bluuebunny/crossref_metadata_2025 huggingface dataset:
Emerging trends in pancreatic cancer and diabetes.
Authors: Niphadkar Seema , Nathan Rachel , Perimbeti Stuthi , Liang Ya Yu , Marconcini Luiz Antonio Liarte , Lee William May , Nandi Neilanjan , Jain Maneesh Rajiv , Ward Kristine Marie , Styler Michael
Published: September 2018

e13077

Background: Risk factors for cancer and diabetes mellitus (DM) include aging, obesity, smoking, and physical inactivity. Present studies conflict on the role of DM in cancer pathogenesis; however, the link between DM and pancreatic cancer (PC) is well studied. We assessed the prevalence of DM in PC, exploring trends in demographics, length of stay (LOS), cost and inpatient mortality in teaching vs non-teaching hospitals. Methods: The Healthcare Cost and Utilization Project’s Nationwide Inpatient Sample (1999 – 2014) was queried for patients > 18 with primary diagnosis of PC (excluding Whipple procedure) and secondary DM using ICD9 codes. We studied prevalence of DM and PC and compared cost of admission, LOS, mortality, and demographics between teaching and non-teaching hospitals. Chi-square test analyzed categorical variables. Results: Of 113,677 admissions for PC, 35,496 (31%) had DM. PC associated DM prevalence was higher in whites compared to blacks 57.9 % vs 12.7%, patients aged 65-79 47.7%, and southern US 37% with p < 0.0001. Income disparities have decreased between 25th percentile and > 75thpercentiles from 1999 (7.3 and 32.5%) to 2014 (23.6 and 26.1%). The adjusted cost per hospitalization increased from 1999 to 2014 ($34,950 to $78,469) while LOS decreased (9.26 to 7.50 days). In teaching vs non-teaching hospitals, average cost of hospitalization ($60,465 vs $44,955) and LOS (8.8 vs 7.8 days) were higher (p < 0.0001). In-hospital mortality for diabetic PC trended down from 13.09 to 6.81% and average mortality was higher in non-teaching vs teaching 11.25% vs 7.59% (all p < 0.0001). Conclusions: The link between diabetes and PC has been suggested although the complete mechanism is not well understood. Our analysis showed 31% of PC cases had DM. In-hospital mortality and LOS have decreased possibly due to advances in diagnosis and treatment of both conditions. Income disparities in admissions have converged perhaps due to improved access to care for low income and outpatient management for higher income brackets. Mortality is lower in teaching hospitals but is linked with a higher cost and LOS possibly due to utilization of testing and sub-specialty access. The findings of increased white and southern prevalence are unexplained and warrant further investigation.
Trends in synchronous invasive ductal carcinomas of the breast: A SEER database analysis.
Authors: Mehta Rutika Jitesh , Groman Adrienne , Jain Rohit K. , Levine Ellis Glenn
Published: September 2018

e13081

Background: Synchronous breast cancers are uncommon and account for around 2% of all breast cancer diagnosis. Lobular histology is considered a risk factor for synchronous breast cancers. We sought to study the trends in synchronous breast cancer of ductal histology and influence of age by interrogating the SEER database. Methods: The SEER Research data 1973-2013 was interrogated for synchronous infiltrating ductal carcinoma diagnosis (2 diagnosis within 6 months of each other). Overall survival (OS), the primary endpoint, was defined as the time (in months) from diagnosis to death from any cause. Univariate proportional hazards modeling results were used to assess the effect of age, race and stage on overall survival. All associations were considered statistically significant at an alpha error < 0.01. All analyses were performed using SAS version 9.4. Results: 1469 cases were identified. Data was categorized by age group: ≤ 65 years or > 65 years. 60% were 65 years or younger. 85% were Caucasians, 9.6% African Americans and 5.2% others. Younger women (≤ 65 years) had a statistically higher proportion of Stage III/IV breast cancer diagnosis as compared to older women (33.4% vs 25.2%; p = 0.002). The incidence rate of synchronous breast cancers has been rising since 1973, more pronounced in the older age group. Incidence rates overall have risen from 0.09/100,000 persons in 1973-1980 to 0.29/100,000 persons in 2001-2013 (p < 0.001). Incidence rates for synchronous breast cancer in women > 65 years has increased from 0.30/100,000 persons in 1973-1980 to 1.03/100,000 persons in 2001-2013. The adjusted OS among older women is significantly worse than that of younger women (HR 1.05; 95% CI 1.04-1.05; p < 0.001). Conclusions: Better imaging techniques and breast cancer screening guidelines have likely improved breast cancer detection rates thus leading to a rise in the incidence of synchronous breast cancers. It can be speculated that underlying medical problems and advanced age result in more morbidity and subsequent mortality in older women with standard treatment. The finding of more advanced disease among younger women deserves scrutiny as to cause.
BMI change and abdominal girth as risk factors of breast cancer.
Authors: Suzuki Yusuke , Tsunoda Hiroko , Kimura Takeshi , Yamauchi Hideko
Published: September 2018

e13082

Background: While obesity is considered the risk factors of breast cancer, Asian women are tends to be lower BMI compared with Western populations and there are not much reports that studied association between obesity and risk of breast cancer in Asian women. In this study, we analyzed the associations of breast cancer incidence and body mass index at age 18-20 (BMI 18-20y), BMI at research entry (BMI at entry), change of the BMI from BMI 18-20y to BMI at entry (BMI change), abdominal girth at research entry (AG), HbA1c [N] at research entry (HbA1c). Methods: We used data of the women who had undergone medical check-ups and opportunistic breast cancer screening at least twice at the Center for Preventive Medicine of St. Luke’s International Hospital between April 1, 2005 and March 31, 2014. Statistical analysis was done by using multivariate Cox proportional hazards model to investigate the hazard ratio (HR) at 95% confidence intervals (95% CI). Results: In this 10 year period, 30,109 women (20,043 women were premenopausal and 10,066 women were postmenopausal women) received opportunistic breast cancer screening at least twice. After analysis of 131656.6 person-years follow up during 10 years, 325 initial breast cancer cases were identified 202 cases in premenopausal women, and 123 cases in postmenopausal women. Among postmenopausal women, BMI change and AG were positively associated with breast cancer incidence. Women whose BMI change were major gain group (> +5.0) were significantly likely to develop breast cancer compared with stable group (BMI change were between -2.5 to +2.5) [HR: 1.902 (95% CI = 1.202-3.009)]. Large AG ( > 90cm) was significant risk to develop breast cancer versus less than 70cm [HR: 2.500 (95% CI = 1.091-5.730)]. In the analysis classified BMI18-20y more and less than 20 kg/m2, large BMI18-20y ( > 20 kg/m2) postmenopausal women with high HbA1c ( > 6.5) was more likely to develop breast cancer compared with low HbA1c ( < 5.5) [HR: 3.325(95% CI = 1.307-8.460)]. Conclusions: Increase of BMI after age of 18-20 years and large AG in postmenopausal women have positive association with breast cancer development. High HbA1c women whose BMI18-20y was over 20 kg/m2 are significantly to develop breast cancer.
Study to determine whether SNPs in CYP17A1, ESR1, and TNRC9 loci correlate with increased breast cancer risk and serum 25-OH vitamin D levels.
Authors: Yoshimoto Nobuyasu , Dong Yu , Sugiura Hiroshi , Terada Mitsuo , Kondo Naoto , Endo Yumi , Yamashita Hiroko , Toyama Tatsuya
Published: September 2018

e13086

Background: Low serum 25-OH vitamin D (25-OH Vit.D) level is associated with a higher risk of breast cancer. Many single nucleotide polymorphisms (SNP) are associated with breast cancer risk, although the mechanisms underlying this association in most cases remain unclear. We attempted to address this issue by determining whether specific SNPs were correlated with breast cancer-associated biomarkers (BM). Methods: We analyzed estrogen receptor (ER)-positive breast cancer patients treated between Jan 2011 and Dec 2014. We measured serum testosterone and 25-OH Vit.D in pre- and post-menopausal women, and also measured estradiol in the latter group. We genotyped 7 individual SNPs both in premenopausal and postmenopausal women. We then looked for correlations between BMs and SNPs in all three genotypes (homozygotes of major alleles, heterozygotes and homozygotes of minor alleles) using the Kruskal-Wallis test. For each SNP locus associated with a trend or significant effect with regard to BM levels, a t-test was then applied to determine which of the two genotypes was responsible for the effect. Results: Four hundred thirteen women were enrolled (163 premenopausal patients, and 250 postmenopausal patients). There was a trend difference between CYP17A1 rs743572 and 25-OH Vit.D (p = 0.0888), ESR1 rs204210 and 25-OH Vit.D (p = 0.0534) in premenopausal women, and a significant difference between TNRC9 rs3803662 and 25-OH Vit.D (p = 0.026) in postmenopausal women. Among premenopausal women, 25-OH Vit.D levels were significantly lower in those with the high-risk rs743572 genotype TC when compared with TT individuals (19.2 +/- 6.7 ng/ml vs 22.9 +/- 8.7 ng/ml; p = 0.0125). Similarly, 25-OH Vit.D was significantly lower in women with the high-risk rs204210 genotype AG when compared with GG individuals (19.1 +/- 6.9 ng/ml vs 21.7 +/- 6.4 ng/ml; p = 0.0219). In postmenopausal women, 25-OH Vit.D was significantly lower in women with the high-risk rs3803662 genotype GG than those with the AA genotype (20.5 +/- 9.2 ng/ml vs 24.4 +/- 8.0 ng/ml; p = 0.0104). Conclusions: Specific SNPs in CYP17A1, ESR1, and TNRC9 genes may modulate breast cancer risk due to their influence on serum 25-OH Vit.D levels.
Epidemiology of lung cancer: A joinpoint analysis of temporal incidence and mortality trends in 38 countries.
Authors: Wong Martin CS , Chan Stephen Lam , Lao Xiang Qian , Tse Lap Ah , Ho KF , Goggins William
Published: September 2018

e13091

Background: Lung cancer is the leading cause of cancer death worldwide. We examined the correlation between lung cancer incidence/mortality and country-specific socioeconomic development, and evaluated the most recent global patterns and trends of this cancer in 38 countries. Methods: We retrieved age-standardized incidence rates of lung cancer in 2012 from the GLOBOCAN database. Temporal patterns were assessed for all countries obtained from the Cancer Incidence in Five Continents volumes I-X and the WHO mortality database. Simple linear regression analysis was used to evaluate their correlations with Human Development Index (HDI) and Gross Domestic Product (GDP) per capita. The average annual percent change (AAPC) of the incidence and mortality trends in the most recent 10 years were evaluated from join-point regression analysis according to country and gender. The statistical significance of AAPC was ascertained comparing with zero, and all insignificant AAPCs were regarded as having “stable trends”. Results: The global incidence and mortality of lung cancer varied by 31-fold. Country-specific HDI was strongly correlated with age-standardized incidence (r = 0.70) and mortality (r = 0.67), and so was GDP per capita to a lesser extent (r = 0.24 to 0.55) (all p < 0.001). Among men, 22 and 30 (out of 38 and 36) countries showed declining incidence and mortality trends, respectively; whilst among women, 19 and 16 countries showed increasing incidence and mortality trends, respectively. The AAPCs ranged from -2.8 to -0.6 (incidence) and -3.6 to -1.1 (mortality) among countries with declining trend in men, whereas the AAPC range was 0.4 to 8.9 (incidence) and 1 to 4.4 (mortality) among countries with increasing trends in women. Among women, Brazil, Spain and Cyprus had the greatest incidence increase, and all countries in Western, Southern and Eastern Europe had increasing mortality. Conclusions: Countries with higher socioeconomic development had higher lung cancer incidence and mortality. The incidence and mortality rates of lung cancer were increasing in many countries among women but declining in most countries among men, highlighting the need for regular surveillance and global preventive measures.
Somatic versus germline BRCA mutations screening in ovarian cancer.
Authors: Nunes Hugo SM , Machado Patricia , Fragoso Sofia , Santos Sidonia , Silva Fernanda , Felix Ana , Luís Ana , Opiniao Ana , Clara Ana , Bento Sandra , Miranda Ana , Francisca Ana , Vaz Fatima H.
Published: September 2018

e13100

Background: ovarian cancer (OC) with germinal or somatic BRCA mutations responds better to platinum and to PARP-inhibitors. There is great enthusiasm about BRCA somatic screening. Our aim was to analyse the correlation between BRCA somatic and germline mutational profile. Methods: a cohort of 23 pts was obtained by cross-linking OC pts from the South Portuguese Cancer Registry, between 2009-2014 and BRCA mutation carriers identified in our Clinic. Medical records were reviewed: demographic and clinico-pathologic data obtained. Germinal screening: pts were pre-screened for the BRCA2 Portuguese founder mutation (PFM), analysed for BRCA point mutations (different screening methodologies were used in diagnostic timeline: initially CSGE, then CSCE and finally NGS) and for large rearrangements by MLPA. Somatic screening: DNA was extracted from 5 sections of 10µm of FFPE tissue and analysed for BRCA1/2 genes by NGS. Results: clinico-pathological features of the 23 pts revealed mainly high-grade serous histology (96%). Mean age at diagnosis was 54 years old (33-76); BRCA2 were older than BRCA1 carriers (62 vs 51). Most pts presented at advanced stage (70% stages III-IV; 30% stage I-II). Seventeen were BRCA1 carriers and 6 were BRCA2 (5 of those PFM, a large insertion of an Alu element). Somatic correlation: 8 pts (5 BRCA1, 3PFM) were already analysed and 100% correlation was observed for all point mutations. One additional BRCA2 somatic mutation was detected (with a variant allele frequency of 53% whereas 2 others were < 7%); interestingly exclusive somatic mutations were only observed in PFM carriers (known not to be NGS detectable). The remaining 15 pts are under analysis. Conclusions: it was expected that the PFM and other large rearrangements would not be detected with NGS. A specific somatic screening for the PFM may be possible but other rearrangements are found by MLPA in our population (10% of all BRCA mutations). Preliminary data adds to the evidence that NGS OC somatic screening will identify all germinal point mutations and an indeterminate number of additional pts with exclusive somatic mutations. An ideal correlation needs integration of differenttechniques that may increase complexity, time and cost.
Comprehensive next generation sequencing assay and bioinformatic pipeline for identifying pathogenic variants associated with hereditary cancers.
Authors: Puig Oscar , Joseph Eugene , Jaremko Malgorzata , Kellogg Gregory , Wisotzkey Robert , Shraga Roman , Patel Bonny , Pollock Andrew , Fox Rebecca , Niknazar Mohammad , Parets Sasha , Duverger Georges , Chang Chihyu , Bisignano Alexander
Published: September 2018

e13105

Background: Diagnosis of hereditary cancer syndromes involves time-consuming comprehensive clinical and laboratory work-up, however, timely and accurate diagnosis is pivotal to the clinical management of cancer patients. Germline genetic testing has shown to facilitate the diagnostic process, allowing for identification and management of individuals at risk for inherited cancers. However, the laboratory diagnostics process requires not only development and validation of comprehensive gene panels to improve diagnostic yields, but a quality driven workflow including an end-to-end bioinformatics pipeline, and a robust process for variant classification. We will present a gene panel for the evaluation of hereditary cancer syndromes, conducted utilizing our novel end-to-end workflow, and validated in the CLIA-approved environment. Methods: A targeted Next-Generation Sequencing (NGS) panel consisting of 130 genes, including exons, promoters, 5’-UTRs, 3’-UTRs and selected introns, was designed to include genes associated with hereditary cancers. The assay was validated using samples from the 1000 genomes project and samples with known pathogenic variants. Elements software was utilized for end-to-end bioinformatic process ensuring adherence with the CLIA quality standards, and supporting manual curation of sequence variants. Results: Preliminary data from our current panel of genes associated with hereditary cancer syndromes revealed high sensitivity, specificity, and positive predictive value. Accuracy was confirmed by analysis of known SNVs, indels, and CNVs using 1000 Genomes and samples carrying pathogenic variants. The bioinformatics software allowed for an end-to-end quality controlled process of handling and analyzing of the NGS data, showing applicability for a clinical laboratory workflow. Conclusions: We have developed a comprehensive and accurate genetic testing process based on an automated and quality driven bioinformatics workflow that can be used to identify clinically important variants in genes associated with hereditary cancers. It's performance allows for implementation in the clinical laboratory setting.
Comparing actionable results for breast and colorectal cancer patients across multigene panels.
Authors: Fulk Kelly , Espenschied Carin , Profato Jessica , Reineke Patrick , LaDuca Holly , Smith Robina
Published: September 2018

e13109

Background: Many multigene panel (MGP) options are available for hereditary cancer testing. Previously, management guidelines were only published for a few high-risk genes, but now such guidelines exist for most genes on MGPs. Many clinicians question which MGP(s) may be most appropriate for their patients. We examined the likelihood of a positive result for patients diagnosed with breast cancer (BC) or colorectal cancer (CRC) across several MGPs and assessed the potential impact of these results on patient care. Methods: Positive results, defined by the presence of at least one pathogenic or likely pathogenic variant, were assessed for patients with BC or CRC across various MGPs ordered 6/2012-6/2016 at one commercial laboratory. For BC, the MGPs used for comparison were a high-risk BC panel (up to 6 genes), a comprehensive BC panel (up to 17 genes), and a multi-cancer panel (up to 32 genes). For CRC, a comprehensive CRC panel (up to 17 genes) was compared to the 32 gene multi-cancer panel. Results: For both BC and CRC patients, the utilization of a MGP with more genes led to more positive results than a MGP with fewer genes, with the vast majority of additional findings occurring in genes with published management guidelines (Table). Conclusions: The majority of positive results occurring in genes on larger MGPs, but not smaller MGPs, are in genes with published management guidelines.These results can impact treatment decisions and cancer risk management, including earlier and/or more frequent screening, chemoprevention, and/or other measures. In some cases, positive results occurred in genes not associated with the patient’s cancer diagnosis, but may still impact risk management for other cancer(s). Further studies are needed to determine the impact of larger MGPs on clinical outcomes for patients and their families. [Table: see text]
Performance study of an amplification-based NGS test on clinical FFPE specimens in China’s first multi-center study.
Authors: Ye Feng , Zhou Xiaoyan , Shi Huaiyin , Liu Haijing , Liang Li , Teng Xiaodong , Wang Zhe , Xu Sanpeng , Wang Guoping , Chen Gang , Hou Yingyong , Wu Huanwen M. , Tang Tingdong , Liu Rui , Zhang Bo , Liang Zhiyong , Bu Hong
Published: September 2018

e13112

Background: Next Generation Sequencing (NGS) assays provide a comprehensive view of clinically actionable variations in patients. The increasing application of NGS holds new promise towards accurate diagnosis, personalized treatment and precision medicine. Formalin-fixed Paraffin-embedded (FFPE) treatment remains to be the most popular format of tissue preservation. To further standardize the whole process of the application of NGS assays on FFPE tissues, the Chinese Medical Association Pathology Division organized a multi-center performance study of a NGS assay on more than 1,000 clinical FFPE specimens by inviting top pathology departments in the country. Methods: OncoAim Tumor Mutation and PharmGx Detection Kit (Singlera Genomics, Shanghai) was used for this study. Reference samples with known mutations and allele frequencies together with 1045 clinical FFPE specimens from 11 participating hospitals were tested. Among them, 615 Colorectal Cancer (CRC) and 430 Non-Small Cell Lung Cancer (NSCLC) FFPE samples were processed and sequenced on Illumina Miseq platform and Thermo ion torrent PGM platform, respectively. Results: The results on reference materials show 100% (Confidence interval = 100%) analytical sensitivity for mutations with MAF ≥ 10% when median coverage is ≥ 500X.Positive predictive value of > 99% was observed for mutations with MAF at 5% (data not shown). The median depth for CRC and NSCLC samples were 977Xand 828X, respectively. Among all CRC samples, 564 (91.7%) samples were found containing at least 1 clinical hotspot alteration. The top mutated genes were TP53, KRAS, APC, PIK3CA, SMAD4, BRAF, FBXW7, NRAS, PTEN, and ERBB2. For all the NSCLC samples, 304 (70.69%) were detected containing at least 1 clinical hotspot mutation. The top 10 mutated genes were EGFR, TP53, KRAS, PIK3CA PTEN, VHL, ERBB2, SMAD4, NFE2L2 and CTNNB1. Conclusions: In this study, we showed that the amplification-based NGS assay can achieve very high sensitivity and specificity for samples with median depth over 500X. The samples containing at least 1 clinical hotspot mutation were about 83% on average, suggesting NGS could be of great use for further characterization of the tissues.
Blood biomarker analysis to differentiate between pseudo-progression and true disease progression in post-treatment glioblastoma.
Authors: Hassan Bilal , Johnson Kimberly J. , Campian Jian Li
Published: September 2018

e13501

Background: Current standard treatment for patients with glioblastoma (GBM) includes glucocorticoid therapy, temozolomide (TMZ), and radiation (RT) which may result in lymphotoxic and immunosuppressive effects. MRI use is currently unreliable in differentiating true from pseudo-progression pathology. Recent studies have suggested that total lymphocyte count (TLC) and CD4 cell count are associated with clinical outcomes. Our objective was to investigate whether TLC or CD4 may help to differentiate treatment effect (pesudoprogression) from tumor progression. Methods: Patients were eligible for this retrospective study if they had 1) GBM diagnosed between February 2010 and July 2015, 2) series of cell counts and clinical follow-ups monitored at Washington University, and 3) tumor progression documented by MRI and pathology. The data were analyzed using descriptive statistics, chi-square tests, Kaplan-Meier survival curves, and progression-free survival. Results: A total of 728 charts were reviewed, of which 45adults met eligibility criteria. The median age and KPS scores were 58 years and 80, respectively. MGMT was detected in 33% of patients and 69% of patients had undergone a gross total resection. Median TLC at baseline was 1700 cells/mm3 (range 400-3100). After the completion of RT/TMZ, TLC dropped 41% to a median of 1000 cells/mm3 (range 200-2900). Median TLC was 1000 cells/mm3 (range 300-2900) at the first MRI documented progression. Patients underwent surgery for this MRI documented progression. Pathology revealed that 62% of patients had true tumor progression, 33% had mixed treatment effect and residual tumor, and 4% had necrosis. The median time from diagnosis to progression was 15 months. There were no statistically significant differences in overall survival or progression free survival found in patients with higher vs lower TLC at baseline, completion of RT/TMZ, and time of progression. Conclusions: These preliminary results do not indicate that TLC level in GBM patients can differentiate between true disease progression and pseudo-progression. A larger sample size that includes patients with CD4 data is needed to confirm these results.
Targeting myeloid derived suppressor cells: Phase 0/1 trial of low dose capecitabine + bevacizumab in patients with recurrent glioblastoma.
Authors: Peereboom David M. , Lathia Justin D. , Alban Tyler , Sinyuk Maksim , Ahluwalia Manmeet Singh , Mohammadi Alireza Mohammad , Brewer Cathy J. , Vogelbaum Michael A.
Published: September 2018

e13507

Background: Glioblastoma (GBM) creates an immunosuppressive environment that allows tumor growth. Myeloid derived suppressor cells (MDSCs), a heterogeneous class of immunosuppressive cells, mediate immune suppression in GBMs. MDSCs are up-regulated in the blood of patients with GBM and multiple other tumor types. We have developed a novel strategy to target GBM immunosuppression using low dose 5-fluorouracil (5-FU) that, targets immune cells and does not depend on blood brain or blood tumor barrier penetration. Marked MDSC depletion occurs at 5-FU doses in mice equivalent to < 10% of the normal human dosing. Goal: proof of concept that MDSC suppression in feasible in GBM pts with low-dose capecitabine [cap], an oral 5-FU analogue). Methods: Eligibility: Recurrent GBM in need of surgical resection; no prior cap or bevacizumab (bev). Cohorts of 3-6 patients receive low-dose cap 150 mg/m2/d (dose level [DL] 1) for 7 days before surgery. After surgery, patients resume cap for one cycle after which bev is added. Blood MDSC, immune cell levels, and relevant secreted factors are measured at baseline; pre- and post-op; and after the addition of bev. Tumors are assayed for MDSCs and glioma stem-like cells (GSCs). Primary endpoint: MDSC and T-Regulatory cell reduction after cap. Secondary endpoints: Tumor concentrations of MDSCs, GSCs, and T-reg cells; safety; and PFS6. Results: Three of the 4 patients enrolled have data available. All patients received 5 days of pre-op cap at DL 1 with MDSC reductions of 20, 26, and 79% from baseline. The first patient reached a reduction of 93% (measured 2 days after pre-op course) whereas the other 2 experienced return to baseline. The regulatory T cells (T-reg) also fell approximately 15, 20, and 50%, respectively. CD8 concentrations appeared to rise at the time of MDSC and T-reg reduction. No patient experienced grade 3 or higher toxicity. Conclusions: Low dose capecitabine appears to reduce MDSC concentrations with minimal toxicity. During this course T-regs also fell and CD8 concentrations rose. Dose escalation continues. (NCT02669173) (Supported by Musella Foundation, Blast GBM, Sontag Foundation, Velosano, Mylan Pharmaceuticals) Clinical trial information: NCT02669173.
Effect of BPM31510 on radiosensitivity of temozolomide-resistant glioblastoma cell model and survival in in vivo C6 glioma rat model supporting phase I clinical investigation in GBM.
Authors: Nagpal Seema , Dadali Tulin , Jang Taichang , Merchant Milton , Diers Anne R. , Gesta Stephane , Stevens Janice , Wilson Megan , Vishnudas Vivek , Kiebish Michael , Akmaev Viacheslav R , Narain Niven R. , Sarangarajan Rangaprasad , Recht Lawrence David
Published: September 2018

e13509

Background: Glioblastoma (GB) is characterized by dysregulated metabolism, utilizing glycolysis for energy production to support unrestricted growth. BPM 31510, an ubidecarenone containing lipid nanodispersion effectuates a switch in cancer energy sourcing from glycolysis towards mitochondrial OXPHOS, i.e. reverses Warburg effect, providing rationale for its potential utility in treatment of GB. The current study investigated utility of BPM31510 alone and in combination with temozolomide. Methods: In vitro (U251-MG human GB cell line) and in vivo (C6 glioma rat model) preclinical models of GB were used to assess the anti-cancer activity of BPM 31510 alone (100 mg/kg/d) and combination with TMZ/bevacizumab (BEV). In addition, an in vitro model of acquired TMZ chemo-resistance was established by progressive adaptation of parental U251-MG cells to increasing doses of TMZ. Parental and resistant subclones (TMZ-R) were used to define activity of BPM31510 in the TMZ-refractory setting. Results: In vitro results demonstrated that BPM 31510 has anti-cancer activity in both parental and TMZ-R U251-MG cells with EC50 values of ~400 µM and 800 µM, respectively. Importantly, BPM 31510 treatment also resensitized TMZ-R cell lines to TMZ. In vivo, BPM 31510 treatment was associated with increasing duration of survival; one fifth of the rats treated achieved survival greater than 15 days post implantation, a response not observed in the control or irradiation arms of the study. Assessment of the combination of BPM 31510 with TMZ or BEV in the in vivoC6 glioma rat model is ongoing. A phase I open-label, non-randomized clinical trial to evaluate the safety and tolerability of BPM31510 in patients with recurrent BEV-refractory GB, as well as the changes in GB metabolism by SUV-PET imaging in response to treatment is under investigation. Conclusions: Preclinical data demonstrate that BPM 31510 has potential anti-cancer activity alone and in combination with standard therapy regimens and alleviates TMZ chemo-resistance in preclinical models of GB. These results provide support of a Phase 1 clinical study of BPM31510 in GB; this study is actively enrolling.
Prospective study of the impact of neuro-oncology multi-disciplinary meetings on clinical decision making.
Authors: Ameratunga Malaka , Miller Dorothea , Ng Wayne , Cher Lawrence , Gonzalvo Augusto , Wada Morikatsu , Gan Hui Kong
Published: September 2018

e13512

Background: Multi-disciplinary team (MDT) meetings are considered essential to quality cancer care. For some malignancies, MDTs have been associated with improved outcomes, but data is limited for their utility in neuro-oncology. The aim of this study was to prospectively describe the MDT at our institution and evaluate its impact on clinical management. Methods: All cases discussed over three months at the Austin Health neuro-oncology MDT were prospectively evaluated. Cases were discussed amongst the treating team and a provisional plan (PP) and reason for discussion (RFD) was documented preceding the MDT. The PP was recorded as: surgery, radiation, chemoradiation, further diagnostic tests, surveillance and other. Patient specific clinical data was captured prospectively, with further pathological and radiological information captured during the MDT. Subsequently, the MDT reached a consensus decision, which was recorded. High impact decisions (HID) were those in which a substantial modification to the PP was made. Subsequent data regarding patient adherence to the MDT plan was recorded. Results: Over the period 79 cases were discussed at the MDT. Twenty-seven (34%) cases were female, 52 (66%) were male. The median age was 53. Six patients were discussed more than once. Forty-three cases were new diagnoses. Forty-two cases were primary brain tumours, twenty-five were metastatic solid organ malignancies. Thirty-four per cent of cases had HID. On chi-square analysis, the RFD was not statistically associated with HID (p = 0.28), nor was the primary versus recurrent setting (p = 0.80) however, the nature of the PP was (p = 0.023). Adherence data was collected for 95% (75) of cases. Adherence to the MDT plan occurred 90% (67) of cases. For cases of non-adherence, six out of eight (75%) were due to patient choice. Conclusions: A significant proportion of treatment modifications are made following discussion at the neuro-oncology MDT. The nature of the provisional treatment plan may influence which cases are likely to have a change in management determined in the MDT. MDT recommendations are broadly adhered to, and in cases of non-adherence, are largely due to patient factors.
Comparative outcomes in glioblastoma based on age and MGMT analysis: The Cleveland Clinic experience.
Authors: Mohapatra Suryanarayan , Choi April , Braun Kelly , Murphy Erin Sennett , Chao Samuel T. , Suh John H. , Stevens Glen , Peereboom David M. , Jia Xuefei , Ahluwalia Manmeet Singh
Published: September 2018

e13514

Background: Half of glioblastoma (GBM) patients are > 65 years old (yo). We report our experience with GBM patients treated at a tertiary care center and compared outcomes in the two age groups. Methods: Half of glioblastoma (GBM) patients are > 65 years old (yo). We report our experience with GBM patients treated at a tertiary care center and compared outcomes in the two age groups. Results: 1165 patients were included in the final analysis. 598 patients were < 65 yo, and 567 were > 65 yo. Patients who received chemotherapy + radiation (chemoRT) had a lower risk of death compared to patients who received RT only (p < 0.001). Although the benefit of chemoRT seems more pronounced in patients ≥ 65 years of age [HR 0.45 (95% CI 0.36, 0.57) vs 0.61 in patients < 65 yo (0.48, 0.80), (p = 0.04)], the difference in effects is not significant (p = 0.07). For both MGMT-unmethylated and MGMT-methylated patients, although chemoRT had a better OS/PFS than RT only, the impact was similar in both age groups. Patients who underwent GTR or STR had a better OS/PFS than biopsy only (all p < 0.0001). The impact of extent of resection was not different in two age groups (all p ≥ 0.09). Patients diagnosed during 2006 – 2008 and 2009 - present had a better OS/PFS (p = 0.01 and 0.003) than those who were diagnosed during 2000-2005. The impact of diagnosis date on PFS was not different in age groups. In OS outcomes, patient diagnosed during 2009 - present had a better OS than those who were diagnosed before 2005, and the impact is more prominent for patient who were younger than 65 years (p = 0.010). Conclusions: Aggressive treatment with chemo-radiation is associated with better outcomes in both young and older GBM patients. MGMT status did not have any impact on outcomes between the two groups although MGMT status was available for only a subset of patients. [Table: see text]
Identifying factors to predict benefit from bevacizumab in progressive glioblastoma multiforme (GBM).
Authors: Gleeson Jack Patrick , Alhusaini Abdullah , O'Halloran Philip , Harrold Emily , Keegan Niamh M. , Karadawi Nabeeha Eltag , Mammadov Emin , Kamel Dalia , Egan Keith , Molloy Susan , Hennessy Bryan T , Breathnach Oscar S. , Grogan William , Morris Patrick G.
Published: September 2018

e13515

Background: Bevacizumab (BEV) has demonstrated activity in GBM, but the benefits have not been clearly defined in prospective randomised phase III trials. Some patients continue BEV for extended periods but little is known about predictors of clinical benefit. It has been suggested that a less intensive dose schedule might offer similar benefits. Methods: In a retrospective analysis of a National Neuro-Oncology centre database we examined biomarkers of BEV benefit on overall survival (OS), including age at diagnosis, time from diagnosis to BEV start, MGMT methylation and IDH-1 status. We compared those who derived clinical benefit (OS of ≥6-months) to those with limited clinical benefit (OS <6 months). At our Institution, there is variable practice between Neuro-Oncologists in terms of BEV dose schedule. In this homogeneous patient population, we examined whether OS was similar for patients who received standard BEV dosing (10mg/kg q 2wks or 15mg/kg q 3wks) or reduced intensity BEV (5mg/kg q 2wks or 7.5mg/kg q 3wks). Results: Between January 1st 2010 and Dec 31st 2016, 170 patients received BEV for progressive GBM. Median OS was 5.5 months (Range: 0.5-54). OS was 42%, 18% and 2% at 6-, 12- and 24-months, respectively. No significant predictors of clinical benefit were identified (table). Importantly, median OS was similar for patients who received standard (N=94) vs. reduced intensity (N=76) BEV (5.2 vs. 5.6mo respectively), p=0.74. Conclusions: In this large cohort of patients, we did not identify predictors of benefit from BEV. OS was similar in patients who received standard or reduced intensity BEV. Given the cost of BEV, these results have important implications for value in cancer care. [Table: see text]
Outcomes of primary central nervous system lymphoma in the era of immunotherapy: Cleveland Clinic experience.
Authors: Balasubramanian Suresh Kumar , Schmitt Philipp , Sadaps Meena , Karivedu Vidhya , Kangisser Debra , Chao Samuel T. , Murphy Erin Sennett , Suh John H. , Ahluwalia Manmeet Singh , Singh Arun D , Peereboom David M.
Published: September 2018

e13516

Background: Primary central nervous system lymphoma (PCNSL), a form of extranodal non-Hodgkin lymphoma represents 3% of primary CNS tumors. It is aggressive but typically confined to the CNS. Despite improvements in the management of PCNSL, more than 50% of patients eventually relapse. There are limited data on PCNSL from larger cohort studies. Methods: With IRB approval, the Cleveland Clinic Neuro-Oncology Center database was used to identify patients treated between 2006-2015 for PCNSL. Overall survival (OS) from the diagnosis of PCNSL and progression free survival (PFS) were the primary and secondary end points respectively. Cox proportional hazards models were used for data analysis. Results: 86 PCNSL patients were included in the analysis. Only 5% (4/76) were HIV positive. The median age of diagnosis was 63 (range 15 - 86) and 50% were males. 88% of patients presented only with brain lesion, 8% only in eye and 4% had both brain and eye involvement. 15% of patients (12/81) had positive CSF findings. Treatment included: chemotherapy (CT) alone (39% of patients); chemoimmunotherapy (CIT) (32%); CIT with radiotherapy (RT) (13%); RT alone (11%); CT with RT (4%); and immunotherapy (IT) alone (1%). Among 23 patients (31%) who received RT upfront, 74% had WBRT (n = 17). The most common upfront therapy was high dose methotrexate (HD MTX) (44%), followed by HD MTX with rituximab (23%), RTOG 0227 (12%), RTOG 1114 (11%) and rest 14% included rituximab or temozolomide or other cytotoxic chemotherapy alone or in combinations. The most common relapse site was brain (72%), followed by eyes (12%) and spine (8%). The median follow-up was 26 months. At last follow up, 41% had died and 93% of which were PCNSL-related. The median PFS and OS were 17.7 months and 84 months, respectively. There was a trend towards superior PFS in upfront IT vs. no IT (20 vs. 14 months, p 0.08). Better performance status (KPS > 80 vs. < 80, HR 0.42 (p = 0.033)) and PFS ≥ 24 months compared to ≤ 24 months (p = 0.0012) were associated with improved OS. Conclusions: We report a large single institution cohort of PCNSL patients treated in the era of immunotherapy. In our cohort, better KPS (≥80) and PFS ≥ 24 months had improved OS. Upfront IT showed a trend towards improved PFS.
Visualisation of normal and abnormal brain vasculature with different ferumoxytol doses.
Authors: Varallyay Peter , Varallyay Csanad , Horvath Andrea , Szidonya Laszlo , Fu Rochelle , Toth Gerda , Neuwelt Edward A.
Published: September 2018

e13517

Background: Ferumoxytol is an iron oxide nanoparticle, marketed for iron replacement therapy. Off label use as an MRI contrast agent allows visualization of cerebral vasculature in the early blood pool phase without early contrast enhancement obscuring the vessels as seen with small molecular gadolinium. This study tested the optimal ferumoxytol dose for visualization of normal and abnormal cerebral vasculature. Methods: MRI images of 75 subjects enrolled in imaging research protocols were analyzed. Vascular visualization was tested in high resolution gradient echo T2*-weighted images acquired after 1mg/kg, 3mg/kg and 7mg/kg (up to 510mg) ferumoxytol doses. Visualization of normal and abnormal vasculature was separately evaluated as “poor, moderate or clear”. Degree of blooming artifact was graded as “none, mild and marked”. Overall clarity of the image was visually assessed as “poor, moderate and very clear”. The probability of abnormal vasculature visualization being “moderate” or “clear” was tested among the three Fe dosages with a mixed effects model while taking correlation among different dosages into account. Results: Visualization of normal brain vasculature was poor with 1mg/kg, moderate with 3mg/kg and very clear with 7mg/kg in 97% of the cases. However, blooming with 7 mg/kg was already marked for all cases causing confluence of larger veins and even smaller vessels close to each other, while images with 3mg/kg showed only mild blooming in all cases, resulting in altogether a better quality/clarity of the images (very clear in 93.3%) with good contrast between normal vessels and brain parenchyma. Not all subjects had abnormal vasculature due to prior surgery. However, when considering all subjects, visualization of abnormal vasculature was moderately or clearly visible in 23% of subjects when using1mg/kg, significantly less than 3mg/kg (42.7%, P = 0.0012) and 7mg/kg (43.9%, P = 0.0007). Conclusions: 3mg/kg ferumoxytol allows adequate visualization of normal and abnormal vasculature with acceptable degree of blooming artifact. Visualization of tumor vasculature may help targeting the most malignant area for surgery/radiotherapy and may help differentiating tumor progression from pseudoprogression. Clinical trial information: NCT00659776, NCT02359097.
Constitutive IFN signaling to modulate the immunogenicity of glioma cells.
Authors: Roth Patrick , Nagy Sara , Happold Caroline , Schneider Hannah , Weller Michael , Silginer Manuela
Published: September 2018

e13528

Background: Interferons (IFN) are cytokines that might be constitutively expressed also in the absence of acute infection and thereby regulate various physiological processes such as cellular proliferation and differentiation, cell viability or immune cell function. Alterations in IFN signaling have been observed in numerous malignancies, but their role in glioblastoma, particularly in glioma-initiating cells, has not been investigated in detail. Methods: We characterized constitutive type I IFN signaling and its functional impact in glioma cells using expression analyses, RNA interference-mediated silencing of various genes involved in the IFN signaling pathway and immune cell lysis assays. Results: We found constitutive expression of pSTAT1 and Myxovirus A (MxA), a classical IFN-response marker, in the absence of exogenous IFN-β in vitro and higher MxA expression in gliomas than in normal tissue in vivo, indicating that IFN signaling is constitutively active in these tumors. Silencing of the type I IFN receptor, IFNAR1/2, or its ligands, IFN-α or IFN-β, decreased MxA levels, providing evidence for the existence of an autocrine type I IFN signaling loop. On a functional level, we observed reduced PD-L1, MHC class I and class II expression and increased susceptibility to immune cell-mediated lysis upon disruption of IFN signaling, suggesting that constitutive IFN signaling in gliomas contributes to the immune evasion of glioma cells. Conclusions: Our findings point to an important role of constitutive IFN signaling in glioma cells in the regulation of anti-tumor immune responses.
Health-related quality of life in patients with recurrent glioma treated with bevacizumab plus daily temozolomide as the salvage therapy.
Authors: Liu Yong , Wang Liang
Published: September 2018

e13541

Background: The therapeutic methods of recurrent glioma are limited. Most studies evaluating treatment effect for brain tumor mainly focused on overall survival and progression-free survival. It is increasingly recognized that the health related quality of life (HRQL) is of great value in clinical practice when choices of treatment for recurrent glioma have to be made. We retrospectively analyzed the HRQL and treatment response of patients with recurrent glioma treated by bevacizumab (BEV) plus daily temozolomide (TMZ). Methods: Twenty patients with recurrent glioma were treated with BEV (5-10mg/kg, i.v. every 2 weeks) plus daily TMZ (daily, 50 mg/m2). The treatment response was evaluated via the RANO criteria. HRQL was measured using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire core 30 (QLQ-C30) and Brain Module (QLQ-BN20). HRQL was assessed at the baseline (before salvage therapy) and after every two cycles of BEV. Results: Twenty patients totally received 85 cycles of BEV with the median number of 4 cycles (range: 2-10). There was no patient with complete response (CR), 12 patients with partial response (PR), 5 patients with stable disease (SD), and 3 patients with progressive disease (PD). Objective response rate (CR+PR) was 60.0%. The clinical benefit rate (CR+PR+SD) was 85.0%. In the functioning domains of QLQ-C30, physical functioning, cognitive functioning and emotional functioning were significantly improved after the second cycle of BEV compared to baseline. In the symptom scales, the scores of pain and nausea/vomiting were significantly decreased. Score of global health status was significantly increased. In the QLQ-BN20, motor dysfunction, weakness of legs, headache, and drowsiness after the second cycle of BEV were also significantly improved. Conclusions: BEV plus daily TMZ could improve HRQL in patients with recurrent glioma. BEV plus daily TMZ as the salvage therapy is an effective treatment for recurrent glioma.
Analysis of chemo-predictive assay for targeting cancer stem cells in 41 glioblastoma patients.
Authors: Howard Candace M , Alberico Anthony , Valluri Jagan , Griswold Michael , Claudio Pier Paolo
Published: September 2018

e13544

Background: We have developed a drug response assay (ChemoID) that identifies effective chemotherapy against cancer stem cells (CSCs) vs. bulk of tumor cells from of a panel of potential treatments. A prospective study was conducted evaluating the use of the CSC drug response assay in glioblastoma patients treated with standard-of-care. Methods: 41 glioblastoma patients were enrolled in an IRB-approved protocol. Patients were all treated with standard-of-care TMZ plus radiation with or without maximal surgery. Patients were prospectively monitored for tumor response, time to recurrence, progression-free survival (PFS), and overall survival (OS). Results: For every 5% increase in in-vitro CSC cell kill by TMZ, 12-month patient response (non-recurrence of cancer) increased 2-fold, OR=2.2 (p=0.016). Similar associations with the bulk tumor test were seen, OR=2.75 (p=0.07) for each 5% bulk tumor cell kill by TMZ. Combining CSC and bulk tumor assay results in a single model yielded a statistically supported CSC association, OR=2.36 (p=0.036) but a much attenuated remaining bulk tumor association, OR=1.46 (p=0.472). Areas under the curve (AUC) and [sensitivity/specificity] at optimal outpoints (>40% CSC cell kill and >55% bulk tumor cell kill) were AUC=0.989 [Sens=100/Spec=97], 0.972 [100/89] and 0.989 [100/97] for the CSC only, bulk tumor only, and combined models, respectively. Risk categorization of patients was improved by 11% when using the CSC test in conjunction with the bulk test (risk reclassification non-event NRI and overall NRI = 0.111, p=0.030). Median recurrence time was 20 months for patients with a positive (>40% cell kill) CSC test versus only 3 months with a negative CSC test, whereas median recurrence time was 13 months versus 4 months for patients with a positive (>55% cell kill) bulk test versus negative. Similar favorable results for the CSC test were observed for PFS and OS. Results across 14 potential other treatments indicated that 34/41 (83%) and 27/41 (66%) potentially more optimal alternative therapies may have been chosen using CSC results and Bulk results, respectively. Conclusions: The ChemoID assay has the potential to increase the accuracy of bulk tumor assays.