tbuckley/cabot-search huggingface dataset:
Results of conversion surgery after the triple combination chemotherapy of SOXIRI (S-1/oxaliplatin/irinotecan) in patients with unresectable pancreatic cancer.
Authors: Naoya Ikeda, Takahiro Akahori, Sohei Satoi, Hiroaki Yanagimoto, Minako Nagai, Kenji Nakagawa, Satoshi Nishiwada, Kota Nakamura, Tadataka Takagi, Satoshi Hirooka, Tomohisa Yamamoto, So Yamaki, Masayuki Sho
Journal: Journal of Clinical Oncology (2019)

366 Background: Recent improvements in chemotherapy for initially unresectable pancreatic ductal adenocarcinoma (UPDAC) occasionally show remarkable antitumor effect and lead to conversion surgery (CS). However, the optimal indication and clinical impact of CS remains unknown. We have recently developed a new regimen consisted of biweekly S-1, oxaliplatin, and irinotecan (SOXIRI). In this regimen, we used S-1 in alternate-day administration instead of 5-FU, that can be more feasible than FOLFIRINOX. The aim of this study was to evaluate the clinical impact of CS after SOXILI treatment for initially UPDAC. Methods: We conducted an open-label, single-arm, phase II study that was carried out at Nara Medical University and Kansai Medical University in Japan. Patients with untreated metastatic and locally advanced PDAC were enrolled. They received 80 mg/m 2 twice a day of S-1 for 2 weeks in alternate-day administration, 150 mg/m 2 of irinotecan on day 1, and 85 mg/m 2 of oxaliplatin on day 1 of a 2-week cycle. Results: The 35 enrolled patients received a median of six (range: 2-15) treatment cycles. The RR was 22.8%; median OS, 17.7 months; and median PFS, 7.4 months. Major grade 3 or 4 toxicity included neutropenia (54%), anemia (17%), febrile neutropenia (11%), anorexia (9%), diarrhea (9%), and nausea (9%). Twenty-three out of 35 patients of UR-PDAC were unresectable locally advanced pancreatic cancer (UR-LAPA). Seven out of 23 patients with UR-LAPA underwent CS. Distal pancreatectomy with celiac axis resection was performed in three patients, central pancreatectomy was performed in one patient. Pancreatoduodenectomy (PD) was performed in two patients, and PD with portal vein resection in one patient. Two out of seven patients had postoperative complications. One case had grade B pancreatic fistula, and the other case underwent cholecystectomy due to acute cholecystitis. The median OS in patients who received CS was 31.4 months. Conclusions: SOXIRI regimen has shown promising clinical efficacy with acceptable tolerability in patients with unresectable pancreatic cancer. Furthermore, it may be a potent first-line treatment when considering conversion surgery. Clinical trial information: UMIN000014339.
The value of lymphadenectomy in esophageal cancer after neoadjuvant chemoradiation.
Authors: Basem Azab, Francisco Igor Macedo, Omar Picado, Caroline Ripat, Dido Franceschi, Alan S Livingstone, Danny Yakoub
Journal: Journal of Clinical Oncology (2019)

79 Background: There are conflicting reports on the value of the extent of post neoadjuvant chemoradiation (NCRT) lymphadenectomy (LND) in locally advanced esophageal adenocarcinoma (E-ADC) and squamous cell carcinoma (E-SCC). We sought to study the impact of LND variables [positive and total lymph node (LN) number and LN ratio (LNR)] on oncological outcomes in these patients. Methods: The National Cancer Data Base 2004-2014 was queried for patients with NCRT followed by esophagectomy. The median examined LN number was used to divide the patients into a higher (&gt; 12) and lower (≤ 12) LND groups. The primary outcome was overall survival (OS) and secondary outcomes were 30- and 90-day postoperative mortality. Results: A total 4708 patients were included. The median of positive, negative LN, and LNR were and (0, 11, 0%). The median and 5-year OS for higher LND group were higher than the lower LND group (39 vs. 32 months, 38% vs. 34%), p &lt; 0.0001. OS was not significantly different among E-SCC subset or among those who achieved pathological complete response (pCR). The higher LND group had better 30- and 90-day postoperative mortality rates (61/2335 = 2.6%, 141/2308 = 6.1%) than lower LND group (86/2262 = 3.8%, 184/2251 = 8.2%), p = 0.01 and 0.001, respectively . In multivariate Cox regression analysis, higher LND group (HR 0.88, 95% CI 0.81-0.96, p = 0.004) and LNR (per 10% increase: 1.11, 95% CI 1.09-1.13, p &lt; 0.0001) were significant predictor of OS. Conclusions: The LND (&gt; 12 examined LN) remains as a crucial treatment goal after NCRT with potential survival benefit, especially among E-ADC and those did not achieve pCR.
Stereotactic radiosurgery with concurrent HER2-directed therapy is associated with improved objective response for breast cancer brain metastasis
Authors: Joseph M Kim, Jacob A Miller, Rupesh Kotecha, Samuel T Chao, Manmeet S Ahluwalia, David M Peereboom, Alireza M Mohammadi, Gene H Barnett, Erin S Murphy, Michael A Vogelbaum, Lilyana Angelov, Jame Abraham, Halle Moore, G Thomas Budd, John H Suh
Journal: Neuro-Oncology (2019)

Patients with breast cancer positive for human epidermal growth factor receptor 2 (HER2) remain at high risk of intracranial relapse following treatment and experience increased rates of intracranial failure after stereotactic radiosurgery (SRS). We hypothesized that the addition of concurrent lapatinib to SRS would improve intracranial complete response rates. Patients with newly diagnosed HER2-amplified breast cancer brain metastases from 2005–2014 who underwent SRS were included and divided into 2 cohorts based on timing of treatment with lapatinib. Outcome variables included the proportion of patients who achieved an intracranial complete response or progressive disease according to the RECIST 1.1 criteria, as well as individual lesion response rates, distant intracranial failure, and radiation necrosis. Eighty-four patients with 487 brain metastases met inclusion criteria during the study period. Over 138 treatment sessions, 132 lesions (27%) were treated with SRS and concurrent lapatinib, while 355 (73%) were treated with SRS without lapatinib. Compared with patients treated with SRS alone, patients treated with concurrent lapatinib had higher rates of complete response (35% vs 11%, P = 0.008). On a per-lesion basis, best objective response was superior in the concurrent lapatinib group (median 100% vs 70% reduction, P < 0.001). Concurrent lapatinib was not associated with an increased risk of grade 2+ radiation necrosis (1.0% with concurrent lapatinib vs 3.5% without, P = 0.27). Lapatinib had no protective effect on distant intracranial failure rates (48% vs 49%, P = 0.91). The addition of concurrent lapatinib to SRS was associated with improved complete response rates among patients with HER2-positive brain metastases.
Robust CTCF-Based Chromatin Architecture Underpins Epigenetic Changes in the Heart Failure Stress–Gene Response
Authors: Dominic Paul Lee, Wilson Lek Wen Tan, Chukwuemeka George Anene-Nzelu, Chang Jie Mick Lee, Peter Yiqing Li, Tuan Danh Anh Luu, Cheryl Xueli Chan, Zenia Tiang, Shi Ling Ng, Xingfan Huang, Motakis Efthymios, Matias I. Autio, Jianming Jiang, Melissa Jane Fullwood, Shyam Prabhakar, Erez Lieberman Aiden, Roger Sik-Yin Foo
Journal: Circulation (2019)

The human genome folds in 3 dimensions to form thousands of chromatin loops inside the nucleus, encasing genes and cis-regulatory elements for accurate gene expression control. Physical tethers of loops are anchored by the DNA-binding protein CTCF and the cohesin ring complex. Because heart failure is characterized by hallmark gene expression changes, it was recently reported that substantial CTCF-related chromatin reorganization underpins the myocardial stress-gene response, paralleled by chromatin domain boundary changes observed in CTCF knockout.We undertook an independent and orthogonal analysis of chromatin organization with mouse pressure-overload model of myocardial stress (transverse aortic constriction) and cardiomyocyte-specific knockout of Ctcf. We also downloaded published data sets of similar cardiac mouse models and subjected them to independent reanalysis.We found that the cardiomyocyte chromatin architecture remains broadly stable in transverse aortic constriction hearts, whereas Ctcf knockout resulted in ≈99% abolition of global chromatin loops. Disease gene expression changes correlated instead with differential histone H3K27-acetylation enrichment at their respective proximal and distal interacting genomic enhancers confined within these static chromatin structures. Moreover, coregulated genes were mapped out as interconnected gene sets on the basis of their multigene 3D interactions.This work reveals a more stable genome-wide chromatin framework than previously described. Myocardial stress-gene transcription responds instead through H3K27-acetylation enhancer enrichment dynamics and gene networks of coregulation. Robust and intact CTCF looping is required for the induction of a rapid and accurate stress response.
Invariant Natural Killer T Cell Subsets Have Diverse Functions: iNKT2 and iNKT17 Protect from Graft-Versus-Host-Disease, Whereas iNKT1 Have Antitumor Potential
Authors: Kristina Maas-Bauer, Federico Simonetta, Toshihito Hirai, Arielle Wenokur, Furqan Fazal, Neeraja Kambham, Jessica Ribado, Melissa Mavers, Jeanette Baker, Ami S. Bhatt, Howard Y. Chang, Robert S. Negrin
Journal: Blood (2018)
Abstract 16551: Pathways of Prognosis and Effective Treatment Interventions in Hypertrophic Cardiomyopathy
Authors: Barry Maron, Ethan J Rowin, Susan A Casey, Martin S Maron
Journal: Circulation (2015)

Background: Hypertrophic cardiomyopathy (HCM) is a genetic heart disease with diverse clinical course, including extended periods of stability and possibly normal longevity, but also major complications for which there are now effective therapeutic options. The proportion of patients with sudden death (SD), heart failure progression, or atrial fibrillation/stroke within established cohorts and likelihood that patients incur multiple disease pathways during their clinical course is unknown. Methods: We studied 1893 consecutive HCM patients (40 ± 19 years) from the Minneapolis Heart Institute/Tufts Medical Center, over average follow-up of 10.7 years, and identified 3 hallmark endpoints and disease complication pathways: (1) SD or an appropriate ICD intervention for VT/VF; (2) progression of heart failure to NYHA class III/IV refractory to drugs; (3) ≥1 episode or persistent atrial fibrillation (AF). Results: Of 1893 patients, 953 (50%) survived without reaching any endpoint or requiring major interventions, and were in NYHA class I/II at follow-up. Another 680 patients (36%) progressed along 1 major adverse disease pathway, most commonly progressive heart failure (n=376) due to outflow obstruction or diastolic dysfunction, or AF (n=233), or SD events (n=71). Only 237 patients (13%) experienced 2 major complication pathways, most commonly AF or progressive heart failure unrelated to AF (n=198); and 23 patients (1%) incurred all 3 adverse pathways. Of the 1893 patients, 70 (3%) died of HCM, with 5-year and 10-year survival, 98% and 94%, and 1693 patients (89%) were in class I/II at follow-up. HCM mortality was: 1 adverse disease pathway: 7%, 2 pathways: 8%, 3 pathways: 26% (p=0.002 for 3 pathways). Conclusion: In this referral-based HCM population, almost 90% of patients had a benign clinical course or reached one major end-point associated with effective management options. Evolution along 2 or 3 disease pathways was uncommon (14%), but also amenable to treatment, although mortality was highest in patients with 3 complications. With contemporary management strategies, HCM has become a treatable disease with low overall mortality (0.5%/year).
Olopatadine/Mometasone Combination Nasal Spray for the Treatment of Seasonal Allergic Rhinitis: A Pooled Analysis of Efficacy and Safety
Authors: Gary N. Gross, Niran J. Amar, Nelumka Fernando, Cynthia F. Caracta, Sudeesh K. Tantry
Journal: Journal of Allergy and Clinical Immunology (2019)
Individual-level and country-level socioeconomic determinants of disease outcomes in SpA: multinational, cross-sectional study (ASAS-COMOSPA)
Authors: Polina Putrik, Sofia Ramiro, Anna Moltó, Andras P Keszei, Sam Norton, Maxime Dougados, Désirée van der Heijde, Robert B M Landewé, Annelies Boonen
Journal: Annals of the Rheumatic Diseases (2019)

Objective To explore the independent contribution of individual-level and country level socioeconomic status (SES) determinants to disease activity and physical function in patients with spondyloarthritis (SpA). Methods Data from the cross-sectional, multinational (n=22 countries worldwide) COMOSPA (COMOrbidities in SpA) study were used. Contribution of individual SES factors (gender, education) and country of residence to Ankylosing Spondylitis Disease Activity Score (ASDAS) and Bath Ankylosing Spondylitis Functional Index (BASFI) was explored in multilevel regression models, adjusting for clinical and demographic confounders. Next, the additional effects of national macroeconomic indicators (gross domestic product [GDP], Human Development Index, healthcare expenditure and Gini index) were explored. The mediating role of uptake of biologic disease-modifying antirheumatic drugs between education or GDP and ASDAS was explored by testing indirect effects. Results In total, 3370 patients with SpA were included: 65% were male, with a mean age of 43 (SD 14), ASDAS of 2.0 (SD 1.1) and BASFI score of 3.1 (SD 2.7). In adjusted models, patients with low education and female patients had an OR of 1.7 (95% CI 1.3 to 2.2) and an OR of 1.7 (95% CI 1.4 to 2.0), respectively, of having ASDAS ≥2.1. They also reported slightly worse function. Large country differences were observed independent of individual SES and clinical confounders. Patients from less SES developed countries have worse ASDAS, while patterns for BASFI were insignificant. Uptake of biologicals did not mediate the relationship between individual-level or country-level SES and disease activity. Conclusions Individual-level and country-level health inequalities exist also among patients with SpA. Women and lower educated persons had worse disease activity and somewhat worse physical function. While patients in less socioeconomically developed countries had higher disease activity, they reported similar physical function.
uPAR isoform 2 forms a dimer and induces severe kidney disease in mice
Authors: Changli Wei, Jing Li, Brian D. Adair, Ke Zhu, Jian Cai, Michael Merchant, Beata Samelko, Zhongji Liao, Kwi Hye Koh, Nicholas J. Tardi, Ranadheer R. Dande, Shuangxin Liu, Jianchao Ma, Salvatore Dibartolo, Stefan Hägele, Vasil Peev, Salim S. Hayek, David J. Cimbaluk, Melissa Tracy, Jon Klein, Sanja Sever, Sanford J. Shattil, M. Amin Arnaout, Jochen Reiser
Journal: Journal of Clinical Investigation (2019)

Soluble urokinase plasminogen activator receptor (suPAR) is an immune-derived circulating signaling molecule that has been implicated in chronic kidney disease, such as focal segmental glomerulosclerosis (FSGS). Typically, native uPAR (isoform 1) translates to a 3-domain protein capable of binding and activating integrins, yet the function of additional isoforms generated by alternative splicing is unknown. Here, we characterized mouse uPAR isoform 2 (msuPAR2), encoding domain I and nearly one-half of domain II, as a dimer in solution, as revealed by 3D electron microscopy structural analysis. In vivo, msuPAR2 transgenic mice exhibited signs of severe renal disease characteristic of FSGS with proteinuria, loss of kidney function, and glomerulosclerosis. Sequencing of the glomerular RNAs from msuPAR2-Tg mice revealed a differentially expressed gene signature that includes upregulation of the suPAR receptor Itgb3, encoding β3 integrin. Crossing msuPAR2-transgenic mice with 3 different integrin β3 deficiency models rescued msuPAR2-mediated kidney function. Further analyses indicated a central role for β3 integrin and c-Src in msuPAR2 signaling and in human FSGS kidney biopsies. Administration of Src inhibitors reduced proteinuria in msuPAR2-transgenic mice. In conclusion, msuPAR2 may play an important role in certain forms of scarring kidney disease.
Lenalidomide in combination with intravenous rituximab (REVRI) in relapsed/refractory primary CNS lymphoma or primary intraocular lymphoma: a multicenter prospective ‘proof of concept’ phase II study of the French Oculo-Cerebral lymphoma (LOC) Network and the Lymphoma Study Association (LYSA)
Authors: H. Ghesquieres, M. Chevrier, M. Laadhari, O. Chinot, S. Choquet, C. Moluçon-Chabrot, P. Beauchesne, R. Gressin, F. Morschhauser, A. Schmitt, E. Gyan, K. Hoang-Xuan, E. Nicolas-Virelizier, N. Cassoux, V. Touitou, M. Le Garff-Tavernier, A. Savignoni, I. Turbiez, V. Soumelis, C. Houillier, C. Soussain
Journal: Annals of Oncology (2019)
Rationing of Health Care in the United States
Authors: Howard Bauchner
Journal: JAMA (2019)

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Abstract 18375: Inflammatory Macrophage Expansion in Pulmonary Hypertension Depends Upon Mobilization of Blood-borne Monocytes
Authors: Jonathan Florentin, Emilie Coppin, Sathish Babu Vasamsetti, Ying Tang
Journal: Circulation (2017)

Introduction: Pulmonary inflammation has been proposed as a key pathogenic driver of pulmonary hypertension (PH), vascular disease with increasing global significance. Perivascular macrophages have been observed in the lungs of PH patients. However, the mechanisms of expansion of lung macrophages and the role of blood-borne monocytes in PH are poorly understood. Hypothesis: We hypothesize that increased monocyte recruitment and differentiation in the lungs augment inflammatory macrophage content and vascular remodeling in PH. Methods: We recapitulated PH in both hypoxic mouse and monocrotaline injected rat models. We enumerated blood and lung myeloid cell populations in mouse and rat as well as in PH patients using multicolor flow cytometric analysis. To track the origin of lung macrophages, we surgically joined congenically different hypoxic mice (parabiosis). To evaluate the importance of monocyte recruitment to the lungs we reduced monocyte number in two separate rodent models of PH - via genetic defic...
Cereblon-binding proteins expression levels correlate with hyperdiploidy in newly diagnosed multiple myeloma patients
Authors: Katharina Kriegsmann, Marc-Andrea Baertsch, Mohamed H. S. Awwad, Maximilian Merz, Dirk Hose, Anja Seckinger, Anna Jauch, Natalia Becker, Axel Benner, Marc S. Raab, Jens Hillengass, Uta Bertsch, Jan Dürig, Hans Jürgen Salwender, Mathias Hänel, Roland Fenk, Markus Munder, Katja Weisel, Carsten Müller-Tidow, Hartmut Goldschmidt, Michael Hundemer
Journal: Blood Cancer Journal (2019)

Abstract Immunomodulatory drugs (IMIDs) are very effective in the treatment of multiple myeloma (MM). The description of their cereblon-mediated mechanism of action was a hallmark in MM research. Although the importance of IMID-induced degradation of cereblon-binding proteins is well described in vitro, the prognostic value of their expression levels in MM cells is less clear. Based on recently published data showing somewhat conflicting RNA levels, we analyzed the association between the levels of the Ikaros family zinc finger protein 1 (IKZF1), IKZF3, and karyopherin subunit alpha 2 (KPNA2) proteins measured by flow cytometry and prognostic parameters in 214 newly diagnosed MM patients who were randomized in the GMMG HD6 trial. No statistically significant associations between the expression levels and age, gender, light chain type, International Staging System (ISS) stage or cytogenetic high- and normal risk groups could be identified. Hyperdiploid MM cells expressed significantly higher levels of IKZF1, IKZF3 and KPNA2 than nonhyperdiploid cells. In contrast, translocation t(11;14) was associated with significantly lower expression levels. In conclusion, the observed overexpression of cereblon-binding proteins in MM cells with gain of chromosomes 5, 9, 11, 15, and 19 is consistent with the previously proposed positive regulation of MYC by IKZF1 and IKZF3, as well as MYC activation in hyperdiploid MM cells.
Corneal Higher-Order Aberrations in Descemet Membrane Endothelial Keratoplasty versus Ultrathin DSAEK in the Descemet Endothelial Thickness Comparison Trial
Authors: Matthew J. Duggan, Jennifer Rose-Nussbaumer, Charles C. Lin, Ariana Austin, Paula C. Labadzinzki, Winston D. Chamberlain
Journal: Ophthalmology (2019)