Laack, Nadia N.

Abstract PURPOSE To provide a final update on oncologic and cognitive outcomes of high dose versus low dose radiation for low-grade glioma. METHODS Between 1986 and 1994, 203 patients with supratentorial low grade glioma were randomized to 50.4 Gy in 28 fractions versus 64.8 Gy in 36 fractions after any degree of resection. Histologic subtype was oligodendroglioma (71%) or astrocytoma (29%). Primary outcome was overall survival (OS). Cognitive status was followed using Folstein Mini-Mental State Examination (MMSE). RESULTS For the entire cohort of 203 patients, median OS was 8.4 years (95% CI: 7.2 – 10.8). Median progression-free survival (PFS) was 5.2 years (95% CI: 4.3 – 6.6). Median follow-up is 17.2 years for the 33 patients still alive. High-dose radiation did not improve OS (15-yr OS: 22.4% vs. 24.9%, log rank p=0.978) or PFS (15-yr PFS: 15.2% vs. 9.5%, p=0.7142). OS was significantly better for patients with pre-operative tumor diameter < 5 cm (15-yr OS: 39.4% vs. 15.2%, p< 0.001), baseline MMSE > 27 (15-yr OS: 27.3% vs. 9.8%, p=0.001), and for patients who underwent gross total resection (GTR) (15-yr OS: 39.3% GTR vs. 16.4% subtotal resection vs. 24.5% biopsy only, p=0.0119). PFS was improved for patients with oligodendroglioma versus astrocytoma (15-yr PFS: 13.8% vs. 8.6%, p=0.0221). PFS was also improved for patients with pre-operative tumor diameter < 5 cm, patients who had GTR, and patients with baseline MMSE > 27. For patients who had normal MMSE at baseline, at 7 years only 1 patient (5%) had a clinically significant decrease in MMSE from the previous time point, with the remainder (95%) stable. None had decrease in MMSE at 10, 12, or 15 years. CONCLUSIONS Long-term follow-up indicates no benefit to high-dose over low-dose radiation for low-grade gliomas. Minimal late decline in cognitive function after radiation was seen by MMSE. SUPPORT: U10CA180821,U10CA180882. https://acknowledgments.alliancefound.org

AbstractMAPK pathway activation has been recurrently observed in desmoplastic infantile ganglioglioma/astrocytoma (DIG/DIA) with reported disproportionally low mutation allele frequencies relative to the apparent high tumor content, suggesting that MAPK pathway alterations may be subclonal. We sought to expand the number of molecularly profiled cases and investigate if tumor cell composition could account for the observed low mutation allele frequencies. Molecular (targeted neuro-oncology next-generation sequencing/RNA sequencing and OncoScan microarray) and immunohistochemical (CD68-PGM1/CD163/CD14/CD11c/lysozyme/CD3/CD20/CD34/PD-L1) studies were performed in 7 DIG. Activating MAPK pathway alterations were identified in 4 (57%) cases: 3 had a BRAF mutation (V600E/V600D/V600_W604delinsDQTDG, at 8%–27% variant allele frequency) and 1 showed a TPM3-NTRK1 fusion. Copy number changes were infrequent and nonrecurrent. All tumors had at least 30% of cells morphologically and immunophenotypically consistent with microglial/macrophage lineage. Two subtotally resected tumors regrew; 1 was re-excised and received adjuvant treatment (chemotherapy/targeted therapy), with clinical response to targeted therapy only. Even with residual tumor, all patients are alive (median follow-up, 83 months; 19–139). This study further supports DIG as another MAPK pathway-driven neuroepithelial tumor, thus expanding potential treatment options for tumors not amenable to surgical cure, and suggests that DIG is a microglia/macrophage-rich neuroepithelial tumor with frequent low driver mutation allele frequencies.

Abstract Soft tissue sarcomas are a rare and heterogeneous group of malignancies that present significant diagnostic and therapeutic challenges. Patient stratification based on tumor aggressiveness and early therapeutic response based on quantitative imaging may improve prediction of treatment response and the evaluation of new treatment strategies in clinical trials. The purpose of this pilot study was to determine the technical feasibility of magnetic resonance elastography (MRE) and dynamic contrast-enhanced (DCE) MRI for the evaluation of sarcoma stiffness and perfusion in 9 patients with histologically confirmed sarcoma. Additionally, we assessed the feasibility of utilizing MRE and DCE-MRI for the early evaluation of response to radiation therapy in 4 patients to determine the utility of further evaluation in a larger cohort study. Tumor size, stiffness, and perfusion parameters all decreased from baseline at the time of the pre-surgery or follow-up MRI, and results were compared to pathology or conventional imaging. MRE and DCE-MRI may be useful for the quantitative evaluation of tumor stiffness and perfusion, and therapy response assessment in soft tissue sarcomas.

Abstract BACKGROUND Patients with persistent or recurrent Cushing disease (CD) after prior transsphenoidal surgery require further treatment to reduce the disease's metabolic consequences. OBJECTIVE To assess patient outcomes after stereotactic radiosurgery (SRS) for persistent or recurrent CD from adrenocorticotropin hormone (ACTH)-secreting pituitary adenomas and propose a management algorithm. METHODS Retrospective review of 38 patients without prior radiation treatment having SRS for ACTH-secreting pituitary adenomas from 1990 to 2015. Favorable outcome was defined as biochemical remission and tumor growth control. Patients were evaluated separately if they underwent bilateral adrenalectomy (Adx). RESULTS Twenty patients (53%) were treated with Adx and SRS (median margin dose, 25 Gy) and 18 patients (47%) received SRS alone (median margin dose, 22.5 Gy). Median follow-up after SRS was 76 mo. Of patients undergoing Adx, 18/20 (90%) had a favorable outcome. Two patients (10%) had tumor growth requiring additional treatment. A favorable outcome was achieved in 13/18 patients (72%) having SRS alone (median, 14 mo; interquartile range, 8-23). Five patients (28%) required additional treatment due to persistent hypercortisolemia (n = 4) or hypercortisolemia and tumor growth (n = 1). Favorable outcomes were more frequent in the Adx and SRS group at 1 yr (100% vs 33%; P < .001) and 3 yr (100% vs 62%; P < .01), but no different at 5 yr (88% vs 77%; P = .63). CONCLUSION SRS was effective for patients with persistent or recurrent CD. Patients with mild to moderate CD can be safely managed with SRS alone; patients with severe CD should be considered for Adx with either concurrent SRS or SRS performed at a later date if tumor growth occurs.

Abstract Background This study evaluated the association between health-related quality of life (HRQOL) and cognition in patients receiving memantine for prevention of cognitive dysfunction during whole-brain radiotherapy (WBRT). Methods Adult patients with brain metastases received WBRT and were randomized to receive placebo or memantine, 20 mg per day, within 3 days of initiating radiotherapy, for 24 weeks. The Functional Assessment of Cancer Therapy-Brain module (FACT-Br) and Medical Outcomes Scale-Cognitive Functioning Scale (MOS-C) were completed in coordination with serial standardized tests of cognitive function. Results Of the 508 eligible patients, 442 (87%) consented to participate in the HRQOL portion and contributed to baseline analyses. Evaluable patients at 24 weeks (n = 246) included surviving patients completing FACT-Br, MOS-C, and objective cognitive assessments (n = 146, 59%) and patients alive at time of missed assessment (n = 100, 41%). Baseline cognitive function correlated significantly with FACT-Br and MOS-C self-reports. All domains of objective cognitive function showed declines over time. Neither FACT-Br nor MOS-C differed between the treatment arms. Emotional and functional well-being subscales of the FACT improved over time while the remainder of the FACT-Br domains remained stable. MOS-C scores declined over time. Conclusion Baseline cognitive function correlated significantly with FACT-Br and MOS-C scores. No by-arm differences in HRQOL were observed despite differences in objective cognitive function. Patient attrition and poor testing compliance remain significant problems in studies of cognitive function of brain metastases patients and further effort is needed to improve compliance with testing and sensitivity of patient-reported measures.

With robust optimization for spot scanning proton therapy now commercially available, the ability exists to account for setup, range, and interfield uncertainties during optimization. Robust optimization is particularly beneficial for craniospinal irradiation (CSI) where the large target volume lends itself to larger setup uncertainties and the need for robust match lines can all be handled with the uncertainty parameters found inside the optimizer. Suggested robust optimization settings, parameters, and image guidance for CSI patients using proton therapy spot scanning are provided. Useful structures are defined and described. Suggestions are given for perturbations to be entered into the optimizer in order to achieve a plan that provides robust target volume coverage and critical structure sparing as well as a robust match line. Interfield offset effects, a concern when using multifield optimization, can also be addressed within the robust optimizer. A robust optimizer can successfully be employed to produce robust match lines, target volume coverage, and critical structure sparing under specified uncertainties. The robust optimizer can also be used to reduce effects arising from interfield uncertainties. Using robust optimization, a plan robust against setup, range, and interfield uncertainties for craniospinal treatments can be created. Utilizing robust optimization allows one to ensure critical structures are spared and target volumes are covered under the desired uncertainty parameters.

Object Gangliogliomas comprise less than 1% of all brain tumors and occur most often in children. Therefore, there are a limited number of patients and data involving the use or role of adjuvant therapy after subtotal resections (STRs) of gangliogliomas. The objective of this study was to examine and review the Mayo Clinic experience of 88 patients with gangliogliomas, their follow-up, risk of recurrence, and the role of radiation therapy after STR or only biopsy. Methods Eighty-eight patients with gangliogliomas diagnosed between 1970 and 2007 were reviewed. Data on clinical outcomes and therapy received were analyzed. The Kaplan-Meier method was used to estimate progression-free survival (PFS) and overall survival. Results The median age at diagnosis was 19 years. The median potential follow-up as of June 2008 was 142 months (range 9–416 months). Fifteen-year overall survival was 94%, median PFS was 5.6 years, with a 10-year PFS rate of 37%. Progression-free survival was dramatically affected by extent of initial resection (p < 0.0001). Conclusions This single-institution retrospective series of patients with gangliogliomas is unique given its large cohort size with a long follow-up duration, and confirms the excellent long-term survival rate in this group. The study also shows the importance of resection extent on likelihood of recurrence. Patients with gangliogliomas who undergo STR or biopsy alone have poor PFS. Radiation therapy may delay time to progression in patients with unresectable disease.