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mp3 file (11 MB). In the May edition of the Cancer Discovery podcast, Science Writer Elizabeth McKenna talks with Ingo K. Mellinghoff about his paper, which suggests that the disappointing clinical activity of first-generation EGFR inhibitors in glioblastoma versus lung cancer may be attributed to the different conformational requirements of mutant EGFR in these two cancer types.

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OBJECTIVES Although the impact of surgery in glioblastoma (GBM) is well-established, there is insufficient data to determine how surgical resection affects overall survival (OS). The impact of other GBM genomic alterations on EOR-induced survival remains poorly understood. Here, we leverage a large cohort of GBM patients with genomic data to establish the impact of genomic alterations on resection-dependent overall survival in GBM. METHODS 537 IDH WT GBMs from UPMC were analyzed using Glioseq next generation sequencing panel. Using molecular profiles derived from Glioseq data, semi-supervised Monte Carlo reference-based consensus clustering was used to define 5 distinct groups. Cox Proportional Hazards models were used to identify predictors of OS within molecular groups. RESULTS Clustering of 537 IDH wild-type GBM identified 5 distinct groups: 1: TERT mutated/MGMT methylated/EGFR mutated or gain; 2: TERT mutated /MGMT methylated/p53 mutated; 3: TERT WT; 4: TERT mutated/MGMT methylated/CDKN2A loss; 5: TERT mutated/MGMT unmethylated. Thresholds in postoperative residual contrast enhancing volume (rCEV) and residual non-contrast enhancing volume (rNCEV) were identified which marked significant differences in median overall survival (MOS) between molecular groups in rCEV -Group 1: 11.7cc, Group 2: 14.4cc, Group 3: 1.1cc, Group 4: 0.1cc, and Group 5 1.1cc. Sex, age, KPS >70, temozolomide, and radiation along with thresholded rCEV and rNCEV were used in multivariate Cox analyses. Groups demonstrated distinct predictors of OS: radiation only in Group 1 tumors, low rCEV in Group 2 tumors, younger age, temodar, low CEV, and KPS >70 in Group 3 tumors, female sex, younger age, radiation, KPS >70 low rCEV in Group 4 tumors, and KPS >70, temodar, and low rCEV in Group 5 tumors. CONCLUSIONS Clustering results suggest that there are clinically distinct molecular groups of IDH wild-type glioblastomas. Age, sex, KPS >70, temozolomide treatment, radiation therapy, and EOR have varying affects on these molecular groups.

BACKGROUND KRT232 is an orally bioavailable, selective small molecule inhibitor of MDM2 that blocks the protein-protein interaction between MDM2 and p53. We performed a surgical window of opportunity trial of KRT232 in patients with recurrent GBM. METHODS The primary endpoint was to determine the tumor tissue concentration of KRT232. Prior to surgery, patients received KRT232 at either 120mg (n = 10, minimal dose that is consistently associated with alterations in serum MIC-1) or 240mg (n = 10; recommended phase 2 dose as monotherapy) for two days prior to surgical resection. Surgery was performed 3-6 hours following the last administration of KRT232. Tissue was analyzed for KRT232 concentration by LC/MS and for correlative studies. Participants with TP53 wild-type tumors were eligible to continue KRT232 following recovery from surgery at the RP2D of 240mg QD x 7 days q3weeks. RESULTS Twenty-one patients were enrolled from July 2018 to April 2020. One patient was deemed ineligible after surgery due to non-GBM tumor. Study met the prespecified criteria of target intra-tumor drug concentration of ≥ 25nM in contrast enhancing tissue in more than 50% of the patients in the 120mg cohort (67.1 ± 42.7nM in 8/10 patients) and 240mg (328.7 ± 468.1nM in 10/10 patients) cohort. Serum MIC-1 fold-changes from baseline (FCB) approximately 24 hours after a single dose of KRT232 were higher in the 240mg cohort (9.1 ± 4.1-FCB) than the 120mg cohort (3.6 ± 2.0-FCB). CDKN1A (p21), a downstream marker of p53, was significantly upregulated in analyzed participants whose GBM was TP53 wildtype, but not in TP53 mutant GBM or control samples (GBM treated with standard of care). CONCLUSION KRT232 at both 120mg and 240mg achieves adequate tumor tissue penetration and affects downstream pathways in TP53 wildtype GBM. The study has moved to Alliance to complete a phase 1 study of radiation + KRT232 in patients with newly diagnosed MGMT unmethylated GBM.

BACKGROUND The clinical trial NRG/RTOG 0825 sought to determine if the addition of bevacizumab to temozolomide and radiation improves survival in patients with newly diagnosed glioblastomas. Tertiary objectives included measuring the effect of the addition of bevacizumab to standard chemoradiation on neurocognitive function and quality of life. In this study, we describe brain atrophy changes as measured by ventricular volume expansion. METHODS We analyzed longitudinal MRI brain studies obtained from NRG/RTOG-0825. Volume changes in the contralesional (non-tumor) lateral ventricle were measured. Patients were included if they had either a scan at post operative (week 0) or post radiation baseline (week 10). Patients were also required to have at least one follow-up MRI brain scan 6 months or more from their baseline scans (at Week 0 or Week 10). Volumes were delineated using tissue segmentation in Slicer software. RESULTS 177 patients were identified with eligible baseline scans at Week 0 and 162 patients at Week 10. For participants analyzed at 6 months from the Week 0 scan, mean ventricular volume increased by 54.70% (SEM: 3.21%, t = 6.41, p < 0.001, N = 135). For patients analyzed at 6 months from the Week 10 scan, mean ventricular volume increased by 31.89% (SEM: 2.52%, t = 3.96, p < 0.001, Nf117). CONCLUSIONS This study presents evidence of progressive brain volume loss in patients with glioblastoma treated with standard chemoradiation with or without anti-VEGF therapy. This is one of the largest sample sizes of volumetric analysis in real world patients with glioblastoma. These volume changes begin early in the disease course and may precede treatment. Next directions include correlating these volumetric changes with neurocognitive score changes, quality of life scores and analyzing these changes by treatment arm.

INTRODUCTION Glioblastoma (GBM) is the most malignant brain tumor in adults, with a dismal prognosis despite aggressive therapy. Immunotherapy is currently being evaluated as a treatment modality for recurrent GBM. MRI is not adequate for response assessment to immunotherapy even after using refined response assessment criteria. Thus, there is a need for the development of neuroimaging techniques for response assessment. T-cells are key mediators of cancer immunotherapy responses and upregulation of CD69 is a marker of T-cell activation. Our aim is to use PET/CT imaging to non-invasively quantify CD69 in vivo, following immunotherapy, and correlate the expression to survival. METHODS CD69 was evaluated by flow cytometry and immunofluorescence staining on human and mouse in vitro activated T-cells and on dissociated tumors from GL261 glioma-bearing mice treated with anti-PD1/anti-CTLA4 immunotherapy (ICI). Single-cell RNA sequencing (ScRNAseq) datasets from recurrent GBM patients receiving (n=20) or not receiving (n=22) ICI were examined for CD69 expression on tumor infiltrating lymphocyte (TIL) populations. PET/CT was performed on mice (n=30) receiving radiolabeled anti-CD69 antibody (89Zr-DFO-anti-CD69) to evaluate response to ICI therapy. Standard uptake values (SUV) were compared between ICI and controls and in relationship to survival. RESULTS We confirmed CD69 upregulation upon T-cell activation in vitro. Ex vivo, CD69 expression significantly increased on TILs early after ICI treatment compared to control (63.46% vs 24.37% CD69+/TILs, respectively; p=0.017). ScRNAseq demonstrated significant elevated CD69 expression in almost all TIL populations tested in recurrent GBM patients treated with ICI compared with a control group. ImmunoPET demonstrated significantly higher anti-CD69 tracer uptake in ICI-treated mice compared with controls. Most importantly, we observed a strong positive correlation between survival and immunoPET SUV (r=0.9425, p=0.016) in the ICI-treatment group, but not within the control group. CONCLUSIONS Our study demonstrates the potential incorporation of CD69 ImmunoPET as response assessment to ICI for GBM patients.

Recurrent glioblastoma (GBM) is an aggressive disease with poor survival and limited treatment options. SL-701 is a novel immunotherapy comprised of synthetic peptides designed to elicit an anti-tumor immune response against GBM antigens IL-13Rα2, ephrinA2, and survivin. Here we describe an 18-color flow cytometry analysis from stage 2 of a Ph2 clinical trial of SL-701+poly-ICLC+bevacizumab (NCT02078648), in which 12-month overall survival (OS) was 50%. Of the 27 patients in stage 2, 24 (89%) developed heterogeneous T-cell responses against 1, 2, or 3 of the SL-701 CD8 peptides. Magnitude and kinetics of peptide responses were variable among these patients with no clear relationship to OS. Therefore, a phenotypic analysis of the T-cell response in all 27 patients was conducted using terraFlow, a unique data analysis approach utilizing machine learning to identify T-cell phenotypes associated with clinical response from all possible combinations of markers. In total, 10,184 unique SL-701 induced phenotypes were measured, including 223 phenotypes (P < 0.05) and 16 core phenotypes that uniquely represent differences between patients with OS above or below 12 months (P < 0.05). 50% of the core phenotypes were CD8+ CD57+ CD107a+ PD-1- SL-701-specific T-cells, which are highly-differentiated memory T-cells primed for cytotoxicity. The frequency of the CD57+ core phenotypes (8%-18%) was enhanced 1.6- to 2.3-fold in patients with an OS > 12 months (P < 0.05). Similarly, 2 core phenotypes identified cytotoxic CD4+ and CD8+ T cells, which were enhanced 1.9- and 2.5-fold in patients with an OS >12 months. The final 6 core phenotypes identified activated CD4+ CD154+ SL-701-specific T-cells (5%-19%) that were enhanced 0.3- to 0.5-fold in patients with an OS < 12 months (P < 0.05), suggesting helper T-cell responses in the absence of cytotoxic T-cell responses are associated with an OS < 12 months. Deep sequencing of SL-701-specific T-cells using whole transcriptome-based molecular cytometry is planned.

Diffuse midline gliomas (DMGs) bearing driver mutations of histone 3 lysine 27 (H3K27M) are incurable brain tumors with unique epigenomes. Here, we generated a syngeneic H3K27M mouse model to study the amino acid metabolic dependencies of these tumors. H3K27M mutant cells were highly dependent on methionine. Interrogating the methionine cycle dependency through a short-interfering RNA screen identified the enzyme methionine adenosyltransferase 2A (MAT2A) as a critical vulnerability in these tumors. This vulnerability was not mediated through the canonical mechanism of MTAP deletion; instead, DMG cells have lower levels of MAT2A protein, which is mediated by negative feedback induced by the metabolite decarboxylated S-adenosyl methionine. Depletion of residual MAT2A induces global depletion of H3K36me3, a chromatin mark of transcriptional elongation perturbing oncogenic and developmental transcriptional programs. Moreover, methionine-restricted diets extended survival in multiple models of DMG in vivo. Collectively, our results suggest that MAT2A presents an exploitable therapeutic vulnerability in H3K27M gliomas.

Oligodendrogliomas are therapy-responsive tumors, which have better prognosis compared to their astrocytic counterparts. The goal of treatment in such cases is not only prolongation of the patients' survival, but maintaining high neurologic functioning and quality of life. Traditionally, after maximal surgical resection fractionated radiation therapy was given. However, prospective randomized trials comparing irradiation alone and its combination with chemotherapy demonstrated strong impact of the latter on prolongation of overall survival in 1p/19q co-deleted anaplastic and "high-risk" low-grade gliomas. In such cases the median survival of patients is well beyond a decade. The optimal chemotherapy regimen (PCV or temozolomide) remains an active clinical trial question, which may be resolved after completion of the ongoing phase III CODEL study (clinicaltrials.gov identifier NCT00887146). Additional investigations should also refine further the prognostic and predictive role of molecular markers in oligodendroglial tumors.

Background and PurposeThe informal care demands of primary malignant brain tumor (PMBT) patients include unique issues associated with neurological and cognitive symptoms. Existing caregiver needs questionnaires do not include these disease-specific symptoms, which are particularly distressing. Therefore, we have developed the neuro-oncology Caregiver Needs Screen (CNS) and evaluated its psychometric properties.MethodsThe 32-item instrument was developed based on PMBT caregiver interviews (N= 109) and expert review. The CNS was tested along measures of depression, anxiety, burden, and mastery in 122 PMBT caregivers. Principal components analysis was used to examine item properties and internal structure. Internal consistency reliability and construct validity were assessed.ResultsSix subscales were identified with internal consistency ranging between alpha = .653 and .857. Convergent validity was verified by moderate/high correlations between measures of caregiver well-being and CNS scale scores.ConclusionsFindings provide preliminary evidence of reliability and validity for the CNS. This instrument can be useful when assessing caregivers' needs for supportive care.

The activity of single-agent targeted molecular therapies in glioblastoma has been limited to date. The North American Brain Tumor Consortium examined the safety, pharmacokinetics, and efficacy of combination therapy with sorafenib, a small molecule inhibitor of Raf, vascular endothelial growth factor receptor 2, and platelet-derived growth factor receptor-β, and temsirolimus (CCI-779), an inhibitor of mammalian target of rapamycin. This was a phase I/II study. The phase I component used a standard 3 × 3 dose escalation scheme to determine the safety and tolerability of this combination therapy. The phase II component used a 2-stage design; the primary endpoint was 6-month progression-free survival (PFS6) rate. Thirteen patients enrolled in the phase I component. The maximum tolerated dosage (MTD) for combination therapy was sorafenib 800 mg daily and temsirolimus 25 mg once weekly. At the MTD, grade 3 thrombocytopenia was the dose-limiting toxicity. Eighteen patients were treated in the phase II component. At interim analysis, the study was terminated and did not proceed to the second stage. No patients remained progression free at 6 months. Median PFS was 8 weeks. The toxicity of this combination therapy resulted in a maximum tolerated dose of temsirolimus that was only one-tenth of the single-agent dose. Minimal activity in recurrent glioblastoma multiforme was seen at the MTD of the 2 combined agents.

(2000). Advances in Neurofibromatosis 2 (NF2): A Workshop Report. Journal of Neurogenetics: Vol. 14, No. 2, pp. 63-106.

Estimating survival time in cancer patients is crucial for clinicians, patients, families, and payers. To provide appropriate and cost-effective care, various data sources are used to provide rational, reliable, and reproducible estimates. The accuracy of such estimates is unknown.The authors prospectively estimated survival in 150 consecutive cancer patients (median age 62 years) with brain metastases undergoing radiosurgery. They recorded cancer type, number of brain metastases, neurological presentation, extracranial disease status, Karnofsky Performance Scale score, Recursive Partitioning Analysis class, prior whole-brain radiotherapy, and synchronous or metachronous presentation. Finally, the authors asked 18 medical, radiation, or surgical oncologists to predict survival from the time of treatment.The actual median patient survival was 10.3 months (95% CI 6.4-14). The median physician-predicted survival was 9.7 months (neurosurgeons = 11.8 months, radiation oncologists = 11.0 months, and medical oncologist = 7.2 months). For patients who died before 10 months, both neurosurgeons and radiation oncologists generally predicted survivals that were more optimistic and medical oncologists that were less so, although no group could accurately predict survivors alive at 14 months. All physicians had individual patient survival predictions that were incorrect by as much as 12-18 months, and 14 of 18 physicians had individual predictions that were in error by more than 18 months. Of the 2700 predictions, 1226 (45%) were off by more than 6 months and 488 (18%) were off by more than 12 months.Although crucial, predicting the survival of cancer patients is difficult. In this study all physicians were unable to accurately predict longer-term survivors. Despite valuable clinical data and predictive scoring techniques, brain and systemic management often led to patient survivals well beyond estimated survivals.

In this study the authors evaluated the role of stereotactic radiosurgery (SRS) in the management of progressive or newly diagnosed small-volume oligodendrogliomas. Tumor control, survival, and complications were assessed in patients with oligodendroglioma who underwent Gamma Knife radiosurgery as a primary or adjuvant procedure.The authors retrospectively reviewed 30 patients with oligodendroglioma (12 Grade II and 18 Grade III) who underwent SRS between 1992 and June 2006 at the University of Pittsburgh. The median patient age was 43.2 years (range 10.8-75.4 years). Twenty-four patients had previously undergone resection of the tumor, whereas tumors in 6 were diagnosed based on biopsy findings. The SRS was performed in 25 patients who had imaging-defined tumor progression despite prior fractionated radiation (22 patients) and/or chemotherapy (20 patients). The median target volume was 15.4 cm(3) (range 0.07-48.7 cm(3)) and the median margin dose was 14.5 Gy (range 11-20 Gy).At an average of 39.2 months of follow-up (range 12-133 months), 17 patients were dead and 13 were living. The overall survival rates from diagnosis to 5 and 10 years were 90.9 and 68.2%, respectively, for Grade II and 52.1% at 5 years and 26.1% at 10 years for Grade III. Factors associated with an improved progression-free survival included lower tumor grade and smaller tumor volume. In 13 patients who had loss of heterozygosity testing, patients with 1p19q loss of heterozygosity had a significantly improved survival after diagnosis (p = 0.04).The SRS modality is a minimally invasive additional option for patients with residual or recurrent oligodendrogliomas. It may also be considered as an alternative to initial resection in small-volume tumors located in the cortical brain region.

PurposeFenretinide induces apoptosis in malignant gliomas in vitro. This two-stage phase II trial was conducted to determine the efficacy of fenretinide in adults with recurrent malignant gliomas.Patients and MethodsTwenty-two patients with anaplastic gliomas (AG) and 23 patients with glioblastoma (GBM) whose tumors had recurred after radiotherapy and no more than two chemotherapy regimens were enrolled. Fenretinide was given orally on days 1 to 7 and 22 to 28 in 6-week cycles in doses of 600 or 900 mg/m2bid.ResultsSix of 21 (29%) patients in the AG arm and two of 23 (9%) patients in the GBM arm had stable disease at 6 months. One patient with AG treated at 900 mg/m2bid dosage had a partial radiologic response. Median progression-free survival (PFS) was 6 weeks for the AG arm and 6 weeks for the GBM arm. PFS at 6 months was 10% for the AG arm and 0% for the GBM arm. Grade 1 or 2 fatigue, dryness of skin, anemia, and hypoalbuminemia were the most frequent toxicities reported. The trial was closed after the first stage because of the inadequate activity at the fenretinide doses used. The first-administration mean plasma Cmaxfor fenretinide was 832 ± 360 ng/mL at the 600 mg/m2bid dosage and 1,213 ± 261 ng/mL at the 900 mg/m2bid dosage.ConclusionFenretinide was inactive against recurrent malignant gliomas at the dosage used in this trial. However, additional studies using higher doses of the agent are warranted based on the tolerability of the agent and the potential for activity of a higher fenretinide dosage, as suggested in this trial.

Article abstract A 49-year-old woman with immunoglobulin Gκ multiple myeloma developed progressive visual loss with bilateral upper and lower central arcuate scotomas. Funduscopic and electrophysiologic studies indicated bilateral optic neuropathy. The immunoglobulin G fraction of the patient’s serum reacted with retinal ganglionic cells in bovine retina. The visual abnormalities remitted after myeloablative chemotherapy and disappearance of the paraprotein.

We studied the nervous systems and tumors of two patients with anti-Yo-associated paraneoplastic cerebellar degeneration (PCD). In both patients the underlying tumor was an ovarian adenocarcinoma that expressed Yo antigens and contained extensive infiltrates of lymphocytes and plasma cells. The major central nervous system findings were a complete loss of cerebellar Purkinje cells with Bergmann astrogliosis. One patient had inflammatory infiltrates in the medulla and pons, and moderate axonal loss and demyelination involving the spinal cord. No inflammatory infiltrates were identified in the cerebrum, cerebellum or brain-stem of the other patient. Using quantitative Western blot analysis, deposits of anti-Yo IgG could not be demonstrated in the nervous system, possibly as a result of the loss of cells expressing Yo antigens. The detection of the anti-Yo antibody as a common marker of PCD in one patient with inflammatory infiltrates and another without infiltrates suggests that some PCD pathologically classified as “non-inflammatory” may represent a final burn-out stage of a cellular immune-mediated disorder. Our findings indicate that Purkinje cells are the main, but not necessarily the exclusive, targets of this disorder.

IgG fractions of sera containing anti-Hu antibodies or control sera were incubated with Hu-positive and Hu-negative cell lines. Anti-Hu IgG specifically localized in the nucleus of Hu-positive cells. Anti-Hu-positive and control sera were incubated with Hu-positive cells and human complement or peripheral blood mononuclear cells. Hu antibody caused neither complement-mediated lysis nor augmented antibody-dependent cell-mediated cytotoxicity. Anti-Hu IgG did not affect proliferation of Hu-positive cells. Anti-Hu antibodies may not play a direct role in tissue injury in patients with paraneoplastic encephalomyeloneuropathy and anti-Hu antibodies.

Headaches in a cancer hospital are common and often require extensive diagnostic evaluation to exclude metastatic intracranial disease or infection. However, one does not expect to encounter headache in an individual with no other neurologic illness who donates bone marrow. We have seen two patients develop positional headaches, which were typical of low pressure headaches occurring after lumbar puncture, after bone marrow harvest. In both patients, the headaches resolved without specific therapy. ### Patient 1. A 44-year-old woman underwent elective bone marrow harvest to provide marrow for an HLA compatible sibling. She was morbidly obese. For several years, she suffered diffuse headache on awakening that would abate as she stood up and began her daily activities. The physician performing the bone marrow harvest noted the patient's obesity obscured the usual landmarks. When the surgical drapes were removed, several puncture marks were noted over the lateral sacrum. When the patient awoke from general anesthesia, she complained of severe …

We report the cases of two adult patients with cystic fibrosis affecting the pancreas and liver, who also had severe vitamin E deficiency and neurologic disease. The most prominent clinical features were abnormal eye movements, diminished reflexes, decreased vibratory and position sense, ataxia, and muscle weakness. Treatment with intramuscular injections of vitamin E partially corrected the neurologic deficits. Vitamin E absorption tests documented severe malabsorption, which was later alleviated by the addition of dessicated ox bile to the regimen of alpha-tocopheryl acetate. These studies suggest that a decreased intraluminal concentration of bile salts is an important factor in the development of severe vitamin E deficiency and in the poor response to oral replacement therapy that is seen in some patients with cystic fibrosis.