tbuckley/cabot-search huggingface dataset:
Outcomes of Patients With Double-Hit Lymphoma Who Achieve First Complete Remission
Authors: Daniel J. Landsburg, Marissa K. Falkiewicz, Joseph Maly, Kristie A. Blum, Christina Howlett, Tatyana Feldman, Anthony R. Mato, Brian T. Hill, Shaoying Li, L. Jeffrey Medeiros, Pallawi Torka, Francisco Hernandez-Ilizaliturri, Nishitha M. Reddy, Arun Singavi, Timothy S. Fenske, Julio C. Chavez, Jason B. Kaplan, Amir Behdad, Adam M. Petrich, Martin A. Bast, Julie M. Vose, Adam J. Olszewski, Cristiana Costa, Frederick Lansigan, James N. Gerson, Stefan K. Barta, Oscar Calzada, Jonathon B. Cohen, Jennifer K. Lue, Jennifer E. Amengual, Xavier Rivera, Daniel O. Persky, David J. Peace, Sunita Nathan, Ryan D. Cassaday
Journal: Journal of Clinical Oncology (2017)

Purpose Patients with double-hit lymphoma (DHL) rarely achieve long-term survival following disease relapse. Some patients with DHL undergo consolidative autologous stem-cell transplantation (autoSCT) to reduce the risk of relapse, although the benefit of this treatment strategy is unclear. Methods Patients with DHL who achieved first complete remission following completion of front-line therapy with either rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or intensive front-line therapy, and deemed fit for autoSCT, were included. A landmark analysis was performed, with time zero defined as 3 months after completion of front-line therapy. Patients who experienced relapse before or who were not followed until that time were excluded. Results Relapse-free survival (RFS) and overall survival (OS) rates at 3 years were 80% and 87%, respectively, for all patients (n = 159). Three-year RFS and OS rates did not differ significantly for autoSCT (n = 62) versus non-autoSCT patients (n = 97), but 3-year RFS was inferior in patients who received R-CHOP compared with intensive therapy (56% v 88%; P = .002). Three-year RFS and OS did not differ significantly for patients in the R-CHOP or intensive therapy cohorts when analyzed by receipt of autoSCT. The median OS following relapse was 8.6 months. Conclusion In the largest reported series, to our knowledge, of patients with DHL to achieve first complete remission, consolidative autoSCT was not associated with improved 3-year RFS or OS. In addition, patients treated with R-CHOP experienced inferior 3-year RFS compared with those who received intensive front-line therapy. When considered in conjunction with reports of patients with newly diagnosed DHL, which demonstrate lower rates of disease response to R-CHOP compared with intensive front-line therapy, our findings further support the use of intensive front-line therapy for this patient population.
Dual-Responsive Molecular Probe for Tumor Targeted Imaging and Photodynamic Therapy
Authors: Xiaoqing Meng, Yueting Yang, Lihua Zhou, li Zhang, Yalin Lv, Sanpeng Li, Yayun Wu, Mingbin Zheng, Wenjun Li, Guanhui Gao, Guanjun Deng, Tao Jiang, Dapeng Ni, Ping Gong, Lintao Cai
Journal: Theranostics (2017)

The precision oncology significantly relies on the development of multifunctional agents to integrate tumor targeting, imaging and therapeutics.In this study, a first small-molecule theranostic probe, RhoSSCy is constructed by conjugating 5′-carboxyrhodamines (Rho) and heptamethine cyanine IR765 (Cy) using a reducible disulfide linker and pH tunable amino-group to realize thiols/pH dual sensing.In vitro experiments verify that RhoSSCy is highly sensitive for quantitative analysis and imaging intracellular pH gradient and biothiols.Furthermore, RhoSSCy shows superb tumor targeted dual-modal imaging via near-infrared fluorescence (NIRF) and photoacoustic (PA).Importantly, RhoSSCy also induces strongly reactive oxygen species for tumor photodynamic therapy (PDT) with robust antitumor activity both in vitro and in vivo.Such versatile small-molecule theranostic probe may be promising for tumor targeted imaging and precision therapy.
Epidermal growth factor receptor inhibition downregulates<i>Helicobacter pylori</i>-induced epithelial inflammatory responses, DNA damage and gastric carcinogenesis
Authors: Johanna C Sierra, Mohammad Asim, Thomas G Verriere, M Blanca Piazuelo, Giovanni Suarez, Judith Romero-Gallo, Alberto G Delgado, Lydia E Wroblewski, Daniel P Barry, Richard M Peek, Alain P Gobert, Keith T Wilson
Journal: Gut (2017)

Objective Gastric cancer is the third leading cause of cancer death worldwide and infection by Helicobacter pylori is the strongest risk factor. We have reported increased epidermal growth factor receptor (EGFR) phosphorylation in the H. pylori -induced human carcinogenesis cascade, and association with DNA damage. Our goal was to determine the role of EGFR activation in gastric carcinogenesis. Design We evaluated gefitinib, a specific EGFR inhibitor, in chemoprevention of H. pylori -induced gastric inflammation and cancer development. Mice with genetically targeted epithelial cell-specific deletion of Egfr ( Efgr Δ epi mice) were also used. Results In C57BL/6 mice, gefitinib decreased Cxcl1 and Cxcl2 expression by gastric epithelial cells, myeloperoxidase-positive inflammatory cells in the mucosa and epithelial DNA damage induced by H. pylori infection. Similar reductions in chemokines, inflammatory cells and DNA damage occurred in infected Egfr Δ epi versus Egfr fl/fl control mice. In H. pylori -infected transgenic insulin-gastrin (INS-GAS) mice and gerbils, gefitinib treatment markedly reduced dysplasia and carcinoma. Gefitinib blocked H. pylo ri-induced activation of mitogen-activated protein kinase 1/3 (MAPK1/3) and activator protein 1 in gastric epithelial cells, resulting in inhibition of chemokine synthesis. MAPK1/3 phosphorylation and JUN activation was reduced in gastric tissues from infected wild-type and INS-GAS mice treated with gefitinib and in primary epithelial cells from Efgr Δ epi versus Egfr fl/fl mice. Epithelial EGFR activation persisted in humans and mice after H. pylori eradication, and gefitinib reduced gastric carcinoma in INS-GAS mice treated with antibiotics. Conclusions These findings suggest that epithelial EGFR inhibition represents a potential strategy to prevent development of gastric carcinoma in H. pylori -infected individuals.
Dabigatran Compared With Rivaroxaban vs Warfarin—Reply
Authors: Anna L. Parks, Rita F. Redberg
Journal: JAMA Internal Medicine (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 Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast 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) 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 Internal Medicine journal
Effects of NEPA (novel combination of netupitant and palonosetron) on ECG of healthy volunteers: A randomized, controlled, thorough ECG trial.
Authors: Tulla Spinelli, Cecilia Moresino, Sybille Baumann, Wolfgang Timmer
Journal: Journal of Clinical Oncology (2013)

e20538 Background: Despite advances in supportive cancer care, chemotherapy-induced nausea and vomiting (CINV) is ranked by patients among the worst side effects of chemotherapy. NEPA is a new antiemetic under development composed of a unique fixed-dose combination of netupitant (NETU, 300 mg), a new, highly selective NK 1 receptor antagonist (RA), and palonosetron (PALO, 0.5 mg), a pharmacologically and clinically distinct 5-HT 3 RA. NEPA targets the 2 most important emetic pathways with a single oral dose. Although PALO is not associated with cardiovascular issues, this study aimed to evaluate the tolerability and cardiovascular safety of different doses of NETU + PALO. Methods: This randomized, double-blind, parallel-group, placebo- and open-label positive-controlled study in 197 volunteers (106 men) included 4 treatment groups: placebo, 200 mg NETU + 0.5 mg PALO (NEPA 200/0.5 ), 600 mg NETU + 1.5 mg PALO (NEPA 600/1.5 ), and 400 mg moxifloxacin. Assessments, based on ICH E14 Guidelines, included a 24-h baseline ECG after which volunteers received a single dose of treatment, followed by ECG measurements for 2 days. The primary objective was to determine the individual heart rate-corrected QT interval (QTcI) (n=196). Safety and tolerability of NEPA groups were also assessed (n=197). Results: Mean placebo-corrected QTcI change from baseline was +5 and +4 ms for NEPA 200/0.5 and NEPA 600/1.5 , respectively. Mean placebo-corrected change from baseline for heart rate (HR) was -3 bpm for the 2 NEPA groups. Placebo-corrected changes in pulse rate (PR) and QRS durations were similar in both NEPA groups (0 to 1 ms) and not clinically different from placebo. These data show no signs of an effect of NEPA groups on QTcI. In comparison, the moxifloxacin showed the expected increase in QTcI vs placebo (+8/9 ms). The frequency of all treatment-related AEs (TRAEs) for NEPA 200/0.5 was lower than placebo but slightly higher in volunteers treated with NEPA 600/1.5. The most commonly reported TRAEs in the NEPA groups were constipation, upper abdominal pain, and headache. Conclusions: NEPA treatments produced no significant effects on QTcI, HR, PR, QRS interval, or cardiac morphology relative to placebo.
Mutational analysis of circulating tumor cells in breast cancer patients by targeted clonal sequencing.
Authors: Xunhai Xu, Yufeng Shen, William Dewitt, Deep Pandya, Farideh Z. Bischoff, Katherine D. Crew, Dawn L. Hershman, Matthew A. Maurer, Ramon Parsons, Kevin Kalinsky
Journal: Journal of Clinical Oncology (2012)

10516 Background: The molecular signature of circulating tumor cells (CTCs) may serve as a surrogate marker for accurate description of the metastatic tumor of interest, especially in the setting of treatment response and selection. We present a method for mutational analysis of CTCs in metastatic breast cancer (MBC) patients by using an emulsion-formulated, semiconductor-based, targeted clonal sequencing platform. Methods: CTCs in MBC patients were enriched by a microfluidic OncoCEE device using antibodies against both epithelial and mesenchymal markers. Genomic DNA was extracted from enriched CTC samples. Emulsion-based multiplex-PCR targeted for various cancer genes was performed, after which semiconductor-based deep sequencing was completed. The read error rates were analyzed based on quality score and context of sequence including homopolymers. Statistical significance for each mutational analysis was assessed using a method based on beta-binomial distribution. Results: Of the 17 patients samples obtained, we were able to enrich CTC samples in 9 of them (CTC range 1-1063, median=12). Multiplex targeted sequencing was performed on DNA from the enriched CTC patient samples (purity range 0.3-6%). Greater than 3000-fold coverage was accomplished. Missense mutations at E545D on PIK3CA (p= 2.0e-07), F354L on STK11 (p=2.0e-04), and Q61R on NRAS (p=2.0e-07) were detected. Novel mutations of L540F and Q1033K within the hot spot regions of PIK3CA were observed (p=1.3e-04). Genomic DNA from WBCs from a healthy female was analyzed concurrently as a negative control, in which none of the mutations were observed. Conclusions: Mutational analysis of CTCs in MBC patients can be accomplished by deep sequencing. We developed a de novo protocol for clonal mutation analysis on CTCs in MBC and detected various significant and novel mutations. We anticipate reporting sequencing results on CTCs and matched WBCs, as negative controls, from 40 MBC patients. This will provide the foundation for the future studies in which we will compare the mutational profile between CTCs and primary/metastatic tumors. We intend to validate clonal mutational analysis of CTCs as a predictive blood-based biomarker in subsequent trials.
Long-term management of moderate-to-severe atopic dermatitis with dupilumab and concomitant topical corticosteroids (LIBERTY AD CHRONOS): a 1-year, randomised, double-blinded, placebo-controlled, phase 3 trial
Authors: Andrew Blauvelt, Marjolein de Bruin-Weller, Melinda Gooderham, Jennifer C Cather, Jamie Weisman, David Pariser, Eric L Simpson, Kim A Papp, H Chih-Ho Hong, Diana Rubel, Peter Foley, Errol Prens, Christopher E M Griffiths, Takafumi Etoh, Pedro Herranz Pinto, Ramon M Pujol, Jacek C Szepietowski, Karel Ettler, Lajos Kemény, Xiaoping Zhu, Bolanle Akinlade, Thomas Hultsch, Vera Mastey, Abhijit Gadkari, Laurent Eckert, Nikhil Amin, Neil M H Graham, Gianluca Pirozzi, Neil Stahl, George D Yancopoulos, Brad Shumel
Journal: The Lancet (2017)
A phase I study of the combination of intravenous Reolysin (REO) and gemcitabine (GEM) in patients (pts) with advanced cancer
Authors: H. Arkenau, J. Evans, M. Lokelma, P. Roxburgh, R. Morisson, M. Coffey, G. Gill, K. Mettinger, B. Thompson, J. de Bono
Journal: Journal of Clinical Oncology (2009)

3584 Background: REO (reovirus serotype 3) is a Dearing strain, naturally occurring, non-enveloped virus with limited pathogenecity in humans. REO replicates specifically in transformed Ras-activated cells due to inhibition of the dsRNA-activated protein kinase, resulting in cell-lysis. GEM has shown efficacy in a wide range of tumors commonly driven by activated Ras, and causes cell cycle arrest in S phase. Results from isobologram analysis suggest potential synergies of REO and GEM. Methods: This open-label, dose-escalating, two-centre phase-I trial studied the combination of iv REO, d1–5 and iv GEM, d1 and 8, qw3. The REO starting dose was 3x10 9 TCID 50 over 1-hour, increasing in successive cohorts and GEM was given at a fixed dose of 1,000 mg/m 2 over 30-min. Endpoints were the maximum tolerated dose (MTD), dose limiting toxicity (DLT), and safety profile of REOGEM and to establish a RP2D. Secondary endpoints were to evaluate the immune response, to evaluate pharmacokinetics of REOGEM and to describe any antitumor activity. Results: Since July 2007, 15 heavily pre-treated pts with disease progression prior to trial entry (9M/6F, median age 56 years, ECOG 0/1: 3/12) were entered into this trial. After 2 pts had Grade &gt;3 toxicities during the first cycle (1 pt: GGT and Trop-I increase and PD; 1 pt: Trop-I increase and unspecific ST-changes) considered probably related to both agents the protocol was amended and the dose of REO was adjusted to 1x10 9 TCID 50 , d1 of each cycle (C-1) and increased in subsequent cohorts to 3x10 9 , 1x10 10 , and 3x10 10 TCID 50 . In total 45 cycles were administered (median 3) resulting in mild and expected toxicities including fever, headaches, rhinorrhea, fatigue and myelosupression. The MTD was not reached. Of the 10 pts evaluable for response, 2 pts (breast and nasopharyngeal) had PR and/or clinical response and 5 pts had SD for 4–8 cycles, amounting for a total disease control rate (CR+PR+SD) of 70%. Conclusions: The combination of REOGEM was well tolerated and resulted in disease control for a majority of pts. A RP2D, of REO 3x10 10 , d1 and GEM 1000mg/m 2 , d1 and 8, qw3, was recommended and phase-2 trials are underway. [Table: see text]
Brigatinib in Patients With Crizotinib-Refractory Anaplastic Lymphoma Kinase–Positive Non–Small-Cell Lung Cancer: A Randomized, Multicenter Phase II Trial
Authors: Dong-Wan Kim, Marcello Tiseo, Myung-Ju Ahn, Karen L. Reckamp, Karin Holmskov Hansen, Sang-We Kim, Rudolf M. Huber, Howard L. West, Harry J.M. Groen, Maximilian J. Hochmair, Natasha B. Leighl, Scott N. Gettinger, Corey J. Langer, Luis G. Paz-Ares Rodríguez, Egbert F. Smit, Edward S. Kim, William Reichmann, Frank G. Haluska, David Kerstein, D. Ross Camidge
Journal: Journal of Clinical Oncology (2017)

Purpose Most crizotinib-treated patients with anaplastic lymphoma kinase gene ( ALK)–rearranged non–small-cell lung cancer (ALK-positive NSCLC) eventually experience disease progression. We evaluated two regimens of brigatinib, an investigational next-generation ALK inhibitor, in crizotinib-refractory ALK-positive NSCLC. Patients and Methods Patients were stratified by brain metastases and best response to crizotinib. They were randomly assigned (1:1) to oral brigatinib 90 mg once daily (arm A) or 180 mg once daily with a 7-day lead-in at 90 mg (180 mg once daily [with lead-in]; arm B). Investigator-assessed confirmed objective response rate (ORR) was the primary end point. Results Of 222 patients enrolled (arm A: n = 112, 109 treated; arm B: n = 110, 110 treated), 154 (69%) had baseline brain metastases and 164 of 222 (74%) had received prior chemotherapy. With 8.0-month median follow-up, investigator-assessed confirmed ORR was 45% (97.5% CI, 34% to 56%) in arm A and 54% (97.5% CI, 43% to 65%) in arm B. Investigator-assessed median progression-free survival was 9.2 months (95% CI, 7.4 to 15.6) and 12.9 months (95% CI, 11.1 to not reached) in arms A and B, respectively. Independent review committee–assessed intracranial ORR in patients with measurable brain metastases at baseline was 42% (11 of 26 patients) in arm A and 67% (12 of 18 patients) in arm B. Common treatment-emergent adverse events were nausea (arm A/B, 33%/40%), diarrhea (arm A/B, 19%/38%), headache (arm A/B, 28%/27%), and cough (arm A/B, 18%/34%), and were mainly grades 1 to 2. A subset of pulmonary adverse events with early onset (median onset: day 2) occurred in 14 of 219 treated patients (all grades, 6%; grade ≥ 3, 3%); none occurred after escalation to 180 mg in arm B. Seven of 14 patients were successfully retreated with brigatinib. Conclusion Brigatinib yielded substantial whole-body and intracranial responses as well as robust progression-free survival; 180 mg (with lead-in) showed consistently better efficacy than 90 mg, with acceptable safety.
Preclinical activity of MCLA-128, an ADCC enhanced bispecific IgG1 antibody targeting the HER2:HER3 heterodimer.
Authors: Cecile Geuijen, Eric Rovers, Roy Nijhuis, Renate den Blanken-Smit, Therese Visser, Willem Bartelink, Arjen Kramer, Vanessa Zondag-van der Zande, Carina Clements, Linda Kaldenberg, Nellie Nieuwenhuizen, Pieter Fokko van Loo, Rob Roovers, Tristan Gallenne, Leo Price, Setareh Van Driel Shamsili, Lex Bakker, Ton Logtenberg, John de Kruif, Mark Throsby
Journal: Journal of Clinical Oncology (2014)

560 Background: Amplification and dimerization of HER2 promotes growth and survival of malignant cells. Tumor responses to available therapeutic agents targeting HER2 are variable. Re-activation of the potent HER2:HER3 signaling dimer by up-regulation of the HER3 ligand heregulin (HRG) has recently been identified as an important resistance mechanism. Treatment of patients with tumors expressing HER2 could be improved with agents that specifically target and potently inhibit the HER2:HER3 heterodimer. Methods: Inhibition of HRG mediated cell growth and invasiveness was assessed by proliferation inhibition and high content imaging. ADCC activity was measured by standard PBMC assays and reporter cell lines. The trastuzumab-resistant, HER2 amplified JIMT-1 xenograft model was used to assess in vivo activity. Activation status of HER dimers was determined by specific phosphorylation readouts. Results: MCLA-128 is a human common light chain bispecific antibody targeting HER2 and HER3 selected from > 500 bispecific antibody candidates. MCLA-128 inhibits HER2:HER3 heterodimer phosphorylation. This molecular phenotype correlated with potent inhibition of HRG driven growth and invasiveness in BT474, SKBR3 and N87 cell lines [IC50 100 – 200 pM]. In contrast, HER3 antibodies, trastuzumab alone or combined with either pertuzumab or HER3 antibodies could not inhibit growth under these conditions even at concentrations two orders of magnitude higher. The ADCC activity of MCLA-128, a low fucosylated IgG1, was equivalent to trastuzumab when targeting HER2hi cell lines but significantly superior when targeting HER2lo cell lines and when low affinity FcgRIII effector cells were used. In vivo, weekly dosing of MCLA-128 at 25 mg/kg reduced tumor burden significantly compared to lapatinib or trastuzumab + pertuzumab treatment groups. Conclusions: MCLA-128 specifically and potently inhibits ligand dependent HER2:HER3 signaling resulting in suppression of tumor growth in vitro and in vivo. The unique functional profile of this novel full-length bispecific antibody, including its strong ADCC activity, supports further development and clinical evaluation in patients with HER2 positive tumors.
Annals Story Slam - The Problematic Prayer
Authors: Stephen Ludwig
Journal: Annals of Internal Medicine (2017)

Web Exclusives2 May 2017Annals Story Slam - The Problematic PrayerFREEStephen Ludwig, MDStephen Ludwig, MDFrom Children's Hospitals of Philadelphia, Philadelphia, Pennsylvania.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/W17-0046 SectionsAboutVisual Abstract ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Video. Annals Story Slam - The Problematic Prayer "The Problematic Prayer," by Dr. Stephen Ludwig (Duration 5:39)Building on the popular Annals feature “On Being a Doctor,” storytellers share stories about the experience of doctoring on video.For more videos from and information on Annals Story Slam, visit go.annals.org/StorySlam. Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAffiliations: From Children's Hospitals of Philadelphia, Philadelphia, Pennsylvania.Current Author Address: Stephen Ludwig, MD, Children's Hospital of Philadelphia, Philadelphia, PA; e-mail, [email protected]chop.edu. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 2 May 2017Volume 166, Issue 9Page: SS1KeywordsChildren ePublished: 2 May 2017 Issue Published: 2 May 2017 Copyright & PermissionsCopyright © 2017 by American College of Physicians. All Rights Reserved.Loading ...
Molecular Aspects of Tonic B-Cell Receptor Signaling in Diffuse Large B-Cell Lymphoma Provide Biomarkers and Targets for Specific Inhibition
Authors: Ondrej Havranek, Jingda Xu, Stefan Koehrer, Zhiqiang Wang, Justin M Comer, Lisa Becker, Allen F Yi, Jan A. Burger, Jason R. Westin, Tomasz Zal, Richard Eric Davis
Journal: Blood (2016)