bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical efficacy of tumor-treating fields for newly diagnosed glioblastoma.
Authors: Liu Yang , Richardson Margie , Warren Kwanza , Strawderman Myla S. , Mohile Nimish , Milano Michael T. , Walter Kevin 
Published: May 2019

2046 Background: Recent clinical trials have shown that adding tumor treating fields (TTF) to the Stupp protocol (SP) has increased survival after glioblastoma (GBM) diagnosis. However, whether this regimen improves population-based survival for patients with GBM remains unknown. Methods: We retrospectively identified adult patients with newly diagnosed GBM treated at our institution from January 2000 to July 2017 (n = 438, median age: 63 years).We grouped patients into three time periods for comparison: 2000-2004 (group 1, prior to SP), 2005-2013 (group 2, SP) and 2014-2017 (group 3, adding TTF to SP). The Kaplan-Meier method was used to estimate survival. Statistical analysis included unadjusted group comparisons by Chi-square and Log-rank tests and adjusted group comparisons using logistic and Cox models. Results: Thirty-seven percent (43/117) of patients with GBM in group 3 received TTF with SP therapy; when compared to those who received SP only, these patients had significant improvements in 6-month and 1-year overall survival (OS) rates (100.0% vs. 82.4%, p < 0.01; 86.0% vs. 66.2%, p < 0.05, respectively) (unadjusted for prognostic factors including sex, age, KPS and extent of resection) and an increased trend of median OS (479.0 vs. 448 days, p = 0.269). However, after adjusting for those prognostic factors, we didn’t find a statistically better survival for patients treated with TTF (OR: 6.156, p = 0.097, OR: 2.102, p = 0.185, respectively). Furthermore, multivariate Cox proportion hazards model after adjusting for those prognostic factors showed no significant survival benefits for patients treated with TTF and SP compared to those treated with SP only (HR = 0.797, p = 0.648). In addition, we didn’t find significant increases of 6-month, 1-year survival rates and median OS for patients in group 3 when compared to those in group 2 who had seen increased trends of survival trends when compared to those in group 1. Conclusions: Although adding TTF to SP appeared to benefit patients with GBM, this effect might be due to selection bias, e.g., TTF was offered to those patients with better prognostic factors. Ascertaining the long-term benefits of TTF requires further investigation.
Evaluating the capacity of connectome analysis to predict survival in high-grade astrocytoma.
Authors: Harrison Rebecca A. , Liu Rongjie , Rao Vikram , Petersen Melissa , Dyson Hannah , Weathers Shiao-Pei S. , Alfaro-Munoz Kristin , De Groot John Frederick , Kesler Shelli 
Published: May 2019

2049 Background: While factors such as age, histology and tumor molecular variants (e.g. IDH status) contribute to prognosis in patients with high grade astrocytoma (HGA), there remains a wide variability in patient survival outcomes. The connectome, or brain network organization, incorporates biologic, molecular and environmental processes providing a uniquely parsimonious summary of key prognostic factors. This study compared the capacity of machine learning (ML) models based on baseline connectomics and clinical variables to predict patient survival in HGA. Methods: Patients with a new diagnosis of HGA and a presurgical 3D, T1-weighted MRI available were retrospectively identified. Individual patient connectomes were derived from MRI with 90 cortical/subcortical features. Presurgical clinical features included age, gender, histology, tumor grade and IDH status. Three ML algorithms were implemented: extreme learning machine with Buckley–James estimator (ELMBJ), random survival forest (RSF) with logrank splitting and RSF with concordance index (CI) splitting. For each algorithm, we used a 60/40 training/testing split with 50 iterations and CI as the performance metric. We tested three models: 1) connectome only, 2) clinical only, and 3) connectome plus clinical variables. Results: Of patients identified (n = 105), 66 had glioblastoma and 39 had anaplastic astrocytoma. Thirty-eight harbored IDH mutation. Median overall survival was 27.43 months (SD 39.57). Connectome-only models showed better prediction performance compared to clinical-only models across all algorithms. ELMBJ showed the best performance (connectome median CI = 0.522, clinical CI = 0.201). Connectome models also performed as well as combined models (e.g. median CI = 0.523 for ELMBJ). Conclusions: This study demonstrates the potential of a connectome model to predict survival of patients with HGA. Replication in a larger sample is required to validate these results and refine ML models including examination of additional clinical features. If successful, use of a simple T1 MRI could provide additional variables to augment existing prognostic prediction, especially in scenarios where tumor genotyping is not available.
Decision making in surveillance of high-grade gliomas using perfusion MRI as adjunct to conventional MRI and artificial intelligence.
Authors: Bisdas Sotirios , Shakallis Loizos , McEvoy Andy , Miserocchi Anna , Samandouras George , Brandner Sebastian , Rees Jeremy , Ferscht Naomi , Cardoso Jorge M , Panovska-Griffiths Jasmina , Sudre Carole , Shaikh Faiq , Roettger Diana 
Published: May 2019

2054 Background: Surveillance of High-Grade Gliomas (HGGs) remains a major challenge in clinical neurooncology. Histopathological validation is not an option during the course of disease and imaging surveillance suffers from ambiguous features of both disease progression and treatment related changes. This study aimed to differentiate between Pseudoprogression (PsP) and Progressive Disease (PD) using an artificial intelligence (support vector machine - SVM) classification algorithm. Methods: Two groups of patients with histologically proven HGGs were analysed, a group with a single time point DSC perfusion MRI (45 patients) and a group with multiple time point DSC perfusion MRI (19 patients). Both groups included conventional MRI studies prior and after each perfusion MRI. This study design aimed to replicate decision making in clinical practice including multiple previous studies for each patient. SVM training was performed with all available MRI studies for each group and classification was based on different feature datasets from a single or multiple (subtracted features) time points. Classification accuracy comparisons were performed by calculating prediction error rates for different feature datasets and different time point analyses. Results: Our results indicate that the addition of multiple time point perfusion MRI combined with structural (conventional with gadolinium-enhanced sequences) MRI features results in optimal classification performance (median error rate: 0.016, lowest value dispersion). Subtracted feature datasets improved classification performance, more prominently when the final and first perfusion studies were included in the analysis. On the contrary, in the single time point group analysis, structural feature-based classification performed best (median error rate: 0.012). Conclusions: Validation of our results with a larger patient cohort may have significant clinical importance in optimising imaging surveillance and clinical decision making for patients with HGG.
Molecular genetic, host-derived and clinical determinants of long-term survival in glioblastoma: First results from the ETERNITY study (EORTC 1419).
Authors: Weller Michael , Reifenberger Guido , Le Rhun Emilie , Clarke Jennifer Leigh , Soffietti Riccardo , Wick Antje , Chinot Olivier L. , Ducray Francois , Hau Peter , McDonald Kerrie Leanne , Marosi Christine , Schnell Oliver , Hottinger Andreas Felix , Reijneveld Jaap C. , Lombardi Giuseppe , Wen Patrick Y. , Klein Martin , Gorlia Thierry , Felsberg Joerg , Hertler Caroline ,   for the BTFC Consortium on Long-term Survival with Glioblastoma & the EORTC Brain Tumor Group
Published: May 2019

2056 Background: Glioblastoma represents the most aggressive primary brain tumor in adults, and less than 5% of patients survive 5 years from diagnosis. Factors influencing this long-term survival are poorly understood. Methods: In cooperation with the European Organisation for Research and Treatment of Cancer (EORTC) in Brussels, Belgium, more than 20 clinical sites in the US, Europe and Australia have registered patients with centrally confirmed glioblastoma who survived ≥ 5 years, collecting clinical data including therapy and quality of life-related factors, as well as biospecimens allowing to analyse molecular and immunological parameters. Results: At the cut-off of December 31, 2018, 392 patients were registered, of which 232 had glioblastoma confirmed by central pathology review; 59 dropped out due to histology other than glioblastoma. Glioblastomas were isocitrate dehydrogenase (IDH)-wildtype in 70.7% and had a positive O6-methylguanine DNA methyltransferase (MGMT) promotor methylation status in 75.9%. Median age at diagnosis was 52 years (range: 21-77 years). There was enrichment for patients with gross total resection. Further analyses are ongoing. Conclusions: In a comprehensive effort, the consortium funded by the US Brain Tumor Funders’ Collaborative characterizes factors modulating long-term survival in glioblastoma in a unique large patient cohort. Clinical trial information: NCT 03770468.
Oncolytic polio/rhinovirus recombinant (PVSRIPO) against WHO grade IV malignant glioma (MG): Experience with retreatment of survivors from the phase I trial.
Authors: Desjardins Annick , Gromeier Matthias , Herndon James Emmett , Randazzo Dina , Threatt Stevie , Lipp Eric S. , Miller Elizabeth S. , Jackman Jennifer , Bolognesi Dani P. , Friedman Allan H. , Friedman Henry S. , McSherry Frances , Peters Katherine B. , Johnson Margaret O , Sampson John H. , Ashley David M. , Bigner Darell D. 
Published: May 2019

2060 Background: We completed a study evaluating a single intratumoral delivery of PVSRIPO in recurrent WHO grade IV MG patients (N Engl J Med. 2018 Jul 12;379(2):150-161). Some patients who originally benefitted from the infusion of PVSRIPO demonstrated tumor recurrence, and we hypothesized that retreatment could trigger an immune recall effect, further extending their survival. We now report the impact of second and third intratumoral reinfusion of PVSRIPO in patients treated in the original dose finding study. Methods: Eligible patients were adults with recurrent supratentorial WHO grade IV MG who were experiencing disease recurrence after having benefitted from the first infusion of PVSRIPO. Additional eligibility criteria included: solitary tumor 1-5.5cm in diameter; ≥4 weeks after chemotherapy, bevacizumab or study drug; adequate organ function; KPS≥70%; and positive anti-polio titer. One patient each was retreated at 1 x 107 TCID50 and 1 x 1010 TCID50, and three patients were retreated on the identified phase 2 dose of 5 x 107 TCID50. Results: As of 2/09/2019, five patients have received a second intratumoral dose of PVSRIPO on study, one of which received a total of 3 doses. The patients who received two infusions of PVSRIPO were retreated 72 months, 43 months, 34 months, and 6 months after the first infusion. One additional patient received a second infusion of PVSRIPO 60 months after the first infusion and a third infusion of PVSRIPO 78 months after the first infusion. All patients demonstrated soap bubble degeneration on imaging, and two patients demonstrated tumor contraction. No grade 3 or higher adverse events related to PVSRIPO were observed after retreatment. Three of these patients remain alive more than 81, 80 and 52 months following the first PVSRIPO infusion and more than 9, 20 and 18 months after the second infusion, respectively. Two patients died 63 months and 20 months after the first infusion of PVSRIPO and 19.6 and 14 months after the second, respectively. The patient treated 3 times received the third infusion more than 2 months ago. Conclusions: Intratumoral reinfusion of PVSRIPO via CED is safe, and encouraging efficacy results have been observed. Clinical trial information: NCT01491893.
Phase I/II study of depatuxizumab mafodotin (ABT-414) monotherapy or combination with temozolomide in Japanese patients with/without EGFR-amplified recurrent glioblastoma.
Authors: Narita Yoshitaka , Muragaki Yoshihiro , Maruyama Takashi , Kagawa Naoki , Asai Katsunori , Kuroda Junichiro , Kurozumi Kazuhiko , Nagane Motoo , Matsuda Masahid , Ueki Keisuke , Ocampo Christopher Joseph , Matsumoto Ikiru , Odagawa Reiko , Nishimura Yasuko , Mishima Kazuhiko 
Published: May 2019

2065 Background: The poor prognosis of glioblastoma (GBM; WHO grade IV) results from a high rate of disease recurrence and lack of effective treatment options. Depatuxizumab mafodotin (depatux-m, ABT-414) is comprised of an EGFR-directed antibody, depatuxizumab (depatux, ABT-806), conjugated to the microtubule toxin monomethyl auristatin F (MMAF, mafodotin). Once bounded with tumor cells, depatux-m is internalized and releases the cytotoxin, resulting in cell death. Here, we report safety, pharmacokinetic (PK) and efficacy in an ongoing phase 1/2 study of Japanese patients with/without EGFR-amplified recurrent GBM (rGBM). Methods: M13-714 (INTELLANCE-J, NCT02590263) is a non-randomized, phase 1/2 study in Japanese patients. Phase 1 assessed tolerability and PK where the dose escalation of depatux-m was from 0.5 to 1.25 mg/kg/Q2W at day 1 and 15 during 28-day cycle until progression disease (PD) or intolerable toxicity. Phase 2 assessed efficacy and safety of depatux-m in EGFR-amplified, rGBM and patients received 1.0 mg/kg of depatux-m on day 1 and 15 + 150 mg/m2 temozolomide (TMZ) on days 1-5 during each 28-day cycle until PD or intolerable toxicity. Results: As of 10 Jan 2019, 38 patients (WHO grade ≥3) were enrolled (9 in phase 1, 29 in phase 2). There was no dose limiting toxicity in phase 1. The recommended phase 2 dose was 1.25 mg/kg where the most common adverse events (AEs) were punctate keratitis in 21 patients (72%); lymphopenia in 14 patients (45%), thrombocytopenia in 13 patients (41%). Grade 3/4 AEs included thrombocytopenia and lymphopenia in 20 patients (69%). Ocular AEs were reported in 27 patients (93%) including punctate keratitis (72%). PK results (31 patients) in both phases were similar to those of non-Japanese result. Progression Free Survival (PFS) of 27 patients in phase 2 for 12 and 6 months were 8% and 27.5% respectively. The median PFS was 4 months. The overall survival (OS) for 24, 12 and 6 months were 28%, 62.5% and 93% respectively. The median OS was 15.5 months. Conclusions: Preliminary safety, PK and efficacy in Japanese patients with/without EGFR-amplified, rGBM suggests depatux-m was tolerated and showed encouraging anti-GBM effects. Clinical trial information: NCT02590263.
Results of a phase I study of bispecific anti-CD19, anti-CD20 chimeric antigen receptor (CAR) modified T cells for relapsed, refractory, non-Hodgkin lymphoma.
Authors: Shah Nirav Niranjan , Zhu Fenlu , Schneider Dina , Taylor Carolyn , Krueger Winfried , Worden Andrew , Longo Walter L. , Hamadani Mehdi , Fenske Timothy , Johnson Bryon , Dropulic Boro , Orentas Rimas , Hari Parameswaran 
Published: May 2019

2510 Background: Anti-CD19 CAR-T cell therapy is a breakthrough treatment (tx) for patients (pts) with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (NHL). Despite impressive outcomes, non-response and relapse with CD19 negative disease remain challenges. Through dual B-cell antigen targeting of CD20 and CD19, with a first-in-human bispecific lentiviral CAR-T cell (LV20.19CAR), we aim to improve response rates while limiting CD19 negative relapse. Methods: Pts were treated on a Phase 1 dose escalation + expansion trial (NCT03019055) to demonstrate safety of a 41BB/CD3z LV20.19CAR T cell for adults with R/R B-cell NHL. Safety was assessed by incidence of dose limiting toxicities (DLTs) within 28 days post-infusion. Starting dose was 2.5 x 10^5 cells/kg with a target dose of 2.5 x 10^6 cells/kg. All pts received fludarabine+cyclophosphamide for lymphodepletion. Results: 11 pts have completed tx to date. 9 pts in dose escalation and 2 pts in expansion phase. Median age was 54 years (46-67) and histology included DLBCL = 5 pts, MCL = 4 pts, and CLL = 2 pts. In dose escalation, 3 pts were treated at 2.5 x 10^5 cells/kg, 3 pts at 7.5 x 10^5 cells/kg, and 3 pts at 2.5 x 10^6 cells/kg with no DLTs. As a result, 2.5 x 10^6 cells/kg was selected for expansion. In terms of safety, 6 pts developed Grade 1-2 cytokine release syndrome (CRS) and 3 pts had Grade 1-2 neurotoxicity (NTX). No patient had grade 3-4 CRS or NTX and none required ICU level care. 4 pts required 1-2 doses of tocilizumab for CRS. The day 28 overall response rate (ORR) for all pts was 82% (6/11 = complete response (CR) and 3/11 = partial response). All CR pts remain in remission, the longest > 1 year. All progressing pts underwent repeat biopsy, and all retained either CD19 or CD20 positivity. Additional pts are being enrolled in the expansion phase and updated data will be presented. Conclusions: Phase 1 results from the LV20.19 CAR T clinical trial demonstrate that infusion of 2.5 x 10^6 cells/kg is safe for further investigation with no DLTs among treated pts. Down-regulation of target antigens was not identified as a mechanism of resistance in progressing pts. With limited toxicity and encouraging ORR, dual targeted LV20.19CAR T cells merits further investigation. Clinical trial information: NCT03019055.
Regional delivery of mesothelin-targeted CAR T cells for pleural cancers: Safety and preliminary efficacy in combination with anti-PD-1 agent.
Authors: Adusumilli Prasad S. , Zauderer Marjorie Glass , Rusch Valerie W. , O'Cearbhaill Roisin , Zhu Amy , Ngai Daniel , McGee Erin , Chintala Navin , Messinger John , Cheema Waseem , Halton Elizabeth , Diamonte Claudia , Pineda John , Vincent Alain , Modi Shanu , Solomon Stephen Barnett , Jones David Randolph , Brentjens Renier J. , Riviere Isabelle , Sadelain Michel 
Published: May 2019

2511 Background: We conducted a phase I dose escalation trial of first-in-human autologous chimeric antigen receptor (CAR) T-cell immunotherapy targeting mesothelin (MSLN), a cell-surface antigen that is highly expressed in pleural cancers- malignant pleural mesothelioma (MPM) and metastatic lung and breast cancers. Methods: A single dose of CD28-costimulated MSLN CAR T cells with the I-caspase-9 safety gene was administered intrapleurally in patients with MSLN-expressing pleural tumors. Following a 3+3 design, patients were treated in dose escalating cohorts (dose range 3E5 to 1E7 CAR T cells/kg) following IV cyclophosphamide lymphodepletion (first 3 patients did not receive cyclophosphamide). A subset of MPM patients received subsequent anti-PD-1 therapy, off-protocol, which we have shown to prolong CAR T-cell functional persistence in preclinical models. Results: Twenty patients (18 MPM, 1 lung cancer, 1 breast cancer) were treated (prior lines of therapy 1–8, 35% received ≥3 lines of therapy). No CAR T-cell–related toxicities higher than grade 1 were observed. Intense monitoring for on-target, off-tumor toxicity by clinical (chest or abdominal pain), radiological (CT/PET or echocardiogram for pericardial effusion, ascites), laboratory (troponin elevation), and EKG evaluation found no evidence of toxicity. Fourteen MPM patients received subsequent anti-PD1 therapy (1–21 cycles, pretreatment tumor PD-L1 < 10% in all patients except one), with 1 patient developing grade 3 pneumonitis that responded to steroid treatment. CAR T cells were detected in the peripheral blood of 13 of 14 patients (1-39 weeks). At data cut-off date (Jan 31, 2019), among 14 MPM patients that received combination therapy (follow-up 13-77 weeks, median 31 weeks), best responses included 2 patients with complete metabolic response on PET (62 and 39 weeks ongoing); 5 partial responses and 4 stable disease by investigator assessment. Conclusions: Intrapleurally administered MSLN-targeted CAR T cells were safe. Encouraging antitumor activity of MSLN-targeted CAR T-cell therapy was observed when combined with anti-PD1 therapy and shows promise for future development of this approach. Clinical trial information: NCT02414269.
A phase I study of ALX148, a CD47 blocker, in combination with established anticancer antibodies in patients with advanced malignancy.
Authors: Chow Laura Quan Man , Gainor Justin F. , Lakhani Nehal J. , Chung Hyun Cheol , Lee Keun-Wook , Lee Jeeyun , LoRusso Patricia , Bang Yung-Jue , Hodi F. Stephen , Fanning Philip , Zhao Yonggang , Jin Feng , Wan Hong , Pons Jaume , Randolph Sophia , Messersmith Wells A. 
Published: May 2019

2514 Background: CD47 is a myeloid checkpoint upregulated by tumor cells to evade the host’s immune response. ALX148 (A) is a fusion protein comprised of a high affinity CD47 blocker linked to an inactive human immunoglobulin Fc region. ALX148 is well tolerated in combination with pembrolizumab (P) or trastuzumab (T) with no maximum tolerated dose (MTD) identified (ASCO 2018 #3068, SITC 2018 #P335). Safety and antitumor activity of ALX148 (10 mg/kg QW) in combination with T or P are reported in patients (pts) including those with anti-HER2 or checkpoint inhibitor (CPI) relapsed/refractory diseases. Methods: Patients with malignancy including non-small cell lung cancer (NSCLC: CPI resistant/refractory or PD-L1 tumor proportion score <50%) and head and neck squamous cell carcinoma (HNSCC: progressed on platinum therapy) received A+P. Patients with HER2 malignancy including gastric/gastroesophageal junction (GEJ) cancer (progressed on T + fluoropyrimidine-based therapy) received A+T. Safety, response, pharmacokinetic (PK), and pharmacodynamic (PD) markers were assessed. Preliminary data from fully enrolled cohorts are reported as of 20 Jan 2019 (safety)/28 Jan 2019 (efficacy). Results: Seventy-nine pts received A+P (All, n=50; NSCLC, n=23; HNSCC, n=20) or A+T (All, n=29; Gastric/GEJ, n=23) as of data cutoff. Forty-seven pts reported mostly low grade treatment related adverse events. The most common were fatigue (11%), AST increase (9%), ALT increase (8%), anemia (8%), and platelets decreased (6%). In select tumor histologies, anticancer activity was observed in initial response-evaluable pts [NSCLC (n=23) 1PR, 8SD; HNSCC (n=17) 3PR, 4SD; and Gastric/GEJ (n=21) 4PR, 6SD]. Preliminary results indicate favorable ALX148 PK and CD47 target occupancy profiles, and positive effects on tumor infiltrating immune cells. Results will be updated at presentation. Conclusions: ALX148 demonstrates excellent tolerability with favorable PK/PD characteristics to date. Objective responses were observed in patients with late line NSCLC, HNSCC, and Gastric/GEJ, including disease relapsed/refractory to prior CPI and HER2-targeted therapies. Clinical trial information: NCT03013218.