tbuckley/cabot-search huggingface dataset:
Real-world characterization of patients with cancer admitted with immune-related adverse events (irAEs).
Authors: Lawson Eng, RuiQui Chen, Elliot Charles Smith, Sze Wah Samuel Chan, Katrina Hueniken, M. Catherine Brown, Habeeb Majeed, Kendra Ross, Diana Gray, Wei Xu, David Hogg, Srikala S. Sridhar, Adrian G. Sacher, Natasha B. Leighl, Monika K. Krzyzanowska, Geoffrey Liu, Marcus O. Butler
Journal: Journal of Clinical Oncology (2019)

82 Background: Immune checkpoint inhibitors (ICI) are improving the care of cancer patients. Despite being better tolerated than chemotherapy, there is a risk of developing irAEs which may require hospitalization. Although ICI and irAEs are well studied in clinical trials, there is a paucity of studies characterizing the care patterns for real-world irAEs hospitalizations. Methods: A single centre retrospective chart review (Princess Margaret Cancer Centre, Toronto, ON) identified patients receiving standard of care ICI (2012-2017) hospitalized for irAEs. For hospitalizations, clinico-pathological, investigation and treatment details were collected. Descriptive statistics helped to characterize hospitalizations. Results: Among 697 patients (266 lung, 381 melanoma and 50 genitourinary (GU)) on ICI, 8% (14 lung, 41 melanoma and 2 GU) had at least 1 irAE (range 1-4) hospitalization for a total of 69 hospitalizations. Average length of stay was 12 days (range 1-105). Among hospitalized patients, median age was 60; 63% were male; 29% received ipilimumab monotherapy, 28% pembrolizumab, 22% nivolumab and 22% received combination ICI. The most common irAEs were colitis (52%), pneumonitis (20%), hepatitis (10%) and CNS disease (demyelination, hypophysis) (9%). Cases were admitted directly from clinic (39%), emergency rooms (29%), urgent care clinic (18%) or transferred from another hospital (13%). Most patients (72%) were admitted to oncology; 28% to general medicine. Endoscopy was performed in 21% of admissions with 60% showing evidence of irAE; biopsies were obtained in 16% of admissions and 73% had evidence of irAE. Subspecialty services were involved in 60% of admissions. Most patients received steroids (94%); 17% received Infliximab. While age did not impact length of stay (p = 0.63), patients admitted to oncology had longer admissions compared to general medicine (14 vs 6 days, p = 0.009). Conclusions: irAEs occur at similar rates in the real-world compared to clinical trials. There is significant heterogeneity in the care patterns for irAEs. Patients admitted to oncology had longer average lengths of stay. Further characterizing irAE can help to develop quality indicators that may improve irAE outcomes.
PTU-149 Barrett’s Oesophagus Patients Attending Hospital: Baseline Clinical, Patient History and Quality of Life Data from Boss and Aspect
Authors: S Love, G Reilly, C Roberts, P Moayyedi, C Foy, C Stokes, J De Caestecker, S Attwood, P Watson, Y Ang, P Bhandari, O Old, J Hapeshi, I Penman, C Rodgers, C Edwards, D Monk, K Ragunath, D Morris, D Johnston, J Jankowski, H Barr
Journal: Gut (2016)

<h3>Introduction</h3> From 2005 to 2011 two large UK studies recruited 6,327 evaluable patients with Barrett’s Oesophagus attending hospital clinics. Baseline clinical, patient history and quality of life data was collected prior to randomisation and this rich dataset is the basis for this abstract. <h3>Methods</h3> Patients were recruited to AspECT and BOSS at local centres through normal endoscopy clinics and surveillance lists including those newly diagnosed or with an existing diagnosis of Barrett’s oesophagus. Baseline information was collected on age, gender, ethnicity, length of Barrett’s, presence of hiatus hernia, intestinal metaplasia and low grade dysplasia, concomitant medications, comorbidities, duration and severity of symptoms and patients’ self-reported Quality of Life data. <h3>Results</h3> The sample was mainly male (75%, n = 6,327) with median age of 64 years (range 18–92 years, n = 6,327). Median Barrett’s length was 4 cm (range 1–24 cm, n = 6,029) and median time since diagnosis of Barrett’s was 2 years (range 0–41 years, n = 5,805). At least one symptom of reflux was experienced by 60% of patients and 46% of patients experienced at least one symptom at least once per week (n = 1,072). Length of Barrett’s was associated with age (n = 6,029), gender (n = 6,029), presence of low grade dysplasia (n = 5,955), presence of intestinal metaplasia (n = 6,026) and time since diagnosis (n = 5,913). <h3>Conclusion</h3> This is our first release of data from AspECT and BOSS with more to follow. It is a large set of data on Barrett’s patients which we expect to be typical of Barrett’s patients attending hospital clinics in the UK. The average person was a male age 62 with 4 cm Barrett’s having had a Barrett’s diagnosis for 2 years. <h3>Acknowledgements</h3> Our thanks to the patients and the sites. AspECT is sponsored by the University of Oxford with grant funding from CR-UK (A4584) and support from the Investigator-Sponsored Study Program of AstraZeneca with trial management provided by OCTO. BOSS is funded by the HTA grant number HTA 05/12/01 with trial management provided by BOSS trial office Gloucestershire Hospitals NHS Trust. The Centre for Statistics in Medicine provides statistical input to both AspECT and BOSS. <h3>Disclosure of Interest</h3> None Declared
Prediction of Lymph Node Metastasis in Early Gastric Cancer by Collagen Signature—Endoscopists’ Viewpoint—Reply
Authors: Weisheng Chen, Dexin Chen, Jun Yan
Journal: JAMA Surgery (2019)

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 Surgery 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 Surgery journal
Abstract 15553: The sGC Stimulator Vericiguat Improved Outcome in a Rodent Model of Heart Failure With Preserved Ejection Fraction (HFpEF)
Authors: Ilka Mathar, Mira Pavkovic, Nina Scheerer, Elke Hartmann, Peter Sandner
Journal: Circulation (2018)

Introduction: Heart failure (HF) is amongst the leading causes of death worldwide. HFpEF represents roughly 50 % of all HF patients and is characterized by impaired diastolic function, associated w...
Hepatobiliary cancers in South America: disparity strikes
Authors: Jose D Debes, Andre Boonstra, Domingo Balderramo, Angelo Z Mattos, Marco Arrese, Juan C. Roa, Juan W. Valle, Jesus M. Banales, Enrique Carrera, Pablo A. Romagnoli, Jhon E. Prieto, Bettina E. Hansen, Arndt Vogel, Angela Lamarca
Journal: The Lancet. Gastroenterology & hepatology (2019)
A Statistical Study of Six Hundred and Seventy-One Cases of Appendiceal Peritonitis
Authors: Henry H. Faxon, Horatio Rogers
Journal: New England Journal of Medicine (1942)

Original Article from The New England Journal of Medicine — A Statistical Study of Six Hundred and Seventy-One Cases of Appendiceal Peritonitis — Two Hundred and Twenty-Seven Cases with Palpable Mass on Admission to the Hospital
ID1 Is Critical for Tumorigenesis and Regulates Chemoresistance in Glioblastoma
Authors: Rohit Sachdeva, Megan Wu, Sandra Smiljanic, Oleksandra Kaskun, Kimia Ghannad-Zadeh, Angela Celebre, Keren Isaev, A. Sorana Morrissy, Jennifer Guan, Jiefei Tong, Jeffrey Chan, Taylor M. Wilson, Sayf Al-Omaishi, David G. Munoz, Peter B. Dirks, Michael F. Moran, Michael D. Taylor, Jüri Reimand, Sunit Das
Journal: Cancer Research (2019)

Glioblastoma is the most common primary brain tumor in adults. While the introduction of temozolomide chemotherapy has increased long-term survivorship, treatment failure and rapid tumor recurrence remains universal. The transcriptional regulatory protein, inhibitor of DNA-binding-1 (ID1), is a key regulator of cell phenotype in cancer. We show that CRISPR-mediated knockout of ID1 in glioblastoma cells, breast adenocarcinoma cells, and melanoma cells dramatically reduced tumor progression in all three cancer systems through transcriptional downregulation of EGF, which resulted in decreased EGFR phosphorylation. Moreover, ID1-positive cells were enriched by chemotherapy and drove tumor recurrence in glioblastoma. Addition of the neuroleptic drug pimozide to inhibit ID1 expression enhanced the cytotoxic effects of temozolomide therapy on glioma cells and significantly prolonged time to tumor recurrence. Conclusively, these data suggest ID1 could be a promising therapeutic target in patients with glioblastoma. SIGNIFICANCE: These findings show that the transcriptional regulator ID1 is critical for glioblastoma initiation and chemoresistance and that inhibition of ID1 enhances the effect of temozolomide, delays tumor recurrence, and prolongs survival.
Abstract 16082: Predictors of the Long-Term Outcomes in Patients With Secondary Hypertension Caused by Primary Aldosteronism
Authors: Chun-Chih Chiu, Chin-Chou Huang, Hsin-Bang Leu, Tao-Cheng Wu, Po-Hsun Huang, Shing-Jong Lin, Jaw-Wen Chen
Journal: Circulation (2013)

Background: Secondary hypertension caused by primary aldosteronism plays an important role in end-organ damage. However, there are few studies about the long-term outcomes in this population. The a...
CDKN2A homozygous deletion is a strong adverse prognosis factor in diffuse malignant IDH-mutant gliomas
Authors: Romain Appay, Caroline Dehais, Claude-Alain Maurage, Agusti Alentorn, Catherine Carpentier, Carole Colin, François Ducray, Fabienne Escande, Ahmed Idbaih, Aurélie Kamoun, Yannick Marie, Karima Mokhtari, Emeline Tabouret, Nesrine Trabelsi, Emmanuelle Uro-Coste, Jean-Yves Delattre, Dominique Figarella-Branger
Journal: Neuro-Oncology (2019)

The 2016 World Health Organization (WHO) classification of central nervous system tumors stratifies isocitrate dehydrogenase (IDH)-mutant gliomas into 2 major groups depending on the presence or absence of 1p/19q codeletion. However, the grading system remains unchanged and it is now controversial whether it can be still applied to this updated molecular classification.In a large cohort of 911 high-grade IDH-mutant gliomas from the French national POLA network (including 428 IDH-mutant gliomas without 1p/19q codeletion and 483 anaplastic oligodendrogliomas, IDH-mutant and 1p/19q codeleted), we investigated the prognostic value of the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene homozygous deletion as well as WHO grading criteria (mitoses, microvascular proliferation, and necrosis). In addition, we searched for other retinoblastoma pathway gene alterations (CDK4 amplification and RB1 homozygous deletion) in a subset of patients. CDKN2A homozygous deletion was also searched in an independent series of 40 grade II IDH-mutant gliomas.CDKN2A homozygous deletion was associated with dismal outcome among IDH-mutant gliomas lacking 1p/19q codeletion (P < 0.0001 for progression-free survival and P = 0.004 for overall survival) as well as among anaplastic oligodendrogliomas, IDH-mutant + 1p/19q codeleted (P = 0.002 for progression-free survival and P < 0.0001 for overall survival) in univariate and multivariate analysis including age, extent of surgery, adjuvant treatment, microvascular proliferation, and necrosis. In both groups, the presence of microvascular proliferation and/or necrosis remained of prognostic value only in cases lacking CDKN2A homozygous deletion. CDKN2A homozygous deletion was not recorded in grade II gliomas.Our study pointed out the utmost relevance of CDKN2A homozygous deletion as an adverse prognostic factor in the 2 broad categories of IDH-mutant gliomas stratified on 1p/19q codeletion and suggests that the grading of these tumors should be refined.
Impact of time from diagnosis to initiation of curative chemotherapy on survival of patients with diffuse large B-cell lymphoma (DLBCL).
Authors: Kevin A. Hay, Benny Lee, Ozge Goktepe, Joseph M. Connors, Laurie Helen Sehn, Kerry J. Savage, Tamara Nina Shenkier, Richard John Klasa, Diego Villa
Journal: Journal of Clinical Oncology (2013)

8552 Background: DLBCL is potentially curable with combination chemotherapy such as CHOP-R. Although it is generally regarded appropriate to start chemotherapy promptly after diagnosis, the impact of the time from diagnosis to treatment initiation on treatment outcome is unknown. Methods: Patients diagnosed with DLBCL and treated with at least one cycle of CHOP-R with curative intent during 2003 – 2008 in British Columbia were identified in the Lymphoid Cancer Database. Additional demographic data were obtained from the BC Cancer Registry. The BC Cancer Agency provincial pharmacy database was used to obtain dates of chemotherapy administration. The impact of the time interval from the date of pathologic diagnosis to treatment on overall survival (OS) and progression-free survival (PFS) was evaluated. Results: A total of 793 patients were identified: 199 (25%) received CHOP-R &lt;2 weeks after diagnosis, 244 (31%) at 2-4 weeks, 293 (37%) at 5-8 weeks, and 57 (7%) at &gt;8 weeks. High international prognostic index, primary mediastinal DLBCL, and hospitalization at the time of CHOP-R start were associated with earlier initiation of chemotherapy (p&lt;0.001 for all factors). Distance to chemotherapy from home (p=0.237), rural vs. urban location (p=0.952), geographic region (p=0.458), and median household income (p=0.127) were not associated to treatment start. Five-year PFS and OS respectively were 54% (SD 4%) and 61% (SD 4%) for treatment &lt;2 weeks, 63% (SD 3%) and 66% (SD 3%) for 2-4 weeks, 70% (SD 3%) and 74% (SD 3%) for 5-8 weeks, and 60% (SD 7%) and for 61% (SD 8%) &gt;8 weeks, p=0.006 (PFS) and p=0.024 (OS). A multivariate analysis demonstrated no significant difference between the groups. Conclusions: In a publicly funded healthcare system, earlier initiation of chemotherapy was strongly associated with poor prognostic factors, as well as inferior PFS and OS. The timing of chemotherapy initiation appears to be related to clinical factors instead of system or socioeconomic barriers. Notwithstanding the lack of detrimental outcomes in those commencing CHOP-R after 8 weeks, clinicians should endeavor to initiate curative chemotherapy as soon as possible after a diagnosis of DLBCL is established.
International Union of Basic and Clinical Pharmacology. CVII. Structure and Pharmacology of the Apelin Receptor with a Recommendation that Elabela/Toddler Is a Second Endogenous Peptide Ligand
Authors: Cai Read, Duuamene Nyimanu, Thomas L. Williams, David J. Huggins, Petra Sulentic, Robyn G. C. Macrae, Peiran Yang, Robert C. Glen, Janet J. Maguire, Anthony P. Davenport
Journal: Pharmacological Reviews (2019)

The predicted protein encoded by the APJ gene discovered in 1993 was originally classified as a class A G protein-coupled orphan receptor but was subsequently paired with a novel peptide ligand, apelin-36 in 1998. Substantial research identified a family of shorter peptides activating the apelin receptor, including apelin-17, apelin-13, and [Pyr<sup>1</sup>]apelin-13, with the latter peptide predominating in human plasma and cardiovascular system. A range of pharmacological tools have been developed, including radiolabeled ligands, analogs with improved plasma stability, peptides, and small molecules including biased agonists and antagonists, leading to the recommendation that the APJ gene be renamed APLNR and encode the apelin receptor protein. Recently, a second endogenous ligand has been identified and called Elabela/Toddler, a 54-amino acid peptide originally identified in the genomes of fish and humans but misclassified as noncoding. This precursor is also able to be cleaved to shorter sequences (32, 21, and 11 amino acids), and all are able to activate the apelin receptor and are blocked by apelin receptor antagonists. This review summarizes the pharmacology of these ligands and the apelin receptor, highlights the emerging physiologic and pathophysiological roles in a number of diseases, and recommends that Elabela/Toddler is a second endogenous peptide ligand of the apelin receptor protein.
Costs of preventable harm could pay for thousands of nurses, <i>BMJ</i> study finds
Authors: Elisabeth Mahase
Journal: BMJ (2019)

Preventable harm affects around one in 20 patients (6%) in medical care, with around 12% of those dying or becoming permanently disabled as a result, a systematic review and meta-analysis published in The BMJ has found.1

The review of 70 studies conducted mainly in the US and Europe showed that the harm mostly related to drug incidents and invasive procedures and was more common in …
Targeting BCR-ABL1 in Chronic Myeloid Leukemia by PROTAC-Mediated Targeted Protein Degradation
Authors: George M. Burslem, Anna Reister Schultz, Daniel P. Bondeson, Christopher A. Eide, Samantha L. Savage Stevens, Brian J. Druker, Craig M. Crews
Journal: Cancer Research (2019)

Abstract Although the use of ATP-competitive tyrosine kinase inhibitors of oncoprotein BCR-ABL1 has enabled durable responses in patients with chronic myeloid leukemia (CML), issues of drug resistance and residual leukemic stem cells remain. To test whether the degradation of BCR-ABL1 kinase could offer improved response, we developed a series of proteolysis-targeting chimera (PROTAC) that allosterically target BCR-ABL1 protein and recruit the E3 ligase Von Hippel-Lindau, resulting in ubiquitination and subsequent degradation of the oncogenic fusion protein. In both human CML K562 cells and murine Ba/F3 cells expressing BCR-ABL1, lead compound GMB-475 induced rapid proteasomal degradation and inhibition of downstream biomarkers, such as STAT5, and showed increased sensitivity compared with diastereomeric controls lacking degradation activity. Notably, GMB-475 inhibited the proliferation of certain clinically relevant BCR-ABL1 kinase domain point mutants and further sensitized Ba/F3 BCR-ABL1 cells to inhibition by imatinib, while demonstrating no toxicity toward Ba/F3 parental cells. Reverse phase protein array analysis suggested additional differences in levels of phosphorylated SHP2, GAB2, and SHC associated with BCR-ABL1 degradation. Importantly, GMB-475 reduced viability and increased apoptosis in primary CML CD34+ cells, with no effect on healthy CD34+ cells at identical concentrations. GMB-475 degraded BCR-ABL1 and reduced cell viability in primary CML stem cells. Together, these findings suggest that combined BCR-ABL1 kinase inhibition and protein degradation may represent a strategy to address BCR-ABL1–dependent drug resistance, and warrant further investigation into the eradication of persistent leukemic stem cells, which rely on neither the presence nor the activity of the BCR-ABL1 protein for survival. Significance: Small-molecule–induced degradation of BCR-ABL1 in CML provides an advantage over inhibition and provides insights into CML stem cell biology.
Oncogene Amplification in Growth Factor Signaling Pathways Renders Cancers Dependent on Membrane Lipid Remodeling
Authors: Junfeng Bi, Taka-Aki Ichu, Ciro Zanca, Huijun Yang, Wei Zhang, Yuchao Gu, Sudhir Chowdhry, Alex Reed, Shiro Ikegami, Kristen M. Turner, Wenjing Zhang, Genaro R. Villa, Sihan Wu, Oswald Quehenberger, William H. Yong, Harley I. Kornblum, Jeremy N. Rich, Timothy F. Cloughesy, Webster K. Cavenee, Frank B. Furnari, Benjamin F. Cravatt, Paul S. Mischel
Journal: Cell Metabolism (2019)
Phase lb combination trial of a MEK inhibitor, pimasertib (MSC1936369B), and a PI3K/mTOR inhibitor, SAR245409, in patients with locally advanced or metastatic solid tumors.
Authors: Jeffrey R. Infante, Leena Gandhi, Geoffrey Shapiro, Howard A. Burris, Johanna C. Bendell, José Baselga, Karl Hsu, Théa Faivre, Ekatherine Asatiani, Rebecca Suk Heist
Journal: Journal of Clinical Oncology (2012)

TPS3118 Background: The PI3K/mTOR and MAPK signaling pathways are frequently aberrantly activated in tumors and interact to promote growth and resistance to treatment. Simultaneous inhibition of both pathways may enhance antitumor activity. This trial investigates the combination of pimasertib, a highly selective MEK1/2 inhibitor, and SAR245409, a dual PI3K/mTOR inhibitor (ClinicalTrials.gov NCT01390818). Maximum tolerated dose (MTD) when administered once daily (qd) as a single agent to solid tumor patients (pts) is 90 mg for both compounds. Methods: Pts with advanced solid tumors characterized by frequent alterations of the MAPK or PI3K/mTOR pathways (pancreatic, thyroid, colorectal, non-small cell lung, endometrial, renal, breast, ovarian and melanoma) and/or with identified alterations in genes activating these pathways, adequate performance status and organ function, and no retinal disease are eligible for entry. The primary objective of the trial is to determine the MTD of the combination therapy. Secondary objectives include: safety, pharmacokinetics (PK), pharmacodynamics (PD), biomarker identification and antitumor efficacy (response rate via RECIST v1.1). Both compounds are dosed together qd continuously in 21 day cycles. The study uses a classical 3 + 3 design, with modified Fibonacci (decreasing increments) dose escalation based on occurrence of dose-limiting toxicities (DLTs). In parallel with dose escalation, more pts may be enrolled in already tested lower dose level (DL) cohorts to further evaluate PK, PD, safety and antitumor activity. After MTD confirmation, additional pts may be enrolled in up to 4 disease-specific cohorts based on scientific rationale, and observed preclinical and clinical activity signals. As of January 25th 2012, 20 pts have been treated. No DLTs have been reported.
Tumor suppressor TET2 promotes cancer immunity and immunotherapy efficacy
Authors: Yan-ping Xu, Lei Lv, Ying Liu, Matthew D. Smith, Wen-Cai Li, Xian-ming Tan, Meng Cheng, Zhijun Li, Michael Bovino, Jeffrey Aubé, Yue Xiong
Journal: Journal of Clinical Investigation (2019)

Loss-of-function mutations in genes encoding TET DNA dioxygenase occur frequently in hematopoietic malignancy, but rarely in solid tumors which instead commonly have reduced activity. The impact of decreased TET activity in solid tumors is not known. Here we show that TET2 mediates interferon γ (IFNγ)-JAK-STAT signaling pathway to control chemokine and PD-L1 expression, lymphocyte infiltration and cancer immunity. IFNγ stimulated STAT1 to bind TET2 and recruit TET2 to hydroxymethylate chemokine and PD-L1 genes. Reduced TET activity was associated with decreased TH1-type chemokines and tumor-infiltrating lymphocytes (TILs) and the progression of human colon cancer. Deletion of Tet2 in murine melanoma and colon tumor cells reduced chemokine expression and TILs, enabling tumors to evade anti-tumor immunity and to resist anti-PD-L1 therapy. Conversely, stimulating TET activity by systematic injection of its co-factor, ascorbate/vitamin C, increased chemokine and TILs, leading to enhanced anti-tumor immunity and anti-PD-L1 efficacy and extended lifespan of tumor-bearing mice. These results suggest an IFNγ-JAK-STAT-TET signaling pathway that mediates tumor response to anti-PD-L1/PD-1 therapy and is frequently disrupted in solid tumors. Our findings also suggest TET activity as a biomarker for predicting the efficacy and patient response to anti-PD-1/PD-L1 therapy, and stimulating TET activity as an adjuvant immunotherapy of solid tumors.