bluuebunny/crossref_metadata_2025 huggingface dataset:
Design of eSyM: An ePRO-based symptom management tool fully integrated in the electronic health record (Epic) to foster patient/clinician engagement, sustainability, and clinical impact.
Authors: Hassett Michael J. , Hazard Hannah , Osarogiagbon Raymond U. , Wong Sandra L. , Bian Jessica J , Dizon Don S. , Wedge Jason , Basch Ethan M. , Mallow Jennifer , McCleary Nadine Jackson , Dougherty David W. , Remick Scot C. , Brooks Gabriel A. , Mecchella John , Solberg Peter , Tasker Laura , Faris Nicholas Ryan , Pacheco Alicia , Cronin Christine , Schrag Deborah ,   eSyM Project Managers
Published: May 2020

e14120

Background: Chemotherapy and surgery can cause distressing symptoms, which can be a burden for health system to address. Programs that directly engage patients, including electronic tracking of patient-reported outcomes (ePROs), can improve symptom control and decrease the need for acute care. Previous ePRO programs have relied on third party vendors with limited EHR integration, constraining their clinical utility and scalability. An integrated solution could offer distinct advantages. Methods: As part of NCI’s Moonshot-funded IMPACT consortium, 6 health systems and Epic built an electronic symptom management program (eSyM) based on the PRO-CTCAE questionnaire that is fully integrated into the EHR. The agile, user-centered design process engaged patients, clinicians, and institutions. The core functional components include: 1) symptom surveys in the postoperative period or between chemotherapy visits, 2) self-management tip sheets, 3) clinician alerts, and 4) dashboards for population management. Critical points of integration with supporting EHR functions and workflow impacts were identified; and major challenges of integration and implementation were described. Results: eSyM, which was implemented at two health systems (Baptist Memorial in Tennessee and Mississippi and West Virginia University Health) in the fall of 2019, required multiple supporting EHR functions: 1) access a secure, HIPPA-compliant patient portal/messaging system (MyChart); 2) record diagnosis, procedure and chemotherapy treatment plan data; 3) identify target populations and track metrics/events; 4) define and execute autonomous logic-based workflow rules; 5) generate reports for clinicians/patients; and 6) documentation. Major challenges included: 1) working within pre-existing EHR system standards and capabilities, which limited the ability to customize interfaces and workflows specifically for the eSyM use case; and 2) adapting to different EHR configurations and polices across multiple health systems. Conclusions: The eSyM build leveraged many existing EHR capabilities and addressed regulatory hurdles; but it required design and workflow compromise. Integration of ePRO-based symptom management programs into the EHR could help overcome barriers, consolidate clinical workflows, and foster scalability/sustainability. Ongoing efforts include launching eSyM at four more sites and evaluating its adoption, usability, and impact on clinical outcomes.
Sickness absence and disability pension among Swedish women before breast cancer relapse.
Authors: Elham Hedayati , Gernaat Sofie a.m. , Johnsson Aina , Wilking Ulla m , Altena Renske
Published: May 2020

e14121

Background: Sickness absence (SA) and disability pension (DP) from diagnosis of primary breast cancer (BC) among patients who in a later stage will develop a recurrence or metastatic disease is unknown. This study explores the prevalence and risk factors of SA and DP in this study population before and after primary breast cancer diagnosis. Methods: Longitudinal register data on 1,310 female patients living in Sweden (age 20 to 63 years) diagnosed with primary BC between 1996 to 2011, were analyzed for annual prevalence of SA days and DP starting 2 years pre- to 5 years postdiagnosis. Logistic regressions were used to explore associations between primary BC characteristics and future SA. Results: 579 (44.2%) had loco-regional recurrence after a median of 2.5 years (interquartile range (IQR) = 1.3-4.3) and 731 (55.8%) had a metastatic disease after a median of 2.3 years (IQR = 1.3-4.1). 320 (24.4%) of 1,310 were still relapse-free 5 years postdiagnosis. SA was high during year 1 postdiagnosis but decreased steadily through year 5 (67.9%, 40.3%, 29.0%, 23.9%, 19.4%, respectively), while DP steadily increased during this time period (16.4%, 17.5%, 19.7%, 24.9%, 28.7%, respectively). The annual prevalence of SA over 180 days among patients who later were diagnosed with metastatic disease was constantly higher compared to patients who later were diagnosis of loco-regional recurrence. Pre-diagnosis SA, age < 50 years at the time of diagnosis, higher tumor stage, chemotherapy and future metastatic disease were associated with higher odds ratios for SA (odds ratio range, 1.56 to 4.42) Conclusions: In conclusion, longitudinal rates of SA and DP in a cohort of women with early BC, of whom a part developed disease relapse during follow-up were higher compared to previous studies. These are unique findings as previously published studies excluded patients with disease relapse. Patients at increased risk for SA, should be assessed and triaged to optimize chances for a smooth transition to return to work after oncological treatment.
Medicaid expansion and trends in cancer stage at diagnosis.
Authors: Withington John , Tramontano Angela , Schrag Deborah
Published: May 2020

e14129

Background: Cancer stage distribution offers an early window into the effect of the ACA’s 2014 Medicaid expansion. If Medicaid expansion enabled uninsured adults to access preventive care, then the proportion of cancers diagnosed at early stage should be higher in states that adopted it. Methods: Patient level data were retrieved from SEER-18, New York and Texas cancer registries from January 2010 to December 2015, for eight common tumor types; including N = 2,493,589 (breast, cervical, colorectal, prostate, lung) screen detectable and N = 369,203 (testis, kidney and uterine corpus) not detected by routine screening. Patients were categorized by residence in states that were: 1) Non-expanders; 2) Expanders - income eligibility thresholds increased from 0% to 138% of the federal poverty level (FPL) in 2014; and 3) Pre-Expanders, with pre-2014 eligibility thresholds > 70% of FPL. Stage distributions were compared before and after January 2014, categorized by AJCC stage and using ordinal stage equivalent (OSE) which assigns a numeric score based on AJCC stage. Difference in difference in difference (D3) methods compared patients ≥65 versus < 65, and screen-detectable versus not. Multivariable logistic regression was used to adjust for variation in age, sex, race, ethnicity and tumor site across states. Results: No differences in stage distribution were observed across the three categories of state. (Table). D3 analysis revealed no difference between trends in the over 65s, or for screen-detectable cancers. Adjustment for age, sex, race, ethnicity and tumor site made no significant difference to these results. Conclusions: States’ Medicaid expansion status in 2014 was not associated with a significant difference in early stage diagnoses for adults with cancer diagnosed before age 65. Obstacles to early cancer detection other than financial access must be addressed to improve population-level outcomes. [Table: see text]
How to better anticipate innovative anticancer drugs and their potential challenges: A European survey from the iPAAC WP9.
Authors: Denis Hélène , Bermudez Elisabeth , Aurélie Krol , Duperray Marianne , Negellen Sophie , Breton Thierry , Ifrah Norbert
Published: May 2020

e14134

Background: The European joint action iPAAC, funded by the European Commission, aims to develop innovative approaches to advances in cancer control. The field of anticancer drugs has strongly evolved over the past years and the clinical development remains very important. Horizon scanning systems (HSS) help policy makers and healthcare professionals to anticipate new medicines and their main impacts before their marketing authorization. The Work package 9 (WP9) of iPAAC, dedicated to innovative therapies in cancer, wanted to evaluate the need for more finesse in the anticipation of innovative therapies in the oncology field. Methods: A survey among organizations in charge of an HSS was conducted to point out methodologic features needed to enable a better anticipation of anticancer drugs, gene and cell therapies, biomarkers and pediatric indications. In addition, a retrospective analysis of the efficiency of HSS was conducted based on the review of 11 approved indications of checkpoint inhibitors and CAR-T cells. For each indication, organizations indicated if it was anticipated via their HSS and provided eventual challenges encountered. Results: Eleven main organizations in charge of HSS were identified in Europe, from which 9 participated to the iPAAC WP9 study. Time frames of these HSS ranged from 3 years to only a few months prior marketing authorizations. While most of the organizations included all innovative drugs in their scope, 2 were focusing only on oncology drugs and had developed specific methods to prioritize innovative medicines. To enable a good anticipation of biomarkers and gene & cell therapies, it appeared important to screen earlier phases clinical trials and to collect additional data. The retrospective analysis showed that biomarker expression threshold and centers authorized to provide gene and cell therapies or biomarker tests were some of the hardest parameters to anticipate. Having a structured database in the HSS process was seen as helpful, as it allowed the generation of ad hoc queries. Involving the expertise of practicing clinicians for prioritizing and assessing the innovative therapies was seen as an important asset for predicting clinically impacting drugs. Conclusions: Anticipating innovative drugs in oncology requires specific characteristics, especially given the variety of drugs, the earliness of data supporting marketing authorization and the dynamics of this therapeutic area. HSS is a valuable resource for the proper introduction and diffusion of innovative drugs.
The impact of patients’ and physicians’ characteristics on surgery decision for head and neck cancer: Results of a national survey.
Authors: Dupret-Bories Agnès , Grosclaude Pascale , Lamy Sebastien , Nebout Antoine , Bories Pierre , Cros Fanny
Published: May 2020

e14151

Background: The choice between surgical or medical treatments in head and neck cancer is a function of many patient-related and disease-related factors. We investigated how physicians' behavioral characteristics and patients’ socioeconomic status could affect medical decision-making. Methods: A nationwide cross-sectional online survey of surgeons and (radiation) oncologists specialized in head and neck oncology collected data on medical decision-making for 7 clinical vignettes involving head and neck squamous cell carcinoma patients that were representative of routine practice. Questionnaires elicited physicians' demographic and occupational characteristics along with their individual behavioral characteristics according to the decision theory framework. Patients’ gender and socioeconomic position were distributed across vignettes using a Latin square design. Results: We obtained 206 assessable answers. A multivariate analysis shows that surgeons suggested surgery more often than other professionals, which is mostly related to vignettes corresponding to clinical cases for which there is no consensus, so oncologists are 68% less likely than surgeons to choose surgery. For clinical vignette with an absence of consensus, physicians with lower risk aversion recommend more often surgery compared to those with higher risk aversion (OR = 1.88, p = 0.052). When the vignette corresponds to a clinical case for which there is a surgical consensus decision the isolated male blue-collar worker has a 75% lower chance of being offered surgery compared to the married male small business owner (OR = 0.25, p = 0.024). We did not observe any differences based on the patient's gender. Conclusions: Patients’ socioeconomic status did affect our clinical management decisions in head and neck oncology. The significant association between medical decision and individual behavioral characteristics of the physician documented still understudied mechanisms that involved nonbiological factor to explain clinical practices variations.
Association of leukocyte count (neutrophilia and lymphopenia) with poor prognosis in patients with high-grade gliomas in a Guatemalan cohort.
Authors: Ramirez Rixci , Rosales Lopez Daniel Estuardo , Dominguez Jennifer , Gramajo Marisol , Camey Carolina
Published: May 2020

e14500

Background: In previous studies separately, it has already been determined how the inflammatory response measured by it neutrophilia and also lymphopenia s with temozolamide have determined that they are important at the time of initiation of treatment and have a prognostic value in patients with high-grade gliomas, the objective This study was the prognostic value of leukocyte disorders, absolute neutrophil count and absolute lymphocyte count in a retrospective cohort of patients with high-grade glioma who receive concomitant temozolomide and radiation plus maintenance. Methods: Clinical records of patients treated at the Guatemalan Social Security Institute were registered in the Oncology service within the period from January 1, 2013 to December 2018, the treatment consisted of temozolomide (75 mg / m2 per day) and concomitant radiation and subsequent maintenance with temozolomide (150 mg / m2 D1-5) every 28 days for 6 cycles. The prognostic value of neutrophilia and lymphopenia, prior to treatment in survival, was defined as a neutrophil count greater than 7x10 3 / uL and lymphopenia less than 2 x10 3 / uL. The analysis was performed using Kapplan Mayer curves, log rank test and Cox analysis. Results: We identified 64 high-grade patients (grades III and IV according to WHO), all treatments with concomitant chemoradiotherapy based on temozolomide and subsequent maintenance with temozolamide. The initial surgery was lost in the majority (75%), with resection > 90% in 25 patients (34%). 79.4% were treated with radiotherapy plus concomitant chemotherapy followed by adjuvant chemotherapy with temozolamide of these, 69% completed the treatment, thirty-two patients (50%) with pre-treatment neutrophilia. The overall survival at 2 years was 55%. In the univariate analysis, neutrophilia is associated with a worse overall survival (p = 0.019), as well as lymphopenia (p = 0.003), in addition to the age ≥65 years (p = 0.0001), surgical resection < 90% (p = 0.045) and prednisolone consumption ≥50mg / day (p = 0.045). In the multivariate analysis, neutrophilia (p = 0.017), age ≥65 (p = 0.001), lymphopenia (p = 0.0056) were associated with a worse prognosis with reduced survival. Conclusions: In high-grade gliomas treated with temozolomide and concomitant radiation followed by maintenance with temozolamide, neutrophilia and lymphopenia can be a significant prognostic factor for overall survival, with the advantage that it is not an expensive test and is accessible at all times of patient follow-up.
Combination chemotherapy versus temozolomide (TMZ) for patients with MGMT methylated (m-MGMT) glioblastoma (GBM): Results of cellworks omics biosimulation—MyCare-015.
Authors: Castro Michael , Mundkur Nirjhar , Pampana Anusha , Alam Aftab , Alam Aktar , Parashar Rajan , Rajagopalan Swaminathan , Lala Deepak Anil , Ghosh Roy Kunal Ghosh , Basu Sayani , Prakash Annapoorna , Nair Prashant , Christie Jim , Joseph Vishwas , Agarwal Ashish , G Poornachandra , Behura Liptimayee , Kulkarni Shruthi , Choudhary Nikita Ray , Kapoor Shweta
Published: May 2020

e14501

Background: UKT-03 evaluated TMZ plus Lomustine in a single arm phase II trial in newly diagnosed GBM patients. An overall survival of 23 months was a substantial improvement over historical experience. Patients with m-MGMT v. unmethylated tumors had a 2-yr survival of 75% and median survival not reached compared to 20% and 12.5 months, respectively. These data formed the basis for NOA-9, a randomized phase III trial in newly diagnosed, m-MGMT GBM which randomized 141 patients to standard therapy or experimental therapy with Lomustine and TMZ every 6 weeks. A superiority for the combination was observed: 48.1 v. 31.4 months for the standard arm in the ITT analysis. Nevertheless, many neurooncologists are reluctant to adopt this approach. The current standard of care uses single biomarker, m-MGMT, in contrast to comprehensive pathway analysis (CPA). We sought to determine if CPA could discriminate more effectively among each patient’s likelihood of benefiting from combination treatment. Methods: Cellworks Singula employs a novel Cellworks Omics Biology Model (CBM) to predict patient-specific biomarker and phenotype response of personalized GBM avatars to drug agents, radiation, and targeted therapies. The CBM was developed and validated using PubMed to generate protein network maps of patient-specific activated and inactivated disease pathways. CBM was used to simulate the TMZ and TMZ-Lomustine therapies for each patient in a TCGA cohort of 368 GBM patients. Omics data including methylation, whole exome sequencing, and copy number alterations were input into CBM. The Singula Composite Inhibition Score (CIS) was calculated based on the measured quantitative drug effects. Results: Though incremental gain from the combination was seen in all patients, CIS varied across the population with relative scores ranging from 32-82, with best responders have more than twice the benefit. Conclusions: CPA shows that m-MGMT is an excellent biomarker for determining the likelihood of benefit from TMZ and lomustine, with the caveat that CBM identifies 18% could be spared from TMZ exposure and would benefit from Lomustine alone. Otherwise, these data lend support for evolving the standard of care with combination therapy for patients with m-MGMT GBM and should help overcome a reluctance to employing combination therapy. Additionally, CBM has utility to individualize clinical decision making. [Table: see text]
Evaluation of tumor growth inhibition activity of a novel multi-TRK inhibitor ABP-1130 on glioblastoma xenograft model.
Authors: Zhan Zheng-Yun James , Pan Wanlong , Zhang Hao
Published: May 2020

e14507

Background: Glioblastoma, also known as glioblastoma multiforme (GBM), is the most aggressive cancer that begins within the brain. Glioblastoma is a difficult to treat tumor with therapeutics limited by their ability to cross the blood brain barrier. Receptor tyrosine kinases (TRK) inhibitor is reported one of therapies for glioblastoma. ABP-1130 is a novel and potent small molecular multi-TRK Inhibitor for several prime tyrosine kinases (TRKs), such as EGFR, HER2, C-Met, and BTK with potential to treat glioblastoma. Pre-clinical studies with ABP-1130, especially study to evaluate its tumor growth inhibition effect on glioblastoma xenograft model, are planned in progress. Methods: (1) Mobility-Shift Assay used to Analyze the multi-TRK (such as EGFR, HER2, C-Met, and BTK) Inhibition activity of new anti-tumor compounds, (2) CTG Assay used to analyze the inhibition activity of LN-229 Cell Line, (3) Anti-tumor inhibition study of ABP-1130 with the brain cancer nude mice, (4) Safety studies of ABP-1130 for Ames, hERG, and MTD. Results: It was determined that its multi-TRK inhibition activity (IC50) of ABP-1130 was 7nM to EGFR, 3.6nM to HER2, 3.2nM to C-Met, and 3.7nM to BTK, respectively. Its inhibition activity for Cell Line LN-229 was 0.02 µM. In anti-tumor inhibition study with the LN-229 tumor nude mice for 28 days, the anti-tumor inhibition activity of ABP-1130 (40 mg/kg, QD) was significantly observed, and the average volume of brain tumors in nude mice (six mice/each group) was reduced from 122 mm3 to < 10mm3 (vs Pazopanib as a positive control, 50mg/kg, tumor volume increased from 123 to 867mm3). Moreover, for other safety issues, its Ames is negative and hERG is > 30 µM, and no test-article related death or adverse events occurred in maximum tolerated dose (MTD) studies with ABP-1130 (100mg/kg, QD) for 14 days. ABP-1130 also had very good metabolic stability in Human (T1/2 = 193min). Conclusions: Based on our completed preclinical study results, ABP-1130 is a novel and potent multi-TRK Inhibitor, showing excellent enzymatic activity, prominent in-vitro anti-cancer activity, and significant tumor growth inhibition activity with tolerable toxicity in glioblastoma tumor xenograft in nude mice model. It is highly warranted to continue further investigation in glioblastoma.
Treatment outcomes in melanoma with brain metastases in the era of immunotherapy: An analysis of the National Cancer Database.
Authors: Moyers Justin , Chong Esther G , Sufficool Daniel , Nagaraj Gayathri
Published: May 2020

e14513

Background: Brain metastases (BM) are a major cause of morbidity and mortality in metastatic melanoma. Radiotherapy (RT) and/or surgery are the standard of care for treating brain metastases. The introduction of immune checkpoint inhibitors has drastically improved disease outcomes since approved in 2011 and recent trials have exhibited intracranial activity. We aim to assess the added survival benefit of immuno-oncologic agents (IO) for melanoma with BM in National Cancer Database. Methods: We queried the database from 2011 to 2015 for Stage IV melanoma with BM. RT treatments were divided into stereotactic radiosurgery (SRS), whole brain radiotherapy (WBRT), or no brain radiation; those with insufficient documentation were excluded. Patients were further divided into receipt of IO or no receipt of IO; those without documentation were excluded. Concurrent (CC) treatment was defined as IO begun before or during RT treatment; sequential (SQ) therapy was defined as IO begun after RT. Survival analyses were performed by Kaplan-Meier method and log-rank test. Results: Among 8,561 metastatic melanoma patients with documentation of metastatic sites, 3,008 (35.1%) had documented BM. Median overall survival (mOS) for all stage IV melanoma was 10.5 months with worse survival for those with BM compared to those without (mOS 6.0 v 14.7 m; p < 0.01). Among 3,008 cases with survival data available, 2,762 met criteria for survival analysis of BM treatments. Table summarizes treatment outcomes between cohorts by RT and IO treatment categories. IO + SRS had improved survival compared to all other treatment groups (mOS 19.9 m; p < 0.01). No difference in survival between SRS and IO alone was observed (mOS 10.9 v 11.5 m; p = 0.56). WBRT as single modality did not appear to improve survival over no therapy (mOS 4.2 v 3.3 m; p = 0.35). 436 cases had documented time course between IO and RT. IO was given SQ with RT in 69% of SRS (n = 158/230) and 67% of WBRT (n = 137/206) treated patients. In SRS + IO cohort, survival was longer for SQ compared to CC treatment (23.5 v 13.1 m; p < 0.01). Survival was similar in WBRT for SQ v CC groups (6.8 v 7.9 m; p = 0.62). Conclusions: Superior survival is realized for those who receive IO in addition to SRS for BM. IO and SRS as single modality have similar outcomes, while WBRT seems to add little survival benefit to IO or no therapy. [Table: see text]
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.