bluuebunny/crossref_metadata_2025_split huggingface dataset:
Study of the impact of cytomegalovirus-encephalopathy on survival of brain cancer patients undergoing treatment with radio(chemo)therapy.
Authors: Goerig Nicole Lydia , Frey Benjamin , Korn Klaus , Fleckenstein Bernhard , Ueberla Klaus M , Schmidt Manuel A. , Doerfler Arnd , Engelhorn Tobias , Eyüpoglu Ilker , Merkel Andreas , Ruehle Paul F , Putz Florian , Semrau Sabine , Gaipl Udo S , Fietkau Rainer 
Published: September 2018

2036 Background: As recently demonstrated (Neurooncology, 2016), neurological decline of patients with brain cancer (high grade glioma, brain metastases) during radio(chemo)therapy (RCT) of the brain is oftentimes caused by CMV-encephalopathy but not disease progression or therapeutic complications. We examined the impact of clinical and serological CMV-status on the survival one year after the onset of radio(chemo)therapy of the brain. Methods: 118 patients requiring whole-brain radiotherapy for brain metastases (n = 55) or local RCT of the brain for high-grade gliomas (n = 63) were observed in the prospective GLIO-CMV-01 study. MRIs and blood samples were obtained before, halfway through, and at the end of radiotherapy. MRIs were screened for disease progression or increased intracranial pressure. Blood was tested for anti-CMV immunoglobulin (Ig)M, anti-CMV IgG, and CMV DNA. Results: 68 of 118 (58%) patients were positive for anti-CMV IgG before radio(chemo)therapy. 28 of those 68 (41%) developed CMV-viremia during or up to 28 days after the end of irradiation. 21 of those 28 (75%) required treatment for symptomatic CMV-associated encephalopathy. One year after the start of RCT, survival was 72% (34/47) (no encephalopathy, anti-CMV-IgG+) or 68% (34/50) (no encephalopathy, anti-CMV-IgG-) versus 38% (8/21) (encephalopathy) (p = 0.0034). Conclusions: Symptomatic CMV-encephalopathy all but doubles the mortality of brain cancer patients within one year of RCT, despite antiviral treatment with ganciclovir. These findings heavily underline the importance to identify patients with increased risk profile for developing CMV-encephalopathy before initiating RCT.
Phase 2 study to evaluate safety and efficacy of MEDI4736 (durvalumab [DUR]) in glioblastoma (GBM) patients: An update.
Authors: Reardon David A. , Kaley Thomas Joseph , Dietrich Jorg , Clarke Jennifer Leigh , Dunn Gavin P , Lim Michael , Cloughesy Timothy Francis , Gan Hui Kong , Park Andrew J. , Schwarzenberger Paul , Ricciardi Toni , Macri Mary J. , Ryan Aileen , Venhaus Ralph Rudolph 
Published: September 2018

2042 Background: DUR is a human IgG1 monoclonal Ab against PD-L1. PD-1/PD-L1 blockade has shown benefit in solid tumors. PD-L1 is expressed by many GBM tumors while cytotoxic lymphocytes infiltrating GBM tumors often express PD-1; thus, there is a rationale for exploring PD-1/PD-L1 blockade in GBM. Bevacizumab (BEV) is a VEGF-specific angiogenesis inhibitor approved for recurrent GBM. PD-L1 blockade and angiogenesis inhibition may be synergistic. Methods: This ongoing Phase 2, multicenter, open-label study (NCT02336165) evaluates safety/efficacy of DUR (10 mg/kg every 2 wks) in 5 GBM cohorts. Secondary endpoints are safety/tolerability, median PFS/OS, overall response rate and quality of life measures. Exploratory endpoints: neurologic function and immunocorrelative biomarkers. Results: Enrollment as of 16 Dec 2016: Cohort A = 35, B = 31, B2 = 34, B3 = 34, and C = 20 pts. Enrollment is ongoing for Cohorts A and C. This is an update to the interim analysis that was reported for Cohort B (male: 83.9%; mean age: 54.0 [24-77] years; baseline ECOG PS0: 51.6%, PS1: 48.4%; baseline measurable lesions: 77.4%). Incidences of treatment-related adverse events (TRAEs) by max CTCAE grade (Gr) were Gr1: 35.5%; Gr2: 41.9%; Gr3: 9.7%; and Gr4/5: 0%. Most common TRAEs (≥3 pts): fatigue, headache, hemiparesis, gait disturbance, increased AST, and decreased platelets/WBCs/lymphs. Six of 30 evaluable pts were progression free at 6 months (Kaplan-Meier, 20.0% [90% CI: 9.7, 33.0]); best overall response: partial response, 4 (13.3%) pts and stable disease, 14 (46.7%). At 1 year, 4 pts remained progression free (longest PFS ongoing at 80 wks, n=2). OS-6 and OS-12 are 59.0 and 44.4%, respectively. As of 16 Dec 2016, 7 pts remain alive (longest OS ongoing at 86 wks). Conclusions: DUR monotherapy appears to be well tolerated and shows durable activity in a subset of BEV-naïve recurrent GBM pts. Study is ongoing. Clinical trial information: NCT02336165. [Table: see text]
Radiomics method to predict loss of heterozygosity on chromosome 1p/19q of oligodendroglial tumor.
Authors: Wei Jingwei , Tian Jie 
Published: September 2018

2043 Background: Oligodendroglial tumor (OT) is one of the main types of gliomas, which is incurable in current situation. As a tumor-specific genetic alteration of OTs, loss of heterozygosity (LOH) on chromosome 1p/19q indicates a preferable response to chemo/radiotherapy and a better survial, which could be used as a key molecular signature for personalized treatment decision making. However, 1p/19q LOH status is now commonly obtained by fluorescence in situ hybridization after the tumor resection, which is highly likely to lead functin deficit with tumor locating on eloquent area. Thus, a noninvasive predicition on 1p/19q LOH is required. Here, we used a "Radiomics" method to achieve the prediction based on magnetic resonance imaging in this study. Methods: A cohort of 113 OT patients was collected from Beijing Tiantan Hospital. 593 three-dimensional imaging features were extracted on T2-weighted images including textural and non-textural features. We used "minimum redundancy maximum relevance" and "iterative backward elemination and forward inclusion" algorithms to pick up the most effective features with a p-value < 0.05. With the selected features as the input, support vector machine algorithm was adopted to predict the 1p/19q LOH status with 10-fold cross validation. Comparisons were made between the traditional clinical predictors and the established model. Results: The prediction accuracy for 1p/19q LOH turned out to be 86.6%. The top three features contributing most to the prediction were respectively: GlobalUniformity, GaborBankD4GLRLMLGRE and GaborBankD4GLRLMSRLGE. The predictive performance of the radiomics model was proved to be far more valid than the clinical predictors (indistict tumor border and heterogeneous signal intensity) with the higher area under curve (AUC). Compared with the best single feature (GlobalUniformity, AUC: 0.749), this combined-feature model has the best diagnostic performance with an AUC of 0.898. Conclusions: This study reveals the intrinsic association between the imaging features and 1p/19q LOH status, meanwhile, realizes the high precision prediction, providing reliable basis for the pre-operative treatment regime.
Characterizing glioma microenvironment with ultra-high gradient diffusion MRI.
Authors: Ly Ina , Wichtmann Barbara , Huang Susie Yi , Nummenmaa Aapo , Andronesi Ovidiu , Fan Qiuyun , Curry William T. , Cahill Daniel P. , Golby Alexandra J , Batchelor Tracy , Kalpathy-Cramer Jayashree , Rosen Bruce R. , Gerstner Elizabeth Robins 
Published: September 2018

2050 Background: The infiltrating nature of gliomas, particularly into the peritumoral area, is a major barrier to improving clinical outcome as microscopic disease remains even after apparent gross total resection. Conventional T1 post-contrast and T2/FLAIR MRI do not capture full tumor extent. A better imaging biomarker is needed to improve differentiation between tumor, peritumoral area and normal brain. Methods: 4 pre-surgical patients with non-enhancing, FLAIR-hyperintense lesions suspicious for glioma underwent ultra-high gradient diffusion MRI on the Connectome MRI scanner, a unique scanner with maximum gradient strength of 300 mT/m enabling mapping of cellular microstructures on a micron-level scale. The FLAIR area was defined as the tumor region of interest (ROI). Radiographically normal appearing brain up to 1 cm around the FLAIR area was defined as the peritumoral ROI. Using a novel 3 compartment diffusion model (Linear Multiscale Model), the volume fraction of water (VFW) was calculated within restricted (intracellular), hindered (extracellular) and free (CSF) spaces. VFW in the tumor, peritumoral ROI, contralateral normal white matter (WM) and cortex were compared. Results: Within the tumor ROI, the median VFW in the restricted compartment was decreased vs. the peritumoral ROI (↓ 34%), WM (↓ 46%) and cortex (↓ 18%) while median VFW in the hindered compartment was increased vs. the peritumoral ROI (↑ 26%), WM (↑ 54%) and cortex (↑ 25%). Within the peritumoral ROI, median VFW in the hindered compartment was increased compared to WM (↑ 23%). 3 patients had available histopathology revealing isocitrate dehydrogenase-mutant gliomas. Conclusions: Using ultra-high gradient diffusion MRI and a novel diffusion model, we detected distinct diffusion patterns in the tumor and peritumoral area not seen on conventional MRI. Lower VFW in the restricted compartment within the tumor may reflect decreased intracellular water mobility due to enlarged nuclei. Higher VFW in the hindered compartment in the tumor and peritumoral area may reflect higher degree of tissue permeability and edema. MRI-pathology and larger cohort validation studies are underway to elucidate microenvironment changes in response to treatment.
Association of SDF1 inhibition with local control and relative cerebral blood volume of glioblastoma.
Authors: Thomas Reena Parada , Nagpal Seema , Iv Michael , Soltys Scott G. , Recht Cathy Kahn , Bertrand Sophie , Makar Sherif Mark , Corbin Zachary , Mandic Kseniya , Coffey Gwen , Pelpola Shanika , Prado Isabel P , Brown Martin , Recht Lawrence David 
Published: September 2018

2058 Background: Glioblastoma is the most common and aggressive primary brain tumor, with 75-85% of patients historically having recurrence within the original tumor site. We have shown in preclinical studies that inhibition of the SDF1/CXCR4 pathway by the CXCR4 inhibitor Plerixafor increases tumor response to irradiation by inhibition of the recovery of tumor blood vessels. Methods: Newly diagnosed glioblastoma patients were enrolled to the clinical trial using the investigational agent Plerixafor after standard radiation therapy and temozolomide (NCT01977677). To date, 28 patients out of the planned accrual of 29 have been enrolled to this study. Normalized relative cerebral blood volume (rCBV) ratios were calculated by the mean rCBV within the 95% isodose radiation field one month post-radiation as compared to contralateral white matter outside of the radiation field. Our imaging analysis compares patients treated with Plerixafor compared to a control group receiving standard therapy (chemo-RT). Results: There was a significant reduction in rCBV measured by DSC-MRI within the 95% isodose field one month after radiation therapy in patients receiving Plerixafor compared to control (p < 0.02). The rCBV out of the radiation field was similar between patients receiving Plerixafor compared to control patients one-month post radiation therapy. As of February 7, 2017, only 2 of the total of 9 recurrences occurred within the irradiated field. The rate of out of field recurrence (77%) was therefore much higher than expected (20%), with statistical significance (p < 0.03, Fisher’s exact test). Conclusions: We show that Plerixafor has a meaningful impact on local control of glioblastoma. Furthermore, DSC-MRI could be a useful biomarker of its efficacy.
Pituitary carcinoma: The University of Texas MD Anderson Cancer Center experience.
Authors: Santos Pinheiro Fernando , Penas-Prado Marta , McCutcheon Ian E. , Mahajan Anita , Brown Paul D. , Kamiya-Matsuoka Carlos 
Published: September 2018

2068 Background: Pituitary carcinoma (PC) is a rare and aggressive neuroendocrine tumor diagnosed once a pituitary adenoma (PA) becomes metastatic. Although no standard treatment currently exists, surgery, radiation (XRT) and/or chemotherapy are most commonly used. Recently, treatment with temozolomide (TMZ) has shown promising results, although the lack of prospective trials limits accurate outcome assessment. Methods: We describe a single-center multidisciplinary team experience in managing PC patients over a 13-year period (Oct, 2003 to Jan, 2017). Results: A total of 17 patients (9 males) were seen. Median age at diagnosis of PC was 44 years (range 16-82 years) and the median time from PA to PC conversion was 6 years (range 1-29 years). Median follow-up time: 28 months (range 8-158 months) with 7 reported deaths. The majority of PC was hormone-secreting (HS) subtype (n = 12): ACTH (n = 5), PRL (n = 4), FSH/LH (n = 2), GH (n = 1). After PC diagnosis, all pituitary tumors were locally invasive, all underwent at least one resection (mean 2.3) and all received at least one course of XRT alone (IMRT = 76%, SRS = 29%, IMPT = 12%) or concurrent with chemotherapy (18%). Immunohistochemistry showed high Ki-67 labeling index ( > 3%) in 9 (53%) cases. Most cases (n = 14) had metastases to the CNS, 35% of those had combined CNS and systemic foci. Ten (59%) cases underwent focal treatment of metastases, 90% of which underwent XRT. The most common chemotherapy used was TMZ [n = 14 (82%): single agent (n = 10); TMZ+capecitabine (n = 5); concurrent TMZ+XRT (n = 3); concurrent TMZ+XRT with adjuvant TMZ (n = 1)]. The median longest progression-free survival (LPFS) was 18 months (range 4-45 months). TMZ was associated with the chemotherapy-related LPFS in 9 (75%) cases. The 2, 3 and 5 year survival rate was 65%, 53% and 35%, respectively. All patients surviving > 5 years were treated with TMZ (n = 5, 2 survived > 10 years). Two refractory cases are currently on PD-1 inhibitor agent. Eighty percent of non-functioning PC were alive at last follow-up (HS-PC, 58%). Recurrence occurred in 11 (65%) cases. Conclusions: Treatment of PC requires a multidisciplinary approach. Multimodality therapy with surgery, radiation and TMZ was associated with higher survival rates and longer PFS.
What drives patient outcomes in brain metastases: Number, volume, or biology?
Authors: Kotecha Rupesh , Miller Jacob A , Chao Samuel T. , Mohammadi Alireza Mohammad , Murphy Erin Sennett , Suh John H. , Barnett Gene H. , Vogelbaum Michael A. , Angelov Lilyana , Ahluwalia Manmeet Singh 
Published: September 2018

2071 Background: To delineate the prognostic importance of number of brain metastases (BM), lesion volume, and biology on overall survival. Methods: Patients treated for BM with whole-brain radiation therapy (WBRT), surgery, and/or stereotactic radiosurgery (SRS) at a single tertiary care institution from 1997-2015 were reviewed. The primary outcome was overall survival. Multivariable proportional hazards regression was used to adjust for confounding factors. Results: 3,955 patients with 16,189 BM were included in the analysis. There was a reduction in median survival with increasing number of lesions [1 lesion, 10.2 months; 2-4 lesions, 7.2 months, Hazard Ratio (HR) 1.36; 5-10 lesions, 5.6 months, HR: 1.69; > 10 lesions, 5.5 months, HR: 1.57, p< 0.001]. Among 1,651 patients (35%) who underwent SRS, there was a similar reduction in median survival with increasing lesion number [1 lesion, 12.2 months; 2-4 lesions, 10.1 months, HR 1.20; 5-10 lesions, 8.4 months, HR 1.41; > 10 lesions, 6.9 months, HR 1.19], p< 0.001). Among patients who underwent upfront SRS, increasing number of BM did not adversely affect survival in those with the smallest intracranial disease volume (≤0.4 cc, 10th percentile, p= 0.39), but was associated with inferior survival in patients with larger disease volumes (≤1.1 cc, 25th percentile, p= 0.05; ≤2.6 cc, 50th percentile, p= 0.005; ≤6.3 cc, 75th percentile, p= 0.006, and ≤12.2 cc, and 90th percentile, p =0.004). After partitioning the cohort into molecular subsets, patients with ALK+ disease had no difference in survival based on either lesion number or volume. Patients with EGFR+, HER2+, and luminal B disease had no difference in survival based on number of metastases, while patients with BRAF V600+and luminal A disease had no difference in survival based on intracranial disease volume. Conclusions: Number of BM closely correlates with survival in the majority of patients and intracranial disease volume impacts survival independent of number of metastases. For patients with certain tumor subtypes ( ALK+), intracranial disease burden appears to have no correlation with survival. Molecular profile characterization is important to identify patients with favorable subtypes given available treatment options.
Phase I study of nab-paclitaxel, gemcitabine, and bevacizumab in advanced cancers.
Authors: Sen Shiraj , Piha-Paul Sarina Anne , Kato Shumei , Karp Daniel D. , Janku Filip , Fu Siqing , Naing Aung , Pant Shubham , Tsimberidou Apostolia Maria , Subbiah Vivek , Kurzrock Razelle , Meric-Bernstam Funda , Hong David S. 
Published: September 2018

2526 Background: Gemcitabine (gem) with nab-paclitaxel (nab-p) is known to have antitumor activity and a favorable toxicity profile. The addition of bevacizumab (bev) to nab-paclitaxel has also been found to enhance nab-paclitaxel cytotoxicity. Methods: We therefore performed a modified 3+3 dose escalation study with 15 dose levels of fixed dose gem 1000 mg/m2IV (day 1, 8, 15) and escalating doses of nab-p IV (day 1,8, 15) and bev IV (day 1,15) every 28 days. The study design allowed for the possibility of multiple MTDs. Correlative studies on VEGF polymorphism and response were planned. (NCT01113476). Results: 103 patients (45 male) with advanced cancers were enrolled (19 ovarian, 18 pancreatic, and 18 gastroesophageal (GE) cancers among the most common). All patients were ECOG PS 0-2, median age was 60 years (range 17-85), and 51 patients (50%) were gem refractory with a median of 3 prior lines of therapy. 3 DLTs were observed during dose escalation - one with nab-p 50 mg/m2 and bev 10 mg/m2 (grade 3 dysphagia, dehydration), one with nab-p 75 mg/m2 and bev 10 mg/m2 (grade 3 cellulitis) and one with nab-p 150 mg/m2 and bev 5 mg/m2 (grade 3 bacteremia, hypotension). 2 DLTs were observed among the 13 patients in the nab-p 100 mg/m2 and bev 5 mg/m2 expansion cohort (one grade 3 diarrhea, one grade 3 fatigue) and 1 DLT among the 12 patients in the nab-p 75 mg/m2 and bev 10 mg/m2 expansion cohort (grade 3 rectal bleed). Dose escalation up to nab-p 125 mg/m2 and bev 15 mg/m2was well tolerated with no MTD. One patient with gem refractory peritoneal papillary carcinoma achieved a complete response, 13 patients (13%) had partial responses (PR), and 54 patients (52%) had prolonged stable disease (pSD) ≥ 12 weeks. 4 patients achieving PR and 26 patients with pSD were previously gem refractory. 3/6 (50%) small cell cancers achieved PR and all 6 of these patients had tumor shrinkage of at least 25%. 4/19 (21%) ovarian cancers achieved PR, 3/18 (17%) GE cancers achieved PR, and 1/18 (6%) pancreatic cancers achieved PR. Conclusions: The combination of gem 1000 mg/m2, nab-p 125 mg/m2 and bev 15 mg/m2 is safe, well-tolerated, and has activity even at lower doses in advanced malignancies, including gem refractory tumors. Correlative VEGF polymorphism studies are ongoing. Clinical trial information: NCT01113476.
A phase I dose escalation study of SCB01A, a micro-tubular inhibitor with vascular disrupting activity, in patients with advanced solid tumors refractory to standard therapy.
Authors: Chiang Nai-Jung , Shiah Her-Shyong , Lin Chia-Chi , Yen Chia-Jui , Tsai Hui-Jen , Wu Shang-Yin , Su Wu-Chou , Chang Kwang-Yu , Chen Li-Tzong 
Published: September 2018

2531 Background: SCB01A is a novel anti-microtubular agent with vascular disrupting activity. The Phase I study aimed to determine the dose-limiting toxicity (DLT), maximum tolerated dose (MTD), safety, and pharmacokinetic (PK) profiles of SCB01A in patients with advanced solid tumor. Methods: This was an open-label, phase I clinical trial with a rapid titration followed by a 3 x 3 study design. Eligible patients would receive a 3-hr intravenous infusion of SCB01A, every 21 days as one cycle. All adverse events were classified according to the CTCAE V4.0. DLT was defined as the occurrence of grade 3 with complications and grade 4 hematoloigcal, or ≥grade 3 non-hematological toxicities. Results: From June 2011 to November 2015, a total of 33 eligible patients were enrolled to eight dose levels: 2 mg/m2 (n = 1), 3 mg/m2 (n = 1), 4 mg/m2 (n = 6), 6.5 mg/m2 (n = 9, with 3 additional subjects were recruited for safety concern), 10 mg/m2 (n = 3), 16 mg/m2 (n = 3), 24 mg/m2 (n = 6) and 32 mg/m2 (n = 4). Six episodes of DLTs were observed in 5 patients (each one in dose levels of 4/6.5/24 mg/m2 and two in dose level of 32 mg/m2), including grade 4 blood creatine phosphokinase elevation (4 mg/m2), grade 3 gastric hemorrhage (6.5 mg/m2), grade 2 venous thrombosis (24 mg/m2), grade 3 peripheral neuropathy manifested as weakness of lower limbs, grade 3 aspartate aminotransferase elevation, and grade 3 hypertension (32 mg/m2). The MTD was determined to be 24 mg/m2. Pharmacokinetic profiles revealed a linear AUC-dose response with an average elimination half-life (t1/2) of 2.5 hours. Partial response was observed in one subject with buccal cancer. A total of 57.6% (19/33) subjects had stable disease for at least 2 cycles. Conclusions: SCB01A is safe and tolerable in patients with solid tumor. The MTD of SCB01A is 24 mg/m2 every 21 days, which deserves further development. Clinical trial information: NCT011159522.
Large scale adverse event data mining for targeted therapies development.
Authors: Sarangdhar Mayur , Aronow Bruce , Jegga Anil Goud , Turpin Brian , Breese Erin Haag , Perentesis John Peter 
Published: September 2018

2538 Background: Targeted anti-cancer small molecule drugs & immune therapies have had a dramatic impact in improving outcomes & the approach to clinical trials. Increasingly, regulatory approvals are expedited with small studies designed to identify strong efficacy signals. However, this may limit the extent of safety profiling. The use of large scale/big data meta-analyses can identify novel safety & efficacy signals in "real-world" medical settings. Methods: We used AERSMine, an open-source data mining platform to identify drug toxicity signatures in the FDA’s Adverse Event Reporting System of 8.6 million patients. We identified patients (n = 732,198) who received either traditional and targeted cancer therapy & identified therapy-specific toxicity patterns. Patients were classified based on exposures: anthracyclines (n = 83,179), platinum (117,993), antimetabolites (93,062), alkylators (81,507), antimicrotubule agents (97,726), HER2 inhibitors (40,040), VEGFis (79,144), VEGF-TKis (90,734), multi TKis (34,457), anaplastic lymphoma Kis (7,635), PI3K-AKT-mTOR inhibitors (33,864), Bruton TKis (9,247), MEKis (4,018), immunomodulatory agents (174,810), proteasome inhibitors (44,681), immune checkpoint inhibitors (20,287). Pharmacovigilance metrics [Relative Risks & safety signals] were used to establish statistical correlation & toxicity signatures were differentiated using the Kolmogorov–Smirnov test. Results: To validate the use of the AERSMine to detect AEs, we focused on cardiotoxicity. It identified classic drug associated AEs (e.g. ventricular dysfunction with anthracyclines, HER2is & VEGFis; VEGFi hypertension & vascular toxicity; multi TKIs vascular events). AERSMine also identified recently reported uncommon toxicities of myositis/myocarditis with immune checkpoint inhibitors. It indicated a higher frequency of myositis/myocarditis with combination immune checkpoint therapy, paralleling industry corporate safety databases. These toxicities were reported at higher frequencies in patients > 65 yrs. Conclusions: AERSMine “big data” analyses provide a sensitive tool to detect potential new patterns of AEs simultaneously across multiple clinical trials & in the real-world setting.