bluuebunny/crossref_metadata_2025_split huggingface dataset:
Quantitative imaging biomarkers of CNS lymphoma and its correlation with genotypic markers.
Authors: Filippov Aleksandr , Ally Feras , Song Joo Y , Zain Jasmine M. , Chaudhry Ammar 
Published: May 2020

e14520 Background: Central nervous system (CNS) lymphoma can be divided into primary CNS lymphoma (PCNS) versus secondary involvement of the CNS in systemic lymphoma. Traditionally radiology-pathology correlation is needed to accurately stage these entities, but the invasive nature of intracranial biopsies can add to patient morbidity. As such, there is an unmet need for noninvasive imaging biomarkers of CNS lymphoma. We aim to assess whether quantitative imaging analysis can characterize improve diagnostic specific and identify underlying genomic alterations in CNS lymphoma. Methods: 42 cases of CNS lymphoma (26 males, 16 females) were reviewed. Inclusion criteria required MRI (1.5Tesla or 3.0Tesla) of the brain and time-concordant histopathologic evaluation (i.e. MRI obtained within 72 hours of histologic evaluation) confirming diagnosis of CNS lymphoma. 19 patients met the inclusion criteria: 16 patients with large B-cell and 3 patients with T-cell lymphoma. All diagnoses were confirmed by evaluating biopsies through morphological and immunohistochemical analysis. MRI studies included T1-weighted pre- and post-contrast images, T2-weighted images and diffusion weighted images. Quantitative analysis included 3D-volumetric and textural analysis. Results: In B-cell lymphoma, mean patient age was 57 (22-91) while in T-cell lymphoma mean age of diagnosis was 43 (20-59). On MRI, all cases of CNS lymphoma (B- and T-cell) demonstrated enhancement. All T-cell lymphoma lesions were intra-axial and demonstrated homogeneous enhancement. Meanwhile, B-cell lymphomas demonstrated variable pattern of enhancement (homogenous; reticulonodular; subcortical U-fiber; peripheral). 80% (4/5) patients tested for MYC alterations demonstrated peripheral enhancement. 70% (7/10) tested for BCL2 expression demonstrated homogenous enhancement; while BCL2 & MYC dual-expression was noted in the remaining 30% (3/10) with MRI showing peripheral enhancement. All CNS lymphomas demonstrated restricted diffusion with variable ADC range: 292-980. 84.2% (16/19) of the cases were intra-axial while 15.2 (3/19) were extra-axial (all of which were B-cell lymphoma). Conclusions: Our study shows all lymphomas enhance and demonstrate variable degree of restricted diffusion. Patients with Myc-alterations or dual-expression of BCL2-MYC showed peripheral enhancement, while isolated BCL2 expressed tumors showed homogeneous enhancement.
Apparent diffusion coefficient as a valuable quantitative parameter for predicting clinical outcomes in patients with newly diagnosed primary CNS lymphoma.
Authors: Baek Dong Won , Lee Soo Jung , Kang Byung Woog , Moon Joon Ho , Kim Jong Gwang , Sohn Sang Kyun , Chae Yee Soo 
Published: May 2020

e14532 Background: Primary central nervous system lymphoma (PCNSL) is a rare subtype of non-Hodgkin lymphoma (NHL). Although, there are various treatment options for PCNSL which include methotrexate based chemotherapy and whole brain radiotherapy (WBRT), half of the patients who initially achieved complete response experience disease relapse. Accordingly, we attempted to identify novel prognostic factors using MRI in patients with newly diagnosed PCNSL. Methods: We retrospectively evaluated 672 patients who were diagnosed with central nervous system (CNS) cancers between January 2011 and May 2018. Enrollment criteria were i) pathologic diagnosis of CNS lymphoma, ii) no evidence of systemic involvement, iii) no evidence of human immunodeficiency virus-1 infection or other immunodeficiencies, and iv) available magnetic resonance imaging (MRI) examinations at diagnosis. Fifty-two patients met these criteria and were enrolled. Results: Patients with low apparent diffusion coefficient (ADC) showed inferior overall survival (OS) compared to those with high ADC. Patients with a hyperintense signal on T2-weighted image and homogenous enhancement showed better failure-free survival (FFS), while patients with low ADC and necrosis showed poor FFS. In the multivariate survival analysis, old age ( > 60) (hazard ratio (HR) 20.372, p= 0.001), Eastern Cooperative Oncology Group performance status ((ECOG PS) ≥ 2 (HR 10.429, p < 0.001), higher levels of lactate dehydrogenase (LDH) (HR 7.408, p= 0.001), and low ADC (HR 0.273, p= 0.009) were associated with inferior OS, while ECOG PS ≥ 2 (HR 10.319, p= 0.021), presence of necrosis (HR 6.372, p= 0.008), and low ADC (HR 0.226, p= 0.020) were unfavorable factors for FFS. Conclusions: We conclude that ADC, a characteristic MRI finding, had significant prognostic value for long-term survival in our study of patients with newly diagnosed PCNSL Specifically, low ADC was an independent unfavorable prognostic factor, suggesting that ADC measurements through non-invasive MRI can improve the current prognostic scoring system.
Characterization of hypoxia signature to evaluate the tumor immune microenvironment and predict prognosis in glioma.
Authors: Wu Shihong , Lin Wanzun , Weng Youliang , Pan Yuhui , Huang Zongwei , Li Miaomiao , Lin Ting , Chen Xiaochuan , Zhang Lurong , Qiu Sufang 
Published: May 2020

e14534 Background: Glioma, the most common primary brain tumor, accounts for more than 50% of all primary brain tumors. Malignant gliomas, especially glioblastomas, are associated with a dismal prognosis. Hypoxia is a driver of the malignant phenotype in glioma; it triggers a cascade of immunosuppressive processes and malignant cellular responses (tumor progression, metastases, and resistance to chemoradiotherapy), which result in disease progression and poor prognosis. However, approaches to determine the extent of hypoxia in the tumor microenvironment are still unclear. Methods: Here, we enrolled 1626 glioma patients with RNA sequence and survival data in two independent cohorts, and developed a hypoxia risk model to reflect the immune microenvironment in glioma and predict prognosis. Results: High hypoxia risk score was associated with poor prognosis and indicated an immunosuppressive microenvironment. Hypoxia signature significantly correlated with clinical and molecular features and could serve as an independent prognostic factor for glioma patients. Moreover, Gene Set Enrichment Analysis showed that gene sets associated with the high-risk group were involved in carcinogenesis and immunosuppression signaling. Conclusions: In conclusion, we developed and validated a novel hypoxia risk model, which served as an independent prognostic indicator and reflected overall immune response intensity in the glioma microenvironment.
EF-19, a post-approval registry study of tumor treating fields (TTFields) in recurrent glioblastoma (rGBM).
Authors: Zhu Jay-Jiguang , O'Donnell Robert , Ram Zvi 
Published: May 2020

e14536 Background: Tumor Treating Fields (TTFields) are an anti-mitotic non-invasive therapy of low intensity alternating electric fields delivered to the tumor via a portable medical device. In phase 3 studies that led to FDA approvals, TTFields plus maintenance temozolomide significantly extended survival in newly diagnosed GBM, and achieved comparable survival outcome to best standard of care (BSC) as monotherapy in recurrent GBM (rGBM). The EF-19 study aimed to confirm efficacy of TTFields vs BSC in rGBM in post-approval real-life setting. Methods: This non-inferiority, prospective, non-randomized, post approval registry trial enrolled 192 rGBM patients (>21 yrs, KPS > 70). Patients were treated with TTFields (200 kHz, > 18h/day). Eligibility criteria: histologic GBM, past treatment per Stupp protocol for primary disease and radiological evidence of progression in the supratentorial region. Primary endpoint was overall survival (OS); secondary endpoints were OS in the per protocol (PP) population ( > 1 course of TTFields or BSC in each respective arm), time to treatment failure and adverse events. The TTFields patient registry data were compared to OS of all 117 rGBM patients in the BSC group of the EF-11 trial (Stupp R, EJC 2012). The sample size of 192 patients (10% loss to follow up) was based on non-inferiority log-rank test with a two-sided alpha level of 0.05 and a power of 80%, comparing time to event (i.e., death) between patients treated with TTFields and BSC. The analysis was based on true hazard ratio (HR) of 1.0 comparing TTFields to control with an upper one-sided 95% confidence bound of HR not exceeding 1.375. Results: Median OS with TTFields versus EF-11 BSC was 7.4 vs. 6.4 months, p = 0.053; HR = 0.64 (95%CI 0.46-0.91, Cox-test P = 0.012). Median OS (PP population) with TTFields versus EF-11 BSC was 8.1 months vs. 6.5 months; p = 0.045; HR 0.65. The results showed a significant superiority in HR of OS between the 2 groups, as the 95% confident interval upper limit of the HR was lower than the pre-defined threshold for non-inferiority for interval bound of 1.375. The overall incidence of adverse event was lower with TTFields than EF-11 BSC (67% vs. 95%). The median time to treatment failure was longer in the TTFields arm (3.3 months (95% CI 2.6, 3.9) versus BSC arm (1.6 months; 95% CI 1.1, 1.9); HR = 0.53 (95% CI 0.41, 0.68, p < 0.0001). Skin AE was the most frequently reported AEs in TTFields arm; no unexpected adverse events were reported with TTFields. Conclusions: The results of the EF-19 registry study confirm the effectiveness and safety of TTFields monotherapy in rGBM.
Genomic profiling identified novel prognostic biomarker in Chinsese glioma patients.
Authors: Li Hainan , Shan Changguo , Fan Chongzhu , Wu Shengnan , Lai Mingyao , Cai Linbo , Zhu Dan , Wang Fufeng , Chen Yedan , Shi Yuqian , Liu Kaihua , Zhang Xian , Bao Hua , Wu Xue , Wang Xiaonan , Shao Yang , Li Zhi 
Published: May 2020

e14538 Background: Molecular charactersitcs are essential for the classification and grading of gliomas. However, majority of current understanding is based on public databases that might not accurately reflect the Asian population. Here, we studied the mutation landscape of Chinese glioma patients in hope to provide new insights for glioma prognosis and treatment. Methods: Tissue samples from 112 glioma patients underwent next-generation sequencing targeting 425 cancer-relevant genes. Gene mutations and copy number variations were investigated for their prognostic effect using overall survival data. Pathway-based survival analysis was peformed using top ten predefined oncogenic pathways. Results: We identified similar prevalence of currently established molecular diagnostic markers of glioma, including TP53 (33%), EGFR(26%), TERT (24%), PTEN (21%), ATRX (14%), BRAF (13%) and IDH1/2 (6%). Among all genetic abberations with more than 5% occurrence rate, four mutations and four copy number gains were significantly associated with poor overall survival (univariate, P < 0.05). Of these, TERT mutations (hazard ratio [HR], 3.14; 95% confidence interval [CI], 1.31 to 7.49; P = 0.01) and EGFR amplification (HR, 2.67; 95% CI, 1.20 to 5.95; P = 0.02) remained significant after adjusting for clinical parameters. Similarly, PIK3CA mutations, which was also frequently mutated in glioma but not used for clinical classification, were found to correlate with poor prognosis (HR, 2.61; 95% CI, 1.19 to 5.74; P = 0.02). Additionally, we have also identified MCL1 amplification as a potential novel biomarker for glioma (HR, 2.73; 95% CI, 1.47 to 5.07; P < 0.001), which was seldom reported in the TCGA database and might possibly be ancestral specific giving its high prevelance in our cohort (found in 32% patients). Pathway analyses revealed significantly worse prognosis with abnormal PI3K (HR, 1.81; 95% CI, 1.12 to 2.95; P = 0.02) and cell cycle pathways (HR, 2.04; 95% CI, 1.2 to 3.47; P < 0.001), both of which stayed meaningful after adjusting for clinical factors. Conclusions: In this study, we discovered PIK3CA mutations and MCL1 amplification as novel prognostic markers of glioma. We also demonstrated shorter survival with abnormal PI3K and cell cycle pathways that provided an intergrative understanding of glioma.
Clinical features and outcomes of neuroblastomas in adults.
Authors: Findakly Dawood , Nguyen Eric , Wang Jue 
Published: May 2020

e14546 Background: Neuroblastomas (NBs) are a spectrum of primitive tumors that include Esthesioneuroblastoma (ENB), and both neuroblastoma (NB) and ganglioneuroblastoma (GNB). NB and GNB are prevalent in children and rare in adults with a paucity of data on their therapy and outcomes. This review is to investigate the clinicopathologic features, treatment, and outcomes of NBs in adults. In addition, we highlight genomic findings of a 63-year-old man treated at our institution and discuss ALK-inhibition as a novel treatment strategy for ALK-driven adult-onset NB. Methods: PubMed literature search for NB adults (19+ years) for the period 2000 – 2020 pooled with a case from our institution. Results: Of the 163 included cases, 105 were ENB, 40 were NB, and 18 were GNB. Male:female ratio (1.50:1, 1.29:1, and 1.83:1 respectively). Mean age at diagnosis (49.8, 39.3, and 38.8 respectively). Most common primary site was sinonasal (60%) in ENB, retroperitoneal (20%) in NB, and adrenal (22%) in GNB. Metastasis found in 31.4%, 42.0%, and 16.7% with a mortality rate of 45%, 53%, and 33% respectively. Most common treatment modality overall was surgery with radiation in ENB (35%), Surgery with chemotherapy in NB (28%) and surgery alone in GNB (50%). Most common treatment modality in metastatic cases was surgery with chemoradiation in ENB (50%), surgery with chemotherapy in NB (36%), and surgery alone in GNB (33%). In our patient, ALK gene (R1275Q) gain of function mutation found both in molecular profiling and genomic circulating DNA analysis. Conclusions: Metastatic NB in adults is associated with very high mortality. Their rarity, heterogeneity of clinical behaviors, diverse treatment regimens, and variable outcomes make them even more challenging. The findings of this study would improve our understanding and develop multidisciplinary management strategies for this rare malignancy in adults. Moreover, further research focusing on the potential novel treatment with ALK-targeted inhibitors may hold promise to improve survival outcomes in adult-onset ALK-positive NB. [Table: see text]
Nanoliposomal irinotecan and metronomic temozolomide for patients with recurrent glioblastoma: BrUOG329, a phase IB/IIA Brown University Oncology Research Group (BrUOG) trial.
Authors: Elinzano Heinrich , McMahon Jessica B. , Mohler Alex B. , Robison Jordan B. , Carcieri Arieana B. , Toms Steven A , Cielo Deus B. , Turchetti Wendy B. , Vatkevich John , Wood Roxanne , Webber Amy , Safran Howard 
Published: May 2020

e14548 Background: Nanoliposomal irinotecan (nal-IRI)) is a novel formulation of irinotecan, encapsulating drug molecules within long-circulating liposome-based nanoparticles with resulting favorable pharmacokinetic and biodistribution properties. Nanoliposomes improve the solubility and bioavailability of drugs and potentially increase their ability to cross the blood brain barrier. We performed a phase I study to determine the maximum tolerated dose (MTD) and preliminary efficacy of nal-IRI in combination with metronomic temozolomide (TMZ) in patients with recurrent glioblastoma. Methods: Patients with recurrent glioblastoma who had progressed after at least 1 line of therapy with a KPS of > 60 were eligible. All patients received TMZ 50 mg/m2 PO daily with nal-IRI IV every 2 weeks until disease progression. Three dose levels of nal-IRI were planned, 50 mg/m2, 70 mg/m2 and 80 mg/m2. Dose limiting toxicities (DLTs) were defined as those occurring during the first 2 cycles (28 days) of treatment. Patients were accrued in a 3+3 design. Accrual at the MTD level was to be expanded to 25 patients, unless the study was terminated early if 0-1 responses were observed in the first 13 evaluable patients. Results: Twelve patients were treated over 2 dose levels (nal-IRI 50-70 mg/m2). At dose level 2, nal-IRI 70mg/m2, 2 of 3 patients developed DLTs, including one patient who developed grade 4 neutropenia, grade 2 diarrhea and grade 3 anorexia and one patient with grade 3 diarrhea, grade 3 hypokalemia and grade 3 anorexia. Accrual at nal-IRI 50 mg/m2, defined as the MTD, was expanded to 9 patients. Treatment-related toxicities at this dose level included grade 3 ALT (N = 1). As there were no responses seen in the initial 12 patients (0/12, 0%), the BrUOG Data Safety Monitoring Board terminated the study. Conclusions: The MTD of nal-IRI was 50 mg/m2 every 2 weeks with TMZ 50mg/m2/day. DLTs were grade 3 diarrhea and anorexia. No antitumor activity was seen in the first 12 patients and the study was terminated. Clinical trial information: NCT03119064.
Role of miR-122-5P, miR-107, miR-22-3P, and miR-330-3P microRNAs in regulation of HIF1A expression in high-grade gliomas.
Authors: Pushkin Anton A. , Alliluev Ilya A. , Rostorguev Eduard E. , Kavitskiy Sergey E. , Kuznetsova Natalya S. , Timoshkina Natalya N. , Kit Oleg I. 
Published: May 2020

e14550 Background: HIF1-alfa is a powerful regulator of angiogenesis and cell invasion activating a wide range of oncogenes. Control of the HIF1-alpha transcription is strictly regulated by many molecular pathways, including miRNAs which can become targets for gene therapy of cancer. Methods: The study included 30 patients with histologically verified high-grade gliomas. RNAs were isolated from 30 paired (tumor and control) samples using the TRIzol reagent (Thermo Fisher, USA). The cDNA synthesis was performed using the Reverta MMLV kit (Sintol, Russia). Expression of miRNAs and HIF1A was evaluated by RT-PCR using the CFX96 system (Bio-Rad, USA). The 2−ΔΔ Сt method was used to analyze the qPCR data. Statisical processing of the results was performed with the Statistica 10 program (StatSoft Inc., USA). Results: Using analysis of TargetScan and miRTarBase databases and appropriate literature, miRNAs (miR-122-5p, miR-107, miR-22-5p and miR-330-3p) able to regulate HIF1A expression were selected. The HIF1A expression in the tumor was 1.8 times higher, compared to normal tissue (p = 0.0031). The 2−ΔΔ Сt value for miR-122-5p, miR-107, miR-22-3p and miR-330-3p decreased by 40%, 45%, 36%, and 91.5%, respectively, in tumor samples relative to the control point (p < 0.05 in all cases). A correlation was found between the expression of miRNA 122-5p and HIF1A (Spearman’s r = -0.46 at p < 0.05). Conclusions: An increase in the HIF1A miRNA level was found, together with a decrease in the expression of four potentially targeting miRNAs in high-grade gliomas. A negative correlation between the expression of miR-122-5p and HIF1A in high-grade gliomas was revealed, which can be used for the development of new therapy options.
Epidermal growth factor receptor expression as a molecular determinant of glioblastoma response to the dopamine receptor D2 antagonist, ONC201.
Authors: He Yuyu , Ma Jun , Dhawan Sanjay , Koga Tomoyuki , Furnari Frank , Prabhu Varun Vijay , Allen Joshua E. , Chen Clark C 
Published: May 2020

e14552 Background: Durable response in glioblastoma patients have been reported in phase I/II clinical trials for the blood-brain penetrant dopamine receptor D2 (DRD2) antagonist, ONC201. Here we examine potential molecular determinants of response to DRD2 inhibition. Methods: The Cancer Genome Atlas (TCGA) glioblastoma database and other published mRNA profiles were used to analyze the DRD2 expression pattern. In vitro and in vivo responses to ONC201 were determined using patient derived xenograft glioblastoma models. Immunohistochemical studies were performed on clinically annotated glioblastoma samples derived from phase I/II clinical trials involving ONC201. Results: For the majority of clinical glioblastoma specimens in both the TCGA and non-TCGA dataset, epidermal growth factor receptor (EGFR) expression was inversely correlated with DRD2. This observation was recapitulated in a panel of patient-derived glioblastoma lines. In this panel of DRD2 expressing lines, high EGFR expression was associated with poor response to ONC201 in vitro and in vivo. Moreover, ectopic expression of EGFR reduced DRD2 expression and ONC201 sensitivity, suggesting functional redundancy between DRD2 and EGFR. In cell lines and clinical glioblastoma samples, DRD2 expression closely associated with the expression of rate-limiting enzymes for dopamine synthesis, suggesting dependency of a subset of glioblastomas on autocrine DRD2 signaling. Analysis of specimens from patients treated with ONC201 (n = 15) showed an inverse correlation between the intensity of EGFR staining and clinical response. The median overall survival for patients with high and low EGFR staining was 162 and 373 days, respectively (p = 0.037). All patients who exhibited progression free survival beyond 200 days showed low to no EGFR expression. Conclusions: Our results suggest EGFR expression as a determinant of response to ONC201 in glioblastoma patients and should inform the design of future clinical trials.
Never too young: Retrospective study on age and racial disparity in the outcome of primary CNS Lymphoma in south Texas.
Authors: Ananth Snegha , Janania Martinez Michelle , Garza Juan , Surapaneni Prathibha , Snedden Tyler William , Gregorio David , Kakarla Sushanth , Rawlings Jeremy , Michalek Joel , Liu Qianqian , Diaz Duque Adolfo Enrique 
Published: May 2020

e14553 Background: Primary CNS lymphoma (PCNSL) is a rare malignancy, comprising only 2% of primary CNS tumors in the United States.While it’s incidence has decreased in the immunocompromised population (HIV positive) secondary to widespread access of effective anti-retroviral therapy, it is suspected that the rates are increasing among immunocompetent people aged 65+ years at a rate of approximately 1.7% per year. Data from the Surveillance, Epidemiology, and End Results (SEER) looking into survival and incidence patterns in PCNSL have a majority of non-Hispanic (NH) white population with lesser proportion of other ethnicities. Understanding racial and ethnic disparities on outcomes and patterns of care are crucial given the rapid growth of the Hispanic (HI) population in the US. Therefore, our study aims to compare survival outcomes and contributing factors in HI vs NH with PCNSL, who were treated at the only NCI designated Cancer Center in South Texas. Methods: This is a retrospective study, where we identified patients who were diagnosed and treated for PCNSL at UT Health San Antonio, between January 2008 and December 2018. The patient characteristics, treatment patterns, and clinical outcomes were listed as descriptive statistics. Results: From 2008-2018, a total of 29 patients with PCNSL were included. Among those, 62% were HI(Hispanic) and the remaining 38% were NH(Non-Hispanic). The median age at diagnosis was 61 years (58 years in HI and 70 years in NH). 55% were below 65 years and 45% were older than 65 years. Everyone received chemotherapy (89% received R-MPV (DeAngelis protocol) and 9% received other high dose methotrexate containing regimens). However, in terms of receiving Whole Brain Radiation Therapy (WBRT), the patients in the younger group were more likely to receive it than were those in the elderly group (68% versus 23% respectively). Overall Survival (OS) rate at 3 years was 41 % in HI and 33 % in NH (p = 0.08) and at 5 years was 41 % in HI and 25 % in NH (p = 0.03). Conclusions: While there is increasing data on higher incidence of non-HIV PCNSL in elderly population > 65 years, HI in our study population had a significantly lower median age at diagnosis with better survival and outcomes. Further studies on a larger patient population may help to describe the differences in incidence, tumor biology, genetics and outcomes in HI population.