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Background: Data on the clinical activity of venetoclax (ven) in lymphoplasmacytic lymphoma (LPL) are primarily limited to a phase 2 trial of ven monotherapy for a 2-year duration in 32 patients (pts) with relapsed/refractory IgM LPL who received a median of 2 prior treatments (tx), including 16 pts with prior BTK inhibitors (BTKi) (Castillo et al, JCO 2021). Overall response rate (ORR) was 84% and median progression-free survival (PFS) was 30 months (mos). We report the clinical activity of ven and prognostic factors associated with outcomes in a larger cohort. Methods: We included pts with LPL treated with ven alone at 9 US centers. The primary outcome was ORR, which included minor response (MR), partial response (PR), very good PR (VGPR), and complete response (CR) per IWWM-7. Secondary outcomes included PFS, overall survival (OS), safety of ven, and predictors of ORR, PFS, and OS. Results: Sixty-two pts were included. Twenty pts (32%) received ven on a clinical trial. At ven initiation, median age was 65 years (range 38 - 87) , 61% were male, serum monoclonal (M) protein was IgM in 50 pts (91%) (IgG/IgA in 3 (5%), absent in 2 (4%), missing n=7), median hemoglobin (Hb) was 10.4 g/dL (range 5.7-16.4), and median serum IgM was 2580 mg/dL (range 5-9300). Mutations of MYD88 and CXCR4 were present in 52 (95%; missing n = 7) and 19 (38%; missing n = 12) pts, respectively. Median lines of tx (LOT) before ven was 3 (range 1-11, 58% ≥3) including antiCD20 monoclonal antibody n=54 (87%), BTKi n=48 (77%), proteasome inhibitor n=40 (65%), and bendamustine n=31 (50%). Pts who received ven on a clinical trial were less heavily pretreated (median prior LOT = 1.5, 20% ≥3) compared with pts treated off trial (median prior LOT = 4, 76% ≥3). ORR to prior BTKi was 71% (CR 4%, VGPR 10%, PR 35%, MR 21%) (missing n=5), with a median duration of tx of 14 mos (range 0.5-119). BTKi was stopped due to progressive disease (PD) in 60% and toxicity in 40%. ORR to most recent tx before ven was 58% (CR 3%, VGPR 8%, PR 32%, MR 15%); 21% SD, 7% PD, and 15% missing. BTKi was the most frequently used tx immediately before ven (48%). Six pts (10%) required plasmapheresis up to 30 days before starting ven. Median time from diagnosis to ven initiation was 5.9 years (range 0.3-23). Ven starting dose was 200 mg in 33 pts (55%), 20 mg in 11 (18%), and 100 mg in 10 (17%) (other n=6, missing n=2). Ten pts (17%) were admitted for ven tx initiation. Maximum ven dose was 400 mg in 16 (27%) and 800 mg in 38 pts (63%) (other n=6, missing n=2). ORR to ven (missing n=3) was 73% (95% confidence interval [CI] 63-86%) (CR 2%, VGPR 21%, PR 44%, MR 7%); 23% were refractory (SD 13%, PD 10%). Median time to best response was 4 mos (range 0.5-30). Median time to peak Hb was 5 mos (range 0.1-24) and to nadir serum M protein level was 8 mos (range 0.5-34). With a median follow-up of 21.9 mos (range 2.3-70.4), the median and 3-year PFS were 30.4 mos (95% CI 11.0-38.6) and 40% (95% CI 25-54%), respectively (Figure). Median and 3-year OS were not reached (NR) (95% CI NR-NR) and 83% (95% CI 70-91%), respectively. Lymphoma was the most common cause of death (n=8/11, 73%). In univariable analyses (UVA), tx with ven on a clinical trial was associated with higher ORR (90% vs 64%; odds ratio = 8.67, 95% CI 1.04-72.16, p=.046) and superior PFS (median 39 mos (95% CI, 28.4-NR) vs 11 mos (95% CI 6.4-NR), p=.028) without a significant difference in OS. Other factors evaluated in UVA to assess association with ORR, PFS and OS were age at ven start, response to last prior tx, prior tx with BTKi, and CXCR4 mutation status. Of these, receipt of prior tx with BTKi was associated with inferior PFS (HR=2.7, 95% CI 1.1-6.5, p=.024), whereas age >65 years at ven start (HR=8.6, 95% 1.1-67.8, p=0.042) and receipt of ≥3 prior tx (HR=12.0, 95% 1.5-95.9, p=.019) were associated with inferior OS. Four pts (7%) developed laboratory tumor lysis syndrome (TLS) including 2 (3%) with clinical TLS. TLS occurred at the 400 or 800 mg dose in 3 pts (missing n=1). Ven dose interruptions and/or reductions occurred in 39%. Three pts (5%) had febrile neutropenia. Ven was stopped due to PD in 21 pts (34%), planned tx completion in 15 (24%) (median tx duration = 25 mos, range 24-28), toxicity 6 (10%), and other 4 (6%); 16 pts (26%) remain on ven. Median duration of tx for those who stopped ven was 12 mos (range 1-33). Conclusion: Ven is an effective tx option for pts with relapsed or refractory LPL. Compared with the phase 2 study, ORR and PFS were lower in this cohort of more heavily pretreated pts.

Introduction: BCMA-directed CAR-T and Bispecific T-cell engager (BiTE) therapies have shown remarkable overall response rates in heavily pretreated patients with relapsed/refractory multiple myeloma (RRMM). This has led to the approval of idecabtagene vicleucel, ciltacabtagene autoleucel and teclistamab by the FDA, EMA and other regulatory agencies. We performed a global survey on accessibility, practice patterns, and toxicity management of commercially available CAR-T and BiTE therapies. Methods: An online survey was completed by clinicians attending the International Myeloma Society's Immune Effector Cell Therapies in Multiple Myeloma Workshop, in-person or virtually, made available for 30 days after the meeting held in March 2023, Boston, MA. Results: 87 clinicians from 16 countries completed the survey, most practicing in an academic practice (86%) and in an urban environment (89%). Sixty-four percent of the respondents practice in North America followed by Europe (25.3%) including Germany, United Kingdom, Ireland, Italy, Netherlands, Spain, France, Greece, and Cyprus, and 6.9% from Asia and 3.4% from Australia. Seventy-seven percent reported CAR-T cell therapy was approved in their country with 44.8% treating 1-5 patients and 14.9% treating >5 patients per month; 67% reported BiTE therapy was approved in their country with 14.9% treating >5 patients per month. Of evaluable responses (n = 40), 62% administered CAR-T therapy inpatient and 15% administered CAR-T therapy outpatient ≥ 50% of the time. Length of time between decision to treat with CAR-T therapy to infusion was 6-12 weeks for 42% of responders and <6 weeks for only 20%. Most (75%) reported inpatient administration of BiTE therapy step-up dosing; 17.5% reported outpatient step-up dosing administered ≥ 50% of the time. Use of institutional or practice SOPs for CAR-T and BiTE therapy patient selection was reported by 85% and 58%, respectively, with the factors influencing SOP outlined in Table 1. Of available CAR-T therapies, 53% prefer cilta-cel and 23% reported CAR-T therapy preference depended most on patients' co-morbidities/frailty (89%), timing of next available apheresis (67%), age (56%), CNS disease (44%) and other factors. Maintenance therapy after CAR-T therapy was reportedly used by 25% and 5% of respondents in 1-10% and 11-50% of their patients, respectively, to “maintain level of response achieved” (50%) or “achieve a deeper level of response” (25%). About half (43%) of the respondents reported using an SOP or particular criteria for secondary Hemophagocytic Lympho-Histiocytosis/Macrophage Activation Syndrome/CAR-related-HLH (sHLH/MAS/CarHLH) management that varied between the use of ASTCT Working Group IEC associated HLH-like syndrome Criteria (47%) (Hines 2023), CARTOX HLH Criteria (24%) (Neelapu 2017) and HLH-2004 criteria (6%). Tocilizumab was used as cytokine release syndrome (CRS) prophylaxis only by one responder. Keppra neurologic prophylaxis was used by 47.5% and 15% of responders for CAR-T and BiTE therapy, respectively. Delayed neurotoxicity with CAR-T was reported in 1-5% of patients by 57.5% of responders and 6-10% of patients by 15% of responders; most common manifestations were other movement/neuromuscular disorder (62%), nerve palsy (55%), and Parkinsonism (45%). Infectious prophylaxis was used to protect against HSV (92.5%), PJP (90%), bacterial pathogens (55%), fungal pathogens (60%), and IVIG (77.5%). However, criteria for infectious prophylaxis use varies widely incorporating IgG levels, infectious history, CD4+ count, B-cell aplasia and cytopenias (48.1 - 88.9%). Most respondents (46.3 - 86.5%) reported completing an infectious work-up including CMV, EBV, Hep B/C, and HIV ( Table 2). Conclusions: Trends of CAR-T and BiTE therapy use and patterns of concurrent prophylactic and supportive care in MM vary widely among academic centers across the globe, demonstrating a need for further understanding of toxicity pathogenesis, toxicity management and consistent guidelines. This survey also demonstrates the great unmet need for access beyond urban centers among the international myeloma community. Prospective studies and claims data analysis should be utilized to evaluate the longitudinal cost of care, quality of life, duration of response and management of infectious disease, neurological or related complications of CAR-T and bispecific TCE therapies.

Lepore hemoglobins (Hbs) such as Hb Lepore-Boston-Washington [δ(1-87) β(116-146)], Hb Lepore-Baltimore [δ(1-50) β(86-146)], Hb Lepore-Hollandia [δ(1-22) β(50-146)] are δβ gene fusion/deletion variants (ε- Gγ- Aγ-[δβ] v )(Figure 1). They are controlled by the weak δ-globin gene promoter and synthesized at approximately 10-15% of hemoglobin fractions. This results in a similar phenotype as β +-thalassemia (microcytosis and hypochromia ± mild anemia). Anti-Lepore hemoglobins such as Hb P-Nilotic (β(1-22) δ(50-146) are βδ gene fusion/duplication variants (ε- Gγ- Aγ-δ-[βδ] v-β) associated with normal CBC values. Herein we describe a novel βδβ double fusion variant (ε- Gγ- Aγ-δ-[βδβ] v). Due to high homology between the δ and β genes, this double fusion event encodes an identical protein to Hb Lepore-Hollandia, albeit linked to the β-promoter and therefore expressed at ~40% of hemoglobin fractions, which would be expected to enhance any intrinsic properties of the variant. This novel hemoglobin variant is named Hb Lepore Rochester-MN. Two cases have been identified (Table 1). Case 1 was a 10-month-old Caucasian/Native American infant referred for an abnormal newborn screen and a reported family history of Hb G-Coushatta (β22, GAA>GCA, Glu>Ala; HGVS: c.68A>C, p.E23A). Case 2 was a 3-month-old infant referred for an abnormal newborn screen. CBCs were normal for age including MCV. Cation-exchange high performance liquid chromatography (HPLC) showed a shouldered peak in the Hb A 2 window typical for Hb Lepore (elution time: 3.41-3.46 mins), although the variant percentage was higher than expected, mimicking Hb G-Coushatta (expected elution time: 3.33 mins). Capillary electrophoresis identified a peak in the D zone (Z(D) zone), which is expected for Hb Lepore or Hb G-Coushatta. Intact mass spectrometry was consistent with Hb Lepore-Hollandia at 15836 amu, differing from Hb G-Coushatta (Glu>Ala, 15809 amu). Multiplex ligand probe amplification (MLPA) was normal because the highly variable fusion regions are unsuitable for probe placement. Sanger sequencing of the β-globin gene identified multiple single base substitutions which were challenging to interpret but matched the sequence expected for a complex double crossover event (NM_000518.4:c.28_68delins41 (p.Ser10_Glu23delins14TAVNALWGKVNVDA). The first crossover is located between c.-29 and c.9, the second crossover is located between c.69 and c.92+17. Long-read sequencing was performed (Sequel, Pacific Biosciences) which detected the multiple missense mutations in cis conformation, as was corroborated by the mass spectrometry data. In summary, Hb Lepore Rochester-MN represents a novel double fusion [βδβ] variant class that will pose a diagnostic challenge for laboratories. Although it is likely a result of sequential crossover events (deletion and duplication) between Lepore and anti-Lepore variants, MLPA analysis is normal due to technical constraints and high homology. DNA sequencing (both Sanger and long read methods) yielded complex results that require sophisticated analysis and correlation with protein data including intact mass spectrometry. HPLC and CE data including variant percentage are very similar to Hb G-Coushatta. In addition, although resulting in an identical protein, the variant should not be mistaken for Hb Lepore-Hollandia, which is produced at lower levels and causes a thalassemic phenotype. Hb Lepore Rochester-MN is controlled by the β-promoter and therefore is associated with approximately 40% variant and apparently normal CBC values in the two infants.

Introduction Artificial Intelligence (AI) is an emerging technology that promises advancements across blood cancer discovery and care delivery. There are already FDA-approved uses of AI in hematology and oncology but few data available about its use or utility. Concerns have been raised over AI's potential biases, “explainability,” and who is responsible for its use. Oncologists' familiarity with AI and perspectives on these issues are not well known and are critical to understanding the ethical deployment of AI in blood cancer care. Methods From January to July 2023, we performed a national cross-sectional survey of practicing oncologists. A draft survey instrument was developed by a team with content and methodological expertise. Iterative refinement occurred through cognitive debriefing with 5 practicing hematologist/oncologists. The final instrument included 24 questions covering domains of AI familiarity, predictions, explainability, and responsibilities. A random sample of US oncologists was identified using the National Plan & Provider Enumeration System. Paper surveys were mailed with $25 incentivizing gift cards. Reminder letters and phone calls were used for non-responders with an electronic survey option provided. Responses were analyzed descriptively. X2 testing assessed bivariate associations between responses and participant practice setting, with odds ratios (OR) reported. Results Of 399 mailed surveys, 12 were undeliverable and 201 were completed for a response rate of 51.9%. Question missingness was <1%. Participants were 63.2% White, 16.9% Indian Asian, 10.0% Eastern Asian or Pacific Islander, and 4.5% Black; 6.0% were Hispanic. They represented 37 states. The majority were male (63.7%), 40-59 years old (54.2%), and had no specific training in AI (52.2%); 68.2% had at least 11 years in practice and 29.9% practiced at a primary academic hospital. Questions assessing overall familiarity with and predictions related to AI are shown in Table 1. Those at primary academic hospitals were more likely to be familiar with radiology models (OR 2.82, p<0.001) but not pathology, prognostic, or clinical decision models (all p>0.05). They were more likely to predict that AI would improve side effect management (OR 2.01, p=0.03) and end-of-life decision making (OR 2.07, p=0.02). High proportions of respondents thought that AI prognostic (67.1%) and clinical decision models (62.1%) needed to be explainable by clinicians and researchers to be used in clinic. When posed with a scenario where an FDA-approved AI model selects a different regimen than the oncologist planned to propose (Figure 1), the largest proportion reported they would present both options and let the patient decide (37.3%). Of those recommending a regimen, respondents from primary academic hospitals more frequently recommend the AI-generated regimen (56.1%), while respondents from elsewhere recommended their original regimen (69.0%; OR 2.85, p=0.007). Acceptability of some direct-to-patient AI model applications is shown in Table 1. A majority of respondents (90.5%) thought that AI developers should be responsible for medico-legal problems caused by AI use; 47.8% thought that physicians using the tool should be responsible. Though most (76.1%) agreed that it was oncologists' responsibility to protect patients from biased AI tools, few (27.3%) were confident in their ability to identify how representative the data used in an AI model was relative to the population with that cancer (including 66.7% of those who agreed it was oncologists' responsibility). More respondents thought that patients should need to consent to the use of AI tools in cancer treatment decisions (81.1%) than cancer diagnosis (55.7%); those from primary academic hospitals were less likely to respond that patients should consent for treatment or diagnosis (OR 0.43, p=0.02 and OR 0.44, p=0.009). Conclusions In this national survey of oncologists' views on AI, there was optimism about its impact on care with notable caveats related to end-of-life care, patient trust, and care disparities. Despite many approving use of AI models too complex for patients to explain, a substantial proportion deferred to patient choice when AI and physician recommendations differed. There was also dissonance between accepting responsibility to protect patients from bias and respondents' self-perceived ability to do so.

Key Points Using multiple markers may improve GFR estimation especially in settings where creatinine and cystatin C are known to be limited. Panel eGFR is a novel multimarker eGFR equation consisting of age, sex, cystatin C, and nuclear magnetic resonance–measured creatinine, valine, and myo-inositol. eGFR-Cr and eGFR-Cr-CysC may underestimate measured GFR, while panel eGFR was unbiased among younger Black male individuals. Background Using multiple markers may improve accuracy in GFR estimation. We sought to externally validate and compare the performance of a novel multimarker eGFR (panel eGFR) equation among Black and White persons using the Genetic Epidemiology Network of Arteriopathy cohort. Methods We included 224 sex, race/ethnicity, and measured GFR (mGFR) category–matched persons, with GFR measured using urinary clearance of iothalamate. We calculated panel eGFR using serum creatinine, valine, myo-inositol, cystatin C, age, and sex. We compared its reliability with current eGFR equations (2021 CKD Epidemiology Collaboration creatinine [eGFR-Cr] and creatinine with cystatin C [eGFR-Cr-CysC]) using median bias, precision, and accuracy metrics. We evaluated each equation's performance in age, sex, and race subgroups. Results In the overall cohort, 49% were Black individuals, and mean mGFR was 79 ml/min per 1.73 m 2 . Panel eGFR overestimated mGFR (bias: −2.4 ml/min per 1.73 m 2 ; 95% confidence interval [CI], −4.4 to −0.7), eGFR-Cr-CysC underestimated mGFR (bias: 4.8 ml/min per 1.73 m 2 ; 95% CI, 2.1 to 6.7), while eGFR-Cr was unbiased (bias: 2.0 ml/min per 1.73 m 2 ; 95% CI, −1.1 to 4.6). All equations had comparable accuracy. Among Black male individuals younger than 65 years, both eGFR-Cr (bias: 17.0 ml/min per 1.73 m 2 ; 95% CI, 8.6 to 23.5) and eGFR-Cr-CysC (bias: 14.5 ml/min per 1.73 m 2 ; 95% CI, 6.0 to 19.7) underestimated mGFR, whereas panel eGFR was unbiased (bias: 1.7 ml/min per 1.73 m 2 ; 95% CI, −3.4 to 10.0). Metrics of accuracy for all eGFRs were acceptable in all subgroups except for panel eGFR in Black female individuals younger than 65 years (P30: 73.3%). Conclusions Panel eGFR can be used to estimate mGFR and may have utility among Black male individuals younger than 65 years where current CKD Epidemiology Collaboration equations are biased.

Abstract The sparse vascularity of pancreatic ductal adenocarcinoma (PDAC) presents a mystery: What prevents this aggressive malignancy from undergoing neoangiogenesis to counteract hypoxia and better support growth? An incidental finding from prior work on paracrine communication between malignant PDAC cells and fibroblasts revealed that inhibition of the Hedgehog (HH) pathway partially relieved angiosuppression, increasing tumor vascularity through unknown mechanisms. Initial efforts to study this phenotype were hindered by difficulties replicating the complex interactions of multiple cell types in vitro. Here we identify a cascade of paracrine signals between multiple cell types that act sequentially to suppress angiogenesis in PDAC. Malignant epithelial cells promote HH signaling in fibroblasts, leading to inhibition of noncanonical WNT signaling in fibroblasts and epithelial cells, thereby limiting VEGFR2-dependent activation of endothelial hypersprouting. This cascade was elucidated using human and murine PDAC explant models, which effectively retain the complex cellular interactions of native tumor tissues. Significance: We present a key mechanism of tumor angiosuppression, a process that sculpts the physiologic, cellular, and metabolic environment of PDAC. We further present a computational and experimental framework for the dissection of complex signaling cascades that propagate among multiple cell types in the tissue environment. This article is featured in Selected Articles from This Issue, p. 201

Abstract During aging, muscle gradually undergoes sarcopenia, the loss of function associated with loss of mass, strength, endurance, and oxidative capacity. However, the 3D structural alterations of mitochondria associated with aging in skeletal muscle and cardiac tissues are not well described. Although mitochondrial aging is associated with decreased mitochondrial capacity, the genes responsible for the morphological changes in mitochondria during aging are poorly characterized. We measured changes in mitochondrial morphology in aged murine gastrocnemius, soleus, and cardiac tissues using serial block‐face scanning electron microscopy and 3D reconstructions. We also used reverse transcriptase‐quantitative PCR, transmission electron microscopy quantification, Seahorse analysis, and metabolomics and lipidomics to measure changes in mitochondrial morphology and function after loss of mitochondria contact site and cristae organizing system (MICOS) complex genes, Chchd3 , Chchd6 , and Mitofilin . We identified significant changes in mitochondrial size in aged murine gastrocnemius, soleus, and cardiac tissues. We found that both age‐related loss of the MICOS complex and knockouts of MICOS genes in mice altered mitochondrial morphology. Given the critical role of mitochondria in maintaining cellular metabolism, we characterized the metabolomes and lipidomes of young and aged mouse tissues, which showed profound alterations consistent with changes in membrane integrity, supporting our observations of age‐related changes in muscle tissues. We found a relationship between changes in the MICOS complex and aging. Thus, it is important to understand the mechanisms that underlie the tissue‐dependent 3D mitochondrial phenotypic changes that occur in aging and the evolutionary conservation of these mechanisms between Drosophila and mammals.

Abstract Methylation profiling has revealed unexpected relationships between traditional histopathology-based versus biologically-based classifications of brain tumors. Methylation class pleomorphic xanthoastrocytoma (mcPXA) comprises tumors with the same methylation signature as classical PXA but with additional morphologic patterns, including overlap with glioblastoma (GBM). To characterize mcPXA, we examined epidemiologic, histologic, and molecular features as well as clinical behavior of a cohort (n=313) of tumors matching to mcPXA by the DKFZ classifier (v12 score >= 0.85). Patient median age was 19 (range 1-73) with a female predominance (178 female/135 male). CDKN2A/B homozygous deletion was observed in 273 (87%) cases. In the subset of cases tested for BRAF p.V600E (n=120), 111 (93%) harbored the mutation. Concomitant chr7+/chr10- was observed in 66 (21%) cases. In the subset of cases tested for TERT promoter mutations (n=50), 11 (22%) harbored the mutation, always with co-occurrence of BRAF p.V600E (11/11) and infrequently with chr7+/chr10- (3/11). MGMT promoter methylation was observed in 40 (13%) cases. Overall and progression-free survival (OS, PFS) in mcPXA were similar to grade 2-3 IDH-mutant astrocytoma (A-IDH). Prognostic factors in mcPXA included GBM-like histopathology (defined as cases diagnosed as GBM prior to methylation profiling), concomitant chr7+/chr10-, and MGMT promoter methylation. GBM-like histopathology was associated with shorter OS (p=0.02) and PFS (p< 0.01) compared to cases without GBM-like histopathology. Concomitant chr7+/chr10- was associated with shorter PFS (p=0.02), and MGMT promoter methylation was associated with shorter OS (p=0.03). Our findings demonstrate that mcPXA tumors affect adolescents and young adults, share molecular features of classical PXA, and manifest clinical behavior similar to classical PXA, but subsets of tumors with atypical features (chr7+/chr10-, MGMT promoter methylation, and/or GBM-like histopathology) are more aggressive. The use of a molecular definition of PXA reveals that this tumor type is more common than previously appreciated and warrants in-depth study for therapeutic options.

Abstract PURPOSE For large brain metastases, it is unknown whether single fraction stereotactic radiosurgery (sSRS) or multi-fraction stereotactic radiosurgery (fSRS) is optimal. We aimed to compare rates of local progression and necrosis between sSRS and fSRS for large brain metastases. METHODS Patients with intact or resected brain metastases with a target volume ≥ 4.2 cc (corresponding to a diameter ≥ 2 cm) treated with Gamma Knife (GK) or linear accelerator-based SRS from 2014-2022 were included in this retrospective review. RESULTS A total of 343 large brain metastases in 276 patients were included; 171 lesions were treated with sSRS (96% with GK) and 172 lesions with fSRS (100% with linear accelerator). Median lesion volume was 19.8 cc and 8.4 cc for fSRS and sSRS, respectively. Resection was performed prior to SRS in 228 (66%), with the remaining 115 metastases treated intact. There was no difference in rate of local progression between sSRS versus fSRS, or between resected versus intact targets (p >0.8 for both). Cumulative incidence of local progression (with death as a competing risk) at 1 and 3 years for patients receiving sSRS was 24% and 30%, respectively, compared to 22% and 34% for fSRS. FSRS was associated with significantly higher rates of necrosis than sSRS (HR 5.58, 2.38-13.08, p < 0.001). This association remained significant after controlling for target volume. Cumulative incidence of necrosis (with death as a competing risk) at 1 and 3 years for patients receiving sSRS was 1% and 3%, respectively, compared to 10% and 18% for fSRS. Necrosis rates were significantly higher with fSRS for both intact and resected targets (P < 0.02 for both). CONCLUSION While local control for large resected or intact brain metastases appears similar after sSRS or fSRS, this retrospective study shows higher rates of necrosis after fSRS. Prospective validation is needed.

Abstract Methylation profiling of brain tumors has revealed novel clusters whose biological and clinical significance is unknown. These include three entities termed by the 12.5 version of the Heidelberg methylation classifier as adult-type diffuse high grade glioma, IDH-wildtype, subtype B (HGG_B), subtype E (HGG_E), and subtype F (HGG_F). We have identified 75 cases belonging to these groups: HGG_B (25 cases, 32% female), HGG_E (40 cases, 42% female), and HGG_F (18 cases, 33% female). Although originally characterized as “adult-type,” we find that 70% of HGG_E cases are pediatric, with a median age at diagnosis of 11 years. HGG_B cases are predominantly seen in young adults, and HGG_F in older adults. The histology varies among methylation classes, with HGG_B cases demonstrating high-grade, predominantly astrocytic, morphology, while HGG_E cases demonstrate high-grade glial histology with distinct nuclear features, and HGG_F cases show highly infiltrative but lower grade glial morphology. Patient outcome data obtained to date shows a collective median survival exceeding 5 years, suggesting re-consideration of the proposed grading for these tumors. MGMT promoter methylation differs across the HGG_B (0%), HGG_E (12%), and HGG_F (0%) subtypes. Mutational analyses show enrichment of TERT promoter mutations in the HGG_F group, while HGG_E samples are enriched for tumors with POLE mutations and elevated tumor mutation burden. HGG_E tumors show epigenetic similarity to pediatric high-grade diffuse gliomas (pedHGG_RTK1A); we therefore propose that HGG_E be considered a pediatric-type HGG. HGG_B tumors show demographic and genomic similarities to high-grade astrocytomas with piloid features, including a subset of cases with CDKN2A/2B loss and ATRX mutation. HGG_F separate into two groups dictated by brain location, and despite the presence of TERT promoter mutations, appear distinct from GBMs. Overall, our work represents an initial effort to understand the morphologic, genomic and clinical characteristics of these previously uncharacterized subtypes of gliomas.