bluuebunny/crossref_metadata_2025_split huggingface dataset:
CTNI-33. CSNO2012001 STUDY: A PHASE III TRIAL ON ADJUVANT TEMOZOLOMIDE CHEMOTHERAPY WITH OR WITHOUT INTERFERON-ALPHA IN NEWLY DIAGNOSED HIGH-GRADE GLIOMAS
Authors: Chen ZhongPing , Guo Chengcheng , Chen JianGen 
Published: November 2022

Abstract
Purpose The therapeutic efficacy and toxicity of the combination of temozolomide (TMZ) with interferon-alpha (IFN-α) and TMZ alone were compared in newly diagnosed high-grade glioma (HGG) patients.Patients and Methods Following surgery, patients with newly diagnosed HGG (World Health Organization [WHO] grade 3 or 4)were eligible and randomized into two groups. All the patients were received standard radiotherapy concurrent with TMZ. After a 4-week break,patients in group A received standard TMZ (200mg/m2 for 5 days) combined with interferon-α (3mIU, subcutaneous, d1, d3, and d5) every 28 days. Patients in group B were received standard TMZ.Results A total of 199 HGG patients were enrolled, with a median follow-up time of 77.9 months. The median overall survival (OS) of patients in the TMZ+IFN group was significantly longer than that in the standard group, although the progression-free survival (PFS) of both groups was similar . In grade 3 gliomas, the median OS was 39.57 months in the TMZ+IFN group versus 29.40 months in TMZ alone. The median PFS was also longer in the TMZ+IFN group (24.33 months) than that in the TMZ group (14.13 months) . In grade 4 gliomas, the difference in PFS survival between TMZ+IFN and TMZ group showed no significant difference . However, the TMZ+IFN group had a longer OS than that of the TMZ alone group. TMZ+IFN also significantly improved the OS in O6-methylguanine-DNA methyltransferase (MGMT) unmethylation patients. The incidence of toxic effects such as neutropenia, thrombocytopenia, anemia, increased transaminase, skin reactions, fatigue, nausea, or vomiting, and skin reactions were similar in both groups. However, seizure and influenza-like symptoms were more common in the combination group but can be easily controllable.Conclusions Compared with the standard regimen, TMZ+IFN combination treatment could prolong the survival time of HGG patients, especially MGMT promoter unmethylated patients, and the toxicity remained tolerable.
CTNI-34. PRECISION NEURO-ONCOLOGY - A PILOT ANALYSIS OF PERSONALIZED TREATMENT IN RECURRENT GLIOMA
Authors: Lazaridis Lazaros , Schmidt Teresa , Oster Christoph , Blau Tobias , Pierscianek Daniela , Siveke Jens , Bauer Sebastian , Schildhaus Hans-Ulrich , Sure Ulrich , Keyvani Kathy , Kleinschnitz Christoph , Stuschke Martin , Herrmann Ken , Deuschl Cornelius , Scheffler Björn , Kebir Sied , Glas Martin 
Published: November 2022

Abstract

PURPOSE
When brain cancer relapses, treatment options are scarce. The use of molecularly matched targeted therapies may provide a feasible and efficacious way to treat individual patients based on the molecular tumor profile. Since little information is available on this strategy in neuro-oncology, we retrospectively analyzed the clinical course of 41 patients who underwent advanced molecular testing at disease relapse.

METHODS
We performed Sanger sequencing, targeted next generation sequencing, and immunohistochemistry for analysis of potential targets, including programmed death ligand 1, cyclin D1, phosphorylated mechanistic Target of Rapamycin, telomerase reverse transcriptase promoter mutation, cyclin-dependent kinase inhibitor 2A/B deletion, or BRAF-V600E mutation. In selected patients, whole exome sequencing was conducted.

RESULTS
The investigation included 41 patients of which 32 had isocitrate dehydrogenase (IDH) wildtype glioblastoma. Molecular analysis revealed actionable targets in 31 of 41 tested patients and 18 patients were treated accordingly (matched therapy group). Twenty-three patients received molecularly unmatched empiric treatment (unmatched therapy group). In both groups, 16 patients were diagnosed with recurrent IDH wildtype glioblastoma. The number of severe adverse events was comparable between the therapy groups. Regarding the IDH wildtype glioblastoma patients, median progression-free survival (mPFS) and median overall survival (mOS) were longer in the matched therapy group (mPFS: 3.8 versus 2.0 months, p = 0.0057; mOS: 13.0 versus 4.3 months, p = 0.0357).

CONCLUSIONS
These encouraging data provide a rationale for molecularly matched targeted therapy in glioma patients. For further validation, future study designs need to additionally consider prevalence and persistence of actionable molecular alterations in patient tissue.
CTNI-38. UPDATE ON GBM AGILE: A GLOBAL, PHASE 2/3 ADAPTIVE PLATFORM TRIAL TO EVALUATE MULTIPLE REGIMENS IN NEWLY DIAGNOSED AND RECURRENT GLIOBLASTOMA
Authors: Buxton Meredith , Alexander Brian , Berry Donald , Cavenee Webster , Colman Howard , de Groot John , Ellingson Benjamin , Gordon Gary , Khasraw Mustafa , Lassman Andrew , Lee Eudocia , Li Wenbin , Lim Michael , Mellinghoff Ingo , Mikkelsen Tom , Nelli Apoorva , Perry James , Sulman Erik , Tanner Kirk , Weller Michael , Wen Patrick Y , Alfred Yung W K , Cloughesy Timothy 
Published: November 2022

Abstract

BACKGROUND
GBM AGILE (Glioblastoma Adaptive, Global, Innovative Learning Environment) is a biomarker based, multi-arm, international, seamless Phase 2/3 response adaptive randomization platform trial designed to rapidly identify experimental therapies that improve overall survival and confirm efficacious experimental therapies and associated biomarker signatures to support new drug approvals and registration. GBM AGILE is a collaboration between academic investigators, patient organizations and industry to support new drug applications for newly diagnosed and recurrent GBM.

METHODS
The primary objective of GBM AGILE is to identify therapies that effectively improve the overall survival in patients with ND or recurrent GBM. Bayesian response adaptive randomization is used within subtypes of the disease to assign participants to investigational arms based on their performance. Operating under a Master Protocol, GBM AGILE allows multiple drugs from different pharmaceutical/biotech companies to be evaluated simultaneously and/or over time against a common control. New experimental therapies are added as information about promising new drugs is identified while therapies are removed as they complete their evaluation. The master protocol/ trial infrastructure includes efficiencies through an adaptive trial design, shared control arm and operational processes to serve the goal of helping patients receive optimal care in a fast and efficient manner. GBM AGILE has screened over 1200 patients and enrollment rates are 3 to 4 times greater than traditional GBM trials, with active sites averaging 0.75 to 1 patients/sites/month. There are 41 active sites in the US, 4 active sites in Canada and 3 active sites in Europe with more sites anticipated to open across 5 countries in Europe. Expansion to China and Australia are under progress. Through the use of improved and flexible processes, GBM AGILE serves as a global trial that supports the efficient and rapid incorporation and evaluation of new experimental therapies for patients with GBM.Clinical trial information: NCT03970447.
CTNI-41. TRANSITION OF LONG-TERM TREATMENT RESULTS OF 493 CASES OF NEWLY DIAGNOSED GLIOBLASTOMA AND SURVIVAL BENEFIT BY COMBINATION WITH PDT AND AFTV - AIMING TO ESTABLISH NEW STANDARD TREATMENT
Authors: Nitta Masayuki , Muragaki Yoshihiro , Saito Taiichi , Tsuzuki Shunsuke , Koriyama Shunichi , Kuwano Atsushi , Ikuta Soko , Kawamata Takakazu 
Published: November 2022

Abstract

INTRODUCTION
Glioblastoma has the worst prognosis of brain tumors. Evidence for improving prognosis by maximal tumor removal is being established, and in recent years, new treatments such as photodynamic therapy (PDT, 2014 in Japan), and TTF therapy (2018) have been approved, the treatment results are improving. In principle, our facility performs maximum tumor removal using intraoperative MRI (iMRI) follow by the standard chemoradiation. Intraoperative PDT and autologous tumor vaccine (AFTV) will be given to desired patients. We retrospectively analyzed the long-term clinical results of the patients with newly diagnosed glioblastoma who underwent surgical treatment at our facility, and the treatment results by era and treatment method.

METHODS
The clinical features, extent of removal (EOR), OS and PFS of the adult patients with newly diagnosed glioblastoma treated from 2001 to 2021 were analyzed retrospectively. Clinical results of those patients who received PDT and AFTV treatment was also investigated.

RESULTS
The number of cases was 493, median age 58 years (18-85 years), 293 males, 200 females. The median and average EOR of contrast-enhanced lesions were 98% and 96.6%, respectively. The median PFS and OS of all cases (including biopsy) were 9.4 months and 22.7 months, respectively. When the cases were analyzed separately for 2001-2006 (before TMZ), 2007-2010, 2011-2015, and 2016-2021, the median OS for each age group was 12.9 months, 22.9 months, 23 months, and 31.1 months. The treatment results improved with age ( p &lt; 0.0001). In particular, the median OS of 23 cases treated with PDT and AFTV was 63.1 months. The efficacy of AFTV for newly diagnosed glioblastoma is currently being verified in a multicenter Investigator-led clinical trial.

CONCLUSION
The treatment results for glioblastoma have improved over the years. The combination of maximal tumor removal using iMRI, PDT and AFTV may aim for a 5-year survival rate of 50%.
CTNI-42. GENOME-WIDE DNA METHYLATION PATTERNS IN VERTU: A RANDOMIZED PHASE II TRIAL OF VELIPARIB, RADIOTHERAPY AND TEMOZOLOMIDE IN PATIENTS WITH MGMT-UNMETHYLATED GLIOBLASTOMA
Authors: Sim Hao-Wen , Lwin Zarnie , Barnes Elizabeth , McDonald Kerrie , Koh Eng-Siew , Rosenthal Mark , Foote Matthew , Back Michael , Wheeler Helen , Buckland Michael , Walsh Kyle , Fisher Lauren , Leonard Robyn , Hall Merryn , Ashley David , Yip Sonia , Simes John , Sulman Erik , Khasraw Mustafa 
Published: November 2022

Abstract

BACKGROUND
VERTU was a randomized phase II trial evaluating veliparib, a brain-penetrant PARP inhibitor, combined with radiotherapy and temozolomide, for patients with newly diagnosed MGMT-unmethylated glioblastoma. As part of planned correlative work after study completion, we assessed genome-wide DNA methylation patterns to predict methylation class, glioblastoma subtype and MGMT status.

METHODS
Patients were randomized 2:1 to experimental (60Gy/30 fractions with veliparib 200mg bid, then temozolomide 150-200mg/m2 D1-5 + veliparib 40mg bid D1-7 Q28D for 6 cycles) versus standard arm (60Gy/30 fractions with temozolomide 75mg/m2 daily, then temozolomide 150-200mg/m2 D1-5 Q28D for 6 cycles). The primary objective to improve 6-month progression-free survival (PFS-6m) was not met (doi: 10.1093/neuonc/noab111). Methylation data were generated using the Illumina Infinium Methylation EPIC bead chip array. Tumor tissues were categorized using the Heidelberg methylation-based classifier.

RESULTS
Methylation data were successfully generated for 98/125 patients (poor quality DNA [n = 12], no consent [n = 11], insufficient tissue [n = 4]). Those with classifier scores below 0.5 (n = 25), tumor microenvironment only (n = 6) and rediagnosis as pleomorphic xanthoastrocytoma (n = 1) were excluded, leaving n = 66. Methylation classes were GBM RTK II (n = 23, PFS-6m 43% [95%CI 23-62]), RTK I (n = 20, PFS-6m 50% [95%CI 27-69]), MES (n = 20, PFS-6m 40% [95%CI 19-60]), MID (n = 2) and G34 (n = 1). Glioblastoma subtypes were mesenchymal (n = 28, PFS-6m 50% [95%CI 30-66]), proneural (n = 24, PFS-6m 50% [95%CI 29-68]) and classical (n = 14, PFS-6m 36% [95%CI 13-59]). MGMT status were unmethylated (n = 58, PFS-6m 48% [95%CI 35-60]) and methylated (n = 8, PFS-6m 38% [95%CI 9-67]). There was no evidence of interaction between treatment arm and methylation class (excluding GBM MID and G34, P = 0.45), glioblastoma subtype (P = 0.68) or MGMT status (P = 0.52).

CONCLUSIONS
Genome-wide DNA methylation patterns in VERTU identified a spectrum of methylation-defined subgroups, reflecting tumoral heterogeneity. This may have utility for future clinical trials and practice. The effect of veliparib in VERTU appeared to be consistent across subgroups. ACTRN12615000407594.
CTNI-59. MATRIX REGIMEN FOR NEWLY DIAGNOSED PRIMARY CNS DIFFUSE B-CELL LYMPHOMA
Authors: Green Richard , Thornton Colleen , Guzman Ruben 
Published: November 2022

Abstract
We report our experience treating 22 patients with newly diagnosed primary CNS diffuse B-cell lymphoma with the MATRix regimen as reported by Ferreri, et al in 2016. The median age was 64 y (range 45-85); 10 patients were men and 12 were women. Twenty had cerebral mass lesions, 1 had a paraspinal mass, and 1 leptomeningeal disease. Treatment consisted of 4 cycles of rituximab 375 mg/sq m (Days 1, 6); methotrexate 3.5 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. Four patients were switched to MATRix after 6 cycles of methotrexate and rituximab and received only 2 initial cycles including cytarabine and thiotepa. Overall, 16 patients completed initial chemotherapy. Fourteen of these 16 went on to transplantation; one patient had had early disease progression, and in one no stem cells could be collected. Five patients (median 73 y; range 64-85 y) died early after 1-2 cycles. The causes of early death were neutropenic fever, septic thrombophlebitis, and cardiac arrest. One patient who completed the entire regimen including transplantation died of fungal pneumonia and the other 13 experienced no serious acute toxicity. One patient had late disease progression and one developed symptomatic leukoencephalopathy. Fourteen of the 22 patients remain alive. Median OS for the cohort is 663 days. These preliminary data suggest that the MATRix regimen in safe and highly effective in the newly diagnosed setting. However, the high incidence of early death in patients over 65 y suggests that the regimen may be too toxic for older individuals.
CTNI-63. A STUDY OF NIRAPARIB COMBINED WITH RADIOTHERAPY IN PATIENTS WITH RECURRENT GLIOBLASTOMA
Authors: Jiang Wei , Wang Zheng 
Published: November 2022

Abstract

BACKGROUND
There is no standard therapy for recurrent glioblastoma (rGBM), which has a poor survival, from 3 to 10 months. Radiotherapy is an available option for patients with rGBM, and it could invoke DNA damage, thus leading to tumor cell death. Niraparib is a poly(ADP-ribose) polymerase inhibitor. Preclinical data showed that Niraparib enhances the radiosensitivity of glioblastoma cells. Thus we hypothesize that radiotherapy synergizes with Niraparib to improve the clinical efficacy of anti-tumor.Method:We conducted a phase 2 study combining Niraparib, radiotherapy, and maintenance Niraparib in 30 patients with rGBM. Niraparib(300mg QD) was started at cycle 1 of radiotherapy (55Gy total) and continued until progression or unacceptable toxicity The primary endpoint was 6 month PFS. Secondary endpoints included toxicity, QoL, and OS Result：As of 4/31/2022, 14 patients with a median age of 47 years old (range 26-69) were enrolled. 64.29% were female. Eight patients（57.1%）had experienced ≥ 2 previous therapy（range 1-4）. The MGMT methylation status was available for 12 patients, and 9（64.3%）had unmethylated MGMT. The median follow-up was 167 days (95%CI 124-263). PFS 6 was 36% (95%CI 12.17%-60.92%), OS 6 was 82.61%(95%CI 46.51%-95.34%). The mPFS was 157 days (95%CI 93-188), the mOS was not reached (95%CI 188-NA), three patients had an OS of more than 10 months by the data submitted. The ORR was 35.7%, one patient achieved CR,four achieved PR. Niraparib combined radiotherapy showed efficacy in controlling local lesions. At 1 and 3 months, local control rate was 85.7% and 64.3% ,respectively. The most common serious adverse event was thrombocytopenia（28.57%）which could be controlled by adjusting the dosage of Niraparib.

CONCLUSION
Niraparib combined radiotherapy is well tolerated and shows efficacy in rGBM patients. Survival data will be updated.Clinical registration number: NCT04715620
DNAR-05. A ROLE FOR TAZ/YAP IN DNA DAMAGE REPAIR IN GLIOBLASTOMA
Authors: Bhat Krishna , Bhat Krishna , Tang Tiffany 
Published: November 2022

Abstract
Previous studies have shown that glioma stem-like cells (GSCs) evade conventional cytotoxic therapies and repopulate as recurrent tumors. A fuller understanding of the molecular mechanisms underlying the biology and therapy resistance of GSCs is required. Our group has shown that TAZ, a transcriptional co-factor is highly expressed in about 70% of glioblastomas (GBMs). TAZ and its paralog YAP are oncogenic drivers of brain tumor progression. GSCs overexpressing TAZ undergo a proneural (PN) to mesenchymal (MS) subtype transition, which is accompanied by aggressive phenotypes such as increased grade and treatment resistance in GSC xenografts. Although the oncogenic functions of TAZ/YAP are well established, the exact molecular mechanisms underlying TAZ/YAP mediated cell fate transition and therapy resistance in GBM are not fully understood. Here, we present novel functional interaction between TAZ/YAP and DNA-dependent protein kinase (DNA-PK) in response to exposure to ionizing radiation in GSCs. Mass-spectrometric analyses of TAZ-binding proteins showed that DNA-PK complex composed of the catalytic subunit (DNA-PKcs) and a Ku heterodimer of Ku70 and K80 interacted with TAZ. Immunoprecipitation of DNA-PK showed interaction of both YAP as well. Interaction of YAP/TAZ with DNA-PK complex and TEAD was enhanced by ionizing radiation. DNA-PKcs phosphorylated both YAP and TAZ, and phosphorylation level of these proteins were increased after irradiation, consistent with an increased interaction of these proteins. Intriguingly, siRNA knockdown of YAP and TAZ resulted in inactivation of DNA-PKcs, although protein stability of DNA-PKcs was not affected. Pharmacological inhibition of TAZ/YAPTEAD resulted in increased DNA damage and suppressed cell proliferation, and this effect was synergized by irradiation. We conclude that TAZ and YAP are integral components of DNA damage response and that pharmacological targeting of TAZ/YAP/TEAD pathway can overcome radiation resistance in GSCs.
DNAR-10. THE EFFICACY OF TEMOZOLOMIDE AND LOMUSTINE IN GLIOBLASTOMA CELL LINES MAY BE ENHANCED BY CONCOMITANT TREATMENT WITH TUMOR TREATING FIELDS (TTFIELDS)
Authors: Fishman Hila , Monin Roni , Dor-On Eyal , Haber Adi , Giladi Moshe , Weinberg Uri , Palti Yoram 
Published: November 2022

Abstract
Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. Temozolomide (TMZ) is part of the standard of care for patients with newly diagnosed GBM (ndGBM). Expression of the enzyme MGMT involved in TMZ-induced DNA damage repair is associated with irresponsiveness of some patients to TMZ. The addition of lomustine (CCNU) to TMZ demonstrated clinical benefit in patients with ndGBM. Tumor Treating Fields (TTFields) are electric fields that display anti-mitotic effects and lower expression levels of proteins from the FA-BRCA DNA repair pathway in cancerous cells. TTFields therapy concomitant with TMZ is approved for the treatment of ndGBM. The aim of the current study was to examine the effect of TTFields in conjunction with TMZ and CCNU in GBM cells. Human GBM cell lines with different MGMT expression levels (U-87 MG, LN229, U118, and LN18) were treated with TTFields (0.83 V/cm RMS, 200 kHz) concomitant with TMZ and/or CCNU. Cell counts, colony formation, and apoptosis were used to measure effectiveness. The effect of TTFields with concomitant TMZ was additive in all cell lines, regardless of MGMT expression levels. TTFields in conjunction with CCNU displayed an additive effect in cell lines with high MGMT expression, and tendency to synergism in cell lines with low or no MGMT expression. TTFields concurrent with both TMZ and CCNU further increased treatment efficacy. Mechanistically, TTFields elevated the levels of DNA double strand breaks and lowered expression of FA-BRCA pathway proteins, as detected by fluorescence microscopy and western blot, respectively. The involvement of the FA-BRCA pathway in repair of DNA damage induced by CCNU and the BRCAness state induced by TTFields rationalize the synergy seen for TTFields with CCNU, especially in cells absent of MGMT. The results suggest a potential benefit of TTFields therapy concomitant with TMZ/CCNU for the treatment of GBM.
DDEL-02. LUMBAR OMMAYA RESERVOIR- A COST EFFECTIVE ALTERNATIVE TO INTRAVENTRICULAR OMMAYA RESERVOIR FOR TREATMENT OF LEPTOMENINGEAL DISEASE
Authors: Peo Ivo , Kumar Jay , Krafft Paul , Tran Nam 
Published: November 2022

Abstract

Introduction
Lumbar puncture (LP) is a well-established approach for intrathecal (IT) delivery of chemotherapeutics for leptomeningeal disease (LMD). Intraventricular Ommaya reservoir (OR) has supplanted LPs as an easier and safer route for IT administration. Radiotherapy for treatment of LMD must be delayed in order for surgical wound healing following OR placement. Furthermore, prior cranial radiation can thin the scalp, predisposing to wound breakdown. Placement of lumbar Ommaya reservoir (LOR) provides an alternative to IT delivery, but this has not reached a wide-spread acceptance. Objective Provide cost-analysis and report patient outcomes after placement of LOR.

METHODS
Following IRB approval, all patients undergoing LOR placement between 2018 and 2020 were retrospectively reviewed. Patients age, primary tumor, survival lengths and complications were reviewed. Average procedure-related treatment cost was obtained from an uncomplicated representative case excluding the surgeon’s fee.

RESULTS
Fourteen patients (mean age 46.35 years) were identified. The mean follow-up was 440.7 (25-1003) days post-surgery. Acute lymphoblastic leukemia (n = 4), acute myeloblastic leukemia (n = 3), breast carcinoma (n = 3), ependymoma (n = 3), lymphoma (n = 2) and lung adenocarcinoma (n = 1) were identified as underlying malignancy. LMD was diagnosed on average after 581.1 days after the diagnosis of the underlying malignancy. 8 patients succumbed to their malignancy on average after 463.9 and 314.6 days after the diagnosis of LMD and LOR surgery, respectively. There were 2 complications – pain at the site of the LOR and a fractured catheter caused by inadvertent puncture of the catheter. No infections or wound healing complications were noted. Typical cost for placement of LOR and OR was – 17,350 USD and 29,052 USD, respectively. Placement of the LOR proved to be more cost-effective in this cohort by approximately 40% cost reduction.

CONCLUSION
Placement of LOR is a cost effective alternative to cranial OR with low complication profile, and well tolerated by patients.