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Background Surgical resection has been shown to prolong survival in patients with glioblastoma multiforme (GBM), although this benefit has not been demonstrated for reoperation following tumor recurrence. Laser interstitial thermal therapy (LITT) is a minimally invasive ablation technique that has been shown to effectively reduce tumor burden in some patients with intracranial malignancy. The aim of this study was to describe the safety and efficacy of LITT for recurrent and newly diagnosed GBM at a large tertiary referral center. Methods Patients with GBM receiving LITT were retrospectively analyzed. Overall survival from the time of LITT was the primary end point measured. Results There were 69 patients identified for inclusion in this study. The median age of the cohort was 56 years (range, 15–77 years). Median tumor volume was 10.4 cm3 (range, 1.0–64.0 cm3). A Kaplan-Meier estimate of median overall survival for the series from the time of LITT was 12 months (95% confidence interval 8–16 months). Median progression-free survival for the cohort from LITT was 4 months (95% confidence interval 3–7 months). Adjuvant chemotherapy significantly prolonged progression-free survival and overall survival (P Conclusions LITT can safely reduce intracranial tumor burden in patients with GBM who have exhausted other adjuvant therapies or are poor candidates for conventional resection techniques.

BackgroundPineal parenchymal tumors are exceedingly rare brain tumors responsible for less than 1% of all adult primary intracranial malignancies in the United States. In this study, we describe the clinicopathologic features, management, and outcomes of patients with pineal parenchymal tumor of intermediate differentiation (PPTID).MethodsWe describe a single-center, multidisciplinary team experience in managing PPTID patients over a 15-year period (January 2000 to January 2015) at The University of Texas MD Anderson Cancer Center (MDACC). Pathology was reviewed by the pathology collaborators (A.G. and G.N.F.) and retrospective chart review was performed for treatment and clinical outcomes.ResultsWe identified 17 patients (9 male) with diagnosis of PPTID. Median age at diagnosis of PPTID was 37 years (range, 15-57 years). Follow-up ranged from 0.1 to 162.8 months with 6 reported deaths. Most patients presented with headaches and diplopia. Three patients had neuroaxial dissemination at initial diagnosis, and recurrence of tumor was common (7/16) despite treatment.ConclusionsNo clear prognostic factors were identified in this series. Extension of resection showed a trend toward improved survival. PPTID with neuroaxial dissemination benefits from aggressive initial treatment including craniospinal irradiation and adjuvant chemotherapy, whereas localized disease may be treated traditionally with maximum debulking followed by adjuvant radiotherapy alone. Long-term monitoring is recommended for neurotoxicity and/or late recurrence.

The immune cell composition of isocitrate dehydrogenase wild type (IDH-wt) glioma patients significantly differs compared to IDH-mutant (IDH-mut) yet a detailed and unbiased understanding of their transcriptomic and epigenetic landscapes remains elusive. To this end, we performed single-cell RNA-sequencing (scRNA-seq) and single-cell Assay for Transposase-Accessible Chromatin using sequencing (sc-ATAC-seq) on ~100,000 tumor-associated immune cells from seventeen IDH mutation classified primary and recurrent human gliomas and non-glioma brains (NGBs). Our analyses revealed sixty-two transcriptionally distinct myeloid and lymphoid cell states within and across glioma subtypes and we noted microglial attrition with increasing disease severity concomitant with invading monocyte-derived cells (MDCs) and lymphocytes. Specifically, certain microglial and monocyte-derived subpopulations were associated with antigen presentation gene modules, akin to cross-presenting dendritic cells. As tissue macrophages exhibit multifaceted polarization in response to microenvironmental cues, we clarify the existence of microglia/macrophage functional states beyond M1/M2 paradigms exemplified by the presence of palmitic-, oleic- acid, and glucocorticoid responsive polarized states. We identified cytotoxic T cells with poly-functional cytolytic states mostly in recurrent IDH-wt gliomas. Furthermore, ligand-receptor interactome analyses showed a preponderance of antigen presentation/phagocytosis over the checkpoint axis in IDH-wt compared to IDH-mut gliomas. Additionally, our sc-ATAC-seq analyses revealed differences in regulatory networks in NGBs, IDH-mut, and IDH-wt glioma-associated immune cells. In particular, we noted reduced microglial usage of an iron recycling SPIC transcription factor and Interferon Regulatory Factors (IRFs); IRF1 and IRF2 in IDH-wt relative to IDH-mut and NGBs. Unique features such as amplification of 11-Zinc Finger Protein accessibility were restricted to MDCs. Finally, sc-ATAC-seq profiles of CD8+ exhausted T cells from IDH-wt showed strong enhancer accessibility on CTLA-4, Layilin, and TIM-3 but no enrichment on PD1 was seen. In summary, our study provides unprecedented granular detail of transcriptionally and epigenomically defined glioma-specific immune contexture that can be exploited for immunotherapy applications.

BCR-ABL1 tyrosine kinase inhibitors (TKIs) alone and with chemotherapy led to a dramatic increase in survival of chronic myeloid leukemia (CML) and Philadelphia-positive acute lymphoblastic leukemi...

Immune checkpoint inhibitors (CPIs) (anti-cytotoxic T-lymphocyte antigen-4, anti-programmed death 1, and anti-programmed death-ligand 1) have transformed the landscape of cancer therapy. However, their increasing use has unleashed immune-related adverse events in various organs, among which neurologic ones, while rare, are increasingly being recognized and remain incompletely characterized. Herein, we report five patients with nonmelanoma cancers who developed weakness after receiving CPIs. The etiology was attributed to radiculoneuritis (one patient), myositis (one patient), Miller Fisher/myasthenia gravis (MG) (one patient), neuropathy/myositis/MG (one patient), and myositis/MG (one patient). Weakness developed after a median of two doses (range: 1–3) and 4 weeks (range: 3–10) from initiation of therapy. Two patients had severe manifestations without improvement while the other three experienced partial improvement despite discontinuation of the CPI (s) and initiation of immunosuppressive therapy. A review of literature identified 62 similar cases. This report highlights the challenges in the diagnosis and management of neurologic adverse events related to the use of CPIs. It also addresses the crucial need for early recognition, proper workup, and better biomarkers to help improve the outcomes of these adverse events.

Background It is estimated only 8–11% of patients with glioblastoma (GBM) enrol in clinical trials, limiting treatment development. We analysed the clinical and demographic features of patients with GBM enroled in clinical trials at the University of Texas MD Anderson Cancer Center (MDACC). Methods We reviewed the records of adult patients treated for primary GBM between 2007 and 2012 at the MDACC. A total of 755 patients were identified: 133 were deemed non-eligible, 111 were deemed trial eligible but received standard care and 511 participated in a clinical trial (311 for newly diagnosed glioblastoma [nGBM] and 200 for recurrent glioblastoma [rGBM]). Population characteristics were analysed using descriptive statistics, and survival end-points were evaluated with the Kaplan–Meier method. Results The median age of clinical trial participants and trial eligible patients was 53.2 years (standard deviation 12.1). Most patients (49.4%) were enroled in a clinical trial protocol for nGBM. The majority of nGBM trial participants were male patients (65.1%), white (86.3%), married (84.4%) and in state (59.9%). Employment status, education, symptoms, tumour location, performance status, extent of resection and treatment facility differed between nGBM trial participants and non-participants. Patients who were eligible but did not enrol tended to be older, have worse performance status and live farther away from the MDACC. Conclusion Numerous disease and demographic barriers exist in trial enrolment in patients with GBM. This study highlights some of these obstacles, which require attention to improve patient enrolment to clinical trials. Patient and physician engagement in novel therapeutic strategies is essential to improving outcomes in this disease.

Background: Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. Management includes surgical resection followed by chemoradiation, and prognosis remains poor. Surgical resection is not possible for some deep-seated or eloquent tumors. Laser interstitial thermal therapy (LITT) has emerged as a new, minimally invasive surgical option for deep-seated GBM. Case Description: We report a case of newly diagnosed thalamic GBM managed with LITT followed by radiation and chemotherapy. Conclusion: The patient remains well at 50-month post-LITT, indicating a potentially unique durability of LITT treatment in GBM.

BACKGROUND Primary spinal high-grade gliomas(S-HGG) are rare, aggressive tumors and radiation therapy(RT) plays a dominant role in the management given their infiltrative nature. We conducted a single-institution retrospective review to study the clinicopathological features and management of S-HGGs. METHODS Patients with biopsy-proven S-HGG who received RT from 2001-2020 were analyzed for patient, tumor, and treatment characteristics. Kaplan-Meier estimate and Cox proportional hazard regression method were used for survival analyses. RESULTS Twenty-nine patients were identified with a median age of 25.9 years (range 1-74y). Four patients had gross total resection(GTR) while 25 underwent subtotal resection or biopsy. Nineteen patients had WHO grade 4 tumor. IDH1 mutation and MGMT promoter methylation were analyzed in 14 and four patients respectively; all were IDH wildtype and MGMT-promoter unmethylated. H3K27M mutation was present in five out of 10 patients tested. Twenty-two patients received photon-based radiation and 7 received proton therapy. Median RT dose was 50.4 Gy (range 39.6-54Gy) with 79% receiving >45Gy. 65% patients received concurrent chemotherapy, most commonly temozolomide. Twenty-three (79%) patients had documented recurrence. Overall, 16 patients relapsed locally, 10 relapsed in the brain and 8 developed leptomeningeal disease; only 8(35%) had isolated local relapse. Median OS from diagnosis was 21.3 months and median PFS after RT was 9.7 months. On univariate analysis, age, sex, GTR, grade, RT modality, RT dose and concurrent chemotherapy did not predict for survival. Patients with H3K27M mutation had a poorer median PFS after RT compared to those without the mutation but the difference did not reach statistical significance (p = 0.26). CONCLUSIONS Although 86% of patients had gross disease at RT and received a lower median RT dose than typically used in cerebral high-grade gliomas, only 55% of patients failed locally. H3K27M mutation may portend worse survival; future studies to improve the therapeutic approach in these patients are warranted.

Background Glioblastoma (GBM) is the most common and most aggressive primary malignant brain tumour. The standard of care is surgical resection, followed by radiotherapy with concurrent and adjuvant temozolomide. In Latin America, there is scarcity of information about the incidence of GBM and even less data regarding outcomes. In this study, we describe the clinicopathologic features, management and outcomes of GBM patients. Methods We describe a single-centre multidisciplinary team experience in managing GBM patients over an 11-year period (Jan 2005 to Dec 2016). Pathology was reviewed by the pathology collaborator and retrospective chart review performed for treatment and clinical outcomes. Results We identified 74 patients (50 males) with diagnosis of GBM. Median age at diagnosis was 58 years (range 24-79 years), and median Karnofsky performance status was 80%. Forty-three (58.1%) went to gross total resection, 20 (27%) partial resection and 11 (14.9%) biopsy. Sixty-four (87%) patients received Stupp regimen. The median overall survival (OS) was 13.9 months (standard error (SE) 1.71; 95% confidence interval (CI), 10.56-17.23). In patients treated according to Stupp regimen, the progression-free survival (PFS) was 10 months (SE 1.8; 95% CI, 6.481-13.519), the selfcare survival was 11.8 months (SE 1.61; 95% CI, 8.632-14.968) and the OS was 16.1 months (SE 1.53; 95% CI, 13.01-19.099). Conclusions This study reports the most complete analysis of epidemiology, clinical management and outcomes of patients with diagnosis of GBM in Chile treated with Stupp regimen. The PFS and OS are consistent with reports of US and Europe.

Pituitary carcinoma is an aggressive tumor characterized by metastatic spread beyond the sellar region that leads to debilitating symptoms and poor survival. Pituitary carcinomas recur despite conventional multimodality treatments. Given the recent advances in the use of immune checkpoint inhibitors (CPIs) to treat various solid cancers, there is interest in exploring the role of immunotherapy for treating aggressive, refractory pituitary tumors. We treated four pituitary carcinoma patients with pembrolizumab as part of a phase II clinical trial (NCT02721732). Here, we present their clinical course and outcomes and correlate responses with available molecular data: hypermutation status, PD-L1 staining, tumor-infiltrating lymphocyte score, microsatellite status and tumor mutational burden. Patients 1 and 2, with heavily pretreated, refractory corticotroph pituitary carcinoma, had partial radiographic (60% and 32% per irRECIST, respectively) and hormonal responses. Patient 1’s response continues 42 months after initiation of pembrolizumab and his baseline tumor tissue obtained after treatment with temozolomide demonstrated a hypermutator phenotype with MSH2 and MSH6 gene mutations. Patient 2’s tumor was not sampled after exposure to temozolomide, but prior somatic mutational testing was negative. Patient 3 (non-functioning corticotroph tumor) had a best response of stable disease for four months. Patient 4 (prolactin-secreting carcinoma) had progressive disease. The latter two patients’ tumors did not demonstrate a hypermutator phenotype after treatment with temozolomide. PD-L1 staining was negative in all tumors. TIL score was 2 in Patients 1 and 4, negative in Patient 3 and not available in Patient 2. All patients tolerated the treatment well with mild adverse events. Our study generates the hypothesis that an alkylating agent-induced hypermutator phenotype may be an indicator of response to CPIs in pituitary carcinomas. The role of CPI in treating patients with pituitary carcinoma and mechanisms of hypermutation in this population require further study.

BACKGROUND WHO grade II and III IDH wild-type astrocytomas behave more aggressively than their IDH mutated counterparts. A subpopulation shares molecular features with the novel entity proposed in cIMPACT-NOW Update 3 “Diffuse astrocytic glioma, IDH wild-type, with molecular features of glioblastoma (GBM), WHO IV”. METHODS We performed a retrospective analysis of clinical and molecular features, management and survival of 134 adult patients treated for grade II and III IDH wild-type astrocytoma between 06/2012 and 12/2018 at MD Anderson Cancer Center (MDACC - 112) and UT Health Science Center at Houston (UTHSC - 22). All patients had IDH1 sequenced, all but 2 had IDH2 sequenced, and 73 had further next generation sequencing. RESULTS Median age at diagnosis was 53 (interquartile range 18-83). 82 patients (61%) were male. 31 patients were histologically diagnosed with grade II astrocytoma, 102 with grade III astrocytoma, and one with diffuse glioma (insufficient tissue to render histologic grade or perform sequencing). EGFR alterations were found in 31 patients and TERT promoter mutations in 22. 84 (63%) received concurrent chemoradiation and adjuvant temozolomide (grade II, n=9; grade III, n=74; NOS, n=1). PFS overall was 12.0 months (grade II = 17.9; grade III = 10.7). OS in patients treated with concurrent chemoradiation and adjuvant temozolomide was 17.1 months versus 17.7 in patients treated with sequential radiation and temozolomide (p = NS), and 10.6 in patients treated with RT alone or surveillance (p< 0.016). The highest 2-year OS was seen in grade II patients treated with concurrent chemoradiation and adjuvant temozolomide (60%). CONCLUSIONS WHO grade II and III IDHwt astrocytoma survival is similar to historical GBM cohorts. The proportion meeting molecular criteria for GBM is yet undefined. Groups who received chemotherapy may perform better than those who do not. Further analysis of MGMT methylation and other molecular factors is ongoing.

Peripheral nervous system damage from hematologic malignancies is related to neoplastic cells infiltration of peripheral nerves or to monoclonal antibody production cross-reacting with peripheral nerves' antigens. Neurolymphomatosis (NL), a rare manifestation of hematologic malignancies, occurs when malignant cells invade the peripheral nerves leading to various manifestations. Here, we report a case of NL with 2 hematologic malignancies in a 79-year-old woman presenting with lower extremity pain/weakness. Investigation revealed anemia, IgM kappa monoclonal gammopathy, and elevated anti-MAG titer. Electrodiagnostic studies were consistent with mononeuropathy multiplex while imaging suggested malignancy in her ovaries and right S1 nerve root. Bone marrow and ovarian biopsies revealed chronic myelomonocytic leukemia, Waldenstrom macroglobulinemia, and diffuse large B-cell lymphoma. She received standard chemotherapy resulting in radiographic resolution of disease and symptomatic relief. NL can precede the diagnosis of hematologic malignancy but its symptoms are not easily identifiable, whereas management depends on the treatment of the underlying tumor.

BACKGROUND Patients with high-grade gliomas (HGG) often receive anti-angiogenic therapy with bevacizumab to slow disease progression and/or palliate neurological symptoms. Bevacizumab has been associated with an increased risk of two major vascular complications: venous thromboembolism (VTE) and intracranial hemorrhage (ICH). We sought to identify clinical, pathologic, and radiographic variables correlated with risk of either event occurring in patients with HGG receiving bevacizumab. METHODS We retrospectively identified 94 patients with HGG who received bevacizumab at our center from 2015-2021. Variables included demographics, performance status, IDH, MGMT, vascular risk factors, baseline anti-coagulant/anti-platelet use, concurrent chemotherapy, and presence of macrobleeds on MRI (>1 cm3 susceptibility) at the time of bevacizumab initiation. We conducted competing risk analysis using subdistribution hazard models with death as competing risk for ICH or VTE. The effects of covariates on the incidence of hemorrhage or VTE were evaluated in univariate and multivariate settings. RESULTS Of 94 patients, 36 (38.3%) and 27 (28.7%) developed VTE and ICH, respectively. 31 (33%) did not develop either. ICH and VTE events occurred after a mean of 4.46 and 5.94 cycles of bevacizumab, respectively. 20 had baseline anti-platelet/anticoagulant use, and 16 had prior VTEs. Patients with macrobleeds on MRI had a larger HR of developing acute hemorrhage [HR=2.368 (1.112, 5.043), p=0.0254]. Patients older than 50 trended toward larger HR of developing VTE in univariate analysis that approached significance [HR=1.799 (0.889, 3.637), p=0.1023]. Sex, performance status, IDH, MGMT, vascular risk factors, baseline anticoagulant/anti-platelet use and concurrent chemotherapy were not significantly associated with occurrence of VTE. CONCLUSIONS The presence of macrobleeds on MRI is associated with increased risk of developing acute ICH while on bevacizumab. Older age at diagnosis of HGG may be associated with an increased risk of VTE in patients receiving bevacizumab. Larger studies are needed to confirm these findings.

BACKGROUND Checkpoint inhibitor therapy has demonstrated overall limited efficacy in the treatment of GBM. Mechanisms of resistance to checkpoint blockade need to be better elucidated. Analysis of the tumor microenvironment is critical to identify correlates of response to immune checkpoint blockade. 60 newly diagnosed GBM patients unselected for MGMT status underwent treatment with concurrent atezolizumab with radiation therapy and TMZ followed by adjuvant atezolizumab and TMZ (NCT03174197). Clinical data has been reported previously. METHODS Tissue image immunoprofiling was conducted using 2 multiplex immunofluorescence (mIF) panels against; CD3, CD8, PD-1, PD-L1, Granzyme B, FOXP3, CD45RO, CD68, and GFAP antibodies. PDL-1 (Clone SP263) malignant cells expression was assessed by immunohistochemistry. Correlations between mIF biomarkers co-expressions, IHC PD-L1, and clinical outcome including OS, radiographic response, and PFS were evaluated. RESULTS Of 60 patients enrolled, image immunoprofiling was performed successfully on pre-treatment tissue in 48 patients. 20 of 60 patients underwent re-resection for suspected recurrent disease of which 10 patients had immunoprofiling performed successfully on pre and post treatment samples. An analysis of CD3CD8+ cytotoxic T lymphocytes was consistent with prior work, showing no or relatively low levels at baseline, and no association with clinical outcome. PDL-1 expression by IHC, at thresholds of >1% or >5%, was not associated with clinical outcome. Tumors with a higher number of GFAP-expressing cancer cells had a significantly lower tumor response (p< 0.05) and median OS (430 vs. 799 days, p< 0.01). CONCLUSIONS For newly diagnosed GBM patients treated with standard of care radiation and temozolomide in combination with atezolizumab, T-cell levels and PDL-1 expression were not predictive of outcome. GFAP may represent a novel predictive biomarker of overall survival. Ongoing studies to evaluate the gut microbiome and tumor genomic (WES, CNA) and transcriptomic (RNAseq) features of these and matched tumors are underway.

The brain tumor immune microenvironment (TIME) continuously evolves during glioma progression, but a comprehensive characterization of the glioma-centric immune cell repertoire beyond a priori cell states is uncharted. In this study, we performed single-cell RNA-sequencing (scRNA-seq) and single cell- Assay for Transposase-Accessible Chromatin using sequencing (sc-ATAC-seq) on ~100,000 tumor-associated immune cells from seventeen isocitrate dehydrogenase (IDH) mutation classified primary and recurrent human gliomas and non-glioma brains (NGBs). Our analyses revealed sixty-two transcriptionally distinct myeloid and lymphoid cell states within and across glioma subtypes and we noted microglial attrition with increasing disease severity concomitant with invading monocyte-derived cells and lymphocytes. Specifically, certain microglial and monocyte-derived subpopulations were associated with antigen presentation gene modules, akin to cross-presenting dendritic cells (DCs). We identified cytotoxic T cells with poly-functional cytolytic states mostly in recurrent IDH-wt gliomas. Furthermore, ligand-receptor interactome analyses showed a preponderance of antigen presentation and phagocytosis over the checkpoint axis in IDH-wt compared to IDH-mut gliomas. Additionally, our sc-ATAC-seq analyses revealed differences in regulatory networks in NGBs, IDH-mut and IDH-wt glioma associated immune cells. In particular, we noted abundant usage of inflammatory transcription factors (TFs) as exemplified by Nuclear factor kappa B and Activator Protein-1 TF family in IDH-wt microglia when compared with microglia from IDH-mut and NGBs. Unique features such as amplification of 11- Zinc Finger Protein accessibility were restricted to monocyte derived cells and were not observed in microglia. Finally, sc-ATAC-seq profiles of CD8+ exhausted T cells from IDH-wt showed strong enhancer accessibility on Cytotoxic T-lymphocyte-associated protein 4, Layilin and Hepatitis A Virus Cellular Receptor 2 but no enrichment on PDCD1 (gene encoding Programmed cell death protein 1) was seen. In summary, our study provides unprecedented granular detail of transcriptionally defined glioma- specific immune contexture that can be exploited for immunotherapy applications. This study in K.B. laboratory was supported by the generous philanthropic contributions to The University of Texas (UT) MD Anderson Cancer Center (MDACC) Moon Shots Program™, Marnie Rose Foundation, NIH grants: R21 CA222992 and R01CA225963. This study was partly supported by the UT MDACC start-up research fund to L.W. and CPRIT Single Core grant RP180684 to N. E. N.

BACKGROUND The role of adjuvant radiation after gross total resection (GTR) for grade II meningioma is evolving, prompting further evaluation in NRG-BN003, a phase 3 national trial. Furthermore, the relationship between facility volume and outcomes in patients with grade II meningioma after GTR has not been examined at a national level. We aim to assess overall survival (OS) of patients with grade II meningioma after GTR by surgical case volume and OS by receipt of adjuvant radiation. METHODS We used the National Cancer Database to identity 2823 patients diagnosed with grade II meningioma who underwent GTR. Propensity score matching was applied to balance covariates in patients with grade II meningioma after GTR stratified by adjuvant radiation status. Multivariable logistic regression was used to assess factors associated with radiation receipt. Kaplan-Meier and log-rank tests were used to assess OS by facility volume. RESULTS As facility volume increased, OS increased, with a 5-year OS of 72.8% for facilities with GTR grade II meningioma volumes of ≤8 cases per decade and 87.5% for >8 cases per decade (P < 0.0001). There was no difference in 5-year OS between GTR alone and GTR with adjuvant radiation (84.8% vs. 86.4%; P = 0.151). Covariates significantly associated with radiation receipt included facility location, facility volume, distance, and tumor size. CONCLUSIONS Treatment at higher surgical case volume facilities is associated with improved OS for GTR grade II meningioma. These facilities also have more patients receiving adjuvant radiation. However, we observed no difference in OS between adjuvant radiation and surgery alone.

Purpose of review Checkpoint inhibitors (CPIs) represent the forefront of novel immunotherapeutic approaches for the treatment of solid cancers. However, the clinical development of CPIs in glioblastoma (GBM) has been challenging owing to an immunosuppressive tumor microenvironment and, possibly, low tumor mutation burden. Here, we review possible mechanisms responsible for the success of programmed cell death-1 (PD-1) blockade in patients with hypermutated GBM, recent clinical trials of anti-PD-1 monotherapy, trials incorporating neoadjuvant strategies, and trials of immunotherapy combination approaches in GBM. Mechanisms of resistance to immunotherapy and methods to overcome these challenges are also discussed. Recent findings Although two large phase III trials failed to demonstrate the superior efficacy of CPI in comparison with the standard of care in newly diagnosed and recurrent GBM, recent studies suggest that opportunities exist in some patients with GBM. A phase II study showed longer survival in patients with recurrent GBM who received neoadjuvant anti-PD-1 therapy than in those who received it as adjuvant therapy. In addition, cases of response to anti-PD-1 therapy in GBM patients with clonal hypermutator tumors have been reported. Summary Even though anti-PD-1 therapy does not seem to provide a benefit for molecularly unselected GBM patients, the success of PD-1 blockade in certain subsets of patients is encouraging.

Craniopharyngioma is a rare tumor in adults. Although histologically benign, it can be locally aggressive and may require additional therapeutic modalities to surgical resection. Analyses including next generation sequencing, chromogenic and in situ hybridization, immunohistochemistry, and gene amplification were used to profile craniopharyngiomas (n=6) for frequently altered therapeutic targets. Four of six patients had the BRAFV600E missense mutation, frequent in the papillary craniopharyngioma subtype. One patient had a missense mutation in the WNT pathway, specifically CTNNB1, often associated with the adamantinomatous subtype. Craniopharyngiomas lacked microsatellite instability, had low tumor mutational burden, but did express PD-L1 protein, indicating potential therapeutic value for immune checkpoint inhibition. We identified mutations not previously described, including an E318K missense mutation in the MITF gene, an R1407 frameshift in the SETD2 gene of the PIK3CA pathway, R462H in the NF2 gene, and a I463V mutation in TSC2. Two patients testing positive for EGFR expression were negative for the EGFRvIII variant. Herein, we identified several alterations such as those in BRAFV600E and PD-L1, which may be considered as targets for combination therapy of residual craniopharygiomas

2520 Background: Pembrolizumab (Pembro), anti-PD1 therapy, is FDA approved for refractory microsatellite instability high (MSI-H)/deficient mismatch repair (dMMR) advanced/metastatic solid tumors. The robust activity of anti-PD1 therapy in these tumors argues for a neoadjuvant organ-sparing approach. However, the role of anti-PD1 monotherapy in the neoadjuvant setting is unknown. Methods: This is a phase 2 open-label, single center trial (NCT04082572) of MSI-H/dMMR non-metastatic solid tumors with localized unresectable or high risk resectable (defined as ≥ 20% recurrence) with measurable disease per RECISTv1.1 and ECOG PS 0/1. Treatment is Pembro 200mg every 3 wks for 8 cycles (6 months) followed by surgical resection with option to continue therapy for 18 cycles (12 months) followed by observation. First restaging is at 6 wks and includes baseline and 3-week 70-gene ctDNA assessment. To continue on study, patients are required to have PR/CR, SD with tumor shrinkage or SD with decline in ctDNA [highest variant allele frequency (VAF) baseline mutation]. The co-primary endpoints are safety and pathological complete response (pCR). Key secondary endpoints are response rate and organ-sparing at one year for patients who declined surgery. Results: Between 12/2019 and 2/2021, 32 pts were enrolled and treated. Enrolment goal of 35 anticipated to be met by 4/2021. Baseline characteristics included 13 females, median age of 63 yrs (range 26 - 91), Lynch syndrome in 12 pts, BRAF V600E mutation in 11 pts. Tumor type included 24 CRC and 8 non-CRC (1 endometrial, 1 gastric, 1 meningeal, 2 duodenal, 1 ampullary, 2 pancreatic). At baseline disease was resectable in 23 (72%). Among 30 evaluable pts, best overall response rate was 77%: 30% CR (n = 9), 47% PR (n = 14), 20% SD (n = 6), 3% PD (n = 1). Only one pt progressed after initial SD of -18%. Median follow-up is 6.1 months (range 0.1 - 14). Among the 6 (20%) pts who underwent surgery, pCR was seen in 3 (50%). A non-operative approach (pembro for 12 months) has been chosen in 15 pts and 1-year organ-sparing was seen in 2/2 evaluable pts. Treatment-related grade 3/4 immune adverse events (TRAE) were seen in 3 (9%) pts: grade 3 immune hepatitis (2) and grade 3 type 1 diabetes (1). Baseline ctDNA was positive in 17 (53%) pts with a median of 4 mutations per pt (1 - 35) and median highest VAF of 0.9% (range 0.3% to 38.2%). Among 26 pts with successful tumor tissue testing, median tumor mutations were 10.5, range 1 to 21 (Oncomine 134 gene panel). ctDNA decline at 3 weeks was seen in 14/17 (82%) patients. Luminal disease was present in 24 pts with endoscopic response of: CR in 13 (54%), major response 1, pending follow-up evaluation 6, not evaluated 3, and no response in 1. Conclusions: Neoadjuvant pembrolizumab is safe with encouraging clinical activity and this data suggests that a non-operative management for dMMR/MSI-H localized solid tumors should receive further investigation. Clinical trial information: NCT04082572.

Pituitary carcinoma is an aggressive tumor characterized by metastatic spread beyond the sellar region. Symptoms can be debilitating due to hormonal excess and survival is poor. Pituitary carcinomas recur despite conventional multimodality treatments. Given the recent advances in the use of immune checkpoint inhibitors (CPIs) to treat various solid cancers, there has been interest in exploring the role of immunotherapy for treating aggressive, refractory pituitary tumors. We treated 4 patients with pituitary carcinoma with pembrolizumab as part of a phase II clinical trial. Two patients (patients 1 and 2) with functioning corticotroph pituitary carcinomas (refractory to surgery, radiotherapy and chemotherapy) had partial radiographic (60% and 32% per Immune-Related Response Evaluation Criteria In Solid Tumors, respectively) and hormonal responses. Patient 1’s response continues 42 months after initiation of pembrolizumab and his tumor tissue obtained after treatment with temozolomide demonstrated a hypermutator phenotype with MSH2 and MSH6 gene mutations. Patient 2’s tumor after exposure to temozolomide was not sampled, but prior somatic mutational testing was negative. One patient with a non-functioning corticotroph tumor (patient 3) had a best response of stable disease for 4 months. One patient with a prolactin-secreting carcinoma (patient 4) had progressive disease. The latter 2 patients’ tumors did not demonstrate a hypermutator phenotype after treatment with temozolomide. Programmed death-ligand 1 staining was negative in all tumors. We report 2 cases of corticotroph pituitary carcinoma responsive to pembrolizumab after prior exposure to alkylating agents. The role of CPIs in treating patients with pituitary carcinoma, the relationship between tumor subtype and response to immunotherapy and mechanisms of hypermutation in this orphan disease require further study.Trial registration number: NCT02721732.

BACKGROUND The impact of COVID-19 on patients with nervous system tumors is not known. This population is often immunosuppressed, susceptible to neurological complications, and requiring of frequent cancer care, all of which may confer vulnerability to poorer outcomes after infection. METHODS Clinical data were obtained from structured electronic medical record elements, clinical note text and laboratory RESULTS: Each source was identified, integrated and analyzed using the Palantir Foundry platform (Syntropy), part of the Context Engine Data Management System through the MD Anderson Cancer Center (MDACC) IRB approved D3CODE initiative. The population of interest was patients diagnosed with COVID-19 who had been seen at the Brain and Spine Center for nervous system tumors. RESULTS 8,177 ambulatory patients were seen at the Brain and Spine Center from 3/1/20–9/1/20. COVID status was known for 1,753 (21%). Sixty-one (0.7%) were COVID-19 positive. Of these, 17 had primary nervous system tumors. Seven (41%) were treated in the emergency department or hospital for infection. Two were symptomatic but did not require further care. Eight were asymptomatic. Nine (53%) had alterations in cancer management within one week of COVID-19 diagnosis – delayed surgery (3), delayed/interrupted chemotherapy (2), delayed/interrupted radiation (2), cancer treatment discontinued (2). Eight patients (47%) had no clear impact of infection on their cancer treatment, three were on surveillance. Three (18%) unique patients had neurological symptoms attributed to/exacerbated by COVID-19 – encephalopathy (2), seizure (2), stroke (1). CONCLUSION No deleterious effects of alterations in cancer management after COVID-19 infection have been identified thus far, though longitudinal follow up is warranted. Our results suggest that COVID-19 infection frequently incurs medical complications or alterations in cancer treatment. The potential impacts of COVID-19 on our vulnerable neuro-oncology patient population should be further explored, and attention to these potential implications for our patients is warranted by treating clinicians.

BACKGROUND Selection of systemic therapy for recurrent meningiomas with progression after resection and/or radiation therapy represents a challenge. The combination of everolimus, an mTOR inhibitor, plus octreotide long-acting repeatable (LAR), a somatostatin agonist, suggests synergistic activity in preclinical studies. Its long-term clinical impact in recurrent meningiomas warrants further study. METHODS We reviewed the records of adult patients with recurrent intracranial or spinal meningioma (WHO grade I, II, or III), not candidates for further surgery or radiation therapy, who were treated with everolimus and octreotide, between 1/1/2015 and 06/1/2020 at MD Anderson Cancer Center. Patients received everolimus (10 mg PO daily) each 28-day cycle and octreotide 30 mg SC once monthly. Molecular features were determined by next generation sequencing (T-200–1, Oncomine). RESULTS A total of 18 patients were identified, including WHO grade I tumors (n=4), grade II (n=10), and grade III (n=4); furthermore, 8 patients harbored NF2 mutation, followed by mutations in CREBBP (n=2), NOTCH2 (n=1), MHL1 (n=1), PTEN (n=1), SETD2 (n=1), and TP53 genes (n=1). One patient had spinal meningioma. The 6- and 12-month PFS were 77.8% and 61.1%, 6- and 12-month OS were 94.4% and 83.3% respectively. Seven (38.9%) patients had tolerated treatment for more than 12 cycles, 3 (16.7%) remain on treatment for more than 24 cycles and 1 patient is still on treatment for 31 cycles. Only 1 patient required dose reduction to 7.5 mg daily due to pneumonitis, otherwise there is an acceptable toxicity profile. Four patients had resolution of trigeminal neuralgia. CONCLUSIONS In our patient population, combination treatment with everolimus and octreotide seems to have antitumor activity and proved to be safe without major side effects from long-term exposure. It also contributed to control of neuralgia. Further tissue analysis of the role of mTOR pathway and SSTR2A expression is ongoing.

Glioblastoma (GBM) is the most common and aggressive primary brain cancer. Current standard-of-care for glioblastoma (GBM) includes surgery followed by concurrent therapy with radiation and temozolomide (TMZ) followed by adjuvant TMZ (days 1-5 every 28 days). Almost all GBM patients experience recurrent/progressive disease, with a median survival of 3-9 months after recurrence. Second-line treatment for recurrent GBM with bevacizumab (BEV) has not improved survival, and effective therapies for GBM are lacking. Unmethylated promoter status for O6-methylguanine DNA methyltransferase (MGMT) is a validated biomarker for TMZ-resistance and is correlated with poor prognosis. VAL-083 is a bi-functional DNA-targeting agent rapidly inducing interstrand cross-links at N7-guanine, leading to DNA double-strand breaks and cell death. VAL-083's cytotoxicity is independent of MGMT status, and VAL-083 overcomes TMZ-resistance in GBM cell lines, GBM cancer stem cells, and in vivo GBM models. The trial described here is an open-label two-arm biomarker-driven phase 2 clinical trial in MGMT-unmethylated GBM patients with either recurrent disease (Group 1) or newly diagnosed GBM patients requiring adjuvant therapy after chemoirradiation with temozolomide (Group 2). Patients receive VAL-083 IV at 30 or 40 mg/m2/day on days 1, 2, and 3 of a 21-day cycle. The primary objective of this study is to determine the effect of VAL-083 on median overall survival (mOS) in MGMT-unmethylated recurrent GBM patients (Group 1) compared to historical control, and progression-free survival (PFS) in newly diagnosed GBM patients requiring adjuvant therapy after chemoirradiation with temozolomide (Group 2), compared to historical control. Secondary efficacy endpoints include progression-free survival (PFS) (Group 1), overall response rate (ORR), duration of response (DOR), and quality-of-life (QoL). Tumor response will be assessed by MRI approximately every 42 days, as per RANO criteria. The initial starting dose in this study was 40 mg/m2/day, which was subsequently reduced to 30 mg/m2/day to improve tolerance due to myelosuppression. As of 21st January 2020, thirty-five (35) subjects had enrolled at a starting dose of 40 mg/m2/day, and 31 subjects had enrolled at a starting dose of 30 mg/m2/day in Group 1, and 9 subjects enrolled at a starting dose of 30 mg/m2/day in Group 2. As anticipated from prior studies with VAL-083, myelosuppression (thrombocytopenia and neutropenia) has been the most common adverse event observed. Enrollment and safety data update will be provided at the meeting. Clinicaltrials.gov identifier: NCT02717962 Citation Format: Barbara J. O'Brien, Carlos Kamiya-Matsuoka, Shiao-Pei Weathers, Alfred Yung, Monica Loghin, Rebecca Harrison, Nazanin Majd, Jeffrey A. Bacha, Dennis M. Brown, Anne Steino, Gregory Johnson, Sarath Kanekal, John Langlands, Lorena M. Lopez, Richard M. Schwartz, Marta Penas-Prado, John F. de Groot. Phase 2 study of dianhydrogalactitol (VAL-083) in patients with MGMT-unmethylated, bevacizumab-naïve glioblastoma in the recurrent or adjuvant setting [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT272.

2515 Background: Cytomegalovirus (CMV) antigens are present in > 90% of GBMs but not in normal brain making it an attractive immunological target. Methods: Highly functional autologous polyclonal CMV pp65 specific T cells were expanded under GMP-compliant conditions from GBM patients and administered after 3 weeks of lymphodepleting dose-dense temozolomide (ddTMZ, 100 mg/m2). The phase I component used a 3+3 design ascending through four dose levels (5 x 106 cells to 1 x 108 cells). Treatment was repeated every 6 weeks for a total of 4 cycles. Dose expansion was conducted in recurrent GBM patients undergoing resection and in newly diagnosed GBM patients following concurrent chemoradiation. In vivo persistence and effector function of the adoptively transferred CMV-specific T cells was determined by dextramer staining and multiparameter flow cytometry in serially-sampled peripheral blood and in the tumor microenvironment. Results: 65 patients were screened, 25 underwent leukapheresis, and 20 completed at least 1 cycle. Median age 48 (27-69), 35% were MGMT methylated, and 10% were IDH mutated. No dose limiting toxicities (DLTs) observed. Complete radiographic response was observed in 1 patient, partial responses in 2, stable disease in 9, and progressive disease in 8. The median PFS time was 1.3 months (95% CI: 0-8.3 months) and the median OS time was 12 months (95% CI: 6 months to not reached). Repeated infusions of CMV-TC were associated with significant increase in circulating CMV+ CD8+ T cells, but cytokine production reflective of effector activity (CD107a, TNFα, IFNγ, IL2) was suppressed in these cells including directly from the GBM microenvironment. Conclusions: Adoptive infusion of CMV-specific T cells after lymphodepleting ddTMZ was well-tolerated. However, effector function of the adoptively transferred T cells was attenuated indicating further modulation of the T cell is required to prevent its dysfunction prior to proceeding to large scale clinical studies. Clinical trial information: NCT02661282 .

2511 Background: Immunotherapy strategies such as PD-1/PD-L1 inhibition may work synergistically with radiation, which is known to increase antigen presentation and promote a pro-inflammatory tumor microenvironment. This trial evaluated the safety and clinical efficacy of concurrent atezo with radiation therapy and TMZ followed by adjuvant atezo and TMZ in patients with newly diagnosed GBM, unselected for MGMT status. Methods: Eligibility criteria included patients with newly diagnosed GBM age > 18 yrs who had undergone only surgery. The primary endpoint was safety in Phase I (n = 10) and OS in Phase II (n = 50). Secondary endpoints included progression free survival (PFS), overall response rate (ORR), and duration of response. All 60 patients were evaluated for efficacy. Correlative endpoints include profiling of tumor immune cell populations and peripheral blood for evaluation of circulating chemokines/cytokines. Results: 60 patients were enrolled. With median follow-up time of 16.7 months (data cutoff = 30 Dec 2019), 24 patients had died and 32 had progressed. Median OS was 17.1 months (95% CI: 13.9, not reached). Median PFS was 9.7 months (95% CI: 7.6-15). Median PFS in MGMT methylated patients (n = 18) was 16.7 months (95% CI: 7.85, not reached) and 7.9 months (95% CI: 6.70-12.4) in MGMT unmethylated patients (n = 33). Treatment-related adverse events with maximum CTCAE grade > 3 occurred in 33 patients; the most common were LFT elevation (n = 5) and lymphopenia (n = 23). To date, 17 of the enrolled 60 patients underwent re-resection post treatment with atezo. The matched paired tumor analysis of pre and post treatment tissue will provide valuable insights into mechanisms of anti-PD-L1 therapy resistance. Tumor immunocorrelative studies are pending. Conclusions: Concurrent use of atezo with radiation and TMZ was tolerable and demonstrated modest efficacy. Clinical trial information: NCT03174197 .

BACKGROUND: Glioblastoma (GBM) is the most common glioma, with an incidence of 3.2 per 100,000 adults, and approximately 12,500 new diagnoses each year in the US. With limited treatment options, there is a constant push to improve patient outcome by testing experimental therapies in clinical trials. However, it is estimated that only 8%-11% of patients with newly diagnosed GBM enroll to clinical trials. METHODS: In an effort to better prioritize patients into appropriate clinical trials and understand barriers to trial enrollment, a weekly Tumor Planning Conference was instituted at MD Anderson Cancer Center in August 2016 to discuss eligibility of each patient with newly diagnosed GBM for available clinical trials. RESULTS: We performed a retrospective review of 112 patients presented over the course of 17 months; data collected included age, gender, date, location and extent of surgery, post-operative day at time of conference, available molecular data and the date(s) it was reported, patients residence and Karnofsky Performance Scale score. A total of 2 to 4 clinical trials for newly diagnosed GBM were available for enrollment at any one time during the analysis. Of the total patients consented for trial participation, 8 were ultimately enrolled and treated into clinical trials (7.14%). The primary reason for no trial participation was study-specific eligibility/ineligibility criteria (such as lack of necessary molecular markers) (46.3%), followed by being out-of-window for trial enrollment (27.4 %). CONCLUSIONS: The weekly tumor planning conference did not improve the number of accruals to trials for newly diagnosed GBM compared to what has been previously reported. However, it provided valuable insights about barriers to trial enrollment, such as the importance of timely outside referrals, efficient new patient scheduling, and need for expedited trial-specific molecular testing.

Background Pituitary carcinoma (PC) is an aggressive neuroendocrine tumor diagnosed when a pituitary adenoma (PA) becomes metastatic. PCs are typically resistant to therapy and develop multiple recurrences despite surgery, radiotherapy and chemotherapy. Recently, treatment with temozolomide (TMZ) has shown promising results, although the lack of prospective trials limits assessment of benefit. Methods We describe a single-center multidisciplinary experience in managing PC patients over a 22-year period and review previously published PC series. Results Seventeen patients were identified. Median age at PC diagnosis was 44 years (range 16–82 years), and the median time from PA to PC transformation was 5 years (range 1–29 years). Median follow-up time was 28 months. Most PCs were hormone-positive (n = 12): ACTH (n = 5), PRL (n = 4), LH/FSH (n = 2) and GH (n = 1). All patients underwent at least one resection and at least one course of radiation after PC diagnosis. Immunohistochemistry showed high Ki-67 labeling index (>3%) in 10/15 cases. Eight patients (47%) had only central nervous system (CNS) metastases; six (35%) had combined CNS and systemic metastases. The most commonly used chemotherapy was TMZ, and TMZ-based therapy was associated with the longest PFS in 12 (71%) cases, as well as the longest period from PC diagnosis to first progression (median 30 months). The 2, 3 and 5-year survival rate of the entire cohort was 71, 59 and 35%, respectively. All patients surviving >5 years had been treated with TMZ-based therapy. Conclusions PC management benefits from multidisciplinary care and multimodality therapy. TMZ-based regimens were associated with high survival rates and long disease control.

Background: Pituitary carcinoma (PC) is an aggressive neuroendocrine tumor diagnosed when a pituitary adenoma (PA) becomes metastatic. PCs are typically resistant to therapy and frequently recur. Recently, treatment with temozolomide (TMZ) has shown promising results, although the lack of prospective trials limits accurate assessment. Methods: We describe a single-center experience in managing PC over a 22-year period and review previously published PC series. Results: 17 patients were identified. Median age at PC diagnosis was 44 years (range 16-82), and the median PA-to-PC conversion time was 5 years (range 1-29). Median follow-up was 28 months (range 8-158) with 7 deaths. Most PC were hormone-positive based on immunohistochemistry (n=12): ACTH (n=5), PRL (n=4), LH/FSH (n=2), GH (n=1). All patients underwent at least one resection and one course of radiation after PC diagnosis. Immunohistochemistry showed high Ki-67 labeling index (>3%) in 10/15 cases. Eight patients (47%) had metastases only to the CNS, and 6 (35%) had combined CNS and systemic metastases. The most commonly used chemotherapy was TMZ, and TMZ-based therapy was associated with the longest period of disease control in 12 (71%) cases, as well as the longest period from PC diagnosis to first progression in 8 (47%) cases. The 2, 3 and 5-year survival rate of the entire cohort was 71%, 59% and 35%, respectively. All patients surviving >5 years were treated with TMZ-based therapy. Conclusions: PC treatment requires a multidisciplinary approach and multimodality therapy including surgery, radiation and chemotherapy. TMZ-based therapy was associated with higher survival rates and longer disease control.PrecisWe describe 17 PC patients who were diagnosed and treated at MDACC over a 22-year period. We have found that TMZ-based therapy correlated with longer disease control and higher survival rate.

Neurofibromatosis type 1 (NF1) is a common tumor predisposition syndrome in which glioma is one of the prevalent tumors. Gliomagenesis in NF1 results in a heterogeneous spectrum of low- to high-grade neoplasms occurring during the entire lifespan of patients. The pattern of genetic and epigenetic alterations of glioma that develops in NF1 patients and the similarities with sporadic glioma remain unknown. Here, we present the molecular landscape of low- and high-grade gliomas in patients affected by NF1 (NF1-glioma). We found that the predisposing germline mutation of the NF1 gene was frequently converted to homozygosity and the somatic mutational load of NF1-glioma was influenced by age and grade. High-grade tumors harbored genetic alterations of TP53 and CDKN2A, frequent mutations of ATRX associated with Alternative Lengthening of Telomere, and were enriched in genetic alterations of transcription/chromatin regulation and PI3 kinase pathways. Low-grade tumors exhibited fewer mutations that were over-represented in genes of the MAP kinase pathway. Approximately 50% of low-grade NF1-gliomas displayed an immune signature, T lymphocyte infiltrates, and increased neo-antigen load. DNA methylation assigned NF1-glioma to LGm6, a poorly defined Isocitrate Dehydrogenase 1 wild-type subgroup enriched with ATRX mutations. Thus, the profiling of NF1-glioma defined a distinct landscape that recapitulates a subset of sporadic tumors. An integrated analysis of glioma samples from patients with neurofibromatosis 1 annotates their mutational, epigenetic, transcriptional, and immunological features and uncovers similitudes with a subset of sporadic gliomas.

SUMMARY Glioblastoma, the most aggressive of the gliomas, has a high recurrence and mortality rate. The nature of this poor prognosis resides in the molecular heterogeneity and phenotypic features of this tumor. Despite research advances in understanding the molecular biology, it has been difficult to translate this knowledge into effective treatment. Nearly all will have tumor recurrence, yet to date very few therapies have established efficacy as salvage regimens. This challenge is further complicated by imaging confounders and to an even greater degree by the ever increasing molecular heterogeneity that is thought to be both sporadic and treatment-induced. The development of novel clinical trial designs to support the development and testing of novel treatment regimens and drug delivery strategies underscore the need for more precise techniques in imaging and better surrogate markers to help determine treatment response. This review summarizes recent approaches to treat patients with recurrent glioblastoma and considers future perspectives.

Background Extracranial and extraspinal ependymomas are extremely rare tumors mostly published in the literature as case reports. Methods MD Anderson Cancer Center institutional database was screened for patients with extra CNS ependymomas over a 25 year period. Results Eight patients with extra CNS ependymoma were identified. Five cases originated in the sacrum or subcutaneous sacral area, and the other 3 cases originating in the breast, lung and adnexa of the uterus. By histology, most cases were myxopapillary ependymomas (5 cases), 2 cases were grade II ependymoma and 1 case was an anaplastic ependymoma. Metastases occurred in 6 cases and 3 patients died due to progressive disease. Most cases required surgery, radiation and chemotherapy. Conclusion Extra CNS ependymomas are very rare tumors that tend to metastasize, even though most cases are histologically classified as low grade ependymomas.

Background Neurolymphomatosis (NL) is a rare clinical entity characterized by infiltration of malignant lymphocytes into the peripheral nervous system. We analyzed the clinicoradiological features, treatments, and outcomes in NL patients. Methods We identified six patients with NL seen at The University of Texas MD Anderson Cancer Center from 01/2010 to 10/2012. We extracted clinical presentations, imagings, CSF cytology, and electrodiagnostic studies from medical records. One patient had a nerve biopsy. We defined therapy response as clinical improvement of neurological deficits. Findings The mean age at onset was 57.1 years. Most were predominantly men with non-Hodgkin lymphoma. Positron emission tomography (PET) was positive in five patients. Nerve conduction demonstrated mononeuritis multiplex, plexopathy, demyelination, and axonal polyradiculoneuropathy, whereas electromyography was nonspecific. All patients received systemic chemotherapy, four intrathecal chemotherapy, and three intravenous immunoglobulin, plasma exchange or both. One patient who received intravenous immunoglobulin showed mild neurological improvement. Two patients responded, and the median overall survival was 15 months. Conclusions NL is an increasingly recognized complication of NHL and leukemia. A high clinical suspicion is necessary for correct diagnosis. In the present series, patients with leukemia had mononeuritis multiplex, whereas those with lymphoma had plexopathy. Electrodiagnosis and PET scans were useful diagnostic tools. No factors correlated with poorer prognosis. International collaborative studies will help to better determine the risk factors of NL, response to treatment and outcomes.

Ipilimumab is a novel FDA-approved recombinant human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4 and has been used to treat patients with metastatic melanoma. Immune-related neurological adverse effects include inflammatory myopathy, aseptic meningitis, posterior reversible encephalopathy syndrome, Guillain-Barré syndrome, myasthenia gravis-type syndrome, sensorimotor neuropathy, and inflammatory enteric neuropathy. To date, there is no report for ipilimumab-induced chronic inflammatory demyelinating polyneuropathy (CIDP), transverse myelitis (TM), or concurrent myositis and myasthenia gravis-type syndrome. Our objective is to raise early recognition of atypical neurological adverse events and to share our therapeutic approach.We report 3 cases of metastatic melanoma treated with ipilimumab in which the patients developed CIDP, TM, and concurrent myositis and myasthenia gravis-type syndrome, respectively, at the MD Anderson Cancer Center between July 2012 and June 2013. Patients consented to release of medical information for publication/educational purposes.Our 3 cases of metastatic melanoma treated with ipilimumab developed CIDP, TM, and concurrent myositis and myasthenia gravis-type syndrome, respectively. The median time to onset of immune-related adverse events following ipilimumab treatment ranged from 1 to 2 weeks. Ipilimumab was discontinued due to the severe neurological symptoms. Plasmapheresis was initiated in the patients with CIDP and concurrent myositis and myasthenia gravis-type syndrome; high-dose intravenous steroids were given to the patient with TM, and significant clinical response was demonstrated.Ipilimumab could induce a wide spectrum of neurological adverse effects. Our findings support the standard treatment of withholding or discontinuing ipilimumab. Plasmapheresis or high-dose intravenous steroids may be considered as the initial choice of treatment for severe ipilimumab-related neurological adverse events. Improvement of neurological symptoms may be seen within 2 weeks.

BACKGROUND: Immunotherapy strategies like PD-1/PD-L1 inhibition may work synergistically with radiation, which has been shown to increase antigen presentation and promote a pro-inflammatory tumor microenvironment. This trial evaluated the safety of concurrent atezo with radiation therapy and TMZ followed by adjuvant TMZ and atezo in newly diagnosed GBM patients. METHODS: Eligibility criteria included patients with newly diagnosed GBM age ≥ 18 yrs who have undergone only surgery. The primary objective of the phase I safety run-in was to evaluate atezo in combination with radiation and TMZ during the concurrent stage and in combination with TMZ during the adjuvant stage. RESULTS: 11 patients were accrued in the concurrent safety run-in phase. 2 dose-limiting toxicities (DLT) were observed in 1 patient who developed both grade 3 hepatitis and pneumonitis related to atezo. 2 patients discontinued treatment during the concurrent stage due to medical complications deemed unrelated to study drug. In the 8 evaluable patients who completed the concurrent phase, no other grade 3 or 4 atezo-related toxicities were observed. 5 of the 8 evaluable patients completed the combination treatment without the need for dexamethasone. The remaining 3 of the 8 evaluable patients required no more than 4 mg daily of dexamethasone during combination treatment. All 8 patients had stable MRI findings following completion of the concurrent phase. 7 of the 8 evaluable patients proceeded with adjuvant treatment with atezo and TMZ with no grade 3 or 4 atezo-related toxicities observed to date (no. cycles range, 1–6). CONCLUSIONS: Concurrent use of atezo with radiation and TMZ was tolerable, and no new safety signals were noted. The majority of evaluable patients were able to complete the combination treatment without the need for concurrent steroid administration. The phase II component of the trial is recruiting patients (n=50) to evaluate clinical efficacy.

Background Immuno-oncology (IO) is an effective strategy for the management of non-glioma tumors and it may be enhanced in hypermutators. Hypermutator glioblastoma (HmGB) is seen as initial tumor diagnosis or at recurrence after temozolomide (TMZ) treatment. We describe clinical and molecular features of HmGB treated with IO. Methods Retrospective review at MD Anderson between Feb, 2012 through Feb, 2017 identified 312 gliomas with tissue analyzed by next-generation sequencing (T200-1, Oncomine, FoundationOne). HmGB was defined as histologically proven GB with tumor mutational burden (TMB-30) of 30 or more mutations (mut) per Mb, or displaying mut in mismatch repair (MMR) or DNA polymerase (Pol) genes. Results 30 (9.6%) patients had HmGB. From those, 9 (30%) received IO. 5 (55%) were men. Median age at HMGB diagnosis was 38 years (31-66). 7 (78%) had mut in MMR and 2 (22%) in Pol gene. 5 cases had IDH1 mut. 5 MGMT were umethylated. HmGB was found as initial diagnosis in 5 (56%) cases, the rest after TMZ. Of those patients with initial HmGB, 3 had MMR mut and 2 Pol mut. 8 had somatic mut and only 1 had germline MMR mut (Lynch Syndrome, MSH2, c.652C>T [p.Gln218*]). For post-treatment/recurrent HmGB, the most common alteration was MMR mut (N = 4). 8 HmGB patients received either CPI off protocol or cellular therapy (T-cells or NK cells) at recurrence of HmGB after TMZ, only 1 patient received CPI at initial HmGB diagnosis, concurrently with standard of care. In HmGB with somatic mut, OS from initial brain tumor and HmGB diagnosis was 39 and 22 months. PFS and 6m-PFS after starting IO was 72 days and 0% respectively. The PFS after TMZ, in those treated with CPI, reactive T-cells and natural killer cells was 51, 41 and 175 days, respectively, whereas the PFS in the one with newly diagnosed HmGB was 96 days. The median cumulative dose of pembrolizumab was 720 mg per patient. The patient with germline HmGB is on pembrolizumab and is the only one with stable disease for more than 12 months. Conclusions IO seems to be ineffective in HmGB with somatic mut regardless the onset of diagnosis (newly/recurrent) or type of Hm phenotype. However, germline HmGB may have durable responses to IO. Further investigation is needed to determine the potential antitumor immune response in this population. Legal entity responsible for the study The authors. Funding This work was supported in part by the Sheikh Khalifa Al Nahyan Ben Zayed Institute for Personalized Cancer Therapy, and the MD Anderson Cancer Center Support grant (P30 CA016672) MD Anderson Cancer Center. Disclosure All authors have declared no conflicts of interest.

BACKGROUND: Leptomeningeal metastasis (LM) is a devastating complication of cancer resulting in progressive neurologic decline. Although intrathecal (IT) methotrexate and cytarabine are commonly used for solid tumor LM, we routinely use IT topotecan due to previously demonstrated similar efficacy and modest side effect profile. We report updated data on our experience. METHODS: We reviewed clinical records of patients with solid tumor LM treated with IT topotecan at MD Anderson Cancer Center from 2008–2018. Patient characteristics and course were summarized by descriptive statistics. Overall survival (OS) was estimated with Kaplan-Meier, and the association of KPS with OS evaluated with log-rank test. RESULTS: 138 patients were treated with IT topotecan. The median age was 54 years (range, 22–76), 81% were female. Breast cancer (62%) was the most common primary, then lung (21%), melanoma (4%). Median time from primary diagnosis to LM was 3.4 (range, 0.07–25.2) years. LM was diagnosed by CSF cytology alone in 8 (6%), MRI alone in 21 (15%), CSF+MRI in 108 (78%). Patients most commonly presented with headache (39%) or sensory changes (18%), and had a median KPS of 80 (range, 60–100). 66% had prior/concurrent brain metastasis. 71 patients (52%) received WBRT following LM diagnosis. 41% had adverse effects, most commonly nausea/vomiting (22%) and headache (20%). The majority were grade 1 (63%); 7 were grade 4 (2 Ommaya malfunctions and 5 infections). Patients received a median of 9 (range, 1–79) doses, most stopped due to CNS progression (42%). Median OS was 6.5 months (95% CI 4.7, 7.8). OS was 3.8 mos with KPS ≤70, vs. 7.5 mos with KPS >70 (p< 0.001). CONCLUSIONS: IT topotecan has a modest side effect profile. Patients with higher functional status at diagnosis had significantly better survival. This study supports the continued use of IT topotecan as a well-tolerated option for LM.

Gliomatosis cerebri is a rare malignant tumour originating from cerebral glial cells. Most experts currently view gliomatosis cerebri as a pattern of extensive glioma infiltration encompassing at least three cerebral lobes.1 It occurs at any age, with peak incidence between 40 years and 50 years and it is slightly more common in men.2 On MRI, gliomatosis cerebri shows no, or minimal, contrast enhancement; however, it has a diffuse hyperintense infiltrative process on T2-weighted fluid-attenuated inversion recovery (FLAIR) sequence. It is usually possible to diagnose gliomatosis cerebri using an open biopsy or a stereotactic biopsy. Despite treatment, its median survival varies from 6 months to 39 months.3 We report an unusual presentation of gliomatosis cerebri, which underscores the difficulty in pinpointing the correct diagnosis after corticosteroids have modified the disease course. A 78-year-old woman had an episode of acute onset slurred speech and confusion. Her initial CT scan of head showed diffuse left hemispherical white matter hypodensity with sulcal effacement and minimal midline shift to the right. Cerebrospinal fluid (CSF) examination suggested viral encephalitis for which she was empirically given intravenous dexamethasone and acyclovir, with oral levetiracetam 500 mg twice daily. After initially improving, she rapidly worsened with corticosteroid tapering. A repeat CT scan of head showed no change. She took dexamethasone 4 mg twice daily before undergoing a brain biopsy, which showed mild hypercellularity suspicious but not definitive for glioma. Two weeks later, we saw her for a second opinion. The MRI of …

Introduction Posterior reversible encephalopathy syndrome (PRES) is a neurotoxic encephalopathic state associated with reversible cerebral vasogenic edema. Seizures are a common clinical presentation in PRES, however its electroencephalographic and radiologic pattern correlation is limited in this subset of patients. The aim of this study is to analyze the origin of electrographic dysfunction according to the radiologic pattern in patients with PRES and seizures. Methods We retrospectively identified 46 cancer patients who developed PRES and seizures at The University of Texas MD Anderson Cancer Center between January 2006 and June 2012. Clinical, radiographic and electroencephalographic data were abstracted from their records and reviewed for our analysis. Results The average age at presentation was 49.9 ± 19.7 years. Thirty-four (73.9%) patients were women. Twenty-two (47.8%) patients had a primary hematological malignancy whereas the rest had a solid tumor. Thirty-three (71.7%) patients had received some form of chemotherapy. The mean systolic blood pressure (SBP) variation was 23.7 ± 16.4 mmHg at onset of symptoms. On brain MRI, 32 (69.6%) patients had typical pattern while 14 (30.4%) had an atypical pattern. Thirty-seven (80.4%) patients had scalp electroencephalogram (EEG) evaluation. Thirty-three (89.2%) had abnormal EEG findings: diffuse theta/delta slowing ( N = 12, 36.4%), followed by diffuse slowing with focal dysfunction ( N = 8, 24.2%), focal dysfunction with epileptiform discharges ( N = 4, 12.1%), non-convulsive status epilepticus ( N = 4, 12.1%), focal seizure activity and burst suppression ( N = 2, 6.1% each). Lateralized Periodic Discharges (LPDs) were recorded in 1 case. Four patients had focal dysfunction localized to areas without conventional MRI signal changes. Four patients had recurrent seizures, of which 3 had an atypical PRES pattern. Conclusion PRES appears to be a diffuse neurotoxic encephalopathic state. Origin of seizures seen on scalp EEG may not correlate with the location of vasogenic edema/MRI signal changes raising the possibility of greater degree of dysfunction which may exist beyond those areas.

Treatment response and survival after bevacizumab failure remains poor in patients with glioblastoma. Several recent publications examining glioblastoma patients treated with bevacizumab have described specific radiographic patterns of disease progression as correlating with outcome. This study aims to scrutinize these previously reported radiographic prognostic models in an independent data set to inspect their reproducibility and potential for clinical utility. Sixty four patients treated at MD Anderson matched predetermined inclusion criteria. Patients were categorized based on previously published data by: (1) Nowosielski et al. into: T2-diffuse, cT1 Flare-up, non-responders and T2 circumscribed groups (2) Modified Pope et al. criteria into: local, diffuse and distant groups and (3) Bahr et al. into groups with or without new diffusion-restricted and/or pre-contrast T1-hyperintense lesions. When classified according to Nowosielski et al. criteria, the cT1 Flare-up group had the longest overall survival (OS) from bevacizumab initiation, with non-responders having the worst outcomes. The T2 diffuse group had the longest progression free survival (PFS) from start of bevacizumab. When classified by modified Pope at al. criteria, most patients did not experience a shift in tumor pattern from the pattern at baseline, while the PFS and OS in patients with local-to-local and local-to-diffuse/distant patterns of progression were similar. Patients developing restricted diffusion on bevacizumab had worse OS. Diffuse patterns of progression in patients treated with bevacizumab are rare and not associated with worse outcomes compared to other radiographic subgroups. Emergence of restricted diffusion during bevacizumab treatment was a radiographic marker of worse OS.

Pituitary carcinomas (PC) are uncommon neuroendocrine tumors, accounting for 0.1 % of all pituitary tumors. The diagnosis of PC is based on the presence of metastases from a pituitary adenoma, and not by local invasion or pathological features alone. PC is typically resistant to therapy, with a median overall survival of only 31 months. There is no standard treatment for PC, but maximal safe resection and radiation are performed when possible. Encouraging preliminary data on the use of temozolomide (TMZ)-based therapy has been previously reported. We report the response to therapy and safety of radiation with concurrent temozolomide (RT/TMZ) in 2 adult patients with heavily pretreated PC and extraneural metastases. Both patients had prior history of pituitary macroadenoma. At the time of diagnosis of PC, Ki-67 % was 24.2 and 10 %, with positive p53 staining in one case. Metastatic sites included lymph nodes, liver and bone. Case-1 received RT/TMZ to the tumor bed in the skull base and to the metastases in the cervical lymph nodes. Case-2 received RT/TMZ to recurrent tumor involving portacaval lymph nodes. Both patients achieved excellent long-term control of the sites of treated extraneural metastases, with no significant acute or delayed toxicity. RT/TMZ was safely delivered and might provide sustained control of extraneural metastases in PC. Although this retrospective report has limitations, RT/TMZ can be considered as a therapeutic option for the management of extraneural metastases in PC.

Background Parvovirus B19 is a single-stranded DNA virus belonging to the family Parvoviridae, genus Erythrovirus . PVB19 infection is most common in the pediatric population, manifesting as erythema infectiosum. In patients with hemoglobinopathy, PVB19 infection is known to cause aplastic anemia. PVB19 infection rarely affects the nervous system — reported manifestations include seizures, encephalitis and meningoencephalitis. Less common presentations include stroke, cerebellar ataxia, optic neuritis, brachial plexitis, Guillain–Barre syndrome and carpal tunnel syndrome. Methods Review the different central nervous system (CNS) manifestations and treatment strategies in all reported cases of adult CNS PVB19 infection. Results Cerebellar ataxia is a very rare manifestation of PVB19 CNS infection. Our patient had refractory chronic lymphocytic leukemia and PVB19 in bone marrow and serum; he presented with 6-week history of progressive pan-cerebellar ataxia. CSF was acellular but PVB19 was present on PCR test. Early treatment with intravenous immunoglobulin (IVIG) led to improvement in the patient's neurological deficits. Conclusions PVB19 CNS infection should be in the differential as a cause of cerebellar ataxia in immunocompromised patients. Recognition is critical to early institution of appropriate therapy. Our patient showed considerable improvement in ataxia after IVIG therapy.

Glioblastoma (GBM) is the most common and aggressive primary brain cancer. Current standard of care includes surgery followed by concurrent therapy with radiation and temozolomide (TMZ) and maintenance TMZ. The vast majority of GBM patients experience recurrent/progressive disease within a year from initial diagnosis, and median survival after recurrence is 3-9 months. Effective therapies for recurrent GBM (rGBM) are lacking and these patients have a dismal prognosis, representing a significant unmet medical need. Unmethylated promoter status for O6-methylguanine-DNA-methyltransferase (MGMT), a validated biomarker for TMZ-resistance, is strongly correlated with TMZ-resistance. Second-line treatment with the anti-angiogenic agent bevacizumab has not improved survival and 5-year survival is less than 3%. VAL-083 is a bi-functional DNA-targeting agent rapidly inducing interstrand cross-links at N7-guanine, leading to DNA double-strand breaks and cell-death. VAL-083's cytotoxicity is independent of MGMT status in vitro and VAL-083 overcomes TMZ-resistance in GBM cell lines, GBM cancer stem cells and in vivo GBM models. We completed a 3:3 dose-escalation trial of VAL-083 in TMZ- and bevacizumab-refractory rGBM. 40mg/m2/day given on days 1, 2, and 3 of a 21-day cycle was well-tolerated with 6% grade 3 or 4 thrombocytopenia. This dose was selected for further clinical development in a pivotal Phase 3 study in TMZ- and bevacizumab-refractory rGBM. The trial described here is an ongoing single-arm, biomarker-driven Phase 2 clinical trial in MGMT-unmethylated bevacizumab-naïve adult rGBM. 48 patients will receive VAL-083 40mg/m2/day on days 1, 2, and 3 of a 21-day cycle. Tumor response will be assessed by MRI approximately every 42 days, according to RANO criteria. The primary objective of this study is to determine if VAL-083 improves overall survival (OS) for MGMT-unmethylated rGBM patients compared to a historical median survival control of 7.2 months for MGMT-unmethylated rGBM patients treated with lomustine (Wick et al, EORTC26101). Secondary efficacy endpoints include progression-free survival (PFS), overall response rate (ORR), duration of response (DOR), and to evaluate the occurrence of symptoms and to evaluate quality of life (QOL) measures during the progression-free period using the MD Anderson Symptom Inventory-Brain Tumor Module (MDASI-BT) self-reporting tool. Enrollment and safety data update will be provided at the meeting. Clinicaltrials.gov identifier: NCT02717962. Citation Format: Barbara J. O'Brien, John De Groot, Carlos Kamiya-Matsuoka, Shiao-Pei Weathers, Jeffrey A. Bacha, Dennis M. Brown, Anne Steino, John Langlands, Richard Schwartz, Sarath Kanekal, Lorena Lopez, Marta Penas-Prado. Phase II study of dianhydrogalactitol (VAL-083) in patients with bevacizumab-naive recurrent glioblastoma, MGMT-unmethylated [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT167.

INTRODUCTION Hypermutation is the excessive accumulation of DNA mutation in cancer cells. This specific hypermutated genotype has been reported in low and high grade gliomas, specifically post-temozolomide treatment and is associated with treatment-resistance. Herein, we sought to identify an imaging-based signature for hypermutated gliomas using a radiomics-based approach. MATERIALS AND METHODS In this IRB-approved retrospective study, we analyzed a total of 101 patients with primary gliomas from the University of Texas MD Anderson Cancer Center. Next generation sequencing (NGS) platforms (T200 and Foundation 1) were used to determine the Mutation burden status in post-biopsy (stereotactic/excisional). Patients were dichotomized based on their mutation burden; 77 hypomutated (=30 mutations or RESULTS We found 100 radiomic features that can discriminate between hypermutated versus hypomutated gliomas, AUC 96.3% (CI: 90.2%-98.9%), Sensitivity 100%, Specificity 95%, p-value=3.769e-6. CONCLUSION Hypermutated gliomas has a unique radiomic quantitative signature that can be used to predict mutation burden regardless of tumor grade or histopathology. Citation Format: Islam Hassan, Aikaterini Kotrotsou, Carlos Kamiya Matsuoka, Kristin D. Alfaro-Munoz, Nabil Elshafeey, Nancy El Shafei, Pascal O. Zinn, John F. de Groot, Rivka R. Colen. A radiomic-based MRI phenotype is uniquely associated with hypermutated genotype in gliomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2955.

2035Background: Cytomegalovirus (CMV) antigens are present in > 90% of GBMs but not in normal brain, and can be targeted as a tumor-specific antigen. CMV-TC present in GBM tumor tissue have their e...

2022Background: Hypermutation is defined as the excessive accumulation of DNA mutation in cancer cells and is reported in several forms of cancer including low and high grade gliomas. Incidence of ...

2014Background: Hypermutator genotype (HMGen) is seen in glioblastoma (GB) and lower-grade gliomas. It may be induced by temozolomide (TMZ) and leads to TMZ resistance. We describe demographics, mu...

Miller Fisher syndrome (MFS), variant of acute inflammatory demyelinating polyradiculoneuropathy, is recognized as clinical triad (ophthalmoplegia-ataxia-areflexia). Ganglioside antibodies play an important role in the pathogenesis of acute polyradiculoneuropathy including MFS. To our knowledge, there has been no report of MFS presenting with atypical alternating ptosis or with concurrent elevation of serum GD1 and asialo-GM1 antibody titers, and negative titers of GQ1b antibody such as our patient. Our objective is to report MFS with unusual symptoms and to share our diagnostic approach. We report a rare case of MFS presenting with alternating eyelid ptosis, paresthesia, and ataxia after a respiratory infection. Initial neurological examination revealed left eyelid ptosis, hyporeflexia, positive Romberg sign, and ataxia. The ice pack test was negative. Three days later, contralateral ptosis was observed, associated with areflexia and worsened ataxia. However, there was significant improvement of the previous left eyelid ptosis. Serology revealed elevated asialo-GM1 and GD1b antibodies. Acetylcholine receptor antibodies were negative. Cerebral spinal fluid revealed elevated IgG index. Nerve conduction studies (NCS) performed four days after the onset of symptoms showed normal nerve conduction velocities and F-waves, and absent bilateral H-reflexes. Repetitive nerve stimulation (3 Hz) showed no decrement of compound muscle action potentials. Trial with a single dose of pyridostigmine showed no clinical improvement. The symptoms resolved without intervention. NCS 18 days after onset of symptoms showed mildly prolonged F-waves and absent H-reflexes. This case highlights an atypical presentation of MFS and raises the awareness of a rare autoantibody associated with it.