tbuckley/cabot-search huggingface dataset:
Survival Outcomes in Cancer Patients Predicted by a Partial EMT Gene Expression Scoring Metric
Authors: Jason T. George, Mohit Kumar Jolly, Shengnan Xu, Jason A. Somarelli, Herbert Levine
Journal: Cancer Research (2017)

Abstract Metastasis is a significant contributor to morbidity and mortality for many cancer patients and remains a major obstacle for effective treatment. In many tissue types, metastasis is fueled by the epithelial-to-mesenchymal transition (EMT)—a dynamic process characterized by phenotypic and morphologic changes concomitant with increased migratory and invasive potential. Recent experimental and theoretical evidence suggests that cells can be stably halted en route to EMT in a hybrid E/M phenotype. Cells in this phenotype tend to move collectively, forming clusters of circulating tumor cells that are key tumor-initiating agents. Here, we developed an inferential model built on the gene expression of multiple cancer subtypes to devise an EMT metric that characterizes the degree to which a given cell line exhibits hybrid E/M features. Our model identified drivers and fine-tuners of epithelial–mesenchymal plasticity and recapitulated the behavior observed in multiple in vitro experiments across cancer types. We also predicted and experimentally validated the hybrid E/M status of certain cancer cell lines, including DU145 and A549. Finally, we demonstrated the relevance of predicted EMT scores to patient survival and observed that the role of the hybrid E/M phenotype in characterizing tumor aggressiveness is tissue and subtype specific. Our algorithm is a promising tool to quantify the EMT spectrum, to investigate the correlation of EMT score with cancer treatment response and survival, and to provide an important metric for systematic clinical risk stratification and treatment. Cancer Res; 77(22); 6415–28. ©2017 AACR.
A Prospective Analysis of High-Dose Interleukin-2 (HD IL-2) following PD-1 inhibitor therapy in patients with metastatic melanoma and renal cell carcinoma.
Authors: Elizabeth Iannotti Buchbinder, Janice P. Dutcher, Jessica C. Perritt, Joseph Clark, Shernan G. Holtan, John M. Kirkwood, Brendan D. Curti, Christopher D. Lao, Howard Kaufman, Mayer N. Fishman, David F. McDermott
Journal: Journal of Clinical Oncology (2016)

e21006 Background: PD-1/PD-L1 inhibitors (aPD-1) have demonstrated efficacy in the treatment of metastatic melanoma (MM) and advanced renal cell carcinoma (RCC). HD IL-2 can produce durable responses in a subset of patients and remains a treatment option. As aPD-1 therapy becomes the backbone of mm and RCC treatment it becomes increasingly important to understand whether HD IL-2 is safe and effective following immune checkpoint blockade (ICB). Methods: PROCLAIMSM (www.proclaimregistry.com, NCT01415167) is an IL-2 observational registry with > 40 participating sites consisting of a retrospective (n = 370, locked) and prospective cohort (n > 942, on-going). We queried the prospective cohort to identify pts treated with HD IL-2 after aPD-1 and report their safety and efficacy outcomes, compared to pts who had not received any ICB prior to HD IL-2. Results: Within the database, there are currently 16 patients who received aPD-1 prior to HD IL-2 therapy, 12 patients (3 RCC and 9 MM) had sufficient data as of 12/17/2015 to analyze outcome. Of these 12 patients, seven with mm also received ipilimumab and 3 with RCC also received anti-VEGF therapy prior to treatment with HD IL-2. The most common and reversible toxicities reported as the reason(s) to stop dosing for Cycle 1 in the patients who had previously been treated with aPD-1 were hypotension, diarrhea, vomiting, hypoxia, renal failure and arrhythmia. These toxicities were similar to those observed among the 681 HD IL-2 patients without prior ICB. There were no IL-2 related deaths noted in the cohort receiving prior aPD-1. The one year overall survival from HD IL-2 was 76% in patients who previously received aPD-1 versus 74% in patients who had not previously been treated with ICB. The ORR was 8.3% in patients with prior aPD-1 vs. 15% in those without prior ICB. Conclusions: Data from the PROCLAIM database suggests that HD IL-2 remains a treatment option for pts who have had progressive disease after prior PD-1 inhibition. Continued analysis of patients treated with HD IL-2 will help guide the optimal sequence of these immunotherapies.
H-1B Visa Applications for Physicians—Reply
Authors: Peter A. Kahn, Tova M. Gardin
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
A platinum-resistant subtype of high-grade serous ovarian cancer identified by a network of somatic mutations.
Authors: John P. Shen, Ana Bojorquez-Gomez, Justin Huang, Matan Hofree, Katie Kurnit, Kristin Klepper, Alex Beckett, Jason F Kreisberg, Cheryl C. Saenz, Trey Ideker
Journal: Journal of Clinical Oncology (2017)

5561 Background: High-grade serous ovarian carcinoma (HGS-OvCa) is a heterogeneous entity with a widely variable clinical course even among patients of the same stage and histological subtype. Although most patients will achieve remission with platinum-based chemotherapy, ~20% will display primary platinum resistance. Currently no biomarker exists to identify these platinum resistant patients. Methods: We have recently developed a method called Network-based Stratification (NBS), which combines genome-scale somatic mutation profiles with genetic interaction networks and performs unsupervised clustering of patients into subtypes. Results: Using NBS HGSOC patients were stratified into subtype, in both TCGA (n = 330) and the ICGC (n = 92) a high-risk (HR) subtype consisting of ~20% of the patients was identified (see table). Propagated mutation scores of the HR tumors from TCGA and ICGC cohorts we remarkably correlated (Pearson r 2 = 0.94, p &lt; 0.001), relative to the correlation between HR and standard risk subtypes within TGCA cohort (r 2 = 0.18). We then identified molecularly matched cell line models for in vitro study, finding that HR cell lines (Kuramochi, Ovkate, OAW28, 59M) were significantly more resistant to cisplatin relative standard risk cell lines (COV318, TYK-NU, OVCAR4), (IC 50 14.4 vs. 3.3 µM, p &lt; 0.0001). There was no significant difference in sensitivity to paclitaxel. A genome-wide knockout screen using CRISPR-Cas9 has identified several candidate genes mediating this observed platinum resistance. Conclusions: NBS can be used to identify a molecularly distinct subtype of HGSOC characterized by poor patient survival and primary platinum resistance. [Table: see text]
Long-term rates of breast cancer in a population of women with ductal carcinoma in situ treated by breast-conserving surgery.
Authors: Eileen Rakovitch, Sharon Nofech-Mozes, Steven Narod, Wedad Hanna, Refik Saskin, Alan Tuck, Sandip Sengupta, Susan Done, Naomi Miller, Bruce Youngson, Lawrence Frank Paszat
Journal: Journal of Clinical Oncology (2012)

1123 Background: Ductal Carcinoma in Situ (DCIS) is a non-invasive form of breast cancer which is often treated by breast-conserving surgery. The addition of radiotherapy to surgery has been shown to reduce the risk of local recurrence (LR), but use of radiotherapy varies. It is not known to what extent women with DCIS are at risk for recurrent cancer due to the omission of radiation therapy. We studied a large provincial cohort of women with DCIS who were treated with breast-conserving surgery for factors which predict local recurrence and estimate the impact of radiotherapy on local recurrence and long-term rates of breast preservation. Methods: All women diagnosed with DCIS in Ontario from 1994 to 2003 were identified. Treatments and outcomes were identified through administrative databases and validated by chart review. Women treated with breast-conserving surgery, alone or with radiotherapy, were included. Survival analyses were used to study local recurrence (DCIS or invasive) in relation to patient characteristics, tumour characteristics and treatment. Results: The cohort included 3975 women who were treated with breast-conserving therapy; of these, 1949 (49%) received radiation. At 10 years median follow-up, 736 developed LR(19%). LR developed in 259 of 1949 women who received radiotherapy (13%) and in 477 of 2026 women who did not (24%;p&lt;0.001). The differences were significant for both invasive LR (7% vs. 14%; p&lt;0.001) and DCIS recurrence (6% vs.9%; p&lt;0.001). The 10-year cumulative rate of mastectomy was 13% for women who received radiotherapy compared to 17% for those who did not (p&lt;0.01).We estimate that 29% (N=214) of all local recurrences diagnosed in Ontario in women treated for DCIS between 1994 and 2003 would be prevented if all patients received radiotherapy. Conclusions: The omission of radiation therapy after breast-conserving surgery in women with DCIS resulted in a substantial number of local recurrences that might have been avoided and lower rates of breast preservation. Improvements in guidelines that facilitate the selection of women in whom radiotherapy can be avoided are needed.
Key challenges in bringing CRISPR-mediated somatic cell therapy into the clinic
Authors: Dianne Nicol, Lisa Eckstein, Michael Morrison, Jacob S. Sherkow, Margaret Otlowski, Tess Whitton, Tania Bubela, Kathryn P. Burdon, Don Chalmers, Sarah Chan, Jac Charlesworth, Christine Critchley, Merlin Crossley, Sheryl de Lacey, Joanne L. Dickinson, Alex W. Hewitt, Joanne Kamens, Kazuto Kato, Erika Kleiderman, Satoshi Kodama, John Liddicoat, David A. Mackey, Ainsley J. Newson, Jane Nielsen, Jennifer K. Wagner, Rebekah E. McWhirter
Journal: Genome Medicine (2017)

Genome editing using clustered regularly interspersed short palindromic repeats (CRISPR) and CRISPR-associated proteins offers the potential to facilitate safe and effective treatment of genetic diseases refractory to other types of intervention. Here, we identify some of the major challenges for clinicians, regulators, and human research ethics committees in the clinical translation of CRISPR-mediated somatic cell therapy.
EAACI Guidelines on Allergen Immunotherapy: Allergic rhinoconjunctivitis
Authors: G. Roberts, O. Pfaar, C. A. Akdis, I. J. Ansotegui, S. R. Durham, R. Gerth van Wijk, S. Halken, D. Larenas‐Linnemann, R. Pawankar, C. Pitsios, A. Sheikh, M. Worm, S. Arasi, M. A. Calderon, C. Cingi, S. Dhami, J. L. Fauquert, E. Hamelmann, P. Hellings, L. Jacobsen, E. F. Knol, S. Y. Lin, P. Maggina, R. Mösges, J. N. G. Oude Elberink, G. B. Pajno, E. A. Pastorello, M. Penagos, G. Rotiroti, C. B. Schmidt‐Weber, F. Timmermans, O. Tsilochristou, E.‐M. Varga, J. N. Wilkinson, A. Williams, L. Zhang, I. Agache, E. Angier, M. Fernandez‐Rivas, M. Jutel, S. Lau, R. van Ree, D. Ryan, G. J. Sturm, A. Muraro
Journal: Allergy (2017)

Abstract Allergic rhinoconjunctivitis (AR) is an allergic disorder of the nose and eyes affecting about a fifth of the general population. Symptoms of AR can be controlled with allergen avoidance measures and pharmacotherapy. However, many patients continue to have ongoing symptoms and an impaired quality of life; pharmacotherapy may also induce some side‐effects. Allergen immunotherapy (AIT) represents the only currently available treatment that targets the underlying pathophysiology, and it may have a disease‐modifying effect. Either the subcutaneous (SCIT) or sublingual (SLIT) routes may be used. This Guideline has been prepared by the European Academy of Allergy and Clinical Immunology's (EAACI) Taskforce on AIT for AR and is part of the EAACI presidential project “EAACI Guidelines on Allergen Immunotherapy.” It aims to provide evidence‐based clinical recommendations and has been informed by a formal systematic review and meta‐analysis. Its generation has followed the Appraisal of Guidelines for Research and Evaluation (AGREE II) approach. The process included involvement of the full range of stakeholders. In general, broad evidence for the clinical efficacy of AIT for AR exists but a product‐specific evaluation of evidence is recommended. In general, SCIT and SLIT are recommended for both seasonal and perennial AR for its short‐term benefit. The strongest evidence for long‐term benefit is documented for grass AIT (especially for the grass tablets) where long‐term benefit is seen. To achieve long‐term efficacy, it is recommended that a minimum of 3 years of therapy is used. Many gaps in the evidence base exist, particularly around long‐term benefit and use in children.
Genomic profiling of resistant tumor samples following progression on EGF816, a third generation, mutant-selective EGFR tyrosine kinase inhibitor (TKI), in advanced non-small cell lung cancer (NSCLC).
Authors: Daniel Shao-Weng Tan, Dong-Wan Kim, Natasha B. Leighl, Gregory J. Riely, James Chih-Hsin Yang, Juergen Wolf, Takashi Seto, Enriqueta Felip, Santiago Ponce Aix, Maud Jonnaert, Chun Pan, Sinead Dolan, Jordi Barretina, Susan Elizabeth Moody, Lecia V. Sequist
Journal: Journal of Clinical Oncology (2017)

11506 Background: Up to 60% of patients (pts) with NSCLC harboring an activating EGFR mutation (mut) and treated with a 1st generation EGFR TKI develop a secondary gatekeeper T790M mut. EGF816 is an irreversible EGFR TKI that is highly potent against activating mut (L858R, ex19del) and T790M mut, while sparing wild-type EGFR. As previously reported, in a Phase I dose escalation study, the overall response rate to EGF816 in pts with advanced EGFR T790M mut NSCLC was 47% and the disease control rate was 87%. However, pts ultimately develop disease progression. Tumor biopsies were obtained from pts who had progressed on EGF816 to identify mechanisms of resistance. Methods: Pts with NSCLC with locally or centrally confirmed T790M status were enrolled in this multicenter, dose escalation study to determine the safety, tolerability and antitumor activity of EGF816 (NCT02108964). EGF816 was administered at 7 dose levels ranging from of 75-350 mg QD. Following disease progression, a tumor sample was obtained and was analyzed by the Foundation Medicine next-generation sequencing (NGS) T7 panel, which interrogates 395 cancer-related genes for base substitutions, insertion-deletions, and copy number changes, as well as introns of 31 genes involved in rearrangements. Results: Tumor samples taken following disease progression on EGF816 were analyzed from 9 pts. Of the 8 pts whose tumors were T790M+ at baseline, this was detected in only 3 pts’ post-EGF816 progression samples. One patient developed an EGFR C797S mut and concurrent deletion in mTOR. Other identified alterations include BRAF fusions (n = 2) and c-MET amplification (n = 1). Only one patient was found to have concurrent TP53 mutation and RB1 truncating mutation. Individual patient response data, including duration of response, will be presented along with detailed genomic parameters. Conclusions: NGS analysis of tumors that developed resistance to EGF816 revealed multiple potential mechanisms of resistance. These data are hypothesis-generating and could lead to rational combination studies with EGF816 to improve the depth and/or duration of response to EGF816. Clinical trial information: NCT02108964.
Myeloablative Allogeneic Hematopoietic Cell Transplantation Performed without Routine Inpatient Admission: A Single Center Experience of 462 Consecutive Patients
Authors: Asad Bashey, Xu Zhang, Stacey Brown, Katelin Jackson, Melhem Solh, Lawrence E. Morris, H. Kent Holland, Scott R. Solomon
Journal: Blood (2016)
Risk of malignancies associated with ustekinumab
Authors: A. Greenspan, P. Marty‐Ethgen, S. Fakharzadeh
Journal: British Journal of Dermatology (2017)

A recently published report by Florek et al.1 associates malignancies with ustekinumab (STELARA®) treatment. Janssen emphasizes patient safety and welcomes rigorous safety analyses from other parties. However, it is unclear how this report adds to the understanding of ustekinumab's safety profile.

This article is protected by copyright. All rights reserved.
Aberrant O-GalNAc glycosylation to enhance AKT/mTOR signaling in pancreatic cancer.
Authors: Bianca T. Hofmann, Aeint-Steffen Picksak, Marcel Kwiatkowski, Jakob R. Izbicki, Maximillian Bockhorn, Cenap Guengoer, Florian Ewald, Gerrit Wolters-Eisfeld
Journal: Journal of Clinical Oncology (2016)

e15673 Background: Immature truncated O-GalNAc glycosylation is an important feature of pancreatic ductal adenocarcinomas and is detected with high frequency in premalignant lesions. Differential expression of O-GalNAc glycans Tn antigen and sialyl-Tn antigen is strongly associated with decreased survival and poor prognosis and frequently occurs in pancreatic cancer due to hypermethylation of the COSMC (C1GALT1C1)gene. COSMC knockdown experiments displayed reduced rate of apoptosis and enhanced migratory behavior, thereby promoting oncogenic properties in pancreatic cancer cells. Since the underlying biological processes are not well understood, we investigated the impact of aberrant O-GalNAc glycosylation on AKT/mTOR signaling in Panc-1 and L3.6pl COSMC knockdown cells. Methods: Lentiviral mediated COSMC knockdown cell lines were subjected to stable isotope labeling by amino acids (SILAC) and subsequently analyzed by mass spectromic quantitative proteomics. Immunoprecipitation, Western blot analysis and real time PCR were used to assess glycotype dependent signaling molecule expression and phosphorylation status. Results: In COSMC knockdown cells, quantitative proteomics identified proteins associated to IGF, EGF and PI3K pathways. We could further identify AKT as novel O-GalNAc-modified protein in Panc-1 pancreatic cancer cell line. AKT downstream substrates S6 ribosomal protein and GSK-3b displayed an enhanced phosphorylation and AKT upstream effectors, such as IGF-I receptor and mTORC2 complex showed an enhanced activation in COSMC knockdown cells. Interestingly, aberrant O-glycosylation was able to modify mTOR S2448 phosphorylation in L3.6pl COSMC knockdown cells treated with mTORC inhibitor AZD8055. Conclusions: Our study revealed an enhanced AKT/mTOR signaling in pancreatic cancer COSMC knockdown cells, which is driven by aberrant O-GalNAc glycosylation and substantiates the previously observed enhancement of oncogenic properties.
Defining Optimal Length of Opioid Pain Medication Prescription After Common Surgical Procedures
Authors: Rebecca E. Scully, Andrew J. Schoenfeld, Wei Jiang, Stuart Lipsitz, Muhammad Ali Chaudhary, Peter A. Learn, Tracey Koehlmoos, Adil H. Haider, Louis L. Nguyen
Journal: JAMA Surgery (2017)

The overprescription of pain medications has been implicated as a driver of the burgeoning opioid epidemic; however, few guidelines exist regarding the appropriateness of opioid pain medication prescriptions after surgery.
Circulating microRNAs (miRNAs) as predictors of relapse in early breast cancer (BC).
Authors: Sofia Agelaki, Chara Papadaki, Michalis Stratigos, Maria Spiliotaki, Georgios Markakis, Georgios Mastrostamatis, Dimitrios Mavroudis
Journal: Journal of Clinical Oncology (2017)

e23030 Background: Disease relapse is usually a lethal development following treatment of early BC. Recurrence could arise from a state of tumour dormancy during which there is growth restriction of undetectable micrometastases. The expression of dormancy and metastasis related miRNAs was evaluated in the plasma of patients (pts) with early BC obtained before adjuvant therapy in order to discover novel biomarkers for the prediction of relapse. Methods: PlasmamiR-21, miR-23b, miR-190, miR-200b and miR-200c expression was assessed by qRT-PCR in 133 pts with early BC (non-relapsed, n = 84; relapsed, n = 49). Expression was classified as high or low according to the median values. Results: No correlation was observed between the expression of miRNAs and the clinicopathological characteristics of pts. After a median follow-up of 94 mo, median Disease Free Interval (DFI) was significantly lower in pts with high compared to low miR-21 [105.03 mo vs not reached (NR); p= 0.001], miR-200c (105.2 mo vs NR; p= 0.007), or both miR-21 and miR-200c expression (81.37 mo vs NR; p= 0.001). miR-21-high was also associated with decreased median Overall Survival (OS; p= 0.041). In multivariate analysis the number of infiltrated axillary lymph nodes (N3 vs N0-N2, HR: 2.86; p= 0.004) and miR-21 expression (high vs low, HR: 2.824; p= 0.001) were independent negative prognostic factors for DFI, whereas negative hormone receptor status (HR: 3.062; p= 0.024) and miR-21 high (HR: 3.545; p= 0.029) independently predicted for worse OS. Moreover, miR-21 expression was higher in pts with early relapse (defined as relapse at ≤ 3 yrs) compared to non-relapsed at 5 yrs ( p= 0.032). In addition, higher miR-21 ( p= 0.038), miR-23b ( p= 0.039), miR-200b ( p= 0.027) and miR-200c ( p&lt; 0.001) levels were observed in pts with late relapse (at ≥ 5 yrs) compared to those without relapse. Conclusions: Differential expression levels of metastasis and/or dormancy related circulating miRNAs are detectable before adjuvant therapy in pts with early BC presenting subsequent relapse compared to non-relapsed pts. Circulating miRNAs can predict for early or late recurrence years before clinical detection of metastases. These results merit prospective validation in an independent patient cohort.
An Advanced Multifunctional Hydrogel‐Based Dressing for Wound Monitoring and Drug Delivery
Authors: Bahram Mirani, Erik Pagan, Barbara Currie, Mohammad Ali Siddiqui, Reihaneh Hosseinzadeh, Pooria Mostafalu, Yu Shrike Zhang, Aziz Ghahary, Mohsen Akbari
Journal: Advanced Healthcare Materials (2017)

Abstract Wound management is a major global challenge and poses a significant financial burden to the healthcare system due to the rapid growth of chronic diseases such as diabetes, obesity, and aging population. The ability to detect pathogenic infections and release drug at the wound site is of the utmost importance to expedient patient care. Herein, this study presents an advanced multifunctional dressing (GelDerm) capable of colorimetric measurement of pH, an indicator of bacterial infection, and release of antibiotic agents at the wound site. This study demonstrates the ability of GelDerm to detect bacterial infections using in vitro and ex vivo tests with accuracies comparable to the commercially available systems. Wireless interfaces to digital image capture hardware such as smartphones serve as a means for quantitation and enable the patient to record the wound condition at home and relay the information to the healthcare personnel for following treatment strategies. Additionally, the dressing is integrated within commercially available patches and can be placed on the wound without chemical or physical irritation. This study demonstrates the ability of GelDerm to eradicate bacteria by the sustained release of antibiotics. The proposed technology holds great promise in managing chronic and acute injuries caused by trauma, surgery, or diabetes.