bluuebunny/crossref_metadata_2025 huggingface dataset:
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.
BRAFv600e mutated gliomas: From biology to radiology and treatments.
Authors: Lhermitte Benoit , Guerin Eric , Chammas Agathe , Namer Izzie Jacques , Gauchotte Guillaume , Kremer Stephane , Roques Gaelle , Chenard Marie Pierre , Dontenwill Monique , Entz-Werle Natacha
Published: May 2019

e13552

Background: BRAF V600E mutation is encountered in brain tumor, mostly low grade pediatric diffuse glioma (LGG) and epileptogenic glioneuronal tumor such as gangliogliomas (GG) or pleomorphic xanthoastrocytomas (PXA). Less frequently this mutation is present in high grade glial or glioneuronal tumors such as pleomorphic xanthoastrocytomas with anaplasia, anaplastic ganglioglioma, anaplastic diffuse astrocytomas or glioblastomas. Recently, few publications were highlighting differently the impact of BRAF mutation and CDKN2A deletion, as independent prognostic factors linked to a worst outcome in low grade forms. Methods: We studied retrospectively a monocentric cohort of 12 LGGs and 9 HGG with BRAFv600e positivity. The patients were aged from 1 to 47 years. Most of the LGG were under 25 years and only 3 patients with HGGs had less than 18 years old. We focused on extended biology assessment by Next generation sequencing of the tumors and their relapses, tumor metabolomics analyses, radiology comprising MRI, PET-scanning and spectroscopy and correlate them to tumor’s evolution and its treatment. Results: Among the LGGs, we had 9 GG and 3 pilocytic astrocytomas and only one had a CDKN2A deletion and one a gain on chromosome 5. 6 had a complete surgical resection, 2 had a minimal residue and 4 had chemotherapeutic treatment after partial surgery and underwent relapses. All HGGs had a surgical resection followed by chemotherapy (mainly Stupp protocol) and radiotherapy. 5 relapsed rapidly, benefit from targeted therapy with vemurafenib and are still in long term remission. In this HGG group, we had two subgroups: 4 patients with “de novo” tumors and 5 patients with a past history of LGG tumors in the same brain region. Both were responding well to targeted treatments and all had an additional CDKN2A deletion. Specific radiological and spectroscopic signs were linked to those two groups and seem to be associated to a specific metabolomic profile in each group. Currently, we are going further in the correlation between MAPK signaling pathway and metabolomic profile to be able to predict in LGG their potential evolution. Conclusions: BRAF mutated gliomas seem to have specific radiological and metabolomic correlations associated to their biology
A critical appraisal of the quality of glioma imaging guidelines using the AGREE II tool: A EuroAIM initiative.
Authors: Bisdas Sotirios , Romeo Valeria , Stanzione Arnaldo , Ugga Lorenzo , Cuocolo Renato , Cocozza Sirio , Brunetti Arturo , Shaikh Faiq , Roettger Diana
Published: May 2019

e13553

Background: Following the EuroAIM initiative to assess the quality of medical imaging guidelines by using the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument, we aimed to evaluate the quality of the current imaging guidelines in patients with gliomas. Methods: A literature search was conducted to identify eligible imaging guidelines considered in the management of adult patients with gliomas. The selected guidelines were evaluated using the AGREE II instrument by four independent appraisers. The agreement among the four appraisers was estimated using the intraclass correlation coefficient (ICC) analysis. Results: Seven guidelines were selected for the appraisal. Six out of the seven guidelines showed an average level of quality with only one showing a low quality. The highest scores were found in Domain 1 “Scope and purpose” (mean score = 81.2%) and Domain 4 “Clarity of presentation” (mean score = 77.6%). The remaining domains showed a low level of quality and, in particular, Domain 5 “Applicability” was the most critical with a mean score of 41.7%. The ICC analysis showed a very good agreement among the four appraisers with ICC values ranging from 0.907 to 0.993. Conclusions: The available guidelines on glioma imaging emerged as of average quality according to the AGREE II tool analysis. Based on these results, further efforts should be made in order to involve different professional bodies and stakeholders and increase patient and public involvement in any future guideline drafting as well as to improve the applicability of these guidelines into the clinical practice.
Exploiting metabolic susceptibilities in glioblastoma via glycolytic inhibition and ketogenic therapy.
Authors: Vallejo Frederic Anthony , Shah Sumedh , Walters Winston , Kostenko Katrina , Torrens Ingrid , Prince Jeffrey , Raez Luis E. , Khatib Ziad , Vanni Steven , Graham Regina M.
Published: May 2019

e13558

Background: Glioblastoma (GBM) remains one of the most lethal primary brain tumors in children and adults. Despite enormous efforts to elucidate the genetic and epigenetic drivers of this disease, the prognosis for patients diagnosed with GBM remains dismal. Because tumor cell metabolism differs greatly from that of normal non-cancerous cells, it is possible to develop therapies which more effectively target the cancer cell while sparing normal cells. Growing in popularity is the ketogenic diet, which is a high fat, very low carbohydrate diet resulting in the production of ketone bodies, acetoacetate (AA) and β-hydroxybutyrate (βHB) to generate ATP. Methods: Analysis conducted by open-access GBM patient database, mts assay, Western blot, neurosphere assay, and TEM. Results: Enzymes required for ketone metabolism (BDH1 and OXCT1) were significantly downregulated in GBM while glycolytic enzymes were significantly upregulated (HK2, HK1, SLC2A3, NAMPT, G6PD). GBM stem cell (GSC) markers (CD44, STAT3) positively correlated with glycolytic enzymes. Ultrastructural analysis of GSCs indicated that about half of the mitochondria were missing cristae, highly suggestive of an increased glycolytic dependency. Treatment of patient-derived GSC lines as well as non-stem cell lines SJGBM2 (pediatric) and U87 (adult) resulted in a dose-dependent decrease in viability in response to the glycolytic inhibitor 2-deoxy-D-glucose (2-DG). When cells were exposed to ketone bodies, AA but not βHB induced a dose-dependent decrease in cell viability with 10 mM reducing viability ranging from 20-80% of non-treated controls. Western blot analysis demonstrated robust caspase activation and PARP cleavage in response to AA. Furthermore, AA significantly reduced GSC neurosphere formation at 2.5 mM suggesting inhibition of GSC self-renewal pathways. Combined treatment of low dose 2-DG (50 μM) with increasing concentrations of AA resulted in more cell death than either treatment. The effect was more than additive at the low concentrations of AA (1- 5 mM) suggesting synergy. Conclusions: Glycolytic inhibition in conjunction with the ketogenic diet may be a promising therapeutic route for this difficult-to-treat cancer.
Low platelet counts in patients with glioblastoma.
Authors: Ali Assad , Barnett Addisson , Saeed Bamashmos Anas , Li Hong , Wei Wei (Auston) , Sagar Soumya , Barnett Gene H. , Angelov Lilyana , Mohammadi Alireza Mohammad , Peereboom David M. , Stevens Glen , Suh John H. , Yu Jennifer S. , Murphy Erin Sennett , Ahluwalia Manmeet Singh
Published: May 2019

e13565

Background: Radiotherapy and concurrent chemotherapy with Temozolomide (TMZ) have myelosuppressive effect, and thrombocytopenia is commonly seen in this patient population seen in 5-10% of glioblastoma (GBM) patients. There is a lack of data analyzing the thrombocytopenia and it’s on the progression free survival (PFS) or overall survival (OS) of these patients. The primary objective of this study was to identify the degree of thrombocytopenia in newly diagnosed GBM patients receiving concurrent TMZ based chemoradiation (CRT). Secondary objectives included associations between thrombocytopenia PFS, and OS. Methods: We retrospectively reviewed 484 newly diagnosed GBM patients who underwent surgery followed by standard of care CRT. We also analyzed the association between platelet counts and age, sex, MGMT methylation status, and extent of surgical resection. Platelet count was collected at the time of surgery, CRT start date, and two, four, six, and ten weeks post-CRT start date. Patients were grouped into quartiles according to their platelets count. Results: Of the 484 patients collected, 308 were males, 139 had gross total resection of the tumor, 229 patients were older than 65 years, and 171 (42.1%) were MGMT methylated. In a univariate analysis, a platelet count less than 180,000 (lowest quartile) was associated with higher mortality (HR 1.63, P < 0.001) but had no significant association with PFS (HR 1.16, P = 0.48). Among the 118 patients who had platelet count lower than 180,000, 4 had platelets count less than 100,000 necessitating their TMZ to be stopped during CRT. In a multivariate analysis model adjusting for age, gender, MGMT status, and type of surgery, platelet counts less than 180,000 was also associated with significantly higher mortality (HR 1.60, P < 0.001). Conclusions: Our study concluded that patients who had platelet counts less than 180,000 at the time of surgery or CRT with TMZ had significantly higher mortality (HR 1.60, P < 0.001) but had no association with PFS (HR 1.16, P = 0.48).[Table: see text]
Using PIK3CB and connexin-43 inhibition to sensitize pediatric glioblastoma cells to temozolomide.
Authors: Shah Farah , Sheng Zhi
Published: May 2019

e13572

Background: Glioblastoma (GBM) is one of the most common high grade gliomas in pediatric patients, accounting for 2.8% of central nervous system tumors. Standard of care for glioblastoma includes surgical resection, radiation, and temozolomide chemotherapy. However, many pediatric patients are not suitable candidates for surgery, and their tumors inevitably develop temozolomide resistance. Despite aggressive treatment, temozolomide (TMZ) resistance leads to tumor recurrence in 90% of patients. Thus, outcome for children with pediatric GBM remains poor with a 2-year survival rate ranging from 10-30%, highlighting the need for new therapeutic approaches. Connexin-43 (Cx43) and PIK3CB are proteins involved in conferring temozolomide resistance in glioblastoma. Combined inhibition of these proteins could improve temozolomide sensitivity and help develop a selective therapy that significantly improves quality of life and prognosis in pediatric glioblastoma patients. Methods: Primary GBM cells were plated in a 96-well plate and treated with vehicle (DMSO), TMZ (50 μmol/L), TGX-221 (20 μmol/L), αCT1 (30 μmol/L), or a combination of the latter three drugs. Cell viability was measured using the MTS assay. Primary pediatric GBM cell lines SJ-GBM2 and CHLA-200 were tested. These drug combinations were also tested in normal human astrocytes to make sure there were no off-target effects. Results: We found that targeting PIK3CB and Cx43 in primary pediatric GBM increases their sensitivity to TMZ. The triple combination of TMZ, TGX-221, and αCT1 significantly decreased cell viability than each drug alone while sparing normal human astrocytes. Conclusions: Our findings suggest that inhibiting PIK3CB and Cx43 enhances therapeutic response to TMZ and limits off-target effects in pediatric GBM. These findings closely mirror our results using the triple combination in adult glioblastoma as well, thus laying the groundwork for a novel combination therapeutic that can be used across age groups.
Study of a smartphone-based symptom assessment (OurBrainBank) for subjects with glioblastomas.
Authors: Morris Jessica , Hellman Bruce , Duprey Kelli , Ellen Jacob , Nayak Lakshmi , Iwamoto Fabio
Published: May 2019

e13574

Background: Self-reports from patients done monthly or every few months in the doctor’s office have several limitations, including poor recall, under- or over-reporting of events, among other biases. Methods: We developed a glioblastoma specific app (OurBrainBank) using a platform designed by uMotif, which was previously used in other conditions but has been customized for glioblastoma. All data are sent to a HIPPA compliant database. The subject can view or export their own data as well and create data reports to their medical team. Inclusion criteria included age 18 years or older, diagnosis of glioblastoma, English-speaking subject, and availability of a smartphone or tablet. After electronic informed consent, patients completed baseline questionnaires about their treatment and validated surveys (EORTC-QLQ, EORTC-BN20). Certain parameters such as sleep quality, exercise, mood, and fatigue were captured for all patients. In addition, patients picked 6 additional symptoms most relevant to their clinical condition. Results: Since the study was IRB-approved and the app made available free of charge on app stores, there have been 305 individual patients who registered on this app. Recruitment has relied heavily on social media and patient run online support groups. The most commonly tracked symptoms were exercise, fatigue, mood, sleep quality, appetite, memory and concentration. Patients were alerted to capture symptoms at least weekly and more than 5,000 datapoints were captured. The median age was 48 (18-83). 53% of patients had received the GBM diagnosis < 1 year and 25% between 1-2 years. Most patients found symptom tracking useful (average rating of 7 in 0-10 scale). Conclusions: At this initial stage, OurBrainBank has shown that it can efficiently collect glioblastoma patients’ symptoms. In the next steps, we plan to collect passive data from smartphones and other device trackers. Additionally, OurBrainBank will enable patients to donate their medical records to a national and international database. The goal over the next few years is to create an unprecedented database of high quality and granularity with tens of thousands of de-identified glioblastoma patients, with open-access to qualified academic researchers. In addition, this powerful ‘real world experience’ database will be useful for pharma/biotech companies.
Access to clinical trials, multidisciplinary environment, and health care providers by facility type and outcomes of patients with newly diagnosed glioblastoma using SEER-Medicare dataset.
Authors: Zhu Ping , Du Xianglin L. , Esquenazi Yoshua , Zhu Jay-Jiguang
Published: May 2019

e13576

Background: Prior studies demonstrated the superior outcomes among glioblastomas patients treated at academic facilities (ACs) verses non-academic facilities (non-AC). However, the factors contributed to the survival benefit observed at ACs remain unknown. Methods: Eligible GBM patients between 2004 and 2014 were derived from the SEER-Medicare database. Patients were categorized by treatment facility status (AC versus non-AC). Outcomes include overall survival (OS) and the receipt of surgery and adjuvant therapies. Kaplan-Meier and Cox proportional hazard model were applied for survival analysis, and multivariable binary/multinomial logistic regression models were performed to compare differences in treatments received and hospital characteristics by facility type. Results: A total of 3263 patients treated at 562 facilities were included. Significantly superior survival was observed at ACs [Hazard ratio (HR): 0.92, 95% CI: 0.85-0.99, P = 0.024], prior to and after adjusting all covariates. Radiation and chemotherapy were utilized more frequently at ACs. For the access to clinical trials, ACs were more likely to be NCI designated cancer center, Radiation Therapy Oncology Group (RTOG), and American College of Surgeons Oncology Group (ACSOG) compared to non-ACs (all P < 0.001). For multidisciplinary resources, ACs had higher probability to provide health care services in emergency, intensive care, inpatient care, nuclear medicine, operative room, and radiation treatment than non-ACs (all P < 0.01). Further, there were more sufficient health care provider resources (number of full-time registered nurses, physicians, and total beds) at ACs over non-ACs (all P < 0.001). Conclusions: This study identified factors that contributed to the superior outcomes when GBM patients are treated at ACs. An increased likelihood of undergoing adjuvant therapies, access to clinical trials, multidisciplinary environment, and available health care provider resources in ACs are important contributors to the improved GBM outcomes.
Single center, open and prospective evaluation of genomic sequencing on cerebro-spinal fluid, brain metastatic lesions and plasma from patients in non-small cell lung cancer with brain metastasis.
Authors: Ma Chunhua , Huang Chuoji , Li Zhi , Jiang Rong , Zhang Juncheng
Published: May 2019

e13578

Background: Leptomeningeal metastases are observed in 9.4% non–small Cell Lung Cancer (NSCLC) patients with EGFR mutations. Depending on patient specific gene mutations, tumor cells may also have different proliferative activity, leading to differential metastatic potential. However, the clinical significance of observed gene mutation differences between CSF, plasma, primary pulmonary tumor and metastatic brain tumor samples remains unclear and should be further explored. Methods: From Apr. 2018 to Jan. 2019, plasma and CSF paired samples were drawn from consented NSCLC patients with diagnosed brain metastasis. Of these 21, brain lesion samples were obtained from 5 patients. All the samples were tested by next-generation sequencing. Patients were treated based on the detection results. Results: For this cohort, the detection rate of EGFR mutations in CSF cfDNA versus plasma cfDNA/CTC was 57.1% and 23.8% respectively (p < 0.05). For patients who had not received tyrosine kinase inhibitor (TKI) therapy, the CSF cfDNA EGFR mutation results were consistent with results for plasma, brain lesion and primary tumor samples. Conversely, for patients who had received TKI therapy, EGFR mutations detected in CSF were consistent with those from brain samples, but different from those observed in plasma or primary tumor samples. A high response rate (ORR, 70%; DCR, 90%) was observed in patients with EGFR positive detected in CSF after treatment with second orthird-generation TKI. Among the EGFR mutations detected in CSF, the EGFR uncommon mutation frequency was 58.3%(7/12), including G7I9A/L861Q/L703P/R776H/G575R/T790M 85.7% (6/7) of these occurred in LM patients. One patient who progressed from BM to LM had an uncommon mutation in the CSF sample. Among these five patients with EGFR G719A or L861Q positive and T790M negative, 4 patients had PR and 1 patient had SD after the second-generation TKI therapy. Conclusions: Differences in EGFR gene mutations were observed between CSF, plasma, primary pulmonary lesion and brain tissue samples in NSCLC patients with diagnosed brain metastasis after TKI therapy. The reasons for this discrepancy remain to be understood. Nevertheless, CSF may be a useful prognostic tool for patient monitoring and metastasis risk evaluation. The detection of uncommon EGFR mutations may increase the risk of LM in NSCLC patients. Clinical trial information: ChiCTR1800017499.
Effect and utility of targeted and immune therapy as single agent treatment for brain metastases in patients with non-small cell lung cancer.
Authors: Shalabna Hassan , Lokiec Alejandro , Haim Nissim , Wollner Mira
Published: May 2019

e13581

Background: Brain metastases are estimated to occur in approximately 30% of patients with metastatic non-small cell lung cancer (NSCLC). Patients with brain metastases experience significant morbidity, often with neurological dysfunction and cognitive impairment. While brain radiation therapy was the foundation of management, it is associated with delays in systemic drug therapy and neurocognitive impairment. The use of immunotherapy or targeted therapy (TKIs) in well-selected patients may be effective in all tumor sites, including the central nervous system with a low toxicity profile.Therefore, this study aims to examine the clinical and radiological effect and efficacy of biological treatment or immunotherapy on brain metastases in patients with NSCLC and to present a new therapeutic approach. Methods: This retrospective/prospective study includes all patients referred to Oncology department- Rambam Medical Center from Oct. 2008 till Jul. 2016, and prospective for one year started from 01 Aug. 2016. The patients were diagnosed with NSCLC with brain metastases, and treated with immunotherapy or targeted therapy as single agent without radiotherapy. Treatment response was defined as symptomatic improvement and/or radiologic regression. Results: Overall, 16 patients were included. 12 patients (75%) with EGFR mutation or ALK TRANSLOCATION. 11 patients were treated with targeted therapy, and 5 were treated with immunotherapy. 7 patients (43%) had neurological symptoms and 5 of these had clinical response lasted 3 to 11 months. Of the 11 patients receiving biological therapy, 9 (82%) had a good response with tolerable treatment. Of the 5 patients treated with immunotherapy, 2 patients had a radiologic response. 6 patients with no smoking history had EGFR mutation or ALK TRANSLOCATION and received biological therapy, all of them had radiologic response, accounting for 55% of the total of patients who responded. However, only 5 out of 10 patients who are active smokers or had smoking history, had a response. This implies that all patients who did not respond to the treatment are either current or past smokers. (P = 0.09). There was no difference in response to targeted therapy or immunotherapy in patients who received brain radiation therapy in the past compared to patients who were not radiated previously. Conclusions: There is an intracranial effect of targeted therapy or immunotherapy in NSCLC patients. These treatments can delay or prevent radiation therapy to the brain and all its related neurological damage.
Molecular profiling using the 92-gene assay for tumor classification of brain metastases.
Authors: Brenner Andrew Jacob , Collazo Raul , Schnabel Catherine A. , Greco F Anthony
Published: May 2019

e13583

Background: Nearly 200,000 patients are diagnosed with brain metastases in the US annually. Advances in targeted therapies make definitive diagnosis of the primary tumor type important but can be challenging in many patients. The 92-gene assay is a validated gene expression classifier of 50 tumor types/subtypes for patients with uncertain diagnoses. Results from a clinical series of brain biopsies and potential impact on treatment were evaluated. Methods: An IRB-approved, de-identified database of clinical and molecular information from biopsies (N = 24,486) submitted for testing with the 92-gene assay (CancerTYPE ID, Biotheranostics, Inc.) as part of routine care were reviewed. Descriptive analysis included patient demographics and molecular diagnoses. Results: Analysis included 464 brain biopsies. A molecular diagnosis was provided in 433 (93.3%) tested ( < 5% assay failure rate) with 24 different tumor types. Six primary tumor types made up the majority (67.4%) with almost one-third of the molecular predictions being Lung (31.2%), followed by Neuroendocrine (NET) (9.9%), Sarcoma (7.9%), Skin (6.4%), Gastroesophageal (6.2%), and Urinary bladder (5.8%). All of these 6 tumor types, for which activity in the CNS has been documented, have immune checkpoint inhibitors or other targeted therapies approved in selected cases by the US Federal Drug Administration (FDA) (Table). Conclusions: Molecular classification of brain metastases can identify distinct tumor types for which there are FDA approved targeted medications. Improving diagnostic precision with the 92-gene assay helps identify a subset of therapy-responsive metastatic brain tumors, thus improving therapy and possibly providing better outcomes and survival. [Table: see text]
Clinical outcomes in patients with melanoma brain metastases at a tertiary cancer center.
Authors: Phillips William J , Lo Bryan , Ong Michael , Smith Tyler , Song Xinni
Published: May 2019

e13586

Background: Brain metastases are observed in more than 40% of all patients with stage IV melanoma. In recent years, more extensive use of stereotactic radiation (STRT) and the advent of immune checkpoint inhibitors and BRAF targeted therapies have positively impacted outcomes in patients with metastatic melanoma (MBM) In this study, we examined real-world clinical outcomes of patients presented with melanoma brain metastases (MBM). Methods: This retrospective review evaluated MBM patients treated at the Ottawa Hospital. Clinical, radiologic, and pathologic variables were collected from the electronic medical records from January 2000 to June 2018. Results: A total of 277 patients fulfilled the inclusion criteria. Median overall survival was 4 months. LDH was the only significant prognostic factor in this study. Over 65% of brain metastases were detected due to the presence of neurological symptoms, while surveillance and restaging identified asymptomatic brain metastases in the remaining patients. Detection by neurological symptoms was related to larger (p < 0.001) and haemorrhagic (p = 0.032) intra-cranial lesions as well as decreased overall survival (HR = 1.2, p = 0.018). With regards to locoregional treatment STRT radiation outperformed WBRT alone in patients with single and oligo (2-6 lesions) brain lesions (HR = 0.149, p = 0.001 for oligo; HR = 0.149, p = 0.003 for single) and was associated with approximately a 3-fold increase in median survival. STRT was used 2-fold less frequently in patients with more than one lesion (54.8% in single; 31.7% in oligo). In patients receiving systemic therapy, immunotherapy is the only modality demonstrated overall survival benefit compared to no systemic treatment (HR = 0.511, p = 0.014). Furthermore, patients receiving STRT in combination with immunotherapy outperformed patients receiving STRT with WBRT (HR = 0.389, p = 0.009). Conclusions: Results from this study support the consideration of routine screening of high-risk asymptomatic patients, the increased use of STRT in patients with multiple intra-cranial lesions. The efficacy of immunotherapy in patients with MBM is consistent with current clinical trial data.
Cytopenia following axicabtagene ciloleucel (axi-cel) for refractory large B-cell lymphoma (LBCL).
Authors: Logue Jennifer Marilyn , Krivenko Gabriel S , Larson Victoria , Bachmeier Christina A , Chavez Julio C. , Davila Marco L. , Khimani Farhad , Lazaryan Aleksandr , Liu Hien D , Pinilla-Ibarz Javier , Shah Bijal D. , Dholaria Bhagirathbhai R. , Jain Michael D. , Locke Frederick Lundry
Published: May 2019

e14019

Background: Axi-cel is an anti-CD19 CAR T-cell therapy that can lead to long term disease control for patients with refractory LBCL including DLBCL, PMBCL, HGBL, and tFL. Beyond day 30, grade 3 or higher cytopenias were reported in 17% of patients (Locke 2019). We sought to further characterize cytopenias after axi-cel. Methods: We evaluated patients with LBCL treated with axi-cel at Moffitt from May 2015 to May 2018. Counts at apheresis and days 30, 90 and 180 after axi-cel infusion were recorded. Data was censored at date of progression, death or last follow-up. AEs were per CTCAE v4.03. Results: 52 patients were identified. Count data at each time is presented in the table. In total, 37.8% (17/45), 17.8% (8/45), and 28.9% (13/45) of patients experienced any grade 3-4 neutropenia, anemia or thrombocytopenia beyond day 30. Beyond day 30: 24.4% (11/45) received G-CSF; one (2.2%) received a TPO-agonist; none received an EPO-agonist; 15.6% (7/45) IVIG; 11.1% (5/45) PRBC; and 8.9% (4/45) platelet transfusion. 11 patients had bone marrow biopsies to evaluate cytopenias, at a median of 50 days (range 29-434) following axi-cel infusion. Median cellularity was 16.3% (range 5-45%), and 3/11 had reticulin staining indicating fibrosis. One patient, previously reported (Locke, Mol. Ther, 2017), had therapy related MDS and evidence of prior CHIP mutation. Conclusions: Prolonged neutropenia, lymphopenia, anemia, and thrombocytopenia occurred at least 180 days following axi-cel therapy in LBCL patients, in the absence of disease progression. Transfusion burden was low, and most patients recovered without an intervention.[Table: see text]
Correlation between circulating cell-free RNA biomarkers and response during combination immunotherapy in previously refractory metastatic TNBC patients.
Authors: Garner Chad , Seery Tara Elisabeth , Nangia Chaitali Singh , Lee John H. , Huang Liyang , Sender Leonard S. , Rabizadeh Shahrooz , Soon-Shiong Patrick
Published: May 2019

e14027

Background: A commercial liquid biopsy test was included as an exploratory component of an integrated immunotherapy clinical trial in previously refractory metastatic TNBC patients, combining innate, high-affinity natural killer cell (haNK) therapy with adenoviral and yeast-based vaccines and an IL-15 superagonist (NCT 03387085). The purpose of the study was to assess the utility of cell-free circulating RNA (cfRNA) as a predictor of treatment response. Methods: Blood was drawn from trial participants at baseline and at 2-6 week intervals throughout the treatment protocol. cfRNA and cfDNA were extracted from plasma and tested for analytes by quantitative PCR (qPCR) in a CLIA and CAP certified laboratory. This study is based on the analysis of 18 the cfRNA analytes (AR, PD-L1, CTLA-4, LAG-3, EGFR, HER2, ERCC1, TIM-3, MGMT, RRM1, SLC29A1, TOP1, TOP2A, TOP2B, TUBB3, TYMP, TYMS, XRCC1) in six patients that had at least three testing time points; new patient recruitment and serial testing are ongoing. The relative expression of each RNA analyte was normalized by beta-actin. Tumor size was evaluated by imaging using the RECIST criteria. Results: The amount and variability of cfRNA was positively correlated with the tumor size. As cfRNA quantity and variability increased or decreased, a corresponding increase or decrease in tumor size was observed, respectively. Not all 18 genes showed consistent patterns of change across the six patients, however the average expression and variability of the 18 genes showed evidence of a correlation with tumor size change from baseline (p-values = 0.08 and 0.03, respectively). Only trace levels of PD-L1 expression were observed in all 6 patients at baseline, prior to the initiation of the combination immunotherapy. Among the 5 patients that showed a reduction in tumor size of at least 10%, 4 also showed an associated increase in cfRNA PD-L1 expression from nearly 0 to normalized values between 2.1 and 6.8. Conclusions: Exploratory analysis in an ongoing combination immunotherapy clinical trial for TNBC showed that increasing and decreasing cfRNA levels are correlated with increasing and decreasing tumor size, respectively. Increased PD-L1 cfRNA levels are correlated with beneficial treatment response. Liquid biopsy of cfRNA could provide an effective biomarker of treatment response. Clinical trial information: NCT03387085.
Circulating tumor cell (CTC) PD-L1 and interferon regulatory factor-1 (IRF-1) expression as biomarkers of anti-PD-(L)1 response.
Authors: Kennedy Laura , Ramirez Arturo B. , U'Ren Lance , Sun Yao , Durenberger Grace , Chow Laura Quan Man , Grivas Petros , Gadi Vijayakrishna K.
Published: May 2019

e14032

Background: Anti-PD-(L)1 checkpoint inhibitors (CPI) are remarkable due to durable responses, tolerability, and improvements in survival across multiple solid tumors. Unfortunately, CPI produce objective responses in only a small subset of solid tumors patients (pts). We hypothesized that PD-L1 and IRF-1 expression on CTC may correlate with CPI response, and evaluate their expression in this pilot study. Methods: Pts with metastatic solid tumors initiating anti-PD(L)-1 mono- or combination therapy were eligible. Pts had 7.5 cc of blood drawn for CTC evaluation at 3 timepoints: baseline, after 1 CPI dose, and 3-6 months after starting CPI or at time of CPI discontinuation. Peripheral blood CTC were isolated with the AccuCyte kit and stained for CK/EpCAM, anti-CD45, nuclear dye, PD-L1, and IRF-1. CTCs were then identified with CyteFinder software. Results: 16 pts have enrolled to date with median age 71 years (range 28-83) and median ECOG = 1 (range 0-3). 50% were female. Diagnoses include NSCLC (50%), head and neck cancer (13%), breast cancer (13%), and others (24%). CTC were identified at baseline in 13/16 pts (# CTCs range 0-101). 12 pts with baseline CTC have had restaging scans since starting CPI. By RECIST 1.1, 3 pts had partial response (PR), 1 had stable disease (SD), and 8 had progressive disease (PD). The pts with PR more frequently had IRF-1 staining on baseline CTC (Table), and 1/3 had PD-L1 staining. 6 pts had tumor PD-L1 staining available for correlation, and 3/6 of those pts were PD-L1+ (tissue PD-L1 ≥ 1%). 1/3 pts with PD-L1+ tumor staining had CTCs that were PD-L1+. In the 3 pts with negative PD-L1 tumor staining, 1 pt had a mixed PD-L1+/PD-L1- CTC population and the others had no PD-L1 staining. Conclusions: CTC isolation and enumeration seem feasible across tumor types. Pts with PR to anti-PD-(L)1/ might have higher prevalence of IRF-1+ CTC; however, results are preliminary and more pts and samples are being evaluated. [Table: see text]