bluuebunny/crossref_metadata_2025 huggingface dataset:
ABO blood group and the risk of lung cancer: Multicenter, case-control, observational study.
Authors: Utkan Gungor , Urun Yuksel , Cangir Ayten Kayi , Oksuzoglu Omur Berna , Özdemir Nuriye , Oztuna Derya Gokmen , Kocaman Gokhan , Demirkazik Ahmet , Okten Ilker , Icli Fikri
Published: March 2020

1596

Background: The role of genetic factors in the development of cancer is widely accepted. Previous studies have observed an association between ABO blood group and risk of certain malignancies, including pancreatic and gastric cancer. The data on the role of ABO blood group and Rh factor in lung cancer is limited. Methods: All patients who had Lung cancer (LC) and treated between 2000-2011 at the involved centers with defined ABO/Rh were included in our retrospective reviews of tumor registry records. A group of volunteer healthy blood donors of Turkish Red Crescent between 2004 and 2011 were identified as a control group. The relationship of ABO/Rh with clinical features such as age at diagnosis, histological subtype and sex were evaluated. We compared the distributions of ABO/Rh among 1954 patients and 3,022,883 controls. Among LC patients, differences between each of aforementioned ABO/Rh groups with respect to various clinical features were explored, respectively. Results: Of these patients the median age was 62 (range: 17-90). The 84% of patients were male. Overall distributions of ABO blood groups as well as Rh factor were statistically different between patients (43.6% A, 8.3% AB, 17.3% B, 30.8% O, and 86.3% Rh+) and controls (42.2% A, 7.6% AB, 16.3% B, 33.9% O, and 87.7% Rh+) (p=0,03). In addition, there were statistically significant differences between patients and controls with respect to O vs. nonO (p=0.004) and marginal significance for A vs. nonA (p=0,065), B vs. nonB (p=0,076), and Rh+ vs. Rh- (p=0,057). Among patients, there weren’t statistically significant differences between blood group with respect to sex and age. However there was statistically significant difference between blood group with respect to histology (p=0,001). Although the distribution of A and O were similar according to histology, patients with squamous histology had antigen B more frequently than other histological sub types (p=0,009). Conclusions: In the study populations, ABO blood type was statistically significantly associated with the LC and having blood type other than O increases the risk of LC. Further studies are necessary to define the mechanisms by which ABO blood type may influence breast cancer risk.
Analyzing excess mortality from cancer among individuals with mental illness.
Authors: Musuuza Jackson S. , Sherman Marion E. , Knudsen Kraig J. , Sweeney HelenAnne , Tyler Carl V , Koroukian Siran M.
Published: March 2020

1598

Background: Previous studies have documented higher cancer-related mortality in individuals with mental illness, compared to their healthier counterparts. The aim of this study was to identify the anatomic cancer sites for which mortality is higher in individuals with mental illness. Methods: We used a linked dataset comprised of death certificate data for the state of Ohio for the years—2004-2007 and data from the publicly funded mental health system in Ohio. Decedents with mental illness were those identified concomitantly in both data sets. We used age-adjusted standardized mortality ratios (SMRs) in race- and sex-specific strata to estimate excess deaths for each of the anatomic cancer sites. Results: Overall, there was excess mortality from cancer associated with having mental illness in Non-Black men and women (SMR: 1.14 (95% confidence interval [CI] = 1.05-1.22), and 1.13 (95% CI= 1.05-1.20, respectively), but lower mortality in Black men, likely due to premature mortality from other causes (0.71 (95% CI= 0.61-0.83). In Black women, we observed no excess mortality from cancer that was associated with having mental illness. There was excess mortality from hepatobiliary cancer in Non-Black men (SMR= 1.65; 95% CI =1.15-2.29), but not in any other sex- and race- stratum. In addition, we observed excess mortality from lung and laryngeal cancers among Non-Black men and women (SMRs for lung cancer of 1.28 (95% CI= 1.13-1.45), and 1.45 (95% CI= 1.29-1.62), respectively; and for laryngeal cancer (2.01 (95% CI= 1.19-3.18 for men, and 2.47 (95% CI= 1.08-4.89) for women). Black women experienced excess mortality from cancer of the kidney and renal pelvis (SMR= 2.91; 95% CI =1.53-5.06), while Non-Black women experienced excess mortality from urinary bladder cancers (SMR=1.89; 95% CI=1.15- 2.92). Conclusions: Compared to the general population in Ohio, individuals with mental illness experienced excess mortality from certain cancers. In part, this excess mortality may be mediated by a higher prevalence of smoking or substance abuse in individuals with mental illness. Further investigation is needed to explain the observed racial variation in cancer mortality, and to examine mortality for specific cancers based on severity of mental illness.
Analysis of KRAS and BRAF mutant colorectal cancers in a multiracial population.
Authors: Acoba Jared David , Lum Christopher A. , Leong Lambert T
Published: March 2020

1599

Background: We previously demonstrated racial disparities in colorectal cancer (CRC) survival despite adjustments for tumor and socioeconomic factors. Molecular differences in breast and lung tumors contribute to racial survival inequality, yet in CRC, molecular tumor characteristics have not been studied extensively in a racially diverse cohort. We performed a comprehensive evaluation of KRAS and BRAF mutations in a multiracial population to determine the prevalence in CRC and the degree to which these molecular traits impact survival. Methods: A retrospective cohort study of patients diagnosed with CRC between 2008 and 2011 from hospital tumor registries was performed. The prevalence of KRAS and BRAF mutations was determined for the study population and individual racial groups. Multivariable Cox proportional hazards regression models for survival were built for KRAS and BRAF mutation status while adjusting for age at diagnosis, race, and stage of disease. Results: Of 706 patients diagnosed with CRC, KRAS mutational analysis was performed on 148 subjects. 14% of subjects were white (W), 64% Asian (A), and 21% Native Hawaiian/Pacific Islander (NH). KRAS mutation was identified in 48 subjects (32%). The prevalence of mutant tumors among racial groups was W 33%, A 36%, and NH 30%. Analysis for KRAS G13D mutations revealed a prevalence of W 11%, A 9%, and NH 7%. When compared to published datasets of predominantly white patients, our multiracial cohort had a significantly higher rate of KRAS G13D mutant tumors, p=0.039. Of 74 subjects tested for the BRAF mutation, two mutant tumors were detected (3%). The prevalence of the BRAF mutation by race was 10% W, 3% A, and 0% NH (p=0.18). BRAF and KRAS G13D mutations were adverse prognostic factors in a multivariate analysis, although the odds ratios failed to meet statistical significance. Conclusions: The prevalence of BRAF and KRAS mutations in this multiracial cohort is similar to what has been previously reported. However the rates of KRAS G13D and BRAF mutant tumors in our cohort are higher than prior reports. Furthermore, KRAS G13D which has been postulated to be a favorable prognostic factor for CRC, may adversely impact survival of minority patients.
Effect of gender on age-specific effects for ulcerated malignant melanomas.
Authors: Richardson Blakely S. , Anderson William F. , Barnholtz-Sloan Jill , Tucker Margaret A. , Gerstenblith Meg R.
Published: March 2020

1603

Background: Gender, age at diagnosis, and ulceration are all independent prognostic factors for melanoma. The purpose of this study was to further examine the interactions among gender, age, and melanoma ulceration. Methods: Using the NCI’s SEER 17 Registries Database (2004-2008), we assessed ulceration status among White men and women with malignant melanoma, stratified by younger (ages 10-39 years) and older (ages 40-84 years) ages at diagnosis as well as by tumor depth. The analysis was restricted to melanomas common to both age groups, i.e. superficial spreading, nodular, and unclassified melanomas. There were 2905 older men, 301 younger men, 1624 older women and 276 younger women that fit our criteria. Relative risks were expressed as incidence rate ratios (IRR) with 95% confidence intervals (CI). Results: At every tumor depth, IRRs for ulcerated melanomas were significantly higher for older than younger persons (IRR>1.0). The trend, however, was different in men as compared to women. In men, the IRR (older to younger) rose continuously with increasing depth [≤1.0mm: IRR 7.81 (CI 6.18-9.98), 1.01mm-≤2.0mm: IRR 9.71 (CI 7.55-12.68), 2.01mm-≤4.0mm: IRR 11.04 (CI 8.78-14.06); and ≥4.01mm: IRR 12.26 (CI 9.60-15.87)]. On the other hand, in women, IRR (older to younger) was stable for all depths ≤4.0mm then nearly doubled for melanomas ≥4.01mm [≥4.01mm: IRR 8.00 (CI 5.85-11.20)]. The IRR trend analysis was statistically significant for men (p = 0.01) but not for women (p = 0.34). Conclusions: Our study confirms that older age at diagnosis is associated with higher incidence rates of ulcerated malignant melanomas. This large-scale population-based analysis also shows an effect modification by gender and tumor thickness, suggesting different biologic behavior in melanoma in younger and older men and women. Future studies should further investigate tumor biology differences in these populations and the interactions among gender, age at diagnosis, and ulceration in melanoma.
American BRCA outcomes and utilization of testing (ABOUT) study.
Authors: Sutphen Rebecca , Bauer Joseph E. , Virgo Katherine S. , Casares Carolina , Walker Gregg , Schwartz Marc D , Armstrong Joanne , Friedman Sue , Lynch Kristian , Andrews James , Aguado Loi Claudia X , Toscano Michele , Kotchko Nancy , Teten Rachel Threet , Kondoff Matt R , Brand Lana , Molina Ashley
Published: March 2020

1608

Background: An estimated 100,000 individuals currently undergo genetic testing for hereditary susceptibility to breast and ovarian cancer annually in the U.S., yet little is known about their characteristics, testing experience or outcomes. Research in this high-risk group has been limited to patients recruited at academic medical centers where case ascertainment, health services delivery, decision-making and, quite likely, outcomes are different from those in the community setting where the majority of individuals currently receive healthcare services. Methods: Eligible subjects include 10,000 consecutive individuals requesting BRCA testing through the nation’s third-largest health insurer, Aetna, beginning in December, 2011. De-identified data are analyzed from each test request form submitted by the ordering provider. Each eligible subject is mailed a study packet inviting them to complete a questionnaire (by mail, online or telephone) designed to investigate informational and healthcare services, test results, knowledge, risk perception and medical intentions. Results: Of 442 subjects contacted during the first two weeks of accrual, 143 (32%) have completed the questionnaire to date. Similar to Aetna member demographics, 7% are African-American and 7% report Hispanic ethnicity. Based on Chi-Square tests, there were no differences between respondents and non-respondents with regard to age (51% under age 50), race, ethnicity or personal history of cancer (58%). Among respondents, deleterious mutations were identified in 8%. Testing for a known familial mutation was performed in 8%. Among women with breast cancer, 13% were undergoing testing prior to initial surgical treatment. Updated results from 3000 eligible subjects will be presented. Conclusions: This innovative, academic-industry collaboration enables an unprecedented investigation of significant issues surrounding individuals at increased risk for hereditary breast and ovarian cancer and undergoing genetic testing in the U.S. The results will guide the development and dissemination of more targeted decision-support tools and strategies to improve medical outcomes for such individuals.
Association between age, gender, residential region, and prevalence of subependymal giant cell astrocytoma among patients with tuberous sclerosis complex: A U.S. Healthcare Claims Database study.
Authors: Kohrman Michael , Sun Peter , Liu Zhimei , Kruger Darcy
Published: March 2020

1609

Background: Subependymal giant-cell astrocytomas (SEGA) are slow growing non-cancerous tumors that can occur in patients with tuberous sclerosis complex (TSC). The objectives of this study were to examine SEGA prevalence among TSC patients in a real world setting, and to ascertain the relationships between SEGA prevalence and age groups, genders, or residential regions. Methods: We conducted a retrospective cohort study based on a large US commercial healthcare claims database. Patients with a TSC claim between 2000 and 2009 and with 12-month continuous enrollment after their first TSC claim were included into the study. SEGA was identified based on ICD-9CM codes in inpatient or outpatient claims. Patients’ genders, residential regions and ages of their first TSC claim and /or their first SEGA claim (if they had SEGA) were extracted from enrollment files respectively. SEGA prevalence was assessed with subgroup analyses of genders, age groups of first TSC claim, and residential regions. Two-sample t tests and Chi-square tests were used to explore the relationships between SEGA prevalence and age groups, genders, or residential regions. Results: The study had 2,767 patients with a mean age of 28.5 years on their first observed TSC claim, and 55.3% were female. Among these TSC patients, 7.7% had SEGA with variations by age groups of their first TSC claim (5.9% for age<1 year, 12.6% for age 1-5 years, 11.0% for age 6-10 years, 11.0% for age 11-18 years, 7.6% for age 19-25 years, and 5.1% for age 26 years or more), by genders (8.7% for males vs. 6.9% for females), and by residential regions (6.0%-11.0%). The associations between SEGA prevalence and age groups, genders or residential regions were all statistically significant with p<0.05. Conclusions: In a real world setting, and by the end of the first post-TSC year, 7.7% TSC patients had an observed SEGA diagnosis. This prevalence varied by age groups, genders, residential regions. Further research is needed to explore the factors that results into these variations.
Relationship between overall survival and progression-free survival for recent NCCTG glioblastoma multiforme trials.
Authors: Wu Wenting , Galanis Evanthia , Buckner Jan C. , Jaeckle Kurt A. , Sargent Daniel J.
Published: March 2020

2004

Background: With the approval of novel agents for glioblastoma (GBM) treatment, reliable historical outcome data for the common phase II endpoint of progression free survival (PFS) is not available. In particular, the association between progression and overall survival (OS) has not been evaluated after temozolomide (TMZ) became the standard therapy for newly diagnosed GBM. Methods: Datasets from 5 TMZ-including NCCTG clinical trials in newly diagnosed GBM (n=325, 2005-2011, 1 phase I only and 4 phase I and single arm phase II trials) were pooled and analyzed to evaluate the individual level correlation between PFS and OS using correlation coefficient, landmark analyses, and time-dependent variable analyses. A historical control group was constructed by pooling datasets from 12 pre-TMZ era NCCTG clinical trials in the same patient population (n=1359, 1980-2004). Each of the 5 newer trials was compared to the control group to estimate the treatment effect (hazard ratio) on PFS and OS, which were analyzed to evaluate the trial level correlation between PFS and OS using correlation coefficient and weighted linear regression. Results: The estimated correlation coefficient between PFS and OS at individual patient level is 0.75 (95%CI, 0.7 to 0.8). The estimated hazard ratios of death in the landmark analysis at 4 and 6 months are 2.15 (95%CI, 1.47 to 3.15) and 2.17 (95%CI, 1.57 to 3.12), respectively, and the estimated hazard ratio of death is 10.1 (95%CI, 6.6 to 15.4) when progression is treated as a time-dependent variable. For trial level correlation (against the historical control group), the estimated correlation coefficient between HRos and HRpfs is 0.51 (95%CI, -0.67 to 0.96), with moderate prediction: the predicted HRos is very close to the observed HRos in 4 of 5 cases, however the predicted HRos is significantly different from 1 in only 2 out of 5 cases due to small sample size in other 3 cases. Conclusions: PFS and OS are highly associated at the individual patient level but only moderately at the trial level, the latter possibly due to small sample size in some of the trials. Additional validation in other trials could support use of PFS as a primary endpoint for randomized phase II trials in GBM.
Bayesian adaptive randomized trial design for patients with recurrent glioblastoma.
Authors: Alexander Brian Michael , Wen Patrick Y. , Lee Eudocia Quant , Batchelor Tracy , Cloughesy Timothy Francis , Parmigiani Giovanni , Trippa Lorenzo
Published: March 2020

2005

Background: Bayesian-based trial design has the ability to utilize accumulating data in real time to alter the course of the trial, thereby enabling dynamic allocation to experimental arms and earlier dropping of ineffective arms. This flexibility results in a potentially more efficient trial framework by increasing the probability of enrollment to arms that show evidence of efficacy. In this study we considered a hypothetical scenario in which patients who have been previously treated on several separate experimental protocols at the Dana-Farber/Harvard Cancer Center and the University of California, Los Angeles were instead enrolled in a single multi-arm protocol utilizing a Bayesian adaptively randomized trial design. The purpose was to determine whether similar scientific results could have been accomplished more efficiently. Methods: We generated an adaptive randomization procedure that was retrospectively applied to primary patient data from four separate phase II clinical trials in patients with recurrent glioblastoma. We then compared AR to more conventional trial designs using realistic hypothetical scenarios consistent with survival data reported in the literature. Our primary endpoint is the number of patients needed to achieve a desired statistical power. Results: If our phase II trials had been a single multi-arm AR trial, bevacizumab would have been identified as an efficacious therapy, and 30 fewer patients would have been needed compared to a multi-arm balanced randomized (BR) design. More generally, Bayesian AR trial design for patients with glioblastoma would result in trials with fewer overall patients with no loss in statistical power, and in more patients randomized to effective treatment arms. For a trial with a control arm, two ineffective arms and one effective arm with hazard ratio 0.6, a median of 47 patients would be randomized to the effective arm compared with 35 in a BR design. Conclusions: Given the desire for control arms in phase II trials, an increasing number of experimental therapeutics for patients with glioblastoma, and a relatively short time for events, Bayesian adaptive designs are attractive for clinical trials in glioblastoma.
Effects of cediranib, a VEGF signaling inhibitor, in combination with chemoradiation on tumor blood flow and survival in newly diagnosed glioblastoma.
Authors: Gerstner Elizabeth Robins , Emblem Kyrre E. , Chi Andrew S. , Eichler April F. , Hochberg Fred , Drappatz Jan , Quant Eudocia Carmen , Norden Andrew David , Pinho Marco C , Polaskova Pavlina , Jennings Dominique , Ancukiewicz Marek , Ivy S. Percy , Wen Patrick Y. , Jain Rakesh K. , Sorensen A. Gregory , Batchelor Tracy
Published: March 2020

2009

Background: Anti-angiogenic therapy is hypothesized to synergize with radiation and chemotherapy by improving tumor blood flow. We evaluated the tolerability, efficacy and potential mechanism of action of radiation, temozolomide, and cediranib in newly diagnosed glioblastoma patients. Methods: Newly diagnosed glioblastoma patients were treated with radiation, temozolomide, and cediranib followed by monthly temozolomide for 6 cycles and daily cediranib until tumor progression or toxicity as part of an IRB-approved, Phase Ib/II clinical trial. MRI scans including measurement of cerebral blood flow were performed at baseline, weekly during the 6 weeks of chemoradiation and then monthly. Radiographic response was determined by RANO criteria. Results: Six patients were enrolled in the phase Ib part of the study with cediranib 30 mg daily in combination with temozolomide and radiation. No dose-limiting toxicities were identified. Forty patients were enrolled in the phase II part of the study. Among the entire cohort of 46 patients, median age was 57 (range 35-74), median KPS was 90% (60-100), 36 patients underwent a subtotal resection and 10 underwent biopsy. 26/30 patients taking corticosteroids were able to taper corticosteroids during chemoradiation. Off study reasons included toxicity (14), disease progression (18), and patient preference (2). Five patients remain on study without disease progression and 20 patients have died. Median duration on study was 158 days. Median progression free survival was 288 days (95%CI 240,∞) and median overall survival was 786 days (95%CI 411 ,∞). Best radiographic response in patients who completed chemoradiation was CR in 2 patients, PR in 20 patients, and SD in 15 patients. Patients with increased tumor perfusion during chemoradiation survived nearly 1 year longer (mean OS=611 days) than patients with decreased perfusion (mean OS=269 days). Conclusions: Cediranib was well tolerated and led to improved PFS and OS compared to historical controls, particularly in those with improved perfusion. This combination is being evaluated in an ongoing randomized trial (RTOG 0837).
Modulation of antiangiogenic resistance: Targeting the JAK/STAT3 pathway in glioblastoma.
Authors: De Groot John Frederick , Liang Ji , Kong Ling-Yuan , Wei Jun , Piao Yuji , Fuller Greg , Qiao Wei , Heimberger Amy B.
Published: March 2020

2011

Background: Determining the mechanism of treatment failure of antiangiogenic therapies would provide insight into either potential combination approaches or salvage therapies. Methods: Tumor and monocyte expression of phosphorylated-signal transducer and activator of transcription 3 (p-STAT3) was compared between recurrent glioblastoma patients treated with either conventional chemotherapy or bevacizumab (BEV), and secondarily validated in murine model systems of intracerebral glioma treated with either BEV or cediranib. The JAK/STAT3 inhibitor AZD1480 alone and in combination with cediranib was evaluated in immunocompetent mice bearing intracerebral GL261 xenografts to evaluate therapeutic synergy. Results: Human glioblastoma patients failing BEV have an increase in intratumoral p-STAT3- expression with a mean number of p-STAT3 expressing cells of 36.5 + 8.6% (n=7) compared to a mean of 20.2 + 4 % (n=5) in patients never receiving antiangiogenic therapy. In a separate cohort of recurrent glioblastoma patients, the up-regulation of p-STAT3 was detected in monocytes within 24 hours after initial BEV administration. In intracranial xenograft models, both BEV and cediranib extended median animal survival time, but during treatment failure BEV increased the mean percentage of p-STAT3-expressing cells to 24.6 + 6.4% (P=0.0011), and cediranib increased this to 16.2 + 1.8% (P=0.0125) relative to 9.0 + 4.4% in controls. Administration of the JAK/STAT3 inhibitor AZD1480 alone and in combination with cediranib reduced tumor hypoxia and infiltration of VEGF inhibitor-induced p-STAT3 macrophages. The combination reduced tumor volume by 80% compared to untreated controls, and by 65% compared to cediranib or AZD1480 treatment alone. Microvascular density and tumor de-differentiation were reduced, indicating that up-regulation of the STAT3 pathway can mediate resistance to antiangiogenic therapy. Conclusions: Cumulatively, these data suggest that a prominent mechanism of failure of anti-VEGF therapy in malignant glioma patients involves up-regulation of the STAT3 pathway, and resistance to antiangiogenic therapy can be modulated with inhibitors of the JAK/STAT pathway.
Modeling radiation dose to circulating lymphocytes during brain tumor treatment: Effects of target volume, dose rate, and treatment technique.
Authors: Yovino Susannah G. , Grossman Stuart A. , Kleinberg Lawrence , Ford Eric C
Published: March 2020

2017

Background: Severe treatment-related lymphopenia (TRL) occurs in 40% of glioblastoma patients despite minimal radiation (RT) doses to bone marrow or nodal sites. In glioblastoma, TRL is associated with decreased survival. To explain the lymphopenia, we sought to estimate radiation doses received by circulating lymphocytes during partial brain RT. Methods: An in-house computer program linked to treatment planning software was used to calculate the mean radiation dose to circulating blood (DCB) and the fraction of blood receiving >0.5 Gy. The model also studied the impact of different target volumes (PTV), dose rates (DR), and delivery techniques (IMRT, 3D-CRT). Results: The mean DCB for a 60-Gy course (8-cm diameter PTV, dose rate 600 MU/minute) was 2.2 Gy. With this the entire blood pool receives a lymphotoxic dose of >0.5 Gy. DCB is correlated with fraction number, PTV size, and DR. Regardless of dose rate or delivery technique, the percent of circulating blood receiving >0.5 Gy approached 100% as the number of fractions increased. Changing dose rate had minimal effects on mean DCB (3.1Gy for 300 MU/min vs 2.2 Gy for 1200 MU/min). Smaller PTV size reduced the percent of blood receiving >0.5 Gy (15% for 2-cm diameter PTV vs 100% for 8-cm PTV). Conclusions: Standard RT for brain tumors delivers a lymphotoxic radiation dose to circulating blood. Altering dose rate may initially affect DCB, but advantages disappear over the course of 30 fractions. Marked reductions in target size appear to be the best way to avoid radiation injury to normal circulating lymphocytes. Other novel approaches are needed to limit radiation exposure to circulating lymphocytes given evidence associating lymphopenia with poorer outcomes in cancer patients.
Blood alterations preceding clinical manifestation of glioblastoma.
Authors: Ilhan-Mutlu Aysegul , Wagner Ludwig , Woehrer Adelheid , Susanne Jungwirth , Marosi Christine , Fischer Peter , Preusser Matthias
Published: March 2020

2024

Background: Glioblastoma is the most common and aggressive primary brain tumour in adults. There is lack of knowledge on biochemical blood alterations prior to clinical diagnosis of glioblastoma. We had the rare opportunity to investigate selected blood markers from plasma samples taken 12, 42 and 72 months before tumor manifestation in a glioblastoma patient. This index patient was enrolled in the longitudinal population based Vienna Transdanube Aging Study (VITA), which prospectively collects blood plasma from 600 participants at baseline (age 75), 30 and 60 months thereafter. Methods: We determined plasma levels of S100B, neuropeptide Y (NPY), secretagogin (SCGN), microRNA-21, microRNA-let7, microRNA-128, and microRNA-342-3p in all three blood samples from our index patient and in consecutive blood samples from five male and five female controls from the VITA cohort. These proteins and microRNAs were previously shown to be relevant for the pathobiology of glioblastomas. None of the controls had a malignant or neurological disease. Protein markers were analysed using commercially available ELISAs and microRNAs were quantified using RT-qPCR. Results: Compared to baseline values, we found a significant increase of microRNA-21 (up to 4-fold) and microRNA-let7 (up to 7-fold) levels in the blood samples of our index patient, whereas control samples showed almost stable levels of these markers. There was no significant difference in S100B, NPY, SCGN, microRNA-128, and microRNA-342-3p plasma levels between the index patient and controls. Conclusions: Increases of microRNA-21 and microRNA-let7 plasma levels may be associated with pre-clinical development of glioblastoma.
Phase II trial of sunitinib malate and lomustine in patients with temozolomide refractory recurrent low-grade and anaplastic gliomas.
Authors: Duerinck Johnny , Du Four Stephanie , Van Binst An , Everaert Hendrik , Michotte Alex , D'haens Jean , Neyns Bart
Published: March 2020

2050

Background: Recurrent low-grade and anaplastic gliomas eventually transform to a higher grade that is characterized by neo-angiogenesis. Sunitinib inhibits multiple tyrosine kinase receptors (including VEGFR, PDGFR and c-Kit) but has no meaningful activity as a mono-therapy for recurrent glioblastoma when given at a daily dose of 37,5 mg (Neyns et al. J Neurooncol. 2011). We investigated sunitinib in combination with lomustine (CCNU) for the treatment of patients (pts) with temozolomide (TMZ) refractory recurrent low-grade or anaplastic glioma. Methods: Pts received a daily dose of 25 mg sunitinib for 28 consecutive days followed by a 14 days treatment-free interval. CCNU was administered as a single dose (80 mg/m²) on day 14 of a 6w cycle. T1 ± Gd and T2/FLAIR weighted MRI images were obtained q6 wks. 18FET-PET was performed at baseline and reassessed in responding pts. Results: 13 pts were enrolled (mean age 40 [range 33-49]; M/F 8/5; KPS 80-90/70-60: 8/5 pts). All pts had PD following surgery, RT and TMZ. In 7 pts, treatment was initiated at 2nd recurrence, in 4 pts at 3rd recurrence and in 2 pts at the 4th recurrence. Most frequent AEs where fatigue (gr 2: n= 3; gr 3: n= 1), thrombopenia (gr 2: n= 1 gr 3: n= 3 gr4: n= 1), neutropenia (gr 2: n= 2; gr3: n= 2; gr4: n= 2) and lymphopenia (gr 2: n=1; gr 3: n=2; gr 4: n=1). In 5/13 pts CCNU had to be discontinued because of AEs. Treatment with sunitinib was continued in these cases without reoccurrence of AEs. BOR according to RANO criteria: 1 CR, 1 PR (not-confirmed) and 2 SD (DCR: 4/13= 31%). In the patient with CR, FET-PET indicated a complete metabolic response. After a mean FU of 7 mths (range 2 -19), 5 pts are alive. The 6-month PFS is 23% (3/13 pts); median PFS is 1,8 mths (95%CI 1.0 - 2,7). A durable disease control was obtained in 3 pts (TTP respectively 14.8, 11.8+ and 19.2+ mths). Conclusions: in this heavily pretreated population with recurrent low-grade and anaplastic glioma the combination of sunitinib and CCNU is associated with acceptable toxicity and offers a durable progression-free survival in a subgroup of pts. Molecular predictive factors identifying the sensitive population would be needed to justify further clinical investigation of this combination.
Management of primary intraocular lymphoma (PIOL): Results from the prospective German PIOL registry (PIOL-R).
Authors: Jahnke Kristoph , Pleyer Uwe , Herwig Martina , Guthoff Rainer , Lueke Matthias , Meyer-ter-Vehn Tobias , Willerding Gregor , Thiel Eckhard , Korfel Agnieszka
Published: March 2020

2054

Background: Primary intraocular lymphoma (PIOL) is a very rare disorder, and the optimal treatment is yet to be defined. Here, we report clinical characteristics and outcome of patients with PIOL enrolled in the prospective German PIOL registry (PIOL-R). Methods: Patient data in this prospective, non-interventional multicenter study were compiled by standardized questionnaires sent to Ophthalmology and Hematology/Oncology centers in Germany. All histologically or cytologically confirmed immunocompetent PIOL patients were eligible. Results: Fifteen patients (8 female, median age 66 years, median Karnofsky performance status 90%) from 4 centers were included between August 2008 and January 2012. Median follow-up was 7 months. Median time from first occurrence of symptoms to PIOL diagnosis was 5 (range, 1-11) months. All PIOL were of diffuse large B-cell histology. Eight patients had concomitant (n=3), prior (n=2) and/or subsequent (n=4) parenchymal brain involvement. First-line treatment included methotrexate (MTX)-, rituximab- and/or ifosfamide-based systemic chemotherapy in 12 (including high-dose chemotherapy [HDCT] with autologous stem cell transplantation [ASCT] in 2), intraocular (i.o.) chemotherapy with MTX (n=2) and/or rituximab (n=6) in 7, and ocular radiation in one patient(s). Two patients received prophylactic intrathecal (i.th.) treatment with MTX and none had whole-brain irradiation. The PIOL remission rate was 100% (complete remission in 11/14 evaluable patients and partial remission in 3 patients). Four patients relapsed in the brain after 5, 6, 21 and 23 months and received salvage treatment with MTX and/or ifosfamide (n=3) and HDCT with ASCT (n=1). No ocular or systemic relapses were observed. Median progression-free survival was 23 (95% confidence interval, 19-26) months. All patients are alive. Conclusions: Although the awareness of PIOL and diagnostic possibilities have improved over the past 2 decades, time from symptom presentation to diagnosis seems to remain at previously reported levels. There appears to be a shift from local ocular treatments and radiation to systemic therapy as compared to anecdotal data with promising response and survival rates.
The association of pretreatment neutrophil to lymphocyte ratio with overall survival in patients with glioblastoma multiforme (GBM).
Authors: Bambury Richard Martin , Teo MinYuen , Yusuf Anny , Murray Susan , Battley Jodie E , Drake Catherine , O'Dea Pauline , Bermingham Niamh , Keohane Catherine , O'Reilly Seamus , Power Derek Gerard , Moylan Eugene J.
Published: March 2020

2062

Background: GBM is the most common and aggressive primary brain tumor. The neutrophil to lymphocyte ratio (NLR) gives a measure of systemic inflammatory response and lymphopenia, both of which are poor prognostic factors in many malignancies. No published study has assessed the prognostic impact of NLR in GBM. Methods: Patients treated for GBM at our regional referral centre with assessable complete blood count at first presentation (prior to corticosteroid therapy or surgery) were identified. Medical notes were reviewed to extract demographic and treatment data. Survival curves were estimated via Kaplan-Meier method and compared via log-rank method. Multivariate analysis was performed via Cox proportional hazards regression modelling. Results: A total of 86 patients were identified, of which 65(76%) were male. Median age at diagnosis was 58 years (range: 18–76). At the time of analysis all patients still alive had ≥ 2 years follow-up. Median overall survival (OS) was 9.3 months (range: 1-82). 57% completed the standard adjuvant Stupp protocol and 43% discontinued early due to disease progression or treatment toxicity. Median OS was 11.2 months in patients with NLR<4 and 7.5 months in patients with NLR>4 (HR 0.59, p=.04). Other significant prognostic factors based on univariate analysis were consistent with published data (Table). After correcting for known prognostic factors NLR remained a significant predictor of survival (Table). Conclusions: Recent advances in immunotherapy have highlighted the importance of the immune system in the treatment and prognosis of cancer patients. Many GBM patients are on corticosteroids for a significant proportion of their disease course which may abrogate the effects of host immunity on outcome. Nevertheless, we have shown that NLR at diagnosis is an independent predictor of survival in GBM patients. Investigation of therapies which harness the immune response are warranted in this disease. [Table: see text]
A preclinical study on the combined treatment of nimotuzumab and sirolimus in glioblastoma.
Authors: Tham Chee Kian , Lam Paula , See Siewju , Lai Siang Hui , Thomas John , Ng Wai Hoe
Published: March 2020

2066

Background: The human epidermal growth factor receptor (EGFR) is an ideal therapeutic target for inhibiting glioblastoma (GBM) growth as the signaling pathway is highly dysregulated in GBM. However, trials so far with EGFR inhibitors have not shown clinically meaningful improvement in response rates and survival. One of the postulated mechanisms of resistance is the constitutive activation of the downstream, PI3K/AKT/mTOR pathway, independent of the upstream EGFR activation status. Hence, the dual blockage of the pathways with an anti-EGFR agent and mTOR inhibitor is postulated to have synergistic anti-tumour effects. We aim to investigate the anti-tumour effect of combined nimotuzumab (anti-EGFR monoclonal antibody) and sirolimus (mTOR inhibitor) in a GBM preclinical model. Methods: Primary human GBM cells were derived from surgical GBM specimens. The endogenous expressions of glial-fibrillary acidic proteins and EGFR were determined by IHC staining and Western Blot analysis. Cell viability assays were then carried out in these GBM cells and immortalized human normal astrocytes (iHNA) using a range of concentrations of nimotuzumab alone, sirolimus alone or combined treatment. Results: GBM cells treated with nimotuzumab showed a dose- dependent cell kill and the optimal concentration was determined to be 2 µg/ml. Treatment of the GBM cells with sirolimus showed that the drug was capable of inducing cell death at varying levels and the optimal level was determined to be 0.1 mM. Combined treatment with nimotuzumab (2µg/ml) and rapamycin (0.1 mM) showed a dose dependent cell kill in GBM cells which was not observed in iNHA cells. The combined treatment resulted in only 10% of residual gliomas at 24 h post treatment. Single treatment with rapamycin has no cytotoxic effect whereas treatment with nimotuzumab alone exerts a cytotoxicity effect of 33%. Taken together, we observed an additive effect of cell kill when rapamycin is used together with nimotuzumab in human glioma cells. Conclusions: In this study, combined treatment of nimotuzumab and sirolimus resulted in a greater cytocidal effects in GBM cells than either agent alone. We will further examine this combination regimen in a subsequent phase I clinical trial.
Bevacizumab failure in glioblastomas.
Authors: Tabatabai Ghazaleh , Felsberg Joerg , Sabel Michael , Hofer Silvia , Westphal Manfred , Weller Michael , Reifenberger Guido
Published: March 2020

2067

Background: Bevacizumab has been approved for the treatment of recurrent glioblastoma in various countries. The phase III registration trial assessing the addition of bevacizumab to standard chemoradiotherapy in newly diagnosed glioblastomas has completed recruitment. Salvage treatment of glioblastoma patients after bevacizumab failure, however, is commonly not successful. In the present study, we aimed at characterizing histological and molecular characteristics associated with glioma recurrence after bevacizumab. Methods: Paired tissue samples from primary and recurrent tumors obtained from 12 patients with glioblastoma (n=11) or anaplastic astrocytoma (n=1) before and after bevacizumab treatment, and 14 non-bevacizumab-treated patients as a reference group, were analyzed for histological features as well as molecular markers. Clinical records and magnetic resonance images were reviewed. Results: Histologically, recurrent tumors after bevacizumab showed more commonly a decreased blood vessel density and reduced glomeroloid microvascular proliferations when compared to recurrent tumors after conventional radiochemotherapy. In contrast, tumor cellularity and proliferation rate were similar. Distant relapse was more common in bevacizumab-treated patients. Molecular genetic studies of the respective tissue specimens are currently under way. Conclusions: Histological and molecular analyses of tumor tissue samples from glioma patients before and after bevacizumab treatment, combined with thorough clinical and radiological correlates, may provide hints for therapy escape mechanisms that can then be validated in preclinical models.
Effect of electrochemotherapy with IV bleomycin on complete response in a preclinical brain tumor study.
Authors: Agerholm-Larsen Birgit , Iversen Helle K. , Moller Jakob M. , Ibsen Per , Jensen Kurt S. , Linnert Mette , Gehl Julie
Published: March 2020

2069

Background: Electrochemotherapy (ECT) describes enhanced chemotherapeutic drug uptake after cell membranes have been made transiently permeable due to application of an electric field to the tumor. ECT is routinely used to treat skin metastases, with high response rates after once-only treatment. We have developed an electrode for use in the brain, both a rodent model and an electrode for clinical use. The aim of the present study was to evaluate ECT using intravenous (iv) bleomycin in a rat brain tumor model. Methods: Sprague Dawley male rats (7-11 week old) were inoculated with rat glial cell derived tumor cells (N32) through a burr hole in the skull. When tumors appeared on MRI, animals were allocated to ECT (iv bleomycin and local electric pulses), iv bleomycin only, iv bleomycin with placement of electrodes (no pulses), or no treatment. Bleomycin was injected iv in the tail vein (600µL, 3 IU/µL) and electrode deployment was made through the burr hole into the brain tissue. Electrochemotherapy parameters were 32 pulses, 100V, 100µs, 1Hz. Tumor size was determined based on contrast enhanced area from MR scans. Kaplan-Meyer events were defined as termination due to extensive tumor progression prior to end of the three independent experiments performed. Immuno-histo-pathology was performed after termination to verify MRI findings. Results: In 88% of the animals (14 of 16) treated with electrochemotherapy we found complete response (no tumor), validated by MRI and immuno-histo-pathology, whereas bleomycin only, bleomycin and electrodes, and no treatment showed progression in 11 out of 13 control animals. A Kaplan-Meier plot showed a pronounced improved survival for the ECT group as compared to controls within 3 weeks from treatment (p<0.001). Treatment was well tolerated. Conclusions: The present data suggest that electrochemotherapy with iv injection of bleomycin is a new promising treatment for brain tumors. In a clinical study using iv bleomycin and electrochemotherapy for brain metastases ( www.clinicaltrials.gov , ID:NCT01322100) the first patient has just been treated successfully with ECT, indicating feasibility of the approach in the clinical setting.
Prospective follow-up of a cohort of 112 patients with leptomeningeal metastases of breast cancer recruited from 2007 to 2011: Prognostic factors.
Authors: Zairi Fahed , Kotecki Nuria , Rodrigues Isabelle , Baranzelli Marie-Christine , Andre Charles , Dubois François , Devos Patrick , Faivre-Pierret Matthieu , Assaker Richard , Bonneterre Jacques , Le Rhun Emilie
Published: March 2020

2070

Background: Around 5% of patients with breast cancers (BC) will develop leptomeningeal metastasis (LM). The incidence may increase. Methods: We reported the description and outcome of 112 consecutive BC patients diagnosed with LM in our institution from 2007 to 2011. Correlations between characteristics and overall survival (OS) were analyzed using usual statistical methods (Kaplan Meier, Log-rank, Cox model). Results: BC were invasive ductal carcinoma in 69.7%. Estrogen and progesterone receptors were detected in respectively 61.6 and 44.6%. HER2 expression was observed in 26%. 23% were triple negative. Median time between BC diagnosis and LM diagnosis was 44 months. At LM diagnosis, median age was 54 and median Performance Status (PS) was 2. CSF cytology and cerebrospinal MRI were positive in respectively 72,5% and 87%. 103 (92%) LM patients received IT liposomal cytarabine as 1st line of treatment (ventricular device in 47%). IT therapy could be associated with systemic treatment in 58% of the cases and cerebral radiotherapy for LM in 14% of the cases. Clinical response after 1st line treatment was observed in 57%, CSF response in 30,5%, MRI response in 62,5%. 24 patients received a 2nd line of IT thiotepa, 6 a 3rd line of IT methotrexate. The more significant prognostic factors (p<0,0001) were initial PS, associated systemic treatment and triple negative BC status. Other significant predictors of OS were thiotepa as 2nd line treatment (p=0,0004), intracranial hypertension at LM diagnosis (p=0,019), associated cerebral radiotherapy (p=0,02), progesterone receptor status (p=0,04). Median OS of the 103 treated patients was 3,8 months (4,75 months for 0-2 PS and 1,6 months for 3-4 PS patients). Conclusions: Median OS was consistent those of other recent cohorts of BC LM. Our results confirm the role of a very early diagnosis, before the degradation of the general status. The association with systemic treatment or cerebral radiotherapy is indicated when possible.
Bevacizumab use and central nervous system (CNS) hemorrhage.
Authors: LeTarte Nathalie , Bressler Linda R. , Villano John L.
Published: March 2020

2073

Background: Bevacizumab is widely used and may cause life-threatening bleeding, usually at sites of disease involvement such as the CNS. We attempted to identify clinical characteristics associated with CNS hemorrhage in a broad population. Methods: We did a retrospective review of the FDA Medwatch database of adverse events reported with bevacizumab from 11/1997 to 5/2009. Results: We searched the database for keywords bleeding, hemorrhage, cerebral, intracranial, subarachnoid, cerebellar, hemorrhagic stroke, and brain. 17,466 reports were included in the database: 154 described CNS hemorrhage in 99 patients, and 1041 reports described non-CNS bleeds. For CNS bleeds, cerebral hemorrhage was the most frequent event reported (n=39), followed by intracranial hemorrhage (n=20) and subarachnoid hemorrhage (n=18). Median age was 62 years; 54% of patients were female. Primary cancer was colorectal (42%), glioma (13%), and breast cancer (10%). Patients received a median of three (1-36) doses of bevacizumab prior to the bleed. 54% of patients received myelosuppressive chemotherapy, and 30% had documented history of hypertension. Sixteen patients with CNS hemorrhage were reported to have CNS metastases. For 70 patients, information on CNS involvement was not reported. Death was reported as a complication of hemorrhage in 48% of patients. Nine patients with brain metastases died and CNS hemorrhage was the cause of death in seven. Six patients with glioma died, and CNS hemorrhage was the cause in three. One patient with brain metastases, and one patient with glioma also experienced a non-CNS bleed. Five patients in each group had received heparin, warfarin or NSAIDs. Low platelet counts were reported in 3 patients with CNS metastases and 2 patients with glioma. The most common factor associated with CNS hemorrhage was medication predisposing to bleeding, followed by thrombocytopenia. Hypertension, a risk factor for CNS hemorrhage, was reported in 4 patients with brain metastases, and 2 patients with glioma. Conclusions: In this database, 154 of 1195 reports of bleeding associated with bevacizumab described a CNS bleed. Although CNS bleeds were not common, they were the reported cause of death in more than half of the cases.