30 sec, prothrombin time-international normalized ratio 1, fibrinogen 370 mg/dl, D-dimer 2.15 ng/ml). Peripheral smear showed no schistocytes but noted 2+spherocytes. Stroke was ruled out with brain magnetic resonance imaging/magnetic resonance angiography. Given the bicytopenia with possible haemolysis along with new neurological symptoms, TTP was considered in the differential diagnosis. A PLASMIC score of 5 suggested a high probability of TTP. Plasma exchange and corticosteroids were initiated within 5 hours of presentation. ADAMTS13 activity <1% confirmed the diagnosis 4 days after presentation. After five plasma exchange sessions, the patient’s platelet count normalized and neurologic deficits resolved by discharge. Conclusion: This case underscores the importance of considering TTP in stroke mimics, even in the absence of schistocytes, if clinical suspicion is high. Early recognition and initiation of treatment significantly improve patient outcomes.

ABSTRACTIdiopathic multicentric Castleman disease (iMCD) is a rare lymphoproliferative disorder classified into three recognized clinical subtypes—idiopathic plasmacytic lymphadenopathy (IPL), TAFRO, and NOS. Although clinical criteria are available for subtyping, diagnostically challenging cases with overlapping histopathological features highlight the need for an improved classification system integrating clinical and histopathological findings. We aimed to develop an objective histopathological subtyping system for iMCD that closely correlates with the clinical subtypes. Excisional lymph node specimens from 94 Japanese iMCD patients (54 IPL, 28 TAFRO, 12 NOS) were analyzed for five key histopathological parameters: germinal center (GC) status, plasmacytosis, vascularity, hemosiderin deposition, and “whirlpool” vessel formation in GC. Using hierarchical clustering, we visualized subgroups and developed a machine learning‐based decision tree to differentiate the clinical subtypes and validated it in an external cohort of 12 patients with iMCD. Hierarchical cluster analysis separated the IPL and TAFRO cases into mutually exclusive clusters, whereas the NOS cases were interspersed between them. Decision tree modeling identified plasmacytosis, vascularity, and whirlpool vessel formation as key features distinguishing IPL from TAFRO, achieving 91% and 92% accuracy in the training and test sets, respectively. External validation correctly classified all IPL and TAFRO cases, confirming the reproducibility of the system. Our histopathological classification system closely aligns with the clinical subtypes, offering a more precise approach to iMCD subtyping. It may enhance diagnostic accuracy, guide clinical decision‐making for predicting treatment response in challenging cases, and improve patient selection for future research. Further validation of its versatility and clinical utility is required.

ABSTRACTCastleman disease is a term that represents a spectrum of diseases whose driving factors are poorly understood. Increased interest prompted by the Castleman's Disease Collaborative Network has led to a better understanding of classification, which will lead to a better understanding of underlying pathology and best practices. It is essential that this entity be recognized and correctly classified by anatomic classification (unicentric, oligocentric, and multicentric), by histopathology (the gradient of hypervascular to plasmacytic), and by clinical phenotype (NOS, TAFRO, IPL, HHV8‐associated, or POEMS‐associated). Most of what we know about therapy is from retrospective studies rather than prospective therapeutic trials, but data are emerging through collaboration. The mainstay of therapy for unicentric disease is surgery. For multicentric disease interleukin‐6 blockade is essential for the non‐POEMS, non‐HHV8 multicentric cases, rituximab‐based (plus or minus antiviral) therapy for HHV8 associated cases, and IL‐6 blockade versus plasma cell directed therapy for the POEMS subtype.

11549 Background: Follicular dendritic cell sarcoma (FDCS) is a rare neoplasm with a subset associated with unicentric Castleman disease (UCD). However, the impact of CD association on clinicopathologic features and survival outcomes remains unclear. This study aims to elucidate differences in disease characteristics and outcomes in FDCS with and without CD to guide future research and clinical practice. Methods: We retrospectively analyzed 41 FDCS patients seen at Mayo Clinic between January 2000 and December 2024. Patients were categorized into CD-related (n = 9) and FDCS-only (n = 32) groups. Demographic, clinical, pathological, and survival data were compared. Kaplan-Meier survival analyses were used to evaluate overall survival (OS) and progression-free survival (PFS). Epstein-Barr virus-associated inflammatory FDCS were excluded. Results: The CD-related group was younger at diagnosis (46.0 vs. 58.0 years, p = 0.041). Among those with CD-related FDCS, FDCS was diagnosed concurrently as CD in 6/9 (66.7%) and after the diagnosis of CD in 3/9 (33.3%). The FDCS-only patients were more likely to have extranodal disease (71.9% vs. 22.2%) and to have metastasis (62.5% vs 22.2%). One CD-related FDCS patient had paraneoplastic pemphigus. Among 11 patients with next-generation sequencing (NGS) results, 9 had pathogenic mutations. The most common pathogenic mutations included CDKN2A, CDKN2B, and TRAF3 copy number losses. Surgery was the preferred first-line intervention in FDCS-only and CD-related FDCS groups (19/32, 59.4% vs. 6/9, 66.7%). Eight out of 32 (25.0%) of the FDCS-only group received chemotherapy at first-line, most commonly Gemcitabine/Docetaxel or Adriamycin/Ifosphamide. While Gemcitabine/Docetaxel was the most preferred in the second line, different regimens were pursued in the third and later lines of therapy, including Pembrolizumab, Pazopanib, and stem cell transplant. Five out of 6 patients in the CD-related FDCS group received either adjuvant radiation or chemotherapy, which led to complete remission during the follow-up periods. The median follow-up was 22.4 months for the whole population. There was a trend for better OS and PFS among CD-related FDCS patients. The respective 2-year OS rates were 100% and 66.7%, and 2-year PFS rates were 57.1% and 43.1% for CD-related FDCS and FDCS-only patients, respectively. Conclusions: This study provides novel insights into clinicopathologic differences and survival trends for FDCS. Our data would suggest a less aggressive disease course among CD-related FDCS, which implies the need for different treatment strategies for CD and non-CD-related FDCS. Further research is warranted to elucidate these mechanisms, such as multi-omic analysis on benign FDC proliferation in the microdissected UCD areas and the adjacent FDCS cells to determine factors associated with progression to sarcoma.

e14601 Background: Immune checkpoint inhibitors (ICIs) provide a long-term survival benefit across multiple cancer types, however immune-related adverse events (irAEs) occasionally disrupt treatments and impact quality of life. Peripheral edema from ICIs can occur due to increased peripheral vascular permeability. Thus, we aimed to evaluate the incidence and outcomes of ICI-related peripheral edema. Methods: MEDLINE, Embase, and Web of Science were searched to identify phase 3 randomized controlled trials (RCTs) reporting peripheral edema events in patients treated with ICIs. Incidence rates of peripheral edema were analyzed based on treatment patterns (monotherapy/combination therapy) and ICI subtypes (PD-1/PD-L1/CTLA-4). A random effect model meta-analysis was utilized to calculate pooled odds ratios of edema incidence between treatment groups. Finally, a systematic review was conducted to summarize treatment outcomes of peripheral edema associated with ICIs. Results: Overall, 58 RCTs comprising 22,590 patients were identified for the incidence analysis. Peripheral edema as treatment-related adverse events (TRAE) (Grade 1-5) occurred in 2.80% of patients receiving ICI monotherapy (n = 195/6969; PD-1 inhibitors: 2.22% [n = 104/4694], PD-L1: 3.73% [n = 58/1557], CTLA-4: 4.60% [n = 33/718]), 4.96% (n = 112/2257) of patients receiving ICI with chemotherapy, and 8.73% (n = 205/2349) of patients receiving ICI with molecular-targeted therapy. Grade 3-5 TRAE peripheral edema occurred in 0.19% (n = 13/6969) of patients treated with ICI monotherapy. Meta-analysis showed ICI monotherapy had lower TRAE peripheral edema compared to chemotherapy (OR = 0.45, 95% CI [0.27, 0.73], p = 0.001). Subgroup analysis based on ICI subtypes showed high heterogeneity in subgroups (p , I 2 = 87.1%), but PD-1 inhibitors were associated with lower incidence than chemotherapy (OR = 0.41, 95% CI [0.23, 0.73], ). Subgroup analysis of chemotherapy regimens revealed that taxane chemotherapy was associated with a higher incidence of TRAE peripheral edema than ICI monotherapy (OR = 0.32, 95% CI [0.18, 0.58], p = < 0.001), but the edema incidence was comparable between ICI monotherapy and non-taxane chemotherapy (OR = 1.05, 95% CI [0.53, 2.08], p = 0.13). A systematic review of irAE peripheral edema treatment outcomes identified 19 studies comprising 40 patients. In total, 82.5% (n = 33/40) of cases received glucocorticoid treatment, with 55.0% (n = 22/40) requiring a high dose (≥ 1 mg/kg/day) of prednisone. ICI was discontinued in 77.5% of patients (n = 31/40) due to peripheral edema with permanent discontinuation in 35% (n = 14/40). Conclusions: Peripheral edema is an occasional but clinically significant side effect of ICI therapy. Management of irAE edema can result in permanent ICI discontinuation, which has implications for cancer treatment outcomes.

e13738 Background: Persistent racial/ethnic and regional disparities in neoplasm mortality remain significant public health challenges. This study evaluates long-term trends in neoplasm mortality by race/ethnicity at the county level in the United States and examines the relationship between hospital density and mortality. Methods: Using data from the Global Burden of Disease Study (2000-2019), we analyzed age-standardized mortality rates (ASR) for neoplasms by ethnicity/raceHispanic (all races) and non-Hispanic American Indian or Alaska Native (AIAN), Asian or Pacific Islander (API), Black, and White. A joinpoint regression analysis was used to identify significant changes in the mortality trends, summarized as average annual percent change (AAPC). Correlation analysis evaluated the relationship between county-level hospital density and neoplasm mortality. Results: Neoplasm mortality rates declined across all racial/ethnic groups from 2000 to 2019, but disparities persisted. ASR per 100,000 population decreased from 240.5 (95% UI: 214.3–269.9) to 203.0 (180.8–228.3) for AIAN, 149.5 (144.9–153.9) to 115.3 (111.7–118.7) for API, 314.5 (312.1–317.0) to 218.7 (217.1–220.3) for Black, 168.4 (164.6–172.0) to 133.8 (131.0–136.4) for Latino, and 241.2 (240.5–242.0) to 187.5 (186.9–188.2) for White. AAPC from 2000 to 2019 ranged from -0.94% (AIAN) to -1.90% (Black). Gender-specific analyses revealed similar trends, with males showing slightly greater declines. Southeast states experienced slower declines compared to the Northeast. Some counties exhibited worsening mortality trends, particularly for AIAN, API, and Latino. The county-level hospital density (table) showed weak but statistically significant correlations in 2019 for AIAN (r = -0.35; p < 0.0001), White (r = -0.15; p < 0.0001), and Black (r = -0.18; p < 0.0001). No inverse correlation was observed for API (r = 0.07; p = 0.071) and Latino (r = 0.06; p = 0.012). Conclusions: While significant progress has been made in reducing neoplasm mortality, racial/ethnic and regional disparities persist, and health care access appears to contribute to this at least in part. Future analyses should evaluate mortality by cancer site and also account for broader clinical and public health infrastructure, as well as social determinants of health to better understand and address underlying disparities. The correlation between hospital density and age-standardized mortality rate from neoplasms by race/ethnicity in 2019. Correlation coefficient with mortality and hospital density AIAN API Black Latino White 2019 -0.35(-0.43 – -0.27) 0.069(-0.0058–0.14) -0.18(-0.23 –-0.13) 0.064(0.014–0.11) -0.15(-0.19 – -0.12)

e15003 Background: Antibody-drug conjugates (ADCs) have shown substantial promise as therapies for metastatic breast cancer (mBC). However, direct comparisons of different ADC-based regimens are limited. We assessed survival outcomes in mBC patients treated with ADCs. Methods: Randomized controlled trials (RCTs) published before October 2024 were searched in Medline, Embase, ClinicalTrials.gov, and Cochrane Library. Progression-free survival (PFS) and overall surcvival (OS) outcomes were extracted from the most updated publications. Participants were stratified based on molecular subtypes, hormone receptor (HR) status, duration of cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) treatment, and sensitivity to endocrine therapy (ET). Bayesian frameworks were deployed, presenting the synthesized outcomes of indirect comparisons using the surface under the cumulative ranking curve (SUCRA), hazard ratio (HR), and 95% credible interval (Crl). This study was prospectively registered on the International Platform of Registered Systemic Reviews and Meta-analysis Protocols (INPLASY) (INPLASY2024110021). Results: A total of 6449 patients from 12 RCTs of ADCs ado-trastuzumab emtansine (T-DM1), sacituzumab govitecan (SG), trastuzumab deruxtecan (T-DXd), and datopotamab deruxtecan (Dato-DXd) were included in the analysis. Compared to chemotherapy, T-DXd significantly improved PFS (HR 0.35, 95% Crl 0.15-0.84) and OS (HR 0.56, 95% Crl 0.32-1.0). SG also significantly extended OS (HR 0.65, 95% Crl 0.43-0.97) but not PFS. In HER2+ mBC, pooled analyses revealed T-DXd was the most effective treatment in terms of PFS, with a SUCRA of 94.2%, followed by T-DM1 (58.9%), and chemotherapy with HER2-directed therapy (34.2%). Synthesized outcomes of OS mirrored the PFS outcomes. In HR+/HER2- mBC (some of which was HER2-low), Dato-DXd (76.1%) showed slightly superior efficacy over SG (67.4%) for PFS, while SG (85.1%) was advantageous over Dato-DXd (49.1%) in terms of OS. Among patients with HR+/HER2+ mBC, T-DXd (80.0%), SG (55.5%), and chemotherapy with HER2-directed therapy (53.1%) were the most effective therapies for prolonging PFS. Regarding OS, SG (70.3%) and T-DM1 (60.3%) were the most effective, with comparable efficacy observed between chemotherapy with HER2-directed therapy (52.1%) and T-DXd (52.0%). In HR-/HER2+ mBC, T-DXd (78.1%), SG (56.1%), and T-DM1 (51.5%) significantly prolonged PFS, while SG (69.4%) had the most substantial benefit for OS, followed by T-DXd (62.8%) and chemotherapy with HER2-directed therapy (57.6%). Dato-DXd showed an advantage over SG in mBC patients received CDK4/6i for > 12 months. Conclusions: This network meta-analysis showed prominent survival benefits with ADC-containing regimens for mBC. Our results provide valuable insights into personalized treatment strategies for mBC patients.