tbuckley/cabot-search huggingface dataset:
Differential Outcomes in Codon 12/13 and Codon 61<i>NRAS</i>-Mutated Cancers in the Phase II NCI-MATCH Trial of Binimetinib in Patients with<i>NRAS</i>-Mutated Tumors
Authors: James M. Cleary, Victoria Wang, Rebecca S. Heist, E. Scott Kopetz, Edith P. Mitchell, James A. Zwiebel, Kevin S. Kapner, Helen X. Chen, Shuli Li, Robert J. Gray, Lisa M. McShane, Larry V. Rubinstein, David R. Patton, Funda Meric-Bernstam, Melissa S. Dillmon, P. Mickey Williams, Stanley R. Hamilton, Barbara A. Conley, Andrew J. Aguirre, Peter J. O'Dwyer, Lyndsay N. Harris, Carlos L. Arteaga, Alice P. Chen, Keith T. Flaherty
Journal: Clinical Cancer Research (2021)

Preclinical and clinical data suggest that downstream inhibition with an MEK inhibitor, such as binimetinib, might be efficacious for NRAS-mutated cancers.Patients enrolled in the NCI-MATCH trial master protocol underwent tumor biopsy and molecular profiling by targeted next-generation sequencing. Patients with NRAS-mutated tumors, except melanoma, were enrolled in subprotocol Z1A, a single-arm study evaluating binimetinib 45 mg twice daily. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS) and overall survival (OS). A post hoc analysis examined the association of NRAS mutation type with outcome.In total, 47 eligible patients with a refractory solid tumor harboring a codon 12, 13, or 61 NRAS mutation were treated. Observed toxicity was moderate, and 30% of patients discontinued treatment because of binimetinib-associated toxicity. The ORR was 2.1% (1/47 patients). A patient with malignant ameloblastoma harboring a codon 61 NRAS mutation achieved a durable partial response (PR). A patient with NRAS codon 61-mutated colorectal cancer had an unconfirmed PR, and two other patients with NRAS codon 61-mutated colorectal had stable disease for at least 12 months. In an exploratory analysis, patients with colorectal cancer bearing a NRAS codon 61 mutation (n = 8) had a significantly longer OS (P = 0.03) and PFS (P = 0.007) than those with codon 12 or 13 mutations (n = 16).Single-agent binimetinib did not show promising efficacy in NRAS-mutated cancers. The observation of increased OS and PFS in patients with codon 61 NRAS-mutated colorectal cancer merits further investigation.
Activity and Safety of Mobocertinib (TAK-788) in Previously Treated Non–Small Cell Lung Cancer with <i>EGFR</i> Exon 20 Insertion Mutations from a Phase I/II Trial
Authors: Gregory J. Riely, Joel W. Neal, D. Ross Camidge, Alexander I. Spira, Zofia Piotrowska, Daniel B. Costa, Anne S. Tsao, Jyoti D. Patel, Shirish M. Gadgeel, Lyudmila Bazhenova, Viola W. Zhu, Howard L. West, Tarek Mekhail, Ryan D. Gentzler, Danny Nguyen, Sylvie Vincent, Steven Zhang, Jianchang Lin, Veronica Bunn, Shu Jin, Shuanglian Li, Pasi A. Jänne
Journal: Cancer Discovery (2021)

Mobocertinib, an oral epidermal growth factor receptor (EGFR) inhibitor targeting EGFR gene mutations, including exon 20 insertions (EGFRex20ins), in non-small cell lung cancer, was evaluated in a phase I/II dose-escalation/expansion trial (ClinicalTrials.gov NCT02716116). Dose escalation identified 160 mg/d as the recommended phase 2 dose and maximum tolerated dose. Among 136 patients treated with 160 mg/d, the most common any-grade treatment-related adverse events (TRAE; >25%) were diarrhea (83%), nausea (43%), rash (33%), and vomiting (26%), with diarrhea (21%) the only grade ≥3 TRAE >5%. Among 28 EGFRex20ins patients treated at 160 mg/d, the investigator-assessed confirmed response rate was 43% (12/28; 95% confidence interval, 24%-63%) with median duration of response of 14 months (5.0-not reached) and median progression-free survival of 7.3 months (4.4-15.6). Mobocertinib demonstrated antitumor activity in patients with diverse EGFRex20ins variants with a safety profile consistent with other EGFR inhibitors. SIGNIFICANCE: No oral EGFR-targeted therapies are currently approved for patients with EGFRex20ins NSCLC. Mobocertinib demonstrated antitumor activity with manageable toxicity in patients with advanced EGFRex20ins NSCLC in this study, supporting additional development of mobocertinib in this patient population.See related commentary by Pacheco, p. 1617.This article is highlighted in the In This Issue feature, p. 1601.
Adjuvant Chemotherapy in Patients With Early-Stage Non–Small Cell Lung Cancer—Reply
Authors: Ranjan Pathak, Daniel J. Boffa
Journal: JAMA Oncology (2021)

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 Oncology 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 Oncology journal
Abstract PS6-58: The impact of baseline modified glasgow prognostic score (mGPS) on survival outcomes in in indigenous and non-indigenous patients with advanced breast cancer patients of Western Australia
Authors: Azim Khan, Hilary Martin, Lisa Spalding, Andrew Redfern
Journal: Cancer Research (2021)

Abstract Introduction: The modified Glasgow prognostic score (mGPS) is known to be useful in prognostication of multiple cancers. The mGPS, which integrates albumin and C-reactive protein, could assist as a possible prognostic marker in breast cancer. Indigenous women have inferior breast cancer survival to non-Indigenous women and may also have a differing inflammatory environment. Here, we examine the utility and impact of baseline mGPS on survival outcomes in women with metastatic breast cancer by Indigenous status. Methods: We retrospectively collected data from the Western Australian Cancer Registry and electronic records for patients diagnosed with breast cancer between 2001 and 2016 with confirmed metastatic disease. Overall survival (OS) were measured from the date of diagnosis until death. mGPS comprised scores of one point given for CRP &amp;gt; 10 mg/L and/or albumin &amp;lt; 3.5 g/dL, therefore having a value of 0 to 2. Results: Of 152 patients with metastatic breast cancer, 89 patients had all relevant data available and were included with a median follow up of 120 months. The median age was 55.3 years. Baseline mGPS was 0 in 46.6 %, 1 in 34.8 % and 2 in 18.6 %. Median OS across Indigenous and non-Indigenous patients combined was significantly worse moving from the mGPS-0 group through mGPS-1 to mGPS 2, 50.0 v 30.0 v 8.0 months respectively (p&amp;lt;0.0001). Looking at the groups separately, both cohorts separately demonstrated inferior median OS in mGPS-2 compared to mGPS-1 patients, 9 v 32 months (p=0.02) for Indigenous patients, and 2.0 vs 25.0 months for non_Indigenous patients (p=0.001). The correlation between mGPS and the neutrophil-to-lymphocyte ratio (NLR) was weak with a Pearson correlation R-value of 0.184 (p=0.085) Conclusion: The study shows that the mGPS is an independent prognostic factor in advanced-stage disease. A higher baseline mGPS score was associated with worse survival in Indigenous and non-Indigenous patients. A larger prospective study is needed to validate the results, inclusive of assessing links between mGPS and OS in different breast cancer sub-types. Citation Format: Azim Khan, Hilary Martin, Lisa Spalding, Andrew Redfern. The impact of baseline modified glasgow prognostic score (mGPS) on survival outcomes in in indigenous and non-indigenous patients with advanced breast cancer patients of Western Australia [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS6-58.
International experiences with co-production and people centredness offer lessons for covid-19 responses
Authors: Eva Turk, Anna Durrance-Bagale, Emeline Han, Sadie Bell, Selina Rajan, Maria Margarita M Lota, Chinwe Ochu, Maria Lazo Porras, Pallavi Mishra, Gasto Frumence, Martin McKee, Helena Legido-Quigley
Journal: BMJ (2021)

<b>Eva Turk and colleagues</b> believe that there is much to learn from the experiences of low and middle income countries in co-producing knowledge and working with communities to find feasible and acceptable solutions to healthcare concerns
Response to Treatment in IgG4-Related Disease Assessed by Quantitative PET/CT Scan
Authors: Olimpia Orozco-Gálvez, Andreu Fernández-Codina, Marc Simó-Perdigo, Iago Pinal-Fernández, Fernando Martínez-Valle
Journal: Clinical Nuclear Medicine (2021)

The aim of this study was to assess disease activity by different PET/CT measurements in IgG4-related disease (IgG4-RD) flares and their correlation with the IgG4-RD responder index (IgG4-RI).Patients were retrospectively recruited from a single center in Barcelona, Spain. They all had IgG4-RD flares with an 18F-FDG PET/CT examination performed within the 2 first weeks of the flare onset and another one after at least 3 months of treatment between 2012 and 2018. Epidemiologic, clinical, laboratory, and therapeutic data were collected at baseline and at follow-up. Semiquantitative and volumetric measurements from PET/CT explorations were recorded. In addition, a 5-point visual scale was (adapted Deauville score) trialed. The IgG4-RI was used as the criterion standard to assess response before and after treatment.Eighteen patients with a total of 23 flares were included. The median time to second PET/CT examination was 7 months. Remission (complete and partial) according to IgG4-RI was observed in 20 flares (87%). All PET/CT measurements (SUVmax and SUVmean, total lesion glycolysis, MTV, and adapted Deauville score) were statistically significantly lower on the follow-up evaluation, except for the size of the lesion. The correlation of all these parameters with the IgG4-RI was positive except for SUVmean and the size of the lesion.Semiquantitative, volumetric, and visual parameters in PET/CT scans correlated with response to treatment assessed by IgG4-RI. Volumetric and visual items are less subject to variations and could be used to improve activity scores and treatment strategies.
Abstract PS7-54: Racial differences in age-related DNA methylation changes in normal breast tissue
Authors: Chunyan He, James Castle, Nan Lin, Yunlong Liu, Chi Wang
Journal: Cancer Research (2021)

Abstract Age is a well-established risk factor for breast cancer development. While age-related epigenetic changes are believed to contribute to overall breast cancer risk, the underlying molecular mechanisms are poorly understood. In addition, racial disparity in breast cancer is well recognized. Compared to European American (EA) women, African American (AA) women are more often diagnosed with breast cancer at younger ages, have a more advanced or aggressive disease, and have poorer outcomes. We hypothesize that age-related DNA methylation (DNAm) may contribute to breast cancer risk differently for distinct racial groups. We investigated epigenome-wide age-related DNAm in normal breast tissue from 178 EA and 272 AA women separately using the Illumina TruSeq Methyl Capture EPIC library and NGS technology. We identified 3,944 and 506 CpG loci that were significantly associated with chronological age, of which 3,534 and 504 CpGs were increasingly hypermethylated with older ages and 410 and 2 loci were increasingly hypomethylated with older ages, in EA and AA women, respectively. Despite the different number, all 506 loci that were significantly associated with age in AA women were also significant for EA women. The low number age-related DNAm loci identified in AA women may reflect a more complex interplay of factors on epigenetic mechanisms in this racial group. Pathway analyses suggested these age-related loci are enriched in biological processes including cell communication, signaling, proliferation, and adhesion. We further examined 181 CpG loci that were previously reported to be associated with age in normal breast tissue but found that only six loci were replicated in our dataset. Our results suggested age-related biological pathways that potentially implicated in breast cancer development and a more complex epigenetic mechanisms in AA women. Citation Format: Chunyan He, James Castle, Nan Lin, Yunlong Liu, Chi Wang. Racial differences in age-related DNA methylation changes in normal breast tissue [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS7-54.
Association of Adoption of Transcarotid Artery Revascularization With Center-Level Perioperative Outcomes
Authors: Jesse A. Columbo, Pablo Martinez-Camblor, A. James O’Malley, David H. Stone, Vikram S. Kashyap, Richard J. Powell, Marc L. Schermerhorn, Mahmoud Malas, Brian W. Nolan, Philip P. Goodney
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Transcarotid artery revascularization (TCAR) may serve as a safer alternative to carotid endarterectomy (CEA) for certain patients with carotid artery stenosis. <h3>Objective</h3> To determine the center-level association of TCAR adoption with overall perioperative outcomes for TCAR and CEA combined at centers performing both procedures. <h3>Design, Setting, and Participants</h3> This comparative-effectiveness research was conducted with a difference-in-difference analysis using retrospective data from 2015 to 2019 from the Vascular Quality Initiative registry, a consortium of more than 400 centers in North America. Included patients underwent TCAR or CEA for carotid artery stenosis. Patients who underwent transfemoral carotid stenting were excluded. Data were analyzed from December 2019 through August 2020. <h3>Exposures</h3> Center-level adoption of TCAR vs not. <h3>Main Outcomes and Measures</h3> The rate of major adverse cardiovascular events (MACE), a composite of in-hospital stroke, myocardial infarction, or death at 30 days, was measured. <h3>Results</h3> Among 86 027 patients who underwent revascularization for carotid artery stenosis, 7664 patients (8.9%) underwent TCAR (mean [SD] age, 73.1 [9.6] years; 2788 [36.4%] women; 6938 White patients [90.6%]; and 3741 patients with symptoms [48.8%]) and 78 363 patients (91.1%) underwent CEA (mean [SD] age, 70.6 [9.2] years; 30 928 [39.5%] women; 70 663 White patients [90.2%]; and 37 883 patients with symptoms [48.3%]). The number of centers performing both TCAR and CEA increased from 15 centers in 2015 to 247 centers in 2019, a more than 16-fold increase. The proportion of all carotid procedures that were TCARs increased from 90 of 12 276 (0.7%) in 2015 to 2718 of 15 956 (17.0%) in 2019, a 24-fold increase. Overall, the crude rate of MACE was similar for TCAR and CEA (178 patients [2.3%] after TCAR vs 1842 patients [2.4%] after CEA;<i>P</i> = .91). However, the rate of MACE over time decreased for CEA (406 of 16 404 patients [2.5%] in 2015 vs 189 of 10 097 patients [1.9%] in 2019;<i>P</i>for trend &lt; .001). The rate of MACE over time decreased for TCAR as well, but the change was not statistically significant (4 of 128 patients [3.1%] in 2016 vs 59 of 2718 patients [2.2%] in 2019;<i>P</i>for trend = .07). Difference-in-difference analysis demonstrated that centers that adopted TCAR had a 10% decrease in the likelihood of MACE at 12 months after TCAR adoption vs if those centers had continued to perform CEA alone (odds ratio, 0.90; 95% CI, 0.81-0.99;<i>P</i> = .04). <h3>Conclusions and Relevance</h3> This comparative-effectiveness study of a cohort of patients who underwent TCAR or CEA found that availability of TCAR at a hospital was associated with a decrease in the likelihood of perioperative MACE after carotid revascularization.
Diagnosing Childhood Tuberculosis
Authors: Jeffrey R. Starke, Andrea T. Cruz
Journal: JAMA Pediatrics (2021)

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 Pediatrics 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 Pediatrics journal
Staff wellbeing: NHS England expands support with 40 hubs
Authors: Abi Rimmer
Journal: BMJ (2021)

NHS staff in England will be able to access evidence based mental health services from 40 hubs nationwide, NHS England has said.

Care will be provided free of charge, and the hubs will proactively contact staff groups who are most at risk. The hubs have been modelled on the Greater Manchester Resilience Hub,1 which was set up to treat people affected …
An approach to hip pain in a young adult
Authors: Alastair G Dick, Jonathan M Houghton, Marcus J K Bankes
Journal: British Journal of Sports Medicine (2021)

### What you need to know

Hip pain in young adults is not normal and can be severe and disabling, affecting work, parenting, and leisure activities.1 2 The causes of hip pain in young adults (aged 16–50) tend to receive less attention than those in children (including Perthes’ disease, slipped capital femoral epiphysis, and septic arthritis) and in older patients (usually osteoarthritis). Imaging studies might not reveal an underlying problem, even where the patient’s symptoms are a consequence of clinically significant pathology.

Research has improved understanding of the causes of hip pain in young adults, including femoroacetabular impingement syndrome (FAI) and dysplasia of the hip, and has identified new treatments, although evidence is still limited.3 4 Importantly, both FAI and hip dysplasia are treatable causes of hip pain in young adults.4–6 This Practice Pointer aims to help the non-specialist evaluate young adults presenting with hip pain, and provides an update on common young adult hip pathologies.

Hip problems in young adults can be considered as problems within the joint itself (intra-articular) or …
Platelets release mitochondrial antigens in systemic lupus erythematosus
Authors: Imene Melki, Isabelle Allaeys, Nicolas Tessandier, Tania Lévesque, Nathalie Cloutier, Audrée Laroche, Nathalie Vernoux, Yann Becker, Hadrien Benk-Fortin, Anne Zufferey, Emmanuelle Rollet-Labelle, Marc Pouliot, Guy Poirier, Natacha Patey, Clemence Belleannee, Denis Soulet, Steven E. McKenzie, Alain Brisson, Marie-Eve Tremblay, Christian Lood, Paul R. Fortin, Eric Boilard
Journal: Science Translational Medicine (2021)

The accumulation of DNA and nuclear components in blood and their recognition by autoantibodies play a central role in the pathophysiology of systemic lupus erythematosus (SLE). Despite the efforts, the sources of circulating autoantigens in SLE are still unclear. Here, we show that in SLE, platelets release mitochondrial DNA, the majority of which is associated with the extracellular mitochondrial organelle. Mitochondrial release in patients with SLE correlates with platelet degranulation. This process requires the stimulation of platelet FcγRIIA, a receptor for immune complexes. Because mice lack FcγRIIA and murine platelets are completely devoid of receptor capable of binding IgG-containing immune complexes, we used transgenic mice expressing FcγRIIA for our in vivo investigations. FcγRIIA expression in lupus-prone mice led to the recruitment of platelets in kidneys and to the release of mitochondria in vivo. Using a reporter mouse with red fluorescent protein targeted to the mitochondrion, we confirmed platelets as a source of extracellular mitochondria driven by FcγRIIA and its cosignaling by the fibrinogen receptor α2bβ3 in vivo. These findings suggest that platelets might be a key source of mitochondrial antigens in SLE and might be a therapeutic target for treating SLE.
Uncontrollable Hemoptysis owing to Pseudoangiosarcomatous Carcinoma of the Lung
Authors: Yue Lin, Jie Lin, Yanyan Xu, Hongliang Sun, Sheng Xie
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

"Uncontrollable Hemoptysis owing to Pseudoangiosarcomatous Carcinoma of the Lung." American Journal of Respiratory and Critical Care Medicine, 204(1), pp. e1–e2
Coagulopathy, Bleeding Events, and Outcome According to Rotational Thromboelastometry in Patients With Acute Liver Injury/Failure
Authors: R. Todd Stravitz, Robert J. Fontana, Caitlyn Meinzer, Valerie Durkalski‐Mauldin, A. James Hanje, Jody Olson, David Koch, Bilal Hamid, Michael L. Schilsky, Brendan McGuire, Daniel Ganger, Iris Liou, Constantine J. Karvellas, Jody A. Rule, Ton Lisman, Kristin Clasen, Adrian Reuben, Michael Cripps, William M. Lee
Journal: Hepatology (2021)

Patients with acute liver injury or failure (ALI/ALF) experience bleeding complications uncommonly despite an abnormal hemostatic profile. Rotational thromboelastometry (ROTEM), which assesses clot formation in whole blood, was used to determine the nature of abnormal hemostasis and whether it contributes to bleeding events, illness severity, or survival.A total of 200 patients were recruited from sites of the ALF Study Group. Blood collected daily for up to 5 days was analyzed using ROTEM delta devices. Consistent with standard laboratory evidence of hypocoagulability (median international normalized ratio = 2.9 and platelet count = 144 × 109 /L), patients frequently exhibited ROTEM parameters outside the normal range (73% and 62% had abnormalities in clot formation from extrinsic and intrinsic clotting cascades, respectively); however, measures of clot stability were generally normal. Eighteen patients (9%) experienced bleeding events, in whom clot initiation, assembly, and firmness were more severely deranged than patients without bleeding. Abnormal ROTEM parameters were more frequently observed in patients with non-acetaminophen ALI/ALF than those with acetaminophen ALI/ALF (clot initiation [P < 0.001], assembly [P = 0.02], firmness at 10 minutes [P = 0.05], and maximal firmness [P = 0.06]). Patients with more severe systemic complications (high-grade hepatic encephalopathy and need for renal replacement therapy) also had a higher incidence of abnormal ROTEM parameters. Finally, more hypocoagulable ROTEM parameters (clot initiation (P = 0.005), stiffness at 10 minutes (P = 0.05), and maximal stiffness by fibrin assembly (P = 0.004)) were observed in patients who died or underwent liver transplantation than those who survived with their native liver.In patients with ALI/ALF, abnormal ROTEM parameters are frequent and proportional to disease severity. Whether the increased bleeding risk associated with abnormal ROTEM indicates hemostatic failure or is a proxy for disease severity requires additional study.