bluuebunny/crossref_metadata_2025 huggingface dataset:
Cancer screening: Source of information and level of trust.
Authors: Morere Jean F. , Viguier Jérôme , Coscas Yvan , Pivot Xavier B. , Blay Jean-Yves , Eisinger Francois , Lhomel Christine
Published: March 2020

1567

Background: Providing public information is critical for cancer control. EDIFICE surveys were conducted to provide a better understanding of the participation of the French population in cancer screening programs (colorectal, breast) or individual cancer screening (prostate). To evaluate sources of information in the general population and their level of trust, specific questions were addressed in the EDIFICE 3 survey. Methods: This third nationwide observational study, EDIFICE 3, was conducted by phone interviews among a representative sample of 1603 subjects aged between 40 and 75 years old, using the quota method. Questions on the source of information were: Concerning cancer screening, what are all your means of information? What level of trust (quoted from 1 to 10) do you have on the following media of information; your own general practitioner, physicians in general, patient associations, national health insurance system, health authorities, your close circle, radio and television, lay press, internet. Results: In the overall population, the most frequently quoted means of information for cancer screening were: radio and television (61%), general practitioners (52%), lay press (33%), institutional letters (19%) and internet (18%). People under 50 years old named significantly more often radio and television (66% vs 58%) and internet (24% vs 15%), while older people above 50 years old (target population for screening programs) more frequently named institutional letters (26% vs 7%). In a trust scale from 0 to 10, the best level of trust was achieved by general practitioners (8.2), patient associations (6.8), national health insurance system (6.6) and health authorities (6.2). In contrast, radio and television (5.7), lay press (5.2) and internet (4.6) were mistrusted. Overall, women and younger subjects were more trustful. Conclusions: Radio and television are the most frequently quoted source of information but paradoxically they are not highly trusted. The general practitioner appears to be the best option (trusted and used) for providing cancer screening information. As institutional letters were frequently quoted and highly trusted, they might be useful for informing the population even before the age of recommended screening.
Predictors of pediatric and adult fibrosarcoma survival: Analyses of the Surveillance, Epidemiology, and End Results (SEER) program, 1973-2008.
Authors: Ognjanovic Simona , Fan Yunhua , Ognjanovic Miodrag , Skapek Stephen , Hawkins Douglas S.
Published: March 2020

1576

Background: Fibrosarcoma (FS) is the second most common group of soft tissue sarcomas in children, however, most FS are diagnosed in adults. The goal of this study was to compare clinical features and outcomes of children and adults diagnosed with FS and identify predictors of survival. Methods: We have analyzed data from 569 children (≤ 19 years) and 5,508 adults (>19 years) diagnosed between 1973 and 2008 with FS (ICCC category IXb) available in the SEER database. Survival estimates were determined using survival time with end point death from any cause. Results: Comparison of two diagnostic periods, 1973-1989 vs. 1990-2008 showed that 5-year survival rates have improved in adults (48.4% vs 60.9%, P<0.0001), but not in children (72.3% vs. 73.9%, P=0.16). Children with FS had significantly better outcome compared to adults (5-year survival rates were 73.4% ± 2%, and 56.7% ± 0.7%, respectively, P<0.0001). Sites with survival rates higher than the median 5-year survival were grouped as favorable (extremities, head and neck, and genitourinary site); trunk, abdomen, and other sites were grouped as unfavorable. Cox proportional hazard regression model identified diagnosis in childhood, fibromyxosarcoma histologic subtype (ICD-O3 code 8811/3), favorable site, and localized stage as positive predictors of survival. Compared to fibromyxosarcoma, other histologic types had hazard ratio (HR) of 11.6 (95% CI= 1.6-83.2, P=0.01) in children, and HR of 1.8 (95%CI=1.5-2.1, P<0.0001) in adults. Diagnosis at unfavorable site was associated with HR=1.9 (95%CI=1.4-2.6) in children and HR=1.4 (95%CI=1.3-1.5) in adults. Compared to localized, distant disease had HR=4.2 in children and HR=5.1 in adults, both highly significant (P<0.0001). Conclusions: Adults diagnosed with FS had worse survival than children. Predictors of good outcome, including histiologic subtype, primary site, and stage, were valid in both children and adults.
Treatment patterns and comorbidities in a population-based cohort of glioblastoma patients diagnosed 1997-2008.
Authors: Oliveria Susan A. , Chu Laura , Casso Deborah , Wells Karen , Dong Wei , Dubrow Robert , Das Asha , Nerenz David R , Ulcickas Yood Marianne
Published: March 2020

1591

Background: Glioblastoma multiforme (GBM) is one of the most common, most malignant and rapidly progressive forms of brain cancer. Published reports of GBM in non-trial populations are limited. The purpose of this study was to assemble a population-based cohort of GBM patients with comprehensive clinical and demographic information and to define treatment patterns and outcomes in this population. Methods: GBM patients served by Henry Ford Health System (HFHS), a major GBM referral center, were identified using ICD-O and histology codes from the HFHS tumor registry. Eligible patients were newly diagnosed with GBM between 1997 and 2008. Comprehensive, population-based data were compiled using tumor registry data (including histology and mortality) with linkages to pharmacy data (including infusion), outpatient and inpatient encounter data, and laboratory results. Results: Overall, 812 GBM patients were identified; mean age was 54 years (standard deviation 15.8). The cohort was 63% male and 84% white. Among the most common post-diagnosis comorbidities/complications, 14% of patients had venous thromboembolism (95% confidence interval [CI] 12-17), 16% had seizures (95% CI 14-19), and 6% had central nervous system hemorrhage (95% CI 4-7). Arterial thromboembolism occurred in 3% of patients (95% CI 2-4), while 7% experienced infections such as candidiasis, herpes simplex, and pneumocystis pneumonia (95% CI 5-9) and 2% experienced wound dehiscence (95% CI 1-3). 94% (95% CI 93-96) of the cohort received some form of treatment with 81% undergoing surgery (95% CI 78-84), 75% receiving radiation therapy (95% CI 72-78), and 67% receiving chemotherapy (95% CI 64-70). Median overall survival after diagnosis was 1.4 years (95% CI 1.3-1.5) among all patients, and 1.6 years (95% CI 1.4-2.0) among those diagnosed 2005-2008. Conclusions: This study presents a well-characterized population-based cohort of GBM patients. Understanding treatment patterns and comorbidities outside the clinical trial setting is important in informing and evaluating real-world treatment decisions. Additional results exploring time trends in systemic cancer therapy and Kaplan-Meier survival curves will be presented.
Secondary breast cancer (s-BC) after hematopoietic cell transplantation (HCT) for leukemia: Role of total body irradiation (TBI).
Authors: Sun Can-Lan , Berano-Teh Jennifer , Gonzales Alicia , Atencio Liezl , Kang Tongjun , Francisco Liton , Stein Anthony Selwyn , O'Donnell Margaret R. , Snyder David , Somlo George , Bhatia Ravi , Forman Stephen J. , Bhatia Smita
Published: March 2020

1592

Background: s-BC after conventional chest radiation for histologically distinct cancer is well-recognized, and has resulted in radiologic screening recommendations by American Cancer Society. However, risk of s-BC after TBI is not well-defined. Methods: We determined the risk of s-BC in 648 consecutive females transplanted for leukemia (ALL [19%], AML/MDS [57%], CML [24%]) between 1976 and 2008 with a post-HCT survival of ≥2 years. The study was restricted to leukemia to understand the role of TBI without the influence of pre-HCT chest radiation. Near-complete ascertainment of s-BC was assured by combining institutional follow-up with California Cancer Registry data. Results: Median age at HCT was 38 years (range, 0-71); 14% had received autologous HCT, 64% related and 22% unrelated donor HCT; 70% had received TBI for myeloablative conditioning. After 5,675 person-years of observation, 16 patients developed s-BC (14 after TBI). Median latency from HCT to s-BC was 16y (2-27). Median age at s-BC was 50y (29-66). Cumulative incidence of s-BC was 6% at 20y after HCT, contributed to largely by TBI (s-BC incidence after TBI: 5.7%). Among TBI-exposed, 8.6% were projected to develop s-BC by age 65y (1.6% among non-TBI-exposed, p=0.03). TBI-exposed patients were 2.4 times more likely to develop s-BC compared with general population (p=0.001); non-TBI exposed were not at increased risk (SIR=0.9, p=0.9). Multivariate analysis (adjusted for age at HCT, follow-up and primary diagnosis) revealed a 4.7-fold (p=0.068) increased risk of s-BC among TBI-exposed.  Conclusions:   Risk of s-BC after TBI as the sole source of radiation to breast is increased. Nearly 9% of those exposed to TBI will develop s-BC by age 65y. Identification of vulnerable sub-populations among the TBI-exposed patients is underway to create targeted screening strategies for early detection of s-BC.
Association of p53 Arg72Pro polymorphism and HPV status with the initiation, progression, and development of cervical cancer (CC): A meta-analysis.
Authors: Habbous Steven , Pang Vincent , Eng Lawson , Mackay Helen , Amir Eitan , Liu Geoffrey
Published: March 2020

1597

Background: CC develops through progression from normal cervical epithelium through squamous intra-epithelial lesions (SILs) to cancer. CC is classically associated with oncogenic human papillomavirus (HPV). Yet, not all CC patients demonstrate HPV infection at diagnosis. HPV+ and HPV– subsets of CC patients may thus represent distinct entities. HPV binds to P53, promoting its degradation; the Arg variant of p53 Arg72Pro binds more ardently to HPV than the Pro variant. Although there have been meta-analyses of Arg72Pro in CC risk, none has evaluated the relationship between Arg72Pro and HPV status together. We hypothesize that p53 Arg72Pro modifies aspects of the carcinogenic process in HPV+ (but not HPV-) subsets of CC. Methods: Pubmed/Embase databases identified 1494 potential studies; 51 were eligible and included. Separate analyses were performed to evaluate CC risk (CC vs normal), initiation of cancer (SIL vs normal), and progression towards cancer (CC vs SIL), by HPV status. Pooled odds ratios (pOR) were generated using RevMan 5.1 software. Results: p53 Arg72Pro was not associated with CC risk in either HPV+ or HPV- patient subsets (pORs 0.92; 95%CI, 0.6-1.3 and pORs 1.07; 95%CI, 0.7-1.7, respectively). Similarly, there was no association with the initiation of disease (SIL vs normal): pORs 0.96; 95%CI, 0.7-1.3 (HPV+ subset); 1.11; 95%CI, 0.9-1.4 (HPV- subset). There was no association with disease progression from SIL to CC in the HPV- subset (pOR, 0.98; 95%CI, 0.7-1.4). However, in the HPV+ subset, comparing the progression from SIL through to CC, there was strong and significant association: pOR, 1.37; 95%CI, 1.2-1.6 (p=4.0x10E-4), with no evidence of heterogeneity (I2 = 0%) or bias (by funnel plot). Sensitivity analyses demonstrated similarly significant results, even after taking into account differing quality of methodological designs and type of biological sample analyzed (tumour vs. blood) of the underlying studies. Associations were mainly restricted to Caucasian studies. Conclusions: In this meta-analysis, the Arg variant of p53 Arg72Pro was associated with progression of SIL to CC only in HPV+ subsets, but not to disease initiation or risk of CC.
Breast cancer survival: Is the Asian population homogenous?
Authors: Caggiano Vincent , Parise Carol
Published: March 2020

1606

Background: Study of the ER-/PR-/HER2- (TN) subtype has generated interest in race/ethnicity with respect to breast cancer. Poor survival of African-American (AA) women with breast cancer has been reported. Less is known about the Asian population. This study examines survival of four ER/PR/HER2 subtypes among 10 self-reported race/ethnicity categories Methods: Using the California Cancer Registry 2000-2010, we examined 136,175 cases first primary female invasive breast cancer. For stages 1 and 2, Kaplan-Meier survival and the Log-Rank test were computed by stage and race for the ER+/PR+/HER2-, ER-/PR-/HER2+, ER+/PR+/HER2+ (TP) and TN subtypes. Results: When the Asian population is combined into the category Asian/Pacific Islander (API): ER+/PR+/HER2-: AAs had worse 5-year survival than whites in stages 1 and 2 but Hispanics and APIs had better survival in both stages; ER-/PR-/HER2+: AAs and Hispanics were no different from whites in stage 1 but APIs had better 5-year survival (0.96 vs 0.89, p<0.001). For stage 2, there were no differences in survival among the races. ER+/PR+/HER2+: AAs had worse and APIs had better survival in both stages; Hispanics had better survival only in stage 1 (0.93 vs 0.92, p<0.03) and were no different from whites in stage 2. ER-/PR-HER2-: AAs and Hispanics were no different from whites in stage 1 but APIs had better survival (0.93 vs 0.88, p< .003); AAs had worse survival than whites in stage 2 (0.71 vs 0.75, p< 0.04) Hispanics were no different, and APIs had better survival (0.81, p < 0.001). When the Asian population was expanded into 7 categories, Pacific Islanders and Koreans were no different than whites in stages 1 or 2 for all four subtypes examined. For Stage 1, Southeast Asians had better survival for all subtypes except for the TN whereas Filipinos had better survival for all subtypes except for TP. For the ER+/PR+/HER2- subtype, women from the Indian Continent had better survival in stage 1 (0.98 vs 0.92, p<0.003) and in stage 2 (0.94 vs 0.88, p<.001) and better survival for stage 1 of the TN subtype (1.00, vs 0.88, p <0.04). Conclusions: There is heterogeneity among the Asian population, but regardless of how categorized, Asians have either the same or better 5-year survival than whites for all subtypes in stages 1 and 2.
Long-term follow-up results of EORTC 26951: A randomized phase III study on adjuvant PCV chemotherapy in anaplastic oligodendroglial tumors (AOD).
Authors: Van Den Bent Martin J. , Hoang-Xuan Khê , Brandes Alba Ariela , Kros Johan M , Kouwenhoven Mathilde C.M. , Taphoorn Martin J. B. , Delattre Jean-Yves , Bernsen Hans J.J.B. , Frenay Marc , Tijssen Cees , Grisold Wolfgang , Sipos Laszlo , Enting Roelien H. , Dinjens Winand N.M. , French Pim , Vecht Charles J , Allgeier Anouk , Lacombe Denis A. , Gorlia Thierry
Published: March 2020

2

The full, final text of this abstract will be available at abstract.asco.org at 12:01 AM (EDT) on Sunday, June 3, 2012, and in the Annual Meeting Proceedings online supplement to the June 20, 2012, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Sunday edition of ASCO Daily News.
Consolidation reduced dose whole brain radiotherapy (rdWBRT) following methotrexate, rituximab, procarbazine, vincristine, cytarabine (R-MPV-A) for newly diagnosed primary CNS lymphoma (PCNSL): Final results and long-term outcome.
Authors: Curry Richard Charles , Correa Denise , Raizer Jeffrey J. , Grimm Sean Aaron , Lai Rose , Schiff David , Grant Barbara W. , Reiner Anne S. , Panageas Katherine , Yahalom Joachim , DeAngelis Lisa Marie , Abrey Lauren E. , Morris Patrick Glyn , Omuro Antonio Marcilio Padula
Published: March 2020

2006

Background: After promising early results in the pilot phase (N= 30) reported by Shah 2007, we report on final results of a multicenter phase II study (N=52) in newly diagnosed PCNSL combining R-MPV-A and rdWBRT, expanded to address long-term disease control and cognitive outcomes in pts who actually received rdWBRT. Methods: Pts received 5 cycles of R-MPV (MTX dose: 3.5g/m2). Those with partial response (PR) received additional 2 cycles. Pts with a complete response (CR) after 5-7 cycles received rdWBRT (23.4 Gy), otherwise standard WBRT was offered (45 Gy). Consolidation cytarabine was given to all pts. Primary end-point was 2-y progression-free survival (PFS) in pts receiving rdWBRT (n=30 pts in CR required). Exploratory end-points included comprehensive neuropsychological testing, white matter changes (WMC) analysis (Fazekas scale) and apparent diffusion coefficient (ADC) on MRI. Results: Accrual was completed (N=52; 22 women); median (med) age= 60 (30-79); med KPS= 70 (50-100). In total, 31 (59%) pts were assessable for the primary endpoint (achieved a CR after induction and received rdWBRT). The 2-y PFS for this group was 78% (95% ci: 64%- 92%); med PFS= 7.7 y; the med OS was not reached (med follow-up= 6y); 3y-OS= 88% (ci 70-95); 5y-OS= 81% (ci 62-91). Cognitive testing showed improvement in executive function (P < 0.01) and verbal memory (P < 0.05) following induction chemotherapy; follow-up scores remained stable across the various domains. Minimal WMC developed in long term survivors: 36% of pts showed no change in Fazekas’ scores, 64% of pts developed scores 1 or 2 and no pt showed scores 3-6. The intent-to-treat (n=52) med PFS was 3.3y; med OS= 6.6 y. Differences in ADC values did not predict response (p=0.15), PFS (p=0.41) or OS (p=0.48). Conclusions: Consolidation rdWBRT is a highly effective and safe treatment for newly diagnosed PCNSL. Long term follow-up showed robust PFS and OS, comparable or superior to full dose WBRT, with excellent cognitive outcomes and no significant WMC over time. An RTOG randomized trial has been initiated comparing R-MPV-A with vs without rdWBRT.
Effects of cediranib (VEGF signaling inhibitor) on edema in newly diagnosed glioblastoma patients during initial chemoradiation.
Authors: Polaskova Pavlina , Pinho Marco C , Kalpathy-Cramer Jayashree , Guimaraes Alexander R , Wen Patrick Y. , Sorensen A. Gregory , Jain Rakesh K. , Batchelor Tracy , Gerstner Elizabeth Robins
Published: March 2020

2012

Background: A significant benefit of antiangiogenic therapy is control of brain edema. We evaluated the impact of adding cediranib to standard chemoradiation (CRT) on peritumoral edema in patients with newly diagnosed glioblastoma(GBM) during the initial 6 weeks of CRT. Methods: Two cohorts of patients were enrolled in two clinical trials. The control group (N=13) received radiation for 6 weeks plus temozolomide. The cediranib (CED) group received standard CRT plus daily cediranib (N=34). MRIs were performed at baseline and weekly during CRT. Volumes of interest (VOIs) were drawn outlining the enhancing tumor on T1-weighted post contrast images and the abnormal FLAIR hyperintensity. ADC (apparent diffusion coefficient) maps were calculated from diffusion-weighted images and histograms of the distribution of ADC values created for each visit using the baseline FLAIR VOI to characterize the peritumoraledema. Patients were on stable or decreasing doses of steroids. Results: In the CED group, T1 and FLAIR VOI decreased during CRT vs controls where T1 VOI did not change and FLAIR VOI increased. By the end of CRT, the mode of the ADC histogram in the CED group shifted to the left while the mode of the controls shifted to the right. The skewness, a measure of asymmetry of the distribution, increased in the CED group and decreased in controls. Conclusions: In patients with newly diagnosed GBM treated with CRT and cediranib, tumor volume decreased on T1 and FLAIR images whereas the FLAIR volume significantly increased in the control group suggesting increased edema. The shift of mode to the right and decreasing skewness in controls (indicating an increase in the proportion of very high ADC values) suggests that adding cediranibprevented the development of edema and contributed to the resolution of existing edema. Preventing the edema by adding anti-VEGF treatment may improve the tolerability of CRT for GBM patients. [Table: see text]
Addition of upfront whole-brain radiotherapy to surgery or stereotactic radiosurgery versus surgery or stereotactic radiosurgery alone for treatment of brain metastases: A systematic review and meta-analysis.
Authors: Soon Yu Yang , Tham Ivan Weng Keong , Lim Keith Hsiu Chin , Koh Wee Yao , Lu Jiade Jay
Published: March 2020

2016

Background: The benefits of adding upfront whole-brain radiotherapy (WBRT) to surgery or stereotactic radiosurgery (SRS) when compared to surgery or SRS alone for treatment of brain metastases are unclear. We performed a systematic review and meta-analysis of published randomized controlled trials (RCT) to determine the efficacy and safety of additional upfront WBRT. Methods: We searched MEDLINE, EMBASE, CENTRAL from date of inception and annual meeting proceedings of ASCO and ASTRO from 1999 to September 2011 for RCTs comparing surgery or SRS plus WBRT with surgery or SRS alone for treatment of brain metastases. The primary outcome was overall survival (OS). Secondary outcomes include progression free survival (PFS), local and distant intracranial disease progression, neurocognitive function (NF), quality of life (Qol) and neurological toxicity. Hazard ratios (HR), confidence intervals (CI), p values (p) were estimated with random effects models using Revman 5.1. Results: We found five RCTs including 663 patients with one to four brain metastases. Adding upfront WBRT decreased the one-year incidence of any intracranial disease progression from 73-76% to 22 - 47% but did not improve OS (HR 1.11, 95%CI 0.83 - 1.48, p = 0.47) and PFS (HR 0.76, 95%CI 0.53 - 1.10, p = 0.14). Subgroup analyses showed that the effects on overall survival are similar regardless of types of focal therapy used, number of brain metastases, dose and sequence of WBRT. The effects of upfront WBRT on NF, Qol and neurological toxicity were variable. Conclusions: Adding upfront WBRT to surgery or SRS significantly decreased any intracranial disease progression at one year but did not improve overall and progression free survival and produced variable effects on neurocognitive function, quality of life and neurological toxicity when compared with surgery or SRS alone. Future research should focus on developing more effective approaches to characterize and ameliorate the potential neurological toxicity of WBRT.
MET and ALK in glioblastoma multiforme (GBM): Comparison of IHC and FISH.
Authors: Kulig Kimary , McLendon Roger E , Locke Susan C. , Young Debra R. , Zhong Xiaoyin , Hudson Lori L. , Abernethy Amy Pickar
Published: March 2020

2021

Background: GBM, the most common and lethal malignant primary brain tumor in adults, has an overall one-year life expectancy of 33.7%. Personalized medicine on the basis of predictive biomarkers remains elusive in GBM; however a recent case report showed clinical improvement after treatment with a mesenchymal-epithelial transition (MET) inhibitor. The authors of that report ascribe clinical response to the MET inhibitor, but the drug is also an inhibitor of anaplastic lymphoma kinase (ALK). We explored the co-expression, gain, or amplification of both MET and ALK by IHC and FISH in GBM. Methods: A convenience sample of 56 available tumors from gross-resected GBM cases within the Duke Brain Tumor tissue bank was stained for MET using clone 8F11 (Leica) and for ALK using clone 5A4 (Novocastra). FISH employed the LSI ALK (2p23) breakpoint-spanning dual-color DNA probe and the LSI D7S486 (MET)/CEP 7 dual color DNA probe (Vysis). Results: Of 56 GBM cases, MET was expressed in 69.6% and ALK in 17.9% by IHC. By FISH, gain or amplification was found in 100% of cases for MET and in 48.2% for ALK. Co-expression of MET and ALK by IHC was 14.3% and 48.2% by FISH. Co-expression by either IHC or FISH was also 48.2%. OS estimation for this cohort is premature, with 77% of patients still alive. Conclusions: MET and ALK are (co-)expressed in a significant proportion of GBM. IHC detection of MET and ALK did not correlate well with FISH results, suggesting that gene gain or amplification does not necessarily lead to abnormal MET and ALK protein expression or that IHC methods or antibodies used can be optimized. Prior studies reported MET amplification in GBM as low as 4%. Our study indicates that MET gain/amplification and protein expression may be much higher, having implications for MET-targeted therapy. Additionally, co-expression of ALK and MET has implications for dual inhibitors of these signaling pathways as well as resistance mechanisms. Our continued work will explore significance of MET and ALK as predictors of therapeutic response, with careful control for clinically relevant patient and disease characteristics. [Table: see text]
Recurrent genetic alterations in primary central nervous system lymphoma of immunocompetent patients.
Authors: Gonzalez Alberto , Idbaih Ahmed , Boisselier Blandine , Jouvet Anne , Polivka Marc , Adam Clovis , Figarella-Branger Dominique , Miquel Catherine , Vital Anne , Ghesquieres Herve , Gressin Remy , Delwail Vincent , Taillandier Luc , Chinot Oliver L. , Soubeyran Pierre-Louis , Gyan Emmanuel , Choquet Sylvain , Soussain Carole , Mokhtari Karima , Hoang-Xuan Khê ,   LOC National Network
Published: March 2020

2023

Background: Little is known about the molecular pathogenesis of primary central nervous system lymphoma (PCNSL) in immunocompetent patients. Our objective was to identify the genetic changes involved in PCNSL oncogenesis and evaluate their clinical relevance. Methods: Twenty nine and four newly diagnosed, HIV-negative PCNSL patients were investigated using high-resolution single nucleotide polymorphism (SNPa) arrays (Infinium Illumina Human 610-Quad SNP array-Illumina; validated by real-time quantitative polymerase chain reaction) and whole-exome sequencing respectively. Molecular results were correlated with prognosis. Results: All PCNSLs were diffuse large B-cell lymphomas, and the patients received high-dose methotrexate-based polychemotherapy without radiotherapy as an initial treatment.SNPa analysis revealed recurrent large and focal chromosome imbalances that target candidate genes in PCNSL oncogenesis. The most frequent genomic changes were (i) 6p21.32 loss (79%), corresponding to the HLA locus; (ii) 6q loss (27-37%); (iii) CDKN2A homozygous deletions (45%); (iv) 12q12-q22 (27%); (v) chromosome 7q21 and 7q31 gains (20%). Sequencing of matched tumor and blood DNA samples identified novel somatic mutations in MYD88 (L265P hot spot mutation) and TBL1XR1 in 38% and 14% of the cases, respectively. The correlation of genetic abnormalities with clinical outcomes using multivariate analysis showed that 6q22 loss (p=0.006 and p=0.01), and CDKN2A homozygous deletion (p=0.02 and p=0.01) were significantly associated with shorter progression free survival and overall survival. Conclusions: Our study identified novel genetic alterations in PCNSL, such as MYD88 and TBL1XR1 somatic mutations, which would both contribute to the constitutive activation of the NFkB signaling pathway and represent potential promising targets for future therapeutic strategies.
The oral transforming growth factor-beta (TGF-ß) receptor I kinase inhibitor LY2157299 plus lomustine in patients with treatment-refractory malignant glioma: The first human dose study.
Authors: Azaro Analia , Baselga José , Sepúlveda Juan Manuel , Seoane Joan , Rodon Ahnert Jordi , Brana Irene , Gueorguieva Ivelina , Cleverly Ann , Lahn Michael M. F. , Pillay Sada , Paz-Ares Luis , Holdhoff Matthias , Blakeley Jaishri O'Neill , Carducci Michael Anthony
Published: March 2020

2042

Background: Activated TGF-b signaling has been associated with poor survival in several tumors, including glioma. TGF-b inhibitors are expected to improve outcome. Part B of this Phase I trial assessed safety, pharmacokinetics, pharmacodynamics, and antitumor activity of the intermittent treatment with LY2157299 in combination with lomustine. Methods: After evaluating safety of LY2157299 monotherapy in part A of the study, 2 cohorts of patients were treated with LY2157299 at 160 or 300 mg/day with intermittent dosing (each cycle=14 days on followed by 14 days off) in combination with lomustine at standard dose (100 to 130 mg/m2 every 6 weeks) for ≥2 cycles. Toxicity was assessed using the Common Terminology Criteria for Adverse Events, version 3. Results: Twenty-six patients with glioma (18 WHO Grade IV; 5 Grade III; 3 unspecified grade) were treated with LY2157299 and lomustine (160 mg/day, n=15; 300 mg/day, n=11). There were no dose-limiting toxicities. No clinically meaningful cardiotoxicities were observed. Twenty-one SAEs occurred in 10 patients, all considered to be related to lomustine and none to LY2157299. Of the 26 patients, 7 had thrombocytopenia (27%), and recovery around weeks 4 to 6 was not impacted by the second cycle of LY2157299. Two patients taking 160 mg/day were treated for >6 cycles, with 1 of the 2 patients showing an unconfirmed partial response. At the 300 mg/day dose, no responses were observed; 2 patients were treated for >6 cycles. Co-administration of lomustine did not alter LY2157299 exposure. Observed exposure of LY2157299 increased with dose escalation between the 2 cohorts. On Day 7, the variability estimates (coefficients of variation) of exposure and maximum concentration were slightly higher in presence of lomustine (58%) when compared with LY2157299 alone (47%) and then again reduced on Day 14 (53%). Pharmacodynamic results will be reported at a later date. Conclusions: The 14 days on/14 days off treatment with LY2157299 did not increase the known lomustine toxicity. Given the overall safety profile and antitumor effect, LY2157299 is being investigated in Phase II studies.
Expression of CXCR7, CXCR4, CXCR3 and their chemokine ligands in glioblastoma.
Authors: Berahovich Robert D. , Walters Matthew J. , Sullivan Timothy J. , Kohrt Holbrook Edwin , Karamchandani Jason , Jaen Juan C. , Schall Thomas J.
Published: March 2020

2043

Background: The chemokine receptors CXCR4 and CXCR7, and their shared ligand CXCL12/SDF-1, have been implicated in multiple aspects of tumorigenesis, including tumor cell proliferation, angiogenesis, vasculogenesis, and metastasis. Recently, a role for CXCR4 and CXCR7 has been postulated in the control of glioblastoma growth and vasculogenesis. We set out to define the expression patterns of these proteins on primary glioblastoma tumors and associated vasculature. Methods: First, a tumor microarray containing grades 1, 3, and 4 glioma samples were analyzed by immunohistochemical techniques for the expression of CXCR7. Second, two glioblastoma microarrays were analyzed by the same technique for CXCR7, CXCR4, and their shared chemokine ligand CXCL12. The same microarrays were also probed for the expression of the additional CXCR7 ligand, CXCL11/ITAC, as well as the chemokine receptor CXCR3, which is also a receptor for CXCL11. Tissues were scored in a blinded fashion by a certified neuropathologist for both the intensity of signal and location of signal for all proteins tested. Results: CXCR7 expression was largely dependent on tumor grade, as the receptor was usually absent on most grade 1 gliomas but was moderately-to-highly expressed in the majority of anaplastic astrocytomas and glioblastomas. CXCR7 expression on tumor-associated vasculature was seen in all samples and its expression level also increased with glioma grade. In contrast to CXCR7, CXCR4 expression in glioblastoma was usually limited to the glioma cells, with only infrequent expression on the vasculature. Conversely, CXCL12 expression in glioblastoma was usually limited to the vasculature. CXCR3 was detected in a subset of glioblastomas, and only on the glioma cells. The CXCR7 and CXCR3 ligand CXCL11 was, like CXCR7, expressed on both the glioma cells and vasculature. Conclusions: These results, in light of prior evidence for CXCR7 in tumor growth, suggest a positive role for CXCR7 in the development of glioblastoma. Because CXCR7 colocalizes with its ligands, CXCL12 and CXCL11, as well as their other receptors, CXCR4 and CXCR3, the function of CXCR7 in glioblastoma may lie in the regulation of both the CXCR4/CXCL12 and CXCR3/CXCL11 axes.
Impaired expression of ketone metabolizing enzymes in malignant gliomas: Implication for ketogenic diet therapy.
Authors: Chang Howard T. , Olson Lawrence Karl , Schwartz Kenneth A.
Published: March 2020

2056

Background: Malignant glial cells may have altered expression of mitochondrial enzymes that are key for deriving energy from ketones. The novel strategy of treating malignant gliomas with a ketogenic diet has been tested in animal models with promising results. To evaluate the applicability of these findings to human patients we tested the hypothesis that high grade human gliomas may lack or have decreased expression of mitochondrial enzymes that are important for metabolizing ketones. Methods: We evaluated the expression of 2 key mitochondrial enzymes involved in ketone metabolism in 22 patients (17 males and 5 females, mean age 55,range 30-85) with either glioblastoma (GBM, WHO grade IV) or anaplastic glioma (WHO grade III) (Table). Immunohistochemistry reactions were performed on formalin-fixed paraffin-embedded sections from brain biopsies, using antibodies raised against succinyl CoA: 3-oxoacid CoA transferase (OXCT1) and 3-hydroxybutyrate dehydrogenase 1 (BDH1). Immunoreactivities were graded using a semi-quantitative scale based on the percentage of positive cells: negative (NEG) ≤ 5%; intermediate (INT) 5-20%; and positive (POS) more than 20%. Focal non-neoplastic “normal” brain tissue present within the specimens expressed both enzymes and served as an internal positive control. Results: Either absent or marked decreased expression of OXCT1 and BDH1 were observed in most GBM and anaplastic glioma. Concordance for absent or marked decrease expression of both OXCT1 and BDH1 was observed in 14 of the 17 (82%) GBM’s, and 1 of 5 (20%) anaplastic gliomas. Conclusions: These data support the rationale for a pilot clinical study investigating the therapeutic utility of a ketogenic diet in selected glioma patients. Malignant gliomas with diminished expression of key enzymes (e.g., OXCT1, BDH1) may benefit from the ketogenic diet therapy, whereas those with positive expression of these enzymes likely will not. [Table: see text]
Impact of duration of bevacizumab (Bev) treatment in the prognosis of adults with recurrent malignant gliomas.
Authors: Hamza Mohamed Ali , Conrad Charles A. , De Groot John Frederick , Gilbert Mark R. , Groves Morris D. , Yung W. K. Alfred , Puduvalli Vinay K.
Published: March 2020

2064

Background: Bev is the standard treatment for patients with recurrent glioblastoma (GB) but is also used in treating recurrent anaplastic gliomas (AG). Differences in outcome between these groups and optimal duration of treatment with Bev in pts with recurrent malignant gliomas are not well defined. We examined the relationship between the duration of Bev treatment and the outcome in pts with GB and AG. Methods: In this retrospective chart and data review derived from our longitudinal database, we identified pts with recurrent AG and GB who were treated with Bev alone or Bev-containing regimens between 2005 and 2009; the data was analyzed to determine the overall survival (OS) and the progression free survival (PFS). Results: A total of 261 patients with recurrent malignant gliomas (196 with GB and 65 with AG) were identified. There was no significant difference between the median length of treatment between AG and GB (5.81±0.66 months vs. 6.77±0.52 months, p=0.32). PFS6 was 34.2% (95% CI, 27.8-41.3) for patients with GB and 44.2% (95% CI, 32.5-56.7) for patients with AG. Patients with GB who were treated ≥6 months had a significantly higher OS (29.13 months vs. 20.16 months, p= 0.001) compared to those treated <6 months, and a significantly higher PFS compared to those treated <6months (11.33 months vs. 3.7 months, p=0.0001). For patients with AG, although treatment ≥6 months had a significantly higher PFS (13.93 months vs. 3.53 months, p<0.0001), OS was not significantly different (months 38.6 vs. 52.5 months, p=0.6) compared with those treated <6 months. Conclusions: Length of treatment ≥6 mo with Bev or Bev-containing regimen was associated with improved PFS in both AG and GB but only the GB subgroup showed improved OS. These results suggest equivocal survival benefit in patients with AG with longer duration of bevacizumab treatment, which requires further study in prospective trials.
Plasma levels of IL-8 and g-CSF in high-grade gliomas treated with bevacizumab.
Authors: Eoli Marica , Rabascio Cristina , Cuppini Lucia , Anghileri Elena , Pellegatta Serena , Calleri Angelica , Mancuso Patrizia , Porrati Paola , Bertolini Francesco , Finocchiaro Gaetano
Published: March 2020

2083

Background: Bevacizumab, an anti-VEGF antibody, has shown significant activity in high grade gliomas (HGG). However, tumor recurrence inevitably occurs. Methods: We treated 63 recurrent HGG patients with poor prognostic factors with bevacizumab (10 mg/kg) and irinotecan (125 or 340 mg/m2) every 2 weeks, and investigated IL-12, IL-13, IL-17, FGF basic, G-CSF, MIP-1b, PDGF-beta, plasma levels before starting treatment and every 8 weeks by Bioplex. Ten age- and sex-matched healthy controls were used for comparison. Results: After a median follow-up of 27 weeks, median OS and PFS were 33 and 18 weeks, respectively. PFS at 6 and 12 months were 32% and 12%, respectively. OS at 6 months was 60%. Toxicity was mild. Baseline higher amounts of IL-13 (48±174 pg/ml vs 3.44±0.9 pg/ml, p=0.0001) and lower amounts of MIP-1b (35.3±20.9 pg/ml vs 67.2±18.8 pg/ml, p=0.0002), PDGF-beta (1585.5±1585 pg/ml vs 7098±1585 pg/ml, p=0.0001) and VEGF (27±39.8 pg/ml vs 54.5±32 pg/ml, p=0.001) were detected in patients than in healthy controls. In a cohort of 15 non-responders (patients who progressed 8 weeks after treatment onset), baseline IL-8 (15.7±10.8 pg/ml vs 10.9±9.4 pg/ml, p=0.03) and G-CSF (113.3±54 pg/ml vs 84.9±59.2 pg/ml, p=0.03) were significantly higher than in patients responding to treatment. In the same cohort no significant reduction of VEGF and other cytokines was observed after 8 weeks of treatment, while a decrease of plasma VEGF was observed in the remaining patients (26±32 pg/ml vs 13.3±28.5 pg/ml, p=0.001). Furthermore, in a cohort of 22 long-term responders (patients who progressed after more than 18 weeks of treatment), levels of VEGF decreased after 8 weeks of treatment when compared to baseline, whereas no difference was observed in baseline levels (23.9±22.6 pg/ml vs 9.8±9.4 pg/ml, p=0.001). Conclusions: Data suggest that high levels of IL-8 and G-CSF at baseline associated with a lack of VEGF decrease after 8 weeks of treatment identify patients who are resistant to bevacizumab. This hypothesis should be tested in a large number of patients.
Comparison of fractionated and single session radiosurgery for radiation resistant brain metastases.
Authors: Oermann Eric Karl , Wu Jing , Collins Brian Timothy , Morris David E. , Ewend Matthew G.
Published: March 2020

2091

Background: Melanoma and renal cell carcinoma are commonly called radiation resistant tumors due to the decreased response rate to traditional radiation (1.8-2 Gy /Fraction). Large brain metastases from radioresistant primaries are clinical challenges. This study examines the impact of fractionation on the treatment of intracranial metastases from radiation resistant tumors. Methods: Patients with a primary diagnosis of melanoma or renal cell carcinoma and intracranial metastases who completed treatment at The University of North Carolina with frameless robotic radiosurgery between 2007-2011 were retrospectively analyzed. Patients were treated with either single or 3-5 fractions depending on volume. The study’s primary endpoints were overall survival (OS) and local control (LC), and its secondary endpoint was patient steroid requirements. Outcomes data and pre-treatment variables were analyzed for significance using appropriate non-parametric tests. Results: 25 patients were included in the single fraction arm and 13 patients in the multi-fraction arm, and both had equivalent pre-treatment characteristics with the exception of tumor volume which was larger in the multi-fraction arm (p=0.01). At a median follow-up of 4.7 months (range, 1.8-11.6), the median OS for all patients was 6.2 months. One year survival was 35.1% and 5 patients (13%) had local failures at a median time to local failure of 5.5 months. Patients in the multi-fraction arm failed at a higher rate (10.5%) than patients in the single fraction arm (2.6%) (p=0.04), but there was no difference in OS (p=0.34). There was no difference between pre-treatment and post-treatment steroid requirements between the two arms (p=0.351). Conclusions: Fractionation is intended to facilitate radiosurgery in large tumors by limiting high doses of radiation to a large portion of normal brain. In our study of radioresistant intracranial metastases, large tumors receiving multi-fraction radiosurgery had decreased local control with no difference in toxicity or OS. These results suggest a need for either dose escalation, or combination therapy designed to reduce tumor size (resection or aspiration) in order to facilitate single fraction treatment.
Safety and efficacy of the addition of bevacizumab to temozolomide and radiation therapy followed by bevacizumab, temozolomide, and irinotecan for newly diagnosed glioblastoma multiforme.
Authors: Vredenburgh James J , Desjardins Annick , Peters Katherine B. , Reardon David A. , Herndon James Emmett , Coan April D. , Kirkpatrick John , Bailey Leighann , Threatt Stevie , Sampson John Howard , Friedman Allan H. , Friedman Henry S.
Published: March 2020

2094^

Background: Glioblastoma (GBM) has a very poor prognosis, and the majority of patients die within 2 years of diagnosis. GBMs have high concentrations of vascular endothelial growth factor (VEGF), and the more VEGF, the worse the prognosis. Bevacizumab is a humanized antibody to VEGF and is active in recurrent GBMs. The study aims to improve the survival of newly diagnosed GBM patients by incorporating an anti-angiogenic agent with radiation and temozolomide, and adding a topoisomerase I inhibitor, and an anti-angiogenic agent to temozolomide post-radiation therapy. Methods: Patients received standard radiation and temozolomide at 75 mg/m2/day, with bevacizumab at 10 mg/kg every 14 days beginning a minimum of 28 days post-operatively. Following the completion of radiation therapy, patients received 6-12 cycles of bevacizumab, temozolomide and irinotecan. Each cycle was 28 days. Bevacizumab was given at a dose of 10 mg/kg days 1 and 15, temozolomide 200 mg/m2 days 1-5 and irinotecan on days 1 and 15 at 125 mg/m2 for patients not on an enzyme inducing anti-epileptic (EIAED) and 340 mg/m2 for patients on an EIAED. The statistical design was a goal of 60% overall survival at 16 months. Results: 125 patients were enrolled between 8/07 and 3/09. All the patients have completed therapy. Nine patients had thromboembolic complications (DVT or PE). Two patients had wound dehiscence, one bowel perforation, one secondary AML and two pneumocystis carinii pneumonias (PCP). Seventeen had grade 4 hematologic toxicity requiring dose decrements. There were 4 toxic deaths, one each with a myocardial infarction PCP, PE and sepsis. At a median follow-up of 40 mos, the median overall survival was 20.9 mos, the median progression-free survival was 13.8 mos and the 2-year overall survival was 42.4%. Conclusions: Adding bevacizumab to temozolomide and radiation therapy followed by bevacizumab, temozolomide with irinotecan is tolerable and efficacious.
Effects of lazaroid U-74389G liposomes in a glioblastoma mouse model.
Authors: Ibrahim Fady , New Pamela Z. , Cui Kemi , Zhao Hong , Wang Lulu , Chow Diana , Wong Stephen
Published: March 2020

2098

Background: Lazaroid U-74389G (LAZ) is a 21-aminosteroid that has radioprotective effects against radiation-induced lipid peroxidation. Also in vitro antiproliferative effects have been reported against glioblastoma cell lines. The aim of this study was to use a liposomal formulation to evaluate LAZ radioprotective and antiproliferative effects in a glioblastoma mouse model. Methods: LAZ PEGylated liposomes (Lipo G) were developed at the University of Houston, College of Pharmacy. Glioblastoma cell line U87-expressing firefly luciferase reporter gene (100,000 cells in 2 μL) was injected intracranially in each male SCID hairless outbred mouse. There were 4 treatment groups (n=8-9, each): brain model (M) without treatment (control), radiation 2Gy weekly (M+R), Lipo G at 5 mg/kg dose IP twice per week (M+L) and radiation with Lipo G (M+R+L). Treatment lasted three weeks. Tumor size was monitored using non-invasive bioluminescence imaging (BLI), in each mouse. Mice were sacrificed after 3 weeks. Brain was harvested for immunohistochemistry examinations. Lipid peroxidation of brain tissues was quantified by measuring malondialdehyde (MDA) as a surrogate biomarker. Survival was evaluated using Kaplan Meier analysis at P= 0.05. Results: The relative BLI intensity was 4002.03±1737.67, 2034±737.72, 1387.36±684.53 and 2498.89±2521.32 % for M, M+R, M+L and M+R+L, respectively. The tumor size of the M+L group was reduced by 65% compared to control . For the radiation treated groups (M+R and M+R+L), there was no significant difference in tumor size compared to control group. MDA brain concentration in M+L and M+R+L groups was significantly less than in M+R group (8.27±0.78 and 10.37±3.30 µM/gm vs. 23.09± 3.79 µM/gm). The survival mean was 22.67, 25.33, 25.22 and 27.13 days for M, M+R, M+R+L and M+L groups, respectively. Mean survival of LAZ treated groups (M+L and M+R+L) was significantly longer than that of the control group Conclusions: LAZ liposomal formulations administered at 5 mg/kg dose reduced tumor growth by 65%. LAZ also protected brain tissue from radiation-induced lipid peroxidation by reducing MDA concentration by 50%. These provocative data warrant further investigation of LAZ as a radiation protectant and chemotherapeutic agent.
Ascending dose trials of the safety and tolerability of Toca 511, a retroviral replicating vector encoding cytosine deaminase, in patients with recurrent high-grade glioma.
Authors: Pertschuk Daniel , Cloughesy Timothy Francis , Chang Susan Marina , Aghi Manish K. , Vogelbaum Michael A. , Liau Linda M. , Shafa Bob B. , Yong William H. , Chen Clark , Kesari Santosh , Ibanez Carlos E. , Perez Omar D. , Robbins Joan M. , Jolly Douglas J. , Gruber Harry E.
Published: March 2020

2101

Background: Patients with the most common and aggressive form of brain cancer, glioblastoma multiforme (GBM), have a poor prognosis and current treatments are only palliative. Gene therapy approaches using replication-deficient viral vectors have been investigated previously for GBM with limited efficacy, likely due to poor gene delivery throughout the tumor. Methods: Toca 511 is a novel retroviral replicating vector (RRV) that is engineered to deliver a modified cytosine deaminase prodrug activator gene (CD) selectively to cancer cells. In those cancer cells expressing the CD gene, the antifungal prodrug 5-FC is converted to 5-FU. We are currently evaluating the safety and tolerability of a single dose of Toca 511 administered by direct intratumoral injection to subjects with recurrent high grade glioma (rHGG). After a period of time during which the vector is allowed to spread through the tumor, the patient begins oral 5-FC which is repeated cyclically. Results: Three subjects have been enrolled in each of the first two dose groups. No dose limiting toxicities (DLTs) have been identified in these groups and the treatment was well tolerated. There have been no grade 3 or 4 AEs considered related to either Toca 511 or 5-FC. A further 9 subjects were then enrolled at the 3rd dose level and are being followed. A second study has been initiated in which Toca 511 is injected into the walls of the resection cavity at the time of surgery for rHGG and followed by cyclic treatment with oral 5-FC. Conclusions: These clinical studies are the first to investigate a RRV to deliver genes to human brain tumors and further dose escalation is anticipated.