Uhm, Joon H.

Abstract BACKGROUND Interpretation of serial magnetic resonance imaging (MRI) for glioblastoma following radiation therapy (RT) is complicated by difficulty differentiating tumor from treatment-related changes, even using updated RANO criteria. The incorporation of novel imaging such as 3,4-dihydroxy-6-[18F]-fluoro-L-phenylalanine (18F-DOPA) PET/CT to post-treatment serial imaging may improve prognostication and better facilitate future treatment decisions. METHODS The secondary analysis of a recent phase II prospective clinical trial of 18F-DOPA PET/CT-directed dose-escalated RT included patients with IDH-wildtype, MGMT-unmethylated glioblastoma who underwent post-treatment serial 18F-DOPA PET/CT surveillance. Quantitative features were extracted from pre-RT and post-RT serial PET/CT images, and robust prognostic features were selected using an in-house workflow. Both an automated machine learning (ML) algorithm and an interpretable ML algorithm were utilized to correlate surveillance PET image features with subsequent survival of greater than 12 months versus less than 12 months from the surveillance timepoint. Changes from pre-RT to post-RT PET/CT (delta model) were also assessed for association with post-RT survival and validated with a separate cohort. RESULTS Thirty-five patients with IDH-wildtype, MGMT-unmethylated glioblastoma who had at least one available (range: 1-14) post-treatment 18F-DOPA PET/CT were included. Twenty-four were used for model training, while 11 were used for validation. Ultimately, a five-feature post-RT model utilizing two shape, two texture, and one first-order radiomic feature was selected. For the delta model, five texture, two shape, and one first order radiomic feature were selected. The models show 90% accuracy in predicting survival < 12 months post-surveillance on the training set, and 68%-73% accuracy (AUC 0.64-0.73) for the validation cohort. Delta features were significantly associated with overall survival (p < 0.05). CONCLUSIONS Post-RT serial 18F-DOPA PET/CT imaging can help distinguish true tumor progression in patients with glioblastoma using a radiomics model. Tumor response evaluated for changes from pre-RT to post-RT 18F-DOPA PET/CT also predicted subsequent overall survival.

Abstract Atypical meningiomas (CNS WHO grade 2) show an intermediate risk of recurrence/progression, and molecular parameters informing management following gross total resection (GTR) remain to be established. We performed comprehensive genomic analysis in 63 patients who underwent GTR of an atypical meningioma. Median age was 59.8 years, 41 patients (65.1%) were female, and 8/62 patients (12.9%) underwent radiation therapy following resection. Follow-up was available for all patients (median 10 years), with recurrence/progression in 17 (5-year PFS: 84.2%; 10-year PFS: 71.0%). Tumors were evaluated by next generation sequencing (n=61), chromosomal microarray (n=63), DNA methylation profiling (n=62), and H3K27me3 immunohistochemistry (n=62). Next generation sequencing using a CLIA-certified 50-gene Neuro-Oncology specific panel identified pathogenic alterations in NF2 (n=31; 50.8%), SMARCB1 (n=5; 8.2%), AKT1 (n=2; 3.3%), TERT (n=1, 1.6%), SMO (n=1), SUFU (n=1), TP53 (n=1), and PTEN (n=1). There was trend toward decreased PFS in patients with NF2 alterations (p=0.078) which was not statistically significant. Copy number variants (CNVs) were identified using OncoScan (ThermoFisher). The most frequent CNVs were loss -22 (n=45; 71.4%), -1p (n=30, 47.6%), -14 (n=21, 33.3%), -6q (n=18, 28.6%), -10q (n=15, 23.8%), -X (n=13, 20.6%), and -18 (n=11, 17.4%). CNVs associated with decreased PFS included -1p (p=0.015), -7p (p=0.007), -10q (p=0.0007), and -18 (p=0.0376). DNA methylation profiling was performed using the Illumina MethylationEPIC array (n=62) and evaluated using the DKFZ classifier (v12.3). Based on the highest score, tumors matched to benign (n=32; 51.6%) or intermediate (n=29; 46.7%) meningioma subclasses or showed non-contributory profiles (n=1; 1.6%). Methylation class (benign vs. intermediate) showed no association with PFS (p=0.96). H3K27 trimethylation (H3K27me3) was unequivocally lost in 4 (6.5%) tumors, which was insufficient for PFS analysis. Overall, our study supports CNV profiling of atypical meningiomas following GTR, which can be implemented using existing, clinically validated technologies. Molecular predictors could guide use of radiotherapy in these patients.

Abstract INTRODUCTION Medulloblastomas (MB) are embryonal tumors arising in the cerebellum, predominantly affecting pediatric patients. Recognition of molecularly defined subgroups has advanced management. Factors influencing the prognosis and management of adult MB patients remain poorly understood. METHODS We retrospectively reviewed our experience with adult (> 18 years at initial diagnosis) MB patients, diagnosed between 1992-2020. Molecular subtyping corresponding to the 2021 WHO Classification was performed. Kaplan-Meier estimates (Log-rank test assessing for group differences) were performed for univariate survival analysis with cox regression used for multivariate (subgroup, age, gender, disseminated disease, extent of resection) analyses. RESULTS Our cohort included 76 adult MB patients (62% male), with a median age of 31.7 years (range: 18-66) at diagnosis, and median follow-up of 7.7 years (range: 0.6-26.9). 58 patients had sufficient tissue for molecular characterization by immunohistochemistry and corresponded to the SHH-activated (n=37; 64%), non-WNT/non-SHH (n=12; 21%), WNT-activated (n=9; 15%) subgroups. At initial diagnosis, all patients underwent radiotherapy, with 97% (n=66) receiving craniospinal irradiation with a boost either to the posterior fossa (75%) or tumor bed (22%); and underwent gross total resection (n=51; 67%) and chemotherapy (n=56; 75%). Median overall survival (OS) for the whole cohort was 14.8 years (93% 2-year OS; 86% 5-year OS; 64% 10-year OS) and was longer for younger patients (< 30: > 15.4 years, > 30: 9.9 years; Log-rank p< 0.001). No significant OS difference was identified by MB molecular subgroup (SHH, TP53-wt: 14 years, WNT: 11.4 years, non-WNT/non-SHH: > 14.8 years; Log-rank p=0.1167) or extent of resection. Only age at diagnosis remained significant in multivariate survival analyses. DISCUSSION We report one of the largest retrospective cohorts in adult MB patients with molecular subtyping. Survival and molecular subgroup frequencies were similar to previous reports. Survival was longer for younger patients and was not significantly different by MB molecular subgroup or extent of resection.

Abstract Stroke-Like Migraine Attacks after Radiation Therapy (SMART) is a descriptive clinical entity consisting of transient hemispheric dysfunction. We were interested in pragmatic management patterns for patients with Recurrent Stroke-Like Episodes (R-SLE) of transient negative neurologic symptoms after cranial radiotherapy (RT) to define optimal management strategy and assess long-term outcomes. We conducted a retrospective review of all patients with recurrent negative neurologic symptoms after cranial RT who were treated at Mayo Clinic (Rochester), with follow-up extending until February 2021. Descriptive statistics and Chi-Square analysis was performed to assess for differences between patients with clinical cessation of symptoms, death, progressive encephalopathy and therapeutic class, patient and primary treatment characteristics (i.e. whole brain RT). We identified 27 patients with R-SLE after RT. 25 patients were included in analyses. Median age at diagnosis was 28.7 years (3.0-65.8 years, SD: 15.0 years). Median time from RT to symptom onset was 14.6 years (3.3-30.5 years, SD: 8.9 years). The most common presentations included hemiparesis (55.6%), hemisensory loss (22.2%), transient visual field loss (33.3%), encephalopathy (18.5%), and aphasia (22.2%). Antiseizure medications were most used for management of R-SLE (92%) followed by anti-platelets (68%), verapamil (52%), statins (48%), glucocorticoids (24%), antivirals (20%), and ACE inhibitors/angiotensin receptor blockers (16%). Beta blockers were not used. Verapamil use was frequently associated with clinical cessation of recurrent events with cessation being achieved in 64.7% of patients on verapamil versus 35.3% not on verapamil (p=0.0638). Other medical interventions did not approach clinical or statistical significance. Progressive encephalopathy was more common in patients without clinical cessation (87.5% vs. 23.5%, p=0.0026). All patients who died at last follow-up had progressive encephalopathy. We found cessation of recurrent negative neurologic symptoms after cranial RT in most patients. Verapamil use was associated with clinical cessation. Progressive encephalopathy was more common in patients without clinical cessation of recurrent events.

Abstract While dose escalation of radiotherapy (DERT) has failed to improve overall survival (OS) or progression-free survival (PFS) for glioblastoma in previous studies, a recent phase II clinical trial utilizing 18F-DOPA-PET-directed DERT demonstrated improved PFS in MGMT-unmethylated patients and OS in MGMT-methylated patients compared to historical controls. This planned secondary analysis sought to determine 1) how 18F-DOPA-PET changes RT volumes beyond standard MRI-planning, 2) which patients benefit most and least from this protocol, 3) which are mostly likely to experience clinically significant radionecrosis after DERT, and 4) patterns of failure after DERT. For 69 evaluable patients, median MRI-defined, PET-defined, and combined low-dose gross tumor volumes (GTV51) were 54 cc (range 9-248), 23 cc (0.4-179), and 62 cc (10-260), respectively. Median MRI-defined, PET-defined, and combined high-dose GTVs (GTV76) were 32 cc (range 4-136), 6 cc (0.1-138), and 34 cc (4-162), respectively. 18F-DOPA-PET resulted in a median volumetric expansion of 13% (0-243%) and 5% (0-217%) from MRI-defined low-dose and high-dose GTV’s, respectively. Central failures ( >95% of recurrence tumor volume) occurred within the 76 Gy, 60 Gy, and 51 Gy isodose lines in 32 (46%), 60 (87%), and 64 (93%) patients, respectively. Recursive partitioning analysis stratified patients by OS and PFS. Patients with 18F-DOPA-PET-defined GTV76 > 7.8cc, MRI-defined GTV76 > 42.7cc, and MGMT promotor-unmethylated tumors had the shortest OS, while patients with smaller PET and MRI-defined tumors had the longest OS (median 10.4 vs. 64.6 months, p< 0.001). Similarly, PFS was worst in patients with 18F-DOPA-PET-defined GTV76 > 2.17 cc who had biopsy only (median PFS 3.2 months, p< 0.001). Patients with 18F-DOPA-PET-defined GTV51 > 50 cc had the highest risk of grade 3+ radionecrosis (p< 0.001). In conclusion, larger 18F-DOPA-PET and MRI-defined tumor volumes were associated with worse outcomes, and 18F-DOPA-PET-directed DERT appears to reduce risk of central recurrence in high-dose volumes.

OBJECTIVE Recent studies have proposed resection of the T2 FLAIR hyperintensity beyond the T1 contrast enhancement (supramarginal resection [SMR]) for IDH–wild-type glioblastoma (GBM) to further improve patients’ overall survival (OS). GBMs have significant variability in tumor cell density, distribution, and infiltration. Advanced mathematical models based on patient-specific radiographic features have provided new insights into GBM growth kinetics on two important parameters of tumor aggressiveness: proliferation rate (ρ) and diffusion rate (D). The aim of this study was to investigate OS of patients with IDH–wild-type GBM who underwent SMR based on a mathematical model of cell distribution and infiltration profile (tumor invasiveness profile). METHODS Volumetric measurements were obtained from the selected regions of interest from pre- and postoperative MRI studies of included patients. The tumor invasiveness profile (proliferation/diffusion [ρ/D] ratio) was calculated using the following formula: ρ/D ratio = (4π/3) 2/3 × (6.106/[V T2 1/1 − V T1 1/1 ]) 2 , where V T2 and V T1 are the preoperative FLAIR and contrast-enhancing volumes, respectively. Patients were split into subgroups based on their tumor invasiveness profiles. In this analysis, tumors were classified as nodular, moderately diffuse, or highly diffuse. RESULTS A total of 101 patients were included. Tumors were classified as nodular (n = 34), moderately diffuse (n = 34), and highly diffuse (n = 33). On multivariate analysis, increasing SMR had a significant positive correlation with OS for moderately and highly diffuse tumors (HR 0.99, 95% CI 0.98–0.99; p = 0.02; and HR 0.98, 95% CI 0.96–0.99; p = 0.04, respectively). On threshold analysis, OS benefit was seen with SMR from 10% to 29%, 10% to 59%, and 30% to 90%, for nodular, moderately diffuse, and highly diffuse, respectively. CONCLUSIONS The impact of SMR on OS for patients with IDH–wild-type GBM is influenced by the degree of tumor invasiveness. The authors’ results show that increasing SMR is associated with increased OS in patients with moderate and highly diffuse IDH–wild-type GBMs. When grouping SMR into 10% intervals, this benefit was seen for all tumor subgroups, although for nodular tumors, the maximum beneficial SMR percentage was considerably lower than in moderate and highly diffuse tumors.

2019 Background: The mammalian target of rapamycin (mTOR) functions within the PI3K/Akt signaling pathway as a critical modulator of cell survival. We previously demonstrated significant synergy of the mTOR inhibitor sirolimus with RT in glioma xenografts. Methods: The standard cohorts of 3 design was applied with dose escalation of weekly IV CCI-779 in combination with standard TMZ/RT. CCI-779 was given during both RT (60 Gy)/TMZ (75 mg/m2 daily) and adjuvant TMZ (200 mg/m2 daily x 5 every 28 days). Results: A total of 17 patients were enrolled. CCI-779 therapy during RT/TMZ was well tolerated at dose level 0 (25 mg CCI-779, n = 3) and dose level 1 (50 mg CCI-779, n = 6) with 1 of 9 patients experiencing a DLT (Gr 3 fatigue). Dose level 2 (75 mg CCI-779) exceeded the maximally tolerated dose with two of six patients with DLT (<75% CCI-779 delivered; Gr 4 dyspnea). Despite reasonable tolerance during RT/TMZ, the overall regimen was associated with a high rate of infection associated with lymphopenia. After a patient died from PCP on cycle 2 of adjuvant TMZ/CCI-779, antibiotic prophylaxis was mandated. Two other patients died of gram-negative sepsis despite prophylaxis: one after their first dose of CCI-779 and one during cycle 4 of adjuvant therapy. In contrast to our 18% grade 5 infection rate, only 4% grade 3 (no grade 4/5) infections were observed in 26 other CTEP-sponsored clinical trials involving 1,006 patients treated with CCI-779. Results from translational studies evaluating the effects of treatment on immune function will be presented. Further infections were avoided on this trial after CCI-779 therapy was limited to RT/TMZ. Conclusions: Although CCI-779 in combination with RT/TMZ was well-tolerated, adjuvant therapy with TMZ/CCI-779 was associated with an increased risk of opportunistic infections. [Table: see text]

2025 Background: Although adjuvant radiation has demonstrated a clear survival benefit in anaplastic astrocytomas (AA), the role of concurrent temozolomide (TMZ) remains controversial. Methods: All adult patients diagnosed with AA from 2001 to 2011 and treated with standard doses of adjuvant radiation were identified retrospectively using the neuro-oncology database at the Mayo Clinic (Rochester, MN). Clinical data was extracted from the electronic medical record. IDH mutation status was also determined by obtaining either IDH1R132H immunostain on existing unstained slides or paraffin block sections, or by sequencing. Cumulative survival probabilities were estimated using the Kaplan-Meier method. Univariable and multivariable Cox proportional hazards regression models were fit to compare patients who did/did not receive TMZ. Results: 218 patients were identified that met inclusion criteria. 34 patients were excluded due to missing data on adjuvant chemotherapy. 146 patients had received adjuvant TMZ while 38 had not. Of these, IDH mutation status was determined on 124 patients who received TMZ and 33 of those who had not. The median duration of follow up was 36.4 months. On univariable analysis, adjuvant TMZ demonstrated a trend towards improved median survival from 35.2 to 53.1 months (p=0.06). As an independent variable, patients with IDH mutations had longer median survivals (111.7 months) when compared to IDH wild-type patients (23.3 months) (p<0.001). On multivariable analysis, five-year-survival was significantly impacted by receipt of adjuvant TMZ (HR = 0.56, p=0.03) and IDH mutation status remained a significant prognostic factor (HR = 0.19, p < 0.001) (see Table). Conclusions: IDH mutation strongly predicts a favorable outcome in patients with AA. Secondarily, concurrent TMZ is also associated with improved survival in patients with AA who are receiving adjuvant radiotherapy. [Table: see text]

2031 Background: The mammalian target of rapamycin (mTOR) functions within the PI3K/Akt pathway as a critical modulator of cell survival. Preclinical studies in GBM indicate that the combination of mTOR inhibitors, such as everolimus (RAD001), with either radiation therapy (RT) or temozolomide (TMZ) provide increased tumor cell killing. Methods: Newly diagnosed GBM pts were eligible for the study. RAD001 was dosed orally at 70 mg/week weekly, starting 1 week prior to RT/TMZ, and continued throughout RT/TMZ, adjuvant TMZ and then until progression. This was a single arm phase II design powered to detect a true overall survival at 12 months (OS12) of 73% (vs 58% in historical controls). Secondary endpoints were toxicity, response rate, and time to progression (TTP). A subgroup of patients with measurable residual disease were eligible for the PET imaging component of the study, consisting of an 18FLT-PET/CT scan performed before and after the initial two doses of RAD001 but before the first dose of RT or TMZ. Results: 103 patients were accrued to phase II of which 100 were evaluable. The median age was 60.5 years (23-81), median ECOG PS was 1, 46 patients had GTR, 33 STR, and the remainder had biopsy at diagnosis. Treatment tolerance was acceptable: 17% patient had at least one grade 3 hematologic toxicity; 14% had at least one grade 4 hematologic toxicity, 42% had at least one grade 3 non-heme toxicity, while 12% had at least one grade 4 non-heme toxicity. No increased incidence of infectious complications was observed and there were no treatment related deaths. Median PFS was 5.3 months (1.3-21.4), with 22 patients progression free. Mature OS data will be available at the meeting. MGMT methylation status analysis is ongoing. Of the pts who had evaluable FLT-PET data, three of eight (37.5%) had a drop in SUVmax >25% after two treatments of RAD001. Conclusions: RAD001 with standard of care chemoradiation had moderate toxicity. Serial 18FLT-PET was feasible for evaluating drug-induced changes in tumor proliferation following RAD001. Final outcome data and association of MGMT status with outcome will be reported at the meeting.

Abstract Craniopharyngiomas are surgically challenging brain tumors. Postoperatively, quality of life is often significantly impaired due to neurological and endocrinological complications. Currently, FDA approved systemic treatments are not available for patients in whom craniopharyngiomas recur after surgery and radiation. Papillary craniopharyngiomas are characterized by the presence of BRAFV600E mutations. To date, five case reports have been published on the treatment of BRAFV600E mutant papillary craniopharyngiomas with BRAF and/or MEK inhibitors. In this presentation, authors from all five previously published reports share their collective experience and provide updated follow-up on their patients, thus generating an overview of all currently available information on targeted therapy in patients with BRAFV600E mutant papillary craniopharyngiomas. We have also included information on an additional patient with a papillary craniopharyngioma recently treated with BRAF and MEK inhibitors after tumor biopsy alone, in the absence of recurrence, highlighting the potential for a neo-adjuvant therapeutic approach. All six cases in our series showed dramatic responses to targeted treatment with BRAF (and MEK) inhibitors. Collectively, our cases are highly promising and informative for patient treatment, although uncertainty remains with regards to the optimal timing, the specific agents (single agent or dual therapy) to be used and the duration of treatment. The ongoing multicenter phase II Alliance A071601 trial (NCT03224767) of vemurafenib and cobimetinib for patients with biopsy-proven residual or recurrent papillary craniopharyngiomas should provide additional information to help guide patient management.