tbuckley/cabot-search huggingface dataset:
A multicenter phase II randomized study of docetaxel (D)/gemcitabine (G) weekly followed by erlotinib (E) after progression versus erlotinib followed by docetaxel/gemcitabine after progression in advanced non-small cell lung cancer (NSCLC) in fit elderly patients selected with a comprehensive geriatric assessment (CGA): Groupe Français de Pneumocancerologie (GFPC)*0504.
Authors: H. Le Caer, F. Barlesi, R. Corre, H. Jullian, S. Bota, L. Falchero, A. Vergnenegre, C. Dujon, J. Y. Delhoume, C. Chouaid
Journal: Journal of Clinical Oncology (2010)

7536 Background: Elderly pts is an heterogeneous population in which anticancer therapeutic decision is often difficult. The objective of this study was to evaluate the feasibility and activity of weekly D/G followed by E after progression versus E following by D + G after progression in fit elderly advanced NSCLC patients selected on the basis of a CGA and Charlson score. Methods: This multicenter phase II study randomized chemonaive pts with stage IV and IIIB with pleural effusion received D 30 mg/m2 weekly for 6 consecutive weeks (wks) plus G 900 mg/m2 days 1, 8, 22, 29 followed by 2 wks off, for a maximum of 24 wks or until progression, followed by E until second progression (arm A) versus E in first line followed by D+G until second progression (arm B). Only fit pts (without dependence for ADL or IADL and geriatric syndrom) selected by CGA using a software (EGSK) included in a palm assistant with 10 items: socio-economic conditions, cognitive assessment,depression scale, nutritional risk, quality of life (QOL), ADL, IADL, incontinence, falls, pain. Major endpoint was time to second progression (TTP2), secondary endpoints were response, time to first progression (TTP1), safety, QOL. Results: 100 pts (99 available) were enrolled from July 2006 to November 2008. Patients: Male/Female 59/40, median age 75.9; PS 0/1/2:43/49/6, median comorbidity 0, 4 (0-4) median global geriatric index: 18.5/20. Respectively for arm A and B: partial response was 26.3% and 18.8%, stable disease 42.1% and 33.3%, progressive disease 31.6% and 47.9%,TTP1: 4.7 and 3.1 months, TTP2: 7.7 and 6.6 months, median survival 9.4 and 7.1 months. The main WHO grade 3/4 toxicity was neutropenia 29.2% and fatigue 10.4% in arm A and fatigue 11.8% and cutaneous 11.8% in B. Conclusions: Preliminary analysis suggests that either the combination of weekly D and G followed by E or E followed by D+G appears to be promising with a favourable toxicity profile in fit elderly NSCLC pts with mild comorbidity. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen, Boehringer Ingelheim, Lilly, Roche Amgen, Lilly, Roche Amgen, Lilly, Pfizer, Roche, sanofi-aventis
Phase II study of docetaxel and vinorelbine plus GM-CSF in malignant melanoma
Authors: J. P. Fruehauf, K. M. Kong, J. G. Jakowatz
Journal: Journal of Clinical Oncology (2006)

18017 Background: Patients having locoregional or metastatic melanoma have a poor prognosis, with 50% to 10% of patients dying from the disease within 5 years. Current chemotherapy regimens offer limited benefits to these patients and more effective and less toxic treatments are needed. Methods: We developed a phase II clinical trial to evaluate the activity of an every two week schedule of docetaxel (40mg/m 2 , d1), vinorelbine (30 mg/m 2 , d1) IV and sargramostim (GMCSF, 250 ug/m 2 sq d2–11). This regimen was developed based on preclinical synergistic activity of paclitaxel plus vinorelbine (Neale et al. Melanoma Res 11:601, 2001), and evidence that the docetaxel plus vinorelbine combination can be given safely to lung cancer patients (Sanchez et al. Lung Ca 38:309, 2002). Sargramostim was included based on preliminary clinical data that it delays time to progression in stage IV melanoma patients resected for cure (Spitler, JCO 18:1614, 2000). We report here an interim analysis for the initial 21 patients with stage IV melanoma treated in first or second line. Results: The primary endpoint was time to progression. Grade III/IV toxicities included anemia (12.5%) and neutropenia (5%), with one patient requiring 25% dose reduction. To date, median time to progression (TTP) is 7 months, with 30% of cases showing greater than 8 months TTP. Conclusions: This result compares favorably with biochemotherapy, which has a median TTP of 5 months and overall survival of 8.4 months (Atkins Proc ASCO 22:708. 2003), while being significantly less toxic. Based on these favorable findings, we are continuing to accrue patients to this trial. [Table: see text]
Genetic Association Of a MAPK8 Expression Quantitative Trait Locus With Pre-Capillary Pulmonary Hypertension In Sickle Cell Disease
Authors: Xu Zhang, Wei Zhang, Shwu-Fan Ma, Ankit A. Desai, Galina Y. Miasnikova, Adelina Sergueeva, Tatiana Ammosova, Min Xu, Sergei A. Nekhai, Taimur Abbasi, Nancy G. Casanova, Martin H. Steinberg, Clinton T. Baldwin, Paola Sebastiani, Josef Prchal, Rick Kittles, Joe GN Garcia, Roberto F. Machado, Victor R. Gordeuk
Journal: Blood (2013)
Management of Systemic Right Ventricular Failure in Patients With Congenitally Corrected Transposition of the Great Arteries
Authors: Aleksei A. Filippov, Pedro J. del Nido, Nikolay V. Vasilyev
Journal: Circulation (2016)

In recent decades, significant progress has been made in the diagnosis and management of congenitally corrected transposition of the great arteries (ccTGA). Nevertheless, gradual dysfunction and failure of the right ventricle (RV) in the systemic circulation remain the main contributors to mortality and disability for patients with ccTGA, especially after adolescence. Anatomic repair of ccTGA effectively resolves the problem of failure of the systemic RV and has good early and midterm results. However, this strategy is applicable primarily in infants and children up to their teens and has associated risks and limitations, and new challenges can arise in the late postoperative period. Patients with ccTGA manifesting progressive systemic RV dysfunction beyond adolescence represent the major challenge. Several palliative options such as cardiac resynchronization therapy, tricuspid valve repair or replacement, pulmonary artery banding, and implantation of an assist device into the systemic RV can be used to improve functional status and to delay the progression of ventricular dysfunction in patients who are not suitable for anatomic correction of ccTGA. For adult patients with severe systemic RV failure, heart transplantation currently remains the only long-term lifesaving procedure, although donor organ availability remains one of the most limiting factors in this type of therapy. This review focuses on current surgical and medical strategies and interventional options for the prevention and management of systemic RV failure in adults and children with ccTGA.
Abstract IA25: Hallmark capabilities modulated by the tumor microenvironment during tumor progression and adaptive resistance to therapy
Authors: Douglas Hanahan, Douglas Hanahan
Journal: Cancer Research (2016)

Abstract The hallmarks of cancer constitute an organizing concept that may provide a rational basis for distilling the diversity and complexity of human cancers so as to better understand mechanisms of the disease and its manifestations. The integration of these hallmark capabilities in symptomatic disease involves multiple cell types populating the tumor microenvironment, including heterogeneous populations of cancer cells, and three prominent classes of stromal support cells - angiogenic vascular cells, cancer associated fibroblasts, and infiltrating immune cells. Dynamic interactions amongst these cell types convey hallmark capabilities whose roles and functional importance vary during multi-step tumorigenesis and tumor progression, and in the context of adaptive responses to hallmark-targeting therapies, suggesting potential benefits in multi-targeting the TME. A few examples from our research program will seek to be illustrative. Citation Format: Douglas Hanahan, Douglas Hanahan. Hallmark capabilities modulated by the tumor microenvironment during tumor progression and adaptive resistance to therapy. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr IA25.
A Missense Genetic Variant in <i>LRRC16A</i>/<i>CARMIL1</i> Improves Acute Respiratory Distress Syndrome Survival by Attenuating Platelet Count Decline
Authors: Yongyue Wei, Paula Tejera, Zhaoxi Wang, Ruyang Zhang, Feng Chen, Li Su, Xihong Lin, Ednan K. Bajwa, B. Taylor Thompson, David C. Christiani
Journal: American Journal of Respiratory and Critical Care Medicine (2016)

Rationale: Platelets are believed to contribute to acute respiratory distress syndrome (ARDS) pathogenesis through inflammatory coagulation pathways. We recently reported that leucine-rich repeat–containing 16A (LRRC16A) modulates baseline platelet counts to mediate ARDS risk.Objectives: To examine the role of LRRC16A in ARDS survival and its mediating effect through platelets.Methods: A total of 414 cases with ARDS from intensive care units (ICUs) were recruited who had exome-wide genotyping data, detailed platelet counts, and follow-up data during ICU hospitalization. Association of LRRC16A single-nucleotide polymorphisms (SNPs) and ARDS prognosis, and the mediating effect of SNPs through platelet counts were analyzed. LRRC16A mRNA expression levels for 39 cases with ARDS were also evaluated.Measurements and Main Results: Missense SNP rs9358856G>A within LRRC16A was associated with favorable survival within 28 days (hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.38–0.87; P = 0.0084) and 60 days (P = 0.0021) after ICU admission. Patients with ARDS who carried the variant genotype versus the wild-type genotype showed an attenuated platelet count decline (∆PLT) within 28 days (difference of ∆PLT, −27.8; P = 0.025) after ICU admission. Patients with ∆PLT were associated with favorable ARDS outcomes. Mediation analysis indicated that the SNP prognostic effect was mediated through ∆PLT within 28 days (28-day survival: HRIndirect, 0.937; 95% CI, 0.918−0.957; P = 0.0009, 11.53% effects mediated; 60-day survival: HRIndirect, 0.919; 95% CI, 0.901−0.936; P = 0.0001, 14.35% effects mediated). Functional exploration suggested that this SNP reduced LRRC16A expression at ICU admission, which was associated with a lesser ∆PLT during ICU hospitalization.Conclusions: LRRC16A appears to mediate ∆PLT after ICU admission to affect the prognosis in patients with ARDS.
Acute Zoster Pain (AZP) and Post-Herpetic Neuralgia (PHN) in the Course of Lymphoproliferative Disorders (LPD): Durable Pain Relief Provided by Oxycodone in Patients Unresponsive to Standard Therapy.
Authors: Pasquale Niscola, Claudio Romani, Alessio Pio Perrotti, Giovanni Del Poeta, Claudio Cartoni, Massimiliano Palombi, Marco Giovannini, Luca Cupelli, Paolo De Fabritiis
Journal: Blood (2006)
Quality and Safety in Health Care, Part XVIII
Authors: Jay A. Harolds
Journal: Clinical Nuclear Medicine (2016)

An important way to improve outcomes after colorectal surgery is to follow the recommendations of the enhanced recovery pathway after surgery (ERAS). The ERAS guidelines are recommendations that address certain aspects of what should be done before surgery, in the operating room, and following surgery. There is a substantial fall in complications and a decrease in the length of stay for the patient if the recommendations are followed. Elements of the ERAS program are now being adopted for other surgical procedures besides colorectal surgery.
Simultaneous regulation of apoptotic gene silencing and angiogenic gene expression for myocardial infarction therapy: Single-carrier delivery of SHP-1 siRNA and VEGF-expressing pDNA
Authors: Dongkyu Kim, Sook Hee Ku, Hyosuk Kim, Ji Hoon Jeong, Minhyung Lee, Ick Chan Kwon, Donghoon Choi, Sun Hwa Kim
Journal: Journal of Controlled Release (2016)
Abstract B21: Exostosin 1 regulates cancer cell stemness in breast cancer cells
Authors: Sarala Manandhar, Chang-gu Kim, Su Young Oh, Sun-Hee Lee, Jiyoon Seok, Yuk-Dong Jung, Hye-Eun Lee, Young-Sun Choi, You Mie* Lee
Journal: Cancer Research (2016)

Abstract Cancer stem cells (CSCs), a group of cancer cells, are associated with resistance to radiation and chemotherapy and are implicated in recurrent of cancer. Exostosin 1 (EXT1) gene is widely reported as tumor suppressor and its indispensable role in elongation of heparan sulfate (HS) can speculate probable role as tumor promotor. In recent years, a number of tumors are reported to over express EXT1. Here, we investigated the role of EXT1 in the maintenance of cancer cell stemness. MCF7/ADR cells developed by exposing MCF7, breast cancer cells, to doxorubicin for several months in culture, showed high resistance to doxorubicin compared to MCF7, parental cell line. Doxorubicin resistant MCF7/ADR cells have enhanced P-glycoprotein (P-gp) expression. In FACs analysis, MCF7/ADR cells were accounted for high number of CSC population; they possessed large number of ALDH+ and CD44+/CD24- population compared to MCF7. CSC marker, CD44, was found overexpressed in MCF7/ADR compared to MCF7. Besides that, in mammosphere culture, MCF7/ADR cells formed large number of mammospheres in contrast to MCF7. In microarray data analysis, several genes were found upregulated in MCF7/ADR cells and EXT1 was selected as a candidate gene. Overexpressed EXT1 in MCF7/ADR cells was confirmed by real time PCR. The critical role of EXT1 in maintaining cancer cell stemness was confirmed by siRNA mediated knockdown of EXT1. Knockdown of EXT1 repressed CSC markers, reduced population of ALDH+ and CD44+/CD24-, and suppressed expression of CD44. As a molecular mechanism, we detected suppressed expression of heparan sulfate, syndecan1(SDC1) with siEXT1. With these results, we can suggest that EXT1 level might be a determining factor for doxorubicin sensitive breast cancer cells and enhanced expression of EXT1 can take part in development of CSC phenotype on exposure to anthracycline based therapy through upregulation of SDC1. Citation Format: Sarala Manandhar, Chang-gu Kim, Su Young Oh, Sun-Hee Lee, Jiyoon Seok, Yuk-Dong Jung, Hye-Eun Lee, Young-Sun Choi, You Mie Lee*. Exostosin 1 regulates cancer cell stemness in breast cancer cells. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr B21.
Glycerophosphocholine Metabolites and Cardiovascular Disease Risk Factors in Adolescents
Authors: Catriona Syme, Simon Czajkowski, Jean Shin, Michal Abrahamowicz, Gabriel Leonard, Michel Perron, Louis Richer, Suzanne Veillette, Daniel Gaudet, Lisa Strug, Yun Wang, Hongbin Xu, Graeme Taylor, Tomas Paus, Steffany Bennett, Zdenka Pausova
Journal: Circulation (2016)

Glycerophosphocholine (GPC) metabolites modulate atherosclerosis and thus risk for cardiovascular disease (CVD). Preclinical CVD may start during adolescence. Here, we used targeted serum lipidomics to identify a new panel of GPCs, and tested whether any of these GPCs are associated, in adolescence, with classical risk factors of CVD, namely excess visceral fat (VF), elevated blood pressure, insulin resistance, and atherogenic dyslipidemia.We studied a population-based sample of 990 adolescents (12-18 years, 48% male), as part of the Saguenay Youth Study. Using liquid chromatography-electrospray ionization-mass spectrometry, we identified 69 serum GPCs within the 450 to 680 m/z range. We measured VF with MRI.We identified several novel GPCs that were associated with multiple CVD risk factors. Most significantly, PC16:0/2:0 was negatively associated with VF (P=1.4×10-19), blood pressure (P=7.7×10-5), and fasting triacylglycerols (P=9.0×10-5), and PC14:1/0:0 was positively associated with VF (P=3.0×10-7), fasting insulin (P=5.4×10-32), and triacylglycerols (P=1.4×10-29). The Sobel test of mediation revealed that both GPCs mediated their respective relations between VF (as a potential primary exposure) and CVD risk factors (as outcomes, P values<1.3×10-3). Furthermore, a GPC shown recently to predict incident coronary heart disease in older adults, PC18:2/0:0, was associated with several CVD risk factors in adolescents; these associations were less strong than those with the newly identified GPCs.We identified novel GPCs strongly associated with multiple CVD risk factors in adolescents. These GPCs may be sensitive indicators of obesity-related risk for CVD outcomes in adults, and may improve biological understanding of CVD risk.
Small-Molecule XIAP Inhibitors Derepress Downstream Effector Caspases and Induce Apoptosis of Leukemia Cell Lines and Patient Samples.
Authors: Aaron D. Schimmer, Marcela Gronda, Zhiliang Wang, Kate Welsh, Clemencia Pinilla, Michael Andreeff, Wendy D. Schober, Adel Nefzi, Richard Houghten, Joseph Brandwein, Mark D. Minden, Andre Schuh, Richard A. Wells, Hans Messner, John C. Reed, Bing Z. Carter
Journal: Blood (2004)
Precision Medicine, Diabetes, and the U.S. Food and Drug Administration
Authors: Robert J. Meyer
Journal: Diabetes Care (2016)

The U.S. Food and Drug Administration (FDA) has long sought to achieve the broader use of personalized medicine, which is better targeting of FDA-approved therapies through incorporating precise knowledge of a patient’s underlying condition to therapies optimally chosen to match those needs. While some strides have been made in precision medicine—particularly in oncology and rare genetic diseases—most of the standard general medicine indications have yet to realize the benefits of precision-guided therapies. This includes those for diabetes mellitus (DM), both type 1 and type 2. Although the scientific and regulatory considerations needed to move to a more “precise” future of DM prevention and treatment differ between the two disease subsets, scientific advances in both must occur before the FDA can incorporate precision medicine into its oversight of DM drug development and approval. This article provides an overview of the regulatory expectations and challenges in realizing a future where the therapeutics for DM are informed by precise knowledge of a patient’s genetics and specific phenotype.
Outcomes after complete pathologic response (pCR) to neoadjuvant treatment for gastric and gastroesophageal junction (GEJ) adenocarcinoma.
Authors: R. C. Fields, V. E. Strong, M. Gonen, M. F. Brennan, D. G. Coit, M. A. Shah
Journal: Journal of Clinical Oncology (2011)

75 Background: pCR is rare following neoadjuvant chemotherapy (NAChemo) ± radiation therapy (RT) for locally advanced gastric/GEJ adenocarcinoma. Recurrence and survival after pCR are not well characterized. Methods: A retrospective review of a prospective database identified patients with pCR after NAChemo ± RT for gastric/GEJ adenocarcinoma. Recurrence, overall survival (OS), recurrence free survival (RFS), and disease specific survival (DSS) were analyzed. Results: From 1985 – 2010, 2,676 patients underwent resection for gastric/GEJ adenocarcinoma, and 714 (27%) received NAChemo ± RT. There were 102 (14%) patients with a pCR. 60 patients (8%) had adequate pre-operative staging and follow-up and comprised the study group: 47 (78%) GEJ and 13 (22%) gastric tumors. 51 (85%) received neoadjuvant RT. With 46 month median follow-up, 14 patients (23%; 12 GEJ, 2 gastric) developed a recurrence (Table); 13 of 14 (93%) occurred within 2 years of follow-up with a median time to recurrence of 13.5 months. 5 (42%) recurred in the CNS. Median time to death after recurrence was 11.5 months. 5-year OS, RFS, and DSS were 56%, 70%, and 65%, respectively. Conclusions: pCR occurs in less than 15% of cases after neoadjuvant therapy for gastric and GEJ adenocarcinoma. Despite a pCR, there is a significant risk of recurrence and cancer-specific death during follow-up. As CNS recurrence is more prevalent in this group of patients, whole brain imaging should be considered. [Table: see text] No significant financial relationships to disclose.
Prognostic value of serum protein biomarkers in patients with epithelial ovarian cancer.
Authors: M. Wang, S. Bush, S. A. Ghamande, J. She
Journal: Journal of Clinical Oncology (2010)

10567 Background: Study was designed to identify biomarker candidate proteins (bcp) in discovery phase and validate them in confirmation phase using serum samples from healthy control and epithelial ovarian cancer (EOC) patients. Then bcp's were examined in EOC patients in context of current disease status; during chemotherapy treatments (c), remission (RM), and recurrence (RC). Methods: We combined mass spectrometry-based Multidimensional Protein Identification Technology (MUDPIT) proteomics strategy with high throughput Multiplex beads-based LUMINEX assay and enzyme-linked immunosorbent assay (ELISA) to identify and validate the bcps in serum. 88 healthy controls and 83 EOC patients were analyzed; 18 during chemotherapy, 28 in remission and 34 with recurrent disease. Results: Expression levels of acute phase protein Serum amyloid A (SAA), C-reactive protein (CRP), alpha 1 antitrypsin (SERPINA1), secreted phosphoprotein 1 (SSP1), and matrix metallopeptidase 1 (MMP1) were increased in cancer patients, while chemokine ligand 2 (CCL2) showed lower expression level in the cancer samples versus controls (Table). Elevated serum levels of CRP (p=0.027)and MMP1(p=0.015) were associated with cancer recurrence when compared to remission. Conclusions: Serum levels of bcps SAA, MMP1, CRP, SSP1, SERPINA1, and CCL2 were significantly changed in cancer and some protein level changes correspond to EOC clinical status. These bcp's may be important in CA125 negative patients and deserve further study. Symbol Study phases RC/control p C/control p RC + C/control p RC/RM p SAA MS discovery 2.62 0.0272 1.89 0.2664 2.24 0.0400 2.93 0.0112 ELISA/LUMINEX confirmation 3.37 0.0212 4.59 0.0956 3.80 0.0055 2.30 0.0748 SERPINA1 MS discovery 2.01 0.1814 3.29 0.0067 2.68 0.0157 0.84 0.6201 ELISA/LUMINEX confirmation 1.18 0.0343 1.31 0.02 1.23 0.0027 0.82 0.0871 CRP MS discovery 4.93 0.0016 6.00 0.0019 5.49 0.0000 2.98 0.0081 ELISA/LUMINEX confirmation 4.09 0.0003 5.38 0.0172 4.54 0.0000 2.03 0.0270 SPP1 ELISA/LUMINEX confirmation 2.51 0.0004 3.12 0.1100 2.72 0.0013 1.48 0.1089 MMP1 ELISA/LUMINEX confirmation 1.90 0.0005 1.80 0.0183 1.86 0.0000 1.56 0.0159 CCL2 ELISA/LUMINEX confirmation 0.80 0.0445 1.17 0.4893 0.93 0.5348 0.87 0.3513 No significant financial relationships to disclose.