tbuckley/cabot-search huggingface dataset:
OS07.2 Bevacizumab plus hypofractionated radiotherapy versus radiotherapy alone in elderly patients with glioblastoma: the ARTE trial
Authors: H. G. Wirsching, G. Tabatabai, A. Hottinger, L. Plasswilm, U. Roelcke, K. Conen, L. Held, E. J. Rushing, A. Ochsenbein, M. Weller
Journal: Neuro-Oncology (2017)

BACKGROUND: Two phase III trials of bevacizumab (BEV) in newly diagnosed glioblastoma demonstrated prolonged progression-free survival (PFS), but failed to prolong overall survival (OS). Retrospective reports and early phase trials of bevacizumab in glioblastoma patients emphasized that benefit was preferentially seen in frail or elderly patients, but such patients are underrepresented in most clinical trials. Here, we report the outcome of an elderly population with newly diagnosed glioblastoma randomized to receive hypofractionated radiotherapy alone or in combination with bevacizumab. METHODS: ARTE (NCT01443676) is a 2-arm, 2:1 randomized, parallel group, explorative, open-label trial of hypofractionated radiotherapy (RT) (15 x 2.66 Gy = 40 Gy) in combination with intravenous BEV every two weeks until progression (BEV+RT) versus RT alone. Major inclusion criteria included age 65 years or older, newly diagnosed glioblastoma, and Karnofsky performance score of 60 or more. An amendment (11/2013) requested demonstrating the absence of O6-methylguanine DNA methyltransferase (MGMT) promoter methylation when it became clear that MGMT promoter methylation predicted larger benefit from temozolomide alone than from radiotherapy alone in patients with glioblastoma aged 65 years or older. Cognitive functioning was monitored by Mini Mental Status Examination and quality of life by utilizing the EORTC QLQ-C30/BN20 modules. Cox proportional hazard models were applied to obtain prognostic factors. Results: Of 75 randomized patients, 50 received BEV+RT and 25 received RT alone. Isocitrate dehydrogenase (IDH)-1 mutation status was uniformly wildtype in all 41 patients with available documentation and MGMT was unmethylated in 55 (76%) of 72 patients with MGMT testing. Established prognostic factors were balanced between both treatment arms, including age, MGMT promoter methylation, Karnofsky performance score, or steroid intake at randomization. Common Terminology Criteria for Adverse Events grade 3 or 4 toxicity was infrequent in both treatment arms. Prior to progression, no differences in cognitive functioning or quality of life were noted between treatment arms. BEV+RT was superior to RT alone for median PFS (7.6 months [95% CI 6.2–9.0] vs. 4.8 months [95% CI 3.0–6.6], P=0.003), but not OS (12.1 months [95% CI 10.2–14.0] vs 12.2 months [95% CI 9.2–15.2], P=0.77). In a Cox model controlling for established prognostic factors to determine predictors of inferior PFS, an association with outcome was detected for BEV+RT versus RT (HR 0.36 [95% CI 0.20–0.65], p=0.001) and for KPS 90–100% versus 60–80% (HR 0.50 [95% CI 0.28–0.89], p=0.018). CONCLUSION: The results of the randomized ARTE trial fail to support the notion that the addition of BEV improves outcome specifically in elderly patients with glioblastomas without MGMT promoter methylation.
Drinking water salinity and kidney health in southwest coastal Bangladesh: baseline findings of a community-based stepped-wedge randomised trial
Authors: Abu Mohd Naser, Mahbubur Rahman, Leanne Unicomb, Solaiman Doza, Kazi Matin Ahmed, Mohammad Nasir Uddin, Shahjada Selim, Matthew O Gribble, Shuchi Anand, Thomas F Clasen, Stephen P Luby
Journal: The Lancet (2017)
P12.13 Long-term outcomes following gamma knife radiosurgery for small, newly diagnosed meningiomas
Authors: J. Kim
Journal: Neuro-Oncology (2017)

Although stereotactic radiosurgery were established as an effective treatment modality for intracranial meningiomas, there have been no comprehensive studies focused on long-term outcomes and histologic results for purely small-sized meningiomas after radiosurgery. Therefore, we investigated long-term outcomes and histology of small-sized meningiomas after radiosurgery. The authors reviewed the data retrospectively of a total of 920 patients treated with single-session Gamma Knife radiosurgery with intracranial meningioma (Radiosurgery center, Asan Medical Center). After stratifying meningiomas by size, it was defined as small-sized meningiomas less than 1000 mm(3) in tumor volume. The patients with newly diagnosed small-sized meningiomas were enrolled in this study (113 patients). All patients had a minimum follow up of 12 months (12-120 months), clinical symptoms and brain MRI were checked by neurosurgeons. When the tumors grew readily with newly developed neurologic symptoms, microsurgical resection was performed. Histologic analysis was done with resected tumors by neuropathologists. Among 113 patients, 9 patients (7.9%) showed the increased tumors with clinical symptoms after radiosurgery, followed by microsurgical resection in 4 patients (3.5%). The other 5 (4.4%) patients showed that the size of tumor slightly increased after GKRS that is transient. Interestingly, the histologic results of resected meningiomas due to increased volume after radiosurgery were all revealed as WHO grade II meningiomas (1 clear cell type and 3 atypical meningiomas). Although the histologic confirmation was performed only in 4 patients underwent surgery, it is interesting that all tumors readily grew after radiosurgery were high grade meningiomas. In this study, we revealed the long-term outcomes of small meningiomas following stereotactic radiosurgery in the aspect of tumor control. The tumor control rate of radiosurgery in small meningiomas reached to 92.1% and there were perilesional edema in 6.1%. The 7.9% of tumors grew readily and 3.5% were finally underwent microsurgical resection. The histologic results were all WHO grade II meningiomas (1 clear cell and 3 atypical meningiomas).
P01.02 The role of dopamine signaling in GBM recurrence
Authors: S. P. Caragher, C. H. Park, F. Atashi, D. Guo, M. S. Lesniak, C. James, A. K. Tryba, A. U. Ahmed
Journal: Neuro-Oncology (2017)

Normal 0 false false false EN-US JA X-NONE /* Style Definitions */ table.MsoNormalTable {mso-style-name:”Table Normal”; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-parent:“”; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:Calibri; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin;} Glioblastoma multiforme (GBM) is the most common adult primary brain tumor and is universally lethal due to its high rate of recurrence. The Cancer Stem Cell (CSC) hypothesis posits that GBMs are driven by a rare subset of cells called Glioma Stem Cells (GSCs). GSCs are capable of resist intensive radio- and chemotherapy and give rise to recurrent disease. Recent studies from our laboratory and others have shown that normal GBM cells acquire a stem-like state during anti-glioma therapy. Termed conversion, this process increases the proportion of therapy resistant GSCs and initiate recurrence. We hypothesize that a drug capable of blocking such conversion may prevent the generation of therapy-resistant GSCs, thereby delaying, if not preventing, tumor recurrence. Based on this, we utilized GSC specific reporter system to perform a high-throughput drug screening to identify compounds target conversion. Our initial screening has identified several novel FDA-approved compounds that act as antagonists of neurotransmitter receptors, and that are commonly used as anti-psychotic medication. Further investigation revealed that treatment of patient-derived xenograft (PDX) GBM lines with temozolomide (TMZ) led to the formation of a population of cells that express both CD133, a marker of CSCs, and dopamine receptors 2 and 3 (DR2/3) (control mean CD133+/DRD2+: 19.7%, TMZ mean: 83.8%, p=0.0001). Treating the same PDX lines with a dopamine receptor agonist increased cellular expression of GSC associated transcription factors SOX2, OCT4 and c-Myc. As DRD activation can modulates ion flow and membrane potential, electrophysiology examination revealed that the DR agonist (30nM) depolarizes GBM cells by 6.0 ± 1.3mV (n=7) and we are investigating whether there are differences in the DRD response of GSC versus non-GSC. we found that two anti-psychotics, chlorprothioxene and loxapine, which act as antagonist to DRs, blocked the chemotherapy induced conversion and enhanced the therapeutic efficacy of anti-glioma chemotherapy TMZ (p<.0001). Based on this, we propose that inhibition of dopamine receptor signaling represents a novel strategy by which chemotherapy-induced molecular changes can be targeted to prevent conversion and disease recurrence in GBM. <!--EndFragment-->
Analysis of Peripheral Blood CD4+/CD25high Treg Cells and FOXP3 mRNA Expression in Patients Treated with Ipilimumab (Monoclonal Human Anti-CTLA4, MDX-010) for Relapse of Malignancy Following Allogeneic Hematopoietic Transplantation.
Authors: Jiehua Zhou, Rui-kun Zhong, Iveta Kalcheva, Bridget Medina, Edward D. Ball, Asad Bashey
Journal: Blood (2006)
Selective antiestrogenic character of dichlorotriarylcyclopropanes on estrogen receptors α and β
Authors: Mark Nichols, Peng Cheng, Beatriz Kanterewicz, Pamela A. Hershberger, Billy W. Day
Journal: Cancer Research (2004)

Proc Amer Assoc Cancer Res, Volume 45, 2004

2875 

We previously reported the synthesis and biological activity of a novel class of antiestrogens, 1,1-dichloro-2,2,3-triarylcyclopropanes (DTACs). DTACs are competitive inhibitors of estradiol binding, lack estrogenic activity in a mouse uterotrophic assay, and inhibit the growth of estrogen-sensitive MCF-7 breast cancer cells. Here we report an improved, solid phase-based synthesis primed for rapid library preparation and the screening of the products in mechanism-based assays. The new synthesis involved linking 4-(2-hydroxyethoxy)benzophenones to solid support via a 4-methoxytrityl linker, on-resin Grignard conversion to the E - and Z -olefins and cyclopropanation with dichlorocarbene. The products were cleaved from the resin, the primary hydroxyl converted to a bromide then to a tertiary amine, and the Z -isomers of the resulting 1,1-dichloro-2-(4-β-dialkylethoxyaryl)-2,3-diarylcyclopropanes isolated by flash chromatography. To gain further understanding of the antiestrogenic action of DTACs, reporter assays were used to evaluate their effect on ERα and ERβ mediated transcription from either classical estrogen-response elements (EREs) or non-classical AP-1 elements. Compounds BDRM72 and BDRM81 displayed weak agonist activity on EREs, which was less than that observed for the well-characterized ER partial agonist, 4-hydroxytamoxifen (ZOHT). However, the majority of DTACs displayed no estrogenic activity. In competition experiments, DTACs blocked estradiol-stimulated transcription from an ERE in a concentration-dependent manner and were more effective inhibitors than ZOHT. DTACs did not modulate either basal or highly stimulated transcription (by TPA) from an AP-1 element in the absence of ERα. In contrast, they increased basal transcription and negatively regulated TPA-stimulated transcription from an AP-1 element in the presence of ERα. These data indicate that DTACs are not general inhibitors of transcription and that their ability to modulate gene expression is dependent on ERα. GST pull-down assays were subsequently used to determine whether DTACs disrupt estrogen signaling by altering the interaction between ERα and the p160 coactivator, GRIP-1. BDRM35, which has the same dimethylaminomethoxy and 4-OH modifications as ZOHT, reduced binding more than 50%. Thus, disruption of p160 coactivator recruitment by ERα represents one mechanism by which DTACs function as antiestrogens. Several of the compounds differed in their effects on ERα- and ERβ-mediated transcriptional responses and therefore may be useful in discerning receptor specific biology. (Supported in part by NIH grants CA87414, DK59516 and CA78039).
OS08.9 Management of Primary Central Nervous System Lymphoma in Spain in the last decade: a case series of the Spanish Group of Neuro-Oncology and GELTAMO
Authors: R. Velasco, S. Mercadal, N. Vidal, J. Bruna, E. González-Barca, A. López-Guillermo, F. Graus
Journal: Neuro-Oncology (2017)

Background: Primary central nervous system lymphoma (PCNSL) is a challenging tumor frequently misdiagnosed and associated with a considerable diagnostic delay. Outcome of PCNSL patients not included in clinical trial may be substantially different. We describe the clinical outcome of a non-selected, representative series of PCNSL diagnosed in the last decade in Spain. Methods: We present a retrospective case series of 276 immunocompetent adults with PCNSL from 22 institutions in Spain, diagnosed between 2005 and 2014. Results: 53% were men. Median age was 65 [22–88] years and 95% were of B-cell origin. Most frequent symptoms at presentation were focal deficit (46%) and cognitive impairment /or psychiatric (39%). MRI was performed at a median of 23 [0–707] days after the first symptom. Atypical contrast enhancement (ring or non-homogeneous) on MRI was present in 29.5% of patients. Steroids were administered before surgery in 52.5% of patients and withheld before surgery in 32% of them. Diagnosis was done by biopsy or resection in 75% and 20%, respectively. Median time to pathological diagnosis from clinical onset was 46 [4–816] days. Time from MRI to pathological diagnosis was longer in those who had received steroids (40 vs 20 days, p=0.011). Fifty-three percent had a poor functional status with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥2 at diagnosis. No further treatment was given to 20% of patients whereas 80% received specific oncologic treatment that included radiotherapy alone (10.2%); chemotherapy alone (55.1%) or with RT (13.4%) or autologous hematopoietic cell transplantation (21.3%). Overall survival (OS) of treated patients was 14.8 months (IC 95% 7.5–22.0). Multivariate analysis identified age (≤60 years: HR: 0.60 (0.41–0.86), p=0.007), gender (men: 0.61 (0.44–0.86), p=0.005) and PS (ECOG 0–1: 0.57 (0-40-0-82), p=0.003) as independent prognostic factors for outcome. Patients with PS ≥ 2 at diagnosis carried longer diagnostic delay (31 vs 56 days, p=0.015). Age (HR: 1.02 (1.0–1.049), p=0.045) and diagnosis in more than 46 days from clinical onset (HR: 2.4 (1.38–4.22), p=0.002) were identified as risk factors for having poorer PS. Conclusion: Steroid administration was associated with a diagnostic delay. Younger patients, PS < 2, and, surprisingly, male gender were independent prognostic factors of better survival in treated patients. OS, even for treated patients was clearly inferior to that reported in clinical trials.
P12.14 Long-term follow-up result of Hydroxyurea chemotherapy for recurrent meningiomas
Authors: O. Kim
Journal: Neuro-Oncology (2017)

Objective: Meningiomas represent 18-20% of all intracranial tumors and have a 20-50% 10-year recurrence rate, despite aggressive surgery and irradiation. Hydroxyurea, an inhibitor of ribonucleotide reductase, is known to inhibit meningioma cells by induction of apoptosis. We report the long-term follow-up result of hydroxyurea therapy in the patients with recurrent meningiomas. Methods: Thirteen patients with recurrent WHO grade I or II meningioma were treated with hydroxyurea (1000mg/m2/day orally divided twice per day) from June 1998 to February 2013. Nine female and 4 male, ranging in age from 32 to 83 years (median age 61.7 years), were included. Follow up assessment included physical examination, computed tomography (CT), and magnetic resonance imaging (MRI). Standard neuro-oncological response criteria (Macdonald criteria) were used to evaluate the follow-up MRI scans. The treatment was continued until there was objective disease progression or onset of unmanageable toxicity. Results: Ten of the 13 patients (76.9%) showed stable disease (SD) after treatment, with time to progression ranging from 8 to 128 months (median 72.4 months; 6 patients still accruing time). However, there was no complete response (CR) or partial response (PR) in any patients. Three patients had progressive disease after 88, 89, 36 months, respectively. There was no severe (Grade III-IV) blood systemic disorders and no episodes of non-hematological side effects. Conclusion: This study showed that hydroxyurea is a modestly active agent against recurrent meningiomas and can induce long-term stabilization of disease in some patients. We think that hydroxyurea treatment is well tolerated and convenient, and could be considered as an alternative treatment option in patients with recurrent meningiomas prior to reoperation or radiotherapy.
P05.05 Post whole-brain radiotherapy hippocampal volumetry and neuronal changes measured by MR spectroscopy
Authors: T. Kazda, M. Bulik, P. Pospisil, J. Nahodilova, K. Holikova, P. Burkon, L. Hynkova, R. Lakomy, P. Slampa, R. Jancalek
Journal: Neuro-Oncology (2017)

Introduction: Although cognitive impairment after radiotherapy is likely multifactorial, hippocampus (Hipp) is believed to be particularly sensitive to radiation injury due to presented neuronal stem cells involved in memory formation. Biomarkers of radiation injury can help elucidate the mechanism of post WBRT cognitive decline. In our previous prospective study, we demonstrated Hipp MR spectroscopy to be feasible and sensitive method for non-invasive measurement of radiotherapy injury. We observed decline in Hipp concentration of N-acetyl aspartat (NAA), the marker of neuronal viability and density, within left as well as right Hipp 4 months after WBRT. Herein, we present pilot data of Hipp volumetry in this patients cohort. METHODS: Structural MRI of patients involved in our previous study, where we measured Hipp NAA concentrations before and 4 months after WBRT, were retrieved. Left and right Hipp was contoured by experienced radiation oncologist and neuroradiologist. Volumes of Hipp were compared pre and post WBRT and changes were correlated to NAA concentrations. Results: First 15 patients from our previous study were included in this pilot volumetry study (10 mens, median age 58 years, 26% renal cancer, 20% NSCLC, median overall survival 14.6 months). Mean NAA concentration in the right Hipp significantly decreased by 12% from 8.53mM to 7.43mM (p<0.001). Corresponding concentrations within left Hipp are 8.58mM and 7.69mM leading to significant decrease by 10.5% (p=0.004). Volume of right Hipp decreased by 9.2% (from median 2.52cc to 2.47cc; not significant) and left Hipp by 5.6% (from median 2.42cc to 2.27cc, not significant). DISCUSSION: We observed non significant decrease in volume of Hipp after WBRT. With no known normative standards, it is not possible to estimate an effect of small sample size to calculated p values. Remarkable difference in Hipp contouring results was observed within this pilot study. Hipp volumetry after WBRT may shed more lights into brain radioinjury, however more robust volumetry approach is needed for valid final results including correlations between volumetric data and concentrations. CONCLUSION: Significant decrease in mean Hipp NAA concentrations and non significant decrease in median Hipp volumes was observed in our patients cohort, four months after WBRT. Although presented pilot data are hypothesis generating, more patients as well as more robust approach in Hipp volumetry is needed for drawing valid conclusions.
Peer effects on adolescent sexual debut and pregnancy : an analysis of a national survey of adolescent girls. Journal summary.
Authors: Bearman P, Bruckner H
Journal: BMJ (2002)

Adolescents influence their peers by modeling behaviors and setting social norms.  This document presents a summary by the Resource Center for Adolescent Pregnancy Prevention of a Columbia University study on peer effects on girls first intercourse and pregnancy risk.  It is noted that the study used data from the National Longitudinal Study of Adolescent Health.  The first section of this paper provides the background for whole study.  The second section presents a summary of the data.  A description of the approach used is covered in the third section.  The fourth and fifth sections deal with the findings of the study and the conclusion respectively.  Finally the sixth section details the implications for researchers educators and parents.
Low-dose-rate brachytherapy for cervical cancer: Long-term clinical results of outcomes and associated toxicity.
Authors: Tamer Refaat, Eric Donald Donnelly, Michelle Sara Gentile, Caroline J. Novak, Ye Yuan, Gehan Abd Elatti Khedr, Irene B. Helenowski, John Robert Lurain, Julian C. Schink, Alfred Rademaker, Vythialinga Sathiaseelan, Jonathan Blake Strauss, William Small
Journal: Journal of Clinical Oncology (2014)

e16500 Background: To review and report the long-term treatment induced adverse events and outcomes of concomitant chemoradiotherapy (CRT) boosted by low-dose-rate (LDR) conventional brachytherapy (BT) planning in patients with local-regionally advanced cervical cancer. Methods: After obtaining institutional review board approval, we reviewed the records of patients with stage IB1 through IVA, intact cervical cancer who were treated at our institution between 1983 and 2009. Eligible patients underwent definitive radiotherapy with external beam radiation concomitant with cisplatin-based chemotherapy and boosted by LDR BT. Patient, tumor and treatment characteristics, treatment induced adverse events; namely gastrointestinal (GI), and genitourinary (GU) toxicities, as well as treatment outcomes; local-regional control (LRC), distant control (DC), progression free survival (PFS), and overall survival (OS) were reviewed and reported. Results: The study included 129 eligible cervical cancer patients; the median age was 46 years (range 28 – 81, mean 47 ± 11), consisting of stages I, II, III, IV (29.5%, 48.1%, 17.8% and 4.6% respectively). The median follow up was 37 months (mean 58 ± 59, range 3 – 275,). The 3-years OS, PFS, LRC, and DC were 75.9%, 71.6%, 84.7%, and 80.2%, respectively. The 5-years OS, PFS, LRC, and DC were 70.7%, 68.7%, 84.7%, and 78.3%, respectively. The 10-years OS, PFS, LRC, and DC were 68.7%, 62.3%, 82.5%, and 73.2%, respectively. Gastrointestinal (GI), and genitourinary (GU) grade 3 and 4 acute AEs were reported in 3.9%, and 0%, and chronic grade 3 and 4 AEs were reported in 20.9 %, and 12.4 % of all patients respectively. Conclusions: Definitive CRT followed by conventional LDR BT boost is effective, feasible and tolerable treatment modality for cervical cancer. A comparison with MRI Image-guided brachytherapy (IGBT) shows comparable treatment outcomes with superior OS in favor of LDR BT but inferior LC with a relatively worse toxicity profile.
Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment
Authors: Ok Hee Jeon, Chaekyu Kim, Remi-Martin Laberge, Marco Demaria, Sona Rathod, Alain P Vasserot, Jae Wook Chung, Do Hun Kim, Yan Poon, Nathaniel David, Darren J Baker, Jan M van Deursen, Judith Campisi, Jennifer H Elisseeff
Journal: Nature Medicine (2017)