tbuckley/cabot-search huggingface dataset:
Mitochondrial DNA haplogroups influence the risk of incident knee osteoarthritis in OAI and CHECK cohorts. A meta-analysis and functional study
Authors: Mercedes Fernández-Moreno, Angel Soto-Hermida, María E Vázquez-Mosquera, Estefanía Cortés-Pereira, Sara Relaño, Tamara Hermida-Gómez, Sonia Pértega, Natividad Oreiro-Villar, Carlos Fernández-López, Rafael Garesse, Francisco J Blanco, Ignacio Rego-Pérez
Journal: Annals of the Rheumatic Diseases (2016)

Objective To evaluate the influence of the mitochondrial DNA (mtDNA) haplogroups in the risk of incident knee osteoarthritis (OA) and to explain the functional consequences of this association to identify potential diagnostic biomarkers and therapeutic targets. Methods Two prospective cohorts contributed participants. The osteoarthritis initiative (OAI) included 2579 subjects of the incidence subcohort, and the cohort hip and cohort knee (CHECK) included 635, both with 8-year follow-up. The analysis included the association of mtDNA haplogroups with the rate of incident knee OA in subjects from both cohorts followed by a subsequent meta-analysis. Transmitochondrial cybrids harbouring haplogroup J or H were constructed to detect differences between them in relation to physiological features including specific mitochondrial metabolic parameters, reactive oxygen species production, oxidative stress and apoptosis. Results Compared with H, the haplogroup J associates with decreased risk of incident knee OA in subjects from OAI (HR=0.680; 95% CI 0.470 to 0.968; p&lt;0.05) and CHECK (HR=0.728; 95% CI 0.469 to 0.998; p&lt;0.05). The subsequent meta-analysis including 3214 cases showed that the haplogroup J associates with a lower risk of incident knee OA (HR=0.702; 95% CI 0.541 to 0.912; p=0.008). J cybrids show a lower free radical production, higher cell survival under oxidative stress conditions, lower grade of apoptosis as well as lower expression of the mitochondrially related pro-apoptotic gene BCL2 binding component 3 (BBC3). In addition, J cybrids also show a lower mitochondrial respiration and glycolysis leading to decreased ATP production. Conclusions The physiological effects of the haplogroup J are beneficial to have a lower rate of incident knee OA over time. Potential drugs to treat OA could focus on emulating the mitochondrial behaviour of this haplogroup.
Contemporary Assessment of Left Ventricular Diastolic Function in Older Adults
Authors: Amil M. Shah, Brian Claggett, Dalane Kitzman, Tor Biering-Sørensen, Jan Skov Jensen, Susan Cheng, Kunihiro Matsushita, Suma Konety, Aaron R. Folsom, Thomas H. Mosley, Jacqueline D. Wright, Gerardo Heiss, Scott D. Solomon
Journal: Circulation (2016)

Background: Although age-associated changes in left ventricular diastolic function are well recognized, limited data exist characterizing measures of diastolic function in older adults, including both reference ranges reflecting the older adult population and prognostically relevant values for incident heart failure (HF), as well as their associations with circulating biomarkers of HF risk. Methods: Among 5801 elderly participants in the ARIC study (Atherosclerosis Risk in Communities; age range, 67–90 years; mean age, 76±5 years; 42% male; 21% black), we determined the continuous association of diastolic measures (tissue Doppler imaging [TDI] e’, E/e’, and left atrial size) with concomitant N-terminal pro-brain natriuretic peptide and subsequent HF hospitalization or death. We also determined sex-specific 10th and 90th percentile limits for these measures using quantile regression in 401 participants free of prevalent cardiovascular disease and risk factors. Results: Each measure of diastolic function was robustly associated with N-terminal pro-brain natriuretic peptide and incident HF or death. ARIC-based reference limits for TDI e’ (4.6 and 5.2 cm/s for septal and lateral TDI e’, respectively) were substantially lower than guideline cut points (7 and 10 cm/s, respectively), whereas E/e’ and left atrial size demonstrated good agreement with guideline cut points. TDI e’ was nonlinearly associated with incident HF or death, with inflection points for risk supportive of ARIC-based limits. ARIC-based limits for diastolic function improved risk discrimination over guideline-based cut points based on the integrated discrimination improvement ( P &lt;0.001) and continuous net reclassification improvement ( P &lt;0.001), reclassifying 42% of the study population as having normal diastolic function. We replicate these findings in the Copenhagen City Heart Study. With these limits, 46% had normal diastolic function and were at low risk of HF hospitalization or death (1%/y over a mean 1.7-year follow-up), 49% had 1 or 2 abnormal measures and were at intermediate risk (2.4%/y), and all 3 diastolic measures were abnormal in 5% who were at high risk (7.5%/y). Conclusions: Our findings suggest that left ventricular longitudinal relaxation velocity declines as a part of healthy aging and is largely prognostically benign. The use of age-based normative values when considering an elderly population improves the risk discrimination of diastolic measures for incident HF or death.
Transfusion of CMV Seronegative T-Deplete Allogeneic Stem Cell Transplant Recipients with CMV Unselected Blood Products Confers a Zero Risk of CMV Transmission in the Era of Universal Leucodepletion: A UK Single-Centre Experience
Authors: Suzanne Hall, Sandeep Nagra, Husam Osman, Mark Cook, Charles F. Craddock, Sridhar Chaganti
Journal: Blood (2014)
Capecitabine in operable triple receptor–negative breast cancer: A subgroup analysis of a randomized phase III trial.
Authors: C. M. Kelly, M. C. Green, K. Broglio, L. Pusztai, E. Thomas, A. Brewster, V. Valero, N. K. Ibrahim, A. M. Gonzalez-Angulo, D. J. Booser, K. Hunt, G. N. Hortobagyi, A. Buzdar
Journal: Journal of Clinical Oncology (2011)

292 Background: Recent data suggest that patients with operable triple negative breast cancer (TNBC) may derive greater benefit from the addition of capecitabine to anthracycline-taxane regimens. Methods: We examined pathological complete response (pCR), relapse-free survival (RFS) and overall survival (OS) in patients with TNBC randomized to paclitaxel 80mg/m 2 weekly (WP) x 12 followed by fluorouracil (500mg/m 2 ), epirubicin (100mg/m 2 ), cyclophosphamide (500mg/m 2 ) every 3 weeks x 4 cycles (FEC) vs. docetaxel (75mg/m 2 ) 3 weekly and capecitabine D1-14 (1500mg/m 2 daily; DX) followed by FEC. Patients were stratified by timing of chemotherapy (preoperative vs. adjuvant). Results: 149 patients with TNBC comprising 25% of all patients randomized (N=601). Median age; 49 years (IQR; 41 to 55). The number and proportion of patients by stage were; I (n=32: 21.5%), IIA (n=72: 48.3%), IIB (n=34: 22.8%), IIIA (n=9: 6.0%) and IIIC (n=2; 1.3%). Preoperative therapy was administered to 58 patients (39%) and adjuvant to 91 (61%). There were 17 events (21%) in the DX arm and 10 events (15%) in the WP arm (P=0.36) including 11 distant recurrences in the DX arm and 9 in the WP arm (P=0.99). We observed a pCR in 11 patients (37%) and 10 (36%) in the DX and WP arms respectively (P=0.94). The odds ratio for pCR for patients with TNBC given DX vs. WP was 0.98 (95% CI; 0.33 to 2.80: P=0.94). At 50-months median follow-up the RFS and OS in patients with TNBC randomized to DX or WP was 77% (66 to 86%) and 83% (73 to 92%) (P=0.41) and 78% (67 to 87%) and 87% (77 to 95%) (P=0.16) respectively. RFS and OS for WP vs. DX for non-TNBC was 93% (87 to 95%) and 92% (88 to 96%) (p=0.91) and 96% (92 to 98%) and 97% (94 to 99%) for WP and DX respectively (P=0.39). Conclusions: In this unplanned subgroup analysis there was no difference in pCR, RFS or OS in patients with operable TNBC randomized to WP or DX however, power is limited and should be considered when interpreting these data.
Prevalence of risk factors among patients with hepatocellular carcinoma (HCC) and the general population in an employer group database.
Authors: QuynhChau Diem Doan, Annette Beiderbeck, Qingshan Qian
Journal: Journal of Clinical Oncology (2012)

190 Background: Most US studies evaluating risk factors for HCC have used data from hospitals, cancer registries, or Veterans Affairs database. These data sources have small patient populations and limited generalizability. Methods: This study investigated the association between HCC and potential risk factors [hepatitis B and C virus (HBV, HCV), diabetes, alcoholism, cirrhosis, obesity, liver disease, dyslipidemia, hemochromatosis, and hypothyroidism] and compared to the general (non-HCC) population of ~60 million lives from an employer group database. A retrospective cohort analysis was conducted using the Marketscan Research Database from Thomason Reuters. Case patients had an ICD-9 diagnosis for HCC between 1/1/2001 – 12/31/2009 (index date) but no HCC diagnosis during 1-year prior to index date. Randomly selected control patients did not have HCC diagnosis, were matched 3:1 ratio and enrolled during same time period as matched case patients, and matched for age (+/− 1 year), gender, and geographical region. All patients were 18 - 65 years old and did not have any cancer diagnosis (except HCC for case patients). Data from 1-year prior to index date were used to identify risk factors. Demographic variables and prevalence of risk factors were analyzed using descriptive statistics. Multiple logistic regression was used to predict the odds of developing HCC compared to non-HCC patients for these risk factors. Results: The study included 1,208 case and 3,624 control patients. Mean age of cases and controls was 54 years and 67% were male. In unadjusted multiple logistic regression models, the risk for HCC was 48-fold and 135-fold increased for patients with HBV and HCV, respectively [95% confidence interval (CI): 6.2 – 374.4 for HBV, 31.5 – 580.8 for HCV]. Diabetes increased the risk for HCC by 3.85 (95% CI 2.5 – 5.9). Alcoholic cirrhosis and nonalcoholic (NA) fatty liver disease/NA steatohepatitis increased the risk for HCC by nearly 200-fold. Conclusions: Using a larger database, these study findings were consistent with previous research and provided further evidence that the risk of HCC is greatly increased in individuals diagnosed with hepatitis, diabetes, liver disease, and alcoholism.
Abstract 1683: Pharmacokinetic/pharmacodynamic (PK/PD) and toxicokinetic/toxicodynamic (TK/TD) modeling of preclinical data of FGFR2-ADC (BAY 1187982) to guide dosing in phase 1
Authors: Sabine Wittemer-Rump, Anette Sommer, Charlotte Kopitz, Hung Huynh, Christoph Schatz, Ruprecht Zierz, Manuela Braun, Kirstin Meyer, Dirk Laurent, Jörg Lippert, Klaas Prins
Journal: Cancer Research (2015)

Abstract BAY 1187982 is an antibody drug conjugate (ADC) directed against fibroblast growth factor receptor 2 (FGFR2). FGFR2 is overexpressed in several cancer indications, such as gastric, breast, and ovarian cancer. Anti-tumor efficacy of BAY 1187982 has been demonstrated in several FGFR2-positive cancer cell line as well as patient-derived xenograft models. Toxicology findings from repeated dose preclinical safety studies in monkeys indicated effects related to the liver, kidney, heart and coagulation system. To predict the therapeutic index of BAY 1187982 in humans and to support the design of the first-in-human (FIH) study with respect to selection of dose and regimen, preclinical efficacy and toxicity findings were quantified. All available preclinical PK, TK, tumor response and toxicity data from mouse models and monkey studies were used to create a model framework to describe the PK, TK, PK/PD and TK/TD relationship as functions of BAY 1187982 dose, regimen and time. Human PK parameters based on scaling from monkey were used to predict PK profiles in humans for a range of doses and schedules. These sets of predicted exposure models were combined with the PK/PD as well as the TK/TD model to assess the expected efficacy (according to RECIST criteria) and toxicity range in humans, respectively. The dosing schedule leading to the largest therapeutic index and the dose escalation schema for the FIH study were determined. The FIH study is currently under preparation. Citation Format: Sabine Wittemer-Rump, Anette Sommer, Charlotte Kopitz, Hung Huynh, Christoph Schatz, Ruprecht Zierz, Manuela Braun, Kirstin Meyer, Dirk Laurent, Jörg Lippert, Klaas Prins. Pharmacokinetic/pharmacodynamic (PK/PD) and toxicokinetic/toxicodynamic (TK/TD) modeling of preclinical data of FGFR2-ADC (BAY 1187982) to guide dosing in phase 1. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1683. doi:10.1158/1538-7445.AM2015-1683
Results by treatment modalities in multifocal/multicentric breast cancer: Retrospective analysis of 162 patients.
Authors: H. Kadioglu, M. Kayahan, Y. E. Ersoy, N. Memmi, S. Bozkurt, G. Cipe, M. Muslumanoglu
Journal: Journal of Clinical Oncology (2011)

266 Background: The prognostic value of multifocal, multicentric breast cancer is still not well known. Although some studies have suggested that it is associated with a worst prognosis some have not suggest. We evaluated the effect of treatment modalities on overall survival and disease-free survival in breast cancer. Methods: One hundred and sixty two women with multifocal multicentric breast cancer diagnosed at our oncology center between January 2004 and December 2010 were retrospectively evaluated. Multifocality was defined as the presence of 2 or more foci of the tumor clearly separated in the same breast. Multicentricity was defined as the presence of 2 or more foci at different quadrants. Patients received neoadjuvant chemotherapy were excluded. Results: Median age of 162 women was 48 y ± 13,63 y. Eighty two of 162 patients were treated with breast-conserving surgery and 80 were treated with mastectomy. Radiotherapy was added to adjuvant therapy to patients with 4 or more positive axillary nodes and/or treated with breast conserving surgery. Three (1.8%) patients were excluded because of bilateral cancer and 1 (0.6%) was excluded because of Tx tumor. Eleven of 162 (6.7%) patients were not seen after surgery so data about adjuvant treatment was not known. Fifty of 147 patients were stage III, 68 were stage II and 30 were stage I. 27 (17.2%) patients received anthracycline based chemotherapy, 30 (20.3%) patients received hormonotherapy and 91 (56.1%) patients received taxane based chemotherapy. Trastuzumab added to the treatment at all patients, if HER2 neu-positive. Median follow up was 41 ± 4.1 (72-9 months) months. 30 systemic diseases at 24 patients were seen on follow up. 18 patients were in taxane group, 4 patients were in anthracycline group, 2 patients were in hormonotheraphy group. Nine patients were died in taxane group, 1 died in anthracycline group and 1 died in hormonotherapy group. Conclusions: Our retrospective analysis showed worst prognosis at taxane group but; patients with positive lymph nodes and perinodal invasion gets taxane based treatments. This retrospective analysis showed that systemic recurrence and survival in multifocal breast cancer are similar with unifocal disease.
Small cell carcinoma of the genitourinary tract: A 10-year single institution experience.
Authors: Faraj El-Gehani, Arunee Dechaphunkul, Muna Kamal, Danielle Pertschy, Kurian Joseph, Scott A. North, Peter Venner, Nadeem Pervez
Journal: Journal of Clinical Oncology (2012)

312 Background: Small cell carcinoma (SCC) of the genitourinary (GU) tract is rare and there is no standard treatment strategy for managing these patients. The objective of this study is to report the clinical experience and management of patients with SCC of the GU tract, treated in the Cross Cancer Institute, Edmonton, AB, Canada from 1999 to 2009. Methods: A retrospective chart review of all patients diagnosed with SCC of the GU tract between 1999 to 2009 was undertaken. Data was collected on demographics, clinical and pathological characteristics, and patient outcomes. Results: Fifty-eight patients were identified with primary sites as follows: urinary bladder (UB) 35 (60%), prostate 17 (29%) and upper urinary tract (UUT) 6 (11%). Mean age for the entire group was 68 years; 12/58 were female and 46/58 were male. Sixty-six percent (37/58) had pure SCC; the rest had mixed histology. Seventy percent (41/58) were positive for at least one neuroendocrine marker. Overall, 27/58 had limited stage disease, 25/58 had extensive disease and six were unknown. Treatment of limited stage patients was 10/27 (37%) concurrent chemotherapy with radiation, 5/27 (19%) surgery +/- adjuvant chemotherapy, 5/27 (19%) chemotherapy alone, 2/27 (7%) radiation alone and 5/27 (19%) supportive care only. For extensive stage patients, 5/25 (20%) received chemotherapy alone, 3/25 (12%) received radiation alone, 4/25 (16%) received RT and chemotherapy, 4/25 (16%) surgery alone and 9/25 (36%) supportive care only. One patient with limited stage disease received prophylactic cranial irradiation. Despite this, only one patient in the entire cohort presented with brain metastases as the site of initial relapse. Median survival for the entire cohort was 24 months (28 months for limited stage disease and 7 months for extensive). Prostate patients tended to do worse, with a survival of only eight months. Conclusions: SCC of the GU tract is aggressive with an overall poor prognosis. As there is no standard of care for these patients, they are treated according to local protocols. Further efforts should be made to develop more effective treatments and the role of PCI should be investigated in the setting of a clinical trial, in conjunction with other extrapulmonary SCCs.
Regression of a CD30-Positive Primary Cutaneous T-Cell Lymphoproliferation after Ribavirin Treatment of Chronic Hepatitis E Virus Infection
Authors: Julie Bruneau, Vincent Mallet, Julien Zuber, Cecile Alanio, Stephanie Leclerc, Zakia Choucair, Kraft Anke, Dominique Roulot, Anne-Marie Roque, Heiner Wedemeyer, Stanislas Pol, Patrick Hillon, Bruno R. Varet, Olivier Hermine
Journal: Blood (2016)
Addressing the Role of Obesity in Endometrial Cancer Risk, Prevention, and Treatment
Authors: Michaela A. Onstad, Rosemarie E. Schmandt, Karen H. Lu
Journal: Journal of Clinical Oncology (2016)

In sharp contrast to many other cancer types, the incidence and mortality of endometrial cancer continue to grow. This unfortunate trend is, in no small part, a result of the worldwide obesity epidemic. More than half of endometrial cancers are currently attributable to obesity, which is recognized as an independent risk factor for this disease. In this review, we identify the molecular mechanisms by which obesity and adipose tissue contribute to the pathogenesis of endometrial cancer. We further discuss the impact of obesity on the clinical management of the disease and examine the development of rational behavioral and pharmaceutical interventions aimed at reducing endometrial cancer risk, improving cancer outcomes, and preserving fertility in an increasingly younger population of patients with endometrial cancer.
Adolescent intakes of alcohol and folate and risk of proliferative benign breast disease.
Authors: Y. Liu, R. M. Tamimi, C. S. Berkey, W. C. Willett, L. C. Collins, S. J. Schnitt, G. A. Colditz
Journal: Journal of Clinical Oncology (2011)

169 Background: Given the importance of exposure between menarche and first childbirth in breast cancer risk, adolescent alcohol consumption may influence the risk of proliferative benign breast disease (BBD). Folate may modify the adverse effect of alcohol on breast cancer. Methods: We used data from 29,329 women in the Nurses’ Health Study II who completed both adolescent alcohol consumption questions in 1989 and an adolescent diet questionnaire in 1998. A total of 666 women with proliferative BBD between 1991 and 2001 were confirmed by centralized pathology review. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), adjusted for established risk factors of breast cancer. Results: Adolescent alcohol consumption was dose-dependently associated with an increased risk of proliferative BBD (HR = 1.12 per 10g/day consumption; 95% CI, 1.03-1.22). There was no significant association with adolescent folate intake. While the interaction between adolescent alcohol and folate intake was not statistically significant, among women with low folate intake (&lt;279 mg/day) the BBD risk was significantly increased with moderate alcohol intake (HR = 1.62; 95% CI, 1.14-2.28) and with high alcohol intake (HR = 1.90; 95% CI, 0.98-3.70; P trend &lt;0.01). Adolescent alcohol consumption was not associated with increased risk among women with higher adolescent folate intake. Conclusions: Adolescent alcohol consumption is associated with higher risk of proliferative BBD, especially in women with low adolescent folate intake.
Exemestane for primary prevention of breast cancer in postmenopausal women: NCIC CTG MAP.3—A randomized, placebo-controlled clinical trial.
Authors: P. E. Goss, J. N. Ingle, J. Ales-Martinez, A. Cheung, R. T. Chlebowski, J. Wactawski-Wende, A. McTiernan, J. Robbins, K. Johnson, L. Martin, E. Winquist, G. Sarto, J. E. Garber, C. J. Fabian, P. Pujol, E. Maunsell, P. Farmer, K. A. Gelmon, D. Tu, H. Richardson
Journal: Journal of Clinical Oncology (2011)

LBA504 Background: Limited efficacy and serious toxicities have limited uptake of tamoxifen or raloxifene as preventatives of breast cancer. Aromatase inhibitors (AIs) prevent contralateral breast cancers more than tamoxifen in adjuvant trials and have fewer serious side effects. This is the first report of an AI used in primary prevention. Methods: NCIC CTG MAP.3 is a randomized trial designed to detect a 65% reduction in annual incidence of invasive breast cancer (IBC) on exemestane (E) versus placebo (P). Eligible postmenopausal women had ≥ one of the following risk factors: Gail score &gt;1.66%, prior ADH, ALH, LCIS or DCIS with mastectomy, age over 60. Health-related and menopause-specific quality of life (QOL) were assessed by SF-36 and MENQOL questionnaires. Results: From 2004-2010, 4,560 women were randomized: age 62.5 yrs (37-90); Gail Score 2.3 % (0.6-21); BMI 28.0 kg/m2 (15.9-65.4). Risk factors included: age &gt;60 yrs (49%); Gail score &gt;1.66 (40%); and prior ADH, ALH, LCIS or DCIS with mastectomy (11%). At median follow-up of 35 months there were 11 IBCs on E and 32 on P (annual incidence 0.19% vs 0.55%; HR= 0.35, 95% CI 0.18-0.70, p = 0.002); ductal (10E/27P), lobular (1E/5P). Most tumors were ER positive (7E/27P); Her2/neu negative (10E/26P); TNM stage T1 (8E/28P), N0 (7E/22P), M0 (11E/30P). E was superior in all subgroups: by Gail score, age, BMI, prior LCIS and DCIS. The annual incidence rate of IBC or DCIS was 0.35% E and 0.77% P (HR=0.47;95% CI 0.27-0.79; p = 0.004) based on 64 IBCs or DCISs (20E/44P). Clinical bone fractures, osteoporosis, hypercholesterolemia or cardiovascular events were equal in both arms. No clinically meaningful differences in QOL were detected. Conclusions: Exemestane significantly reduced invasive and pre-invasive breast cancers in postmenopausal women at increased risk for breast cancer with no serious toxicities. Exemestane should be considered a new option for primary prevention of breast cancer. Supported by the Canadian Cancer Society; Pfizer Inc. PEG supported in part by Avon Foundation.
Possible predictive role of the soluble cd40 ligand (scd40l) in metastatic pancreatic ductal adenocarcinoma (PDAC) patients (pts) treated with first line folfirinox or gemcitabine/nab-paclitaxel combination
Authors: O. Brunetti, L. Porcelli, G. Graziano, V. Lorusso, M. Signorile, S. Delcuratolo, L. Palermo, G. Massiah, A. Azzariti, N. Silvestris
Journal: Annals of Oncology (2015)