bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pediatric glioblastoma: Results with adjuvant chemoradiation using temozolomide.
Authors: Joshi Nikhil Purushottam , Mallick Supriya , Gandhi Ajeet , Goyal Shikha , Puri Tarun , Julka Pramod Kumar , Sharma Dayanand , Rath Goura Kishor 
Published: March 2020

2072 Background: Paediatric glioblastoma patients are underrepresented in major trials for this disease. The value of concurrent and adjuvant temozolomide is not known in this subset of patients. Methods: We retrospectively analysed our database between 2004 and 2010. All patients were treated with maximally safe surgical resection. This was followed by a uniform treatment schedule of post-operative radiation according to RTOG guidelines with concurrent daily temozolomide at 75 mg per meter square. The radiation dose was 60 Gy in 30 fractions planned by 3 dimensional conformal radiotherapy. 4 weeks later, adjuvant temozolomide was started at 150 mg per meter square, day 1 to 5 every 28 days and escalated to 200 mg per meter square if well tolerated. Log-rank test was used to compare survival distribution. The data was analysed using SPSS 16. Results: 23 patients were analysed. The median age was 11 years (range: 5 to 19 years). 15 males and 8 females were noted. 4 patients had seizures at presentation while 19 did not. 13 patients underwent a gross total resection while 10 underwent a subtotal resection. 5 patients received only concurrent temozolomide while 18 received concurrent and adjuvant temozolomide. The median number of adjuvant temozolomide cycles were 6 (range 2 to 12). The median follow up was 11.9 months (range: 1.6 to 30.1 months). 6 patients were dead and 17 were alive at the time of analysis. The median overall survival was not reached. The median survival for patients receiving only concurrent temozolomide was 13 months while that for patients receiving concurrent and adjuvant temozolomide was not reached and the difference was statistically significant (p=0.0009). The overall survival was not statistically different for age less or more than 10 years, gender, and type of surgery or the number of adjuvant cycles of temozolomide (less or more than 6). Conclusions: Temozolomide may have a role in paediatric Glioblastoma. Both concurrent and adjuvant temozolomide seem to be important for superior overall survival in this group of patients.
MRI-based vessel function maps for high-resolution differentiation between tumor and nontumoral tissues in brain tumor patients.
Authors: Zach Leor , Goez David , Grober Yuval , Last David , Daniels Dianne , Hoffmann Chen , Nass Dvora , Nissim Ouzi , Spiegelmann Roberto , Cohen Zvi R , Mardor Yael 
Published: March 2020

2078 Background: Changes in enhancement seen in post treatment brain MRIs in primary and secondary brain malignancies often mimic tumor progression (pseudoprogression, radiation necrosis). Conventional MRI cannot differentiate tumor progression from treatment related effects resulting in suboptimal patient management. Methods: The application of delayed contrast extravasation MRI for depicting unique vessels characteristics with high resolution and high sensitivity to subtle BBB disruption is demonstrated in 17 GBM and 15 brain metastases patients undergoing standard chemoradiation and radiosurgery respectively. Results: 2 primary vessel function populations were defined: a slow population where contrast clearance from the tissue was slower than accumulation, and a fast population where clearance was faster than accumulation. Ten stereotactic biopsies acquired from GBM patients showed complete correlation with the maps, confirming the discrimination between fast population regions, reflecting morphological active tumor and slow regions reflecting necrosis/treatment-induced changes. Typical fast population vessel morphology consisted of proliferating endothelial cells, dilated lumen, peri vascular fibrosis and glumeroloid vessels, while slow regions consisted of necrotic vessels, in agreement with the observed MRI vessel function. The fast component volume 3 weeks post treatment was significantly correlated with the fast volume 4 (r2=0.84, p<0.0005) and 6 months (r2=0.84, p<0.01) later, suggesting early prediction of response. Brain metastases histology showed similar results: 5 brain metastases with a fast population component were confirmed histologically to contain morphologically active tumor. One metastasis consisting of the slow population only significantly decreased in volume in the following MRIs. Conclusions: These results demonstrate the feasibility of applying our delayed contrast extravasation high resolution function vessel maps for improving patient management by clearly depicting tumor and non-tumoral tissues in patients with primary and secondary brain malignancies undergoing standard chemoradiation or radiosurgery.
Primary central nervous system lymphoma: The Cleveland Clinic experience.
Authors: Ahluwalia Manmeet Singh , Xie Hao , Patel Mital , Chao Samuel T. , Suh John H. , Peereboom David M. 
Published: March 2020

2092 Background: Primary central nervous system lymphoma (PCNSL) is an uncommon variant of extranodal non-Hodgkin lymphoma that involves the brain, leptomeninges, eyes, or spinal cord without evidence of systemic disease. Untreated PCNSL has a rapidly fatal course, with survival of approximately 1.5 months from the time of diagnosis. In this study, we sought to describe the demographics, diagnoses, management, and outcomes of patients with PCNSL at a single institution. Methods: After obtaining IRB approval, the Cleveland Clinic Brain Tumor and Neuro-Oncology Center’s database was used to identify patients with histologically proven PCNSL at the Cleveland Clinic between 1986 and 2010. Data were subjected univariate and multivariate analysis followed by recursive partitioning analysis in order to generate a prognostic model. Results: 153 patients were diagnosed with PCNSL with a median age of 61 and Karnofsky performance status (KPS) of 70. The progression-free survival (PFS) was 9.3 months; the overall survival (OS) was 27 months. The treatment regimen included methotrexate-based chemotherapy (MTX) or a combination of methotrexate-based chemotherapy and whole brain radiation therapy (WBRT). Patients treated with the MTX regimen had an OS of 65 months; those treated with the MTX + WBRT regimen had an OS of 74 months. The Cox proportional hazards regression identified age and KPS as the only prognostic indicators to OS and PFS. Recursive partitioning analysis categorized the patients into three groups according to these prognostic factors. Patients with KPS ≥ 70 had a favorable outcome compared to patients with KPS < 70. This held true especially for patients age 60 and younger, whose median OS was 100 months. Conclusions: The survival and prognostic indicators approximate those reported previously and provide independent validation for a simple yet powerful prognostic model that uses age and KPS to predict survival. [Table: see text]
Low-grade gliomas in older patients.
Authors: Fawole Adewale Alade , Robles Irizarry Lizbeth , Hashemi-Sadraei Neda , Patel Mital , Ahluwalia Manmeet Singh 
Published: March 2020

2093 Background: Low grade gliomas account for 10-20% of all primary brain tumors. The outcomes of older patients with low-grade glioma (LGG) are not well known. Methods: After obtaining IRB approval, the Cleveland Clinic Brain Tumor and Neuro-Oncology Center’s database was used to identify older patients defined as those >55 years of age with histologically confirmed grade 2 glioma at the time of diagnosis. Multivariable analysis was conducted with use of a Cox proportional hazards model and a stepwise selection algorithm that used p<.10 as the criteria for entry and p<0.05 as retention in the model to identify independent predictors of survival. Results: Chart records of 61 patients diagnosed between 1991 and 2010 were included for final analysis. In contrast to patients ≤55 years, older patients are more likely to be male (p=.06), have poorer performance status at presentation (p<.0001), more comorbid conditions (p<.0001), present with more neurologic symptoms (p<.0001), have a prior history of cancer (p<.0001). They are more likely to have astrocytic histology (p=.008) and present with multifocal tumors more frequently (p=.001). Older patients received radiation (RT) upfront more frequently (p=.07) and undergo gross total resection less frequently (p=.003). Median Progression free survival (PFS) and median overall survival (OS) was 1.9 and 4.3 years, respectively in these patients. On univariate analysis, patients with poor performance status have worse PFS (p=.01) and OS (p=.003). Patients with memory impairment have worse PFS (p=.009) and OS (p=.0001). Patients treated with adjuvant chemotherapy had better OS (p=.01). Tumor related characteristics associated with poor survival included, "pure" or mixed astrocytoma histology (OS, p=.06), multifocal tumors (OS, p=.08), left-sided tumors (p=.07). In multivariable analysis, performance status was the only independent predictor of either PFS or OS. Conclusions: Older patients with low grade gliomas have less favorable outcomes as compared to younger patients. They have more comorbid conditions and symptoms at presentation. Use of chemotherapy in this patient group was associated with improved survival. Performance status was the only independent predictor of either PFS or OS.
Durability of complete remission by moxetumomab pasudotox (HA22 or CAT-8015) assessed by clone-specific real-time quantitative PCR (RQ-PCR).
Authors: Kreitman Robert J. , Arons Evgeny , Sapolsky Jeffrey , Roth Laura , Zhou Hong , Stetler-Stevenson Maryalice , Wilson Wyndham Hopkins , Raffeld Mark , FitzGerald David JP , Ji Fei , Ibrahim Ramy A. , Pastan Ira 
Published: March 2020

2503^ Background: The anti-CD22 recombinant immunotoxin moxetumomab pasudotox, also known as HA22 or CAT-8015, was recently reported in phase I testing to achieve complete remissions (CRs) in 13 (46%) of 28 patients with relapsed/refractory hairy cell leukemia (HCL); 3 of 13 patients have relapsed. Methods: To complete this trial, 20 additional patients received the highest dose level (50 µg/Kg every other day x 3 doses); none of the 48 HCL patients had dose-limiting toxicity (DLT). Results: Of the first 42 patients with >6 mo of follow up off-treatment, 23 (55%) had CRs, with an overall response rate of 88%. Of the 23 CRs, 21 were evaluable for minimal residual disease (MRD) using flow cytometry of blood and immunohistochemistry of the bone marrow biopsy, and 17 (81%) were negative. Of these 17 patients, 11 (65%) were negative by bone marrow aspirate (BMA) flow cytometry. PCR using consensus primers for the heavy chain immunoglobulin (IgH) rearrangement was less specific than flow cytometry of blood, since IgH rearrangements of normal B cells, which recovered rapidly after immunotoxin treatment, were also amplified. For better MRD detection in blood, patient IgH sequences were cloned and sequence specific primers and probes designed for real-time quantitative PCR (RQ-PCR). RQ-PCR of blood was negative in 6 (100%) of 6 patients achieving flow-negativity in both blood and BMA and positive in 3 (100%) of 3 patients flow-negative in blood but not BMA (p=0.01). No relapses from CR have been observed in 10 patients who became RQ-PCR-negative in blood or flow-negative in BMA, with 5-38 (median 11) mo of follow-up. Conclusions: We conclude that clone-specific RQ-PCR is the most sensitive blood test for MRD in our HCL patients after moxetumomab pasudotox, and could be used to assess the possibility of long-term molecular remissions. We believe these results, including durable CRs without DLT, support a pivotal trial in which moxetumomab pasudotox is compared with alternative therapy. Note: this summary contains investigator reported data. This study was funded by MedImmune, LLC, and supported by NCI’s Intramural Research Program and the Hairy Cell Leukemia Research Foundation.
A phase I study of EpCAM/CD3-bispecific antibody (MT110) in patients with advanced solid tumors.
Authors: Fiedler Walter M. , Wolf Martin , Kebenko Maxim , Goebeler Marie-Elisabeth , Ritter Barbara , Quaas Alexander , Vieser Eva , Hijazi Youssef , Patzak Ingrid , Friedrich Matthias , Kufer Peter , Frankel Stanley , Seggewiss-Bernhardt Ruth , Kaubitzsch Sabine 
Published: March 2020

2504 Background: MT110 is a bispecific T cell engaging antibody construct (BiTE) that directs CD3 expressing T cells to kill target cells that express EpCAM, which is widely found on solid tumors. Methods: Safety, tolerability, pharmacokinetics and anti-tumor activity of MT110 in patients (pts) with advanced solid tumors were studied using a 3+3 design. Continuous IV infusions for at least 28 days of doses ranging from 1 to 48 µg/d have been tested. Stepwise intra-patient dose escalations within cycle 1 or at start of cycle 2 have been explored. Results: 51 pts (6 gastric cancers, 32 CRC, 2 SCLC, 5 NSCLC, 3 HRPC, 1 ovarian cancer) have been treated in 12 dose cohorts. The maximally administered dose includes day 1 dose of 3 µg/d escalated up to 48 µg/d. The maximum tolerable dose (MTD) has not yet been established. Diarrhea and elevations in liver function tests have been reported as dose limiting toxicity (DLT) for individual patients. Transaminase elevations were fully reversible and mitigated by dexamethasone at initiation or escalation of dose. Other adverse events of grade 3 or higher included transient lymphopenia, increase in lipase or amylase, nausea, vomiting, and hypoalbuminaemia. No CNS safety signal was observed. The mean serum half-life of MT110 was 4.5 hours. Mean steady state serum concentrations of MT110 were linear with dose across treatment cycles. At 48 µg/d, the mean Css was 3.2 ng/mL. This compares to preclinical EC90 of 1.35 – 3.85 ng/ml in CRC cell lines. Sixteen pts who received a dose of ≥ 24 µg/d were evaluable for anti-tumor response. Best response of SD was reported in 38%; median duration was 155 days (95% CI 92; 161). Anti-tumor activity was demonstrated on biopsy of liver metastases in one patient. Following at least 1 week of MT110 treatment at 48 µg/d, a decrease in circulating tumor cells was observed with a median nadir 74% below baseline. Conclusions: The use of stepwise dose escalation and concomitant dexamethasone resulted in improved tolerability. A dose of 48 µg/d appears tolerable. Tumor biopsy evaluation on treatment and pharmacodynamic evidence of anti-tumor activity are encouraging. Additional dose cohorts will seek to identify the recommended phase II dose and further evidence of anti-tumor activity.
Effect of stimulation of natural killer cells with an anti-CD137 mAb on the efficacy of trastuzumab, cetuximab, and rituximab.
Authors: Kohrt Holbrook Edwin , Houot Roch , Weiskopf Kipp , Goldstein Matthew , Lund Peder , Scheeren Ferenc , Czerwinski Debra , Colevas A. Dimitrios , Weng Wen-Kai , Clarke Michael F. , Carlson Robert W. , Sunwoo John , Tedder Thomas , Chen Lieping , Levy Ronald 
Published: March 2020

2514 Background: Antibody-dependent cell-mediated cytotoxicity (ADCC), mediated by natural killer (NK) cells, plays an important role in the efficacy of monoclonal antibodies (mAb)s. CD137 is a costimulatory molecule expressed on immune cells following activation, including NK cells. We hypothesize that as the antitumor efficacy of mAbs is due to ADCC, their activity can be enhanced by stimulation of NK cells with an anti-CD137 agonistic mAb. Methods: Upregulation of CD137 on NK cells was assessed using CD20+lymphoma, HER2+breast, and EGFR+head and neck cell lines and primary patient samples. NK cell degranulation, cytokine release and cytotoxicity were assessed by CD107a mobilization, IFN-γ secretion, and chromium release. Mechanism of synergy was explored by cell depletion in an immune competent mouse model. Xenotransplanted models were used to demonstrate anti-tumor activity and sufficiency of an innate immune response. Results: NK cells in human primary patient samples do not express CD137 at baseline, however CD137 is highly upregulated when encountering mAb-coated tumor cells. MAb-induced NK cell degranulation and cytotoxicity are enhanced by anti-CD137 agonistic mAb. In a murine lymphoma model, anti-CD137 mAb significantly enhances anti-tumor activity of anti-CD20 mAb leading to complete tumor resolution and prolonged survival. NK cell depletion completely abrogates the therapeutic effect. In seven xenotransplant models, sequential administration of rituximab, trastuzumab or cetuximab plus anti-CD137 mAb provided superior reduction in tumor burden and prolonged overall survival. In a phase 0 biomarker study, level of CD137 expression on circulating and intratumoral NK cells was influenced by disease burden, prior treatment, FcγRIII polymorphism, and time since mAb therapy. Conclusions: Our results demonstrate the synergy of anti-CD137 mAb and a tumor-targeting mAb by stimulation of mAb-activated NK cells with anti-CD137 mAb to enhance ADCC. These results support a novel, sequential antibody approach against CD20+B cell, HER2+breast, and EGFR+head and neck malignancies by targeting first the tumor and then the host immune system.
Investigating genes and pathways that play a role in immune responses mediated by anti-CTLA-4 therapy.
Authors: Gao Jianjun , Chen Hong , Ng Tang Derek , Sharma Padmanee 
Published: March 2020

2520^ Background: Blockade of the inhibitory T cell molecule CTLA-4 with a monoclonal antibody has led to enhanced anti-tumor immune responses and clinical benefit. Ipilimumab, an anti-CTLA-4 antibody (BMS), was recently FDA-approved for the treatment of metastatic melanoma. Only a subset of patients benefit from anti-CTLA-4. In order to identify genes and pathways that are induced by anti-CTLA-4, which may be used in future studies for potential correlation with clinical outcomes or provide additional targets for therapy, we purified and analyzed CD4 T cells from patients treated with anti-CTLA-4 for changes in gene expression profile. We also obtained tumor tissues from treated patients for similar studies. Methods: On an IRB-approved Phase Ia pre-surgical clinical trial, 6 patients with localized bladder cancer were treated with two doses of Ipilimumab at 10 mg/kg at weeks 1 and 4. Blood was collected pre-therapy and post-therapy (3 weeks after each dose). CD4 T cells were enriched from peripheral blood by using the CD4 T cell isolation kit from Miltenyi Biotec (Auburn, CA). Total RNA was isolated from purified CD4 T cells using Qiagen RNeasy kit for Affymetrix microarray analyses. Microarray data were then analyzed using Ingenuity iReport (Redwood City, CA). RT-PCR, RPPA and Western blot were used to confirm significant changes in genes or pathways identified in microarray analyses. Results: Ipilimumab treatment resulted in modulation of differentially expressed genes (DEGs). After dose #1, Ipilimumab only modulated 16 DEGs >2-fold (p<0.05) in CD4 T cells. After two doses of treatment, Ipilimumab significantly changed expression of a total of 100 DEGs. Further pathway analyses indicated that Ipilimumab induced a variety of pathways involved in cell cycle control, cell proliferation, apoptosis, and immune modulation. Specifically, these pathways include PI3K/AKT, MAP/ERK, IFN/JAK-STAT, granzyme, and protein ubiquination. Conclusions: Ipilimumab treatment results in modulation of multiple genes and pathways, which likely play important roles in anti-tumor immune responses and need to be considered for future optimization of anti-CTLA-4 therapy and design of combination immunotherapy strategies.
Immune responses and association with clinical outcome of advanced colorectal cancer patients treated with the multi-peptide vaccine IMA910.
Authors: Kuttruff Sabrina , Weinschenk Toni , Schoor Oliver , Lindner Juha , Kutscher Sarah , Maurer Dominik , Mayer-Mokler Andrea , Ludwig Joerg , Nowara Elzbieta , Torday Laszlo , Cseh Jozsef , Hoehler Thomas , Hitre Erika , Maughan Tim , Adams Richard A. , Mayer Frank , Reinhardt Carsten , Singh Harpreet , Walter Steffen 
Published: March 2020

2522 Background: IMA910 is a novel multi-peptide cancer vaccine consisting of 10 HLA class I and 3class II tumor-associated peptides (TUMAPs), which were selected based on natural presentation on colorectal tumors by the XPRESIDENT antigen discovery platform. Methods: 92 HLA-A*02+ advanced colorectal cancer (aCRC) patients (pts) with stable or responding disease after 12 weeks of first-line oxaliplatin-based therapy were enrolled in this phase I/II trial. After pre-treatment with cyclophosphamide (300 mg/m2), patients were immunized intradermally with IMA910 plus the immune modulator GM-CSF without (cohort 1; n=66) or with (cohort 2; n=26) topically applied imiquimod, another immune modulator acting via toll-like receptor 7 on antigen presenting cells. T-cell responses to individual IMA910 peptides were analyzed by HLA multimer and intracellular cytokine staining (ICS) assays. Results: IMA910 elicited immune responses towards multiple class I (43%) and class II TUMAPs (65%). 34% of pts responded to multiple class I and class II TUMAPs. Pts that received imiquimod were more often multi-peptide class I responders in the ICS assay (p=0.016) and showed an approx. 2x higher frequency of T-cell response (p=0.12). Responses to multiple class I and class II TUMAPs were associated with higher disease control rate at all time points (all p<0.02), increased time to progression (p=0.006), progression-free survival (p=0.009) and OS (p=0.088, HR=0.53). Baseline characteristics of multi vs. non-multi responders were overall well comparable. In a prospectively defined, blinded matched-pair analysis with patients in arm C of the COIN trial, multi-peptide responder patients showed a prolonged survival vs. corresponding COIN patients (p=0.04), while the non-multi responder patients had comparable survival. Conclusions: IMA910 is immunogenic. Imiquimod increases the quality of immune responses. Responses to multiple TUMAPs are associated with better clinical outcome. Several observations indicate that this association is not a reflection of better prognosis of the immunologically responding subset of patients. These results suggest further development of IMA910.