tbuckley/cabot-search huggingface dataset:
Ribonucleotide Reductase Catalytic Subunit M1 (RRM1) as a Novel Therapeutic Target in Multiple Myeloma
Authors: Morihiko Sagawa, Hiroto Ohguchi, Takeshi Harada, Mehmet K. Samur, Yu-Tzu Tai, Nikhil C. Munshi, Masahiro Kizaki, Teru Hideshima, Kenneth C. Anderson
Journal: Clinical Cancer Research (2017)

Abstract Purpose: To investigate the biological and clinical significance of ribonucleotide reductase (RR) in multiple myeloma. Experimental Design: We assessed the impact of RR expression on patient outcome in multiple myeloma. We then characterized the effect of genetic and pharmacologic inhibition of ribonucleotide reductase catalytic subunit M1 (RRM1) on multiple myeloma growth and survival using siRNA and clofarabine, respectively, in both in vitro and in vivo mouse xenograft models. Results: Newly diagnosed multiple myeloma patients with higher RRM1 expression have shortened survival. Knockdown of RRM1 triggered significant growth inhibition and apoptosis in multiple myeloma cells, even in the context of the bone marrow microenvironment. Gene expression profiling showed upregulation of DNA damage response genes and p53-regulated genes after RRM1 knockdown. Immunoblot and qRT-PCR analysis confirmed that γ-H2A.X, ATM, ATR, Chk1, Chk2, RAD51, 53BP1, BRCA1, and BRCA2 were upregulated/activated. Moreover, immunoblots showed that p53, p21, Noxa, and Puma were activated in p53 wild-type multiple myeloma cells. Clofarabine, a purine nucleoside analogue that inhibits RRM1, induced growth arrest and apoptosis in p53 wild-type cell lines. Although clofarabine did not induce cell death in p53-mutant cells, it did trigger synergistic toxicity in combination with DNA-damaging agent melphalan. Finally, we demonstrated that tumor growth of RRM1-knockdown multiple myeloma cells was significantly reduced in a murine human multiple myeloma cell xenograft model. Conclusions: Our results therefore demonstrate that RRM1 is a novel therapeutic target in multiple myeloma in the preclinical setting and provide the basis for clinical evaluation of RRM1 inhibitor, alone or in combination with DNA-damaging agents, to improve patient outcome in multiple myeloma. Clin Cancer Res; 23(17); 5225–37. ©2017 AACR.
Abstract 355: Systems Epigenomics of Chromatin Structure in the Heart
Authors: Sarah Franklin, Haodong Chen, Elaheh Karbassi, Emma Monte, Thomas M Vondriska
Journal: Circulation Research (2012)

Except during metaphase, endogenous chromatin structure is unknown. DNA - invariant between cells - and the cell type-specific modifiers of the genome establish chromatin structural features, both local (e.g. at the scale of individual nucleosomes) and global (e.g. chromosomal territories). A fundamental question is how these cell type-specific modifiers, including DNA modification, non-coding RNAs, and proteins, establish the chromatin environment conducive to gene expression for the correct cell type: in cardiac muscle, how is the genome structurally poised to confer cardiac (and not, say, renal) transcriptomes and proteomes, and what physical reprogramming events occur during disease? To address these questions, we are conducting a systems analysis of the epigenetic features of the healthy and diseased heart. In adult mice, we have used quantitative mass spectrometry to dissect distinct fractions of the nucleus and reveal the itineraries of chromatin structural proteins, enzymatic nucleosome remodelers, histone molecules and histone post-translational modifications. These studies have revealed rules for global reprogramming of gene expression, which involve altered abundance of non-histone chromatin structural proteins, a shift from hetero- towards euchromatic post-translational marks and a decreased linker to core histone ratio in heart failure. Furthermore, interrogation of genome-wide binding patterns of known cardiac transcription factors within the genes that encode proteins operative in cardiac genomic structure reveals hierarchical relationships between these protein, transcript and gene networks. Complementary investigations in isolated myocytes are characterizing the global rearrangement of chromatin following hypertrophic agonist treatment using conventional and super-resolution microscopy to directly visualize the chromatin backbone. Lastly, a combination of multiple genomic scale sequencing studies have revealed regions under control of specific chromatin structural proteins. Together, these studies aim to address the basic question of how global chromatin structure is maintained in cardiac myocytes and how diseases like heart failure result from deranged chromatin structure on a genomic scale.
P11.13 Metachronous spinal primitive neuroectodermal tumor after treatment of a hemispheric anaplastic oligodendroglioma through p53 germline mutation
Authors: R. Renda, C. Fonte
Journal: Neuro-Oncology (2017)

Introduction: Acquired mutations in the p53 tumor-suppressor gene have been detected in several human cancers, including sarcoma, colon, breast, and lung cancer. Li-Fraumeni syndrome (LFS) is a rare familial association of malignant neoplasms in children and young adults, transmitted through germline mutations of this gene. On the other hand, some families having a germ-line mutation in p53 display some, but not all features of LFS. Tumors with p53 mutation are associated with decreased survival rate, increased resistance to chemotherapy and radiation and an elevated risk to relapse. Materials and methods: We report a case of a 17-years-old male patient with no family history of malignancy, who presented with confusion, speech disorder, weakness and mood disorders. A MRI showed a large brain tumor located in the left temporo-parietal lobe. Following the debulking the histologic examination showed an anaplastic oligodendroglioma (WHO-grade III). The patient underwent radiotherapy for a total dose of 60 Gy (2 Gy/fractions, 5 fractions per week) and sequential chemiotherapy with Procarbazina, Lomustine and Vincristine according to EORTC schedule. Seven months after the end of treatmentthe boy developed leg weakness and difficulty walking. Brain MRI was negative. Because of clinical worsening, the patient underwent to spine MRI that showed the presence of intradural extramedullary spinal solid masses with contrast enhancement. The boy underwent to decompressive laminectomy (T5-T6) and partial resection of the lesion. The histopathologic evaluation of the resected tissue revealed malignant small round blue cells, such as a primitive neuroectodermal tumor. The clinical conditions deteriorated rapidly and he died within few months. Results: We performed a p53 gene analysis in the two metachronous primary lesions of our patient A novel germline p53 splicing mutation was identified.. Both tumors underwent PCR amplification of three segments that included exons 6-7-9 of the TP53 gene. Direct DNA sequencing of the amplified segment identified heterozygous C>T mutation in codon 742 in exon 7. Genomic DNA from the second tumor showed the same mutation and loss of heterozygosity at the p53 locus. Familial p53 testing revealed homozygous wild-type alleles. Conclusion: We detected a rare, de novo, germline p53 mutation in a patient with no family history of malignancies presenting with methachronous tumors and exhibiting a more fulminant course than typical cases of Li-Fraumeni. This case emphasizes the importance of a genetic evaluation in the setting of multiple malignancies, synchronous or methachronous, even in the absence of family history.
Use of Expanded Allogeneic Third Party BK Virus Specific Cytotoxic T Cells to Target Progressive Multifocal Leukoencephalopathy
Authors: Muharrem Muftuoglu, Sairah Ahmed, Amanda Olson, Victor Mulanovich, Li Li, Srdan Verstovsek, Indreshpal Kaur, Glorette Abueg, David Marin, Eric Yvon, Richard E. Champlin, Elizabeth J. Shpall, Katayoun Rezvani
Journal: Blood (2016)
P14.06 Central nervous system symptoms as the first manifestation of malignant neoplasm
Authors: V. Espírito Santo, R. Almendra, M. Mendes, A. Veiga, A. Velon, P. Guimarães
Journal: Neuro-Oncology (2017)

Introduction: Neurological involvement is a frequent complication of systemic neoplasm, but not all secondary lesions have clinical manifestations, and there are fewer cases in which first symptom is neurological. Materials and Methods: Retrospective study between January 2006 through November 2016 of patients in whom neurological manifestations due to metastases were the inaugural manifestation of systemic neoplasm. Results: Twenty-six patients (19 male, 7 female) between the ages of 48 and 85 were identified. The main complaints were motor deficit (n = 10), headache (n = 7), behaviour change (n = 3), sensory deficit (n = 2), language disorder (n=1), visual disorder (n=1), syncope (n = 1) and dizziness (n = 1), with 11 patients presenting with symptoms other than the main complaint. Twenty-four patients had brain metastases, in 9 patients, it was solitary, in 5 patients, 2 lesions were found and in the remaining 9, 3 or more lesions were found. Two patients had multiple spinal metastases and 1 patient presented meningeal carcinomatosis. The primary neoplasm were of pulmonary origin (n = 17), gastric (n = 1), prostatic (n = 1), rectal (n = 1) and skin (n=1). In 5 patients the primary lesion remained hidden. Histology results were available in 19 patients: adenocarcinoma (n = 13), small cell carcinoma (n = 3), spinous cell carcinoma (n = 1), melanoma (n = 1) and linitis plastica (n=1). The treatment consisted in corticosteroid treatment (n = 23), chemotherapy (n = 11), radiotherapy (n = 11), surgery (n = 2) and hormonal treatment (n = 1). The mean survival was 225 days, ranging from 9 to 801 days. Conclusions: With this work we verified a broad spectrum of central nervous system symptoms as clinical presentation of malignant neoplasm. In these cases, a detailed investigation is essential for the treatment and prognosis of these patients.
P09.08 Hypofractionated versus standard radiotherapy with or without temozolomide for elderly patients with glioblastoma
Authors: P. Gkogkou, S. Hamm, K. Geropantas, T. Ajithkumar, S. Jefferies
Journal: Neuro-Oncology (2017)

Introduction: The optimal management of patients aged ≥ 65 years with newly diagnosed glioblastoma (GB) is evolving. In the UK, hypofractionated radiotherapy (HRT: 30 Gy in 6 fractions over 2 weeks) has been the standard of care for individuals aged >70 years with PS=0-1, any age with PS≥2, and/or multifocal tumours. Occasionally, patients aged >70 years with PS 0-1 and no medical comorbidities may be considered for standard radiotherapy (SRT - 60 Gy in 30 fractions over 6 weeks) with or without temozolomide (TMZ). Materials and methods: In this retrospective study we analysed the outcome of radiotherapy for patients aged ≥ 65 years with glioblastoma treated between 2009 and 2015. Survival was calculated the Kaplan -Meier method. Differences in patient- and disease-related factors between the HRT and SRT groups were compared using the Fisher exact test. The Cox-proportional hazard regression analysis was used to correlate these factors with survival. Results: Patients received HRT (n=45), SRT (n= 8) or SRT with TMZ (n=15). The median age was 71.5 years (range: 65 to 83 years). 30 patients were aged 65-70 years and 38 were >70 years. 35 patients underwent debulking surgery and the remaining had either a biopsy (n=29) or a radiological diagnosis (n=4). 21 patients had multifocal disease. Patients receiving HRT were significantly older (median age 75 years vs. 69 years, p=0.003), had worse PS (≥2) (p=0.000), and the majority had only a biopsy or radiological diagnosis (p=0.021), compared with those receiving SRT with or without temozolomide Patients who received SRT+/-TMZ had a better median overall (11 vs. 5 months; p=0.000) and progression-free survival (9 vs. 3 months, p=0.040) compared with patients who received HRT. The corresponding 1-year OS for both groups were 43.5% and 6.7% respectively. On univariate analysis, overall survival correlated with PS (HR=0.42, 95% CI:0.24-0.74), multifocality (HR=2.07, 95% CI 1.21-3.55), and age (HR=0.96, 95% CI: 0.99-1.09), but not with the extent of resection (HR=1.44, 95% CI 0.95-2.18). MGMT methylation status was not available for all patients and therefore, not analysed. CONCLUSION: SRT with or without TMZ may improve survival in selected patients aged ≥ 65 years with newly diagnosed glioblastoma. The survival of patients treated with SRT+/-TMZ in our cohort is better than that of patients treated with chemo-radiotherapy in the recently published EORTC 26062-22061 study. An individualised-approach should be favoured over a one-fits-all strategy in the management of elderly patients with glioblastoma.
The Microbiota: A New Variable Impacting Cancer Treatment Outcomes
Authors: Jessica L. Fessler, Thomas F. Gajewski
Journal: Clinical Cancer Research (2017)

Abstract Preclinical evidence has established that the host commensal microbiota can contribute to therapeutic response in cancer models, a finding supported by early clinical data. This connection between the microbiome and clinical outcome in oncology is cause for new consideration in the administration of antibiotics and microbiota-modulating interventions to improve outcomes. Clin Cancer Res; 23(13); 3229–31. ©2017 AACR. See related article by Galloway-Peña et al., p. 3263
P16.01 Surgery for recurrent high grade glioma after treatment with bevacizumab
Authors: D. T. Blumenthal, F. Bokstein
Journal: Neuro-Oncology (2017)

Bevacizumab is a monoclonal antibody to vascular endothelial growth factor (VEGF) which is FDA-approved for the treatment of recurrent glioblastoma. There is some evidence for bevacizumab inducing a treatment-resistant tumor phenotype, by selecting for more infiltrative cells which can subsist without angiogenesis through mechanisms such as cooption of existing blood vessels. Genomic changes may be induced by treatment with bevacizumab, which promote invasion and resistance. While a fraction of recurrent high grade gliomas may be amenable to re-resection, this number is further reduced following treatment with bevacizumab, for several reasons: one, that the tumor is often at an advanced stage after failing bevacizumab, and the patient’s performance status may not be amenable to surgical intervention; two, the tumor may have progressed to a more diffuse and infiltrative phenotype; and three, bevacizumab treatment may increase surgical risks of infections and wound complications, as anti-angiogenic drugs can interfere with the process of wound healing and lead to dehiscence. We report a series of 15 patients, 6 female and 9 male, who underwent tumor resection for recurrent high grade glioma at our center, following progression on bevacizumab treatment. The cohort consists of 12 primary glioblastomas (including one gliosarcoma); 2 secondary glioblastomas transformed from lower grade gliomas; and one anaplastic oligodendroglioma. The mean age of patients was 40 (18-73). Patients were treated with an average of 1.8 therapy lines for recurrent/progressive tumor (including re-operation) before receiving bevacizumab. Median overall survival from time of tumor diagnosis was 21.8 months (7.6-82.0) and median survival from post-bevacizumab surgery was 4.9 months (1.1-19.1). Post-surgical complications included 3 incidences of hemorrhage requiring surgical evacuation and 3 incidences of wound dehiscence or infection, requiring intervention. We did not see overt changes in histopathology or tumor vasculature in tumors resected after treatment with bevacizumab, compared to original samples at diagnosis. We will present detailed data on complications, imaging, and histopathologic findings, comparing pre-bevacizumab to post- bevacizumab samples.
Benefits and Risks of Screening Mammography in Women With BRCA1 and BRCA2 Mutations
Authors: Estelle Gilson
Journal: JAMA (1997)

<h3>To the Editor.</h3> —As a writer on the subject of<i>BRCA1</i>and<i>BRCA2</i>mutations,<sup>1</sup>I read the Consensus Statement "Recommendations for Follow-up Care of Individuals With an Inherited Predisposition to Cancer: II.<i>BRCA1</i>and<i>BRCA2"2</i>with particular interest and find the recommendations inconsistent and troublesome. The paragraph in the abstract headed "Conclusions" (page 997) states, "Based on expert opinion concerning presumptive benefit, early breast cancer and ovarian cancer screening are recommended for individuals with<i>BRCA1</i>mutations and early breast cancer screening for those with<i>BRCA2</i>mutations.<sup>"</sup> The paragraph headed "Mammography" (page 999) states, "There is a potential increased risk of breast cancer when mammography is started at an early age, and this risk may be greater in individuals with an inherited cancer predisposition than in women of average risk." Further, the authors state that for this population there is a "likelihood that mammography screening provides benefit, although there are
OS01.5 Development of TERT-targeting therapy using eribulin mesylate in mouse glioblastoma model
Authors: M. Takahashi, S. Miki, K. Fukuoka, M. Yasukawa, M. Hayashi, A. Hamada, A. Mukasa, R. Nishikawa, K. Tamura, Y. Narita, K. Masutomi, K. Ichimura
Journal: Neuro-Oncology (2017)

Introduction: Despite of recent extensive genome analysis, no effective molecular targeting therapy has been successfully developed in patients with glioblastomas (GBMs). Approximately 60–80% of GBM harbour mutations in the promoter region of telomerase reverse transcriptase (TERT) that leads to upregulation of its protein production, making it the most common single genetic abnormalities in GBM. TERT has been an attractive candidate for molecular targeting therapy because of their observed upregulation in a wide variety of cancers, including GBMs, a phenomenon that presumably helps maintain telomeres for their indefinite proliferation. It has been reported recently that TERT has an RNA-dependent RNA polymerase (RdRP) activity, with which TERT is involved in maintenance of stem cell phenotype and mitotic progression. We have previously identified eribulin as a specific inhibitor of RdRP activity of TERT through drug screening and shown that eribulin suppressed growth of ovarian cancers with high TERT expression. In order to validate an efficacy of eribulin as a novel TERT-targeting therapy against GBM, we investigated the anti-tumor effect of eribulin in cultured cell and mouse brain tumor model using GBM cell lines. Methods: The TERT promoter status was examined in 20 glioma cell lines. Seven cell lines were subjected to in vitro cytotoxicity assay. U87MG cells were either subcutaneously or intracranially transplanted in athymic mice. Tissue or plasma concentration of eribulin was measured by LC-MS/MS. Results: All GBM cell lines tested that harboured TERT promoter mutations including U87MG, U251MG, U118MG as well as several patient-derived glioblastoma sphere culture cells were highly sensitive to eribulin, IC50 below 1nM. Intraperitoneal administration of eribulin completely suppressed the growth of U87MG subcutaneous tumors in athymic mice, and the RdRP activities in treated tumors were significantly decreased in a dose-dependent manner. In U87MG brain tumor model, a high concentration of eribulin was detected in the brain tumour tissues as early as 15 minutes after intravenous injection of eribulin, which remained stable even 24 hours later when the plasma concentration of eribulin became undetectable. Finally, intraperitoneal administration of eribulin significantly prolonged the survival of mice with intracranially transplanted U87MG xenograft (p<0.001). Conclusion: Our results showed that eribulin efficiently transfers into brain tumour tissues and has a strong anti-tumour effect against GBM cells through inhibition of RdRP activity. Eribulin thus appears to be a promising novel TERT-targeting therapeutic agent against GBM. A clinical trial is being scheduled.
P08.06 Convection-enhanced delivery of theranostic microbubbles brain tumor therapy
Authors: P. Chen, C. Yeh, C. Lin, C. Huang, K. Wei, H. Liu
Journal: Neuro-Oncology (2017)

Introduction: Convection-enhanced delivery (CED) is a useful procedure for infusing a therapeutic agent through a cannula with a pressure gradient to create continuous flow for improving agent spread into the brain. So far, gadopentetate dimeglumine (Gd-DTPA) is the most frequently applied coinfusion agent for predicting drug distribution under magnetic resonance imaging (MRI). However, Gd-DTPA provides only brief observation duration, and concurrent infusion provides an indirect estimate of the exact drug distribution. Here, we propose using microbubbles as a contrast agent for distribution monitoring under MRI, and evaluate the possibility of their use as a drug-loaded vehicle to monitor the infused drug directly. Material and Methods: lipid-based microbubbles loaded with doxorubicin (MB-Dox) were synthesized. Cytotoxicity of MB-Dox was evaluated both in vitro and in vivo. Optimized R2 relaxometry of MRI was accomplished to reveal the contrast capacity and pharmacokinetics of MB-Dox through CED in brain. U87MG xenograft-bearing mice were organized for efficacy study. Results: It shows that MB-Dox can provide great detectability through MRI relaxometry and correctly represent drug distribution after CED infusion. Compared with the short half-life of Gd-DTPA (1–2 hours), microbubbles allow an elongated observation period of up to 12 hours. Moreover, microbubbles provide a sufficiently high drug payload, Thus glioma mice that underwent a CED infusion of MB-dox presented significant tumor growth suppression and a appreciably improved survival rate. Conclusions: This study recommends drug-loaded microbubbles is a great theranostic tool for CED procedures. This study is supported by Center for Advanced Molecular Imaging and Translation, Chang Gung Memorial Hospital for equipments and Ministry of Science and Technology, Taiwan (102-2314-B-182-067-MY3, 101-2221-E-182-002-MY3).
P11.11 The assessment of intellectual development in children with pediatric craniopharyngioma
Authors: T. Oyoshi, S. Fujio
Journal: Neuro-Oncology (2017)

Introduction: Intellectual assessment in children with craniopharyngioma after tumor removal is still unknown. We assessed the treatment results, outcomes and intellectual development in children who underwent microsurgical resection for pediatric craniopharyngioma in our institute over the last decade. Materials and Methods: Ten children among 54 patients with craniopharyngioma treated and followed at Kagoshima University Hospital between 2007 and 2016 were reviewed. We reviewed treatment results and outcomes, and also assessed intellectual development in children with craniopharyngioma one year after tumor removal. Intelligence was assessed using the Wechsler Intelligence Scale for Children-Fourth Edition (WISC-IV). Results: Eight children out of ten underwent microsrgical near-total removal. The mean age at surgery was 5.8 (range 1-10) years. Transcranial approach was performed in 8 children, transsphenoidal approach in two children. The mean follow up period was 73 (range 1-118) months. Gamma knife surgery (GKS) was performed in 4 children less than 6 months after first surgery, Regional recurrences occurred in 5 children, and additional GKS was performed in four children, second microsurgical removal in one child. Severe obesity with a transient electrolyte imbalance occurred in one child. Five children with GH deficiency underwent GH replacement therapy (GHRT). Nine children out of ten were assessed working memory index (WMI), processing speed index (PSI), and Perceptual reasoning index (PRI) using WISC 4. Each mean value of WMI, PSI, and PRI was lower than mean verbal comprehension index (VCI), except for 2 children with normal full scale intelligence quotient (FSIQ). CONCLUSION: WMI, PSI and PRI in children with intellectual disabilities were lower tendency than VCI after surgical removal of craniopharyngiomas in the present study.