tbuckley/cabot-search huggingface dataset:
Efficacy, Safety, and Correlative Biomarkers of Toripalimab in Previously Treated Recurrent or Metastatic Nasopharyngeal Carcinoma: A Phase II Clinical Trial (POLARIS-02)
Authors: Feng-Hua Wang, Xiao-Li Wei, Jifeng Feng, Qi Li, Nong Xu, Xi-Chun Hu, Wangjun Liao, Yi Jiang, Xiao-Yan Lin, Qing-yuan Zhang, Xiang-Lin Yuan, Hai-Xin Huang, Ye Chen, Guang-Hai Dai, Jian-Hua Shi, Lin Shen, Shu-Jun Yang, Yong-Qian Shu, Yun-Peng Liu, Weifeng Wang, Hai Wu, Hui Feng, Sheng Yao, Rui-Hua Xu
Journal: Journal of Clinical Oncology (2021)

As yet, no checkpoint inhibitor has been approved to treat nasopharyngeal carcinoma (NPC). This study was aimed to evaluate the antitumor activity, safety, and biomarkers of toripalimab, a new programmed death-1 (PD-1) inhibitor for recurrent or metastatic NPC (RM-NPC) refractory to standard chemotherapy.In this single-arm, multicenter phase II study, patients with RM-NPC received 3 mg/kg toripalimab once every 2 weeks via intravenous infusion until confirmed disease progression or unacceptable toxicity. The primary end point was objective response rate (ORR). The secondary end points included safety, duration of response (DOR), progression-free survival (PFS), and overall survival (OS).Among all 190 patients, the ORR was 20.5% with median DOR 12.8 months, median PFS 1.9 months, and median OS 17.4 months. Among 92 patients who failed at least two lines of systemic chemotherapy, the ORR was 23.9%. The ORRs were 27.1% and 19.4% in PD-L1+ and PD-L1- patients, respectively (P = .31). Patients with ≥ 50% decrease of plasma Epstein-Barr virus (EBV) DNA copy number on day 28 had significantly better ORR than those with < 50% decrease, 48.3% versus 5.7% (P = .0001). Tumor mutational burden had a median value of 0.95 muts/mega-base in the cohort and had no predictive value for response. Whole-exome sequencing results from 174 patients revealed that the patients with genomic amplification in 11q13 region or ETV6 genomic alterations had poor responses to toripalimab.The POLARIS-02 study demonstrated a manageable safety profile and durable clinical response of toripalimab in patients with chemorefractory metastatic NPC. An early decrease in plasma EBV DNA copy number correlated with favorable response.
The Complex Clinical and Genetic Landscape of Hereditary Peripheral Neuropathy
Authors: Soumitra Ghosh, Warren G. Tourtellotte
Journal: Annual Review of Pathology Mechanisms of Disease (2021)

Hereditary peripheral neuropathy (HPN) is a complex group of neurological disorders caused by mutations in genes expressed by neurons and Schwann cells. The inheritance of a single mutation or multiple mutations in several genes leads to disease phenotype. Patients exhibit symptoms during development, at an early age or later in adulthood. Most of the mechanistic understanding about these neuropathies comes from animal models and histopathological analyses of postmortem human tissues. Diagnosis is often very complex due to the heterogeneity and overlap in symptoms and the frequent overlap between various genes and different mutations they possess. Some symptoms in HPN are common through different subtypes such as axonal degeneration, demyelination, and loss of motor and sensory neurons, leading to similar physiologic abnormalities. Recent advances in gene-targeted therapies, genetic engineering, and next-generation sequencing have augmented our understanding of the underlying pathogenetic mechanisms of HPN.
Heterogeneity of pollen food allergy syndrome in seven Southern European countries: The @IT.2020 multicenter study
Authors: Theresa Lipp, Aydan Acar Şahin, Xenophon Aggelidis, Stefania Arasi, Andrea Barbalace, Anne Bourgoin, Blerina Bregu, Maria Antonia Brighetti, Elsa Caeiro, Sule Caglayan Sozmen, Lucia Caminiti, Denis Charpin, Mariana Couto, Luís Delgado, Andrea Di Rienzo Businco, Claire Dimier, Maria V. Dimou, João A. Fonseca, Ozlem Goksel, Aykut Guvensen, Dolores Hernandez, Tara Maria Hoffmann, Dah Tay Jang, Fusun Kalpaklioglu, Blerta Lame, Ruth Llusar, Michael P. Makris, Angel Mazon, Eris Mesonjesi, Antonio Nieto, Ayse Öztürk, Laurie Pahus, Giovanni Battista Pajno, Ilenia Panasiti, Nikolaos G. Papadopoulos, Elisabetta Pellegrini, Simone Pelosi, Ana M. Pereira, Mariana Pereira, Munevver Pinar, Ekaterina Potapova, Alfred Priftanji, Fotis Psarros, Cansin Sackesen, Ifigenia Sfika, Javier Suarez, Michel Thibaudon, Alessandro Travaglini, Salvatore Tripodi, Valentine Verdier, Valeria Villella, Paraskevi Xepapadaki, Duygu Yazici, Paolo M. Matricardi, Stephanie Dramburg
Journal: Allergy (2021)

Abstract Background Pollen food allergy syndrome (PFAS) is a frequently underdiagnosed disease due to diverse triggers, clinical presentations, and test results. This is especially relevant in geographic areas with a broad spectrum of pollen sensitization, such as Southern Europe. Objectives To elucidate similarities and differences of PFAS in nine Southern European centers and identify associated characteristics and unique markers of PFAS. Methods As part of the @IT.2020 Multicenter Study, 815 patients with seasonal allergic rhinitis (SAR), aged 10–60 years, were recruited in seven countries. They completed questionnaires regarding SAR, comorbidities, family history, and PFAS, and underwent skin prick testing (SPT) and serum IgE testing. Results Of the 815 patients, 167 (20.5%) reported PFAS reactions. Most commonly, eliciting foods were kiwi (58, 34.7%), peach (43, 25.7%), and melon (26, 15.6%). Reported reactions were mostly local (216/319, 67.7%), occurring within 5 min of contact with elicitors (209/319, 65.5%). Associated characteristics included positive IgE to at least one panallergen (profilin, PR‐10, or nsLTP) ( p = 0.007), maternal PFAS (OR: 3.716, p = 0.026), and asthma (OR: 1.752, p = 0.073). Between centers, heterogeneity in prevalence (Marseille: 7.5% vs. Rome: 41.4%, p &lt; 0.001) and of clinical characteristics was apparent. Cypress played a limited role, with only 1/22 SPT mono‐sensitized patients reporting a food reaction ( p &lt; 0.073). Conclusions PFAS is a frequent comorbidity in Southern European SAR patients. Significant heterogeneity of clinical characteristics in PFAS patients among the centers was observed and may be related to the different pollen sensitization patterns in each geographic area. IgE to panallergen(s), maternal PFAS, and asthma could be PFAS‐associated characteristics.
Y572 is a functionally important amino acid for autoinhibition of the FLT3 receptor tyrosine kinase
Authors: Jingrui Jiang, James D. Griffin
Journal: Cancer Research (2006)

1458  FLT3 is a member of the receptor tyrosine kinase III subfamily and shares strong sequence and structural similarities with c-Kit, FMS, PDGFRα and PDGFRβ. FLT3 plays an important role in hematopoiesis, and is also involved in the pathogenesis of hematopoietic malignancies. Mutations of FLT3 gene have been found in about 35% of acute myeloblastic leukemia (AML) patients, most commonly as in frame insertions of variable length (internal tandem duplications, or ITDs) in the juxtamembrane (JM) domain. These mutations result in receptor autophosphorylation without ligand stimulation, which then leads to the constitutive activation of many down stream targets/signaling pathways. It is likely that these ITD mutations cause the receptor to adopt an “active configuration” despite the absence of ligand. Studies from the crystal structure of the FLT3 cytoplasmic domain (Griffith et al, 2004. Molecular Cell. 13:169-178) have suggested the JM domain interacts with the kinase domain and plays a critical role in maintaining the kinase in an inactive configuration in the absence of ligand. These studies further suggested that the first amino acid of the JM domain, Y572, is a key element for the kinase autoinhibition by forming a stable network with the surrounded kinase subdomains. To test this hypothesis, two different FLT3 cDNAs harboring mutations at Y572, Y572N or Y572V, were each introduced into the growth factor IL3 dependent murine Ba/F3 cells, and stable, polyclonal cell lines were generated. These Ba/F3 cells could proliferate in the absence of IL3, and the mutated receptors were auto-phosphorylated in the absence of FLT3 ligand stimulation, with resulting constitutive activation of STAT5 and ERK kinases. Exposure to the FLT3 inhibitor PKC412 (Novartis Pharma AG), resulted in an inhibition of the growth of both Ba/F3- FLT3-Y572N and Ba/F3- FLT3-Y572V cells with an IC50 of 5 nM; reduced autophosphorylation of the mutant receptors, and inhibited STAT5 and ERK phosphorylation. These results demonstrate that, like ITD mutations in the JM domain, the mutations of Y572 are sufficient to confer constitutive kinase activity to the receptor, and suggest that any mutation that interferes with the ability of FLT3 to maintain an inactive configuration of the JM/kinase domain is likely to be transforming.
Stanniocalcin 1 is a phagocytosis checkpoint driving tumor immune resistance
Authors: Heng Lin, Ilona Kryczek, Shasha Li, Michael D. Green, Alicia Ali, Reema Hamasha, Shuang Wei, Linda Vatan, Wojciech Szeliga, Sara Grove, Xiong Li, Jing Li, Weichao Wang, Yijian Yan, Jae Eun Choi, Gaopeng Li, Yingjie Bian, Ying Xu, Jiajia Zhou, Jiali Yu, Houjun Xia, Weimin Wang, Ajjai Alva, Arul M. Chinnaiyan, Marcin Cieslik, Weiping Zou
Journal: Cancer Cell (2021)
Missing the Forest for the Trees
Authors: Marianne Cloeren
Journal: Annals of Internal Medicine (2021)

On Being a PatientJanuary 2021Missing the Forest for the TreesMarianne Cloeren, MD, MPHMarianne Cloeren, MD, MPHUniversity of Maryland School of Medicine, Baltimore, MarylandAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/M20-0706 Audio Reading - "Missing the Forest for the Trees" Audio. Michael A. LaCombe, MD, Annals Associate Editor, reads "Missing the Forest for the Trees" by Marianne Cloeren, MD, MPH Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail One evening in September 2017, I found myself alternately covering my eyes and trying to make out the words on my phone. I couldn't see well enough to read or even watch television, and my eyes hurt all the time. I was not yet 60 years old and was 6 months into a prized and exciting academic position but was now facing the real possibility of work disability due to increasing vision impairment. I was scared.In February 2016, I agreed to a left epiretinal peel to correct warped vision and decreased acuity after a vitreous detachment. The retinal specialist ... Author, Article, and Disclosure InformationAffiliations: University of Maryland School of Medicine, Baltimore, MarylandCorresponding Author: Marianne Cloeren, MD, MPH, 11 South Paca Street, Suite 200, Baltimore, MD 21201; e-mail, [email protected]umaryland.edu. PreviousarticleNextarticle Advertisement Audio Reading - "Missing the Forest for the Trees" Audio. Michael A. LaCombe, MD, Annals Associate Editor, reads "Missing the Forest for the Trees" by Marianne Cloeren, MD, MPH Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ FiguresReferencesRelatedDetails Metrics January 2021Volume 174, Issue 1Page: 122-123KeywordsCataract surgeryCorneaDisabilitiesGlaucomaInflammationOphthalmologySurgeryVisionVisual acuityWalking ePublished: 19 January 2021 Issue Published: January 2021 Copyright & PermissionsCopyright © 2021 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
AB1233 GENDER DIFFERENCE IN DISEASE SEVERITY AND TREATMENT OUTCOMES AMONG PATIENTS WITH RHEUMATOID ARTHRITIS (RA), AXIAL SPONDYLOARTHRITIS (AXSPA) AND PSORIATIC ARTHRITIS (PSA) STARTING TREATMENT WITH TARGETED THERAPY IN THE CZECH REPUBLIC
Authors: J. Zavada, L. Nekvindova, K. Pavelka, P. Horak, J. Vencovský
Journal: Annals of the Rheumatic Diseases (2020)

Background: The ATTRA registry captures more than 95% of patients with RA, AxSpA, or PSA treated with biologics in the Czech Republic (CZ). In CZ, anti-TNF therapy is reimbursed for RA if DAS28&gt;5.1 despite therapy with csDMARDs, for PSA if disease is not “adequately controlled” with csDMARDs and for AS if BASDAI&gt;4 and CRP/ESR elevated above normal. Objectives: We aimed to investigate gender-related differences in baseline characteristics and treatment effectiveness among patients with RA, AxSpa, and PsA starting first targeted therapy (TT) in CZ. Methods: In this observational cohort study, the ATTRA register provided prospectively collected data on RA, AxSpA and PsA patients who initiated their first TT (mostly by TNFi) in 2012–6/2018. Treatment effectiveness and adherence was assessed at 12 months by a change in patient-reported outcomes (PROs), CRP and % drug survival. Differences in categorical and continuous data btw males and females were assessed using the Pearson X 2 test (of Fisher exact test, as appropriate), or Mann-Whitney test resp. This study was largely descriptive, and no statistical adjustments have been made. Results: A total of 1602 RA, 1306 AxSpa, and 493 PsA patients were included. The difference in baseline characteristics btw women and men starting TT are shown in table 1. Their response and adherence to TT after one year is shown in table 2. Conclusion: When starting their first TT, males tended to have higher levels of CRP, while females were more often (ex)smokers and reported worse parameters of quality of life across the diagnostic groups. The improvement of PROs was similar in males and females, while males with axSpA and PsA showed larger improvements in CRP. Survival on drug at one year was similar, save for AxSpA, where males showed better survival. References: Acknowledgments: Supported by project 00023728 of Ministry of Health, CZ Disclosure of Interests: Jakub Zavada Speakers bureau: Abbvie, UCB, Sanofi, Elli-Lilly, Novartis, Zentiva, Accord, Lucie Nekvindova: None declared, Karel Pavelka Consultant of: Abbvie, MSD, BMS, Egis, Roche, UCB, Medac, Pfizer, Biogen, Speakers bureau: Abbvie, MSD, BMS, Egis, Roche, UCB, Medac, Pfizer, Biogen, Pavel Horak Speakers bureau: Pfizer, Abbvie, Eli lilly. Novartis, Roche, Sanofi, Jiří Vencovský: None declared
A Graded, Porous Composite of Natural Biopolymers and Octacalcium Phosphate Guides Osteochondral Differentiation of Stem Cells
Authors: Elisabeth Amann, Amisel Amirall, Albina R. Franco, Patrina S. P. Poh, Francisco J. Sola Dueñas, Gastón Fuentes Estévez, Isabel B. Leonor, Rui L. Reis, Martijn van Griensven, Elizabeth R. Balmayor
Journal: Advanced Healthcare Materials (2021)

Lesions involving the osteochondral unit are difficult to treat. Biomimetic scaffolds are previously shown as promising alternative. Such devices often lack multiple functional layers that mimic bone, cartilage, and the interface. In this study, multilayered scaffolds are developed based on the use of natural extracellular matrix (ECM)-like biopolymers. Particular attention is paid to obtain a complex matrix that mimics the native osteochondral transition. Porous, sponge-like chitosan-collagen-octacalcium phosphate (OCP) scaffolds are obtained. Collagen content increases while the amount of OCP particles decreases toward the cartilage layer. The scaffolds are bioactive as a mineral layer is deposited containing hydroxyapatite at the bony side. The scaffolds stimulate proliferation of human adipose-derived mesenchymal stem cells, but the degree of proliferation depends on the cell seeding density. The scaffolds give rise to a zone-specific gene expression. RUNX2, COL1A1, BGLAP, and SPP1 are upregulated in the bony layer of the scaffold. SOX9 is upregulated concomitant with COL2A1 expression in the cartilage zone. Mineralization in presence of the cells is prominent in the bone area with Ca and P steadily increasing over time. These results are encouraging for the fabrication of biomimetic scaffolds using ECM-like materials and featuring gradients that mimic native tissues and their interface.
SAT0169 Influence of vitamin d receptor (vdr) genotype in the bone loss induced by corticosteroid therapy
Authors: M Gantes, A Arteaga, Y Barrios, E Uruburu, I Ferraz, B Rodríguez-Lozano, A Alvarez, E Trujillo, T González
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Corticosteroid therapy (CST) is a risk factor for developing decreased bone mineral density (BMD). Previous studies suggest that VDR genotipe is involved on loossing BMD. <h3>Objectives</h3> To investigate the influence of VDR genotype in changes of BMD induced by CST. <h3>Methods</h3> In 53 patients (age 41,7 ± 12,6) without osteoporosis, who received a dose greater than 5 mg daily of prednisone or equivalent for 3 months (mean dose 1,9 g). VDR genotypes were determined by PCR to demonstrate the presence (b) or absence (B) of a restriction target for Bsm I, in intron 7. Bone mineral density (BMD) by DEXA at spine, femoral neck (FN) and Ward´s triangle (WT) were measured baseline and 3 months after CST and expressed as a Z- score. <h3>Results</h3> The BMD was reduced 3 months after CST (cumulative steroid dosage, mass index, and age was adjusting) without significant difference in both VDR groups: bb, and bB-BB; (Z- score before/3 months after) at Spine: 0,40/0,17 bb; 0,32/0,10 bB-BB; FN: 0,87/0,75 bb; 0,40/0,15 bB-BB; WT: 0,84/0,86 bb; 0,22/0,14 bB-BB. However, when the patients were adjusting to receive more or lesser than 1,3 g cumulative dose, those patients had bb genotype and greater dose had significant lower BMD at WT (p &lt; 0,05), respective bB- BB genotypes. <h3>Conclusion</h3> Data suggest that the VDR genotype identifies the patients with greater risk to bone loss when high corticosteroids dose is used.
MEKiAUTO: A phase I/II open-label study of combination therapy with the MEK inhibitor cobimetinib, Immune-checkpoint blockade with atezolizumab, and the AUTOphagy inhibitor hydroxychloroquine in <i>KRAS</i>-mutated advanced malignancies.
Authors: Alexander Raufi, Winston Wong, Shing Mirn Lee, Gulam Abbas Manji
Journal: Journal of Clinical Oncology (2021)

TPS450 Background: Pancreatic ductal adenocarcinoma (PDAC) and colorectal carcinoma (CRC) are aggressive diseases which account for the third and second leading causes of cancer-related death, respectively. Limited progress has been made towards effective treatments or cure. K RAS is mutated or amplified in nearly 30% of all cancers, including up to 95% of PDAC and 45% of CRC. Although no successful KRAS directed therapy has been approved to date, data has emerged demonstrating that inhibition of downstream targets of KRAS, namely MEK/ERK, increases autophagic flux in KRAS-mutated tumors. This catabolic process is used by many tumors to maintain viability and recent preclinical studies have shown that combining MEK/ERK and autophagy inhibitors in KRAS-mutated tumors can synergistically suppress cancer cell proliferation. Inhibition of autophagy has demonstrated an increase in antigen presentation which sensitize tumors to immune checkpoint inhibitors. Presented here is a trial-in-progress that will evaluate combination of cobimetinib (MEK inhibitor), atezolizumab (anti-PDL1), and hydroxychloroquine (autophagy inhibitor) in KRAS-mutated advanced malignancies. Methods: This is a phase 1/2 multicenter, open-label study of combination cobimetinib (40-60mg) orally once daily on days 1-21, hydroxychloroquine (600mg) orally twice daily on days 1-28, and atezolizumab 840 mg IV on days 1 and 15 of each 28 day cycle. Patients with histologically confirmed metastatic or unresectable KRAS-mutant adenocarcinoma for which standard curative or meaningful life-prolonging treatment options do not exist or are no longer effective will be enrolled. The primary objective of the phase I portion of this trial, which seeks to enroll 18 patients, is to estimate the maximum tolerated dose (MTD) of these agents using a two-stage time-to-event continual reassessment method (TITE-CRM). The primary objective of the phase II portion of this trial, which seeks to enroll approximately 66-157 patients, is to evaluate the preliminary efficacy of this combination, based on the objective response by 16 weeks. Secondary endpoints include PFS, OS, and safety. Correlative aims include analyses of pre- and on-treatment biopsies with quantitative multiplex immunofluorescence, RNA-sequencing, reverse phase protein array for association with clinical benefit and to determine mechanisms of action/resistance. An interim analysis will be performed at the conclusion of the phase I portion of the study. This study is open with 4 patients enrolled at the time of submission. Clinical trial information: NCT04214418 . This trial is being conducted as part of the imCORE collaboration. Clinical trial information: NCT04214418.
Pembrolizumab Plus Ipilimumab or Placebo for Metastatic Non–Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score ≥ 50%: Randomized, Double-Blind Phase III KEYNOTE-598 Study
Authors: Michael Boyer, Mehmet A. N. Şendur, Delvys Rodríguez-Abreu, Keunchil Park, Dae Ho Lee, Irfan Çiçin, Perran Fulden Yumuk, Francisco J. Orlandi, Ticiana A. Leal, Olivier Molinier, Nopadol Soparattanapaisarn, Adrian Langleben, Raffaele Califano, Balazs Medgyasszay, Te-Chun Hsia, Gregory A. Otterson, Lu Xu, Bilal Piperdi, Ayman Samkari, Martin Reck
Journal: Journal of Clinical Oncology (2021)

PURPOSE Pembrolizumab monotherapy is standard first-line therapy for metastatic non–small-cell lung cancer (NSCLC) with programmed death ligand 1 (PD-L1) tumor proportion score (TPS) ≥ 50% without actionable driver mutations. It is not known whether adding ipilimumab to pembrolizumab improves efficacy over pembrolizumab alone in this population. METHODS In the randomized, double-blind, phase III KEYNOTE-598 trial (ClinicalTrials.gov identifier: NCT03302234 ), eligible patients with previously untreated metastatic NSCLC with PD-L1 TPS ≥ 50% and no sensitizing EGFR or ALK aberrations were randomly allocated 1:1 to ipilimumab 1 mg/kg or placebo every 6 weeks for up to 18 doses; all participants received pembrolizumab 200 mg every 3 weeks for up to 35 doses. Primary end points were overall survival and progression-free survival. RESULTS Of the 568 participants, 284 were randomly allocated to each group. Median overall survival was 21.4 months for pembrolizumab-ipilimumab versus 21.9 months for pembrolizumab-placebo (hazard ratio, 1.08; 95% CI, 0.85 to 1.37; P = .74). Median progression-free survival was 8.2 months for pembrolizumab-ipilimumab versus 8.4 months for pembrolizumab-placebo (hazard ratio, 1.06; 95% CI, 0.86 to 1.30; P = .72). Grade 3-5 adverse events occurred in 62.4% of pembrolizumab-ipilimumab recipients versus 50.2% of pembrolizumab-placebo recipients and led to death in 13.1% versus 7.5%. The external data and safety monitoring committee recommended that the study be stopped for futility and that participants discontinue ipilimumab and placebo. CONCLUSION Adding ipilimumab to pembrolizumab does not improve efficacy and is associated with greater toxicity than pembrolizumab monotherapy as first-line treatment for metastatic NSCLC with PD-L1 TPS ≥ 50% and no targetable EGFR or ALK aberrations. These data do not support use of pembrolizumab-ipilimumab in place of pembrolizumab monotherapy in this population.