bluuebunny/crossref_metadata_2025_split huggingface dataset:
ACTR-16. MATRix REGIMEN FOR NEWLY DIAGNOSED PRIMARY DIFFUSE B-CELL LYMPHOMA OF THE CENTRAL NERVOUS SYSTEM: PRELIMINARY RESULTS
Authors: Green Richard , Thornton Colleen 
Published: November 2019

Abstract
We report our preliminary experience treating 9 patients with newly diagnosed primary diffuse B-cell lymphoma of the central nervous system with the MATRix regimen as reported by Ferreri, et al in 2016. The median age was 63 y; 5 patients were men and 4 were women. Seven had cerebral mass lesions, 1 a paraspinal mass, and 1 leptomeningeal disease. Five patients underwent biopsy; 2 imaging total resection; 1 subtotal resection; and in 1 the extent of resection was indeterminate. Treatment consisted of 4 cycles of rituximab 375 mg/sq m (Days 1, 6); methotrexate 4 g/sq m (Day 2); cytarabine 2 g/sq m every 12 h (Days 3, 4); and thiotepa 30 mg/sq m (Day 5). Patients without disease progression received carmustine 400 mg/sq m and thiotepa 5 mg/kg followed by autologous bone marrow transplantation. Two patients were switched to MATRix after 6 cycles of methotrexate and rituximab and received 2 additional cycles that included cytarabine and thiotepa. Overall, 7 patients completed initial chemotherapy, with 5 complete responses and 2 partial responses. Six of these 7 went on to transplantation and remain alive without disease progression after a median follow-up of 470 days. One patient with initial PR progressed and did not proceed to transplantation. Two patients died after 1 cycle; they were both over 70 y (76 and 84) and succumbed to sepsis with neutropenic fever. No serious acute toxicity occurred in the 6 patients who completed the entire regimen including transplantation; 1 patient has experienced symptomatic leukoencephalopathy. Overall progression free survival was 394 days. These preliminary data suggest that the MATRix regimen in safe and highly effective in the newly diagnosed setting. However, the high early mortality in patients over 70 years in this group suggests that the regimen may be too toxic for very elderly individuals.
ACTR-21. A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED PHASE 3 TRIAL OF DEPATUXIZUMAB MAFODOTIN (ABT-414) IN EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) AMPLIFIED (AMP) NEWLY DIAGNOSED GLIOBLASTOMA (nGBM)
Authors: Lassman Andrew , Pugh Stephanie , Wang Tony , Aldape Kenneth , Gan Hui , Preusser Matthias , Vogelbaum Michael , Sulman Erik , Won Minhee , Zhang Peixin , Moazami Golnaz , Macsai Marian , Gilbert Mark , Bain Earle , Blot Vincent , Ansell Peter , Samanta Suvajit , Kundu Madan , Seidel Clemens , De Vos Filip , Hsu Sigmund , Cardona Andrés , Lombardi Giuseppe , Bentsion Dmitry , Peterson Richard , Gedye Craig , Lebrun-Frénay Christine , Wick Antje , Curran Walter , Mehta Minesh 
Published: November 2019

Abstract

BACKGROUND
Approximately 50% of nGBMs harbor EGFR-amp. Depatuxizumab mafodotin (depatux-m) is an antibody drug conjugate: a monoclonal antibody that binds activated EGFR (wild-type and EGFRvIII mutant) linked to a microtubule-inhibitor toxin. Pre-clinical and earlier clinical trials suggested efficacy.

METHODS
RTOGF 3508/AbbVie M13-813 (INTELLANCE-1, NCT02573324) was a phase 3 academic-industry collaboration (RTOG-Foundation, AbbVie). Eligible adults (KPS ≥ 70, EGFR-amp nGBM, centrally confirmed histology and biomarkers) were randomized 1:1 to radiotherapy (RT) and temozolomide and either depatux-m (2.0 mg/kg during RT, 1.25 mg/kg thereafter, q 14 days) or placebo, stratified by region of world, RPA class, MGMT methylation, and EGFRvIII mutation. Primary endpoint was overall survival (OS), with 640 patients planned for randomization; 441 events yielded 85% power to detect 25% reduction in hazard of death (HR 0.75), one-sided 2.5% level of significance by stratified weighted log-rank.

RESULTS
2229 patients were screened and 639 (median age 60, range 22–84; 394 men, 62%) randomized. Pre-specified interim analysis after 346 events (≥ 75% required) found no OS improvement for depatux-m over placebo (median 18.9 vs. 18.7 months, HR 1.01, 95% CI 0.82–1.25, one-sided p= 0.63). Progression-free survival (PFS) trended toward depatux-m (median 8.0 vs. 6.3 months; HR 0.84, 95% CI 0.70–1.02), particularly among the ~50% with EGFRvIII mutation (median 8.3 vs. 5.9 months, HR 0.72, 95% CI 0.56–0.93) but without an OS improvement (median 19.8 vs. 18.2, HR=0.95, 95% CI 0.71–1.27). Ocular side effects (grade ≥ 1) occurred in 95% of depatux-m treated patients, 61% grade 3–4, causing 12% to discontinue, and were the most common treatment related adverse events.

CONCLUSION
Interim analysis demonstrated no OS benefit for treating EGFR-amp nGBM with depatux-m. PFS trended toward favoring depatux-m, particularly in the EGFRvIII harboring subgroup. No new important safety risks were identified. The trial was stopped for futility. Active patients are permitted to continue treatment.
ACTR-22. INITIAL TREATMENT OF GBM WITH A KETOGENIC DIET ALONG WITH RADIATION AND CHEMOTHERAPY: CLINICAL OUTCOMES
Authors: Schwartz Kenneth , Noel Mary , Nikolae Michele , Olson Karl , Zakem Micheal , Elnabtity Mohamed , Clark Justin , Figueroa Bryan , Chang Howard 
Published: November 2019

Abstract

INTRODUCTION
Combining an adjuvant ketogenic diet (KD) with standard therapy of radiation and chemotherapy right after tissue diagnosis is feasible and safe. We report outcomes of a pilot clinical trial study using a KD combined with radiation and chemotherapy as initial therapy for glioblastoma (GBM).

METHODS
Eligibility criteria included: 1. Tissue diagnosis; 2. Age over 18; 3. ECOG performance status of 2 or better; and 4. Not having diabetes or being pregnant. An isocaloric KD diet with 3:1 weight ratio of fat to combined weight of carbohydrate and protein was supervised by an experienced dietitian and maintained with initial radiation and chemotherapy for 6 weeks.

RESULTS
9 patients (8M, 1F, mean age 45) completed the prescribed 6 week trial. Blood counts, chemistries, lipid profiles and uric acids were not markedly changed. Ketosis was maintained for the 6 week study period with blood ketone and glucose levels checked twice daily. 3 younger patients (mean age 28 at diagnosis) are working and show no progression of their gliomas at 49 (IDH +), 31 (IDH WT with methylated MGMT), and 32 (IDH WT) months since diagnosis. 6 older male patients (mean age 54) have died at 25, 25, 13, 12, 9 and 9 months after diagnosis. A recent report of 6 additional older male pts mean age 53 tx with a KD with daily checks of blood ketones showed limited survival ranging from 12–19 mo. (van der Louw accepted for pub in “Therapeutic Advances in Medical Oncology”).

CONCLUSION
KD may be a helpful in initial treatment of GBM patients, especially in younger patients. Additional studies are needed. However, since 12 older male patients have not substantially benefited from the KD, we suggest that future evaluations of the efficacy of KD for GBM be focused towards younger patients.
ACTR-23. MAINTENANCE TREATMENT WITH IBRUTINIB FOLLOWING FIRST LINE METHOTREXATE-BASED IMMUNO-CHEMOTHERAPY IN ELDERLY PATIENTS WITH PRIMARY CNS LYMPHOMA (PCNSL). A PHASE 2 OPEN-LABEL STUDY
Authors: Bairey Osnat , Benouaich-amiel Alexandra , Yust-Katz Shlomit , Gurion Ronit , Siegal Tali 
Published: November 2019

Abstract

BACKGROUND
Patients older than 60 years account for up to 70% of all PCNSL cases. Elderly PCNSL patients have median overall survival (OS) under 2 years and progression free survival (PFS) ranging between 6–16 months. Older patients have multiple comorbidities associated with low tolerability to high-dose (HD) chemotherapy. As maintenance treatment prolongs PFS and\or OS in several hematological malignancies we sought to investigate whether Ibrutinib maintenance may benefit elderly PCNSL patients. Ibrutinib was selected for maintenance since it has an impressive tolerability and activity in a range of systemic B-cell lymphomas.

METHODS
Single arm, open label, non-randomized study aiming to accrue 30 newly diagnosed PCNSL patients aged 60–85 years who received HD-methotrexate–based first line chemotherapy and have a documented response which is either partial (PR) or complete response (CR). The primary end-point is one and 2-year PFS and ibrutinib dose is 560mg/day. All patients undergo pre-maintenance neurocognitive evaluation which is repeated every 6 months.

RESULTS
Of the 16 patients screened for the study 2 were excluded due to relapse while on screening. 14 patients have been enrolled with a median age of 74 (61–80) years. The median interval between PCNSL diagnosis and start of ibrutinib maintenance is 7.6 (5.6–11.5) months. Currently, the median PFS is 22.5 (12–31.5) months. The adverse effects are largely grade 1/2 with rare grade 3/4 events. One patient discontinued treatment due to skin rash at 4.5 months. Two patients relapsed while on maintenance after 4 and 15 months of treatment. 3 patients with PR at enrolment improved to CR/CRu during maintenance. No invasive fungal infections have been observed.

CONCLUSIONS
Ibrutinib maintenance is feasible and well tolerated in newly diagnosed elderly PCNSL patients after first-line HD-MTX based treatment. The toxicity is mild to moderate. Enrollment is ongoing and updated outcomes will be presented at the meeting.
ACTR-37. ASSOCIATION BETWEEN MGMT PROMOTER METHYLATION SCORE AND SURVIVAL IN PATIENTS WITH GLIOBLASTOMA
Authors: Romo Carlos , Shah Pavan , Sun Yuqing , Ye Xiaobu , Grossman Stuart 
Published: November 2019

Abstract

BACKGROUND
MGMT promoter methylation is associated with longer survival in patients with high-grade gliomas who receive alkylating therapy. Methylation status is commonly determined by methylation-specific PCR and results are reported in two forms: a dichotomization of “present” or “not present,” and as a methylation score (MGMT/beta-actinx1000). The primary objective of this study is to determine the association between the degree of methylation and overall survival (OS) in newly diagnosed patients with glioblastoma.

METHODS
A retrospective IRB-approved study was conducted of 684 patients treated at Johns Hopkins from 2007–2015. Adults with a histologically confirmed glioblastoma treated with standard therapy were included in the analysis. OS was estimated from the date of diagnosis to time of death or last follow up using the Kaplan–Meier method. Cox regression model was used to assess possible positive association between MGMT score and OS. For purposes of this analysis IDH1-mutated patients were excluded.

RESULTS
In 100 evaluable patients, median age at diagnosis was 56 years [45–77]. Fifty-two patients were MGMT promoter methylated (score ≥2.00) and 48 were unmethylated. The median OS was 31 months in the methylated patients and 15 months in the unmethylated (p=0.0001). Methylated patients had MGMT scores ranging from 2.53-1278. The methylated scores were classified into 3 groups; #1: 0-25th percentile, #2: 25-75th percentiles, and #3: >75th percentile. mOS was: 30.8 months for group 1 (n=13); 34.8 months for group 2 (n=27); and 20.9 months for group 3 (n=12) (p=0.19). Difference in mOS between groups 1 and 3 was not statistically significant (HR 0.819 [95% CI, 0.3–2.2], p=0.69).

DISCUSSION
The prognostic value of MGMT promoter methylation in patients with glioblastoma was replicated in our study sample. The degree of methylation reported as a score on routine testing does not appear to be directly related to OS in this patient population.
ACTR-39. PAMIPARIB IN COMBINATION WITH RADIATION THERAPY (RT) AND/OR TEMOZOLOMIDE (TMZ) IN PATIENTS WITH NEWLY DIAGNOSED OR RECURRENT/REFRACTORY (R/R) GLIOBLASTOMA (GBM); PHASE 1B/2 STUDY UPDATE
Authors: Piotrowski Anna , Puduvalli Vinay , Wen Patrick , Campian Jian , Colman Howard , Pearlman Michael , Butowski Nicholas , Battiste James , Glass Jon , Cloughesy Timothy , Schiff David , van den Bent Martin , Walbert Tobias , Ahluwalia Manmeet , Badruddoja Michael , Kalra Amandeep , Aregawi Dawit , Weller Michael , Ramakrishnan Vanitha , Zhang Kathy , Wood Katie , Mellinghoff Ingo , Shih Kent 
Published: November 2019

Abstract
Pamiparib, an investigational, selective PARP1/2 inhibitor that has demonstrated potent PARP trapping and ability to cross the blood-brain barrier, showed synergistic cytotoxicity with TMZ preclinically. We report updated safety and antitumor effects from a phase 1b/2 study of pamiparib + RT and/or TMZ in patients with newly diagnosed or R/R GBM (SNO 2018, ACTR-30). The dose-escalation/expansion study has 3 arms: Arm A, pamiparib (2, 4, or 6 weeks) + RT in newly diagnosed GBM patients with unmethylated MGMT promoter (unmethylated-GBM); Arm B, pamiparib (6 weeks) + RT and increasing TMZ dosed in weeks 1 and 5 of RT in newly diagnosed, unmethylated-GBM patients; and Arm C, pamiparib + increasing TMZ doses in methylated/unmethylated R/R-GBM patients. Arm A and B patients receive maintenance treatment post-RT rest period at the Arm C expansion dose/schedule. As of 10 April 2019, accrual was completed for Arms A and C dose-escalation (A: n=20; C: n=17) and continues in the dose expansion (A: n=28/40; C: n=28/30); accrual was completed in dose escalation for B (n=9). Recommended phase 2 doses were established for Arms A (pamiparib 60 mg BID×6 weeks + 6–7 weeks RT) and C (pamiparib 60 mg BID d1–28 + TMZ 60 mg d1–7/28-d cycle). One dose-limiting toxicity (grade 3 febrile neutropenia) was reported in Arm B. Treatment-related adverse events (≥10%) were (overall/grade 3 [no grade 4/5]): Arm A, nausea (23%/2%); B, decreased WBC count (11%/11%); C (none). Of patients with tumor assessment post-RT: Arm A (n=17), 1 had cPR, 1 uPR, and 9 SD (disease control rate, 64.7% [95% CI, 38.3–85.8]); C (n=26), 1 had cPR (sustained 12 cycles), 1 uPR, and 5 SD (objective response rate, 7.7% [95% CI, 0.9–25.1]). Pamiparib 60 mg BID + RT/TMZ was generally well tolerated in patients with newly diagnosed or R/R GBM. Clinical trial ID: NCT03150862
ACTR-48. CLINICAL DEVELOPMENT TARGETING AXL IN RECURRENT GLIOBLASTOMA
Authors: Nakano Ichiro 
Published: November 2019

Abstract
Glioblastoma (GBM) is a lethal disease without effective therapies. Previously we reported that the TAM receptor tyrosine kinase family member AXL is upregulated in mesenchymal GBM and its knockdown induces apoptosis of mesenchymal but not proneural glioma sphere cultures (GSCs). In this study, we report that BGB324, a novel small molecule inhibitor for AXL, prolongs the survival of immunocompromised mice bearing mesenchymal GSC-derived GBM-like intracranial tumors by inhibition of AXL activation in tumor cells. Mechanistically, we identified that protein S (PROS1), known as a ligand for other TAM receptors, is secreted by tumor-associated macrophages, thereby physically associates and activates AXL in mesenchymal GSCs. The PROS1-driven phosphorylation of AXL resulted in the NF-kB activation in mesenchymal GSCs and this activation was eliminated by BGB324 treatment. In addition, BGB324 downregulated the immune checkpoint protein PD-L1 both in vitro and in vivo. Combination of BGB324 with Nivolumab - the neutralizing antibody for PD-1 (a receptor for PD-L1) was effective to prolong the survival of immunocompetent mice bearing syngeneic GBM models. Clinically, both AXL and PROS1 expression indicated poorer prognosis of GBM patients. These data suggest that the PROS1/AXL pathway regulates intrinsic mesenchymal signaling as well as extrinsic immune microenvironment, contributing to the growth of aggressive GBM tumors. To translate the pre-clinical data to human GBM patients, we designed a surgical PK/PD clinical trial with BGB324 for recurrent GBM. As of May 2019, this trial, termed ABTC1701, is in pending approval by the Brain Malignancy Steering Committee in the National Cancer Institute.
ACTR-56. PHASE II TRIAL OF NILOTINIB IN PDGFR-ALPHA ENRICHED RECURRENT GLIOBLASTOMA
Authors: Picconi David , Juarez Tiffany , Kesari Santosh 
Published: November 2019

Abstract

BACKGROUND
This phase II study was designed to determine the efficacy of nilotinib in a biomarker-selected population of recurrent glioblastoma (GBM), enriched for platelet-derived growth factor receptor-alpha (PDGFR-alpha) activation. Nilotinib is a multi-kinase inhibitor approved as treatment for Philadelphia-chromosome/Bcr-Abl chronic myelogenous leukemia. In addition to targeting Bcr-Abl tyrosine kinase, it also inhibits PDGFR-alpha signaling.

METHODS
Patients with recurrent GBM, with either PDGFR-alpha amplification or PDGFR-alpha overexpression by immunohistochemistry (IHC) were enrolled in a single-arm, single institution phase II study. Nilotinib was administered at 400 mg twice a day. The primary end point was progression-free survival at 6 months (PFS6). Secondary end points were safety, overall survival (OS) and Objective Response Rate (ORR).

RESULTS
34 patients were treated (22 IDH-wild type GBM, 2 IDH-mutant GBM, 10 GBM NOS). 26 were male and 8 were female. Median age was 55.5 (range 22–78 years). Four patients had PDGFR-alpha amplification, and 30 had overexpression by IHC. Median lines of prior therapy were 1 (range 1–7). 6/34 patients (18%) experienced related adverse events grade ≥ 3. There were no grade 5 events. The PFS6 was 9% (3/34), and PFS12 was 6% (2/34). Median PFS was 1.3 months and the median OS was 6.6 months. Best response was stable disease (SD) for 8 patients and complete response (CR) for one patient. ORR was 1/34 patients (3%). The patient with a CR was IDH-wild type, unmethylated, had PDGFR-alpha overexpression by IHC, and had a durable response > 5 years.

CONCLUSION
Nilotinib had limited activity in recurrent GBM enriched for PDGFR-alpha, although there were a small number of durable responders. Further molecular characterization is warranted to determine additional biomarkers of response that could be used to select patients that may benefit from nilotinib.
SURG-02. STAGED SURGERY FOR SELECTED GIANT ADULT PITUITARY ADENOMA
Authors: Ma Jun , Ma Shunchang , Jia Guijun , Yao Fei , Jia Wang 
Published: November 2019

Abstract

PURPOSE
Combined surgical strategy with both trans-cranial surgery and trans-sphenoid surgery is necessary for selected giant pituitary adenoma with both intra-cranial and intra-sphenoidal invasion. Cases of staged surgery were reviewed retrospectively to deeply investigate this treatment strategy.

METHODS
Adult cases received staged surgery were reviewed. Data regarding clinical presentation, laboratory tests, image examination, surgery details, and outcome were analyzed. The size and invasion was evaluated by pre-op MR and intra-op observation. Diagnosis was confirmed by histology examination. Literatures were reviewed.

RESULTS
8 NFPAs were included. 4 received trans-cranial resection first while the other 4 received trans-sphenoidal resection first. Time interval between two operations was 1–2 months. After the first surgery, the rate of visual defects and of pituitary hypofunction improvement were higher in trans-cranial first group. 1 apoplexy and 1 CSF rhinorrhea were observed in trans-sphenoidal first group. After the second surgery, the extend of resection and the rate of complete visual symptoms improvement were higher in trans-cranial first group. All pituitary hypofunction resolved completely in long-term follow-up. 11 literatures were reviewed.

CONCLUSIONS
An appropriate surgical strategy is essential for selective pituitary adenoma requiring combined resection. For staged surgery cases, taking trans-cranial approach for first stage with trans-sphenoidal subsequently, comparing to the inverse resection order, would offer higher extent of resection with less recurrence, earlier and better symptom improvement, and less post-op complications after first stage. Further investigation is necessary.
SURG-07. STEREOTACTIC LASER ABLATION AS A THERAPEUTIC OPTION FOR RECURRENT GLIOBLASTOMA: A LARGE SINGLE INSTITUTIONAL EXPERIENCE
Authors: Hwang Lee , Barnett Gene , Mohammadi Alireza 
Published: November 2019

Abstract

INTRODUCTION
The prognosis of patients diagnosed with recurrent glioblastoma remains dismal, and therapeutic options are limited. The median survival is only 3 to 5 months. Stereotactic laser ablation is a minimally invasive neurosurgical technique used as an ablative treatment. We report outcomes of a large single institutional patient database of recurrent glioblastoma treated with laser ablation.

METHODS
Patients with recurrent glioblastoma, previously treated with biopsy or surgical resection plus standard radiation/temozolomide (and any other additional therapies), who underwent laser ablation with the NeuroBlate system at The Cleveland Clinic were retrospectively reviewed from 2011 through 2017. Primary endpoints were progression free survival (PFS) and overall survival (OS).

RESULTS
Between 2011 and 2017, 31 patients with recurrent glioblastoma were treated with laser ablation out of more than 250 laser ablation cases for brain tumors. This population included 17 males and 14 females. Age at the time of diagnosis ranged from 27 to 77. 84% underwent surgical resection as the initial treatment. 65% were treated with laser ablation after the first recurrence of previously treated glioblastoma. The average number of postoperative hospital days was 2.8, and most patients went home. 54% remained neurologically stable without new postoperative deficits, and 52% had no reported change in Karnofsky Performance Scale from before to after laser ablation. Median PFS was 5 months, and median OS was 13 months.

CONCLUSIONS
Laser ablation has been used to treat various intracranial lesions at The Cleveland Clinic, particularly recurrent glioblastoma. This treatment modality can be utilized at any point of recurrence in patients with appropriate clinical and radiographic characteristics. In addition, the minimally invasive nature and relatively short hospital stay in comparison to surgical tumor resection make laser ablation favorable. Laser ablation is becoming a valuable tool in a multidisciplinary approach to treat recurrent glioblastoma.