tbuckley/cabot-search huggingface dataset:
Neoadjuvant chemotherapy (NACT) selection for advanced stage ovarian cancer (AOC) at a comprehensive cancer center.
Authors: Jennifer J Mueller, Farah Abbas Alvi, Amr S El Haraki, Ane Gerda Eriksson, Qin Zhou, Alexia Iasonos, Roisin Eilish O'Cearbhaill, Dennis Chi, Nadeem Abu-Rustum, Oliver Zivanovic
Journal: Journal of Clinical Oncology (2015)

e16579 Background: This is a retrospective chart review evaluating the use of NACT and primary debulking surgery (PDS) before and after a landmark trial was published demonstrating non-inferiority between NACT and PDS in the management of AOC. Methods: We evaluated consecutive patients with AOC treated at our institution from 2008-2012 which encompassed the 2 years before and after published results from a randomized trial comparing NACT versus PDS. We included all newly diagnosed high-grade histologies, presenting with stage III/ IV disease. Associations between the use of NACT and clinical variables over time were evaluated. Results: Overall, 586 patients were included in the study. Median age was 62 years (range 30-90); 406 (69.3%) had stage III disease and 570 (97.3%) had serous histology. Patient characteristics did not differ between time periods. There were 154/586 (26.3%) patients treated with NACT and 432/586 (73.7%) treated with PDS. NACT use increased significantly from 56/256 (21.9%) before 2010 to 98/330 (29.7%) after 2010 (p=0.037). Before 2010 only stage and co-morbidities were associated with NACT. After 2010 age, stage, and preoperative variables (albumin, baseline CA125 and CT imaging criteria) were associated with NACT. Surgical resection rates did not improve significantly despite the increase in NACT selection. Survival data were similar across time periods (Table). Conclusions: At a single institution we observed a significant increase in selection of NACT as a primary treatment strategy for AOC in the 2 years following the publication of a landmark trial. This increase did not result in significant differences in surgical cytoreduction rates or median PFS between time periods. These data need to be confirmed in larger studies to better understand the effect of NACT use on clinical outcomes. Group Time Period Median PFS (months) Median OS (months) Complete gross resection Optimal (<1cm) resection P value* PDS 2008-2010 20.5 65.6 85 (42.5%) 162 (81%) 0.17 PDS 2010-2012 22.1 Not reached 118 (50.9%) 189 (81.5%) NACT 2008-2010 14.1 37.1 29 (52.7%) 50 (90.9%) 0.51 NACT 2010-2012 14.1 Not reached 53 (56.4%) 81 (86.2%) Total Cohort 2008-2010 18.9 Total Cohort 2010-2012 19.9
Molecular signature of patients with pre-treated urothelial carcinoma (UC) achieving extreme responses to pazopanib (PZP) salvage therapy.
Authors: Patrizia Pinciroli, Gopa Iyer, Helen H. Won, Silvana Canevari, Maurizio Colecchia, Filippo G. De Braud, Maria Grazia Daidone, Patrizia Giannatempo, Daniele Raggi, Marzia Pennati, Nadia Zaffaroni, Nicola Nicolai, Roberto Salvioni, Marco Pierotti, David B. Solit, Jonathan E. Rosenberg, Michael F. Berger, Andrea Necchi
Journal: Journal of Clinical Oncology (2015)

e15514 Background: The clinical impact of molecular drivers in UC remains unclear. Extensive genomic profiling of tumor samples, particularly of defined subsets of patients (pts) who achieved extreme responses to targeted drugs (outlier pts) may help identifying sensitivity or resistance biomarkers. The aim of the INT-MSKCC collaborative study was to delineate the molecular landscape of outlier pts enrolled in a phase 2 trial of PZP (NCT01031875). Methods: We analyzed formalin fixed paraffin embedded (FFPE) tissue from a patient (#1) achieving a 32-m lasting PR to PZP in the third-line metastatic setting. Moreover one 3-m lasting PR (#2, in 4th line) and one primary refractory case (pt #3) were analyzed. Tumor and matching germline DNA was sequenced using the Integrated Molecular Profiling of Actionable Cancer Targets. Briefly, exon capture of 341 cancer related genes was followed by deep coverage next-generation sequencing to identify somatic variants, small indels and copy number alterations. Results: In responding pts we found a significant EGFR copy number amplification (pt #1, fold change = 17, CNA) and an ERBB2 S310F mutation (pt #2), a hotspot and frequent driver mutation in UC. Pt #1 contained the most alterations (74 events). MTOR and ERBB2 mutations occurred at different sites in pt #1,2 and ERBB3 in #1. Patient #1 had alterations in chromatin-regulating genes reported at high frequency in TCGA bladder including KMT2D and EP300 frameshift, CREBBP truncation, and KMT2C point mutations, and pt #2 had ARID1A frameshift and KMT2 point mutations. The resistant case (pt #3) showed deletions of CDKN2B and CDKN2A, and mutations in PIK3CA (1 H1047R), FGFR3 (S249C), KDM6A, and STAG2. Conclusions: Present genomic analyses revealed EGFR amplification, MTOR and ERBB2 mutations in a patient with outstanding response to PZP. This association deserves validation in a wider PZP treated cohort of pts. Alterations on multiple potential therapeutic targets further characterized responding and resistant cases. These data might be useful for the design of combinatorial and/or sequential therapies directed against these targets.
The effects of multidisciplinary clinics on the variability in timeliness of care for lung cancer patients.
Authors: Karyl Blaseg, John M Schallenkamp, Catherine L Stephens, Charles Scott Needham, Jorge J. Nieva
Journal: Journal of Clinical Oncology (2013)

e17533 Background: Implementation of multi-disciplinary clinics (MDC) has the potential to improve the care of cancer patients. Little data presently exists on the impact of MDC based care on cancer patient populations. Methods: A multi-disciplinary lung cancer clinic was implemented at a large, rural, multispecialty medical center in 2009. A retrospective analysis of the impact of MDC implementation on patient care was accomplished from 2009-2010 and was compared to care of patients from a reference period consisting of all patients treated in 2007. Patient survival, time to first appointment, time to treatment, use of clinical trials, and selection of palliative therapy only were analyzed using descriptive statistics. Two sided students t-test was performed to compare results from each cohort. Results: A new diagnosis of lung cancer was identified in 290 patients from 2009-2010. A total of 175 patients received care within the MDC and 115 patients were treated outside of the MDC. One hundred and forty-two patients were analyzed from the pre-MDC period of 2007. Seventy-seven percent of patients had NSCLC in 2007 and 81% of patients had NSCLC in 2009-2010. The time from referral to first appointment, and diagnosis to treatment are shown in the Table. There was a significant improvement in the mean time to initiation of cancer therapy with the introduction of the MDC clinic with patients starting therapy at a mean of 22 days instead of 28 days, however, the median time to treatment increased to 17 days from 5 days. MDC was associated with improvement in clinical trial accrual to 15% from 10%. Conclusions: The implementation of MDC was associated with greater homogeneity in timeliness of care, with fewer patients being outliers with long delays in time to care, hence improvements in mean time to care, with a detriment in median time to care owning to the increased complexity of scheduling. MDC also resulted in improvements in clinical trial accrual. [Table: see text]
Use of pharmacokinetic modeling to optimize direct inhibition of the "undruggable" target EWS-FLI1 of Ewing sarcoma.
Authors: Jeffrey Toretsky, S. Peter Hong, S. Ellen Gamble, Sung-Hyeok Hong, Christina L. Kobs, Karen E. Elsass, Natalie L. South, Stephen J. Summer, Philip J. Monroe, Aykut Uren
Journal: Journal of Clinical Oncology (2012)

9575 Background: Chimeric transcription factors are ideal anti-cancer targets; however, they lack enzymatic activity thus rendering them ‘undruggable’ proteins. The EWS-FLI1 fusion protein of Ewing sarcoma (ES) has been validated as an anticancer target both alone and as a partner of RNA Helicase A (RHA). Our prior work identified the small molecule YK-4-279 as a specific inhibitor that blocks RHA from binding to EWS-FLI1. Blocking this interaction leads to apoptosis. We have modeled YK-4-279 treatment using ES cells to establish the duration of YK-4-279 exposure that leads to apoptosis. Methods: Apoptosis was measured by caspase-3 cleavage. A validated plasma detection method allows for HPLC measurement of YK-4-279. Pharmacokinetic (PK) models of YK-4-279 for both intraperitoneal (IP) and intravenous (IV) administration were developed in SD rats and BL6 mice. Results: ES cell lines were exposed to YK-4-279 over a time-course, followed by a caspase-3 activity assay that demonstrated a minimum of 16 hours exposure was necessary to achieve maximal apoptosis using either 3 or 10 microM compound. A dose-dependency assay demonstrated that while apoptosis could be achieved with 30 – 80 microM YK-4-279 after 4 hours of treatment, caspase-3 activity was less than or equal to 3 microM for 16 hours. Rat PK modeling demonstrated a t1/2 of 30 minutes following IV administration. BL6 mice demonstrated similar kinetics to the rat. SCID/bg mice, which are necessary for tumor efficacy studies, demonstrated approximately 50% faster clearance than either rat or BL6 mice. Absolute bioavailability for IP administration was 41%. Conclusions: Models will be created to optimize IP dosing regimen. The optimized IP dosage and dosing intervals will be evaluated in tumor bearing animals in order to advance development of YK-4-279. The results of these studies will be used to guide toxicology studies in animals. In addition, pharmacodynamics models are being developed to compare YK-4-279 levels with functional activity. The combined results of these investigations will lead to human clinical trials for this first-in-chemical class, first-in-mechanism drug candidate.
miRNA expression profiling of CD20+ plasma cell myeloma (PCM): Upregulation of miR-155 shedding new insight into disease biology and clinicopathologic behavior.
Authors: Ravindra Kolhe, Anand P. Jillella, Kavita Natrajan, Farrukh Tauseef Awan, Elizabeth Manaloor, Vamsi Kota
Journal: Journal of Clinical Oncology (2012)

8108 Background: Up to15-20% of patients with PCM have expression of CD20, although the significance of this remains unclear. The prognostic significance of CD20 expression in PCM is unclear. Recently, a class of noncoding RNAs, miRNAs, were identified as critical gene regulators in cell growth, disease, and development. Our study investigates importance of miRNAs in cases of CD20+ PCM and correlates them with clinicopathological parameters. Methods: The miRNA expression profile of CD20+ PCM (n=6), diffuse large B cell lymphoma (DLBCL) (n=6), and CD20 negative PCM (n=8) were evaluated using the Affeymertrix miRNA microarray platform on GeneChip miRNA 2.0 array in paraffin-embedded samples. After hybridization and data acquisition, we used Partek Genomics Suite software for RMA normalization and to determine statistically significant differences in miRNA expression between experimental groups by ANOVA and pairwise comparisons (two-sided α=0.05). Results: miRNA expression profiles of CD20+ PCM, show upto &gt;4 times upregulation of 7 miRNAs and downregulation of 8 miRNAs. miR-155, the miRNA upregulated in various B cell lymphomas and plays a key role in the lymphomagenesis, was amongst the highest miRNAs that were upregulated. Conclusions: miR-155 is known to repress SH2-domain containing inositol-5-phosphatase-1 (SHIP-1), which is a critical phosphatase that negatively down modulates AKT pathway and has functions during normal B-cell development. Physiologically, miR-155 is upregulated during B-cell activation upon antigen stimulation and so plays a role in antibody class switching and plasma cell formation. We propose that this overexpression of miR-155 in CD20+ PCM unblocks AKT activity, inducing cell proliferation and may explain some of the immunophenotypic behavior of CD20+ PCM. This work is intriguing for the new information it provides about the role of miR-155 in CD20+ PCM. Furthermore, the phenotype of miR-155+ve CD20+ PCM might ultimately provide new insights into regulation of poorly understood steps in B cell differentiation and maturation into plasma cell and more importantly the clinicopathological behavior of this entity.
Panobinostat in combination with bevacizumab for recurrent glioblastoma and anaplastic glioma.
Authors: Eudocia Quant Lee, David A. Reardon, David Schiff, Jan Drappatz, Alona Muzikansky, Sean Aaron Grimm, Andrew David Norden, Lakshmi Nayak, Rameen Beroukhim, Mikael L. Rinne, Andrew S. Chi, Tracy Batchelor, Kelly Hempfling, Christine Sceppa McCluskey, Katrina H. Smith, Sarah C. Gaffey, Brendan Wrigley, Jeffrey J. Raizer, Patrick Y. Wen
Journal: Journal of Clinical Oncology (2014)

2020 Background: Bevacizumab is frequently used to treat recurrent high-grade gliomas, but responses are generally not durable. Panobinostat is a histone deacetylase inhibitor with anti-neoplastic and anti-angiogenic effects in glioma and may work synergistically with bevacizumab. We conducted a multicenter phase II trial of panobinostat in combination with bevacizumab in patients with recurrent grade III and IV gliomas. Methods: Two cohorts were enrolled: one with recurrent glioblastoma (GBM) as the primary study and one with recurrent anaplastic glioma (AG) as the exploratory study. Patients were treated with oral panobinostat 30 mg 3 x per week, every other week, in combination with bevacizumab 10 mg/kg every other week. The primary endpoint was 6-month progression-free survival (PFS6) in the GBM cohort and the study was powered to discriminate between a 35% and 55% PFS6 rate (85% power at an alpha level of 0.07). Results: At planned interim analysis, 13 of the first 21 patients accrued to the GBM cohort had progressed within 6 months of initiating study treatment. The GBM cohort did not meet criteria for continued accrual and was closed early. In the GBM cohort, PFS6 rate was 30.4% [95% confidence interval: 12%, 51%], median PFS was 5 months [3, 9], and median OS was 9 months [6, 19]. Accrual in the AG cohort continued to completion and a total of 15 patients were enrolled. In the AG cohort, PFS6 was 46.67% [21%, 73%], median PFS was 7 months [2, 10], and median OS was 17 months [5, 27]. The most common grade 3 or 4 toxicities related to treatment in the GBM arm were hypophosphatemia (12.5%), thrombocytopenia (12.5%), lymphopenia (8.3%), neutropenia (8.3%), and ALT elevation (8.3%). In the AG arm, the most common grade 3 or 4 toxicities were thrombocytopenia (20.0%) and hypophosphatemia (13.3%). There were no deaths related to study treatment. Conclusions: Although reasonably well-tolerated, this phase II study of panobinostat and bevacizumab in recurrent GBM did not meet criteria for continued accrual and the GBM cohort of the study was closed. However, in the recurrent AG cohort, bevacizumab in combination with LBH589 may delay progression. Updated outcome and safety data will be presented. Study supported by Novartis and Genentech. Clinical trial information: NCT00859222.
Severe toxicity risk factor analysis of salvage radiotherapy for oligo-recurrence in the lymph nodes (LN) of esophagus carcinoma: From multi-institutional retrospective study.
Authors: Toshihiko Matsumoto, Tomohiro Nishina, Yuzuru Niibe, Hideomi Yamashita, Kuniaki Katsui, Masaaki Kataoka, Atsuro Terahara, Hideaki Shimada, Keiichi Jingu
Journal: Journal of Clinical Oncology (2017)

186 Background: This multi-institutional retrospective study suggested that salvage radiotherapy (RT) or chemoradiation therapy (CRT) for oligo-recurrence in the lymph nodes (LN) of esophagus carcinoma was one of therapeutic options. However risk factors of severe toxicities of these therapies are unclear. Methods: Between January 2000 and April 2015, a total of 237 cases that met the study criteria of oligo-recurrence were treated by RT or CRT in five hospitals. We investigated risk factors of severe toxicities in these patients. We used the fisher’s exact test and Cox proportional hazard model. Toxicities were evaluated by CTCAE v4.0. Results: The median follow-up time for 93 living cases was 29.6 months (range; 1.9-154.0 months). Systemic chemotherapy was administrated to 210 cases (88.6%). Median biological effective dose(BED) was 72 Gy(range: 48-84Gy).The 3-year overall survival (OS) was 37%, local control was 45%, progression-free survival was 24%. Radiation induced Grade 3 or worse adverse events were observed in 11 patients (4.6%), which were fistula (4patients,1.7%), pneumonia (2patients,0.8%), pleural effusion (2patients,0.8%), esophageal bleeding (1 patient, 0.4%), esophageal stenosis (1patient,0.4%), cardiac tamponade (1patient,0.4%), and hyperglycemia (1patient,0.4%) ) Treatment related death occurred in 4 patients, these deaths were attributed to drug-induced or radiation-induced interstitial pneumoniae, pleural effusion, esophageal bleeding, and esophago-bronchial fistula. Severe toxicity was only observed in patients with oligo-recurrence in regional lymph nodes or BED ³a60 Gy. In univariate analysis by Fisher’s exact test, Karnofsky performance status (KPS) &lt;80 (p=0.0006) and oligo-recurrence in regional lymph nodes (p=0.0078) were the risk factor of severe toxicity. In multivariate analysis, KPS&lt;80 (HR:11.81,95% CI: 2.67-51.29, p=0.0017) was the risk factor of severe toxicity. Conclusions: This study suggested that KPS&lt;80 and oligo-recurrence in regional lymph nodes is the risk factor for severe toxicity in patients who received RT or CRT for oligo-recurrence in the LNs of esophagus.
DNA methylation changes at infertility genes in newborn twins conceived by in vitro fertilisation
Authors: Juan E. Castillo-Fernandez, Yuk Jing Loke, Sebastian Bass-Stringer, Fei Gao, Yudong Xia, Honglong Wu, Hanlin Lu, Yuan Liu, Jun Wang, Tim D. Spector, Richard Saffery, Jeffrey M. Craig, Jordana T. Bell
Journal: Genome Medicine (2017)

The association of in vitro fertilisation (IVF) and DNA methylation has been studied predominantly at regulatory regions of imprinted genes and at just thousands of the ~28 million CpG sites in the human genome. We investigated the links between IVF and DNA methylation patterns in whole cord blood cells (n = 98) and cord blood mononuclear cells (n = 82) from newborn twins using genome-wide methylated DNA immunoprecipitation coupled with deep sequencing. At a false discovery rate (FDR) of 5%, we identified one significant whole blood DNA methylation change linked to conception via IVF, which was located ~3 kb upstream of TNP1, a gene previously linked to male infertility. The 46 most strongly associated signals (FDR of 25%) included a second region in a gene also previously linked to infertility, C9orf3, suggesting that our findings may in part capture the effect of parental subfertility. Using twin modelling, we observed that individual-specific environmental factors appear to be the main overall contributors of methylation variability at the FDR 25% IVF-associated differentially methylated regions, although evidence for methylation heritability was also obtained at several of these regions. We replicated previous findings of differential methylation associated with IVF at the H19/IGF2 region in cord blood mononuclear cells, and we validated the signal at C9orf3 in monozygotic twins. We also explored the impact of intracytoplasmic sperm injection on the FDR 25% signals for potential effects specific to male or female infertility factors. To our knowledge, this is the most comprehensive study of DNA methylation profiles at birth and IVF conception to date, and our results show evidence for epigenetic modifications that may in part reflect parental subfertility.
Combined analysis of two phase II trials of imatinib in advanced dermatofibrosarcoma protuberans (DFSP)
Authors: S. Schuetze, P. Rutkowski, M. M. Van Glabbeke, C. Rankin, B. P. Rubin, A. Lazar, M. Debiec-Rychter, H. Gelderblom, P. Hohenberger, A. T. van Oosterom
Journal: Journal of Clinical Oncology (2009)

10520 Background: DFSP is an infiltrative, low-grade, dermal tumor with propensity to recur locally and occasionally metastasize. Translocation between COL1A1 on chromosome 17 and PDGFB on chromosome 22, which results in transcriptional upregulation of PDGFB, is characteristic of DFSP. Autocrine/paracrine PDGFB-mediated activation of PDGFRB drives DFSP proliferation. Two distinct phase II trials of imatinib in patients (pts) with locally advanced or metastatic DFSP were conducted, 1 in North America (SWOG) with confirmed objective response rate and 1 in Europe (EORTC) with 14 week progression-free rate as primary end-points. Methods: Pts with locally advanced or metastatic DFSP were eligible. In the EORTC trial confirmation of t(17;22) by FISH was prospectively required for participation, imatinib was started at 400mg bid, surgery was undertaken after 14 weeks if feasible and response was assessed at 14 weeks. Full accrual was to be 44 pts in one step. In the SWOG trial confirmation of t(17;22) by RT-PCR was performed after enrollment, imatinib was started at 400mg daily and response was assessed every 8 weeks. Full accrual was to be 40 pts in 2 steps. Results: 16 pts were enrolled in EORTC and 8 pts enrolled in SWOG trial. The studies were closed early because of slow accrual and regulatory approval of imatinib in DFSP. Pts age ranged from 24 to 70 yrs, DFSP was located on head/neck, trunk and extremity in 7, 11 and 6 pts, respectively, ranged in size from 1.2–49 cm and was classic, pigmented and fibrosarcomatous DFSP in 13, 1 and 7 pts, respectively. One patient did not have DFSP on central review, lacked t(17;22) and thus was ineligible. Metastases were present in 7 pts involving lung in 6 pts. 11 pts (46%) had partial response, 9 pts had stable disease and 4 pts had progressive disease as best response. Median time to progression was 1.7 yrs. Response and progression-free at 1 yr rates were similar between studies. Imatinib was stopped in 11 pts for progression, 1 pt for toxicity, 2 pts resected free of gross disease and 1 pt withdrew. Conclusions: Imatinib is active in DFSP harboring t(17;22) with an objective response rate approaching 50% and is active in fibrosarcomatous DFSP. Response rates and time to progression did not appear to differ between pts taking 400 mg daily versus 400 mg bid. [Table: see text]