tbuckley/cabot-search huggingface dataset:
P08.33 Association of MiR-146aC&gt;G, 149C&gt;T, 196a2C&gt;T, and 499A&gt;G polymorphisms with brain tumors
Authors: J. Lim, J. Kim, I. Han, S. Kim, N. Kim, K. Cho
Journal: Neuro-Oncology (2017)

Background: MicroRNAs(miRNAs) are short noncoding RNAs that are implicated in tumorigenesis and function both as tumor suppressors and oncogenes. However, the clinical significance of miRNA expression profiles in brain tumors remains unclear. Materials and methods: Patients with brain tumors who were confirmed to have gliomas, meningiomas, or schwannomas were enrolled. Genotypes for miR-146a, miR-149, miR-196a2, and miR-499 were analyzed using the polymerase chain reaction-restriction fragment length polymorphism method. Results: Of 362 participants in this study, 183 were in the control group and 179 were in the brain-tumor group. In the analysis according to tumor type, the frequency of the dominant miR-149 genotype and CC genotype was significantly increased in glioma. The odds ratios for the CCCG, CTCG and GCTG haplotypes of miR-146aC>G, miR-149T>C, miR-196a2T>C, miR-499A>G were significantly increased in glioma, as were the GCT haplotype of miR-146aC>G, miR-149T>C, and miR-196a2T>C and the CCG haplotype of miR-149T>C, miR-196a2T>C, and miR-499A>G. In meningmioma, the odds ratios were increased with the GTCG haplotype of miR-146aC>G, miR-149T>C, miR-196a2T>C, miR-499A>G. The odds ratios were also increased in the GCG haplotype of miR-146aC>G, miR-196a2T>C, and miR-499A>G and the CCG haplotype of miR-149T>C, miR-1962T>C, and miR-499A>G. The odds ratios for schwannoma were increased in the GCTG haplotype of miR-146aC>G, miR-149T>C, miR-196a2T>C, and miR-499A>G and the CCG haplotype of miR-149T>C, miR-196a2T>C, and miR-49A>G. Conclusion: Our results suggested that the miR-149 polymorphism might be involved in the development of gliomas and the CCG haplotype of miR-149T>C, miR-196a2T>C, and miR-499A>G had an increased odd ratios for all types of brain tumors in Koreans. Funding source: This research was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI14C1627)
Allegations of Failure to Obtain Informed Consent in Spinal Surgery Medical Malpractice Claims
Authors: Jennifer Grauberger, Panagiotis Kerezoudis, Asad J. Choudhry, Mohammed Ali Alvi, Ahmad Nassr, Bradford Currier, Mohamad Bydon
Journal: JAMA Surgery (2017)

Predictive factors associated with increased risk of medical malpractice litigation have been identified, including severity of injury, physician sex, and error in diagnosis. However, there is a paucity of literature investigating informed consent in spinal surgery malpractice.
P04.25 Susceptibility-weighted MRI to predict recurrence of glioblastoma
Authors: K. van Leyen, J. Berberat, L. Remonda, U. Roelcke
Journal: Neuro-Oncology (2017)

Introduction: The prognosis of glioblastoma (GBM) has been improved by new surgical techniques, optimized radiation and systemic therapy regimen. It becomes all the more important to define surrogate markers for assessment of treatment response and tumor progression. Response Assessment in Neurooncology (RANO) criteria in GBM rely on the measurement of perpendicular tumor diameters on contrast-enhanced T1-MRI. Microbleeds represent a hallmark of GBM and can be detected by ­susceptibility-weighted MRI (SWI-MRI). The limitations of the RANO criteria led us to investigate whether SWI-MRI can be used to assist in early detection of GBM progression. Materials and Methods: We retrospectively analysed patients with newly diagnosed GBM treated with surgery, concomitant radiation therapy with temozolomide-chemotherapy (TMZ-CT) and adjuvant TMZ-CT. We included only patients who remained stable after completion of the 6 cycles of adjuvant TMZ-CT but progressed thereafter. MRI scans of 5 different points in time were analysed: pre-operatively, after the 3rd and 6th cycle of TMZ-CT, last MRI before progression and at progression (RANO). The number of SWI positive tumor pixels was measured by region-of-interest analysis, and was compared between the different time points and with contrast-enhanced T1-MRI. Results: 18 patients were enrolled. The progress of SWI positivity during the course of the disease of each patient was analysed. Statistical analysis demonstrated no significant change between the 3rd and 6th TMZ-CT cycle. However, we found a significant difference (p<0.05) in the number of SWI positive pixels between the MRI after the 6th TMZ-CT cycle and the last MRI before progression, the latter being still defined as stable disease according to RANO criteria. Conclusions: Increases of SWI positivity precede T1-MRI changes at progression. This suggests that the occurrence of microbleeds as surrogate of angiogenic activity could be used as early indicator of tumor progression. This hypothesis should be addressed in a prospective study. If confirmed we recommend SWI-MRI as part of routine MRI examination in the follow-up of patients with GBM.
P08.34 Targeting glioma stem cells with interferon-β
Authors: B. Lohmann, E. Szabo
Journal: Neuro-Oncology (2017)

Glioblastoma is the most common malignant primary brain tumor in adults. Despite surgery, radiotherapy and chemotherapy, patients suffering from this tumor have a poor prognosis with a median survival still limited to approximately one year in population-based studies. Current standard of care is only moderately effective and patients eventually all succumb to their disease. Therefore, the main effort in the field consists in finding new and better therapies based on increasing knowledge of the complex tumor microenvironment and the signalling pathways that drive this devastating disease. A population of cells within the tumor with stem cell features, now commonly referred to as “glioma-initiating cells” (GIC), has been attributed a central role in the escape of glioblastomas from the current clinical approaches of radio- and chemotherapy. We have recently demonstrated that long-term glioma cell lines (LTC) as well as GIC cultures express receptors for interferon (IFN)-β, IFNAR1 and IFNAR2, and respond to IFN-β with induction of STAT-3 phosphorylation and MxA protein accumulation. Single exposure to IFN-β inhibits cell cycle progression, induces a minor loss of viability, and strongly interferes with sphere formation in GIC cultures. Modelling acquired IFN-β resistance in GIC in vitro induces a stable resistant phenotype defined by clonogenic survival assays which allows to identify resistance mechanisms in more detail. Transcriptomic and proteomic profiling of IFN-β-treated GIC in vitro already revealed candidate molecules potentially mediating these biological responses. We also examined the anti-glioma activity of type I interferons in clinically relevant orthotopic xenogeneic animal models in vivo. Treatment with the more stable pegylated IFN-β significantly prolongs survival in the LN-229 and ZH-161 mouse models. In vivo, IFN-β induces a significant increase in MxA expression in the tumor cells but does not change vessel density. Since IFN-β is widely used for the treatment of human patients with multiple sclerosis, there is considerable knowledge on its safety in patients with brain disease, allowing for rapid translation of novel IFN-β-based strategies into the clinic.
Short-Form Charlson Comorbidity Index for Assessment of Perioperative Mortality After Radical Cystectomy
Authors: Paolo Dell'Oglio, Zhe Tian, Sami-Ramzi Leyh-Bannurah, Vincent Trudeau, Alessandro Larcher, Marco Moschini, Ettore Di Trapani, Umberto Capitanio, Alberto Briganti, Francesco Montorsi, Fred Saad, Pierre I. Karakiewicz
Journal: Journal of the National Comprehensive Cancer Network (2017)

Background: The Deyo adaptation of the Charlson comorbidity index (DaCCI), which relies on 17 comorbid condition groupings, represents one of the most frequently used baseline comorbidity assessment tools in retrospective database studies. However, this index is not specific for patients with bladder cancer (BCa) treated with radical cystectomy (RC). The goal of this study was to develop a short-form of the original DaCCI (DaCCI-SF) that may specifically predict 90-day mortality after RC, with equal or better accuracy. Patients and Methods: Between 2000 and 2009, we identified 7,076 patients in the SEER-Medicare database with stage T1 through T4 nonmetastatic BCa treated with RC. We randomly divided the population into development (n=6,076) and validation (n=1,000) cohorts. Within the development cohort, logistic regression models tested the ability to predict 90-day mortality with various iterations of the DaCCI-SF, wherein <17 original comorbid condition groupings were included after adjusting for age, sex, race, T stage, and N stage. We relied on the Akaike information criterion to identify the most parsimonious and informative set of comorbid condition groupings. Accuracy of the DaCCI and the DaCCI-SF was tested in the external validation cohort. Results: Within the development cohort, the most parsimonious and informative model resulted in the inclusion of 3 of the 17 (17.6%) original comorbid condition groupings: congestive heart failure, cerebrovascular disease, and chronic pulmonary disease. Within the validation cohort, the accuracy was 68.4% for the DaCCI versus 69.7% for the DaCCI-SF. Higher accuracy of the DaCCI-SF was confirmed in subgroup analyses performed according to age (≤75 vs >75 years), stage (organ-confined vs non–organ-confined), type of diversion (ileal-conduit vs non–ileal-conduit), and treatment period. Conclusions: DaCCI-SF relies on 17.6% of the original comorbid condition groupings and provides higher accuracy for predicting 90-day mortality after RC compared with the original DaCCI, especially in most contemporary patients.
The utility of clinical pathways (CP) in managing quality and cost in an oncology network.
Authors: Peter G. Ellis, Bert H. O'Neil, Martin F. Earle, Stephanie McCutcheon, Hans Benson
Journal: Journal of Clinical Oncology (2015)

e17778 Background: UPMC CancerCenter utilizes the Via Pathways (VP) for their CP initiative. VP are developed and maintained by evaluating therapies on merit of efficacy, then toxicity, and finally cost (if efficacy and toxicity are comparable) to provide a recommendation for specific patient presentations. Recent data from key studies regarding the use of panitumumab (PAN) or cetuximab (CET) in the setting of metastatic colo-rectal cancer by the colo-rectal committee led to the determination that both treatments were equally effective with no significant difference in toxicity. A subsequent cost comparison utilizing CMS average sales prices demonstrated a 15% monthly cost advantage for PAN. A substitution of PAN for CET across all metastatic lines of therapy in the pathway was initiated as of August 2014. This analysis was undertaken to understand the impact of this change. Methods: We reviewed the UPMC data within the VP database and compared new treatment starts of CET and PAN before and after this change was put in place. Results: There was rapid change in the selection behavior between the two drugs as demonstrated in the table. Conclusions: The results in this simple example of substituting equivalent drugs based on cost exemplify the power of a pathways system to rapidly change prescribing habits across a large integrated network. Pathways serve as an invaluable tool to allow oncology practices to respond to the rapidly changing treatment norms of oncology care. New Treatments Starts Containing 2014 Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec n 22 12 14 5 9 17 11 5 12 20 11 10 Cetuximab 13 (59%) 10 (83%) 14 (100%) 5 (100%) 8 (89%) 16 (94%) 11 (100%) 3 (60%) 3 (25%) 5 (25%) 1 (9%) 3 (30%) Panitumumab 9 (41%) 2 (17%) 0 (0%) 0 (0%) 1 (11%) 1 (6%) 0 (0%) 2 (40%) 9 (75%) 15 (75%) 10 (91%) 7 (70%)
P01.34 Gene expression of mitotic drivers TPX2 and RAN is upregulated dependent on meningioma grade and correlates with MIB-1 labeling index
Authors: S. Telentschak
Journal: Neuro-Oncology (2017)

OBJECTIVE: There is still no effective chemotherapy regimen for malignant meningiomas. Numerous studies on different malignancies indicate that Ran (Ras-related nuclear protein), some components of its pathway and TPX2 (Targeting protein for Xenopus kinesin-like protein 2) are involved in tumorigenesis, cancer progression and tumor cell survival. Mitotic spindle formation is regulated Ran-dependently by TPX2. Due to its Ran-regulated transportation into the nucleus, TPX2 promotes DNA damage response. To evaluate a potential role of TPX2 and Ran pathway in meningiomas we measured their gene expression in different tumor types. METHODS: Using quantitative RT-PCR, gene expression was analyzed in 77 meningiomas including WHO I° (n=27), II° (n=31), III° (n=19) and 10 brain tissues as control. MIB-1 labeling indices were obtained from histopathology reports. Results were depicted by mean values (±SEM) in Arbitrary Units. Statistical analysis was performed using Mann-Whitney U test, Kruskal Wallis test with post hoc analysis, Spearman’s correlation and Receiver Operator Characteristics (ROC) analysis. A value of P<0.05 was considered significant. Results: Significant TPX2 gene overexpression compared to control (0.42 ± 0.12) was detected in all meningioma WHO grades (I°: 0.91 ± 0.15; II°: 1.93 ± 0.28; III°: 4.33 ± 0.67). With increasing WHO grade there was a steady increase of TPX2 (P<0.01). RAN was significantly overexpressed in WHO III° (2.42 ± 0.29) versus control (1.45 ± 0.12) and showed a significant rise from WHO I° to III° and from II° to III°. Spearman’s correlation of RAN and TPX2 was moderate in first diagnosed tumors (r=0.518, P=0.003). In ROC analysis, TPX2 showed predictive properties as biomarker differentiating WHO I° from II°, II° from III° and I° from III° with the areas under the curve of 0.725, 0.791 and 0.912, respectively (each P<0.01). MIB-1 labeling index correlated highly with TPX2 (r=0.865) and moderately with RAN (r=0.619) as well as with Ran pathway components RAN-BP1 (r=0.639) and RCC1 (r=0.675). CONCLUSION: TPX2 and RAN were significantly overexpressed in malignant meningioma and correlated with MIB-1. This could implicate them as potential driving force for malignant transformation. Therefore, TPX2 and components of Ran pathway may represent future markers for diagnosis and prognosis as well as targets for chemotherapy in malignant meningioma.
Abstract 354: Prostaglandin D <sub>2</sub> -F Type Prostanoid Receptor Signaling Is a Novel Cardiomyocyte Survival Pathway
Authors: Yoshinori Katsumata, Motoaki Sano, Tomohiro Matsuhashi, Atsushi Anzai, Cardex Yan, Kentaro Ito, Ken Shinmura
Journal: Circulation Research (2012)

Background: Lipocalin-type prostaglandin D synthase (L-PGDS) is abundantly expressed on cardiomyocytes. We recently demonstrated that dexamethasone stimulates PGD 2 -dominated activation of prostanoid biosynthesis, thereby protecting hearts against ischemia/reperfusion injury. Here, we examined the downstream signaling responsible for cardioprotection mediated through PGD 2 -dominated activation. Methods and Results: (1) In cultured neonatal rat cardiomyocytes, PGD 2 strongly activates ERK in a dose-dependent manner, although canonical PGD 2 receptors, including DP (PGD 2 receptor) and CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) receptors, are hardly expressed on cardiomyocytes. (2) Interestingly, PGD 2 bounds to FP receptor (the canonical PGF 2 α receptor) with an affinity comparable to that for the DP receptor, and the FP receptor is abundantly expressed on cardiomyocytes. (3) PGD 2 -induced ERK activation is completely blocked by FP antagonist or siRNA-mediated knockdown of the FP, but not by DP and CRTH2 antagonist and siRNA-mediated knockdown of DP and CRTH2. (4) PGD 2 activates ERK in Langendorff perfused DP-knock out (KO) and CRTH2-KO mice hearts to comparable levels as those observed for wild-type hearts, while cannot activate it in FP-KO hearts. (5) Consistently, the cardioprotective effect of PGD 2 -dominated activation by dexamethasone was blunted in FP KO hearts. (6) Furtermore, genomewide gene expression profiles by microarray analysis and quantitative real-time RT-PCR analysis identified that Nrf-2 was the downstream target of L-PGDS-mediated PGD 2 biosynthesis. (7) In cultured cardiomyocytes, FP agonist stimulated Nrf2 nuclear translocation and consequently induced Nrf2-target genes expression in an ERK-dependent manner. (8) Finally, The cardioprotective effect by dexamethasone was completely abolished in Nrf-2 KO hearts. Conclusion: FP serves as a functionally relevant PGD 2 receptor in the hearts and PGD 2 -FP signaling plays a substantial role in the improvement of functional recovery after ischemia-reperfusion injury in the heart. Nrf-2 is a major effector molecule responsible for the cardioprotecton elicited by L-PGDS-derived PGD 2 .
VEBEP regimen and highly active antiretroviral terapy (HAART) in patients (pts) with HD and HIV infection (HD-HIV)
Authors: M. Spina, G. Rossi, A. Antinori, B. Allione, M. Fasan, G. Rizzardini, U. Tirelli
Journal: Journal of Clinical Oncology (2007)

8083 Background: The outcome of pts with HD-HIV is still poor, mainly because the duration of complete remission (CR) is short. To improve the prognosis of HD-HIV, a feasibility study with the third generation VEBEP regimen (developed at the NCI, Milan) and radiotherapy and concomitant HAART was started in previously untreated HD-HIV pts within the GICAT (Italian Cooperative Group on AIDS and Tumors). Methods: CT included epirubicin 30 mg/m 2 /day (days 1–3), cyclophosphamide 1,000 mg/m 2 (day 1), vinorelbine 25 mg/m 2 (day 1), bleomycin 10 mg/m 2 (day 3) and prednisone 100 mg/m 2 /day (days 1–3), every 3 weeks. Results: Between September 2001 and June 2006, 43 pts have been enrolled. The median age was 39 yrs. The median CD4 + cell count at entry was 269/mm 3 (range 44–887) and 24 pts had a detectable HIV viral load (median 12780 copies/mm 3 , range 89-&gt;500,000). Stage III and IV disease was present in 30/43 (70%) pts. Histologic subtypes were: MC 72%, NS 16%, LD 5%, LP 2%, and unknown 5%. One toxic death, due to hepatic failure in a HCV positive pt was observed. An absolute neutrophil count &lt;500 was noted in 21/43 pts (49%). Grade 3–4 anemia was observed in 12/43 pts (28%) and severe thrombocytopenia in 6/43 pts (12%). Thirteen pts (30%) had febrile neutropenia with 10 documented infections in 8 pts (2 bacterial pneumonia, 2 bacterial sepsis, 2 varicella, one PCP, one cerebral toxoplasmosis, one salmonellosis, one prostatitis). A grade 2–3 mucositis was observed in 9/43 pts (21%). CR was obtained in 33/43 pts (76%) and PR in 5/43 pts (12%). With a median follow up of 30 months, only 3 pts have relapsed (9%). OS and TTF at 30 months are 80% and 66%, respectively. Conclusions: Our preliminary data demonstrate that VEBEP regimen in combination with HAART is less toxic and as active as Stanford V regimen in pts with HD-HIV. This study was supported by ISS grants. No significant financial relationships to disclose.
P08.24 Metallothinein 1E enhances glioma invasion through modulation MMP-2 and MMP-9 in mouse brain tumor model
Authors: S. JUNG, H. Hur
Journal: Neuro-Oncology (2017)

Malignant glioma cells invading surrounding normal brain are inoperable and resistant to radio- and chemotherapy, and eventually lead to tumor regrowth. Identification of genes related to motility is important for understanding the molecular biological behavior of invasive gliomas. According to our previous studies, Metallothionein 1E (MT1E) was identified to enhance migration of human malignant glioma cells. The purpose of this study was to confirm that MT1E could modulate glioma invasion in vivo. Firstly we established 2 cell lines; MTS23, overexpressed by MT1E complementary DNA construct and pV12 as control. The expression of matrix metalloproteinases (MMP)-2, -9 and a disintegrin and metalloproteinase 17 were increased in MTS23 compared with pV12. Furthermore it was confirmed that MT1E could modulate MMPs secretion and translocation of NFkB p50 and B-cell lymphoma-3 through small interfering ribonucleic acid knocked U87MG cells. Then MTS23 and pV12 were injected into intracranial region of 5 week old male nude mouse. After 4 weeks, for brain tissues of these two groups, histological analysis, and immunohistochemical stain of MMP-2, 9 and Nestin were performed. As results, the group injected with MTS23 showed irregular margin and tumor cells infiltrating the surrounding normal brain, while that of pV12 (control) had round and clear margin. And regrowth of tumor cells in MTS23 group was observed in another site apart from tumor cell inoculation. MT1E could enhance tumor proliferation and invasion of malignant glioma through regulation of activation and expression of MMPs.
P09.60 Determination of different tumors regions by quantitative MRI methods in glioblastoma
Authors: J. Tichy, S. Lescher, U. Noeth, R. Deichmann, L. Weise, E. Hattingen, O. Bähr
Journal: Neuro-Oncology (2017)

BACKGROUND: Recently, many innovative MRI methods were generated to visualize different physiological and tumor biological aspects like the tumor microenvironment including the tumor oxygenation. In this study we want to generate diverse reference ranges of tumor regions in untreated glioblastoma patients. Standard values of quantitative MR imaging in these patients do not yet exist. METHODS: In this prospective study, we included 52 patients with a cerebral mass lesion who are radiologically suspicious for glioblastoma (GBM). Before patients underwent histological validation they received a conventional and a quantitative MRI (qMRI). The diagnosis was proven by stereotactic biopsy. Different areas of the presumably normal brain or the tumor were selected and the average value of the certain area was detected. Results: Mean values of quantitative T1 und T2 maps in milliseconds (ms) were determined in 35 histopathologically proven GBM cases. Therefore, reference ranges for different areas (enhancing tumor, peritumoral edema, necrosis and contralateral, healthy control region) were recorded. We detected significantly prolonged qT1 and qT2 relaxation times in all tumor regions compare to the healthy control region. CONCLUSION: With our data different regions of the tumor are distinguishable by quantitative values. Correlations with histopathologic analysis are ongoing.