tbuckley/cabot-search huggingface dataset:
Evaluating the clinical impact of a shortened infusion duration for ramucirumab: A population pharmacokinetic model-based approach.
Authors: Paolo Abada, Yiu-Keung Lau, Ran Wei, Lisa O’Brien, Amanda Long, Yongzhe Piao, Ling Gao
Journal: Journal of Clinical Oncology (2021)

191 Background: Ramucirumab is a human recombinant immunoglobin G1 monoclonal antibody (mAb) antagonist of vascular endothelial growth factor receptor-2. Ramucirumab dosed at 8 mg/kg every 2 weeks or 10 mg/kg every 3 weeks, either as monotherapy or in combination with chemotherapy, was initially studied with as an intravenous infusion over 60 minutes following premedication with a histamine-1 receptor antagonist. Lengthy intravenous infusions are inconvenient for patients and increase the workloads of nursing and administrative staff. Shortening the infusion duration of ramucirumab could therefore benefit both patients and healthcare professionals. The current analysis determined the impact such a change could have on the pharmacokinetic (PK) profile of ramucirumab. Additionally, the relationship between infusion rate and incidence of immediate infusion-related reactions (IRRs; occurring on the day of administration), common adverse events associated with mAb infusions, was assessed. Methods: A population pharmacokinetic model was established using concentration–time data collected from 2522 patients who received one of five different ramucirumab regimens involving an intravenous infusion over ~60 minutes in 17 clinical studies. The final PK model was used to simulate concentration–time profiles and exposure parameters following ramucirumab infusion durations of 30 vs 60 min. Phase II/III clinical study data from patients receiving ramucirumab were pooled to assess the association between ramucirumab infusion rate and incidence of immediate IRRs using multivariate logistic regression analysis. Results: Ramucirumab infusions of 30- and 60-min durations resulted in equivalent concentration–time profiles and, hence, equivalent systemic exposure to ramucirumab. Among 3216 patients receiving ramucirumab in phase II/III studies, 254 (7.9%) had at least one immediate any-grade IRR; 17 (0.5%) experienced grade ≥3 immediate IRRs. The incidence of immediate IRRs (any grade or grade ≥3) was similar across infusion rate quartiles. Under multivariate logistic analysis, infusion rate was not significantly associated with an increased risk of an immediate IRR (odds ratio per 1 mg/min increase 1.014, 95% confidence interval 0.999, 1.030; p=0.071). Conclusions: Administering ramucirumab using different infusion durations (30 vs 60 min) did not affect ramucirumab exposure. Analysis of clinical study data showed a faster infusion rate was not associated with an increased risk of immediate IRRs. It is considered unlikely that shortening the infusion duration of ramucirumab will impact its clinical efficacy or overall safety profile, and is now an option for administration in the U.S.
Trial-in-progress: A pilot study of combined immune checkpoint inhibition in combination with ablative therapies in subjects with hepatocellular carcinoma (HCC).
Authors: Hailey Kathryn Carroll, Umair Aleem, Pooja Varghese, Marie Galligan, Michele Bourke, Katherine Hoey, Ronan Ryan, Peter Doran, Stephen Stewart, Cliona O'Farrelly, Tim F. Greten, Diarmaid Houlihan, Raymond S. McDermott, Austin G. Duffy
Journal: Journal of Clinical Oncology (2021)

TPS355 Background: Locoregional therapies for hepatocellular carcinoma, such as transcatheter arterial chemoembolization (TACE) or ablation, can induce a peripheral anti-tumor immune response. This may be amplified by immune checkpoint inhibitors (ICI). Early and higher anti-CTLA4 dosing could potentially lead to better priming and a stronger immune response. Recent data has suggested that early (day 1 only), increased doses of anti-CTLA4 therapy, was associated with encouraging clinical activity and a tolerable safety profile. This study will evaluate dual immune checkpoint, CTLA4 (tremelimumab, day 1-only dosing) and PD-L1 (durvalumab) blockade in combination with TACE in patients with advanced HCC. Intensive peripheral immune-monitoring and longitudinal on-treatment tumor biopsies will focus on the role of the innate immune system, particularly Natural Killer cells, in anti-tumor responses. Methods: Patients with HCC (Childs Pugh A/B7; Barcelona Clinic Liver Cancer Stage B/C; ECOG 0/1; sorafenib-naïve or experienced) are being enrolled in a pilot study (Study Number UCDCRC/19/01) of tremelimumab at 2 dose levels (DL1 and DL2) in combination with durvalumab and TACE until disease progression (per irRECIST). DL1: tremelimumab (75mg q28 days for 4 doses) and durvalumab (1500mg q28 days). DL2: tremelimumab (300mg in a single dose on day 1) and durvalumab (1500mg q28 days). Subtotal TACE will be performed during study week 6 with the dose-limiting toxicity (DLT) evaluation period encompassing the first 8 weeks of the study. Primary endpoint is 6-month progression-free survival with secondary efficacy endpoints being safety, tolerability and overall survival. Exploratory objectives will evaluate changes in immune parameters in the tumor and peripheral blood of patients undergoing anti-CTLA4 therapy pre- and post-RFA or TACE. A major focus will be on the role of the innate immune system, particularly Natural Killer cells, in anti-tumor responses. Patients will be enrolled and treated at St Vincent’s University Hospital in Dublin, Ireland. This study is currently open and actively recruiting. Clinical trial information: EudraCT Number 2019-002767-98.
The Ethics of Incentivizing Mammography Screening
Authors: Harald Schmidt
Journal: JAMA (2015)

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
ATP-binding cassette transporters restrict drug delivery and efficacy against brain tumors even when blood-brain barrier integrity is lost
Authors: Mark C. de Gooijer, E. Marleen Kemper, Levi C.M. Buil, Ceren H. Çitirikkaya, Tessa Buckle, Jos H. Beijnen, Olaf van Tellingen
Journal: Cell Reports Medicine (2021)

The impact of a compromised blood-brain barrier (BBB) on the drug treatment of intracranial tumors remains controversial. We characterize the BBB integrity in several intracranial tumor models using magnetic resonance imaging, fluorescent dyes, and autoradiography and determine the distribution and efficacy of docetaxel in brain tumors grafted in Abcb1-proficient and Abcb1-deficient mice. Leakiness of the tumor vasculature varies from extensive to absent. Regardless of the extent of leakiness, tumor blood vessels express ATP-binding cassette transporters (Abcb1 and Abcg2). A leaky vasculature results in higher docetaxel tumor levels compared to normal brain. Nevertheless, Abcb1 can reduce drug distribution and efficacy even in leaky models. Thus, BBB leakiness does not ensure the unimpeded access of ATP-binding cassette transporter substrate drugs. Therapeutic responses may be observed, but the full potential of such therapeutics may still be attenuated. Consequently, BBB-penetrable drugs with little to no affinity for efflux transporters are preferred for the treatment of intracranial tumors.
OP0107 Human parvovirus b19 infection associated arthritis: clinical findings
Authors: JA Román-Ivorra, C Fernández-Carballido, JJ Alegre-Sancho, C Martínez, L Abad
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> <h3>Objectives</h3> Description of clinical findings and evolution in a cohort of patients with recent human parvovirus B19(PB19) infection and arthritis. <h3>Methods</h3> 26 patients with arthritis and recent PB19 infection (high titers of anti-PB19 Ig M antibodies) were studied. Clinical (prodromal symptoms, arthritis pattern, extra-articular features and evolution) and analytical (blood count, Erythrocite sedimentation rate, C-reactive protein, antinuclear antibodies, anti-DNA antibodies, anti-cardiolipin antibodies, C3/C4 levels and urine abnormalities) data were collected. SLE(ACR,1982), RA(ARA,1987), and Fibromyalgia (Wolfe,1995) criteria were reviewed in each case. <h3>Results</h3> Mean age of the 26 patients (23 female, 3 male) was 38.6 years. Three patients (11.5%) fulfilled &gt; = 4 ACR criteria for SLE, and four patients (15.4%) had an SLE-like syndrome. Joint symptoms always manifested as an abrupt-onset arthritis; mainly as a polyarthritis (92.3%) with an additive (76.9%), symmetric (84.6%) pattern. Most of the patients became symptom-free in a period not longer than less than six months (&lt; = 8 weeks: 76.9%; 8–24 weeks: 7.6%), and only 4 patients had a chronic course (SLE-like:2 patients; SLE: 1 patient; fibromyalgia: 1 patient). <h3>Conclusion</h3> Most of the patients with a recent PB19 infection show a self-limited symmetric additive polyarthritis. Some of this patients may fulfil SLE, SLE-like or fibromyalgia criteria. This virus could act as a trigger in the etiopathogenesis of this diseases.
Incidence of hypertension and proteinuria in patients treated with bevacizumab versus bevacizumab biosimilar
Authors: Yun Man, Han Yu, Sarbajit Mukherjee, Olivia Zalewski
Journal: Journal of Clinical Oncology (2021)

83 Background: Biosimilar products are proven to have no clinically meaningful differences in terms of safety and effectiveness with the reference product, however, to our knowledge, there is limited comparative analysis regarding adverse events for the bevacizumab biosimilars and the reference product. The purpose of this study was to evaluate the incidence of hypertension and proteinuria in patients treated with reference versus biosimilar bevacizumab to potentially streamline clinical management. Methods: A retrospective study was conducted with data consisting of gastrointestinal cancer patients who initiated either reference bevacizumab or biosimilar bevacizumab between January 2019 and July 2020 at Roswell Park Comprehensive Cancer Center. For the primary composite endpoint, Electronic Health Records were searched for the presence or absence of hypertension and proteinuria, as well as time to event analysis. In patients treated with bevacizumab biosimilar, demographics, hypertension and proteinuria related risk factors, bevacizumab containing chemotherapy regimen, and bevacizumab dosing were also identified to assess the risk association with hypertension and proteinuria. Results: 75 patients were included with 42 patients received bevacizumab and 33 patients received bevacizumab biosimilar. Hypertension occurred in 52.4% of reference bevacizumab group versus 36.4% of bevacizumab biosimilar group. Median time to hypertension is 84 days (bevacizumab) versus 24.5 days (bevacizumab biosimilar) following the first treatment (p= 0.0064). Proteinuria developed in 35.7% of reference bevacizumab patients compared to 30% of bevacizumab biosimilar patients. Median onset of proteinuria was 213 days (bevacizumab) versus 53.5 days (bevacizumab biosimilar) (p= 0.0022). In patients with a history of hypertension or underlying renal dysfunction, there was an increased risk of further hypertension and proteinuria, respectively. Conclusions: Higher risk of hypertension and proteinuria was associated with the bevacizumab reference product group, although not statistically significant. A shorter onset of hypertension and proteinuria was associated with the bevacizumab biosimilar group. Our results need further validation in larger cohorts, especially due to the more recent implementation of bevacizumab biosimilar products. [Table: see text]
Abstract 10351: Women With Hypertrophic Cardiomyopathy Have Worse Survival
Authors: Jeffrey Geske, Kevin Ong, Virginia Hebl, Michael Ackerman, Rick Nishimura, Bernard Gersh, Steve Ommen
Journal: Circulation (2013)

Background: Gender differences in hypertrophic cardiomyopathy (HCM) demographics and survival remain unclear. Methods: 3,673 adult patients with HCM underwent clinical evaluation at a single referr...
Natriuretic Peptides, Ejection Fraction, and Prognosis: Parsing the Phenotypes of Heart Failure⁎⁎Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Authors: James L. Januzzi
Journal: Journal of the American College of Cardiology (2013)
Correction: FOXO3a-dependent regulation of Puma in response to cytokine/growth factor withdrawal
Authors: Han You, Marc Pellegrini, Katsuya Tsuchihara, Kazuo Yamamoto, Georg Hacker, Miriam Erlacher, Andreas Villunger, Tak W. Mak
Journal: The Journal of Experimental Medicine (2021)

The authors regret that a reference related to Fig. 2 A was missing in the original version of this paper. Data in Fig. 2 A were previously published in a 2006 PNAS article. The same data were reported again in the JEM article to describe the background of the experimental design. The missing sentence with the You et al. (2006) citation is in bold below.
THU0092 The l1 mrna in rheumatoid arthritis encodes a functional retrotransposable element
Authors: M Neidhart, J Rethage, O Distler, MT Peyer, ME Billingham, BA Michel, RE Gay, S Gay
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> L1 retrotransposons have been detected in rheumatoid arthritis (RA) at sites of joint destruction. <h3>Objectives</h3> To caracterise the L1 mRNA in RA. <h3>Methods</h3> RNA was isolated from the synovial tissue of a 35-years old woman with RA. The complete L1 sequence was determined by 3?/5?-RACE and compared with functional L1 retrotransposons in plants, animals and humans using 50% consensus trees of the elements and the neighbour-joining method. Methylation of the genomic 5?UTR was determined by the sodium-disulfite/PCR method. <i>In situ</i> hybridization was performed on synovial tissues with riboprobes recognising the ORF1 of this element to detect intact L1 elements. <h3>Results</h3> A complete L1 mRNA was obtained with the 5?UTR (including a hypoxia inducing factor-responding element and numerous CpG islands), an ORF1 (encoding the p40/RNA binding protein) and an ORF2 (encoding the p150/endonuclease and reverse transcriptase protein). In RA, the genomic 5?UTR appeared hypomethylated, compared to normal control DNA. <i>In situ</i> hybridization showed that the L1 ORF1 transcript is expressed in the sub-lining of patients with RA. Phylogenic trees showed that the 5?UTR nucleotide sequence and the ORF1 peptide sequence have high similarities with human L1.39 and L1.25, two functional L1 retrotransposons, and the ORF2 peptide sequence resembled the M22334 L1 insertion in type A haemophilia. The endonuclease region of ORF2 appears to be highly conserved in functional L1s, but as shown by a phylogenic tree, the small difference appears to be a specific marker for evolution, discriminating L1s in plants, rodents, primates and humans. <h3>Conclusion</h3> Intact L1 elements are expressed in the synovial tissue of patients with RA most likely following hypomethylation of their 5?UTR. The L1 mRNA transcript belongs to the functional L1 retrotransposons, including elements producing insertional mutations. Thus, functional L1s could be involved in the transformed phenotype of some synovial cells. <h3>Reference</h3> Neidhart M, et al. Arthritis Rheum. 2000;43:2634–47
Evaluation of a sensitive blood test for the detection of colorectal advanced adenomas in a prospective cohort using a multiomics approach.
Authors: Jimmy Lin, Eric Ariazi, Michael Dzamba, Teng-Kuei Hsu, Steven Kothen-Hill, Kang Li, Tzu-Yu Liu, Shivani Mahajan, Krishnan K Palaniappan, Amit Pasupathy, Alina Polonskaia, John St. John, Dan Steiger, Peter Ulz, Irving Wang, Jiajie Xiao, Rui Yang, Girish Putcha, Aasma Shaukat, MD, MPH
Journal: Journal of Clinical Oncology (2021)

43 Background: Blood-based screening tests for colorectal cancer (CRC) with high sensitivity and specificity are needed to improve adherence, facilitate early detection, and ultimately reduce mortality from CRC. Current stool-based tests have a sensitivity of 24-42% for colorectal advanced adenomas (AAs), while blood tests that rely on tumor-derived cell-free DNA (cfDNA) methylation signatures have shown limited sensitivity for AAs. Here we demonstrate the ability to detect AAs from blood using a multiomics test that incorporates both tumor- and immune-derived signatures, and compare it to the performance of a cfDNA methylation-only test. Methods: Participants enrolled in a prospective study (NCT03688906) were included in this analysis. The multiomics test includes signatures for cell-free nucleic acids based on next-generation sequencing, and for plasma proteins based on high-throughput multiplexed assays. Signatures are integrated computationally with a combination of convolutional neural networks and regularized logistic regression. We compared the multiomics test with one based on cfDNA methylation only. Results: This sub-study included 542 participants (AA: n = 122; colonoscopy-confirmed negative controls: n = 420). Participants with AA were 56% male with a mean age of 63 years, and colonoscopy-confirmed negative controls were 54% male with a mean age of 61 years. The multiomics test achieved a sensitivity of 41% (n = 50/122, 95% CI 34-48%) at 90% specificity (377/420). By contrast, the cfDNA methylation-only test achieved a sensitivity of 20% (24/122, 95% CI 15-25%) at 91% specificity (383/420). Performance was also analyzed by histological subtype and location, and superiority of the multiomics test to the cfDNA-methylation-only test was consistently observed. Conclusions: A novel multiomics blood test can detect colorectal AAs at a sensitivity and specificity comparable to existing stool-based tests. Combining signatures from both tumor- and immune-derived sources resulted in AA sensitivity greater than that of cfDNA-methylation alone.
SAT0079 Validity of arthroscopic grading system of chondropaty in knee osteoarthritis: correlation with histopathological findings
Authors: C Acebes, I Palacios, E Delgado, G Herrero-Beaumont
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Clinical research in osteoarthritis (OA) requires objective methods able to evaluate cartilage status. Arthroscopic evaluation of the articular cartilage would be a reliable instrument for the measurement of the quantity, integrity or quality of articular cartilage in knee OA. <h3>Objectives</h3> To correlate an arthroscopic grading system of chondropathy (CHGS) with the histopathological findings of the same cartilage lesions in order to establish the validity of this procedure. <h3>Methods</h3> Articular cartilage of medial compartments of three OA knee joints were magnified evaluated and recorded using a 2,7 mm scope. 34 different areas of lesion were individualised and fissures; III: deep fissures; IV: exposure of subchondral bone.73 sections ofarthroscopically normal and OA cartilage were microscopically examined and graded twice by two observers according to Mankin’s histopathological grading system (0–14)(MHHGS). Mathematic categorization in five groups was done to correlate with chondroscopic grades of lesion: normal (0–2), mild (3–5), moderate (6–8), severe (9–11), and very severe (12–14). <h3>Results</h3> Intra and interobserver variability for MHHGS score was determined with Sperman’s correlation coefficient for both observers: r = 0,890 p &lt; 0,001; r = 0,835 p &lt; 0,001 and r = 0,906 p &lt; 0,001; r = 0,822 p &lt; 0,001. Average MHHGS score for chondroscopic grade 0 (1,7 ± 0,59 n = 20), grade I(3,62 ± 2,33 n = 28), grade II (6,82 ± 1,75 n = 52) were as expected, but for grade III (8,13 ± 2,13 n = 34) and grade IV (11,5 ± 3,18 n = 14) were lower. Correlation between CHGS and MHHGS scores were measure computing the kappa index for categorical variables for both observers: kp = 0,50 kp = 0,58. <h3>Conclusion</h3> CHGS score of cartilage might be considered a relevant tool of OA outcome for research. The low tendency to overstimate lesions in advanced stages may be related to the mathematic categorization of the histopathological score.
Tolerogenic anti–IL-2 mAb prevents graft-versus-host disease while preserving strong graft-versus-leukemia activity
Authors: Qingxiao Song, Xiaoning Wang, Xiwei Wu, Hanjun Qin, Yingfei Li, Arthur D. Riggs, Paul J. Martin, Yuan-Zhong Chen, Defu Zeng
Journal: Blood (2021)
Genetic Disease and Therapy
Authors: Theodore L. Roth, Alexander Marson
Journal: Annual Review of Pathology Mechanisms of Disease (2021)

Genetic diseases cause numerous complex and intractable pathologies. DNA sequences encoding each human's complexity and many disease risks are contained in the mitochondrial genome, nuclear genome, and microbial metagenome. Diagnosis of these diseases has unified around applications of next-generation DNA sequencing. However, translating specific genetic diagnoses into targeted genetic therapies remains a central goal. To date, genetic therapies have fallen into three broad categories: bulk replacement of affected genetic compartments with a new exogenous genome, nontargeted addition of exogenous genetic material to compensate for genetic errors, and most recently, direct correction of causative genetic alterations using gene editing. Generalized methods of diagnosis, therapy, and reagent delivery into each genetic compartment will accelerate the next generations of curative genetic therapies. We discuss the structure and variability of the mitochondrial, nuclear, and microbial metagenomic compartments, as well as the historical development and current practice of genetic diagnostics and gene therapies targeting each compartment.
Evaluation of 2 Existing Diagnostic Scores for Heart Failure With Preserved Ejection Fraction Against a Comprehensively Phenotyped Cohort
Authors: Timothy W. Churchill, Shawn X. Li, Lisa Curreri, Emily K. Zern, Emily S. Lau, Elizabeth E. Liu, Robyn Farrell, Mark W. Shoenike, John Sbarbaro, Rajeev Malhotra, Matthew Nayor, Carsten Tschöpe, Rudolf A. de Boer, Gregory D. Lewis, Jennifer E. Ho
Journal: Circulation (2021)