tbuckley/cabot-search huggingface dataset:
Abstract DPOC-002: A NOVEL CELL LINE BASED IMMUNOHISTOCHEMICAL TP53 EXPRESSION PATTERN CONTROL PANEL
Authors: Viqar Syed, Imran Hussain, Jeptha Johnson, Patrick Malafronte, Justin Wells, Yaling Zhou, Deyin Xing, John D. Andersen
Journal: Clinical Cancer Research (2017)

Abstract BACKGROUND: TP53 gene mutation status is known to be manifested through distinct p53 immunohistochemical staining patterns; diffuse, “wild-type” and null. This stratified staining pattern is commonly utilized in subtyping ovarian and endometrial cancer subtypes as well as distinguishing between ovarian low- and high-grade serous carcinoma. EXPERIMENTAL PROCEDURES: Three ovarian cancer cell lines consistently demonstrating either diffuse, wild-type or null p53 staining were utilized in the construction of an immunohistochemical control panel slide that highlights each TP53 expression pattern. Cell lines were expanded, harvested and resuspended in agarose gel and subsequently sectioned onto a microscope slide (Figure 1A). Procured tissue specimens were submitted along with either standard control tissue or the TP53 cell line control panel to three pathologists of varying experience. RESULTS: Interobserver variability was demonstrated to be similar with the use of the TP53 expression panel (Fleiss kappa= 0.79 vs 0.76) and there was a net decrease in categorization errors. The TP53 cell line expression pattern control panel sections demonstrated consistent clean and easily interpretable diffuse, wild-type and null p53 staining (Figure 1B). CONCLUSIONS: We developed a novel cell line-based TP53 expression pattern control panel with refined quality assurance potential that would act, as a minimum, a model for antibody optimization. This study suggests the addition of a cell line TP53 control panel could potentially increase the accuracy of identification for ovarian and endometrial cancer subtypes as well as ovarian low grade versus high-grade serous carcinoma distinction. This control panel has the potential to be utilized in other disease states where TP53 expression pattern assists in diagnosis. Citation Format: Viqar Syed PhD, Imran Hussain, BSc, Jeptha Johnson MD, Patrick Malafronte MD, Justin Wells MD, Yaling Zhou PhD, Deyin Xing MD PhD, John D. Andersen DO. A NOVEL CELL LINE BASED IMMUNOHISTOCHEMICAL TP53 EXPRESSION PATTERN CONTROL PANEL [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 DPOC-002.
Phase I Trial of Cediranib in Combination with Cisplatin and Pemetrexed in Chemonaive Patients with Unresectable Malignant Pleural Mesothelioma (SWOG S0905)
Authors: Anne S. Tsao, James Moon, Ignacio I. Wistuba, Nicholas J. Vogelzang, Gregory P. Kalemkerian, Mary W. Redman, David R. Gandara, Karen Kelly
Journal: Journal of Thoracic Oncology (2017)
A phase I trial of mifepristone (M), carboplatin (C), and gemcitabine (G) in advanced breast and ovarian cancer.
Authors: Erica Michelle Stringer, Poornima Saha, April Swoboda, Masha Kocherginsky, Gabrielle Baker, Simona Olberkyte, Nana Owusu, Brittany Dyer, Lauren Olalde, Elizabeth Olszewski, Olwen Mary Hahn, Philip C. Hoffman, Brooke Elizabeth Phillips, Grace K. Suh, Suzanne D. Conzen, Gini F. Fleming, Rita Nanda
Journal: Journal of Clinical Oncology (2017)

1083 Background: Glucocorticoid receptor (GR) activity inhibits chemotherapy-induced apoptosis, and GR antagonism with m enhances chemotherapy sensitivity in GR+ breast (B) and ovarian cancer (OC) cells. C+G is a commonly used regimen for B and OC. We report the results of a phase I trial of the GR antagonist m plus C+G in patients with advanced B and OC. Methods: A standard “3+3” dose escalation phase I study was performed. Objectives were to assess the safety and tolerability of the regimen, and to determine the recommended phase 2 (RP2D) dose of M+C+G. C+G was administered on days 1 and 8 of a 21 day cycle, and m was administered the day prior to and the day of chemotherapy. The starting dose level (DL) was 1, with additional DLs as follows in the table. Results: 31 patients (pts) with a median age of 54 years (range 32-76) were enrolled. 18 pts had BC (3 ER+, 15 triple-negative), and 13 had high grade serous OC (11 platinum-sensitive, 2 platinum-resistant). The median number of prior therapies for advanced BC was 1 (range 0-5) and for OC was 2 (range 1-3). Dose de-escalation was necessary due to the DLT of neutropenia. After DL -3, prophylactic G-CSF (PGF) was instituted. The RP2D was C AUC 2, G 600 mg/m2, m 300 mg with PGF administered on day 9. Of the BC pts, 2 had a complete response (CR), 2 had a partial response (PR), 8 had stable disease (SD), 4 had progressive disease (PD). Of the OC pts, there was 1 CR (CR2 lasted &gt; 27 mos; CR1 lasted only 8 mos), 1 PR, 6 SD, and 3 PD. 4 pts were inevaluable for response. Conclusions: These data suggest that M+C+G is safe and tolerable, and the most common DLT is neutropenia. This was easily managed with the institution of PGF. Studies correlating tumor GR expression with response are ongoing, and may help identify patients who are most likely to benefit from this combination. Clinical trial information: NCT02046421. [Table: see text]
Lipid and Inflammatory Cardiovascular Risk Worsens Over 3 Years in Youth With Type 2 Diabetes
Journal: Diabetes Care (2013)

OBJECTIVE Type 2 diabetes increases cardiovascular risk. We examined lipid profiles and inflammatory markers in 699 youth with recent-onset type 2 diabetes in the TODAY clinical trial and compared changes across treatment groups: metformin alone (M), metformin plus rosiglitazone (M+R), and metformin plus intensive lifestyle program (M+L). RESEARCH DESIGN AND METHODS Multiethnic youth with type 2 diabetes received M, M+R, or M+L. Statin drugs were begun for LDL cholesterol (LDL) ≥130 mg/dL or triglycerides ≥300 mg/dL. Lipids, apolipoprotein B (apoB), LDL particle size, high-sensitivity c-reactive protein (hsCRP), homocysteine, plasminogen activator inhibitor-1 (PAI-1), and HbA1c were measured over 36 months or until loss of glycemic control. RESULTS LDL, apoB, triglycerides, and non-HDL cholesterol (HDL) rose over 12 months and then stabilized over the next 24 months. Participants with LDL ≥130 mg/dL or using LDL-lowering therapy increased from 4.5 to 10.7% over 36 months, while 55.9% remained at LDL goal (&amp;lt;100 mg/dL) over that time. Treatment group did not impact LDL, apoB, or non-HDL. Small dense LDL (particle size, ≤0.263 relative flotation rate) was most common in M. Triglycerides were lower in M+L than M, and M+L attenuated the negative effect of hyperglycemia on triglycerides and HDL in females. hsCRP, PAI-1, and homocysteine increased over time. However, hsCRP was lower in M+R compared with M or M+L. CONCLUSIONS Dyslipidemia and chronic inflammation were common in youth with type 2 diabetes and worsened over time. Diabetes treatment, despite some treatment group differences in lipid and inflammatory marker change over time, is generally inadequate to control this worsening risk.
Improving the effectiveness of neoadjuvant chemotherapy in patients with breast cancer with positive estrogen receptor (HR) and HER2 negative.
Authors: Serafin Morales, Ariadna Gasol Cudós, Juan Felipe Cordoba Ortega, Maria Jose Panades Siurana, Felip Vilardell, Edelmiro Iglesias, Antonieta Salud Salvia
Journal: Journal of Clinical Oncology (2017)

e12120 Background: The effect of pathologic complete response (pCR) after neoadjuvant chemotherapy is considered independent of the breast cancer subtype, but the pCR rate in HR positive/HER2 negative patients is smaller than other subtype so it is interpreted as pCR is not being prognostic in luminal breast cancer. In large series residual cancer burden (RCB) assessed by Symmans methods is prognostic in luminal patients if RCB-0 and RCB-I are combined. Methods: 166 patients (March 2000-august 2016) with neoadjuvant chemotherapy based treatment were retrospectively analysed in order to find if common clinicopathological factors could select patients with significative better response considered as pCR or RCB type 0 and I. Results: Median age was 53 years (29-82), median tumor size of 41 mm and 54% of tumors had initial nodal involvement. All patients were estrogen positive and 45% progesterone receptor negative with a median of ki67 expression of 32%. A total of 10% pCR rate was found and the response type RCB 0 and 1 according to Symmans method was 22%. In the univariate model we found and association with pCR and: progesterone receptor negative (p=0.017; OR 4,3), initial tumor size (p=0.026; OR 0,95) and Ki67 index &gt; 30% (p=0.009; OR 5.3). An association with progesterona receptor negative (p=0.008; OR 3,1) was found with the the RCB type 0 and I response. Conclusions: Factors related to better response to neaodjuvant chemotherapy are progesterone receptor negative and level of Ki67 index. Considering this parameters we could found a high rate of response with 24% of pCR and 35% of RGB type 0 and I being the best rate of response in luminal patients.
Abstract NTOC-101: INTRAPERITONEAL (IP) THERAPY FOR ADVANCED STAGE EPITHELIAL OVARIAN CANCER (EOC): THE CURRENT SPOTLIGHT IS ON CARBOPLATIN AND QUALITY OF LIFE
Authors: Franco Muggia, Lari Wenzel
Journal: Clinical Cancer Research (2017)

Abstract PURPOSE: First-line treatments for (EOC) have been platinum-based for more than three decades; 16 years ago the landmark Gynecologic Oncology Group (GOG158) non-inferiority trial for optimal stage III patients led to the universal adoption of IV carboplatin/paclitaxel as the standard systemic regimen. However, IV cisplatin-based doublets were the comparators in the first 3 GOG studies assessing IP cisplatin-based regimens. Our purpose is to describe recent randomized trials that have assessed IP carboplatin and highlight quality of life (QOL) findings. METHODS: Gynecology Oncology Group (GOG) studies comparing IP to IV cisplatin regimens formed the basis of the National Cancer Institute (NCI) 2005 Clinical Announcement that considered IP cisplatin-based therapy as a new standard for optimally debulked EOC. Recently, randomized trials with IV carboplatin/paclitaxel-based regimens as comparators have been part of preliminary reports: 1) GOG252 on March 2016 at the Society of Gynecologic Oncology (SGO), completing accrual in 2015, and 2) OV21/PETROC neoadjuvant randomized ‘pick the winner’ study at the June 2016 American Society of Clinical Oncology (ASCO). Beyond 2016, additional data is expected from the ongoing randomized study by the Japan GOG of IP versus IV carboplatin, --both with IV paclitaxel. RESULTS: GOG252, the largest Phase III study of IV versus IP platinum-based therapy for the first line treatment of ovarian cancer, is the first IP GOG trial with a IV carboplatin-based control arm. None of the 3 arms differed in median progression-free survival. However, the companion QOL study, --contrary to prior GOG studies utilizing IV cisplatin-based controls—showed a clear advantage for the two non-cisplatin arms (not different whether IV or IP). In the OV21/PETROC trial, adverse toxicities coupled with no obvious therapeutic advantage led to dropping the IP cisplatin arm. With additional accrual in the two remaining arms, IP carboplatin was superior to IV carboplatin in time to progression. CONCLUSIONS: Cisplatin has an unfavorable impact on QOL in women with ovarian cancer whether given IP or IV relative to carboplatin. With IV carboplatin as part of the comparator, unfavorable effects of cisplatin-based chemotherapy are further highlighted. IP carboplatin randomized studies and their final publications are awaited. On the other hand, revisiting the role of IP cisplatin at this time is not warranted. Citation Format: Franco Muggia MD, Lari Wenzel, PhD. INTRAPERITONEAL (IP) THERAPY FOR ADVANCED STAGE EPITHELIAL OVARIAN CANCER (EOC): THE CURRENT SPOTLIGHT IS ON CARBOPLATIN AND QUALITY OF LIFE [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 NTOC-101.
A phase II trial of the CDK4/6 inhibitor palbociclib (P) as single agent or in combination with the same endocrine therapy (ET) received prior to disease progression, in patients (pts) with hormone receptor positive (HR+) HER2 negative (HER2−) metastatic breast cancer (mBC) (TREnd trial).
Authors: Luca Malorni, Giuseppe Curigliano, Alessandro Marco Minisini, Saverio Cinieri, Carlo Tondini, Grazia Arpino, Lorenzo Pavesi, Angelo Martignetti, Carmen Criscitiello, Fabio Puglisi, Marta Pestrin, Giuseppina Sanna, Erica Moretti, Emanuela Risi, Chiara Biagioni, Luca Boni, Daniela Baldari, Marc E. Buyse, Laura Biganzoli, Angelo Di Leo
Journal: Journal of Clinical Oncology (2017)

1002 Background: P is approved for treatment of HR+/HER2− mBC combined with ET. There is paucity of clinical data of single-agent P in ET resistant pts. Pre-clinical data suggest P may partially reverse endocrine resistance, though this is yet to be tested in pts. Methods: This Phase II, open-label, multicenter study enrolled post-menopausal pts with HR+ HER2− mBC who progressed on 1 or 2 prior ETs. Pts were randomized to P (125 mg/d 3 w on/1 w off) alone or to continue their current ET (aromatase inhibitor or fulvestrant) in combination with P (same schedule as P arm). The primary endpoint was clinical benefit rate (CBR) [complete response (CR), partial response (PR) and stable disease (SD) for &gt; 6 months (mo)]. Secondary endpoints were adverse events (AE) and additional measures of efficacy. A two-stage optimal design assessed treatment activity in each arm assuming activity as CB≥40% (α and β = 10%). Exploratory comparisons were planned for safety and efficacy endpoints. Results: 115 pts were enrolled (ITT population) 58 in the P arm and 57 in the P+ET arm. In both arms, 67% of pts had the study treatment as second line ET, 33% as third line, and about 1/3 of pts also received 1 prior chemotherapy for mBC. CBR was similar in both arms: 54% (95% CI 42 - 67%) with P+ET, and 60% (95% CI 48 -73%) with P alone. Median duration of CB was longer with P+ET (11.5 mo; 95% CI 8.6 – 17.8) than with P (6 mo; 95% CI 3.9 - 9.9) (HR 0.31, 95% CI 0.1 - 0.7, p-value 0.001, exploratory). Objective response rate (ORR; CR, PR) was 11% (95% CI 3 - 19%) and 7% (95% CI 0.4 -13%) with P+ET and P, respectively. PFS was 10.8 mo (95% CI 5.6 - 12.7) with P+ET and 6.5 mo (95% CI 5.4 - 8.5) with P alone (HR 0.69, 95% CI 0.4 - 1.1, p-value 0.13, exploratory). AEs were in line with previous data. Conclusions: Single agent P has clinical activity in ET pre-treated HR+/HER2– mBC pts. The observed increase in PFS and duration of CB with P+ET may suggest that P could reverse resistance to the prior line of ET. Translational studies are ongoing to explore potential biomarkers in this setting. Clinical trial information: NCT02549430.
Early breast cancer in elderly patients: Characteristics, therapy, and long-term outcome.
Authors: Omer Gal, Yael Ishai, Daniel Hendler, Victoria Neiman, Dalia Zoref, Baruch Brenner, Rinat Yerushalmi
Journal: Journal of Clinical Oncology (2017)

e12046 Background: The number of older adults diagnosed with breast cancer and the number of breast cancer survivors is on the rise. The majority of women with breast cancer are diagnosed with an early stage (non-metastatic) potentially curable disease. However, data regarding breast cancer characteristics, treatment, and survival for elderly women are sparse. Methods: We retrospectively reviewed all women with invasive, non-metastatic breast cancer treated in our tertiary medical cancer center from January 2004 to December 2007. Patients were divided into 2 groups: those aged 65-75 years and those aged &gt;75 years. Data on tumor characteristics, treatment modalities, and outcome were retrieved from the patient computerized medical files and compared between the groups. Results: The study group comprised 390 patients. Of them, 252 were aged 65-75 years, and 138 were aged &gt;75 years. Patients were followed for a median of 10.6 years.Tumor characteristics were similar in both groups, although older patients had larger tumors at diagnosis. Patients aged &gt;75 years underwent more mastectomies, but were less likely to receive axillary surgery or adjuvant systemic therapy. When grouped according to subtype (luminal, Her-2+, triple-negative), an independent effect on recurrence rate and overall survival (OS) for both age and subtype was observed with the worst outcome in the women with triple-negative disease aged &gt;75 years, and best outcome in the women with Her-2 positive aged 65-75 years (p=0.16 for recurrence, p &lt;0.001 for OS). The median OS for the follow-up period was 10.3 years for women aged 65-75 years and 8.0 years for women aged &gt;75 years. The disease-free survival rate after 8 years of follow-up was 88% for the younger women and 85% for those aged &gt;75 years (p=0.27). Conclusions: The current study reveals the physicians' approach in treating breast cancer in the elderly age groups. It demonstrates the impact of both age and tumor subtype on recurrence rates and OS. Triple-negative disease had the worst outcome in both age groups. Physicians should be aware of the impact of the different breast subtypes on outcome in the older patients subgroup and consider treatment based on the individual patient comorbidities and life expectancy.
Abstract 77: MiR-125b Regulates Myofibroblast Transition and Cardiac Fibrosis
Authors: Varun Nagpal, Rahul Rai, Aaron T Place, Asish K Ghosh, Douglas E Vaughan
Journal: Circulation Research (2015)

Transforming growth factor-β (TGF-β)-induced fibroblast-to-myofibroblast transition (FMT) is a critical determinant of cardiac fibrosis. However, the contribution of microRNAs leading to TGF-β-induced FMT and cardiac fibrosis are not well-understood. Our results elucidate that blocking the canonical TGF-β pathway protects from FMT in primary cultures of human cardiac fibroblasts and that miR-125b is significantly upregulated during cardiac FMT. Furthermore, we observed significant upregulation of miR-125b in fibrotic human myocardium and two murine models of cardiac fibrosis. Importantly, we discovered that miR-125b is sufficient to induce cardiac FMT. In contrast, the knockdown of miR-125b using an antagomir approach attenuated TGF-β-induced FMT. In silico analysis and biochemical analysis revealed that miR-125b directly targets multiple anti-fibrotic mediators including p53 and apelin. In addition, miR-125b also plays a potent role in the regulation of fibroblast proliferation, an important cause of cardiac fibrosis. Finally, miR-125b was successfully inhibited in vivo by the systemic delivery of locked nucleic acid (LNA) targeted against miR-125b both in the presence and absence of Angiotensin II (Ang II). These results demonstrated that LNA-125b protected against Ang II-induced proliferation and fibrosis in the mouse heart in vivo. We conclude that TGF-β-induced miR-125b is an important regulator of both fibroblast proliferation and FMT, and miR-125b inhibits key anti-fibrotic mediators to promote cardiac fibrosis. We propose that miR-125b may serve as a novel therapeutic target for the preventative therapy for fibrosis.
Comparable Long-term Outcomes of 1-Minute vs 5-Minute Endoscopic Papillary Balloon Dilation for Bile Duct Stones
Authors: Yu-Ting Kuo, Hsiu-Po Wang, Chi-Yang Chang, Joseph W. Leung, Jiann-Hwa Chen, Ming-Chang Tsai, Wei-Chih Liao
Journal: Clinical Gastroenterology and Hepatology (2017)
Abstract P190: Role of mTOR Signaling in LEOPARD-Syndrome-Associated Hypertrophic Cardiomyopathy
Authors: Maike Krenz, Christine Schramm, Deborah Fine, Michelle Edwards, Ashley Reeb
Journal: Circulation Research (2011)

The identification of mutations in PTPN11 (encoding the protein tyrosine phosphatase Shp2) in families with congenital heart disease has facilitated mechanistic studies of various cardiovascular defects. However, the roles of normal and mutant Shp2 in the developing heart are still poorly understood. In particular, how Shp2 loss-of-function (LOF) mutations cause LEOPARD Syndrome, which is characterized by congenital heart defects such as pulmonary valve stenosis and hypertrophic cardiomyopathy (HCM), remains unclear. We employed both in vitro and in vivo models to investigate signaling mechanisms downstream of Q510E-Shp2, a particularly aggressive mutation leading to early-onset HCM. In cultured rat neonatal cardiomyocytes, Q510E-Shp2 expression significantly increased cell size. This increase was accompanied by hyperactivation of signaling through mammalian target of rapamycin (mTOR). mTOR inhibition with rapamycin reversed the pro-hypertrophic effects of Q510E-Shp2 in culture. Mice with cardiomyocyte-specific overexpression of Q510E-Shp2 starting before birth also showed up-regulation of signaling through Akt/mTOR/p70S6K and developed HCM in the early neonatal period. Q510E-Shp2 expression increased cardiomyocyte sizes and septum thickness, and caused cardiomyocyte disarray and fibrosis. Echocardiographically, hearts were hypocontractile and displayed increased wall thicknesses. Importantly, rapamycin administration rescued the Q510E-Shp2-induced phenotype in vivo. Our studies establish a role for mTOR signaling in HCM caused by the LOF mutation Q510E-Shp2. Pharmacological inhibition of mTOR was sufficient to rescue the HCM phenotype in both models. These findings have important implications not only for the development of novel therapeutic approaches for LEOPARD Syndrome patients, but also for closely related forms of congenital heart disease such as Noonan Syndrome.
Late graft failure in heart transplant recipients: incidence, risk factors and clinical outcomes
Authors: Ángela López‐Sainz, Eduardo Barge‐Caballero, Gonzalo Barge‐Caballero, David Couto‐Mallón, María J. Paniagua‐Martin, Leticia Seoane‐Quiroga, Carmen Iglesias‐Gil, José M. Herrera‐Noreña, José J. Cuenca‐Castillo, José M. Vázquez‐Rodríguez, María G. Crespo‐Leiro
Journal: European Journal of Heart Failure (2017)