tbuckley/cabot-search huggingface dataset:
Efficacy and safety of neoadjuvant docetaxel, carboplatin, trastuzumab/pertuzumab [TCH-P] in non-metastatic HER2+ breast cancer: The Cleveland Clinic experience.
Authors: Shruti Rakesh Tiwari, Benjamin Calhoun, Jame Abraham, G. Thomas Budd, Halle C. F. Moore, Alicia Fanning, Stephanie Valente, Robyn Stewart, Steven Ware Andresen, Susan B. LeGrand, Joseph P. Crowe, Andrea Dawson, Jordi Rowe, Christine Booth, Stephen R. Grobmyer, Alberto J. Montero
Journal: Journal of Clinical Oncology (2015)

531 Background: Pertuzumab is FDA approved for use in combination with trastuzumab and chemotherapy as neoadjuvant therapy in women with non-metastatic HER2+ breast cancer. The TRYPHAENA trial reported a pathologic complete response rate (pCR), i.e. ypT0ypN0, of 52% in 77 patients (pts) treated with neoadjuvant TCH-P. Aside from this study, there is limited information regarding the overall safety and efficacy of neoadjuvant TCH-P at FDA approved doses. Our goal was to evaluate the safety and efficacy of neoadjuvant TCH-P in women with non-metastatic breast cancer in a non-clinical trial setting. Methods: After IRB approval, a cancer data registry was utilized to identify all pts with HER2+ non-metastatic breast cancer treated at Cleveland Clinic with neoadjuvant TCH-P. pCR was defined as the absence of invasive tumor in both breast and lymph nodes, i.e. ypT0ypN0. Results: 71 pts met our inclusion criteria, with a median age of 52 years. Clinical staging was as follows: stage I (8%); Stage II (69%); Stage III (22%). 60% of pts were also hormone receptor (HR) positive (42/71). 89% of pts (63/71) have received all 6 planned chemotherapy cycles without dose reductions, with only 11.2% (8/71) requiring a dose reduction for rash, diarrhea, neuropathy, or thrombocytopenia. Seven pts are currently receiving chemotherapy. No patients had symptomatic cardiac toxicity with TCH-P, with only 6.6% of patients having an asymptomatic reduction in LVEF > 10%. The overall observed pCR rate for neoadjuvant TCH-P was 53% in the 60 patients that have completed all planned chemotherapy, and definitive surgery. As expected, the pCR rate was higher in patients with HR negative breast cancer than in those with HR positive disease: 67% (16/24) vs. 42% (14/33), respectively. Conclusions: Neoadjuvant TCH-P was associated with a pCR rate of 53% in a non-clinical trial setting, which was similar to reported rates in the TRYPHAENA trial. Toxicity was manageable, with no patients experiencing symptomatic reductions in LVEF. Long term clinical outcomes are being prospectively followed in all patients being treated with pertuzumab based chemotherapy.
A phase 1/2 study of intermittent, high dose sunitinib in patients with advanced solid tumors.
Authors: Maria Rovithi, Mariette Labots, Richard Honeywell, Albert J. Ten Tije, Rita Ruijter, Mikkjal Skardhamar, Godefridus J. Peters, Jens Voortman, Henk M.W. Verheul
Journal: Journal of Clinical Oncology (2017)

2591 Background: Despite widespread clinical integration, refinement of treatment with sunitinib is actively pursued. Sub-therapeutic blood levels rather than true resistance and tumor adaptation through drug accumulation have been accounted as reasons for treatment failure. Based on our preclinical data with high dose sunitinib and prospective analyses supporting the concept of intermittent dosing, we designed a phase 1 trial to investigate the feasibility and tolerability of high dose, once weekly (1w) or once every two weeks (2w) sunitinib (NCT02058901). Methods: Eligible were patients (pts) with advanced solid tumors, refractory to standard treatment, measurable disease, WHO ≤ 1. Sunitinib was administered orally 1w or 2w. Starting dose was 200 mg, with cohorts escalating in 100 mg steps until maximum tolerated dose (MTD). Response was evaluated by RECIST 1.1. Treatment continued until progression or unacceptable toxicity. Dedicated PK sampling was performed. Sunitinib plasma concentration was measured by LC-MS. Results: 34 (w) and 24 (2w) pts were included, predominantly with mCRC [56% (1w) and 55% (2w)]. MTD was set at 300 mg (1w) and 700 mg (2w). Most common adverse events were fatigue (79%, one pt with G3), nausea (71%, all G1-2), anorexia (29%, all G1-2). Median PFS of evaluable pts was 2.7 mo (1w) and 2.6 mo (2w), while 39% pts (1w) and 25% pts (2w) had PFS &gt; 5 mo. CT scans in pts with treatment benefit showed extensive tumor necrosis. Mean sunitinib plasma Cmax was 190 [300 mg (1w), range: 185-295] and 476 ng/mL [(700 mg (2w), range: 323-580]. Accumulation was minimal. Conclusions: Once weekly or once every two weeks, high dose sunitinib is feasible and clinically efficacious in heavily pretreated pts with advanced solid tumors, while toxicity remains well manageable. Importantly, no accumulation was recorded and sunitinib exposure was significantly increased, compared to the universal, flat dose. Since increased sunitinib exposure has been correlated to improved outcome, we consider this alternative scheduling as promising strategy to produce enduring clinical benefit in a wider patient population. Expansion cohorts are ongoing. Clinical trial information: NCT02058901.
Mutant calreticulin knockin mice develop thrombocytosis and myelofibrosis without a stem cell self-renewal advantage
Authors: Juan Li, Daniel Prins, Hyun Jung Park, Jacob Grinfeld, Carlos Gonzalez-Arias, Stephen Loughran, Oliver M. Dovey, Thorsten Klampfl, Cavan Bennett, Tina L. Hamilton, Dean C. Pask, Rachel Sneade, Matthew Williams, Juliet Aungier, Cedric Ghevaert, George S. Vassiliou, David G. Kent, Anthony R. Green
Journal: Blood (2017)
Forest of Coubron
Authors: Frederick Butzen
Journal: JAMA (1980)

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
Benefits and Risks of Machine Learning Decision Support Systems—Reply
Authors: Federico Cabitza, Raffaele Rasoini, Gian Franco Gensini
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 Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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 journal
A phase I study to assess the safety, pharmacokinetics (PK), pharmacodynamics (PD) and antitumor activities of BAL101553, a novel tumor checkpoint controller (TCC), administered as 48-hour infusion in adult patients with advanced solid tumors.
Authors: Markus Joerger, Anastasios Stathis, Ioannis Metaxas, Dagmar Hess, Aurelius Gabriel Omlin, Gisela Mayer, Sheila Gaggetta, Stephanie Anderson, Marco Gioele Pasqualotto, Franziska Hutter, Nicole Levy, Silvia Stuedeli, Michèle Landau-Salzberg, Phil McKernan, Heidi A Lane, Patrice Larger, Rudi Scheerlinck, Marc Frederick Engelhardt, Roger Von Moos, Cristiana Sessa
Journal: Journal of Clinical Oncology (2017)

TPS2602 Background: BAL101553 (prodrug of BAL27862), is a novel TCC that promotes tumor cell death by modulating the spindle assembly checkpoint. BAL27862 has shown potent antitumor activity in diverse preclinical tumor models, including models refractory to standard therapies. In a completed Phase 1 study using 2-h IV infusions (Days 1, 8, 15, q28d, NCT01397929 , CDI-CS-001, Lopez et al. JCO 34, 2016 suppl; 2525) dose-limiting vascular effects were observed and appeared C max related. The recommended Phase 2 dose for 2-h IV BAL101553 is 30 mg/m 2 . Vascular toxicity was not observed in an ongoing study with oral BAL101553 (NCT02490800, CDI-CS-002) at daily doses up to 30 mg (QD). Preclinical data suggest that antiproliferative effects of BAL101553/27862 are driven by exposure (AUC); thus vascular toxicity and antitumor activity are mediated by different PK drivers. BAL27862 has a half-life of ~15 h. Based on PK-modeling, extending the infusion from 2 h to 48 h was expected to result in ~4-fold higher AUC at a given C max level and thereby improve the therapeutic window. Methods: This is an ongoing multicenter, open-label, Phase 1 dose-escalation study (NCT02895360, CDI-CS-003/SAKK67/15) using a 3+3 design to determine the MTD, characterize dose-limiting toxicities and assess the PK, PD and antitumor activities of 48-h infusions of BAL101553 in consecutive 28-day cycles at a starting dose of 30 mg/m 2 administered on Day 1, 8 and 15 (q28d). The dose escalation scheme foresees up to ~ 50% dose increments depending on observed toxicities. During cycle 2, patients receive 7 days oral (QD) BAL101553 (Day 15–21) instead of the weekly IV infusion to assess absolute oral bioavailability. Patients with histologically-confirmed advanced or recurrent solid tumors are eligible for enrollment. Adverse events are assessed using CTCAEv4; tumor response by RECIST 1.1 (every 2 cycles). PD assessments include optional tumor biopsies and circulating tumor cells. PK profiles are assessed during the first 2 cycles. Two dose cohorts (30 and 45 mg/m 2 ) have completed without DLTs or signs of vascular toxicity. Clinical trial information: NCT02895360.
Abstract 19826: Cardiac Potassium Channel IKs Regulation by Isoform Specific PKC: Implications for Long QT Syndrome
Authors: Chen Kaplan, Coeli M Lopes
Journal: Circulation (2016)

Background:  The cardiac voltage-gated potassium channel (IKs) is composed of KCNQ1 and KCNE1 subunits. Mutations in the KCNQ1 gene lead to the most common form of inherited cardiac arrhythmia, Long QT type 1 (LQT1). Protein kinase C (PKC) is activated in response to stress stimulus and is chronically activated in heart disease, but little is known about IKs regulation by prolonged PKC activation.   Methods:  GFP-KCNQ1 and KCNE1 subunits were co-transfected with alpha1 adrenergic receptor (α1-AR) in HEK293T cells. Channel localization was measured using confocal microscopy and biotinylation technique.   Results:  To determine IKs membrane expression regulation by sustained PKC stimulation (hours) we both stimulated α1-AR and directly stimulated calcium dependent (cPKC) and calcium independent PKC isoforms. Our results show that: 1) prolonged receptor stimulation strongly decreased IKs membrane expression. 2) Prolonged stimulation of cPKC but not the calcium independent isoform PKCe mimicked the effect of receptor stimulation. 3) General PKCβ and PKCβII inhibitors, but not PKCα or PKCβI inhibitors blocked the effect of cPKC. Many LQT1 mutations have decreased membrane expression. In order to investigate the implication of PKCβII regulation of IKs membrane expression to LQT1 syndrome we studied 8 LQT1 associated mutations. For two LQT1 mutants, PKCβ inhibition restored membrane expression, both in the presence and absence of the WT subunit, suggesting an increased sensitivity to basal PKCβ activity. Surprisingly, for one mutant membrane expression was decreased by PKCβ inhibition.   Conclusions:  Our results indicate that membrane expression of IKs is decreased in response to PKCβII isoform stimulation. This is particularly important because PKCβ expression and activation are strongly increased in heart disease. Specific inhibition of PKCβ restored IKs channel localization for two out of eight LQT1 mutant channels tested. Thus, our results suggest that PKCβII inhibition may protect against QT prolongation and may serve as a novel mutation-specific target for treatment of LQT1 patients.
Abstract 12732: Risk of Heart Failure After Contemporary Radiotherapy for Breast Cancer in the Community
Authors: Hirofumi Saiki, Randi R Finley, Christopher G Scott, Elizabeth S Yan, Ivy A Petersen, Margaret M Redfield
Journal: Circulation (2015)

Background: Contemporary breast cancer radiotherapy (RT) results in variable cardiac radiation exposure. While cardiomyocytes are radio-resistant, radiation induces coronary microvascular endothelial damage and inflammation which may ultimately lead to myocardial inflammation, ischemia and fibrosis and put patients at risk for heart failure (HF) and particularly, HF with preserved ejection fraction (HFpEF). Methods: Community based (Olmsted County, MN), HF case-control study of contemporary (1999-2014) breast cancer RT patients with CT-based RT planning for precise mean cardiac radiation dose (MCRD) calculation. HF cases (n=66) and controls (n=129) were matched (1:2) for age at RT, HF risk factors, tumor side and chemotherapy use. Matched controls and cases had identical follow-up (index interval). Proportion of HF and clinical characteristics in categories of MCRD were reported (table) and conditional logistic regression was used to estimate the HF odds ratio (OR) associated with MCRD as a continuous variable. Results: Of the 66 HF cases, 46 (70%) had HFpEF and 20 (30%) had HF with reduced ejection fraction (HFrEF). The proportion of patients with HF (any) or HFpEF increased and proportion with HFrEF tended to increase with increasing MCRD. The prevalence of HF risk factors (hypertension, diabetes, coronary disease) at time of RT did not vary by MCRD while left sided tumor, cancer stage and adriamycin use increased with increasing MCRD. The OR per 1 unit increase in log MCRD was 3.71 (1.98, 6.94) for total HF (p&lt;0.001), 4.91 (1.93, 9.09) for HFpEF (p&lt;0.001) and 2.78 (0.91, 8.47) for HFrEF (p=0.07). The mean index interval was 5.0±3.2 years. Conclusion: Cardiac radiation incident to contemporary breast RT increases the risk of HF, and particularly HFpEF over a short post-RT interval. These data may guide use of proton beam therapy in breast cancer. These data also provide support for the role of coronary microvascular compromise in the pathophysiology of HFpEF.
Acutely decompensated heart failure with preserved and reduced ejection fraction present with comparable haemodynamic congestion
Authors: Lucas N.L. Van Aelst, Mattia Arrigo, Rui Placido, Eiichi Akiyama, Nicolas Girerd, Faiez Zannad, Philippe Manivet, Patrick Rossignol, Marc Badoz, Malha Sadoune, Jean‐Marie Launay, Etienne Gayat, Carolyn S.P. Lam, Alain Cohen‐Solal, Alexandre Mebazaa, Marie‐France Seronde
Journal: European Journal of Heart Failure (2017)
Bilateral Deep Brain Stimulation of the Nucleus Basalis of Meynert for Parkinson Disease Dementia
Authors: James Gratwicke, Ludvic Zrinzo, Joshua Kahan, Amy Peters, Mazda Beigi, Harith Akram, Jonathan Hyam, Ashwini Oswal, Brian Day, Laura Mancini, John Thornton, Tarek Yousry, Patricia Limousin, Marwan Hariz, Marjan Jahanshahi, Thomas Foltynie
Journal: JAMA Neurology (2017)

Deep brain stimulation of the nucleus basalis of Meynert (NBM DBS) has been proposed as a treatment option for Parkinson disease dementia.To evaluate the safety and potential symptomatic effects of NBM DBS in patients with Parkinson disease dementia.A randomized, double-blind, crossover clinical trial evaluated the results of 6 patients with Parkinson disease dementia who were treated with NBM DBS at a neurosurgical referral center in the United Kingdom from October 26, 2012, to July 31, 2015. Eligible patients met the diagnostic criteria for Parkinson disease dementia, had motor fluctuations, were appropriate surgical candidates aside from the coexistence of dementia, were age 35 to 80 years, were able to give informed consent, had a Mini-Mental State Examination score of 21 to 26, had minimal atrophy seen on results of brain magnetic resonance imaging, and lived at home with a caregiver-informant.After surgery, patients were assigned to receive either active stimulation (bilateral, low-frequency [20 Hz] NBM DBS) or sham stimulation for 6 weeks, followed by the opposite condition for 6 weeks.The primary outcome was the difference in scores on each item of an abbreviated cognitive battery (California Verbal Learning Test-II, Wechsler Adult Intelligence Scale-III digit span, verbal fluency, Posner covert attention test, and simple and choice reaction times) between the 2 conditions. Secondary outcomes were exploratory and included differences in scores on standardized measurements of cognitive, psychiatric, and motor symptoms and resting state functional magnetic resonance imaging.Surgery and stimulation were well tolerated by all 6 patients (all men; mean [SD] age, 65.2 [10.7] years), with no serious adverse events during the trial. No consistent improvements were observed in the primary cognitive outcomes or in results of resting state functional magnetic resonance imaging. An improvement in scores on the Neuropsychiatric Inventory was observed with NBM DBS (8.5 points [range, 4-26 points]) compared with sham stimulation (12 points [range, 8-38 points]; median difference, 5 points; 95% CI, 2.5-8.5 points; P = .03) and the preoperative baseline (13 points [range, 5-25 points]; median difference, 2 points; 95% CI, -8 to 5.5 points; P = .69).Low-frequency NBM DBS was safely conducted in patients with Parkinson disease dementia; however, no improvements were observed in the primary cognitive outcomes. Further studies may be warranted to explore its potential to improve troublesome neuropsychiatric symptoms.clinicaltrials.gov Identifier: NCT01701544.
Gut Microbes Egested during Bites of Infected Sand Flies Augment Severity of Leishmaniasis via Inflammasome-Derived IL-1β
Authors: Ranadhir Dey, Amritanshu B. Joshi, Fabiano Oliveira, Lais Pereira, Anderson B. Guimarães-Costa, Tiago D. Serafim, Waldionê de Castro, Iliano V. Coutinho-Abreu, Parna Bhattacharya, Shannon Townsend, Hamide Aslan, Alec Perkins, Subir Karmakar, Nevien Ismail, Morgan Karetnick, Claudio Meneses, Robert Duncan, Hira L. Nakhasi, Jesus G. Valenzuela, Shaden Kamhawi
Journal: Cell Host & Microbe (2017)
Abstract LB-204: Results of a Phase 3 trial evaluating safety and efficacy of specific immunotherapy, recombinant idiotype (Id) conjugated to KLH (Id-KLH) with GM-CSF, compared to non-specific immunotherapy, KLH with GM-CSF, in patients with follicular non-Hodgkin's lymph
Authors: Ronald Levy, M J Robertson, K Ganjoo, J Leonard, J Vose, Dan Denney
Journal: Cancer Research (2008)

Abstract Introduction: MyVax® personalized immunotherapy consists of the tumor-specific Id protein, produced using molecular methods, conjugated to Keyhole limpet hemocyanin (KLH) and administered in a series of sc immunizations with GM-CSF. Methods: This is a multi-center, randomized, blinded, controlled trial examining the safety and efficacy of MyVax compared to a control immunotherapy in patients with previously untreated follicular non-Hodgkin's lymphoma (fNHL). Patients received 8 cycles of CVP followed by a 6-month rest period. Patients who maintained at least a partial response for 6 months post CVP were randomized to receive MyVax or control immunotherapy in a 2:1 ratio. All patients received GM-CSF at each immunization and for the next 3 days. Patients received a series of 7 immunizations over 24 weeks. Sera for Id- and KLH-specific humoral immune response (IR) assays were collected prior to, during, and for 1 year following immunization. Results: 287 patients were randomized and 278 patients received at least one immunization. Anti-Id IRs were observed in 41.0% of evaluable patients. No statistical difference in PFS and time to subsequent anti-lymphoma therapy (SALT) was seen in the patients who received MyVax compared to those who received the control immunotherapy. Both arms of the study have an apparent plateau of PFS &amp;gt;30% at 5 years. A highly statistically significant improvement in PFS (P=0.0017) was seen in patients mounting an anti-Id immune response (IR+) vs. IR- patients with &amp;gt;2-fold increase (39.7 vs 18.1 months) in PFS. The IR+ patients show a statistically significant improvement in PFS over the control immunotherapy patients while there is not a statistically significant difference in PFS between the IR patients and the control immunotherapy patients. The degree of clinical benefit correlates with the titer of the anti-Id IRs, but not with the titer of the anti-KLH IRs. High risk FLIPI patients did as well as the other patients in both PFS and SALT. Clinical response improvements were observed on both arms post immunization. Conclusions: There was no difference in PFS between the patients receiving specific immunotherapy versus those receiving control immunotherapy. As previously reported in Phase II trials, fNHL patients mounting anti-Id IRs have a significantly improved clinical outcome.
The evolution of Cardiovascular Research Onlife: online and on demand
Authors: Charalambos Antoniades, Heather Y Small, Tomasz Guzik
Journal: Cardiovascular Research (2017)

The new editor-in-chief and editorial team are delighted to continue the fruitful partnership with the European Society of Cardiology (ESC) Scientists of Tomorrow to further evolve the Cardiovascular Research online platform, Onlife.Onlife was established in April 2017 with the aim of bringing together commentaries and opinions from both young scientists and world-leading principal investigators in basic and clinical research for the mutual benefit of both fields.Since then, Onlife has become a popular feature of the journal, with its material downloaded 5277 times since its launch.Onlife has been a very successful initiative launched by the previous editor-in-chief, Prof. Karin Sipido, and marks the beginning of a new era for the journal as we move closer to the younger community that increasingly uses new technologies and social media.Of course, creating an ambitious online platform involves a continuous learning process, thus the content of Onlife is dynamically adapted to the continuously changing scientific trends.With the new year, Onlife will take on board the existing feedback from the first 7 months, since it was launched, and will further adapt its content to the needs of its high quality scientific audience.