tbuckley/cabot-search huggingface dataset:
Exhaustive single nucleotide polymorphism (SNP) analysis of <i>DPYD</i> exome in breast cancer patients (pts) receiving capecitabine.
Authors: Marie-Christine Etienne-Grimaldi, Jean-Christophe Boyer, Laurence Llorca, Gilles Romieu, Thomas Denis Bachelot, Veronique Dieras, Jean-Louis Merlin, Frederic Pinguet, Fabienne Thomas, Christophe Ferrand, Christine Bobin-Dubigeon, Xavier B. Pivot, Remy Largillier, Mireille Mousseau, Anthony Goncalves, Henri Hubert Roche, Joseph Ciccolini, Jean-Marc Ferrero, Gerard A. Milano
Journal: Journal of Clinical Oncology (2015)

2571 Background: Consensual DPYD variants *2A, D949V and I560S are associated with fluoropyrimidine toxicity (Caudle, CPT 2013). Full sequencing of DPYD exome was conducted in a prospective cohort of advanced breast cancer pts receiving capecitabine (88.5% monotherapy) to examine relationships between DPYDSNPs and toxicity. Methods: 243 over 303 pts included in 12 French institutions were analyzed. Digestive, neurologic and hematotoxicity over cycles 1-2 showed 10.3% G3 (25 pts) and 2.1% G4 (5 pts), including one toxic death. DPYD exome along with flanking intronic regions (20 bp), 3’UTR and part of 5’UTR (500 bp upstream transcription initiation) were sequenced on MiSeq Illumina (Integragen, PCR multiplex, 97% coverage on average, HWE checked). Results: In addition to consensual variants *2A, D949V and I560S carried by 7 pts (all heterozygous), 45 SNPs were identified: 7 in 3’UTR, 17 in coding regions (4 synonymous including E412E; 13 missenses including V732I, R592W, I543V, S534N, S492L, M406I, D342G, M166V, T65M, C29R), 18 in flanking intronic regions, 3 in 5’UTR. The number of variant alleles per pt varied from 0 (8 pts) to 16. In total, 11 SNPs have not been previously described (dbsnp 141 database), including 3 missense variations each heterozygous in 3 separate pts: R696H (exon 17), F100L (exon 4) and A26T (exon 2). The patient with toxic death carried one D949V allele and 3 variant alleles in 3’UTR (rs291592, rs291593). First analysis of consensual variants showed that they were associated with G3-4 toxicity (RR = 6.69, p < 0.001, sensitivity 16.7%) but not with G4 toxicity. Adding the variants previously shown to possibly decrease DPD activity (Offer, Cancer Res 2014), i.e. R592W, S492L and D342N/G, increased sensitivity on G3-4 (23.3%, RR = 7.03, p < 0.001) and was predictive of G4 toxicity (sensitivity 40%, RR = 15.4, p = 0.015). Of note, adding the new F100L variant further improved predictivity of genotyping on both G3-4 (sensitivity 26.7%, RR = 7.60, p < 0.001) and G4 toxicity (sensitivity 60%, RR = 31.36, p = 0.001). Conclusions: Present data confirm the impact of consensual variants on capecitabine toxicity and reveal the existence of a novel DPYD variant, F100L, associated with G4 toxicity. Clinical trial information: 2008-004136-20.
Disease Monitoring in Multiple Myeloma Patients Using Liquid Biopsy and Next Generation Sequencing of IGH Gene Rearrangements
Authors: Silvia Gimondi, Giulia Biancon, Antonio Vendramin, Silvia Zaninelli, Sara Rizzitano, Sofia Cannara Malan, Anisa Bermema, Vittorio Montefusco, Cristiana Carniti, Paolo Corradini
Journal: Blood (2016)
[<sup>18</sup>F]GE-180 PET Detects Reduced Microglia Activation After LM11A-31 Therapy in a Mouse Model of Alzheimer's Disease
Authors: Michelle L. James, Nadia P. Belichenko, Adam J. Shuhendler, Aileen Hoehne, Lauren E. Andrews, Christina Condon, Thuy-Vi V. Nguyen, Vladimer Reiser, Paul Jones, William Trigg, Jianghong Rao, Sanjiv S. Gambhir, Frank M. Longo
Journal: Theranostics (2017)

Microglial activation is a key pathological feature of Alzheimer's disease (AD).PET imaging of translocator protein 18 kDa (TSPO) is a strategy to detect microglial activation in vivo.Here we assessed flutriciclamide ([ 18 F]GE-180), a new second-generation TSPO-PET radiotracer, for its ability to monitor response to LM11A-31, a novel AD therapeutic in clinical trials.AD mice displaying pathology were treated orally with LM11A-31 for 3 months.Subsequent [ 18 F]GE-180-PET imaging revealed significantly lower signal in cortex and hippocampus of LM11A-31-treated AD mice compared to those treated with vehicle, corresponding with decreased levels of TSPO immunostaining and microglial Iba1 immunostaining.In addition to detecting decreased microglial activation following LM11A-31 treatment, [ 18 F]GE-180 identified activated microglia in AD mice with greater sensitivity than another second-generation TSPO radiotracer, [ 18 F]PBR06.Together, these data demonstrate the promise of [ 18 F]GE-180 as a potentially sensitive tool for tracking neuroinflammation in AD mice and for monitoring therapeutic modulation of microglial activation.
The prognostic significance of the CA125 nadir in patients that achieve a CA125 response
Authors: S. M. Crawford, J. Paul, N. S. Reed, A. Hay, K. Carty, P. A. Vasey
Journal: Journal of Clinical Oncology (2004)

5001 Background:In a series of patients (pts) who had received chemotherapy for epithelial ovarian cancer (EOC) at one hospital, it was observed that survival varied between the groups that attained a nadir (a)≤10 u/ml (best), (b)11–20u/ml and (c)21–30 u/ml (worst). Method:To validate this observation and to assess the ability of nadir CA125 values to discriminate between treatments in a randomised clinical trial, we have analysed data from the SCOTROC trial, which found no progression-free survival (PFS) difference between docetaxel and paclitaxel when either is combined with carboplatin(C) and from the SGCTG study G44 which showed the superiority of C over treosulfan (T) in older and frailer pts. Results:556 pts in SCOTROC attained a CA125 response (Rustin et al,. J Clin Oncol 14:1545–1551;1996). 283 were randomly allocated to a development data set in which was was used to determine prognostic groups based on the Ca125 nadir. PFS of the three groups varied as expected and repeating the analysis in the remaining 273 pts confirmed the reproducibility of the finding so combined results are presented in the Table. In the G44 study 165 pts were assessable for CA125 response. Pts who received C were more likely to attain response than those receiving T (C:53/87[61%] vs T 29/78[37%], p=0.002) or Group (a) (C:18/87[21%] vs T:7/78[9%], p=0.036). Among CA125 responders there was no difference in PFS between C and T (p=0.93) Median PFS results, in months from attainment of the nadir, are shown with 95% confidence intervals in the Table. 2-year PFS in SCOTROC was in Group (a) 39%, (b)23% and (c) 4%, p<0.0001 Conclusions: The CA125 nadir following chemotherapy for EOC is a reproducible predictor of PFS. Our data suggest that the proportion of pts attaining low nadir values discriminates between treatments of differing efficacy in a clinical trial. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis Aventis; Merck
Pilot evaluation of paroxetine for alleviation of hot flashes in men
Authors: C. L. Loprinzi, D. L. Barton, J. A. Sloan, P. J. Novotny, L. Carpenter, M. Gettman, B. J. Christensen
Journal: Journal of Clinical Oncology (2004)

8016 Background: Effective and nontoxic nonhormonal means of alleviating hot flashes are desirable for men with androgen-ablation related hot flashes. Based on positive pilot information suggesting that relatively low doses of paroxetine were able to alleviate hot flashes in women (with subsequent placebo-controlled data in women confirming the efficacy of this agent in women), we developed a phase II trial of paroxetine in men with bothersome hot flashes related to androgen ablation therapy. Methods: Participants kept a daily hot flash diary during a baseline week and then during four treatment weeks while they received paroxetine SR in the following manner: 12.5 mg/d for one week, then 25 mg/d for one week, then 37.5 mg/d for one week, and then either 25 mg/d or 37.5 mg/d for the last week (patient preference). A total of 26 patients were entered on this study between 8/6/2001 and 10/22/2003. Two patients canceled before receiving treatment, 2 patients did not returned any questionnaires, and 4 patients did not complete all 4 weeks of their diaries. Results: Hot flash information on the 18 evaluable study patients are provided in the table, illustrating mean hot flash score (daily frequency times average severity) data compared to the baseline week (where patients had a mean of 14.8 hot flashes per day). For comparison, similarly obtained data from a previous pilot trial, examining venlafaxine in men with hot flashes, is also illustrated. The paroxetine was tolerated well overall, with most patients reporting an improvement, during the weeks they were receiving paroxetine compared to the baseline week, in most of the potential side effects that we followed. Conclusions: These preliminary data support paroxetine as a potentially effective nonhormonal agent for managing hot flashes in men. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Glaxo
Two-Year Outcome after Endovascular Treatment for Acute Ischemic Stroke
Authors: Lucie A. van den Berg, Marcel G.W. Dijkgraaf, Olvert A. Berkhemer, Puck S.S. Fransen, Debbie Beumer, Hester F. Lingsma, Charles B.L.M. Majoie, Diederik W.J. Dippel, Aad van der Lugt, Robert J. van Oostenbrugge, Wim H. van Zwam, Yvo B.W.E.M. Roos
Journal: New England Journal of Medicine (2017)

Several trials involving patients with acute ischemic stroke have shown better functional outcomes with endovascular treatment than with conventional treatment at 90 days after initiation of treatment. However, results on long-term clinical outcomes are lacking.We assessed clinical outcomes 2 years after patients were randomly assigned to receive either endovascular treatment (intervention group) or conventional treatment (control group) for acute ischemic stroke. The primary outcome was the score on the modified Rankin scale at 2 years; this scale measures functional outcome, with scores ranging from 0 (no symptoms) to 6 (death). Secondary outcomes included all-cause mortality and the quality of life at 2 years, as measured by means of a health utility index that is based on the European Quality of Life-5 Dimensions questionnaire (scores range from -0.329 to 1, with higher scores indicating better health).Of the 500 patients who underwent randomization in the original trial, 2-year data for this extended follow-up trial were available for 391 patients (78.2%) and information on death was available for 459 patients (91.8%). The distribution of outcomes on the modified Rankin scale favored endovascular treatment over conventional treatment (adjusted common odds ratio, 1.68; 95% confidence interval [CI], 1.15 to 2.45; P=0.007). There was no significant difference between the treatment groups in the percentage of patients who had an excellent outcome (i.e., a modified Rankin scale score of 0 or 1). The mean quality-of-life score was 0.48 among patients randomly assigned to endovascular treatment as compared with 0.38 among patients randomly assigned to conventional treatment (mean difference, 0.10; 95% CI, 0.03 to 0.16; P=0.006). The cumulative 2-year mortality rate was 26.0% in the intervention group and 31.0% in the control group (adjusted hazard ratio, 0.9; 95% CI, 0.6 to 1.2; P=0.46).In this extended follow-up trial, the beneficial effect of endovascular treatment on functional outcome at 2 years in patients with acute ischemic stroke was similar to that reported at 90 days in the original trial. (Funded by the Netherlands Organization for Health Research and Development and others; MR CLEAN Current Controlled Trials number, ISRCTN10888758 , and Netherlands Trial Register number, NTR1804 , and MR CLEAN extended follow-up trial Netherlands Trial Register number, NTR5073 .).
A retrospective analysis of the proportion of patients responding for &gt; 1 year in two phase III studies of fulvestrant vs. anastrozole
Authors: S. E. Jones, J. Pippen, A. Webster
Journal: Journal of Clinical Oncology (2004)

737 Background: Fulvestrant (Faslodex) is an estrogen receptor antagonist with no agonist effects. Two phase III trials have compared the efficacy of fulvestrant 250 mg (once-monthly, intramuscular injection) and anastrozole (1 mg/daily, p.o.) in patients with advanced breast cancer progressing on prior endocrine therapy. Fulvestrant was at least as effective as anastrozole for the primary endpoint of time to progression and the secondary endpoint of objective response (OR). Here, we report a retrospective analysis of duration of response (DOR) by categorical time period (≥1 year) in patients experiencing an OR (complete [CR] or partial response [PR]) or clinical benefit (CB; CR + PR + stable disease [SD] ≥24 weeks) in these two trials. Methods: Duration of OR and CB was calculated from randomization until disease progression and percentages were calculated using the total number of patients per treatment group as the denominator (fulvestrant n=428; anastrozole n=423). Results: Median follow-up was 22.1 months. A total of 186 patients receiving fulvestrant had CB (CR: n=20; PR: n=62; SD ≥24 weeks: n=104) compared with 173 patients receiving anastrozole (CR: n=11; PR: n=59; SD ≥24 weeks: n=103). A numerically greater proportion of patients receiving fulvestrant achieved OR and CB for ≥1 year than those receiving anastrozole. Conclusion: Fulvestrant has benefits in terms of the numbers of patients with prolonged duration of response. These data support the initial DOR findings in these trials. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca Pharmaceuticals AstraZeneca Pharmaceuticals AstraZeneca AstraZeneca
Survival benefits of second-line chemotherapy in metastatic castrate-resistant prostate cancer (CRPC) in a southeastern oncology community practice.
Authors: James W. Gilmore, Sally Haislip, Stephen Szabo, Sean D Sullivan, Scott David Ramsey, Charles Kreilick, Susan H Foltz Boklage, Syam Sarma, Carl V Asche, Kenneth M. Shermock, Kai Sun, Satish Valluri, Brian S. Seal
Journal: Journal of Clinical Oncology (2012)

e15183 Background: Clinical studies showed that chemotherapy (CT) yields survival benefits for Metastatic Castrate resistant prostate cancer (CRPC) patients. This study investigated the relationship between patients with 2 nd CT and OS using a real-world data. Methods: TheGeorgia Cancer Specialist Database containing chemotherapy, medical and pharmacy information, and lab results for patients with various types of cancer (2005-2011) was used. Patients (PTs) over 18 years of age with initial stage IV CRPC were followed from the first administration of CT (index date, ID) to the earlier of death or loss to follow-up (FU). PTs with one type of CT protocol (PL) were defined as first line CT PTs (1 st ), those with two types were identified as second line PTs (2 nd ), and those with three or more types were (3 rd ) line PTs. Kaplan-Meier survival curve was compared across the three groups using log-rank test. The impact of line of therapy on OS was further examined using multivariate Cox model with adjustment of PTs’ baseline age, race, Charlson Comorbidity Index (CCI), bisphosphonate use, and ECOG performance scores. Sensitivity analyses (SA) was conducted using different definition to define CT lines. Results: The study included148 PTs, with 86 (58.1%) as 1 st , 38 (25.7%) as 2 nd , and 24 (16.2%) as 3 rd , 29 (19.6%) median age 73 with a range from 18 to over 82, 52.7% as race White, 33.8% African American, and 13.5% other or unknown race, average weight was 179 LB (range 100-279), average baseline PSA was 694 ng/ml (range: 0.05-21,743), 14 (9.5%) patients ECOG score of 3 or 4, 131 (88.5%) with one or more CCI comorbid conditions. Median survival was 17 months for overall, and 12, 19, and 23 months for 1 st , 2 nd , and 3 rd line PTs, respectively (P=0.0355). Multivariate COX model found a higher likelihood of survival for 2 nd line PTs (HR=0.361, P=0.006), but not for 3 rd line PTs (HR=1.25, P=0.648). SA showed same results. Conclusions: This study suggested that second line of CT was associated with prolonged OS in metastatic CRPC. 3 rd line CT survival benefit was not observed. Limitations include potential channeling bias and small sample size.
Molecular and Genomic Determinants of Response to Immune Checkpoint Inhibition in Cancer
Authors: Russell W. Jenkins, Rohit Thummalapalli, Jacob Carter, Israel Cañadas, David A. Barbie
Journal: Annual Review of Medicine (2017)

Molecularly targeted therapy and immunotherapy have dramatically changed the landscape of available treatment options for patients with advanced cancer. Improved understanding of the molecular and genomic features of cancers over the last decade has led to the development of successful targeted therapies and the field of precision cancer medicine. As a result of these advances, patients whose tumors harbor select molecular alterations are eligible for treatment with targeted therapies active against the unique molecular aberration. Concurrently, advances in tumor immunology have led to the development of immunomodulatory antibodies targeting T cell coinhibitory receptors CTLA-4 and PD-1 (programmed death-1) that have shown activity in several cancer histologies, reinvigorating antitumor immune responses in a subset of patients. These immunomodulatory antibodies offer the promise of durable disease control. However, discrete genomic determinants of response to cancer immunotherapy, unlike molecularly targeted therapies, have remained elusive, and robust biomarkers are lacking. Recent advances in tumor profiling have begun to identify novel genomic features that may influence response and resistance to cancer immunotherapy, including tumor mutational burden (e.g., microsatellite instability), copy-number alterations, and specific somatic alterations that influence immune recognition and response. Further investigation into the molecular and genomic features of response and resistance to cancer immunotherapy will be needed. We review the recent advances in understanding the molecular and genomic determinants of response to cancer immunotherapy, with an emphasis on immune checkpoint inhibitors.
Extramedullary Sites of Involvement in Hematologic Malignancies
Authors: Asad Dean, Thomas E. Rogers, Jan Diehl, Jonathan E. Dowell
Journal: Journal of Clinical Oncology (2002)

Article Tools DIAGNOSIS IN ONCOLOGY Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2002.20.1.340 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 11773188 Extramedullary Sites of Involvement in Hematologic Malignancies Case 1. Multifocal Intracranial Involvement with Mantle-Cell Lymphoma Asad DeanxAsad DeanSearch for articles by this author , Thomas E. RogersxThomas E. RogersSearch for articles by this author , Jan DiehlxJan DiehlSearch for articles by this author , Jonathan E. DowellxJonathan E. DowellSearch for articles by this author Show More University of Texas-Southwestern and the Dallas Veterans’ Affairs Medical Center, Dallas, TX https://doi.org/10.1200/JCO.2002.20.1.340 First Page Full Text PDF Figures and Tables © 2002 by American Society of Clinical Oncology
Abstract 25: The Use of Voltage Mapping for Slow Pathway Visualization and Ablation of Atrioventricular Nodal Reentry Tachycardia in Pediatric and Young Adult Patients
Authors: Lindsey Malloy, Ian Law, Nicholas Von Bergen
Journal: Circulation Research (2012)

Atrioventricular nodal reentry tachycardia (AVNRT) is a common arrhythmia in both pediatric and adult patients. Ablation of the arrhythmia substrate has typically been guided by anatomical location and electrogram morphology within the triangle of Koch. Using an anatomic approach can be challenging because of unusual pathway locations and anatomic variance. The use of voltage gradient mapping has been proposed in adults to aid in identification of the “slow pathway”, guiding placement of the ablation applications. The purpose of this study was to evaluate this novel technique of voltage guided ablation of AVNRT in a pediatric patient population, with a smaller triangle of Koch. Patients with atrioventricular nodal reentry tachycardia at the University of Iowa Children’s Hospital who underwent voltage mapping within the slow pathway area were included. Using intracardiac electrical recordings, three-dimensional voltage maps of the right atrium were created. A voltage map identified a bridge of lower voltage signals surrounded by even lower voltage tissue. This bridge was used to guide cryoablation of the slow pathway. Patient demographics, appearance of the intracardiac voltage mapping, timing of procedure, lesions to success, and total number of lesions was obtained. In this study there were 29 patients with an average age of 14 years (range 7 to 20 years) who underwent AVNRT ablation with voltage mapping. Ten were male. In these patients there was procedural success (no inducible AVNRT, single AV node echo beat or less) in all patients. In 25 of 29 patients, there was an adequate lower voltage saddle to allow guided ablation. The successful ablation site was within the first three lesions in 15/25 patients. Total lesions ranged from 5-34. There has been recurrence in 1 patient over an average follow-up period of one year (range five months - twenty months). The use of voltage guided ablation of a low voltage saddle in atrioventricular nodal reentry tachycardia is a technique that appears to be effective and safe in the pediatric population and has the advantage of allowing an electrically guided ablation therapy. Voltage guided ablation of atrioventricular nodal reentry tachycardia is a safe and effective technique for ablating AVNRT.
A Tunable Diffusion-Consumption Mechanism of Cytokine Propagation Enables Plasticity in Cell-to-Cell Communication in the Immune System
Authors: Alon Oyler-Yaniv, Jennifer Oyler-Yaniv, Benjamin M. Whitlock, Zhiduo Liu, Ronald N. Germain, Morgan Huse, Grégoire Altan-Bonnet, Oleg Krichevsky
Journal: Immunity (2017)