tbuckley/cabot-search huggingface dataset:
AB0213 Rare complications of paget’s disease
Authors: C Resende, W Castelão, H Canhão, JE Fonseca, JC Romeu, JA Pereira Silva, M Viana Queiroz
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Paget Disease?s (PD) myelopathy and chondrosarcoma are rare entities. The spinal cord compromise is due to the direct compression of the growing bone and also to spine cord ischaemia. Chondrosarcoma is a rare malign degenerescence of the bone disease. <h3>Objectives</h3> <h3>Methods</h3> <h3>Results</h3> Case&nbsp;1: A 74 years old man with the previous diagnosis of polyostotic PD was admitted to our inpatient Unit with lower limbs paraparesis that began 2 months earlier. He had a spastic gait, lower limbs paresis 4/5, increased patellar and Achilles tendon reflexes (more prominent on the left), extension plantar reflexes, T6/T7 sensory level without sphincteric dysfunction. Both alkaline phosphatase and hydroxyprolinuria were high. Thoracic spine CT scan and MRI showed myelopathy at T5, T6 and T7 due to spine PD compression. Therapy consisted of pamidronate 180 mg (2 infusions of pamidronate 90 mg, 2 weeks apart) and 200 UI i.d. of inhaled calcitonin. After therapy a clear clinical and laboratorial improvement was observed. After 1 year the gait and neurological observation were normal. Case&nbsp;2: A 76 years old woman with PD involving the thoracic spine and iliac bone, was admitted to our Unit with lower limbs paraparesis, nocturnal back pain and right gluteal pain irradiating to the posterior aspect of the thigh with 4 months duration. Neurological evaluation showed paraparesis grade 1–2/5 on the right lower limb and grade 4/5 on the left, decreased right patella reflex and sensory level T12-L1. A large stony mass was palpable in the right iliac fossae and in the gluteal area. Bone turnover markers were high. Spine CT scan and MRI showed myelopathy due to PD vertebrae in T12-L1. Thoracic and abdominal CT scan revealed a bone tumour of the right iliac and pulmonary metastases. Histology of the tumour revealed a chondrosarcoma. She started calcitonin 200 UI i.d. and intravenous dexamethasone 5 mg t.i.d. with neurological improvement. She suffered an episode of sudden death 1 month later at home. <h3>Conclusion</h3> In cases of PD with spinal cord symptoms, PD myelopathy should be the first clinical suspicion. Prompt diagnosis and therapy should be instituted to prevent irreversible neurological damage. Chondrosarcoma is an agressive tumour, non responsive to standard therapies for bone malignancies.
Incidence of early-onset gastric and esophagus cancers has changed over time with disproportionate impact on Black and Hispanic patients.
Authors: Nataly Valeria Torrejon, Suneel Deepak Kamath, Wei Wei, Katherine Tullio, Alok A. Khorana
Journal: Journal of Clinical Oncology (2021)

171 Background: The increased incidence of gastro-esophageal junction adenocarcinoma has been well-described, but how the proportion of early versus older onset cancer has changed over time remains incompletely understood. This study characterized the socioeconomic and pathologic characteristics of early-onset gastro-esophageal malignancies. Methods: All patients with gastric cancer (GC) and esophageal cancer (EC) from 2004-2015 in the National Cancer Database were included and categorized by age under or over 60 years. Differences in demographics, disease stage, treatment characteristics and socioeconomic factors between young and older patients were assessed by Chi-square test. The effect of age, race, insurance status, community median income and community educational attainment on overall survival (OS) were assessed using uni- and multivariable Cox models with Bonferonni correction when indicated. Results: The study population comprised 158,599 patients with GC and 139,210 patients with EC. For GC, 43,146 patients (27.2%) were under age 60. The proportion of patients diagnosed under 60 increased over time: 26.7% in 2004-2006, 26.9% in 2007-2009, 27.6% in 2010-2012 and 27.5% in 2013-2015. Compared to older patients, young patients were more likely to be Black (16.7% vs. 13.2%), Asian (7.6% vs. 6.1%) or Hispanic (15.5% vs. 7.7%), diagnosed with stage 4 disease (43.5% vs. 31.3%) and to have poorly differentiated grade (61% vs. 51.7%), p value &lt; 0.0001 for all. For EC, 38,801 patients (27.8%) were under age 60. The proportion of patients diagnosed under 60, decreased over time: 29.6% in 2004-2006, 28.3% in 2007-2009, 27.6% in 2010-2012 and 26.2 % in 2013-2015. Compared to older patients, young patients were more likely to be Black (12.6% vs. 8.2%) or Hispanic (4.2% vs. 3.1%), diagnosed with stage 4 disease (34.3% vs. 26.1%), p value &lt; 0.0001 for all. There was no difference in histologic grade between younger and older patients (41.1% vs. 40.3%, p = 0.85). Age &lt; 60 years was associated with improved OS in both GC and EC. After adjusting for other demographic, socioeconomic, disease stage and treatment-related factors, Black patients had the worst median OS compared to other races in both malignancies as shown in the Table. Conclusions: Early-onset GC has increased over time while early-onset EC has decreased. Patients with early-onset gastric and esophageal cancer are more likely to be Black or Hispanic and to present with stage 4 cancer. Younger patients with GC are also more likely to have poorly differentiated histology. Most concerning, Black patients have the worst OS compared to other races for both GC and EC. [Table: see text]
Abstract 11513: Wrap Around Left Anterior Descending Coronary Artery in Stress Induced Cardiomyopathy: Fiction, or Reality ?
Authors: Byung-il W Choi, Jee Min, Katheryn Umhoefer
Journal: Circulation (2019)

Introduction: Previous studies demonstrated that a significant number of patients with stress induced cardiomyopathy (SIC) may have coronary artery disease (CAD), albeit hemodynamically insignifica...
Feasibility and evaluation of tele-hepatology services during COVID-19 pandemic in India: An observational study (tele-hep-india study)
Authors: N. Verma, S. Singh, R. Kaur, T. Kaur, A. De, M. Premkumar, S. Taneja, A. Duseja, V. Singh
Journal: Hepatology (2020)

Background: Telemedicine has emerged as an essential tool for health-care delivery amidst the COVID-19 pandemic We evaluated the feasibility and impact of tele-hepatology services in a resource-constrained set-up Methods: Consecutive patients with liver diseases availing tele-hepatology services via smartphone 4G network at a tertiary-care centre were recruited The evaluation was done using an adapted MAST-model (content-validity: 99 3%, reliability: 0 778) in a telephonic-survey design between March and July 2020 The feasibility, impact, and safety of tele-hepatology services were evaluated from a random sample of patients, 7-21 days after the consultation Results: Of 1419 registrations, 1281 consultations (90 3%) were completed with 42 manhours (interquartile range;IQR: 40-44) per tele-OPD Twohundred- ten out of 245 random patients (85 7%) responded during survey [age-in years: 46 (IQR: 35-56) and females: 32 3%] Audio (54 3%) or video-calls (45 7%) were common modes of consultation One-hundred-eighty-six patients (88 6%) were suitable for tele-consultations Diagnosis was achieved in 197 patients (94%) (Table 1) and 173 patients (82 4%) complied with the treatment Patient's satisfactionrate, improvement-rate, and success-rate were 85 2%, 49 5% and 46 2%;respectively  Convenience and confidence in tele-consultation during the prevailing situation were expressed in 208 patients (99 0%) and 176 patients (83 8%);respectively Physical-quality of life (QOL) and mental-QOL was improved in 141 patients (67 1%) and 174 patients (82 8%);respectively Median cost (Indian rupees) and manhour saved per tele-consult were 699 (IQR: 399-2999) and 10 6 (IQR: 6 4-15 1)  Dissatisfied patients were likely to have low diagnosis-rate, unsuitability for tele-consultation, noncompliance to treatment, unsuccessful consultation, poor understanding, and uncomfortable conversation during teleconsultation Twenty-two patients were hospitalised and 3 patients died during follow up and none were related to teleconsultation Patient-reported barriers for tele-consultation were connectivity-issues (22 8%), language-barrier (1 4%), unavailability of smart-phone (1 4%) and reimbursement issues (0 4%) Conclusion: Telemedicine is a feasible, acceptable, and reasonably effective tool for rendering healthcare services utilising limited resources during turbulent times of COVID-19 pandemic Systematic implementation and formal cost-effectiveness of telemedicine should further be explored in hepatology services(Table Presented)
Mechanobiological conditioning of mesenchymal stem cells for enhanced vascular regeneration
Authors: Jason Lee, Kayla Henderson, Miles W. Massidda, Miguel Armenta-Ochoa, Byung Gee Im, Austin Veith, Bum-Kyu Lee, Mijeong Kim, Pablo Maceda, Eun Yoon, Lara Samarneh, Mitchell Wong, Andrew K. Dunn, Jonghwan Kim, Aaron B. Baker
Journal: Nature Biomedical Engineering (2021)
Dysfunctional Keratinocytes Increase Dermal Inflammation in Systemic Sclerosis: Results From Studies Using Tissue‐Engineered Scleroderma Epidermis
Authors: Barbara Russo, Julia Borowczyk, Wolf‐Henning Boehncke, Marie‐Elise Truchetet, Ali Modarressi, Nicolò C. Brembilla, Carlo Chizzolini
Journal: Arthritis & Rheumatology (2021)

Evidence suggests that keratinocyte-fibroblast interactions are abnormal in systemic sclerosis (SSc). The present study was undertaken to investigate potential epidermal dysfunction in SSc and its effects on dermal homeostasis.Epidermal equivalents (EEs) were generated using keratinocytes from 6 healthy donors and 4 individuals with SSc. Skin and EE expression of markers of proliferation, differentiation, and activation was evaluated by immunohistochemistry. The transcriptomic profile of SSc EEs and healthy donor EEs was identified by RNA sequencing. EE conditioned medium (CM) was used to stimulate fibroblasts, and their production of interleukin-6 (IL-6), IL-8, matrix metalloproteinase 1 (MMP-1), type I collagen, and fibronectin was assessed by enzyme-linked immunosorbent assay.Compared to healthy donor EEs, SSc EEs exhibited aberrant differentiation, enhanced expression of activation markers, and a lower rate of basal keratinocyte mitosis, reproducing most of the abnormalities observed in SSc epidermis. RNA sequencing analysis revealed that, compared to healthy donor EEs, SSc EEs were characterized by lower expression of homeobox gene family members and by enhanced metabolic and oxidative stress molecular pathways. EE CM enhanced fibroblast production of IL-6, IL-8, MMP-1, type I collagen, and fibronectin (P < 0.05). Except for type I collagen and fibronectin, this effect was 2-fold higher in the presence of CM generated form SSc EEs. IL-1 was responsible, at least in part, for keratinocyte-dependent fibroblast activation.SSc EEs recapitulate the in vivo characteristics of SSc epidermis, demonstrating that SSc keratinocytes have an intrinsically altered differentiation program, possibly due to the dysregulation of genes from the homeobox family. The increased metabolic and oxidative stress associated with SSc epidermis may contribute to chronic inflammation and fibrosis of the dermis.
Evaluation of the ctDNA LUNAR-2 Test In an Average Patient Screening Episode (ECLIPSE).
Authors: Victoria M. Raymond, Linda Higashi, Enrique Marino, Kathryn Lang
Journal: Journal of Clinical Oncology (2021)

TPS142 Background: Population-wide colorectal cancer (CRC) screening has been recommended by the United States Preventive Task Force (USPSTF) since 2008. Despite multiple CRC screening options, screening compliance rates have plateaued well below the 80% compliance goal set by leading health organizations. Almost 1 in 3 Americans are non-compliant with screening recommendations, citing reasons that screening is time consuming, unpleasant, and in the case of colonoscopy, invasive. The potential exists for a blood-based CRC screening test with high sensitivity and specificity to improve uptake and adherence to CRC screening. Methods: ECLIPSE (Evaluation of the ctDNA LUNAR-2 Test In an Average Patient Screening Episode; NCT# 04136002) is a prospective, observational, multi-center study being conducted in the United States. The primary objective is performance of a proprietary blood-based circulating tumor DNA (ctDNA) test (LUNAR-2, Guardant Health, Redwood City, CA) developed to detect CRC in a screen-relevant, average risk population as compared to colonoscopy reference. ECLIPSE involves collection of whole blood prior to a standard of care screening colonoscopy and associated preparation from 10,000 subjects. Eligibility criteria include average risk adults age 45-84 without prior history of cancer, inflammatory bowel disease, or familial predisposition to CRC, and have not received recent CRC screening. Primary outcomes are sensitivity of CRC detection and specificity of advanced neoplasia (AN) detection. Health-related outcomes at one and two-years will be collected as secondary endpoints to investigate the possibility of incidental non-CRC cases and interval CRC cases that had not reached a clinical threshold for detection at time of colonoscopy. Additional secondary objectives are positive predictive value and negative predictive value for AN detection and sensitivity of advanced adenoma detection. Enrollment began in October 2019, continues at over 130 sites nationwide, and is on track for the 24-month enrollment goal. Study enrollment remained open despite the COVID-19 pandemic. Study features including mobile phlebotomy and remote site monitoring were implemented. This contributed to successful study execution during COVID-19, as demonstrated by the enrollment rebound observed as early as June 2020 which saw higher enrollment than prior months, even pre-COVID. Clinical trial information: NCT# 04136002.
Elevated plasma level of Pentraxin 3 is associated with emphysema and mortality in smokers
Authors: Yingze Zhang, John Tedrow, Mehdi Nouraie, Xiaoyun Li, Divay Chandra, Jessica Bon, Daniel J Kass, Carl R Fuhrman, Joseph K Leader, Steven R Duncan, Naftali Kaminski, Frank C Sciurba
Journal: Thorax (2021)

Background Pentraxin 3 (PTX3) influences innate immunity and inflammation, host defence, the complement cascade and angiogenesis. PTX3 expression in lung and blood of subjects with tobacco exposure, and its potential relationship with disease pattern and clinical outcome are poorly understood. Methods Using independent platforms and cohorts, we identified associations of PTX3 gene expression in lung tissue and plasma from current and former tobacco smokers (with and without chronic obstructive pulmonary disease, COPD) to disease phenotypes including quantitative CT determined emphysema, lung function, symptoms and survival. Two putative regulatory variants of the PTX3 gene were examined for association with COPD manifestations. The relationship between plasma PTX3 and hyaluronic acid levels was further examined. Results PTX3 gene expression in lung tissue was directly correlated with emphysema severity (p&lt;0.0001). Circulating levels of PTX3 were inversely correlated with FEV 1 (p=0.006), and positively associated with emphysema severity (p=0.004) and mortality (p=0.008). Two PTX3 gene regulatory variants were associated with a lower risk for emphysema and expiratory airflow obstruction, and plasma levels of PTX3 and hyaluronic acid were related. Conclusions These data show strong and overlapping associations of lung and blood PTX3 levels, and PTX3 regulatory gene variants, with the severity of airflow obstruction, emphysema and mortality among smokers. These findings have potential implications regarding the pathogenesis of smoking-related lung diseases and warrant further exploration for the use of PTX3 as a predictive biomarker.
Catenin α 1 mutations cause familial exudative vitreoretinopathy by overactivating Norrin/β-catenin signaling
Authors: Xianjun Zhu, Mu Yang, Peiquan Zhao, Shujin Li, Lin Zhang, Lulin Huang, Yi Huang, Ping Fei, Yeming Yang, Shanshan Zhang, Huijuan Xu, Ye Yuan, Xiang Zhang, Xiong Zhu, Shi Ma, Fang Hao, Periasamy Sundaresan, Weiquan Zhu, Zhenglin Yang
Journal: Journal of Clinical Investigation (2021)

Familial exudative vitreoretinopathy (FEVR) is a severe retinal vascular disease that causes blindness. FEVR has been linked to mutations in several genes associated with inactivation of the Norrin/β-catenin signaling pathway, but these account for only approximately 50% of cases. We report that mutations in α-catenin (CTNNA1) cause FEVR by overactivating the β-catenin pathway and disrupting cell adherens junctions. We identified 3 heterozygous mutations in CTNNA1 (p.F72S, p.R376Cfs*27, and p.P893L) by exome sequencing and further demonstrated that FEVR-associated mutations led to overactivation of Norrin/β-catenin signaling as a result of impaired protein interactions within the cadherin-catenin complex. The clinical features of FEVR were reproduced in mice lacking Ctnna1 in vascular endothelial cells (ECs) or with overactivated β-catenin signaling by an EC-specific gain-of-function allele of Ctnnb1. In isolated mouse lung ECs, both CTNNA1-P893L and F72S mutants failed to rescue either the disrupted F-actin arrangement or the VE-cadherin and CTNNB1 distribution. Moreover, we discovered that compound heterozygous Ctnna1 F72S and a deletion allele could cause a similar phenotype. Furthermore, in a FEVR family, we identified a mutation of LRP5, which activates Norrin/β-catenin signaling, and the corresponding knockin mice exhibited a partial FEVR-like phenotype. Our study demonstrates that the precise regulation of β-catenin activation is critical for retinal vascular development and provides new insights into the pathogenesis of FEVR.
Tumor Tissue- versus Plasma-based Genotyping for Selection of Matched Therapy and Impact on Clinical Outcomes in Patients with Metastatic Breast Cancer
Authors: Neelima Vidula, Andrzej Niemierko, Giuliana Malvarosa, Megan Yuen, Jochen Lennerz, A. John Iafrate, Seth A. Wander, Laura Spring, Dejan Juric, Steven Isakoff, Jerry Younger, Beverly Moy, Leif W. Ellisen, Aditya Bardia
Journal: Clinical Cancer Research (2021)

Actionable mutations can guide genotype-directed matched therapy. We evaluated the utility of tissue-based and plasma-based genotyping for the identification of actionable mutations and selection of matched therapy in patients with metastatic breast cancer (MBC).Patients with MBC who underwent tissue genotyping (institutional platform, 91-gene assay) or plasma-based cell-free DNA (cfDNA, Guardant360, 73-gene assay) between January 2016 and December 2017 were included. A chart review of records to identify subtype, demographics, treatment, outcomes, and tissue genotyping or cfDNA results was performed. The incidence of actionable mutations and the selection of matched therapy in tissue genotyping or cfDNA cohorts was determined. The impact of matched therapy status on overall survival (OS) in tissue genotyping or cfDNA subgroups was determined with Cox regression analysis.Of 252 patients who underwent cfDNA testing, 232 (92%) had detectable mutations, 196 (78%) had actionable mutations, and 86 (34%) received matched therapy. Of 118 patients who underwent tissue genotyping, 90 (76%) had detectable mutations, 59 (50%) had actionable mutations, and 13 (11%) received matched therapy. For cfDNA patients with actionable mutations, matched versus nonmatched therapy was associated with better OS [HR 0.41, 95% confidence interval (CI): 0.23-0.73, P = 0.002], and this remained significant in a multivariable analysis correcting for age, subtype, visceral metastases, and brain metastases (HR = 0.46, 95% CI: 0.26-0.83, P = 0.010).Plasma-based genotyping identified high rates of actionable mutations, which was associated with significant application of matched therapy and better OS in patients with MBC.See related commentary by Rugo and Huppert, p. 3275.
Penpulimab (Anti-PD-1) combined with anlotinib as first-line therapy for unresectable hepatocellular carcinoma (uHCC): Updated results from a phase Ib/II study.
Authors: Shun Chang Jiao, LI BAI, Jiahong Dong, Chunmei Bai, Chunhong Hu, Liangfang Shen, Qun Qin, Yuxian Bai, Jia Fan, Aimin Zang, Yanyun Zhu, Chun Han, Juan Li, Pengfei Zhang, Sisi Ye, Xindan Kang, Qian Qiao, Zhongmin Maxwell Wang, Baiyong Li, Yu Xia
Journal: Journal of Clinical Oncology (2021)

306 Background: Combined therapy of an immune checkpoint inhibitor with a targeted antiangiogenic agent had been proved to be effective for the treatment of uHCC. Penpulimab was engineered to eliminate FcγR binding and ADCC/ADCP completely, where ADCC/ADCP effects could induce T-cell apoptosis and clearance and then compromise anti-tumor activity. Penpulimab demonstrated a slower PD-1 antigen binding off-rate, which resulted in better cellular activity and higher receptor occupancy. Penpulimab also showed numerous contacts with N58 glycosylation on the BC loop of PD-1 which could be an advantage to facilitate interaction of PD-1 antibody and might contribute to slower binding off-rate. These structural differentiations offer more robust biological effect and enhance anti-tumor activity of penpulimab. Anlotinib is a multi-targeted tyrosine kinase inhibitor selective for VEGF receptors 1/2/3, FGF receptors 1-4, PDGF receptors α and β, and c-kit. Methods: In this open-label, multicenter phase Ib/II study, patients (pts) without prior systemic treatment, and classified as BCLC stage B (not amenable for locoregional therapy) or C, Child-Pugh ≤7, and ECOG PS ≤ 1 received Penpulimab (200mg IV Q3W) and Anotinib (8 mg PO 2weeks on/1 week off). Primary endpoint was ORR (RECIST v1.1); secondary endpoints were safety, DCR, DoR, TTP, PFS and OS. Results: 31 pts (median age 56 years [23–74], ECOG 0/1 [64%/36%], BCLC B/C [23%/77%], HBV/HCV [61%/7%]) received combined therapy. As of August 31, 2020, median follow-up time was 11.9 mons (range 3.7-17.7). Median PFS was 7.6 mons with 6-mons PFS rate was 57.6% while median TTP was 8.5 mons with 6-mons TTP rate was 62.7%. Median overall survival had not been met and 6-mons OS rate was 93.2%. The ORR was 31.0% (9/29) and DCR was 82.8% (24/29). At data cutoff, 77.8% of responders remained ongoing and still on treatment. Treatment-related adverse events (TRAEs) occurred in 90.3% of pts (≥G3 in 16.1% [5/31], no G5, treatment discontinuation in 9.7% [3/31]). Most common TRAEs (≥15%) were increased AST (38.7%) and ALT (35.5%), increased blood bilirubin (22.6%),asthenia (22.6%),decreased platelet count (19.4%) and rash (16.1%). Conclusions: Penpulimab plus Anlotinib showed favorable antitumor efficacy and an acceptable safety profile in pts with uHCC. The further randomized, phase 3 study of Penpulimab in combination with Anlotinib at a higher dose (10 mg PO 2 weeks on/1 week off) in this setting is ongoing (NCT04344158).