tbuckley/cabot-search huggingface dataset:
Pegylated interferon alpha-2B (PEG-Intron) for metastatic renal cell cancer (mRCC): Results of a phase II clinical trial and biologic correlates of response
Authors: G. V. Kondagunta, J. Bacik, N. Ishill, V. Reuter, L. H. Schwartz, J. Korkola, J. Deluca, S. Sweeney, R. S. K. Chaganti, R. J. Motzer
Journal: Journal of Clinical Oncology (2006)

4528 Background: PEG-Intron (PEG-I) is a pegylated derivative of interferon alpha-2b (IFN), recombinant, with a single molecule of mono methoxy polyethylene glycol which increases serum half-life. Methods: A single arm, one-stage phase II trial was conducted between 6/02 and 6/04 in 32 previously untreated patients (pts) with mRCC to assess time to progression and biologic correlates (primary and secondary endpoints). Eligibility included measurable disease and fresh tumor procured at surgery for genetic and immunohistochemical (vascular endothelial growth factor [VEGF] and carbonic anhydrase IX [CAIX]) studies. PEG-I was given SC at a weekly dose of 4.5 μg/kg until progression or intolerability. Quality of life (QOL) was assessed using the FACT-BRM. Results: All 32 were evaluable, 91% had prior nephrectomy, and MSKCC risk group (JCO 20:289–96, 2002) was: 41% good, 53% intermediate, 6% poor. 10 pts (31%; 95% CI: 16%-50%) achieved a partial response (PR). Median time to progression was 5.0 mos (95% C.I. [3, 7]); median survival was 31 mos (95% C.I. [18, not reached]). There were no grade IV toxicities; primary grade III toxicities were hematologic (6/32 pts; 19%) and fatigue (4/32 pts; 13%). FACT-BRM scores showed an initial decrease in QOL at 2 weeks followed by partial recovery. Genomic profiling of tumor samples identified four novel genes that correlated with IFN resistance: ABCD3, Hs.76704, Hs.11325, and Hs.94122. Change in serum VEGF levels did not correlate with response. Tumor tissue samples are being immunohistochemically stained for CAIX. Conclusions: PEG-I treatment results in a 31% response rate and similar median time to progression as standard IFN (JCO 18:2972–80, 2000) in this population with predominantly good and intermediate risk pts. Once weekly dosing was generally well tolerated. Future investigation of PEG-I in combination with novel targeted agents in mRCC is warranted. Further study of the four identified genes may provide insight into IFN resistance. Supported by Schering-Plough, Inc. [Table: see text]
Discovery and Optimization of HKT288, a Cadherin-6–Targeting ADC for the Treatment of Ovarian and Renal Cancers
Authors: Carl U. Bialucha, Scott D. Collins, Xiao Li, Parmita Saxena, Xiamei Zhang, Clemens Dürr, Bruno Lafont, Pierric Prieur, Yeonju Shim, Rebecca Mosher, David Lee, Lance Ostrom, Tiancen Hu, Sanela Bilic, Ivana Liric Rajlic, Vladimir Capka, Wei Jiang, Joel P. Wagner, GiNell Elliott, Artur Veloso, Jessica C. Piel, Meghan M. Flaherty, Keith G. Mansfield, Emily K. Meseck, Tina Rubic-Schneider, Anne Serdakowski London, William R. Tschantz, Markus Kurz, Duc Nguyen, Aaron Bourret, Matthew J. Meyer, Jason E. Faris, Mary J. Janatpour, Vivien W. Chan, Nicholas C. Yoder, Kalli C. Catcott, Molly A. McShea, Xiuxia Sun, Hui Gao, Juliet Williams, Francesco Hofmann, Jeffrey A. Engelman, Seth A. Ettenberg, William R. Sellers, Emma Lees
Journal: Cancer Discovery (2017)

Despite an improving therapeutic landscape, significant challenges remain in treating the majority of patients with advanced ovarian or renal cancer. We identified the cell-cell adhesion molecule cadherin-6 (CDH6) as a lineage gene having significant differential expression in ovarian and kidney cancers. HKT288 is an optimized CDH6-targeting DM4-based antibody-drug conjugate (ADC) developed for the treatment of these diseases. Our study provides mechanistic evidence supporting the importance of linker choice for optimal antitumor activity and highlights CDH6 as an antigen for biotherapeutic development. To more robustly predict patient benefit of targeting CDH6, we incorporate a population-based patient-derived xenograft (PDX) clinical trial (PCT) to capture the heterogeneity of response across an unselected cohort of 30 models-a novel preclinical approach in ADC development. HKT288 induces durable tumor regressions of ovarian and renal cancer models in vivo, including 40% of models on the PCT, and features a preclinical safety profile supportive of progression toward clinical evaluation.Significance: We identify CDH6 as a target for biotherapeutics development and demonstrate how an integrated pharmacology strategy that incorporates mechanistic pharmacodynamics and toxicology studies provides a rich dataset for optimizing the therapeutic format. We highlight how a population-based PDX clinical trial and retrospective biomarker analysis can provide correlates of activity and response to guide initial patient selection for first-in-human trials of HKT288. Cancer Discov; 7(9); 1030-45. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 920.
Perceptions on caring for adult survivors of childhood cancer in the primary care setting
Authors: J. Sima, S. M. Perkins, D. A. Haggstrom
Journal: Journal of Clinical Oncology (2009)

9568 Background: Encouraging cure rates for childhood cancers have resulted in a population of adult childhood cancer survivors (CCS) that are at risk for late effects of cancer-directed therapy. Late effects often occur when CCS are older and receive routine medical care from internists and family practitioners. Our study identifies facilitators and barriers to providing optimal late effects screening as well as evaluating information sources primary care providers (PCPs) perceive as useful, including cancer treatment summaries, survivorship care plans, and Children's Oncology Group (COG) guidelines. Methods: We sampled 1,500 randomly selected general internal medicine and family practice physicians from the American Medical Association Physician Masterfile for a nationwide mail survey. We received 351 surveys with data. Using chi-squared tests or t-tests to compare responders and non-responders we found a higher response rate for family practice (30.2%) compared to general internal medicine (16.5%) (p&lt;.0001). Results were tabulated for descriptive purposes and linear regression and logistic regression were used for the multivariable modeling. Results: Most (84–86%) PCPs stated that they had never received a cancer treatment summary or survivorship care plan; despite this, greater than 90% thought these documents would be useful. Most PCPs (93%) had never used COG guidelines, but 86% agreed that they would follow their recommendations. A minority of PCPs perceived that their medical training was adequate to recognize late effects of chemotherapy (27.6%), cancer surgery (36.6%), and radiation therapy (38.1%). Conclusions: PCPs have a low level of awareness about the medical problems of CCS; receive inadequate training to recognize late effects; and infrequently utilize, cancer treatment summaries, survivorship care plans, and COG guidelines. By evaluating the perceptions of PCPs, we have identified problematic areas for future investigation and have begun to lay the groundwork for incorporating follow-up care for CCS into routine general medical practice. No significant financial relationships to disclose.
Legal Ramifications of Ambiguous Clinical Guidelines—Reply
Authors: Richard S. Klasco, Lewis H. Glinert
Journal: JAMA (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Rapid Rule-out of Acute Myocardial Infarction With a Single High-Sensitivity Cardiac Troponin T Measurement Below the Limit of Detection
Authors: John W. Pickering, Martin P. Than, Louise Cullen, Sally Aldous, Ewoud ter Avest, Richard Body, Edward W. Carlton, Paul Collinson, Anne Marie Dupuy, Ulf Ekelund, Kai M. Eggers, Christopher M. Florkowski, Yonathan Freund, Peter George, Steve Goodacre, Jaimi H. Greenslade, Allan S. Jaffe, Sarah J. Lord, Arash Mokhtari, Christian Mueller, Andrew Munro, Sebbane Mustapha, William Parsonage, W. Frank Peacock, Christopher Pemberton, A. Mark Richards, Juan Sanchis, Lukas P. Staub, Richard Troughton, Raphael Twerenbold, Karin Wildi, Joanna Young
Journal: Annals of Internal Medicine (2017)

This article has been corrected. The original version (PDF) is appended to this article as a Supplement. Background: High-sensitivity assays for cardiac troponin T (hs-cTnT) are sometimes used to rapidly rule out acute myocardial infarction (AMI). Purpose: To estimate the ability of a single hs-cTnT concentration below the limit of detection (<0.005 µg/L) and a nonischemic electrocardiogram (ECG) to rule out AMI in adults presenting to the emergency department (ED) with chest pain. Data Sources: EMBASE and MEDLINE without language restrictions (1 January 2008 to 14 December 2016). Study Selection: Cohort studies involving adults presenting to the ED with possible acute coronary syndrome in whom an ECG and hs-cTnT measurements were obtained and AMI outcomes adjudicated during initial hospitalization. Data Extraction: Investigators of studies provided data on the number of low-risk patients (no new ischemia on ECG and hs-cTnT measurements <0.005 µg/L) and the number who had AMI during hospitalization (primary outcome) or a major adverse cardiac event (MACE) or death within 30 days (secondary outcomes), by risk classification (low or not low risk). Two independent epidemiologists rated risk of bias of studies. Data Synthesis: Of 9241 patients in 11 cohort studies, 2825 (30.6%) were classified as low risk. Fourteen (0.5%) low-risk patients had AMI. Sensitivity of the risk classification for AMI ranged from 87.5% to 100% in individual studies. Pooled estimated sensitivity was 98.7% (95% CI, 96.6% to 99.5%). Sensitivity for 30-day MACEs ranged from 87.9% to 100%; pooled sensitivity was 98.0% (CI, 94.7% to 99.3%). No low-risk patients died. Limitation: Few studies, variation in timing and methods of reference standard troponin tests, and heterogeneity of risk and prevalence of AMI across studies. Conclusion: A single hs-cTnT concentration below the limit of detection in combination with a nonischemic ECG may successfully rule out AMI in patients presenting to EDs with possible emergency acute coronary syndrome. Primary Funding Source: Emergency Care Foundation.
The novel intracellular protein CREG inhibits hepatic steatosis, obesity, and insulin resistance
Authors: Quan‐Yu Zhang, Ling‐Ping Zhao, Xiao‐Xiang Tian, Cheng‐Hui Yan, Yang Li, Yan‐Xia Liu, Pi‐Xiao Wang, Xiao‐Jing Zhang, Ya‐Ling Han
Journal: Hepatology (2017)

Cellular repressor of E1A‐stimulated genes (CREG), a novel cellular glycoprotein, has been identified as a suppressor of various cardiovascular diseases because of its capacity to reduce hyperplasia, maintain vascular homeostasis, and promote endothelial restoration. However, the effects and mechanism of CREG in metabolic disorder and hepatic steatosis remain unknown. Here, we report that hepatocyte‐specific CREG deletion dramatically exacerbates high‐fat diet and leptin deficiency–induced (ob/ob) adverse effects such as obesity, hepatic steatosis, and metabolic disorders, whereas a beneficial effect is conferred by CREG overexpression. Additional experiments demonstrated that c‐Jun N‐terminal kinase 1 (JNK1) but not JNK2 is largely responsible for the protective effect of CREG on the aforementioned pathologies. Notably, JNK1 inhibition strongly prevents the adverse effects of CREG deletion on steatosis and related metabolic disorders. Mechanistically, CREG interacts directly with apoptosis signal‐regulating kinase 1 (ASK1) and inhibits its phosphorylation, thereby blocking the downstream MKK4/7‐JNK1 signaling pathway and leading to significantly alleviated obesity, insulin resistance, and hepatic steatosis. Importantly, dramatically reduced CREG expression and hyperactivated JNK1 signaling was observed in the livers of nonalcoholic fatty liver disease (NAFLD) patients, suggesting that CREG might be a promising therapeutic target for NAFLD and related metabolic diseases. Conclusion : The results of our study provides evidence that CREG is a robust suppressor of hepatic steatosis and metabolic disorders through its direct interaction with ASK1 and the resultant inactivation of ASK1‐JNK1 signaling. This study offers insights into NAFLD pathogenesis and its complicated pathologies, such as obesity and insulin resistance, and paves the way for disease treatment through targeting CREG. (H epatology 2017;66:834–854)
Stenosis of the Sphincter of Oddi
Authors: Richard B. Cattell, Bentley P. Colcock, Jerome L. Pollack
Journal: New England Journal of Medicine (1957)

IN recent years, surgeons who operate upon patients for biliary-tract disease have become increasingly aware of the significant role of obstruction of the common duct at the sphincter of Oddi. This has been particularly true in patients with recurrent biliary symptoms after a cholecystectomy. Recurrent attacks of severe pain in the right upper quadrant or epigastrium, with or without jaundice, may result from obstruction at this point that is not due to commonduct stones, pancreatitis or carcinoma of the ampulla or head of the pancreas. There may be no other demonstrable pathologic change in the entire biliary tract except an . . .
Potential Deaths Averted and Serious Adverse Events Incurred From Adoption of the SPRINT (Systolic Blood Pressure Intervention Trial) Intensive Blood Pressure Regimen in the United States
Authors: Adam P. Bress, Holly Kramer, Rasha Khatib, Srinivasan Beddhu, Alfred K. Cheung, Rachel Hess, Vinod K. Bansal, Guichan Cao, Jerry Yee, Andrew E. Moran, Ramon Durazo-Arvizu, Paul Muntner, Richard S. Cooper
Journal: Circulation (2017)

Background: SPRINT (Systolic Blood Pressure Intervention Trial) demonstrated a 27% reduction in all-cause mortality with a systolic blood pressure (SBP) goal of &lt;120 versus &lt;140 mm Hg among US adults at high cardiovascular disease risk but without diabetes mellitus, stroke, or heart failure. To quantify the potential benefits and risks of SPRINT intensive goal implementation, we estimated the deaths prevented and excess serious adverse events incurred if the SPRINT intensive SBP treatment goal were implemented in all eligible US adults. Methods: SPRINT eligibility criteria were applied to the 1999 to 2006 National Health and Nutrition Examination Survey and linked with the National Death Index through December 2011. SPRINT eligibility included age ≥50 years, SBP of 130 to 180 mm Hg (depending on the number of antihypertensive medications being taken), and high cardiovascular disease risk. Exclusion criteria were diabetes mellitus, history of stroke, &gt;1 g proteinuria, heart failure, estimated glomerular filtration rate &lt;20 mL·min −1 ·1.73 m −2 , or dialysis. Annual mortality rates were calculated by dividing the Kaplan-Meier 5-year mortality by 5. Hazard ratios for all-cause mortality and heart failure and absolute risks for serious adverse events in SPRINT were used to estimate the number of potential deaths and heart failure cases prevented and serious adverse events incurred with intensive SBP treatment. Results: The mean age was 68.6 years, and 83.2% and 7.4% were non-Hispanic white and non-Hispanic black, respectively. The annual mortality rate was 2.20% (95% confidence interval [CI], 1.91–2.48), and intensive SBP treatment was projected to prevent ≈107 500 deaths per year (95% CI, 93 300–121 200) and give rise to 56 100 (95% CI, 50 800–61 400) episodes of hypotension, 34 400 (95% CI, 31 200–37 600) episodes of syncope, 43 400 (95% CI, 39 400–47 500) serious electrolyte disorders, and 88 700 (95% CI, 80 400–97 000) cases of acute kidney injury per year. The analysis-of-extremes approach indicated that the range of estimated lower- and upper-bound number of deaths prevented per year with intensive SBP control was 34 600 to 179 600. Intensive SBP control was projected to prevent 46 100 (95% CI, 41 800–50 400) cases of heart failure annually. Conclusions: If fully implemented in eligible US adults, intensive SBP treatment could prevent ≈107 500 deaths per year. A consequence of this treatment strategy, however, could be an increase in serious adverse events.
Updated survival and biomarker analyses of a randomized phase II study of atezolizumab vs docetaxel in 2L/3L NSCLC (POPLAR).
Authors: David A. Smith, Johan F. Vansteenkiste, Louis Fehrenbacher, Keunchil Park, Julien Mazieres, Achim Rittmeyer, Angel Artal-Cortes, Conrad R. Lewanski, Fadi S. Braiteh, Jing Yi, Pei He, Wei Zou, Marcin Kowanetz, Daniel Waterkamp, Marcus Ballinger, Daniel S. Chen, Alan Sandler, Alexander I. Spira
Journal: Journal of Clinical Oncology (2016)

9028 Background: Atezolizumab (atezo, MPDL3280A), a humanized engineered mAb, is the first anti-PD-L1 agent to show improved OS vs docetaxel (doc) in NSCLC. These results correlate with PD-L1 expression on tumor cells (TC) and/or tumor-infiltrating immune cells (IC) and have shown improvement over time as reflected by the continued late separation of OS curves. Methods: Pts were randomized to receive atezo 1200 mg IV q3w or doc 75 mg/m2IV q3w. Tumors were prospectively evaluated for PD-L1 expression using the SP142 IHC assay and scored from low to high (0-3). Gene expression was analyzed using a Fluidigm platform. The primary endpoint was OS and the primary analysis included 173 events among 287 randomized pts (event/patient ratio [EPR] 60%; min follow up 13 mo). Here we present data as of Dec 1, 2015 with a min follow up of 20 mo. Results: With longer follow up and 200 events (EPR 70%) further separation in survival curves and improvement in OS HR were seen for atezo over doc for ITT (HR 0.69, 95% CI 0.52-0.92) and across PD-L1 and histology subgroups (Table). Longer mDOR was seen for atezo vs doc (18.6 vs 7.2 mo). Improved OS with atezo over doc correlated with high tumor expression of Teff /IFNγ-associated genes (unstratified HR 0.52, 95% CI 0.32−0.83). Atezo continues to have a tolerable safety profile distinct from doc. Conclusions: Extended follow up reveals further separation late in OS curves and increased benefit with atezo monotherapy vs doc. Relative to the primary analysis, OS benefit is improved in ITT and PD-L1 subgroups, including TC0 and IC0, and in pts with squamous NSCLC. In addition, PD-L1 expression measured by IHC and the tumor Teff /IFNγ gene signature, which reflects pre-existing immunity, can identify pts most likely to benefit from atezo. Clinical trial information: NCT01903993. OS Atezo Doc HRa 95% CI PValueb n Median, mo n Median, mo ITT 144 12.6 143 9.7 0.69 0.52-0.92 .011 TC3 or IC3 24 NRc 23 11.1 0.45 0.22-0.95 .033 TC2/3 or IC2/3 50 15.1 55 7.4 0.50 0.31-0.80 .003 TC1/2/3 or IC1/2/3 93 15.1 102 9.2 0.59 0.41-0.83 .003 TC0 and IC0 51 9.7 41 9.7 0.88 0.55-1.42 .601 Squamous 49 10.1 48 8.6 0.66 0.41-1.05 .075 Nonsquamous 95 14.8 95 10.9 0.69 0.49-0.98 .039 aStratified for ITT, unstratified for subgroups bDescriptive only cNot reached
Primary Treatment of Waldenstrom’s Macroglobulinemia (WM) with Dexamethasone, Rituximab and Cyclophosphamide.
Authors: Meletios A. Dimopoulos, Maria Christina Kyrtsonis, Constantinos Tsatalas, Garyfallia Kokkini, Panagiotis Repoussis, Athanasios Zomas, Argiris Symeonidis, Evridiki Michali, Athanasios Anagnostopoulos, Nikolaos Anagnostopoulos, Theophanis Economopoulos, Gerasimos Pangalis
Journal: Blood (2004)
Therapeutic Targeting of Poly(ADP‐Ribose) Polymerase‐1 (PARP1) in Cancer: Current Developments, Therapeutic Strategies, and Future Opportunities
Authors: Jyotika Rajawat, Nidhi Shukla, Durga Prasad Mishra
Journal: Medicinal Research Reviews (2017)

Abstract Poly(ADP‐ribose) polymerase‐1 (PARP‐1) plays a central role in numerous cellular processes including DNA repair, replication, and transcription. PARP interacts directly, indirectly or via PARylation with various oncogenic proteins and regulates several transcription factors thereby modulating carcinogenesis. Therapeutic inhibition of PARP is therefore perceived as a promising anticancer strategy and a number of PARP inhibitors (PARPi) are currently under development and clinical evaluation. PARPi inhibit the DNA repair pathway and thus form the concept of synthetic lethality in cancer therapeutics. Preclinical and clinical studies have shown the potential of PARPi as chemopotentiator, radiosensitizer, or as adjuvant therapeutic agents. Recent studies have shown that PARP‐1 could be either oncogenic or tumor suppressive in different cancers. PARP inhibitor resistance is also a growing concern in the clinical setting. Recently, changes in the levels of PARP‐1 activity or expression in cancer patients have provided the basis for consideration of PARP‐1 regulatory proteins as potential biomarkers. This review focuses on the current developments related to the role of PARP in cancer progression, therapeutic strategies targeting PARP‐associated oncogenic signaling, and future opportunities in use of PARPi in anticancer therapeutics.
Crystal structures, absolute configurations and molecular docking studies of naftopidil enantiomers as α 1D -adrenoceptor antagonists
Authors: Wei Xu, Junjun Huang, Renwang Jiang, Mu Yuan
Journal: Acta Pharmaceutica Sinica B (2017)

Chiral drug naftopidil (NAF), a specific α1D-adrenoceptor (AR) antagonist for the treatment of benign prostatic hyperplasia, was used in racemic form for several decades. Our recent work declared that NAF enantiomers showed the same antagonistic effects on the α1D-AR, but the binding mechanism of these two stereochemical NAF isomers to the α1D receptor remained unclear. Herein, we reported the crystallographic structures of optically pure NAF stereoisomers for the first time and unambiguously determined their absolute configurations. The crystal data of R and S enantiomers matched satisfactorily the pharmacophore model for α1D-selective antagonists. Based on the constructed α1D homology model, molecular docking studies shed light on the molecular mechanism of NAF enantiomers binding to α1D-AR. The results indicated that NAF enantiomers exhibited the very similar binding poses and occupied the same binding pocket.