bluuebunny/crossref_metadata_2025_split huggingface dataset:
A prospective study on the circulation and central nervous system after primary central nervous system B cell lymphoma treatment with rituximab.
Authors: Lin Tongyu , Peng Chen , Liu Shu , Guo Cheng-cheng , Wang Zhao , Huang He , Fang Xiaojie , Hong Huang Ming , Ren Quanguang , Li Fangfang , Li Xue Ying , Tian Ying 
Published: May 2019

e13518 Background: The use of rituximab(RTX)for the treatment of primary central nervous system lymphoma(PCNSL) is controversial, and whether the RTX permeability of the blood-brain barrier can be improved by craniotomy is unknown. Methods: ImmunocompetentPCNSL patients newly diagnosed via craniotomy or stereotactic biopsy were enrolled and received RTX (375 mg/m2, Q3w) treatment. Systemicnon-Hodgkin's B cell lymphoma (systemic-B-NHL)patients without CNS involvement served as the control group. The trough concentrations of RTX (CRTX) and CD19 levels in cerebrospinal fluid (CSF) and plasma were analyzed by ELISA and flow cytometry methods during each treatment cycle.The efficacy and adverse effects were recorded. Results: From December 2016 to February 2018, 21 PCNSL and 32 systemic-B-NHL patientswere enrolled. The CSF CRTXin the craniotomy-PCNSL group (0.2198±0.1866μg/ml) was significantly higher than those in the stereotactic-PCNSLgroup (0.0613±0.0408 μg/ml, P = 0.031) and the systemic-B-NHLgroup (0.0799±0.0614μg/ml, P = 0.046). The BBB penetrabilityof RTX in the craniotomy-PCNSL group (1.52±1.05%) was nearly four times that in the stereotactic-PCNSL group (0.41±0.19%, P = 0.048) and nearly three timesthat in the systemic-B-NHL group (0.54±0.61%, P = 0.012). No significant differences in the CRTXor BBB penetrability of RTX were observedbetween the stereotactic-PCNSL and systemic-B-NHL groups. CD19 levels in plasma fell below 0.1% in all patients before the second cycle of chemotherapy, and the time required for CSF CD19cell clearance in craniotomy-PCNSL patients tended to be reduced compared with that required by stereotactic-PCNSL patients. The CR and ORR rates of craniotomy-PCNSL patientswere 30% higher than those of stereotactic-PCNSL patients. Conclusions: The BBB penetrability of RTXand the CSF CRTXare significantly improved in PCNSL patients diagnosed via craniotomy.Rituximab could be recommended for routine use in craniotomy PCNSL patients. Clinical trial information: ChiCTR-TRC-11001687.
Proteogenomic characterization in glioblastoma multiforme.
Authors: Asif Samia , Fatima Rawish , Krc Rebecca , Bennett Joesph G. , Raza Shahzad 
Published: May 2019

e13521 Background: Glioblastoma (GBM) is an aggressive primary brain tumor carrying a dismal prognosis. Understanding molecular architecture of GBM is crucial for development of successful therapies against it. In this study, we performed an integrated proteogenomic analysis to determine a more comprehensive understanding of GBM phenotype. Methods: We performed quantitative proteomics and integrative genomic analysis based on The Cancer Genome Atlas (TCGA) datasets of GBM on 17 consecutive GBM patients. We collected information on driver mutations, oncogenes, major pathway alterations, mutation burden and molecular changes at both gene and protein level as well as clinical, treatment and survival data for the entire group. Results: Significantly mutated genes include TP53, EGFR, PIK3R1, PTEN, NF1, RET and STAG2. EGFR alterations by DNA amplification with multiple mutation allele frequencies were seen in 5(29.4%) patients including EGFRvIII expression, L816Q EGFR missense mutation on exon 21 and EGFR fusion (FGFR3-TACC3); all three are potential therapeutic targets of novel agents including EGFRvIII-specific dendritic cell vaccine, EGFR inhibitors and FGFR inhibitors. TP53 mutation was noticed in 30% of patients. TP53 Mutations were noticed in COSMIC hot spot driver gene and accompany IDH1 and ATRX mutations suggesting transformation from low to high-grade glioma. Only 1 patient had a high mutation burden and expired 17 months after initial diagnosis. In contrast, proteomics showed significantly high(n = 9,53%) EGFR expression. 75% of GBMs were MGMT methylated, a predictive marker of response to temozolomide. Twelve of the 17 patients are still alive; median overall survival was 16.5 months. Lowest survival observed was 5 months. Conclusions: This study identifies a distinct biological process that may characterize each glioblastoma differently. Proteogenomic data effectively recognizes potential therapeutic targets of GBM such as Exon 21 missense mutation, previously reported in lung adenocarcinoma with promising response to anti-EGFR antibodies. Incorporation of Whole Genome Sequencing into clinical practice will allow identification of new treatment options for GBM.
Access to diagnostics and treatment of neuroendocrine tumors (NETs): The difference between patient perception and reality.
Authors: Leyden Simone , Kolarova Teodora , Bouvier Catherine , Caplin Martyn E. , Conroy Siobhan , Davies Philippa , Dureja Sugandha , Falconi Massimo , Ferolla Piero , Fisher George A. , Goldstein Grace , Hicks Rodney J. , Lawrence Benjamin James , Majima Yoshiyuki , Metz David C. , O'Toole Dermot , Ruszniewski Philippe B. , Wiedenmann Bertram , Hollander Ron ,   International Neuroendocrine Cancer Alliance
Published: May 2019

e13524 Background: The aim of this global patient survey was to better understand the needs and expectations of patients with NETs regarding access to diagnostic tools and treatment. Methods: In 2017, an online, questionnaire survey of NET patients/family members, patient advocates and healthcare professionals (HCPs) was conducted. Results: In total, 443 participants from 26 countries responded: 338 patients/families; 35 advocates; 70 HCPs. Following NET diagnosis, many patients use patient association (69%) and HCP (48%) websites to fulfill their informational needs. Patients overestimated the availability of key diagnostic tools and treatments compared to HCPs: Gallium-68-Dotatate PET/CT scan was believed available by 28% of patients vs. 14% of HCPs; fluorodeoxyglucose PET by 77% of patients vs. 64% of HCPs; peptide receptor radionuclide therapy by 58% of patients vs. 23% of HCPs; genetic test/precision medicine by 75% of patients vs. 71% of HCPs; and transplantation by 86% of patients vs. 55% of HCPs. Reasons reported by patients and advocates for unavailability of treatment were: not provided by healthcare system (28% & 67%, respectively); non-referral (19% & 33%, respectively), unable to afford treatment (18% & 57%, respectively); treatment not covered by insurance (17% & 24%, respectively); distance to treatment centre (15% & 48%, respectively). Almost a third (30%) of patients had to travel more than 300 km/186 miles for treatment or consultation with a NET specialist, while 34% of patients did not have access to an MDT and those that did may be in contact with them less than once per year (14%). In contrast, advocates and HCPs believe there is wider availability of MDTs (94% and 70%, respectively). Conclusions: Patients are increasingly well-educated about NETs and often travel considerable distances to obtain specialist treatment. However, there remains considerable disparity in what patients feel is available to them in terms of the latest tools and treatments, compared to what is there in reality. This significant difference in perception needs to be managed delicately by both advocates and healthcare professionals.
Treatment monitoring of immunotherapy and targeted therapy using FET PET in patients with melanoma and lung cancer brain metastases: Initial experiences.
Authors: Galldiks Norbert , Abdulla Diana S.Y. , Scheffler Matthias , Schweinsberg Viola , Schlaak Max , Kreuzberg Nicole , Landsberg Jennifer , Lohmann Philipp , Ceccon Garry , Werner Jan-Michael , Celik Eren , Ruge Maximilian I. , Kocher Martin , Marnitz Simone , Fink Gereon R. , Langen Karl-Josef , Wolf Juergen , Mauch Cornelia 
Published: May 2019

e13525 Background: Due to the lack of specificity of contrast-enhanced (CE) MRI, the differentiation of progression from pseudoprogression (PsP) following immunotherapy using checkpoint inhibitors (IT) or targeted therapy (TT) may be challenging, especially when IT or TT is applied in combination with radiotherapy (RT). Similarly, for response assessment of RT plus IT or targeted therapy (TT), the use of CE MRI alone may also be difficult. For problem solving, the integration of advanced imaging methods may add valuable information. Here, we evaluated the value of amino acid PET using O-(2-[18F]fluoroethyl)-L-tyrosine (FET) in comparison to CE MRI for these important clinical situations in patients with brain metastases (BM) secondary to malignant melanoma (MM) and non-small cell lung cancer (NSCLC). Methods: From 2015-2018, we retrospectively identified 31 patients with 74 BM secondary to MM (n = 20 with 42 BM) and NSCLC (n = 11 with 32 BM) who underwent 52 FET PET scans during the course of disease. All patients had RT prior to IT or TT initiation (61%) or RT concurrent to IT or TT (39%). In 13 patients, FET PET was performed for treatment response assessment of IT or TT using baseline and follow-up scans (median time between scans, 4.2 months). In the remaining 18 patients, FET PET was used for the differentiation of progression from PsP related to RT plus IT or TT. In all BM, metabolic activity on FET PET was evaluated by calculation of tumor/brain ratios. FET PET imaging findings were compared to CE MRI and correlated to the clinical follow-up or neuropathological findings after neuroimaging. Results: In 4 of 13 patients (31%), FET PET provided additional information for treatment response evaluation beyond the information provided by CE MRI alone. Furthermore, responding patients on FET PET had a median stable clinical follow-up of 10 months. In 10 of 18 patients (56%) with CE MRI findings suggesting progression, FET PET detected PsP. In 9 of these 10 patients, PsP was confirmed by a median stable clinical follow-up of 11 months. Conclusions: FET PET may add valuable information for treatment monitoring in individual BM patients undergoing RT in combination with IT or TT.
The role of postradiation temozolomide in patients with newly diagnosed MGMT methylated glioblastoma.
Authors: Sun Yuqing , Romo Carlos G , Shah Pavan , Grossman Stuart A. 
Published: May 2019

e13530 Background: Standard therapy for patients with newly diagnosed glioblastoma (GBM) includes concurrent temozolomide (TMZ) and radiation (RT) followed by six monthly cycles of adjuvant TMZ. Although TMZ improves survival for MGMT methylated patients, it is unclear if this benefit is from the TMZ given with the radiation, the adjuvant TMZ, or if both are required. This retrospective study was designed to identify MGMT methylated patients who started treatment with near-normal functional status, completed concurrent RT+TMZ, but did not receive adjuvant TMZ to estimate if their survival was significantly less than expected. Methods: We reviewed charts from 190 adults diagnosed with GBM at Johns Hopkins Hospital from 2013 to 2015 recording their Karnofsky Performance Score (KPS), extent of resection, MGMT-methylation and IDH1 mutation status, and treatment records. We selected patients with MGMT-methylated GBM who received concurrent RT+TMZ without adjuvant TMZ for this study. Patients with a KPS < 70 or severe post-radiation complications were excluded. Results: Six patients met the selection criteria. They had a median age of 65 years, average KPS of 80, 2/6 had a gross total resection, and all were IDH1 wildtype. Their overall survival ranged from 17 to > 46 months. Conclusions: The overall survival of these patients who received no adjuvant TMZ is very similar to the median of 23 months reported in the literature for MGMT methylated patients who received adjuvant TMZ. This preliminary data suggests that a prospective study in MGMT methylated patients comparing concurrent RT+TMZ followed by either standard adjuvant TMZ or observation could be considered without placing patients in the experimental arm at excessive risk.[Table: see text]
Safety and pharmacokinetics of BXQ-350 in a phase 1a and 1b trial of solid tumors and high-grade glioma.
Authors: Rixe Olivier , Morris John Charles , Puduvalli Vinay K. , Villano John L. , Wise-Draper Trisha Michel , Wesolowski Robert , Yilmaz Emrullah , Lanverman Sheena M , Karivedu Vidhya , Patterson Maria T , Qi Xiaoyang 
Published: May 2019

e13531 Background: BXQ-350 is composed of the multifunctional, lysosomal-activator protein Saposin C and phosphatidylserine lipid with demonstrated antitumor effects in vitro and in vivo. In this abstract we update the safety and pharmacokinetic (PK) profile based on an ongoing Phase 1 trial. Methods: BXQ-350 was administered in a Phase 1a dose-escalation trial (NCT02859857), and an ongoing Phase 1b trial (data cut off at max of 6 cycles, 01DEC2018) to refractory solid tumor/high-grade glioma patients (pts). In Phase 1a, pts received escalating IV BXQ-350 doses of 0.7, 1.1, 1.4, 1.8, or 2.4 mg/kg on days 1, 2, 3, 4, 5, 8, 10, 12, 15, 22 (cycle 1), 29 (cycle 2), and thereafter 28-day cycles. PK was assessed over a 24-hr period following the first dose. The Saposin C level was analyzed by ELISA and PK parameters were calculated using noncompartmental methods. Results: The 1a cohort of 18 pts (age 24-69) had a median of 3 cycles and 1b cohort of 20 pts (age 31-80) had median of 2 cycles with no treatment-related serious adverse events to date. Moderately severe related adverse events (AEs, n case, n events) are reported with serious non-related events. The most common treatment-related AE was fatigue (2 at dose 1.1, 2 at 1.8, 1 at 2.4mg/kg and 3 in 1b), at 2.4 mg/kg, 1 pt had moderate blood pressure elevation. Exposures in the 1.4 and 1.8 mg/kg cohorts were less than dose-proportional, likely due to higher clearance in those groups. The overall mean clearance and half-live values were 66.8 (mL/kg/h) and 4.03 h, respectively. Conclusions: BXQ-350 has had no serious related AEs during dose-escalation or in the on-going trial supporting a tolerable safety profile at 2.4 mg/kg. Clinical trial information: NCT02859857. [Table: see text]
Factors associated with delays in diagnosis of pediatric, adolescent and young adult patients with central nervous system tumors.
Authors: Puccetti Diane Marie , Winestone Lena , McPheeters Jeffrey , Wilkes Jennifer Jill , Henk Henry J. , Alvarez Elysia Marie 
Published: May 2019

e13532 Background: Central Nervous System (CNS) tumors are the most common solid tumor in children and have the highest mortality. Delays in diagnosis (Dx) may lead to reduced survival. We identify factors associated with delays in Dx in pediatric, adolescent and young adult (AYA) patients with CNS tumors. Methods: A retrospective cohort from the OptumLabs Data Warehouse, which includes claims data for privately insured enrollees in a large US health plan, was identified. Patients diagnosed with CNS tumors between 2001-17 continuously enrolled 6 months prior to diagnosis (Dx) were included. The onset of cancer symptoms was identified by the date of the first encounter associated with cancer symptoms. Time to Dx was calculated as the days between cancer symptom onset and Dx date. The likelihood of presenting with symptoms and the time to Dx (among those with symptoms) was modeled using logistic regression and included sociodemographic and clinical factors. A delay in Dx was defined as > 3 months after a symptom. Results: We identified 6,627 eligible patients, 5,637 (85%) of whom presented with symptoms prior to Dx. Likelihood of a delay appears greatest in those first presenting to a specialist (OR 1.28 vs PCP; P = .24 ) but lowest in those presenting to Urgent care/ER (OR .56 vs PCP; P < 0.001) and was greatest among children < 5 years of age were more likely to present with a symptom (table). However, among those with a symptom, children < 5 had the longest time to Dx (Median 122 days). Males were less likely to present with a symptom prior to Dx (OR .80, P = 0.040) and when experiencing a symptom they experienced shorter time to Dx compared to females (Median 85 vs 110 days). Race, income, and census region were not significant predictors of either likelihood of presenting with symptoms or delay in time to Dx. Conclusions: This study indicates that young children < 5 years had a longer delay in diagnosis compared to older patients. [Table: see text]
The utility of proton MR spectroscopy in diagnosing B cell lymphoma.
Authors: Faiek Saif , McKay Lauren , Zeidwerg David , Stidd David , Zhou Ruifeng 
Published: May 2019

e13536 Background: Diffuse Large B Cell Lymphoma (DLBCL) is the most common and increasingly prevalent subtype of Non-Hodgkin lymphoma in both immunocompromised and immunocompetent patients. Its pathogenesis is thought to represent rearrangements, translocations, and transformations of both the immunoglobulin heavy and light chain genes along with somatic mutations of the variable regions of these same genes. A 66-year old Caucasian male with a past medical history of smoking presented to the hospital due to concerns of mental status change, flat affect, and fronto-orbital headache for one-week duration. The patient denied any drug or substance abuse. Physical exam was diffusely normal with the exception of flat affect. Methods: Magnetic resonance spectroscopy is a noninvasive, non-ionizing diagnostic analytical technique that has been used to measure metabolic changes in brain lesions. Results: Lhermitte’s sign was negative and NIH stroke scale was calculated to be 0. CT demonstrated a 17mm frontal lobe lesion. Follow up with MRI showed three bilateral enhancing brain lesions, but no metastasis or primary tumor was seen via CT of chest, abdomen, and pelvis. Initial differential diagnosis included: Tumefactive Multiple Sclerosis, Acute Demyelinating Encephalomyelitis or CNS lymphoma. EEG did not highlight any focal or epileptiform abnormalities and lumbar puncture was negative for Creutzfeld Jacob Disease and Multiple Sclerosis. The patient was discharged with a course of intravenous steroids only to present a few weeks later with no improvement of symptoms. The patient then had proton magnetic resonance spectroscopy (MRS). MRS pattern spikes and chemical profile suggested lymphoma, which was confirmed by a brain biopsy. The patient was subsequently transferred to the University of Pennsylvania for treatment and further management. Conclusions: This case illustrates the beneficial use of MRS, as data patterns it provides compliments the clinician’s knowledge to proceed with appropriate treatment.
Leptomeningeal spread of glioma in the molecular era.
Authors: Alnahhas Iyad , Guillermo Prieto Eibl Pilar , Gonzalez Javier , Giglio Pierre , Puduvalli Vinay K. 
Published: May 2019

e13537 Background: Leptomeningeal disease (LMD) is an uncommon event in patients with gliomas which is estimated to occur in 4% of cases and is associated with poor outcome. Genomic alterations in gliomas that precipitate LMD have not been characterized. Methods: We performed a retrospective chart review of patients with gliomas (grade II-IV)- for whom we have genomic testing data at The Ohio State University. We identified patients who developed LMD. LMD was defined as leptomeningeal enhancement as seen on brain or spine imaging. Patients with negative cerebrospinal fluid (CSF) cytology were not excluded if imaging was convincing of LMD. Genomic testing was performed through Foundation One. Results: 129 charts of glioma patients were reviewed. We identified 6 patients with LMD. One is still alive. All patients were diagnosed histologically as glioblastoma. One patient had Lynch syndrome. All patients were men with a median age at diagnosis of 44 (range 20-65). All tumors appeared to have extended into the ventricles on brain imaging. 4 tumors had evidence of subependymal spread prior (range 45-93 days) or at the time of LMD enhancement. 4 patients had available CSF studies: 2 of whom had evidence of atypical or malignant cells. CSF protein was elevated in all four samples (range 113-492 mg/dL). CSF glucose was low in all four samples (range < 10-46 mg/dL). 5 tumor samples were IDH wild type whereas 1 had IDH1 R132H mutation. MGMT promoter was methylated in 3 tumors and unmethylated in 3. The genomic alterations varied among samples and included EGFR V765M mutation (N = 1), PDGFR amplification (N = 1), PDGFRA Y849C subclonal mutation (N = 1), CDKN2A/B loss (N = 3), TP53 mutations (N = 4) and TERT promoter mutations (N = 3). No case had EGFR amplification or EGFRvIII mutation. Other alterations observed included DNMT3A mutation, KIT, MYC and MDM2 amplifications and RB1 losses. PD-L1 expression ranged from 5-40%. One intracranial sample had a 20% PD-L1 expression with LMD from this tumor exhibiting 40% PD-L1 expression. Of the five deceased patients (all IDH WT), median overall survival (OS) was 355 days (range 184-557). Median OS after LMD diagnosis was 84 days (range 58-225). Conclusions: In this series, 4.5% of glioma patients developed LMD. Samples were associated with a variety of genomic alterations but without a specific predictor of leptomeningeal involvement. This is possibly due to the small number of cases. Physical proximity of the tumor to the ventricles appears to be a potential risk factor. Larger studies of LMD in gliomas are warranted to identify potential genetic drivers, if any exist.
Efficacy of a novel potent and high water-soluble selective PARP inhibitor CVL218 in glioma.
Authors: Shen Steve , Miao Zehong , Yang‘ Chunhao 
Published: May 2019

e13539 Background: Glioma is the most common, deadly, and difficult-to-treat intracranial tumor. Up to 70% of gliomas are found to carry isocitrate dehydrogenase (IDH) mutations, which induce a homologous recombination defect (HRD) that renders glioma cells sensitive to poly (ADP-ribose) polymerase inhibitors (PARPi). However, 4 launched PARPi have limitation for IDH-mutant glioma because of low concentration level in brain. CVL218 is a novel potent and high water-soluble selective PARP-1/2 inhibitor. Pharmacokinetic studies in rats showed that CVL218 can easily across the BBB, has 10 times higher concentration in brain than in the plasma, indicating its therapeutic potential in glioma. Here, we examined its effect on glioma in vitro and in vivo. Methods: BT142 mut/- glioma cells with a homozygous IDH1 R132H mutation were exploited. Chemotherapeutic agent temozolomide (TMZ), PARPi Olaparib and Niraparib, were used as controls. The inhibition of BT142 cell growth by compounds in vitro was measured by MTT assay. Female NOD/SCID mice with orthotopic xenografts of BT142 glioma cells were used to evaluate the antitumor efficacy of compounds in vivo. Medium survival time (MST) was compared using the Kaplan-Meier method and logrank test. Results: CVL218 inhibited the BT142 cell growth in vitro with an IC50 of 2.07 ± 0.62 μM, better than Olaparib and Niraparib. Orthotopic xenograft glioma mice model study showed that CVL218 group significantly extended the MST to 98.0 days ( p= 0.0206), while MST of TMZ treated group is 85.0 days. Conclusions: CVL218 inhibits IDH1-mutant BT142 glioma cell growth in vitro and in vivo. The present findings suggest that CVL218 is a potential agent which could be useful as a treatment for IDH-mutant glioma. We will start its phase I clinical study for glioma soon.