tbuckley/cabot-search huggingface dataset:
Long-term safety and survival outcomes from the Scandinavian Breast Group 2004–1 (SBG 2004-1) randomized trial of tailored dose adjuvant chemotherapy for early breast cancer.
Authors: Alexios Matikas, Sara Margolin, Mats Hellstrom, Hemming Johansson, Nils-Olof Bengtsson, Lena Carlsson, Per Edlund, Per Karlsson, Elisabet Lidbrink, Barbro Kristina Linderholm, Henrik Lindman, Per Malmstrom, Kenneth Karl Villman, Theodoros Foukakis, Jonas C. S. Bergh
Journal: Journal of Clinical Oncology (2017)

e12036 Background: Although adjuvant polychemotherapy (ACT) improves outcomes for early breast cancer (BC), the significant interpatient variability in pharmacokinetics result in differences in efficacy and both short and long term toxicities. Dose tailored ACT has been shown to improve outcomes, while tailored and dose dense therapy improved 5-year event free survival in the phase 3 PANTHER trial. Methods: The SBG 2004-1 trial was a randomized feasibility/phase II study which assessed dose tailored epirubicin and cyclophosphamide (EC) followed by docetaxel (T), compared to the same fixed dose schedule and to the TAC regimen (table 1). Women aged 18-65 years old, ECOG PS 0-1 with at least one positive lymph node were randomized 1:1:1. The primary endpoint of the study was the safety and feasibility of the administered treatment. The secondary endpoint of the study was to evaluate the dose-intensity of the treatment. Toxicity was graded according to CTC-AE version 3.0. The design and short-term safety results of the trial have been previously published. Here, we report safety and efficacy data after 10 years follow-up. Results: A total of 124 patients were included and &gt;95% of patients without relapse were followed for 10 years.Five secondary malignancies but no myelodysplastic syndrome / acute myeloid leukemias were reported. Long term disease-free and overall survival results will be presented at the meeting. Conclusions: Long term safety results from this study in combination with efficacy results from the PANTHER trial imply the feasibility of a tailor-based approach for ACT in early BC. [Table: see text]
Efficacy/safety of epacadostat plus pembrolizumab in triple-negative breast cancer and ovarian cancer: Phase I/II ECHO-202 study.
Authors: Alexander I. Spira, Omid Hamid, Todd Michael Bauer, Virginia F. Borges, Jeffrey S. Wasser, David C. Smith, Amy Sanders Clark, Emmett V. Schmidt, Yufan Zhao, Janet E. Maleski, Tara C. Gangadhar
Journal: Journal of Clinical Oncology (2017)

1103 Background: Epacadostat is an oral, potent, and selective inhibitor of indoleamine 2,3-dioxygenase 1, a tryptophan-catabolizing enzyme that induces immune tolerance via T-cell suppression and is associated with poor patient (pt) survival when overexpressed in some cancers. The ongoing, open-label, phase 1/2 (P1/2) ECHO-202/KEYNOTE-037 study is evaluating the efficacy, safety, and tolerability of epacadostat plus PD-1 inhibitor pembrolizumab (E + P) in pts with advanced/recurrent cancers. We report P1/2 study outcomes for triple-negative breast cancer (TNBC) pts and P2 outcomes for ovarian cancer (OVC; no P1) pts as of a 29OCT2016 data cutoff. Methods: Eligible pts were ≥18 years old with no prior checkpoint inhibitor treatment (tx); prior platinum/taxane tx was required for OVC pts. As part of P1 dose escalation, TNBC pts received E (300 mg BID) + P (200 mg Q3W). In P2, TNBC and OVC pts received E (100 mg BID) + P (200 mg Q3W). Response (RECIST v1.1) was assessed in evaluable pts. Safety and tolerability were assessed in pts with ≥1 dose of E + P. Results: A total of 39 pts with TNBC and 37 with OVC were enrolled. The majority of TNBC pts (56%, n = 22) and OVC pts (78%, n = 29) received ≥3 prior lines of tx. For TNBC pts, ORR (CR+PR) was 10% (n = 4; all PR) and DCR (CR+PR+SD) was 36% (n = 14; 10 SD); ORR and DCR for pts with ≤2 prior tx were 12% (n = 2) and 29% (n = 5), respectively, and for ≥3 prior tx were 9% (n = 2) and 41% (n = 9). For OVC pts, ORR was 8% (n = 3; all PR) and DCR was 35% (n = 13; 10 SD); ORR and DCR for pts with ≤2 prior tx were 13% (n = 1) and 25% (n = 2), and for ≥3 prior tx were 7% (n = 2) and 38% (n = 11). The most common TRAEs (≥15% of pts) were rash (18%), fatigue (15%), and nausea (15%) in the 39 TNBC pts, and fatigue (19%) in the 37 OVC pts. Grade ≥3 TRAEs occurred in 13% of TNBC pts (n = 5; none in &gt; 1 pt) and 19% of OVC pts (n = 7; only rash occurred in &gt; 1 pt [n = 3]). TRAEs led to discontinuation in 1 TNBC pt (grade 3 ascites) and 1 OVC pt (grade 2 arthralgia). Conclusions: E + P tx was generally well tolerated and showed antitumor activity consistent with previously reported P monotherapy in pts with advanced TNBC or OVC. Biomarker analysis is ongoing to characterize pt populations enrolled in this study. Clinical trial information: NCT02178722.
Nonalcoholic fatty liver disease and COPD: is it time to cross the diaphragm?
Authors: Amedeo Lonardo, Fabio Nascimbeni, Maurizio Ponz de Leon
Journal: European Respiratory Journal (2017)

In this issue of European Respiratory Journal , Viglino et al. [1] report that nonalcoholic fatty liver disease (NAFLD) is highly prevalent in chronic obstructive pulmonary disease (COPD) and might contribute to cardiometabolic comorbidities. Pneumologists should be aware of possible liver comorbidities, including NAFLD, in their COPD patients <http://ow.ly/WudH30btfqE>
Abstract TMEM-033: DEVELOPING A MONKEY MODEL FOR SPONTANEOUS TYPE I OVARIAN CANCER
Authors: Mildred Felder, Arvinder Kapur, Heather Simmons, David Abbott, Manish S. Patankar
Journal: Clinical Cancer Research (2017)

Abstract The goal of this research project is to investigate if Non-Human Primates (NHP) can serve as model for endometriosis-associated Type I ovarian cancer. Endometriosis is a spontaneously occurring condition in both women and rhesus macaques. Endometriosis is likely caused by aberrant retrograde menstruation of endometrial epithelium that implants and grows on the serosal surfaces of the ovaries, uterus, urinary bladder, intestines and abdominal peritoneum. Several studies have shown direct association between endometriosis and two histological subtypes of Type I ovarian cancer- clear cell ovarian carcinoma (CCOC) and low grade serous endometrioid ovarian cancer (EnOC). Genetically altered mouse models for Type I and II ovarian cancer and are contributing significantly to our understanding of the biology of this malignancy. Since rodents do not have menstrual cycles, there are no mouse models for spontaneous endometriosis and Type I ovarian tumors. On the other hand, between 10-30% of female rhesus macaques of reproductive age develop endometriosis. A survey of pathology reports at the Wisconsin National Primate Research Center (WNPRC) identified cases of ovarian and peritoneal neoplasia in monkeys that also had endometriosis. This is a typical feature of CCOC and EnOC in humans where tumors are found adjacent to atypical endometriotic lesions. We are conducting immunohistological analysis to study the molecular phenotype of endometriosis and the ovarian and peritoneal neoplasia in the rhesus macaque. We will discuss our findings on the expression of important molecular markers of ovarian cancer (CA125, EpCAM, mesothelin, ARID1A, and others) in the non-human primate reproductive organs as well as in endometriotic explants and in ovarian and peritoneal neoplasms from the female rhesus. The data we will present and our on-going efforts to sequence the genome and transcriptome of normal and aberrant reproductive tissue samples of female rhesus monkeys will be essential in determining if the rhesus can be used as a model for CCOC and EnOC. Citation Format: Mildred Felder, Arvinder Kapur, Heather Simmons, David Abbott, and Manish S. Patankar. DEVELOPING A MONKEY MODEL FOR SPONTANEOUS TYPE I OVARIAN CANCER [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr TMEM-033.
Genetic History of Xinjiang’s Uyghurs Suggests Bronze Age Multiple-Way Contacts in Eurasia
Authors: Qidi Feng, Yan Lu, Xumin Ni, Kai Yuan, Yajun Yang, Xiong Yang, Chang Liu, Haiyi Lou, Zhilin Ning, Yuchen Wang, Dongsheng Lu, Chao Zhang, Ying Zhou, Meng Shi, Lei Tian, Xiaoji Wang, Xi Zhang, Jing Li, Asifullah Khan, Yaqun Guan, Kun Tang, Sijia Wang, Shuhua Xu
Journal: Molecular Biology and Evolution (2017)

The Uyghur people residing in Xinjiang, a territory located in the far west of China and crossed by the Silk Road, are a key ethnic group for understanding the history of human dispersion in Eurasia. Here we assessed the genetic structure and ancestry of 951 Xinjiang's Uyghurs (XJU) representing 14 geographical subpopulations. We observed a southwest and northeast differentiation within XJU, which was likely shaped jointly by the Tianshan Mountains, which traverses from east to west as a natural barrier, and gene flow from both east and west directions. In XJU, we identified four major ancestral components that were potentially derived from two earlier admixed groups: one from the West, harboring European (25–37%) and South Asian ancestries (12–20%), and the other from the East, with Siberian (15–17%) and East Asian (29–47%) ancestries. By using a newly developed method, MultiWaver, the complex admixture history of XJU was modeled as a two-wave admixture. An ancient wave was dated back to ∼3,750 years ago (ya), which is much earlier than that estimated by previous studies, but fits within the range of dating of mummies that exhibited European features that were discovered in the Tarim basin, which is situated in southern Xinjiang (4,000–2,000 ya); a more recent wave occurred around 750 ya, which is in agreement with the estimate from a recent study using other methods. We unveiled a more complex scenario of ancestral origins and admixture history in XJU than previously reported, which further suggests Bronze Age massive migrations in Eurasia and East-West contacts across the Silk Road.
Abstract MIP-060: EPIGENETIC DYSREGULATION OF A HISTONE MARK REVEALS A METABOLIC VULNERABILITY IN OVARIAN CANCER
Authors: Jagmohan Hood, Marián Novak, Emily MacDuffie, Jenny Lester, Vinita Parkash, Gordon B. Mills, Beth Y. Karlan, Moshe Oren, Ronny Drapkin
Journal: Clinical Cancer Research (2017)

Abstract High-grade serous ovarian cancer (HGSOC) is frequently complicated by the inevitable development of therapeutic resistance, and thus remains an incurable disease. Recent insights supporting the fallopian tube epithelium (FTE) as the tissue of origin and serous tubal intraepithelial carcinomas (STICs) as the precursor lesion for the majority of HGSOCs provide a necessary context to study the mechanisms that drive the development and progression of HGSOC. Understanding these key molecular processes is essential to inform the development of next generation therapies. In this study we investigated the role of the ubiquitin ligase RNF20 and histone H2B monoubiquitylation (H2Bub1) in serous tumorigenesis. H2Bub1, catalyzed largely by RNF20, is an epigenetic mark with tumor suppressor properties. Conversely, the loss of RNF20/H2Bub1 has been linked with cancer progression. By analyzing the TCGA data we found that heterozygous loss of RNF20 defines the majority of HGSOC tumors. Our IHC results show that H2Bub1 is lost or downregulated in a large proportion of STICs and invasive HGSOC tumors, implicating RNF20/H2Bub1 loss as an early event in serous ovarian cancer tumorigenesis. Functionally, we demonstrated that shRNA-mediated RNF20 knockdown, with concomitant H2Bub1 downregulation, was sufficient to increase cell migration and clonogenic growth of immortalized tubal epithelial cells as well as cells derived from invasive HGSOC. Subsequent proteomic profiling (RPPA), of RNF20/H2Bub1-depleted cells revealed pronounced changes in the steady-state levels of a number of metabolic and signaling pathways. In particular, two of the top differentially expressed proteins were glutaminase (GLS) and glutamate dehydrogenase (GLUD1/2), key enzymes in the glutamine metabolism pathway. These changes are predicted to result in elevated levels of glutamate that can fuel the TCA cycle, amino acid biogenesis, and/or glutathione production. We hypothesize that loss of RNF20/H2Bub1 rewires glutamine metabolism in cancer cells and leads to an increase in transamination and glutathione production which fuels the progression of HGSOC. In conclusion, our study identifies that loss of H2Bub1 is an early epigenetic event in HGSOC progression, which rewires glutamine metabolism and may represent a unique therapeutic vulnerability. Citation Format: Jagmohan Hood, Marián Novak, Emily MacDuffie, Jenny Lester, Vinita Parkash, Gordon B. Mills, Beth Y. Karlan, Moshe Oren, and Ronny Drapkin. EPIGENETIC DYSREGULATION OF A HISTONE MARK REVEALS A METABOLIC VULNERABILITY IN OVARIAN CANCER [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr MIP-060.
SWOG S0221 updated: Randomized comparison of chemotherapy schedules in breast cancer adjuvant therapy.
Authors: G. Thomas Budd, William E. Barlow, Halle C. F. Moore, Timothy J. Hobday, James A. Stewart, Claudine Isaacs, Muhammad Salim, Jonathan K. Cho, Kristine Rinn, Kathy S. Albain, Helen K. Chew, Gary Von Burton, Timothy David Moore, Gordan Srkalovic, Bradley Alexander McGregor, Lawrence E. Flaherty, Robert B. Livingston, Danika L Lew, Julie Gralow, Gabriel N. Hortobagyi
Journal: Journal of Clinical Oncology (2017)

521 Background: S0221 investigated weekly vs q 2 week dosing of doxorubicin/cyclophosphamide (AC) and paclitaxel (P) in patients (pts) with high risk early breast cancer as previously reported (JCO 33:58-64, 2015). After enrollment of 2716 pts randomization to the two AC arms was stopped for futility and an additional 578 pts received 4 cycles of q 2 week AC and were randomized to P weekly (Pw) or P q 2 weeks (P2). We report updated results of the original trial design and the first report of the 578 pts treated with AC x 4 and Pw x 12 or P2 x 6. Methods: Between December 2003 and November 2010, 2716 pts were randomized in a 2x2 factorial design to 1) 15 weeks of weekly AC (A 24 mg/m2/week and C 60 mg/m2/day po) vs 6 cycles of q 2 week AC (A 60 mg/m2 and C 600 mg/m2) and 2) Pw (paclitaxel 80 mg/m2/week x 12) vs P2 (paclitaxel 175 mg/m2 q 2 weeks x 6), with growth factor support as previously described. After study amendment 578 patients received 4 cycles of q 2 week AC followed by Pw or P2. Updated survival was assessed using log-rank tests and Cox regression models. Results: At a median follow-up of 8.5 years, among the pts treated in the original protocol, there were no significant differences among the four treatments for DFS (p=0.21) or OS (p=0.08). The triple-negative subset had worse DFS (P&lt;0.001) than the HER2-positive or ER/PR+/HER2- subsets, with 5 year DFS of 75% vs 83% and 84%, respectively. While we previously found in the triple negative subset that the arm using q 2 weeks for both AC and paclitaxel was marginally superior, the differences among the arms are no longer significant for DFS (p=0.12) or OS (p=0.11). Among the 578 pts assigned ACx4 and randomized to Pw v P2 there were no overall differences in DFS (p=0.70) or OS (p=0.63) after 4.4 years median follow-up. Conclusions: There were no significant differences in DFS or OS between any of the schedules with extended follow-up in the original cohort and no difference in outcome by paclitaxel schedule for the 578 additional patients in the revised protocol. Either paclitaxel schedule may be recommended, with selection based on toxicity, cost, or patient preference rather than efficacy. Support: NCI grants CA32102, CA38926, CA21115, CA21076, CA77597, CA25224, CA77202, CCSRI15469, and Amgen, Inc. Clinical trial information: NCT00070564.
Abstract AP09: GENOMIC ALTERATIONS IN ENDOMETRIOSIS
Authors: Michael S. Anglesio, Tayyebeh M. Nazeran, Hugo M. Horlings, Vivian Lac, Amy Lum, Janine Senz, Julie Ho, Amy Wang, Fontayne Wong, Catherine Allaire, Christina Williams, C. Blake Gilks, Paul J. Yong, David G. Huntsman
Journal: Clinical Cancer Research (2017)

Abstract BACKGROUND: Endometriosis affects ~10% of reproductive–aged women and is characterized by extra–uterine biphasic growth of uterine endometrial epithelium and stroma. Endometriosis is widely considered to be a hormonally–dependent inflammatory condition and is classified into three anatomically defined types: deep infiltrating endometriosis that locally invades pelvic organs; ovarian endometriotic cysts, and superficial peritoneal endometriosis. A clonal “precursor–cancer” link to co–occurring clear cell and endometrioid ovarian cancers has been established and somatic mutations occur in these cancer–associated endometriotic cysts, including distant benign–appearing lesions. The spectrum of genetic alteration in non–cancer associated endometriosis is not known. METHODS: We screened a pilot series of 10 deep–infiltrating [pelvic] endometriosis lesions, without co–occurrence or history of cancer, for somatic alterations using laser captured endometrial stroma and epithelium. Two overlapping amplicon panels and digital PCR were used to validate mutations. RESULTS: In four of ten cases we validated the presence of activating codon 12 KRAS mutations. Mutations were restricted to the epithelium and no evidence of any alterations was found in the stromal fraction. CONCLUSIONS: We provide incontrovertible evidence of activating KRAS mutations in 40% of deep infiltrating endometriosis. This frequency of KRAS mutations is substantially higher than what has been observed in clear cell (CCOC) or endometrioid (ENOC) ovarian cancers and the occurrence of non–ovarian primary CCOC/ENOC is largely anecdotal. Our evidence suggests that these mutations represent core features of endometriosis itself, rather than a risk of malignant transformation. Overall we propose this as an opportunity to fundamentally shift the study of endometriosis to a spectrum of neoplasms. This may lead to the generation of a molecularly informed classification system and ultimately to improved prognostication and treatment. Citation Format: Michael S. Anglesio, Tayyebeh M. Nazeran, Hugo M. Horlings, Vivian Lac, Amy Lum, Janine Senz, Julie Ho, Amy Wang, Fontayne Wong, Catherine Allaire, Christina Williams, C. Blake Gilks, Paul J. Yong, and David G. Huntsman. GENOMIC ALTERATIONS IN ENDOMETRIOSIS [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr AP09.
Safety of trastuzumab in women with HER2+ breast cancer.
Authors: Somaira Nowsheen, Khaled Aziz, Jae Yoon Park, Hector R. Villarraga, Joerg Herrmann, Kathryn Jean Ruddy
Journal: Journal of Clinical Oncology (2017)

e12522 Background: Trastuzumab is widely used in management of HER2+ breast cancer patients. A known adverse effect of trastuzumab use is cardiac dysfunction, which can often be reversed with cessation of therapy. Our objectives were to 1) assess if trastuzumab can be safely administered to breast cancer patients with reduced cardiac function and 2) identify patient characteristics that predict susceptibility to trastuzumab-induced cardiac dysfunction. Methods: A retrospective analysis was performed on female patients seen at Mayo Clinic for HER2+ breast cancer and treated with trastuzumab for localized or metastatic disease between January 1, 2000 and August 31, 2015. Eligibility criteria included documentation of and results from at least one echocardiogram prior to and at least one after trastuzumab initiation. Left ventricular (LV) ejection fraction (EF) of 53% or more was considered normal. Any LVEF reduction of 10% or more was considered significant. Among patients with normal EF, age strata of &lt; 45, 45-60, and &gt; 60 at time of trastuzumab initiation were used to assess risk factors for clinically diagnosed cardiac dysfunction (defined as EF &lt; 53 or abnormal strain and physical symptoms of heart failure (HF)). Results: We identified 335 women (mean age 53.3, with 25.3% age &lt; 45, 44.5% age 45-60, and 30.1% age &gt; 60) who had normal LVEF (median EF 64, range: 53-75) and 23 women (mean age 53.4, with 30.4% age &lt; 45, 43.5% age 45-60, and 26.1% age &gt; 60) who had low LVEF at baseline (median EF 52, range: 25-52). Approximately a third (34.3%) of women with normal LVEF prior to initiation of therapy had at least one subsequent echocardiogram showing a drop of 10% or a low LVEF ( &lt; 53). Approximately a quarter (26%) of women with low LVEF at baseline had a 10% drop in LVEF. HF incidence increased with age. Predictive factors for trastuzumab-induced cardiac dysfunction were obesity and history of coronary artery disease (CAD) across all age strata, and chest irradiation (IR) for those aged 45-60 only. Conclusions: Our results suggest that trastuzumab can be administered in women with reduced cardiac function at no greater risk than in those with preserved cardiac function. Some women with no obesity, history of CAD, or history of chest IR may not need echocardiograms during trastuzumab therapy.
Obstructive Sleep Apnea and Retinopathy in Patients with Type 2 Diabetes. A Longitudinal Study
Authors: Quratul A. Altaf, Paul Dodson, Asad Ali, Neil T. Raymond, Helen Wharton, Hannah Fellows, Rachel Hampshire-Bancroft, Mirriam Shah, Emma Shepherd, Jamili Miah, Anthony H. Barnett, Abd A. Tahrani
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

Obstructive sleep apnea (OSA) is associated with several pathophysiological deficits found in diabetic retinopathy (DR). Hence, it's plausible that OSA could play a role in the pathogenesis of sight-threatening DR (STDR).To assess the relationship between OSA and DR in patients with type 2 diabetes and to assess whether OSA is associated with its progression.A longitudinal study was conducted in diabetes clinics within two U.K. hospitals. Patients known to have any respiratory disorder (including OSA) were excluded. DR was assessed using two-field 45-degree retinal images for each eye. OSA was assessed using a home-based multichannel cardiorespiratory device.A total of 230 patients were included. STDR and OSA prevalence rates were 36.1% and 63.9%, respectively. STDR prevalence was higher in patients with OSA than in those without OSA (42.9% vs. 24.1%; P = 0.004). After adjustment for confounders, OSA remained independently associated with STDR (odds ratio, 2.3; 95% confidence interval, 1.1-4.9; P = 0.04). After a median (interquartile range) follow-up of 43.0 (37.0-51.0) months, patients with OSA were more likely than patients without OSA to develop preproliferative/proliferative DR (18.4% vs. 6.1%; P = 0.02). After adjustment for confounders, OSA remained an independent predictor of progression to preproliferative/proliferative DR (odds ratio, 5.2; 95% CI confidence interval, 1.2-23.0; P = 0.03). Patients who received continuous positive airway pressure treatment were significantly less likely to develop preproliferative/proliferative DR.OSA is associated with STDR in patients with type 2 diabetes. OSA is an independent predictor for the progression to preproliferative/proliferative DR. Continuous positive airway pressure treatment was associated with reduction in preproliferative/proliferative DR. Interventional studies are needed to assess the impact of OSA treatment on STDR.