Citations

ABSTRACTDiffuse large B‐cell lymphoma (DLBCL) patients that fail to achieve a complete metabolic response with frontline immunochemotherapy have a poor prognosis. Genomic profiling has led to a broader understanding of the molecular drivers in DLBCL, but it is unknown how well current classifiers identify patients that will experience primary treatment resistance (PTR). Using whole exome and RNA sequencing data from newly diagnosed DLBCL patients, we evaluated the genomic landscape of PTR and compared it to that of non‐PTR DLBCL. We found a significant increase in the frequency of TP53 (34% vs. 15%, p = 0.005) and ARID1A mutations (21% vs. 7%, p = 0.007) in PTR cases, with pathway analysis further demonstrating a downregulation of TP53 and an increase in chromatin modifying pathways. These results suggest that TP53 and ARID1A may be key mediators of PTR and important pathways contributing to the poor outcomes. We found that the current molecular classifiers were unable to identify PTR cases at diagnosis. However, our newly identified high‐risk signature identified 46% of PTR cases at diagnosis. Overall, these results contribute to our understanding of the genomic landscape of patients with primary treatment resistance.

Abstract BACKGROUND Pineocytoma is a rare pineal parenchymal WHO grade 1 tumor, typically well-managed with surgical resection alone. With gross total resection (GTR), 91% 1-year and 84% 5-year survival rates have been reported. Recurrent pineocytoma is rare and optimal management in that setting is unknown, in part owing to the rarity of the condition. METHODS We report an atypical course of pineocytoma in a 58-year-old male involving metastatic disease. RESULTS A pineal mass was identified upon MRI of the brain obtained for vision changes. Patient underwent GTR, pathology was consistent with pineocytoma, WHO grade 1. Ki-67 labeling index was low at 1-2%. Despite low-grade pathology, two years later, surveillance imaging demonstrated recurrence in the pineal region and a second lesion in the right thalamus. The patient underwent gamma knife surgery (GKRS) to both lesions. Three years later, he developed three new lesions in the right cerebellum and again underwent GKRS. Subsequent surveillance imaging identified new lesions in the right cerebellum and along ventricular walls, treated with further GKRS. Nine years after initial diagnosis, focal nodular leptomeningeal metastases were discovered, along with progression at the primary tumor site. Patient was treated with GKRS to the nodular deposits followed by pembrolizumab. Further disease progression as noted despite immunotherapy. Patient was treated with 6 cycles of temozolomide chemotherapy and at further progression 3 cycles of lomustine. Upon additional progression, further radiation therapy was administered with bevacizumab to reduce risk of radiation necrosis. Patient remains on surveillance 13 years after initial diagnosis with visual changes and mild headache representing only clinical issues. CONCLUSIONS Although exceedingly rare, pineocytoma is capable of metastasizing to brain parenchyma and the leptomeninges, as demonstrated in our patient. However, our case demonstrates prolonged survival is possible even in the setting of relentlessly progressive metastatic disease with utilization of multimodality treatment.

Abstract INTRODUCTION Lymphopenia attributed to postoperative chemoradiotherapy (CRT) can accelerate tumor recurrence and contribute to poor prognosis in GBM. We hypothesize that short course (1-2 weeks) CRT can mitigate lymphopenia compared to standard course and may provide immune benefits for future combination therapy. METHODS GBM patients were randomized on a multi-site phase II study comparing short course (35Gy/5Fx or 40Gy/10Fx depending on target volume) (Arm A) versus standard dose fractionation (60Gy/30Fx or 40Gy/15Fx, Arm B). All patients received concurrent and adjuvant temozolomide (TMZ). This unplanned interim analysis evaluates changes of absolute lymphocyte count (ALC), CD4 and CD8 prospectively at 3-timepoints: baseline (prior to CRT), end of CRT, and 1-month post-CRT. RESULTS To date, 72 patients enrolled (34 Arm A, 38 Arm B). Median age 66 (35-86), ECOG 0-2. Patients characteristics as followed in Arm A vs. Arm B, respectively: female 47% vs. 42%, MGMT promotor methylated 31% vs. 34%, steroid use 46% vs. 45%, ALC 1310 cells/mm3 (330 –9730) vs. 1480 (750 –7750), CD4 531 cells/mm3 (86 –1368) vs. 662 (318 –1671), and CD8 151 cells/mm3 (56 –940) vs. 272 (68 –875). Lymphocytes data were collected in 49 patients (21 Arm A, 28 Arm B). There were signficantly fewer reductions of ALC, CD4 and CD8 in Arm A. Median ALC changes were 95% and 99% of baseline (Arm A) vs 52% and 61% of baseline (Arm B) at the end of CRT and 1-month post-CRT, respectively (p<0.01). Median CD4 changes 93% and 96% of baseline (Arm A) vs 51% and 49% (Arm B), and median CD8 changes 97% and 98% of baseline (Arm A) vs 57% and 71% (Arm B) at the end of CRT and 1-month post-CRT, respectively (p<0.05). CONCLUSIONS This interim analysis suggests that short course RT could reduce treatment-related lymphopenia and immune suppression compared to standard RT, thus could be potentially beneficial to combine with immunotherapy.

Abstract BACKGROUND Fatigue is among the most common symptoms managed by patients with cancer. Hypothalamic pituitary axis dysfunction has an established role in a subset of patients with fatigue. Our primary aim was to longitudinally assess the impact of hypothalamic radiation exposure to patient self-reported fatigue. METHODS We included a sample of patients who received radiation therapy treated at a single institution from 2014-2024. The PROMIS-10 questionnaire (“How would you rate your fatigue on average,” scale 1-5) was used in standard clinical practice, with measures from 6 time points over 2 years. We performed descriptive statistics. Linear mixed models were used to assess the impact of hypothalamic radiation dose on fatigue scores. Mixed models were controlled for gender, age, time, tumor category (CNS vs. non-CNS), and modality (photon vs. proton). Models were fit with random intercepts for each Patient ID. RESULTS 1092 patients (43% female) with a median age of 54 years (range: 18-92) were included. Most patients were treated for CNS cancer (76%), with about 50% each photon and proton. Median hypothalamus radiation dose was 1306 cGy (range: 0.01-6138). Mean baseline fatigue (2.4) increased after treatment (2.7) remaining elevated at 3- and 6-months post-treatment (2.6, 2.5), returning near baseline at 1- and 2-years post-treatment (2.4, 2.3). Higher radiation dose (Estimate (SE): 0.014 (0.006), p=0.0266) and CNS cancer treatment (0.11 (0.051), p=0.0319) were significant predictors of higher fatigue in the mixed model. Male patients (-0.16 (0.042), p=0.0001) and time (-0.003 (0.0016), p=0.0398) were associated with lower fatigue. Age and treatment modality were not significant predictors of fatigue. CONCLUSIONS We found that higher hypothalamic radiation dose was related to more self-reported fatigue, which peaked by 6 months. This effect was seen more prominently in female patients and those treated for CNS disease. Treatment modality and age did not influence fatigue scores.

Abstract BACKGROUND Diffuse intrinsic pontine glioma (DIPG) carries a poor prognosis with a median survival of less than 12 months. Histone mutation, K27M, and AKT pathway dysregulation play key roles in tumorigenesis. There is no curative treatment with radiation therapy, which currently remains the standard treatment. METHODS This is a phase I study of vorinostat and temsirolimus in newly diagnosed (stratum 1) and progressive (stratum 2) DIPG. The primary aims are to determine the safety, maximum tolerated dose, and toxicities (NCT02420613). Stratum 1 received radiation concurrently with vorinostat, followed by vorinostat and temsirolimus for up to 10 cycles. Stratum 2 received vorinostat and temsirolimus for up to 12 cycles. In stratum 1, vorinostat was administered daily at 230 mg/m2. The maintenance phase (both strata) included concurrent vorinostat 230 mg/m2 daily and temsirolimus 25 or 35 mg/m2 (Days 1 and 8). RESULTS Six patients were enrolled, three in each stratum. Three of the six patients had confirmed H3 K27M mutations. No dose-limiting toxicity was observed, and most adverse effects were limited to grades 1 or 2, including fatigue, nausea, vomiting, myelosuppression, hyperlipidemia, hyperglycemia, elevated liver enzymes, and creatinine. However, one patient experienced grade 3 leukopenia. Two of the three patients in stratum 1 showed evidence of radiographic response after the chemoradiation phase, of whom one patient had progression-free survival of 12 months and completed the 10 maintenance cycles. All patients at stratum 2 had disease progression with no radiographic response. CONCLUSION Overall, the combination of temsirolimus and vorinostat is well tolerated and safe, prompting the need for larger studies to investigate its efficacy. Due to the small number of patients, the study’s findings are limited, and trends in efficacy should be interpreted with caution.

Abstract BACKGROUND Pineoblastoma is an aggressive, rare tumor of the pineal gland. Due to rarity of pineoblastoma, no large-scale prospective clinical trial data is available to guide clinical practice. Patients often receive treatment based on approaches to other high-grade embryonal central nervous system (CNS) tumors such as medulloblastoma. Multimodality treatment typically consists of maximal surgical resection followed by radiation therapy and chemotherapy. Despite treatment, recurrence is common and five-year survival rate is 60-70%. Pineoblastoma can disseminate through the leptomeninges, which is associated with poor survival. No therapy is known to confer a survival benefit in the setting of leptomeningeal disease (LMD) related to pineoblastoma. MATERIAL AND METHODS We report radiographic response and longer than expected survival for a patient with LMD related to pineoblastoma treated with single-agent temozolomide chemotherapy. RESULTS A 22-year-old male with a history of pineoblastoma presented with periodic headaches and leptomeningeal enhancement on surveillance imaging. 5 years prior to presentation (age 17), he was initially diagnosed with pineoblastoma after gross total resection followed by treatment with proton craniospinal radiation and adjuvant carboplatin/vincristine chemotherapy. Surveillance craniospinal MRIs identified diffuse leptomeningeal enhancement involving the posterior fossa and diffusely throughout the spine and lumbosacral nerve roots. While cerebrospinal fluid (CSF) cytology was negative for tumor cells on three separate occasions, CSF cell-free DNA (cfDNA) analysis isolated tumor DNA. He was started on temozolomide chemotherapy with near complete resolution of leptomeningeal enhancement on MRI after 2 cycles and complete resolution after 6 cycles. Treatment was well-tolerated with grade 1 fatigue as the only toxicity. Patient remains alive 20 months after initial diagnosis of LMD with resolution of headaches and durable radiographic response. CONCLUSION This case highlights utility of CSF cfDNA as a companion tool for diagnosis of LMD. Durable clinical and radiographic response achieved suggests temozolomide can be considered as a salvage treatment option for recurrent pineoblastoma with LMD.

Abstract Aims Radiation therapy (RT) is an integral component of cancer therapy but associated with adverse events. Our goal was to establish risk prediction models for major adverse cardiovascular and cerebrovascular events (MACCE) after chest RT. Methods and results A retrospective study of lung/breast cancer patients who had chest RT with planning CT at Mayo Clinic between 01/2010 and 01/2014. Predictive models were developed based on weighted independent predictors using a derivation (406 lung and 711 breast cancer) and validation cohort (179 lung and 234 breast cancer). Patient characteristics, pre-RT CT for coronary artery calcification (CAC), and post-RT MACCE data were reviewed. Post-RT MACCE occurred in 6.1 and 5.6% in the derivation and validation cohort over a mean follow-up of 42 ± 13 months. Post-therapy model (C2AD2) included CAC (two points), MACCE history (two points), age ≥74 (three points), DM (two points), and mean heart radiation dose ≥ 850 mGy (two points), and pre-therapy model (C2AD) included post-therapy model parameters minus mean heart radiation dose. Both models stratified patients into three risk groups: low (0–2), intermediate (3–5), and high (≥6). Post-RT MACCE across these groups were 2.7, 8.9, and 19.8% in the derivation, and 3.9, 6.6, and 16.4% in the validation cohort for post-therapy model (C2AD2) and 2.8, 9.2, and 20.4% in the derivation and 3.7, 9.2, and 13.2% in the validation cohort for pre-therapy model. Both models showed statistically significant graded survival outcome. Conclusion Post-therapy (C2AD2) and pre-therapy (C2AD) models are simple, easy to use and effective tools to stratify breast and lung cancer patients undergoing chest radiation for post-RT MACCE.

ObjectiveDe novo variants in cullin‐3 ubiquitin ligase (CUL3) have been strongly associated with neurodevelopmental disorders (NDDs), but no large case series have been reported so far. Here, we aimed to collect sporadic cases carrying rare variants in CUL3, describe the genotype–phenotype correlation, and investigate the underlying pathogenic mechanism.MethodsGenetic data and detailed clinical records were collected via multicenter collaboration. Dysmorphic facial features were analyzed using GestaltMatcher. Variant effects on CUL3 protein stability were assessed using patient‐derived T‐cells.ResultsWe assembled a cohort of 37 individuals with heterozygous CUL3 variants presenting a syndromic NDD characterized by intellectual disability with or without autistic features. Of these, 35 have loss‐of‐function (LoF) and 2 have missense variants. CUL3 LoF variants in patients may affect protein stability leading to perturbations in protein homeostasis, as evidenced by decreased ubiquitin‐protein conjugates in vitro. Notably, we show that 4E‐BP1 (EIF4EBP1), a prominent substrate of CUL3, fails to be targeted for proteasomal degradation in patient‐derived cells.InterpretationOur study further refines the clinical and mutational spectrum of CUL3‐associated NDDs, expands the spectrum of cullin RING E3 ligase‐associated neuropsychiatric disorders, and suggests haploinsufficiency via LoF variants is the predominant pathogenic mechanism. ANN NEUROL 2025;97:76–89