bluuebunny/crossref_metadata_2025_split huggingface dataset:
Use of neurovascular imaging in GBM patients (pts) to quantify early physiologic changes after treatment with XL184, an inhibitor of multiple receptor tyrosine kinases: Results from a phase II study
Authors: Sorensen A. G. , Jenning D. , Wang M. , Andronesi O. , Chen P. , Prados M. , Wen P. , Jackson E. , Cha S. , deGroot J. 
Published: August 2020

2048 Background: Treatment of recurrent glioblastoma by targeting VEGF has gained recent attention. Bevacizumab (bev) or cediranib block VEGFR signaling which is detectable within one day by MRI; early changes on MRI may correlate with clinical outcome. XL184 is a potent orally bioavailable inhibitor of MET, RET, KIT, and VEGFR2; MET and VEGFR2 have been shown to play important roles in tumor angiogenesis. In preclinical models, simultaneous inhibition of MET and VEGFR2 with XL184 results in profound regression of tumor vasculature which is qualitatively different from that observed with other antiangiogenic agents. Methods: A multicenter phase II study of XL184 in 46 pts with relapsed or progressive GBM with primary endpoints of 6-month progression free survival and safety is fully enrolled. Vascular neuroimaging including DCE-MRI, CBV/CBF, diffusion, and magnetic resonance spectroscopy (MRS) is performed in these GBM pts treated with XL184. Lesion volumes are also calculated. Assessments are at baseline, 24 hours post first dose, at 4 weeks and 8 weeks. Results: As of January 1, 2009, 38 pts have undergone imaging. In all 9 pts with imaging available at Day 28, decreases in tumor size were seen on post-Gd T1 (mean drop 51%, SD 31%, p = 0.03 by t-test) and FLAIR (mean drop 53%, SD 20%, p = 0.001) consistent with an anti-vascular/anti-edema effect. In 11 of 14 pts T1 volume decrease was visible on Day 1 (mean drop 20%, SD 12%, p = 0.01), consistent with the rapid changes seen with VEGF inhibition. Two of 3 pts with no Day 1 decrease in enhancing lesion volume were bev-pretreated. Pts treated with other VEGF inhibitors (vandetanib, VEGF-TRAP) responded similarly to naïve pts at Day 1 and 28. Assessment of Ktrans in 5 pts showed a 79% decrease (SD 13%, p = 0.04). MRS from 3 pts showed an increase of the NAA/Choline ratio (10–100%) between the baseline and Day 28 scans, and a decrease in lipid levels (50–100%), suggesting inhibition of tumor progression. Conclusions: Treatment with XL184 results in significant decreases in lesion volume and Ktrans at Day 1 and even greater decreases at Day 28, suggestive of biological activity in GBM. [Table: see text]
Correlative tumor molecular profiling and plasma biomarker analysis in a phase II study of XL184 in patients with progressive or recurrent glioblastoma multiforme (GBM)
Authors: DePrimo S. , Wu B. , Huang S. , Bautista R. , Cancilla B. , Vysotskaia V. , De Groot J. , Prados M. , Buller R. , Wen P. 
Published: August 2020

2049 Background: XL184 is an oral inhibitor of MET, RET, KIT, and VEGFR-2 with potent antitumor effects in preclinical models of GBM. Clinically, elevated levels of MET, KIT, VEGFR-2, and VEGF-A are found in GBM, where MET and KIT levels correlate with poor prognosis. XL184–201 is a fully enrolled GBM study (N = 46) which mandated collection of archival tumors and serial plasma samples. The encouraging clinical activity of XL184 in this study is the subject of a separate abstract. Methods: Tumor profiling focused on genomic alterations prevalent in GBM, reflecting dysregulation of key signaling pathways (Nature 2008; 455:1061), or XL184 targets. Plasma samples were analyzed with ELISA assays. Correlation of results with clinical outcomes is a secondary objective of study XL184–201. Results: Tumor genotyping assessments included EGFR and KIT copy number; PTEN, PIK3CA, PIK3R1, and NF1 sequencing, as well as MGMT and PTEN promoter methylation. Results from the first 12 cases indicate sequence variations & frequencies similar to reports in the literature. IHC analysis of MET, RET, and VEGFR-2 protein expression was also performed. In ∼ 80% of samples, tumor cells stained positive for MET with a lower fraction positive for RET and VEGFR-2 in tumor cells (42% and 58%, respectively). RET and VEGFR-2 expression was often seen in tumor-associated blood vessels, while MET signal in blood vessels was more limited (33%). Preliminary biomarker analysis established significant modulation of plasma levels of VEGF-A, sMET, sVEGFR-2, sKIT, and PlGF, consistent with multiple on target effects. Objective response was observed in the presence or absence of tumor EGFR amplification, PTEN mutation, and MGMT promoter methylation. The potential predictive value of these and other biomarkers is under investigation. Conclusions: Plasma biomarkers confirm pharmacodynamic activity of XL184 in advanced GBM where marked clinical activity has been observed. Upon completed analysis of a full set of biological samples and with mature clinical data, predictive markers for clinical activity of XL184 will be evaluated. [Table: see text]
Bevacizumab and irinotecan for recurrent oligodendroglial tumors
Authors: Taillibert S. , Vincent L. A. , Granger B. , Marie Y. , Carpentier C. , Guillevin R. , Bellanger A. , Psimaras D. , Sanson M. , Delattre J. 
Published: August 2020

2054 Background: Treatment with a regimen of bevacizumab/irinotecan has been shown to be effective in recurrent grade 3 and 4 gliomas, but the effect of this regimen against recurrent oligodendroglial tumors has not been specifically studied. Methods: The bevacizumab/irinotecan regimen was retrospectively evaluated in a consecutive series of 25 patients with recurrent oligodendroglial tumors. All patients had failed previous treatment with radiation therapy and at least one line of temozolomide chemotherapy. Bevacizumab (10 mg/kg) and irinotecan (125 or 340 mg/m2 according to the antiepileptic regimen) were delivered every 14 days. Response was measured clinically and on monthly MRI. Results: The objective response rate was 72% (20% complete response, 52% partial response). After a median follow-up (from the first cycle) of 310 days (95% CI, 47–499), the median progression-free survival was 174 days (95% CI, 116–342), and the median overall survival was 328 days (95%CI, 217-not reached). The 6-month progression-free survival was 42 % (95 % CI, 26% to 67%). Among the 20 patients who progressed at the time of the analysis, the radiological pattern of progression was atypical in seven patients with an isolated multifocal or diffuse spread of the FLAIR signal, or an isolated meningeal spread or FLAIR abnormalities preceding contrast-enhancement recurrence. Among the 10 patients who are still alive, two are still on follow-up since 6 months with a complete response after, respectively, 10 and 12 months of treatment. Among the 17 patients in whom the status of the main molecular alterations of gliomas could be evaluated (search for deletions of chromosomes 1p, 19q, 9p, 10q, and amplification of EGFR, MDM2, CDK4), no relation could be found between the response rate and the type of genetic change (including 1p-19q co-deletion). The profile of tolerance was fair, with treatment discontinuation in 20% of patients. Intratumoral hemorrhages occurred in six patients (24%), but the treatment had to be discontinued because of symptomatic bleeding in only one patient (4%). Conclusions: This regimen is effective in recurrent oligodendrogliomas, and the overall tolerance is acceptable. [Table: see text]
Phase II trial of temozolomide (TMZ) followed by myeloablative chemotherapy with autologous peripheral blood progenitor cell rescue (APBPCR) for newly diagnosed anaplastic oligodendroglioma: An Oligodendroglioma Study Group trial
Authors: Kaley T. J. , Raizer J. J. , Paleologos N. , Kewalramani T. , Grimm S. , Louis D. N. , Cairncross J. G. , Abrey L. E. 
Published: August 2020

2055 Background: Treatment of anaplastic oligodendroglioma (AO) and anaplastic oligoastrocytomas (AOA) is controversial. Radiotherapy (RT) remains the standard therapy, but not without toxicity. Exploiting the chemosensitivity of these tumors using myeloablative chemotherapy with APBPCR is a potential strategy to defer RT. We previously reported results using induction PCV chemotherapy; subsequently the induction regimen was changed to temozolomide (TMZ) which is reported here. Methods: Patients were treated with six cycles of TMZ at 200mg/m2 on standard 5/28 day schedule. MRI was performed after three cycles and then after six cycles. Patients with surgical gross total resection who maintained response or patients who responded to temozolomide (CR or PR defined as >50% reduction in tumor) were eligible for myeloablative chemotherapy with thiotepa 250mg/m2/day for three days followed by busulfan 3.2mg/kg/day for three days, followed by APBPCR. 1p19q status was analyzed prospectively; however, patients were enrolled without regard to deletion status. Results: 19 patients (16 AO, 2 AOA, 1 low-grade oligodendroglioma with radiographic features suggestive of high-grade tumor) with a median age of 42 (28–56) and KPS of 90 (70–100) were enrolled. 13 patients had co-deletion of 1p/19q, 2 had intact 1p/19q, 1 pt had biopsy without enough tissue, and pending in 3. Eleven patients were eligible for APBPCR: 10 patients either maintained surgical CR (9) or had a response to TMZ (1) and went on to transplant; one surgical CR pt refused transplant. Six patients were ineligible for transplant because best response of SD (2), PD (2, both 1p19q intact), insurance denial (2). Two patients are still receiving induction TMZ. Median progression-free (PFS) and overall survivals (OS) have not been reached at a median follow-up of 20 months. 2 of the 10 patients who underwent APBPCR recurred, one at 16.1 and one at 34.2 months. No veno-occlusive disease was observed during transplant and no treatment-related deaths occurred. Conclusions: TMZ followed by myeloablative chemotherapy with APBPCR can be safely administered to newly diagnosed AO patients. [Table: see text]
Temozolomide for recurrent intracranial supratentorial platinum-refractory ependymoma
Authors: Johnston S. K. , Chamberlain M. C. 
Published: August 2020

2061 Background: There is no standard therapy for platinum-resistant ependymoma and hence a need exists for new therapies. Objective: A retrospective evaluation of temozolomide (TMZ) in adults with recurrent supratentorial platinum-refractory WHO grade 2 ependymoma with an objective of determining 6-month progression free survival (PFS). Methods: 25 patients, ages 28–63 years, with recurrent ependymoma were treated. All patients had previously been treated with surgery, radiotherapy, and platinum-based chemotherapy (cisplatin: 15; carboplatin 10). Nine patients underwent repeat surgery. Patients were treated at second recurrence with TMZ (5 consecutive days), once every 4 weeks, defined as a single cycle. Neurological evaluation was performed every 4 weeks and neuroradiographic assessment every 8 weeks. Results: A total of 68 cycles of TMZ (median 2 cycles; range 1–6) was administered. TMZ-related toxicity included leukopenia (7 patients; 1 grade 3), constipation (6 patients; 0 grade 3), fatigue (5 patients; 0 grade 3), anemia (2; 0 grade 3), thrombocytopenia (2; 0 grade 3), and deep vein thrombosis (2; 0 grade 3). One patient (4%) demonstrated a partial radiographic response, nine (36%) stable disease, and 15 (60%) progressive disease following two cycles of temozolomide. Time to tumor progression ranged from 1–7 months (median: 2 months). Survival ranged from 2–8 months (median: 3 months). 6-month and 12-month PFS were 2% and 0% respectively. Conclusions: Temozolomide in this dose schedule demonstrated little efficacy in a cohort of adults with recurrent intracranial platinum-refractory ependymoma. No significant financial relationships to disclose.
Efficacy and tolerability of intrathecal liposomal cytarabine for central nervous system embryonal tumors
Authors: Partap S. , Murphy P. A. , Vogel H. , Barnes P. D. , Edwards M. S. , Fisher P. G. 
Published: August 2020

2064 Background: Liposomal cytarabine (DepoCyt) is a sustained-release intrathecal (IT) preparation of cytarabine, formulated by encapsulating the drug in spherical aqueous chambers within a lipid matrix. While proven effective in lymphomatous meningitis, this drug has shown some activity in medulloblastoma (MB) with spinal metastases in limited pediatric phase I study. Methods: We reviewed all patients at our institution treated with liposomal cytarabine for primary central nervous system (CNS) embryonal tumors-MB, primitive neuroectodermal tumor (PNET), and atypical teratoid rhabdoid tumor (ATRT). Results: A cohort of 17 patients were treated with liposomal cytarabine at diagnosis of CNS embryonal tumor (2 PNET, 3 ATRT) or relapse (12 MB [7 average-risk, 5 high-risk]); nine had leptomeningeal metastases. Drug was dosed at 2 mg/kg up to 50, every 2 weeks to monthly, along with dexamethasone. Concurrent systemic chemotherapy was given in 16 patients. Median age at first dose was 10.8 years (range 0.9 to 27.9 years). A total of 102 doses were administered (lumbar IT 76, Ommaya intraventricular 36) with a mean of six treatments (range 1–16). Only three administrations were associated with adverse effects of arachnoiditis or headache; no dose reductions were required. Median overall survival from relapse was 11.8 months. All six evaluable patients with malignant cerebrospinal fluid (CSF) cytology and treated with at least two doses cleared their spinal fluid (mean 3 doses, range 1–5). No patient developed malignant CSF cytology while receiving liposomal cytarabine. Ten patients developed progressive disease and died, with only one later recurrence in the spinal fluid. Seven patients remain alive (4 initial and 3 relapse) with five in continuous complete remission (2 ATRT) for a median 13.7 months from first liposomal cytarabine. Conclusions: Liposomal cytarabine was well tolerated and easily administered. All patients with neoplastic meningitis cleared malignant cells from their spinal fluid after treatment with IT liposomal cytarabine and systemic chemotherapy. One-third of our cohort remains in remission from otherwise fatal diagnoses. Our findings warrant a phase II trial of liposomal cytarabine in newly diagnosed or recurrent CNS embryonal tumors. [Table: see text]
Characteristics and outcomes of elderly patients with primary CNS lymphoma (PCNSL)
Authors: Ney D. E. , Reiner A. S. , Skinner H. D. , Panageas K. S. , DeAngelis L. M. , Abrey L. E. 
Published: August 2020

2070 Background: The incidence of PCNSL is increasing and is highest in those ≥ 65 years of age. Systemic chemotherapy (CT) ± radiotherapy (RT) improves survival, but treatment related toxicity is greatest in this population. The optimal treatment has yet to be determined. The aim of this study was to characterize older patients with PCNSL at our institution and identify outcomes related to treatment. Methods: We identified patients ≥ 65 years of age treated for PCNSL from 1986 to 2008. Charts were reviewed for demographics, treatment details, tumor progression, and survival. Approval for this study was obtained from the IRB at MSKCC. Results: 174 patients were identified with a median age of 72 years (range: 65–89). 60% of patients had a stereotactic biopsy for diagnosis; 93% had a histologic or cytologic diagnosis. 14 patients had evidence of systemic involvement with detailed staging evaluation. 82% of patients received a high-dose methotrexate (3.5g/m2) regimen, only 13% did not receive CT. Among the patients who received CT, 76% had a radiographic response (CR+PR), 3% had stable disease while 12% progressed. Only 26% had RT as part of initial therapy. CR rate to initial therapy was 67%, 52% of these patients eventually relapsed. Median time to progression was 24 months (range: 1–91). Among the patients who relapsed, 85% received salvage therapy consisting of CT (n = 42), RT (n = 14), or both (n = 7) while 15% received no further treatment. 48% of patients had a CR or PR to salvage therapy while 26% had PD; the remainder were not evaluated. Median overall survival for the entire cohort was 25 months (range: 0.5 to 177+) with a 3-year survival of 36%. 17% developed late treatment-related neurologic toxicity. Administration of RT was associated with the development of neurotoxicity (p < 0.0001). 39 patients remain alive with a median follow-up of 34 months (range: 0.5–177). Conclusions: Elderly patients can receive an aggressive chemotherapeutic regimen with good outcomes. Systemic staging is also valuable as a small subset of patients will have systemic involvement at diagnosis. Clinical trials to optimize treatments for this population are critical. No significant financial relationships to disclose.
CXCL13 and CXCL12 in central nervous system (CNS) lymphoma patients
Authors: Fischer L. , Korfel A. , Pfeiffer S. , Kiewe P. , Volk H. , Cakiroglu H. , Widmann T. , Thiel E. 
Published: August 2020

2071 Background: Homing of malignant lymphocytes to the CNS may play a role in the pathogenesis of CNS lymphoma. Recently, the expression of the chemokine receptors CXCR4 and CXCR5 as well as their chemokine ligands CXCL12 and CXCL13 by tumor cells in primary CNS lymphoma (PCNSL) has been demonstrated. In this study, we evaluated CXCL12 and CXCL13 in cerebrospinal fluid (CSF) and serum of patients with CNS lymphoma. Methods: Samples from 30 patients with CNS lymphoma (23 with PCNSL and seven with secondary CNS lymphoma) and 40 controls (10 patients with other CNS malignancies and 30 without a malignant CNS disease) were examined. CXCL12 and CXCL13 concentrations were measured using enzyme-linked immunosorbent assays. The grade of blood brain barrier (BBB) disruption was estimated by the CSF/serum albumin ratio. Results: CNS lymphoma patients and controls did not differ in CXCL12 serum and CSF levels. Serum levels of CXCL13 were generally low. CXCL13 CSF levels, however, were high only in CNS lymphoma patients but not in controls (p < 0.0001). Chemokine levels in CSF and serum did not correlate. In CNS lymphoma CXCL13 concentration in CSF correlated with BBB disruption (R = 0.66, p = 0.003). Elevated CSF levels of CXCL12 and CXCL13 measured in seven CNS lymphoma patients decreased in five patients which responded to chemotherapy, and increased in two with lymphoma progression. Conclusions: Our results suggest a production of CXCL13 within the CNS of CNS lymphoma patients which decreases with response to therapy. Thus, CXCL13 may represent a marker for further diagnostic and prognostic studies. No significant financial relationships to disclose.
Whole-body MRI evaluation of tumor burden in the neurofibromatosis tumor suppressor syndromes
Authors: Plotkin S. R. , Singh M. , Cai W. , O'Donnell C. , Esparza S. , Smith M. J. , Harris G. J. , Muzikansky A. , Bredella M. A. , Kassarjian A. 
Published: August 2020

2074 Background: Neurofibromatosis 1 (NF1), NF2, and schwannomatosis are a group of related genetic disorders in which affected individuals share the predisposition to develop multiple neurofibromas and schwannomas. The prevalence of internal tumors is not known because current estimates are based on regional MRI scans that may not detect occult tumors. A rapid and sensitive method to detect internal tumors is highly desirable since they can cause neurologic dysfunction, compress vital structures, or transform into malignant tumors. Whole-body MRI (WBMRI) is an imaging technique by which the entire body can be imaged in a relatively short time without the use of ionizing radiation. Methods: We performed WBMRI in subjects with NF1, NF2, or schwannomatosis as part of an IRB-approved research study. Each subject was imaged from head to ankles in the supine position using a 1.5 Tesla magnet, integrated body coil, and no intravenous contrast. Using five acquisitions, the entire body was imaged using a fat suppressed fluid sensitive STIR sequence. The images were then fused into a single whole body DICOM image. The number and type of tumors (discrete vs. plexiform) were identified by a board-certified radiologist and tumor volume was calculated using semi-automated analysis. Results: A total of 100 subjects were imaged (NF1–50; NF2–25, schwannomatosis-25). Sixty-one percent of subjects had ≥1 internal tumor. The median number of tumors in affected individuals was 5 (range, 1 to 63 tumors). Overall, the legs harbored the greatest number of tumors (33%), followed by the pelvis (18%), thorax (15%), abdomen (12%), arms (10%), and head/neck (7%). Only 40% of internal tumors were classified as plexiform yet these tumors contributed 78% of the tumor burden by volume. Conclusions: WBMRI scan is a powerful tool to evaluate the number, size, and distribution of internal tumors in patients with neurofibromatosis. This technique provides unique phenotypic information for genetic studies on NF1, NF2, and schwannomatosis. In addition, WBMRI may prove useful in identifying individual patients at high risk for complications (such as neurologic dysfunction or malignant transformation) due to heavy internal tumor burden and in determining the efficacy of antitumor drugs in this unique patient population. No significant financial relationships to disclose.
Uridine glucuronosyltransferase 2B7 pharmacogenetics predicts epirubicin clearance and myelosuppression
Authors: Sawyer M. B. , Damaraju S. , Pituskin E. , Damaraju V. , Scarfe A. G. , Bies R. B. , Hanson J. , Clemons M. , Kuzma M. , Mackey J. R. 
Published: August 2020

2504 Background: Epirubicin (EPI) is widely used to treat breast cancer. EPI is predominantly metabolized by uridine glucuronosyltransferase (UGT) 2B7 to inactive glucuronides. We previously showed that a UGT enhancer single nucleotide polymorphism (SNP) at position -161 T to C correlated with rates of morphine glucuronidation. Methods: We performed a prospective pharmacogenetic study of effects of this SNP on EPI metabolism in M0 breast cancer patients (PTS) receiving adjuvant or neoadjuvant FEC100 (5-fluorouracil 500 mg/m2, EPI 100 mg/m2 and cyclophosphamide 500 mg/m2) given every 3 wks. PTS with ALT and AST ≤ upper limit of normal (ULN), a total bilirubin ≤ ULN, and normal renal and cardiac function were eligible. EPI levels were drawn at approximately 1 and 24 hrs. Cycle 1 toxicities were assessed using NCIC CTG toxicity criteria. Results: 123 PTS entered this study, mean (range): age 51 (28 - 74), sex 122 F/ 1 M, baseline AST 24 U/L (13–66), ALT 22 U/L (5–90), bilirubin 8 μmol/L (2–26), creatinine 74 μmol/L (50 - 126). PTS were genotyped using Pyrosequencing; 26 PTS were TT homozygotes, 59 were CT heterozygotes, and 33 were CC homozygotes. 5 PTS could not be genotyped. A three compartment population pharmacokinetic model in NONMEM V 1.1 for EPI was used incorporating all PTS. The baseline objective function was 1817, and inclusion of genotype significantly improved the objective function to 1764; CC genotype PTS had decreased EPI clearance 88.9 L/hr compared to CT/TT genotype PTS 129 L/hr, p<0.001. Rates of first cycle grade 3/4 leucopenia were 78% in CC PTS and 48% in CT/TT PTS; consistent with the pharmacokinetic analysis. Conclusions: A SNP in UGT 2B7 is common and appears to predicts EPI clearance and myelosuppresion in non-metastatic breast cancer PTS and may form the basis for a method to individualize EPI treatment. No significant financial relationships to disclose.