bluuebunny/crossref_metadata_2025_split huggingface dataset:
Anti-PD-1 for patients with leptomeningeal metastasis from advanced solid tumors: Efficacy, safety, and biomarkers of response.
Authors: Naidoo Jarushka , Schreck Karisa C. , Hu Chen , Douville Christopher Blair , Santa-Maria Cesar Augusto , Connolly Roisin M , Holdhoff Matthias , Lipson Evan J. , Parkinson Rose , Riemer Joanne , Barnes Amanda , Venkatesan Arun , Bettegowda Chetan , Grossman Stuart A. , Brahmer Julie R. 
Published: May 2020

e14506 Background: Leptomeningeal metastasis (LMM) from solid tumors are rare and often refractory to standard therapies. Pembrolizumab (anti-PD-1) has efficacy in patients (pts) with brain metastases from ICI-responsive tumors, however pts with LMM are often excluded from ICI trials. We hypothesized that: 1. Pembrolizumab will lead to CNS response in LMM, and 2. Genomic/immunologic analyses on CSF could identify CNS biomarkers of response. Methods: We conducted an investigator-initiated open-label phase 2 trial of Pembrolizumab in pts with LMM from any solid tumor (NCT03091478). Eligible pts had: LMM on MRI ( > 3mm lesion) or CSF cytology, ECOG PS ≤1, and were PD-naïve. Prior RT to LMM was allowed > 3 months before study start or to non-target areas. Pembrolizumab was administered IV 200mg q3W until disease progression/unacceptable toxicity. The primary endpoint was CNS response after 12 weeks, defined as radiologic (RECIST 1.1)/cytologic/clinical response to therapy. Serial CSF samples were assessed by chromosomal copy number changes using a PCR-based approach (RealSeqS) to detect tumor-derived DNA (CSF-tDNA), and 16-color flow cytometry. Results: Thirteen of a planned 18 pts were treated 04/2017-12/2019, the study was closed early for low accrual. Median age was 58 years (22-79), 53% were female. Pts had breast carcinoma (38%, n = 5), NSCLC (23%, n = 3), high-grade glioma (23%, n = 3), HNSCC (8%, n = 1) and cutaneous squamous cell carcinoma (8%, n = 1). Median no. of prior therapies was 4 (0-8), 76% of pts had prior RT to LMM. CNS response was seen in 38% of pts (5/13: 2 = complete response (NSCLC; Squamous skin); 3 = stable disease (NSCLC, Glioma, HER2+BC) by RECIST 1.1. Treatment-related adverse events were seen in 31% (4/13) of pts, 15% (2/13) G3+ (fatigue = 1, infection = 1). CSF cytology was negative at ICI start in 6 cases, but positive by CSF-tDNA in 5/6 cases. In addition, CSF-tDNA levels can correlate with disease status. CSF flow cytometry demonstrated increase in CD45R0+ activated memory T-cells, and a shift from immature to antibody-secreting B-cells in both pts with CRs in LMM. Conclusions: Pembrolizumab was well-tolerated and demonstrated anti-tumor activity in pts with LMM in ICI-responsive tumors. Correlative analyses identified CSF-tDNA can potentially be used from diagnosis to longitudinally monitor LMM; and that T and B cell populations may be enriched in the CSF of pts whose LMM regressed. These findings support inclusion of pts with LMM in ICI studies and interrogation of CSF biomarkers. Clinical trial information: NCT03091478.
Leptomeningeal metastasis from non-small cell lung cancer- outcomes from a tertiary care center.
Authors: Vallathol Dilip Harindran , Patil Vijay Maruti , Noronha Vanita , Joshi Amit , Menon Nandini Sharrel , Prabhash Kumar 
Published: May 2020

e14508 Background: Leptomeningeal metastasis from Non-Small Cell Lung Cancer is often an underdiagnosed entity. Despite advances in treatment, the outcomes of Leptomeningeal Metastasis continues to be dismal. The data on outcomes of leptomeningeal metastasis from a tertiary care centre is limited. Methods: Data collected from the 4 prospective randomised controlled trials conducted on Non Small cell Lung cancer patients at our centre in the last decade was used in the analysis. These included 1. Patients who had EGFR sensitizing mutations enrolled in the Pemetrexed versus Gefitinib maintenance trial and Gefitinib versus Gefitinib plus chemotherapy trial. 2. Patients who were diagnosed as Squamous Cell Carcinoma of lung enrolled in the Low Dose Gemcitabine versus Standard-Dose Gemcitabine trial. 3. Patients with adenocarcinoma who were enrolled in the Pemetrexed versus Erlotinib maintenance trial. We separated the patients who developed Leptomeningeal Metastasis from these trials and studied its incidence, presenting features and outcomes. Statistical analysis was done using cox regression analysis and kaplan meier plots. Results: Out of 1148 patients, 36 patients (0.031%; 95%CI 0.022-0.043) developed leptomeningeal metastasis. In these patients, the median time to development of LM was 14.92 months (IQR 7.7-21.84). The median overall survival after development of LM was 61 days (95%CI 38.95-83.05). None of the tested factors- Age (Hazard ratio-0.886; 95% CI 0.424-1.851, P-value = 0.747), ECOG PS (Hazard ratio-0.719; 95%CI 0.299-1.729) or driver mutation status ( Hazard ratio-2.080, 95%CI 0.739-5.855) had an impact on OS. The median OS in driver mutated patients was 66 days (95% CI 14.74-117.26) versus 51 days (95% CI 14.5-87.5) (P-value = 0.201). Conclusions: In our study, there was no single factor which impacted survival in patients who developed Leptomeningeal Metastasis. The median survival was in the range of 2 months. This reiterates the overall poor prognosis of development of Leptomeningeal Metastasis in Non small Cell Lung Cancer even with the development of newer therapeutic modalities. Keywords- Leptomeningeal metastasis, Non small cell lung cancer, Incidence, Survival.
Does extent of resection of glioblastoma multiforme affect survival?
Authors: Nabil Emad Eldin , Elyamany Ashraf 
Published: May 2020

e14514 Background: Glioblastoma Multiforme (GBM) is the most common primary intracranial tumor. The effect on survival of extent of tumor resection for GBM tumors remains controversial. Our study aims to detect the role of extent of tumor resection in improvement of survival in patients with GBM. Methods: A prospective study for 84 patients with GBM, was conducted between March 2013 and September 2016 in Sohag University Hospital and Sohag Cancer Center. For all of them surgery was done. Either biopsy (stereotactic or open), debulking or gross total resection (complete). All patients received radical radiotherapy concurrent with Temozolomide chemotherapy followed by six to eight cycles of Temozolomide. All patients were followed by clinical examination and brain imaging. Results: 59% of our patients were males and 41% were females. About 78% of the patients had either Eastern Cooperative Oncology Group (ECOG) Performance Status 1 or 2. Median age was 51years with a range (25-70 years). In 38 patients (45.8%) debulking was done, while complete resection was done in 20 patients (24.1%). only biopsy was done in 30% of patients. We found a statistically significant effect for the extent of resection on overall survival (OS)(22 vs 19.5 months) and progression free survival (PFS)(18.25 vs17.42 months) for patients with complete resection vs patients with debulking only. In addition younger age patients had a statistically significant longer survival. Conclusions: Gross total resection (complete resection) of intracranial GBM was associated with longer survival. Gross total resection should be performed whenever possible.
Survival characteristics of patients with first progression of glioblastoma at Cleveland Clinic Foundation.
Authors: Rauf Yasmeen , Yao Jimmy , Barnett Addison , Chen Yanwen , Hobbs Brian , Stevens Glen , Peereboom David M. , Ahluwalia Manmeet Singh 
Published: May 2020

e14526 Background: Glioblastoma (GBM) is the most common primary central nervous system malignancy, with a median overall survival of 14 to 17 months. First progression refers to progressive disease after initial radiation with or without chemotherapy. The median overall survival of patients with the first progression of GBM is nine months. Currently, there is no standard treatment for progressive GBM. Common treatment options include clinical trials, surgical resection, re-irradiation, stereotactic radiosurgery, cytotoxic chemotherapies, bevacizumab, and tumor treating fields. Methods: This retrospective study reviewed 244 patients with the first progression of GBM who were treated at CCF between Jan 2012 to Jan 2020. Statistical analyses included patients who had biopsy-proven GBM, a known MGMT methylation status, a KPS of more than 70 and presented with the first progression on MRI brain. Four cohorts of patients were evaluated: Group 1 received cytotoxic chemotherapy, Group 2 received bevacizumab alone, Group 3 received surgical or radiation therapy alone, Group 4 received experimental treatments. Results: The median overall survival (OS) and progression-free survival (PFS) was 12.4 months (95% CI: 10.9 to 14.3) and 4.3 months (95% CI: 3.9 to 5.4), respectively. The cohorts demonstrate statistical significant differentiation for PFS (p = 0.021) but not OS (p = 0.19). Second progression was noted at a median interval of 5.6 months in Group 4, 4.3 months in Group 2, 3.8 months Group 3 and 3.2 months in Group 1. Conclusions: Patients with the first progression of GBM had a better progression-free survival on experimental clinical trials than those in other cohorts.
Updated safety/feasibility study of concurrent tumor treating fields (TTFields) and radiation therapy for newly diagnosed glioblastoma.
Authors: Grossman Rachel , Bokstein Felix , Blumenthal Deborah T. , Limon Dror , Ben Harush Carmit , Ram Zvi 
Published: May 2020

e14535 Background: Tumor Treating Fields (TTFields), a non-invasive, loco-regional, anti-mitotic treatment comprises low-intensity alternating electric fields. In the phase III EF-14 study in newly diagnosed glioblastoma (ndGBM), TTFields in combination with temozolomide (TMZ) significantly improved survival compared to TMZ alone. In preclinical studies TTFields had a radiosensitizing effect and increased the efficacy of radiation therapy (RT). This pilot study [NCT03780569] evaluated the feasibility and safety of TTFields administered concurrently with RT and TMZ in ndGBM patients. Methods: Patients with histologically confirmed ndGBM were treated with TTFields/RT/TMZ followed by adjuvant TMZ/TTFields. TTFields (200 kHz) were delivered for ≥18 hours/day with transducer arrays removed during RT delivery. RT was administered to the tumor bed in 30 fractions (total dose 60 Gy) in combination with daily TMZ (75 mg/m2). In the adjuvant phase, patients received monthly TMZ (150–200 mg/m2 for 5 days) plus TTFields. The primary outcome was safety of the combined therapies; secondary outcomes included progression-free survival (PFS) and overall survival (OS). Adverse events (AEs) were graded per CTCAE v4.0. Results: Ten patients were enrolled at a single center between April and December 2017. Median age was 60.2 years, median Karnofsky Performance Score was 90.0, and eight (80%) patients were male. Five (50%) patients had undergone tumor resection while the remainder had biopsy only. Eight patients experienced ≥1 RT treatment delay; delays were unrelated to TTFields treatment. All patients experienced ≥1 AE. Three patients suffered from serious AEs (urinary tract infection, confusional state, and decubitus ulcer) that were considered unrelated to TTFields. The most common AE was skin toxicity, reported in eight (80%) patients; all were of low severity (CTCAE grade 1–2) and were reported as related to TTFields treatment. Median PFS from enrollment was 8.9 months; median OS was not reached at the time of study closure. Conclusions: Eighty percent of patients experienced grade 1–2 TTFields-related skin toxicity. No other TTFields-related toxicities were observed and there was no increase in RT- or TMZ-related toxicities as a result of combining TTFields with these therapies. Based on the safety and preliminary efficacy results of this pilot study, a phase 2 randomized trial (N = 60; NCT03869242) and the Phase 3 TRIDENT trial have been initiated to further investigate the efficacy of concomitant RT/TMZ/TTFields in ndGBM. Clinical trial information: NCT03780569.
NF1 may serve as a novel genetic biomarker of response to treatment and prognosis in glioblastoma (GBM).
Authors: Huang Bin , Yang Ju , Wang Kongcheng , Chen Weitao , Ni Hongbin , Yan Jing 
Published: May 2020

e14539 Background: The intrinsic capacity of glioblastoma (GBM) tumor cells to infiltrate normal brain predictably results in high rates of early recurrence. Little has changed over the last decade in the treatment available for GBM with survival remaining poor and a novel genetic biomarker is necessary found to predict response to treatment and prognosis in GBM. Methods: Biomarker discovery was performed by a genome-wide screen using DNA extracted from tissue and blood samples of GBM patients. The biomarker was then evaluated for its predictability in OS of GBM patients compared with the Chinese Glioma Genome Atlas (CGGA) and revealed the relationship with tumor-associated macrophages (TAMs). Results: Median OS for NF1-deleted/mutated GBM patients (n = 11) treated with surgery and Chemoradiotherapy was 9.1 mon vs 17.2 mon for NF1 wildtype ones(n = 47), HR (95% CI) 1.83 (0.8753,3.817), p = 0.1. In addition, NF1-deleted/mutated GBMs showed reduced tumor purity and more infiltration of tumor-associated macrophages through pathological stainings. Conclusions: These data suggest that NF1-deleted/mutated GBM patients have a poor prognosis and NF1 may play a role in organizing the tumor microenvironment. NF1 in GBM will be further evaluated in a planned randomized ph 2b study in newly diagnosed GBM patients.
Safety and efficacy of bevacizumab biosimilar in glioma.
Authors: Singh Gunjesh Kumar , D'souza Hollis , Srinivas Sujay , Vallathol Dilip Harindran , Boppana Mounika , Rajpurohit Annu , Mahajan Abhishek , Janu Amit , Chatterjee Abhishek , Krishnatry Rahul , Gupta Tejpal , Jalali Rakesh , Patil Vijay Maruti 
Published: May 2020

e14541 Background: Anti-VEGF antibody Bevacizumab (Avastin: Roche Pharma AG) is the recommended drug for recurrent glioma. Multiple low-cost bio-similars of this drug are now available however their clinical efficacy has never been compared against the original molecule. The aim of the current analysis is to compare the overall survival (OS) between recurrent glioma patients with bio-similar and innovator molecule. Methods: Adult recurrent glioma patients treated with bevacizumab from 1st July 2015 to 30th July 2019 were identified from the Neuro-Medical Oncology database. These patients were either offered Avastin or Bevacizumab biosimilar (BevaciRel: Reliance Life sciences or Bryta: Zydus Oncosciences) depending upon the financial affordability. The primary endpoint of the study was OS. It was defined as the time in months from the start of bevacizumab to death. Progression-free survival (PFS) was defined as the time in months from the start of bevacizumab to progression or death. The time to event variables was estimated using Kaplan Meier method. The median with its 95% confidence interval (CI) was calculated using Brookmeyer and Crowley method. The estimates were compared between the original and bio-similar bevacizumab cohort using the log-rank test. The hazard ratio was calculated using COX regression analysis. Results: There were 82 patients, out of which 57 received innovator and 25 received bio-similar bevacizumab. At median follow up of 26 months, 76 patients had an event for progression. The median PFS was 3.66 (95% CI 2.08 to 5.25) and 3.3 months (95% CI 2.38 to 4.21) in innovator and bio-similar arm respectively (Log-rank test P-value = 0.072). The hazard ratio for progression was 0.61 (95% CI 0.35 to 1.05; P-value = 0.075). At the time of data cutoff, there were 69 deaths. The median OS was 5.53 (95% CI, 5.07 to 5.99) vs 7.33 months (95% CI, 5.63 to 9.03) in innovator and bio-similar arm respectively (Log-rank test P-value = 0.51). The hazard ratio for death was 1.21 (95% CI, 0.67 to 2.17; p-value = 0.51). Conclusions: In the brain tumor patients, both innovator and bio-similar bevacizumab seem to have similar clinical efficacy.
Post-operative disposition and readmission rates in repeat resections for glioblastoma.
Authors: Guzner Alex , Bushara Omar , Hou Alexander , Scholtens Denise M. , Burdett Kirsten Bell , Tate Matthew , Kumthekar Priya 
Published: May 2020

e14543 Background: Glioblastoma Multiforme is an aggressive primary brain tumor that will inevitably recur despite initial resection and maximal medical treatment, and re-resection is often pursued. Surgical resection has been shown to impact survival both in the upfront and recurrent settings, but it is unknown if subsequent resections impart worsened neurologic outcomes. The goal of this study was to evaluate patient’s post-operative disposition, hospital length of stay, and readmission within 30 days of discharge as a function of number of resections. Methods: This project was a retrospective chart review. Demographic information was collected regarding patients’ age, sex, IDH-1 mutation, and MGMT methylation status, and each patient’s discharge summary and hospital encounters were reviewed to determine length of hospital stay, location of disposition (home, acute rehabilitation facility, or skilled nursing facility), and readmission within 30 days of initial release. Univariate associations between each clinical predictor and outcome of interest were evaluated. Results: 162 patients with Glioblastoma as indicated on initial surgical pathology report met the inclusion criteria. 108 patients underwent two resections, 48 underwent three resections, and 6 underwent four resections. No statistically significant associations were observed between resection number and age, sex, MGMT methylation status, IDH-1 mutational status, disposition category, hospital length of stay, or readmission within 30 days. Disposition category after first resection was significantly associated with disposition category after second resection (p = 0.041) and readmission within 30 days after second resection was significantly associated with readmission within 30 days after third resection (p = 0.003). Hospital length of stay after second or third resections was not significantly different than a patient’s length of stay after first resection. Conclusions: These data demonstrate for the first time that subsequent resections are not associated with worse patient outcomes and that patient disposition after initial resection is an important predictor of disposition with subsequent resections.
Tolerability of radiation with concurrent temozolomide and effect on survival in chemo-refractory CNS lymphoma.
Authors: Laucis Anna Mary Brown , Selwa Katherine , Sun Yilun , Kim Michelle Miran , Cuneo Kyle Clifford , Lawrence Theodore Steven , Wahl Daniel Richard , Umemura Yoshie , Junck Larry 
Published: May 2020

e14554 Background: There is no consensus for the treatment of central nervous system lymphoma (CNSL) refractory to first line high dose methotrexate-based chemotherapy. Whole brain radiation (WBRT) has often been used but may lead to unacceptable neurocognitive dysfunction. We examined our institutional experience with treating CNSL with radiotherapy (RT) and concurrent temozolomide (TMZ) including the resultant acute and long term toxicities. Methods: This single institution IRB approved retrospective study examined treatment, toxicity, and outcome variables in adults with primary or secondary CNS lymphoma. Inclusion criteria were brain-directed RT and development of the treatment plan at our institution. Three main RT field designs were used, including low and high dose WBRT and low dose WBRT with a focal boost to residual disease (WBRT+boost). We assessed relationships between treatment approach (RT field design and concurrent TMZ use) and clinical outcomes and toxicities using multivariable logistic regression models and Kaplan-Meier methods. Toxicity was recorded using the Common Terminology Criteria for Adverse Events version 5. Results: A total of 93 patients with median age of 57 years (range 24 – 86) treated from 2004 – 2019 were included, and 26 patients received concurrent TMZ. The RT field design of low dose WBRT (median dose: 23.4Gy) plus focal boost (median dose: 21.6Gy) was associated with favorable overall survival (OS) and progression free survival (PFS) without any significant difference in Grade 3+ toxicity compared to low dose WBRT (p = 0.20) or WBRT without boost (p = 0.80). Concurrent TMZ with RT was associated with significantly improved OS (HR 0.46, p = 0.025) and CNS PFS (HR 0.49, p = 0.019). Four of nine (44%) Grade 3+ non-hematologic toxicities occurred in patients receiving concurrent TMZ (p = 0.40). The most common non-hematologic toxicities included fatigue and nausea. Long term neurocognitive dysfunction was similar whether or not patients received concurrent TMZ (21% in TMZ group vs 23% in non-TMZ group; OR 0.87, 95% CI 0.25 – 2.68, p = 0.82) and irrespective of RT field design (WBRT+boost vs low dose WBRT p = 0.25, WBRT+boost vs WBRT without boost p = 0.19). Conclusions: Our findings suggest that concurrent TMZ use with brain RT for chemo-refractory CNSL is a promising strategy, with improved survival and no major additional toxicity. Further research that includes rigorous neurocognitive assessments is needed in prospective clinical trials to guide treatment approaches using concurrent TMZ with brain RT in CNSL patients.
Effect of activating chimeric receptor on IL-15 armored NK cell on providing in vitro and in vivo antigen specific tumor response.
Authors: Chai Louis F. , Guha Prajna , Wadsworth Sarah , Gonzalez Denise , Rahman Nafees , Heatherton Kara R. , Tan Joanne B.L. , Trager James , Ghosh Chandra C. , Katz Steven C. 
Published: May 2020

e15016 Background: Colorectal cancer liver metastases (CRCLM) are a major source of morbidity and mortality. Historically, curative therapy has been limited to surgical resection, but only a small fraction of patients are eligible. Cellular immunotherapy has shown promise in hematologic cancers, but challenges related to solid tumor therapy remain with optimal cell trafficking, elevated interstitial fluid pressures (IFP), and immunosuppression. We hypothesized that engineered natural killer (NK) cells expressing a natural killer group 2, member D (NKG2D) activating chimeric receptor (ACR) and membrane bound IL-15 (NKX101) would increase anti-tumor activity in vitro and in vivo utilizing our established regional delivery strategies. Methods: In vitro cytotoxicity and cytokine release of NKX101 cells or non-transduced NK cells (NT-NK) derived from the same donor were determined by co-culture systems with HCT116 cells that endogenously express NKG2D ligands. CRCLM-bearing NSG™ mice were treated with NKX101, NT-NK, or vehicle (CTRL) via portal vein (PV) for regional delivery (RD) or tail vein (TV) for systemic delivery (SD). Tumor burden (TB) was measured via tumor bioluminescence (TBL) and histopathology (HP). Flow cytometry (FC) determined the quantity of cells delivered. Student’s t-test and Mann-Whitney tests were performed for statistical comparisons. Results: NKX101 transduction efficiencies ranged between 63.5 – 75.6% across 3 separate healthy donors. EC50 values derived from a 4-hour cytotoxicity assay for NKX101 vs. NT-NK were 3-4 fold lower with the greatest difference observed at the 1:1 effector-to-target (E:T) ratio (mean percent cytotoxicity: 72% vs. 20%, p = 0.001). In vitro cytokine assessment revealed 2.0-2.6 fold increases in IFN-γ, GM-CSF, and TNF-α levels compared to NT-NK cells (p < 0.0001 across all groups). In vivo, FC showed 2.89-fold increase in cell delivery using RD vs. SD on PTD1 (n = 3, p = 0.006). TBL was improved with 5 x 106 cells via PV vs. TV (n = 6) from post-treatment day (PTD) 1-7, with greatest difference seen on PTD7 (12.9 vs. 42.6, p = 0.07). HP analysis showed reduction of TB at PTD7 with PV treatment. Conclusions: NKX101 demonstrated improvements in in vitro cytotoxicity and pro-inflammatory cytokine release. RD techniques in vivo revealed increased cell delivery and improved tumor control. Further studies are underway to confirm our initial findings and understand NKX101 cellular kinetics and susceptibility to immunosuppression in the liver, along with planned clinical evaluation in Phase 1 trials.