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Abstract Purpose: Knowledge of prognostic factors and long-term survival in patients with diffuse hemispheric glioma, H3 G34–mutant (DHG, H3 G34), remains limited in this tumor with a poor prognosis. Experimental Design: This retrospective, multi-institutional study investigated prognostic variables for patients with DHG, H3 G34, and their association with progression-free survival (PFS) and overall survival (OS). Uni- and multivariable Cox proportional hazard models were applied with multiple imputed datasets. Results: A total of 153 patients (142 G34R, 9 G34V, 2 via DNA methylation) were included. The median age at diagnosis was 17 years (range, 2–45). Initial gross/near total resection (GTR/NTR) was achieved in 43% of patients. Radiation was given in 91% (85% focal irradiation), and initial chemotherapy was given in 87% [70% temozolomide-based (TMZ), 25% TMZ/lomustine, 5% non-TMZ]. Median OS was 24 months [interquartile range (IQR), 22–28] with a median PFS of 14 months (IQR, 12–19). Twelve patients (8%) were found to be long-term survivors (≥5 years). Exploratory multivariable analysis showed that adjuvant radiotherapy [HR, 0.076; 95% confidence interval (CI), 0.033–0.17] and achieving GTR/NTR compared with < NTR (HR, 0.51; 95% CI, 0.33–0.78) were associated with improved PFS. Multivariable analysis showed improved OS with increasing age at diagnosis (HR, 0.70; 95% CI, 0.57–0.87), initial radiotherapy (HR, 0.38; 95% CI, 0.15–0.96), and initial GTR/NTR compared with < NTR (HR, 0.60; 95% CI, 0.37–0.97). Conclusions: This cohort highlights prognostic factors for patients with DHG, H3 G34, and describes relapse patterns and therapy approaches. Clinical trials and prospective registries are needed to improve outcomes.

7073 Background: The Optimized HLH Inflammatory (OHI) index (Zoref-Lorenz et al., Blood , 2022), based on serum soluble CD25 (sCD25) and ferritin, is a prognostic tool identifying inflammation in the hemophagocytic lymphohistiocytosis (HLH) spectrum and early mortality risk. Prior studies were retrospective and enriched with HLH-suspected cases. We hypothesized that the OHI index would predict outcomes in unselected diffuse large B-cell lymphoma (DLBCL). Methods: 670 newly diagnosed DLBCL patients from a prospective cohort (2002–2015) were analyzed: 335 for discovery and 335 for validation. Pre-treatment serum sCD25 and ferritin levels were quantified via ELISA, and we evaluated original thresholds (sCD25 ≥ 3,900 U/mL; ferritin ≥ 1,000 ng/mL) and developed DLBCL-optimized thresholds (using receiver operator curves) for predicting 500-day mortality. We also evaluated event-free survival (EFS), EFS at 24 months (EFS24), and overall survival (OS). Results: The median age was 64, and 51% were male. Using original thresholds, 4.2% (n=14) of patients were OHI+, with a 5.6-fold higher risk of 500-day mortality (95% CI 1.6–17; p<0.001). Optimized thresholds identified 23.6% (n=78) as OHI+ with a 9.2-fold higher 500-day mortality risk (95% CI 4.0–24; p<0.001). Optimized OHI+ also had a higher risk of EFS24 failure and inferior EFS and OS (Table). OHI+ patients had higher rates of B symptoms (35% vs. 20%; p=0.027), elevated LDH (76% vs. 34%; p<0.001), worse performance status (ECOG ≥2: 38% vs. 12%; p<0.001), and advanced-stage disease (Stage IV: 57% vs 38%; p<0.001), though IPI scores (3–5) were not significantly different (44% vs 36%; p=0.28). Adjusting for age and IPI, OHI+ independently predicted 500-day mortality (OR=5.0; CI 1.9–13; p=0.001), EFS24 failure (OR=3.2; CI 1.5–6.5; p=0.0018), and inferior long-term EFS (HR=2.2; CI 1.1–4.3; p=0.030) and OS (HR=2.0; CI 1.0–4.0; p=0.040) at a median follow up of 9.8 years in living patients. In validation, optimized OHI predicted 500-day mortality, EFS24 failure, and long-term OS and EFS (Table). Cytokine profiling revealed elevated inflammatory markers in OHI+ patients, including IL1a (p=0.008), CCL2 (p=0.03), CXCL10 (p<0.001), and CXCL9 (p<0.001), reflecting systemic hyperinflammation. Conclusions: The OHI index is a powerful predictor of early and long-term outcomes in DLBCL patients. Optimized thresholds identify a larger OHI+ group, highlighting hyperinflammation’s critical role in poor outcomes. These findings support its use in routine management and clinical trial design for novel therapies. Odds ratios or hazard ratios and p-values for optimized OHI+ and DLBCL prognosis. Outcome Discovery Validation OR for 500-day mortality 9.2; p<0.001 4.0; p=0.002 OR for EFS24 failure 5.2; p <0.001 6.3; p<0.001 HR for OS 2.3; p<0.001 1.8; p=0.006 HR for EFS 2.4; p<0.001 2.5; p<0.001

Background: The Optimized Hemophagocytic Lymphohistiocytosis (HLH) Inflammatory (OHI, Zoref-Lorenz et al, Blood, 2022) index, defined by the combined elevation in serum soluble CD25 (sCD25) and ferritin, has emerged as a promising prognostic tool for patients with newly diagnosed hematologic malignancies, demonstrating superior performance in predicting 500-day mortality compared to HLH-2004 criteria. However, previous studies were retrospective, with a substantial proportion (65%) of patients suspected clinically to have HLH. We evaluated the performance of the OHI index in an unselected, prospective cohort of newly diagnosed diffuse large B-cell lymphoma (DLBCL) patients. Methods: We analyzed the predictive utility of the OHI index in 331 newly diagnosed DLBCL patients enrolled from 2002-2015 in the prospective Iowa/Mayo Molecular Epidemiology Resource cohort. Ferritin and sCD25 levels were quantified in pre-treatment serum samples using R&D ELISA kits. OHI values were also optimized based on 500-day mortality in the cohort using receiver operating curve analysis with internal validation. Patients were classified as OHI+ using the original and newly optimized thresholds for sCD25 and ferritin. The primary endpoint was 500-day survival, and the secondary endpoints were event-free survival (EFS) at 24 months (EFS24), EFS, and overall survival (OS). The predictive capability of the OHI index was evaluated using logistic regression to determine odds ratios (OR) and 95% confidence intervals (CI) for 500-day mortality and EFS24, as well as Cox regression to calculate hazard ratios (HR) and 95% CIs for EFS and OS. Results: The median age at diagnosis of the 331 patients was 63.5 years (interquartile range, 54.5-74), and 168 (51%) were male. Using the original thresholds (sCD25 3,900 U/mL and ferritin 1,000 ng/mL), 4.2% of patients were OHI+, with a more than 5-fold higher 500-day mortality risk compared to OHI- patients (OR=5.6; CI 1.6-17, p&lt;0.001). After optimizing thresholds for sCD25 (2,400 U/mL) and ferritin (250 ng/mL) to predict 500-day mortality, 23.6% were OHI+ and the OHI+ group had a 9-fold higher 500-day mortality risk (OR=9.2; CI 4.0-24, p&lt;0.001), with 31% mortality in the OHI+ vs 5% in the OHI- group. OHI+ patients exhibited more B-symptoms (35% vs 20%, p=0.027), elevated LDH levels (76% vs 34%, p&lt;0.001), poorer performance status (Eastern Cooperative Oncology Group 2+: 38% vs 12%, p&lt;0.001), and more advanced stage disease (Stage IV: 57% vs 38%, p&lt;0.001), although the frequency of a high International Prognostic Index (IPI) was not statistically different between the groups (IPI 3-5: 44% vs 36%, p=0.28). After adjusting for age and IPI, OHI+ remained a strong predictor of 500-day mortality (OR=5.0; CI 1.9-13, p=0.001). Further adjustment for the cell of origin did not impact the results. The association of OHI+ status with 500-day mortality was similar in IPI 0-2 (OR=5.8; CI 1.2-29, p=0.033) and 3-5 (OR=6.8; CI 0.6-73, p=0.11). OHI+ patients were also more likely to not achieve EFS24 (45% vs 13%), with a 3-fold greater risk after adjusting for age and IPI (OR=3.2; CI 1.5-6.5, p=0.0018). The OHI index also retained its predictive ability over longer-term follow-up (median 9.8 years for living patients) for both OS (HR=2.0; CI 1.0-4.0, p=0.040) and EFS (HR=2.2; CI 1.1-4.3, p=0.030) after adjusting for age and IPI. Cytokine profiling using multiplex ELISA identified elevated inflammatory markers in OHI+ patients, underscoring the role of systemic inflammation in prognosis. The distribution of cytokines was significantly different between the groups, with consistently higher means in the OHI+ vs OHI- group, including IL1a (1,628 vs 759 pg/ml, p=0.008), CCL2 (1,020 vs 724 pg/ml, p=0.028), CXCL10 (165 vs 53 pg/ml, p&lt;0.0001), and CXCL9 (380 vs 150 pg/ml, p&lt;0.0001). Conclusions: While the original OHI index for prediction of 500-day mortality was validated in this unselected cohort of newly diagnosed DLBCL patients, optimization of the OHI thresholds identified a larger OHI+ group (24%), enhanced the identification of hyperinflammation, improved predictive ability for early (500-day) mortality, and predicted EFS24 status and long-term OS. This underscores the clinical relevance of the OHI index, supports the need to evaluate disease-specific thresholds, and suggests its potential for use in routine management and as enrollment criteria in clinical trials for novel therapies.

PURPOSE This randomized, open-label trial compared the efficacy and safety of adjuvant nab-paclitaxel + gemcitabine with those of gemcitabine for resected pancreatic ductal adenocarcinoma (ClinicalTrials.gov identifier: NCT01964430 ). METHODS We assigned 866 treatment-naive patients with pancreatic ductal adenocarcinoma to nab-paclitaxel (125 mg/m 2 ) + gemcitabine (1,000 mg/m 2 ) or gemcitabine alone to one 30-40 infusion on days 1, 8, and 15 of six 28-day cycles. The primary end point was independently assessed disease-free survival (DFS). Additional end points included investigator-assessed DFS, overall survival (OS), and safety. RESULTS Two hundred eighty-seven of 432 patients and 310 of 434 patients completed nab-paclitaxel + gemcitabine and gemcitabine treatment, respectively. At primary data cutoff (December 31, 2018; median follow-up, 38.5 [interquartile range [IQR], 33.8-43 months), the median independently assessed DFS was 19.4 ( nab-paclitaxel + gemcitabine) versus 18.8 months (gemcitabine; hazard ratio [HR], 0.88; 95% CI, 0.729 to 1.063; P = .18). The median investigator-assessed DFS was 16.6 (IQR, 8.4-47.0) and 13.7 (IQR, 8.3-44.1) months, respectively (HR, 0.82; 95% CI, 0.694 to 0.965; P = .02). The median OS (427 events; 68% mature) was 40.5 (IQR, 20.7 to not reached) and 36.2 (IQR, 17.7-53.3) months, respectively (HR, 0.82; 95% CI, 0.680 to 0.996; P = .045). At a 16-month follow-up (cutoff, April 3, 2020; median follow-up, 51.4 months [IQR, 47.0-57.0]), the median OS (511 events; 81% mature) was 41.8 ( nab-paclitaxel + gemcitabine) versus 37.7 months (gemcitabine; HR, 0.82; 95% CI, 0.687 to 0.973; P = .0232). At the 5-year follow-up (cutoff, April 9, 2021; median follow-up, 63.2 months [IQR, 60.1-68.7]), the median OS (555 events; 88% mature) was 41.8 versus 37.7 months, respectively (HR, 0.80; 95% CI, 0.678 to 0.947; P = .0091). Eighty-six percent ( nab-paclitaxel + gemcitabine) and 68% (gemcitabine) of patients experienced grade ≥ 3 treatment-emergent adverse events. Two patients per study arm died of treatment-emergent adverse events. CONCLUSION The primary end point (independently assessed DFS) was not met despite favorable OS seen with nab-paclitaxel + gemcitabine.

Abstract Background Pineoblastoma is a rare brain tumor usually diagnosed in children. Given its rarity, no pineoblastoma-specific trials have been conducted. Studies have included pineoblastoma accruing for other embryonal tumors over the past 30 years. These included only occasional children with pineoblastoma, making clinical features difficult to interpret and determinants of outcome difficult to ascertain. Patients and Methods Centrally or independently reviewed series with treatment and survival data from North American and Australian cases were pooled. To investigate associations between variables, Fisher’s exact tests, Wilcoxon-Mann-Whitney tests, and Spearman correlations were used. Kaplan-Meier plots, log-rank tests, and Cox proportional hazards models were used in survival analyses. Results We describe a pooled cohort of 178 pineoblastoma cases from Children’s Oncology Group (n = 82) and institutional series (n = 96) over 30 years. Children &lt;3 years of age have significantly worse survival compared to older children, with 5-year progression-free survival (PFS) and overall survival (OS) estimates of 13.5 ± 5.1% and 16.2 ± 5.3%, respectively, compared with 60.8 ± 5.6% and 67.3 ± 5.0% for ≥3 years old (both P &lt; .0001). Multivariable analysis showed male sex was associated with worse PFS in children &lt;3 years of age (hazard ratio [HR] 3.93, 95% CI 1.80-8.55; P = .0006), suggestive of sex-specific risks needing future validation. For children ≥3 years of age, disseminated disease at diagnosis was significantly associated with an inferior 5-year PFS of 39.2 ± 9.7% (HR 2.88, 95% CI 1.52-5.45; P = .0012) and 5-year OS of 49.8 ± 9.1% (HR 2.87, 95% CI 1.49-5.53; P = .0016). Conclusion Given the rarity of this tumor, prospective, collaborative international studies will be vital to improving the long-term survival of these patients.

PURPOSE SJMB03 (ClinicalTrials.gov identifier: NCT00085202 ) was a phase III risk-adapted trial that aimed to determine the frequency and clinical significance of biological variants and genetic alterations in medulloblastoma. PATIENTS AND METHODS Patients 3-21 years old were stratified into average-risk and high-risk treatment groups based on metastatic status and extent of resection. Medulloblastomas were molecularly classified into subgroups (Wingless [WNT], Sonic Hedgehog [SHH], group 3, and group 4) and subtypes based on DNA methylation profiles and overlaid with gene mutations from next-generation sequencing. Coprimary study end points were (1) to assess the relationship between ERBB2 protein expression in tumors and progression-free survival (PFS), and (2) to estimate the frequency of mutations associated with WNT and SHH tumors. Clinical and molecular risk factors were evaluated, and the most robust were used to model new risk-classification categories. RESULTS Three hundred thirty eligible patients with medulloblastoma were enrolled. Five-year PFS was 83.2% (95% CI, 78.4 to 88.2) for average-risk patients (n = 227) and 58.7% (95% CI, 49.8 to 69.1) for high-risk patients (n = 103). No association was found between ERBB2 status and PFS in the overall cohort ( P = .74) or when patients were stratified by clinical risk ( P = .71). Mutations in CTNNB1 (96%), DDX3X (37%), and SMARCA4 (24%) were most common in WNT tumors and PTCH1 (38%), TP53 (21%), and DDX3X (19%) in SHH tumors. Methylome profiling classified 53 WNT (17.4%), 48 SHH (15.7%), 65 group 3 (21.3%), and 139 group 4 (45.6%) tumors. A comprehensive clinicomolecular risk factor analysis identified three low-risk groups (WNT, low-risk SHH, and low-risk combined groups 3 and 4) with excellent (5-year PFS > 90%) and two very high-risk groups (high-risk SHH and high-risk combined groups 3 and 4) with poor survival (5-year PFS < 60%). CONCLUSION These results establish a new risk stratification for future medulloblastoma trials.