tbuckley/cabot-search huggingface dataset:
Effect of continued treatment with pirfenidone following clinically meaningful declines in forced vital capacity: analysis of data from three phase 3 trials in patients with idiopathic pulmonary fibrosis
Authors: Steven D Nathan, Carlo Albera, Williamson Z Bradford, Ulrich Costabel, Roland M du Bois, Elizabeth A Fagan, Robert S Fishman, Ian Glaspole, Marilyn K Glassberg, Kenneth F Glasscock, Talmadge E King, Lisa Lancaster, David J Lederer, Zhengning Lin, Carlos A Pereira, Jeffrey J Swigris, Dominique Valeyre, Paul W Noble, Athol U Wells
Journal: Thorax (2016)

<h3>Background</h3> The assessment of treatment response in idiopathic pulmonary fibrosis (IPF) is complicated by the variable clinical course. We examined the variability in the rate of disease progression and evaluated the effect of continued treatment with pirfenidone in patients who experienced meaningful progression during treatment. <h3>Methods</h3> The source population included patients enrolled in the ASCEND and CAPACITY trials (N=1247). Pearson9s correlation coefficients were used to characterise the relationship between changes in FVC during consecutive 6-month intervals in the placebo population. Outcomes following a ≥10% decline in FVC were evaluated by comparing the proportion of patients in the pirfenidone and placebo groups who experienced a ≥10% decline in FVC or death during the subsequent 6 months. <h3>Results</h3> A weak negative correlation was observed between FVC changes during consecutive intervals in the placebo population (coefficient, −0.146, p&lt;0.001), indicating substantial variability. Thirty-four (5.5%) and 68 (10.9%) patients in the pirfenidone and placebo groups, respectively, experienced a ≥10% decline in FVC by month 6. During the subsequent 6 months, fewer patients in the pirfenidone group compared with placebo experienced a ≥10% decline in FVC or death (5.9% vs 27.9%; relative difference, 78.9%). There was one (2.9%) death in the pirfenidone group and 14 (20.6%) deaths in the placebo group (relative difference, 85.7%). <h3>Conclusions</h3> Longitudinal FVC data from patients with IPF showed substantial intrasubject variability, underscoring the inability to reliably assess therapeutic response using serial FVC trends. In patients who progressed during treatment, continued treatment with pirfenidone resulted in a lower risk of subsequent FVC decline or death. <h3>Trial registration numbers</h3> NCT01366209, NCT00287729, NCT00287716.
Human Colon Adenocarcinoma Cells. II. Tumorigenic and Organoid Expression In Vivo and In Vitro2
Authors: Baldwin H. Tom, Lynne P. Rutzky, Ryoichi Oyasu, Joseph T. Tomita, David M. Goldenberg, Barry D. Kahan
Journal: JNCI Journal of the National Cancer Institute (1977)

A human colon epithelial tumor cell line (LS174T) recultured in vitro following passage through hamsters displayed differences in its cell doubling time and synthesis of carcinoembryonic antigen when compared with the cells grown solely in vitro. These animal-passaged cells more closely resembled the parent tumor cell line (LS180) derived from the primary tumor than LS174T, the trypsinized variant of LS180. Analysis of lactate dehydrogenase isoenzymes indicated that the tumor cells recovered from the hamsters were free of xenogeneic host tissue. Furthermore, LS174T grafted to athymic (nude) mice grew as a mucinous adenocarcinoma microscopically resembling the original tumor. The altered growth potential of LS174T was also demonstrated on confluent feeder monolayers of normal cells and by uninhibited multiplication in vitro. These results suggest that, at least in this one case, short-term passage of long-term cultured cells into xenogeneic hosts may effect a phenotypic reversion such that the cells regain properties observed in the primary tumor and the initial in vitro explant.
Comparative efficacy of S-1 versus best supportive care in advanced hepatocellular carcinoma.
Authors: Pengfei Yu
Journal: Journal of Clinical Oncology (2015)

466 Background: S-1, an oral fluoropyrimidine derivative, has been shown to be clinically effective against hepatocellular carcinoma (HCC). We carried out a retrospective study to evaluate the efficacy of S-1, compared to best supportive care (BSC) in patients with advanced hepatocellular carcinoma. Methods: From 2009.12 to 2013.12, 32 cases of advanced hepatocellular carcinoma (the presence of extrahepatic metastasis or locally advanced disease not amenable to surgical resection or other locoregional therapies) were retrospectively analysed. 18 patients received S-1 (80 mg/m 2 /day, administered during days 1~14 and repeated every 21 days) and 14 patients received best supportive care (BSC). The time to progression (TTP), overall survival (OS) and safety were assessed. Results: 17 of 32 (53.1%) patients had metastatic disease, including the retroperitoneal lymph nodes (7 cases), lung (4 cases), supraclavicular lymph nodes (3 cases), abdominal wall (3 cases), brain (2 cases) and adrenal glands (2 cases). 12 patients (37.5%) had portal vein tumor thrombus. The two groups were well matched at baseline. In S-1 group,a total of 63 cycles were administered with median of 3.5 cycles (range, 2~7).The most common grade 3/4 toxicities were thrombocytopenia (28.1%), neutropenia (21.8%), elevated serum aspartate aminotransferase levels (15.6%) and rash (9.4%). A patient (5.6%) had a partial response,11 (61.1%) had stable disease, and 6 (33.3%) had progressive disease. Median TTP was 4.7 months in the S-1 group compared with 2.3 months in the BSC group (P=0.013). Overall survival was 15.1 months in patients treated with S-1, compared with 8.3 months in those who received BSC (P=0.027). Conclusions: S-1 showed an acceptable safety profile and benefit in survival in patients with advanced HCC.The conclusion needs further evaluation in randomized clinical trials.
Cancer in Families With Xeroderma Pigmentosum&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: M Swift, C Chase
Journal: JNCI Journal of the National Cancer Institute (1979)

In 31 families of xeroderma pigmentosum (XP) patients, significantly more blood relatives than spouse controls had had nonmelanoma skin cancer. These family data support the hypothesis that heterozygosity for XP genes may predispose persons to skin cancer, particularly in association with substantial exposure to sunlight.
Cutaneous Neonatal Lupus Arising in an Infant Conceived From an Oocyte Donation Pregnancy
Authors: Albert Sean Chiou, Grace Sun, Jinah Kim, Kevin Chun-Kai Wang, Ann L. Marqueling
Journal: JAMA Dermatology (2016)

clinical perspective, we suggest that NLE should be considered possible in an infant when there is a history of autoimmune connective tissue disease or appropriate circulating IgG autoantibodies in the gestational mother.
MicroRNA-196a/b Mitigate Renal Fibrosis by Targeting TGF-β Receptor 2
Authors: Jiao Meng, Limin Li, Yue Zhao, Zhen Zhou, Mingchao Zhang, Donghai Li, Chen-Yu Zhang, Ke Zen, Zhihong Liu
Journal: Journal of the American Society of Nephrology (2016)

Organ-specific microRNAs have essential roles in maintaining normal organ function. However, the microRNA profile of the kidney and the role of microRNAs in modulating renal function remain undefined. We performed an unbiased assessment of the genome-wide microRNA expression profile in 14 mouse organs using Solexa deep sequencing and found that microRNA-196a (miR-196a) and miR-196b are selectively expressed in kidney, with 74.37% of mouse total miR-196a and 73.19% of mouse total miR-196b distributed in the kidneys. We confirmed the predominant expression of miR-196a/b in mouse and human kidney, particularly in the glomeruli and tubular epithelium, by quantitative RT-PCR and in situ hybridization assays. During unilateral ureteral obstruction (UUO)-induced mouse renal fibrosis, renal miR-196a/b levels rapidly decreased. Elevation of renal miR-196a/b expression by hydrodynamic-based delivery of a miR-196a/b-expressing plasmid before or shortly after UUO significantly downregulated profibrotic proteins, including collagen 1 and α-smooth muscle actin, and mitigated UUO-induced renal fibrosis. In contrast, depletion of renal miR-196a/b by miR-196a/b antagomirs substantially aggravated UUO-induced renal fibrosis. Mechanistic studies further identified transforming growth factor beta receptor II (TGFβR2) as a common target of miR-196a and miR-196b. Decreasing miR-196a/b expression in human HK2 cells strongly activated TGF-β-Smad signaling and cell fibrosis; whereas increasing miR-196a/b levels in mouse primary cultured tubular epithelial cells inhibited TGF-β-Smad signaling. In the UUO model, miR-196a/b silenced TGF-β-Smad signaling, decreased the expression of collagen 1 and α-smooth muscle actin, and attenuated renal fibrosis. Our findings suggest that elevating renal miR-196a/b levels may be a novel therapeutic strategy for treating renal fibrosis.
Acute Limb Ischemia and Outcomes With Vorapaxar in Patients With Peripheral Artery Disease
Authors: Marc P. Bonaca, J. Antonio Gutierrez, Mark A. Creager, Benjamin M. Scirica, Jeffrey Olin, Sabina A. Murphy, Eugene Braunwald, David A. Morrow
Journal: Circulation (2016)

Background— Patients with peripheral artery disease (PAD) are at heightened risk of acute limb ischemia (ALI), a morbid event that may result in limb loss. We investigated the causes, sequelae, and predictors of ALI in a contemporary population with symptomatic PAD and whether protease-activated receptor 1 antagonism with vorapaxar reduced ALI overall and by type. Methods and Results— The Trial to Assess the Effects of Vorapaxar in Preventing Heart Attack and Stroke in Patients With Atherosclerosis–Thrombolysis in Myocardial Infarction 50 (TRA2°P-TIMI 50) was a randomized, double-blind, placebo-controlled trial of vorapaxar in stable patients, including 3787 with symptomatic PAD. ALI was a prespecified adjudicated end point using a formal definition. A total of 150 ALI events occurred in 108 patients during follow-up (placebo 3-year rate, 3.9%; 1.3% annualized). For patients with symptomatic PAD, previous peripheral revascularization, smoking, and the ankle-brachial index were predictive of ALI. The majority of ALI events occurred as a result of surgical graft thrombosis (56%), followed by native vessel in situ thrombosis (27%). Stent thrombosis and thromboembolism caused ALI in 13% and 5%, respectively. Amputation occurred in 17.6% presenting with ALI. Vorapaxar reduced first ALI events by 41% (hazard ratio, 0.58; 95% confidence interval, 0.39–0.86; P =0.006) and total ALI events by 41% (94 versus 56 events; risk ratio, 0.59; 95% confidence interval, 0.38–0.93; P =0.022). The efficacy of vorapaxar was consistent across types of ALI. Conclusions— In selected patients with symptomatic PAD and without atrial fibrillation, ALI occurs at a rate of 1.3%/y, is most frequently caused by acute bypass graft thrombosis or in situ thrombosis of a diseased vessel, and often results in limb loss. Vorapaxar reduces ALI in patients with symptomatic PAD with consistency across type, including PAD resulting from surgical graft thrombosis and in-situ thrombosis. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00526474.
N-of-1 Policymaking — Tragedy, Trade-offs, and the Demise of Morcellation
Authors: Lisa Rosenbaum
Journal: New England Journal of Medicine (2016)

Anecdotes like those about women who receive a diagnosis of late-stage leiomyosarcoma after morcellation of fibroids can skew risk perception, leading to estimates of outcomes' likelihood based on how easy they are to imagine — and to policies that ignore societal benefit.
Cystinosin deficiency causes podocyte damage and loss associated with increased cell motility
Authors: Ekaterina A. Ivanova, Fanny O. Arcolino, Mohamed A. Elmonem, Maria P. Rastaldi, Laura Giardino, Elisabeth M. Cornelissen, Lambertus P. van den Heuvel, Elena N. Levtchenko
Journal: Kidney International (2016)
Dosing and outcomes study of erythropoiesis-stimulating therapies - D.O.S.E
Authors: J. Fastenau, A. Memisoglu, C. Peake, C. Salva, J. Howell, S. R. McKenzie
Journal: Journal of Clinical Oncology (2005)

6092 Background: D.O.S.E. is the first prospective, observational registry designed to collect information from providers and patients to document real-world practice and outcomes associated with erythropoiesis stimulating therapies (ESTs) in cancer patients. One of the objectives of D.O.S.E. is to examine the dose conversion ratio (DCR) between epoetin alfa (EPO) and darbepoetin alfa (DARB). A pooled analysis of observational data comprised of 7,500 patients, suggested a DCR of ≤ 260:1 (units EPO:mcg DARB) (Papatheofanis F et al. Proc Am Soc Clin Oncol. 2004;23:552). Further, a comparative trial evaluating EPO and DARB at an initial dosing ratio of 400:1 demonstrated significantly greater early Hb response rates and greater Hb increases throughout the study for EPO (Waltzman RJ et al. Proc Am Soc Clin Oncol. 2004;23:763). Methods: Data are drawn from both hospital and community-based outpatient practices during 12/03–11/04. Patients are required to have a diagnosis of a non-myeloid malignancy, be >18 years, and have received ≥ 2 doses of either EPO or DARB for chemotherapy-induced anemia (Hb ≤11g/dL). Outcomes assessed included treatment duration; mean weekly and cumulative doses; Hb change from baseline at weeks 4, 8, 12, and 16; and area under the Hb change curve from baseline through week 16 (Hb AUC16). Results: 266 patients (113 EPO, 153 DARB) from 25 sites are included. Baseline characteristics are the same between treatment groups and are reported for the cohort: 63 years, 165 lbs, 64% female, Karnofsky score 84, and Hb 10.1g/dL. Both groups also have identical mean treatment duration of 59 days. The mean weekly doses are for EPO 34,814 units and DARB 125 mcg. The cumulative doses are for EPO 337,531 units and DARB 1,253mcg. Mean Hb change (g/dL) from baseline to weeks 4 (0.86), 8 (0.97), 12 (1.15), and 16 (1.14) are the same between treatment groups and are reported for the cohort, resulting in an Hb AUC16 of 14.2g/dL. The EPO:DARB dose conversion ratio is 269:1. Conclusions: Results suggest similar hematological outcomes are observed for EPO and DARB when dosed at a ratio of 269:1. This observed DCR is consistent with previously reported clinical studies. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Ortho-Biotech Clinical Affairs, LLC Ortho-Biotech Clinical Affairs, LLC
Timing of catheter drainage in infected necrotizing pancreatitis
Authors: Janneke van Grinsven, Hjalmar C. van Santvoort, Marja A. Boermeester, Cornelis H. Dejong, Casper H. van Eijck, Paul Fockens, Marc G. Besselink
Journal: Nature Reviews Gastroenterology & Hepatology (2016)
A Human Breast Adenocarcinoma With Chromosome and Isoenzyme Markers Similar to Those of the Hela Line&lt;xref ref-type="fn" rid="fn2"&gt;2&lt;/xref&gt;
Authors: S Pathak, M J Siciliano, R Cailleau, C L Wiseman, T C Hsu
Journal: JNCI Journal of the National Cancer Institute (1979)

Pleural effusion was obtained from a 51-year-old black woman who had breast adenocarcinoma and had received chemotherapy and radiation therapy after a radical mastectomy. Cytogenetic and isoenzymic analyses of the cells were performed within a few hours of obtaining the sample. Similar analyses were also done with a cell line established from this effusion. The stemline chromosome number was 35, one of the lowest in human neoplasms. In addition to a marker chromosome involving 1q, which is common in human breast tumors, we found several other marker chromosomes whose G-banding patterns were similar to some of the typical HeLa markers. Genetic signature analysis of 15 isoenzyme loci revealed that 13 were identical to those of HeLa. Both HeLa and the cell line described here express glucose-6-phosphate dehydrogenase type a, yet they were derived from heterozygotic individuals (ab). Our data indicate the necessity to extensive cytogenetic and biochemical analysis before conclusions are made that cell lines are actually intercell-line contaminants.
Safety of STG320 Sublingual Tablets of House Dust Mite Allergen Extracts in Subjects with HDM-Associated Allergic Rhinitis: Results of a Pooled Analysis
Authors: Pascal M. Demoly, Karl-Christian Bergmann, Sandrine Khairallah, Kathy Abiteboul, Robert K. Zeldin
Journal: Journal of Allergy and Clinical Immunology (2016)
Durable Clinical Effectiveness With Paclitaxel-Eluting Stents in the Femoropopliteal Artery
Authors: Michael D. Dake, Gary M. Ansel, Michael R. Jaff, Takao Ohki, Richard R. Saxon, H. Bob Smouse, Lindsay S. Machan, Scott A. Snyder, Erin E. O’Leary, Anthony O. Ragheb, Thomas Zeller
Journal: Circulation (2016)

This randomized controlled trial evaluated clinical durability of Zilver PTX, a paclitaxel-coated drug-eluting stent (DES), for femoropopliteal artery lesions. Outcomes compare primary DES versus percutaneous transluminal angioplasty (PTA), overall DES (primary and provisional) versus standard care (PTA and provisional Zilver bare metal stent [BMS]), and provisional DES versus provisional BMS.Patients with symptomatic femoropopliteal artery disease were randomly assigned to DES (n=236) or PTA (n=238). Approximately 91% had claudication; 9% had critical limb ischemia. Patients experiencing acute PTA failure underwent secondary randomization to provisional BMS (n=59) or DES (n=61). The 1-year primary end points of event-free survival and patency showed superiority of primary DES in comparison with PTA; these results were sustained through 5 years. Clinical benefit (freedom from persistent or worsening symptoms of ischemia; 79.8% versus 59.3%, P<0.01), patency (66.4% versus 43.4%, P<0.01), and freedom from reintervention (target lesion revascularization, 83.1% versus 67.6%, P<0.01) for the overall DES group were superior to standard care in nonrandomized comparisons. Similarly, clinical benefit (81.8% versus 63.8%, P=0.02), patency (72.4% versus 53.0%, P=0.03), and freedom from target lesion revascularization (84.9% versus 71.6%, P=0.06) with provisional DES were improved over provisional BMS. These results represent >40% relative risk reduction for restenosis and target lesion revascularization through 5 years for the overall DES in comparison with standard care and for provisional DES in comparison with provisional BMS.The 5-year results from this large study provide long-term information previously unavailable regarding endovascular treatment of femoropopliteal artery disease. The Zilver PTX DES provided sustained safety and clinical durability in comparison with standard endovascular treatments.URL: http://www.clinicaltrials.gov. Unique identifier: NCT00120406.
Endoplasmic reticulum stress-inducing drugs sensitize glioma cells to temozolomide through downregulation of MGMT, MPG, and Rad51
Authors: Enric Xipell, Tomás Aragón, Naiara Martínez-Velez, Beatriz Vera, Miguel Angel Idoate, Juan José Martínez-Irujo, Antonia García Garzón, Marisol Gonzalez-Huarriz, Arlet M. Acanda, Chris Jones, Frederick F. Lang, Juan Fueyo, Candelaria Gomez-Manzano, Marta M. Alonso
Journal: Neuro-Oncology (2016)

Endoplasmic reticulum (ER) stress results from protein misfolding imbalance and has been postulated as a therapeutic strategy. ER stress activates the unfolded protein response which leads to a complex cellular response, including the upregulation of aberrant protein degradation in the ER, with the goal of resolving that stress. O6-methylguanine DNA methyltransferase (MGMT), N-methylpurine DNA glycosylase (MPG), and Rad51 are DNA damage repair proteins that mediate resistance to temozolomide in glioblastoma. In this work we sought to evaluate whether ER stress-inducing drugs were able to downmodulate DNA damage repair proteins and become candidates to combine with temozolomide. MTT assays were performed to evaluate the cytotoxicity of the treatments. The expression of proteins was evaluated using western blot and immunofluorescence. In vivo studies were performed using 2 orthotopic glioblastoma models in nude mice to evaluate the efficacy of the treatments. All statistical tests were 2-sided. Treatment of glioblastoma cells with ER stress-inducing drugs leads to downregulation of MGMT, MPG, and Rad51. Inhibition of ER stress through pharmacological treatment resulted in rescue of MGMT, MPG, and Rad51 protein levels. Moreover, treatment of glioblastoma cells with salinomycin, an ER stress-inducing drug, and temozolomide resulted in enhanced DNA damage and a synergistic antitumor effect in vitro. Of importance, treatment with salinomycin/temozolomide resulted in a significant antiglioma effect in 2 aggressive orthotopic intracranial brain tumor models. These findings provide a strong rationale for combining temozolomide with ER stress-inducing drugs as an alternative therapeutic strategy for glioblastoma.
A Multicenter Phase II Study Of Bortezomib (VELCADE®) Combined With Rituximab For Untreated High Tumor Burden (HTB) Indolent Non-Hodgkin Lymphoma (NHL): Long-Term Follow-Up Of Outcomes and Examination Of Prognostic Factors
Authors: Andrew M Evens, Mitchell R Smith, Izidore S Lossos, Irene Helenowski, Michael Millenson, Jane N. Winter, Steven T. Rosen, Leo I. Gordon
Journal: Blood (2013)
Neoadjuvant chemotherapy versus surgery alone for locally advanced adenocarcinoma of the stomach and cardia: Randomized EORTC phase III trial #40954
Authors: C. Schuhmacher, P. Schlag, F. Lordick, W. Hohenberger, J. Heise, C. Haag, S. Gretschel, M. E. Mauer, M. Lutz, J. R. Siewert
Journal: Journal of Clinical Oncology (2009)

4510 Background: Combined pre- and postoperative chemotherapy improves overall survival in operable gastric cancer, although postoperative treatment is not feasible in half of the patients. We conducted a randomized phase III trial with thorough attention to preoperative staging and to the extent of surgical resection to assess the value of neoadjuvant chemotherapy (CTx). Methods: Patients with locally advanced adenocarcinoma of the stomach and cardia were randomized between primary surgery or two 48-day cycles of weekly folinic acid 500 mg/m 2 /2h, 5-FU 2,000 mg/m 2 /24h plus biweekly cisplatin 50 mg/m 2 /1h followed by surgery. The study was designed to detect an improvement in median survival from 17 months with surgery to 24 months with CTx plus surgery (HR=0.708, power of 80%, type I error of 4% to allow for an interim analysis). It was planned to randomize 360 patients in order to observe the 262 deaths required for the final analysis. Results: From 7/99 to 2/04, 144 patients were randomized (72:72) with comparable baseline characteristics. Median follow-up is 4.4 years. Based on 67 deaths, overall survival between the two arms did not differ (HR=0.84; 95% CI: 0.52 to 1.35; p=0.466). Median survival exceeded 36 months in both arms. Due to low accrual, this trial was stopped early. The unexpected long median survival in the surgery arm would have made the primary objective difficult to reach anyway. Based on 77 events, difference in time to progression was borderline significant (HR=0.66; 95% CI, 0.42–1.03; p=0.065). Response rate to CTx was 35.2% (95% CI: 23.7%-45.7%). The R0-resection rate was 81.9 % after CTx as compared to 66.7% with surgery alone (P=0.036). There were no major differences in intra- or postoperative complications. Conclusions: This prematurely closed trial showed a significantly increased rate of R0 resections after CTx although it could not demonstrate a survival benefit. The outcome after a radical surgical procedure alone with extended lymphadenectomy was better than expected. No significant financial relationships to disclose.