tbuckley/cabot-search huggingface dataset:
INNV-28. TEMOZOLOMIDE IN RENAL DYSFUNCTION
Authors: Kayla Garzio, Kelly McElroy, Stuart Grossman, Matthias Holdhoff, Byram Ozer, Olga Yankulina
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Temozolomide (TMZ) is a cytotoxic DNA alkylating agent. It is the only chemotherapy known to improve survival in patients with high grade astrocytomas. The active alkylating species, methylhydrazine, is not recovered in the urine and thus renal function is not expected to affect clearance of this agent. It has never been formally evaluated in adults with eGFR &amp;lt; 36 mL/min/1.73 m2, and it is often recommended to administer with caution, dose reduce, or withhold therapy. However, lacking other effective therapies, we have elected to administer TMZ at full dose to these patients. This IRB approved retrospective study was conducted to evaluate the safety of this practice. METHODS The primary endpoint was to characterize the incidence and severity of thrombocytopenia in patients with renal impairment defined as eGFR &amp;lt; 60 mL/min/1.73 m2 who received TMZ for the treatment of their high grade gliomas (HGG) or primary CNS lymphoma (PCNSL). Secondary endpoints included incidence and severity of neutropenia, lymphocytopenia, hepatotoxicity, and number of cycles administered. Medical records were reviewed for adult patients with HGG or PCNSL treated with TMZ from October 1, 2016-September 30, 2019. RESULTS Thirty-four patients met criteria for inclusion. Of the 7 patients with eGFR &amp;lt; 36 mL/min/1.73m2, 33/34 cycles (97%) were completed successfully without grade 3–4 thrombocytopenia. No patients experienced grade 3–4 neutropenia, and grade 3–4 lymphocytopenia occurred in 5 cycles (15%). One patient required discontinuation of TMZ 7 days prior to completion of radiation due to thrombocytopenia. CONCLUSION The side effect profile from TMZ administered to patients with eGFR &amp;lt; 36 mL/min/1.73 m2 appears to be similar to that of patients with normal renal function. This is not an unanticipated finding given what is known about the metabolism of the drug.
NCOG-13. THE IMPACT OF CME ON THE KNOWLEDGE OF NEUROFIBROMATOSIS TYPE 1-RELATED TUMORS
Authors: Michelle Worst, Kinjal Parikh, Rich Caracio, Sara Fagerlie
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic condition characterized by a wide spectrum of clinical findings. Patients with NF1 develop benign and malignant tumors along the nerves of the skin, brain, and other body parts. Due to the unique presentation of each patient, clinicians are challenged to stay current with emerging data and how best to integrate new agents into multidisciplinary treatment paradigms. The objective of this study was to assess changes in neurologists’ and pediatricians’ knowledge and confidence through participation in education regarding NF1 treatment. METHODS The educational activity consisted of a 30-minute online enduring, 1 faculty, chapterized summary of a live symposium. Educational effect was assessed with a repeated pairs pre-/post-assessment study with a 3-item, multiple choice, knowledge questionnaire and one confidence assessment question. For all questions, each participant served as his/her own control. Pre- and post-assessment scores were compared to determine relative changes in the proportion of correct responses. A chi-square test assessed statistical significance at the P &amp;lt; 0.05 level. The activity launched 23rd December 2019; data were collected until 2nd April 2020. RESULTS Overall, statistically significant improvements were seen after education for neurologists (N=171, P &amp;lt; 0.05) and pediatricians (N=260, P &amp;lt; 0.01). The relative improvement in correct answers was 26% for neurologists and 48% for pediatricians (percent of total correct responses pre-/post-assessment were 27%/34% and 23%/34%, respectively). Following the activity, 16% of neurologists and 22% of pediatricians had a measurable increase in confidence regarding their understanding of multidisciplinary management of NF1. CONCLUSIONS Participation in an online, 30-minute enduring CME intervention resulted in statistically significant improvements in knowledge and confidence of neurologists and pediatricians, that result in improvements in clinical care. Continued educational activities are paramount to address residual gaps and further increase clinicians’ confidence in this clinical setting.
COVD-01. ADAPTATION OF A GAMMA KNIFE ICON STEREOTACTIC RADIOSURGERY PROGRAM IN THE FACE OF A GLOBAL PANDEMIC
Authors: Rodney Wegner, Zachary Horne, Linda Xu, Alexander Yu, Matthew Goss, Yun Liang, Jason Sohn, Athanasios Colonias, Russell Fuhrer, Stephen Karlovits
Journal: Neuro-Oncology (2020)

Abstract PURPOSE The COVID-19 pandemic necessitated drastic and rapid changes throughout the field of radiation oncology, some of which were unique to the discipline of radiosurgery. Available guidelines called for reduced frame use, postponing non-urgent cases, and reducing the number of fractions delivered. Our institution enacted many of these guidelines, and herein we show the resultant effect on patient treatments on our Gamma Knife Icon system. METHODS &amp; MATERIALS In early to mid-March of 2020 our institution rapidly implemented suggested changes according to ASTRO and other consensus guidelines as they relate specifically to stereotactic radiosurgery in the COVID-19 era. We reviewed the GK Icon schedule at our institution between January 01 and April 30, 2020. We documented age, condition treated, technique (frame vs. mask), and number of fractions. We then tabulated and graphed the number of patients, framed cases, and fractions across that time period. RESULTS Seventy-seven patients were treated on the GK Icon between January and April 2020, for a total of 231 fractions. The number of unique patients per month varied from 18 (April) to 22 (January). Of the 77 patients only 5 were treated using a frame. The number of fractions per month decreased significantly over time, from 70 in January to 36 in April. Likewise, the percentage of single fraction cases increased from 4.5% per month in January to 67% in April. CONCLUSIONS The results presented here show that it is possible to quickly and efficiently change work flows to allow for reduced fractionation and frame use in the time of a global pandemic. Multidisciplinary cooperation and ongoing communication are integral to the success of such programs.
BIOM-20. PROTEOMICS PROVIDES POTENTIAL THERAPEUTIC APPROACHES TO GLIOBLASTOMA TREATMENT: RESULTS FROM THE CLINICAL PROTEOMICS TUMOR ANALYSIS CONSORTIUM (CPTAC)
Authors: Jill S Barnholtz-Sloan
Journal: Neuro-Oncology (2020)

Abstract Glioblastoma (GBM) is the most common type of primary malignant tumor in adults and contributes disproportionately to cancer morbidity and mortality. The ability to augment current knowledge based on the genome and transcriptome with information regarding protein abundance and post-translational modifications with small molecule and lipid abundance has provided novel biological insights into GBM tumorigenesis. In this presentation we will discuss results from proteogenomic and metabolomic investigations of prospectively recruited, newly diagnosed, treatment-naive glioblastomas (GBMs; N=99). Multiple key findings emerged that were not known from traditional genomic analyses as implemented in most currently available datasets. Analysis of protein phosphorylation identified key signaling intermediates in the RTK/RAS pathway common to multiple RTK genomic alterations, potentially offering common therapeutic targets for different oncogenic drivers in GBM. Phosphoproteomics also identified potential druggable targets based on kinase-substrate pathway analysis, as well as novel phosphoprotein targets associated with the regulation of telomere length by ATRX in IDH mutants. Identification of distinct Immune High and Immune Low phenotypes in GBM from whole genome interrogation of the proteome were driven by tumor-associated macrophage markers, and associated with distinct epigenetic modifications and histone acetylation patterns. Identification of key metabolic changes in IDH mutants facilitating the accumulation of oncometabolite 2-HG were also associated with lipidomic changes. Taken all together this work identifies additional therapeutic channels for GBM and novel information useful for more accurate stratification patients for effective treatment.
RARE-26. RETROSPECTIVE ANALYSIS OF PEDIATRIC CHOROID PLEXUS TUMORS
Authors: Yoshiko Nakano, Atsufumi Kawamura, Yuko Watanabe, Ryuta Saito, Masayuki Kanemori, Chikako Kiyotani, Fumiyuki Yamasaki, Naoki Nakagawa, Akira Gomi, Taishi Nakamura, Noritsugu Kunihiro, Keiko Okada, Hiroaki Sakamoto, Mai Kitahara, Yuko Hibiya, Sumihito Nobusawa, Koichi Ichimura
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Choroid plexus tumors (CPT) include choroid plexus papilloma (CPP), atypical choroid plexus papilloma (aCPP), and choroid plexus carcinoma (CPC). Because of their rarity, limited data are available on the current status of treatment and outcomes for pediatric CPTs. METHOD We retrospectively reviewed clinical information on patients with CPT patients aged between 0 and 30 years at diagnosis and were treated in 8 institutions in Japan. RESULTS Of forty-two cases initially diagnosed as CPT, 18 cases were reviewed by central pathologists. As a result, the diagnosis of CPC or aCPP in five cases were changed to other tumors including AT/RT and astroblastoma. The remaining 37 cases were subjected to analysis. Median age at diagnosis was two years (0 to 25) and the mean follow-up period was seven years. All 26 patients with CPP (n=20) or aCPP (n=6) underwent gross-total resection without adjuvant therapy. Of them 24 patients are alive without recurrence. Four patients of patients with CPC (n=11) died of cancer. Five patients including three patients experienced local relapse, achieved complete remission after resection of tumor plus chemoradiotherapy. All three patients with dissemination of CPC at diagnosis or relapse died of the disease. At least three patients were diagnosed with Li-Fraumeni syndrome: one died of medulloblastoma and one patient developed osteosarcoma. CONCLUSION Compared with the excellent prognosis of CPP, the survival rates for CPC, especially disseminated CPC are unsatisfactory. Our results also underline the importance of considering genetic testing of TP53 for patients with CPC.
Wallace Foulds: founding president of the Royal College of Ophthalmologists
Authors: Penny Warren
Journal: BMJ (2020)

Photo credit: Royal College of Ophthalmologists

In 1951 Wallace Foulds, who has died aged 96, was appointed registrar at Moorfields Eye Hospital in London, where he relished the wide ranging nature of ophthalmology work. In an era before subspecialties, he came across every eye condition and, since car seatbelts were not yet compulsory and industrial accidents were commonplace, he also regularly had to repair facial injuries and treat burns. Foulds, not one to be pigeon-holed, maintained an astonishing breadth of research interests throughout his career.

In 1953 he became a senior registrar at University College London, and in 1958, after presenting his thesis on angle closure glaucoma, a consultant at Addenbrooke’s Hospital in Cambridge. Here, among other things, he had to cope with a backlog of more than 600 cataract patients. He was also spending two days a week as a researcher at the Institute of Ophthalmology in London, and was so short of time he used to tend his garden at night by floodlight. Luckily, he said, he could manage on just four hours’ sleep.

In 1964 Foulds became …
Functional SCD1 Is Critical for Acute Lymphoblastic Leukaemia Maintenance in the Central Nervous System
Authors: Orianne Olivares, Antony Cousins, Elke Markert, Sergey Tumanov, Gillian Mackay, Jurre Kamphorst, Karen Keeshan, Pawel Herzyk, Eyal Gottlieb, Christina Halsey
Journal: Blood (2017)
Psychotherapies for depression: a network meta‐analysis covering efficacy, acceptability and long‐term outcomes of all main treatment types
Authors: Pim Cuijpers, Soledad Quero, Hisashi Noma, Marketa Ciharova, Clara Miguel, Eirini Karyotaki, Andrea Cipriani, Ioana A. Cristea, Toshi A. Furukawa
Journal: World Psychiatry (2021)

The effects of psychotherapies for depression have been examined in several hundreds of randomized trials, but no recent network meta‐analysis (NMA) has integrated the results of these studies. We conducted an NMA of trials comparing cognitive behavioural, interpersonal, psychodynamic, problem‐solving, behavioural activation, life‐review and “third wave” therapies and non‐directive supportive counseling with each other and with care‐as‐usual, waiting list and pill placebo control conditions. Response (50% reduction in symptoms) was the primary outcome, but we also assessed remission, standardized mean difference, and acceptability (all‐cause dropout rate). Random‐effects pairwise and network meta‐analyses were conducted on 331 randomized trials with 34,285 patients. All therapies were more efficacious than care‐as‐usual and waiting list control conditions, and all therapies – except non‐directive supportive counseling and psychodynamic therapy – were more efficacious than pill placebo. Standardized mean differences compared with care‐as‐usual ranged from –0.81 for life‐review therapy to –0.32 for non‐directive supportive counseling. Individual psychotherapies did not differ significantly from each other, with the only exception of non‐directive supportive counseling, which was less efficacious than all other therapies. The results were similar when only studies with low risk of bias were included. Most therapies still had significant effects at 12‐month follow‐up compared to care‐as‐usual, and problem‐solving therapy was found to have a somewhat higher long‐term efficacy than some other therapies. No consistent differences in acceptability were found. Our conclusion is that the most important types of psychotherapy are efficacious and acceptable in the acute treatment of adult depression, with few significant differences between them. Patient preference and availability of each treatment type may play a larger role in the choice between types of psychotherapy, although it is possible that a more detailed characterization of patients with a diagnosis of depression may lead to a more precise matching between individual patients and individual psychotherapies.
Comparing 5-Year and Lifetime Risks of Breast Cancer using the Prospective Family Study Cohort
Authors: Robert J MacInnis, Julia A Knight, Wendy K Chung, Roger L Milne, Alice S Whittemore, Richard Buchsbaum, Yuyan Liao, Nur Zeinomar, Gillian S Dite, Melissa C Southey, David Goldgar, Graham G Giles, Allison W Kurian, Irene L Andrulis, Esther M John, Mary B Daly, Saundra S Buys, Kelly-Anne Phillips, John L Hopper, Mary Beth Terry
Journal: JNCI Journal of the National Cancer Institute (2020)

Clinical guidelines often use predicted lifetime risk from birth to define criteria for making decisions regarding breast cancer screening rather than thresholds based on absolute 5-year risk from current age.We used the Prospective Family Cohort Study of 14 657 women without breast cancer at baseline in which, during a median follow-up of 10 years, 482 women were diagnosed with invasive breast cancer. We examined the performances of the International Breast Cancer Intervention Study (IBIS) and Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) risk models when using the alternative thresholds by comparing predictions based on 5-year risk with those based on lifetime risk from birth and remaining lifetime risk. All statistical tests were 2-sided.Using IBIS, the areas under the receiver-operating characteristic curves were 0.66 (95% confidence interval = 0.63 to 0.68) and 0.56 (95% confidence interval = 0.54 to 0.59) for 5-year and lifetime risks, respectively (Pdiff < .001). For equivalent sensitivities, the 5-year incidence almost always had higher specificities than lifetime risk from birth. For women aged 20-39 years, 5-year risk performed better than lifetime risk from birth. For women aged 40 years or older, receiver-operating characteristic curves were similar for 5-year and lifetime IBIS risk from birth. Classifications based on remaining lifetime risk were inferior to 5-year risk estimates. Results were similar using BOADICEA.Our analysis shows that risk stratification using clinical models will likely be more accurate when based on predicted 5-year risk compared with risks based on predicted lifetime and remaining lifetime, particularly for women aged 20-39 years.
NCMP-18. NEUROTOXICITY AS A POTENTIAL SURROGATE MARKER FOR THERAPEUTIC RESPONSE WITH COMMERCIAL ANTI-CD19 CAR T-CELL THERAPY
Authors: Carlen Yuen, Peter Riedell, Andrew Artz, Satyajit Kosuri, Thomas Kelly, Shasha Wu, Anthony Reder, Kourosh Rezania, Betty Soliven, Tao Xie, James Mastrianni, Deric Park, Wesley Klejch, Saad Ali, Michael Bishop
Journal: Neuro-Oncology (2020)

Abstract Neurotoxicity is a common occurrence and a major form of morbidity in adult patients with relapsed or refractory (R/R) diffuse large B cell lymphoma (DLBCL) patients treated with anti-CD19 directed chimeric antigen receptor (CAR) T-cell therapy. Variables related to the incidence and severity of neurotoxicity have been relatively well delineated, but the association between neurotoxicity and the efficacy of CAR T-cell therapy has not been well studied. We performed a retrospective analysis of the outcomes of DLBCL patients who developed neurotoxicity following anti-CD19 CAR T-cell treatment. The analysis included 26 patients with R/R DLBCL who received commercial anti-CD19 CAR T-cell therapy. All patients received a lymphodepleting chemotherapy regimen consisting of fludarabine and cyclophosphamide. Twenty-five patients received axicabtagene ciloleucel, and 1 received tisagenlecleucel. The overall incidence of neurotoxicity was 88%; 31% developed severe neurotoxicity (Grade III-IV by CTCAE). Higher neurotoxicity was associated with better PFS by both CTCAE (CR 2.4 ± 1.1 vs. PD 1.4 ± 1.3, p = 0.051) and CARTOX-10 (CR 3.78 ± 4.6 vs. PD 7.7 ± 3.8, p = 0.044) grading systems. Higher neurotoxicity continued to show a trend at 6, 9, and 12 months by the CTCAE grading system (CR 2.4 ± 1.0 vs. PD 1.7 ± 1.3, p = 0.085), and no patients had disease recurrence after 6 months. In this limited cohort, neurotoxicity severity was paradoxically positively correlated with progression-free survival with commercial CAR T-cell therapy and may therefore indicate an effective therapeutic response.
Cell-surface antigen profiling of pediatric brain tumors: B7-H3 is consistently expressed and can be targeted via local or systemic CAR T-cell delivery
Authors: Dalia Haydar, Haley Houke, Jason Chiang, Zhongzhen Yi, Zelda Odé, Kenneth Caldwell, Xiaoyan Zhu, Kimberly S Mercer, Jennifer L Stripay, Timothy I Shaw, Peter Vogel, Christopher DeRenzo, Suzanne J Baker, Martine F Roussel, Stephen Gottschalk, Giedre Krenciute
Journal: Neuro-Oncology (2020)

Immunotherapy with chimeric antigen receptor (CAR) T cells is actively being explored for pediatric brain tumors in preclinical models and early phase clinical studies. At present, it is unclear which CAR target antigens are consistently expressed across different pediatric brain tumor types. In addition, the extent of HLA class I expression is unknown, which is critical for tumor recognition by conventional αβTCR T cells.We profiled 49 low- and high-grade pediatric brain tumor patient-derived orthotopic xenografts (PDOX) by flow analysis for the expression of 5 CAR targets (B7-H3, GD2, IL-13Rα2, EphA2, and HER2), and HLA class I. In addition, we generated B7-H3-CAR T cells and evaluated their antitumor activity in vitro and in vivo.We established an expression hierarchy for the analyzed antigens (B7-H3 = GD2 >> IL-13Rα2 > HER2 = EphA2) and demonstrated that antigen expression is heterogenous. All high-grade gliomas expressed HLA class I, but only 57.1% of other tumor subtypes had detectable expression. We then selected B7-H3 as a target for CAR T-cell therapy. B7-H3-CAR T cells recognized tumor cells in an antigen-dependent fashion. Local or systemic administration of B7-H3-CAR T cells induced tumor regression in PDOX and immunocompetent murine glioma models resulting in a significant survival advantage.Our study highlights the importance of studying target antigen and HLA class I expression in PDOX samples for the future design of immunotherapies. In addition, our results support active preclinical and clinical exploration of B7-H3-targeted CAR T-cell therapies for a broad spectrum of pediatric brain tumors.
CTNI-49. PHASE I STUDY OF MGMT-P140K TRANSFECTED HEMATOPOETIC PROGENITOR CELLS COMBINED WITH TMZ/O6BG DOSE ESCALATION FOR NEWLY DIAGNOSED, UNMETHYLATED GLIOBLASTOMA: TOLERANCE AND EVIDENCE OF SURVIVAL BENEFIT
Authors: Andrew E Sloan, Hua Fung, Jane Reese, Lisa Rgers, Christopher Murphy, Hillard Lazarus, Boro Dropulic, Stanton Gerson
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION GBM has median survival of 12 months despite current SOC therapy. The most important mechanism of TMZ resistance is the O6-methylguanine-DNA methyltransferase (MGMT) gene. The MGMT inhibitor O6-benzylguanine (BG) demonstrated efficacy in depleting MGMT but approach led to unacceptable bone marrow toxicity and has thus been abandoned. We hypothesized that chemoprotection of hematopoietic HPC with an MGMT mutant (MGMT-P140K) characterized by normal methyltransferase activity, coupled with low affinity for BG would maximize anti-tumor response while enabling patients to tolerate TMZ &amp; BG dose escalation with minimal toxicity. A phase I trial was performed to test this hypothesis. METHODS 10 adults with newly diagnosed MGMT unmethylated, IDH-1 WT, GBM underwent standard surgery and radiation, followed by transplantation with autologous CD34+ HPC transfected with MGMT-P140K using a lentiviral vector. We tested tolerance and efficacy of three different paradigms for conditioning bone marrow and re-infusion of HPC. RESULTS Treatment was moderately toxic with 3/10 patients suffering grade 3–4 hematologic toxicity; no high grade non-hematologic toxicity was observed. Viral transduction rates ranged from 3–75% and were clearly improved in Arm III utilizing BCNU conditioning and intra-patient dose escalation of TMZ/O6GB. In patients tolerating 3 cycles or more, P140K-MGMT gene markings in peripheral blood and bone marrow cells increased 3-26-fold with only mild (Grade 2–3) myelosuppression consistent with chemo-protection as hypothesized. Median PFS and OS was 24 and 33 months respectfully, and three patients in Arm III were progression free at 36 months with one progression free at 48 months. OS exceeded RPA &amp; Nomogram predicted survival by 3.6-fold, suggesting clinical benefit. Viral insertion site analysis demonstrate no clonal dominance. CONCLUSIONS P140K-MGMT transfected HPC enables TMZ/ BG dose escalation with acceptable toxicity and increased survival in a small cohort of selected patients. A U-01 funded phase II study is ongoing at UH and NIH.