tbuckley/cabot-search huggingface dataset:
Abstract P135: Regional Differences in Epidemiology and Outcomes of Heart Failure Admissions Across the United States
Authors: Akshay Goel, Hakan Paydak, Jawahar Mehta
Journal: Circulation (2019)

Introduction: Periodic surveillance of geographical variations in cardiovascular health is important to achieve the goal of reducing regional disparities in healthcare delivery. We aimed to study differences in epidemiology and outcomes of heart failure admissions by geographic regions in the United States. Hypothesis: We assessed the hypothesis that there exist differences in the outcomes of heart failure admissions based on geographic region. Methods: The National Inpatient Sample database for the year 2016 was queried. Adult patients admitted with a principal diagnosis of heart failure were identified using validated ICD-10 codes. Comparisons were made between four regions - Northeast, Midwest, South and West. Baseline characteristics of heart failure admissions were identified. The main outcomes of interest were inpatient mortality, length of stay and hospital charges. Statistical analysis was performed using STATA. Results: A total of 807,764 hospitalizations with a principal diagnosis of heart failure were identified. Of these, 153,233 (18.97%) were in the Northeast; 184,090 (22.79%) in the Midwest; 331,506 (41.04%) in the South; and 138,935 (17.20%) in the West. The baseline characteristics of these admissions and outcomes of interest are depicted in the table. There was a small difference in the mortality rates (highest in West at 3%, and lowest in South at 2.66%, p=0.03) and length of stay (longest in the Northeast, and shortest in the West, p&lt;0.001) between regions. A significant difference was observed in the total hospital charges per hospitalization (nearly $65,000 in the West, and only $37,000 in the Midwest, p&lt;0.001). The differences in all outcomes persisted after adjusting for variables like age, gender, race and co-morbid conditions. Conclusions: Our study demonstrates the existence of regional differences in the costs and outcomes of healthcare delivery to heart failure patients. Further research is needed to explore the reasons for these differences.
Microfragmented human fat tissue is a natural scaffold for drug delivery: Potential application in cancer chemotherapy
Authors: Giulio Alessandri, Valentina Coccè, Fabio Pastorino, Rita Paroni, Michele Dei Cas, Francesco Restelli, Bianca Pollo, Laura Gatti, Carlo Tremolada, Angiola Berenzi, Eugenio Parati, Anna Teresa Brini, Gianpietro Bondiolotti, Mirco Ponzoni, Augusto Pessina
Journal: Journal of Controlled Release (2019)
Identification of a seasonal pattern to brain metastases.
Authors: Angelos Koutras, Minas Sakellakis, Thomas Makatsoris, Maria Pittaka, Dimitrios Kardamakis, Melpomeni Kalofonou, Haralambos P. Kalofonos, Despina Spyropoulou
Journal: Journal of Clinical Oncology (2015)

e12627 Background: The aim of this retrospective study was to address whether there is a seasonal variability in the diagnosis of brain metastases. Methods: The primary endpoint was to address whether the patients were diagnosed with brain metastases more often during the warm or the cold period of the year. Thus, we divided the year mainly into two equal parts, based on the official meteorological existing data regarding seasonal temperature distribution in our region. The warm period ranges from 15th of April until 15th of October and the cold period from 15th of October until 15th of April, with mean temperatures 23.3oC and 12.4oC, respectively. Results: We found that in our institution, from 2008 until 2013, overall 142 patients developed brain metastases during the cold period of the year, while 199 patients developed metastases during the warm period ( 142 vs 199, p = 0,002 ). This significantly higher diagnosis rates during warm months was mostly evident among patients with colorectal cancer, renal cell cancer and SCLC. Conclusions: Our study provided evidence for the first time, of a seasonality in the incidence of brain metastases, with a predilection toward the warm months of the year.
Discovery and Validation of a Simplified Scoring System (the PRIMA-Prognostic Index) in De Novo Follicular Lymphoma Treated Initially with Immunochemotherapy
Authors: Emmanuel Bachy, Matthew J Maurer, Thomas M Habermann, Benedicte Gelas Dore, Delphine Maucort-Boulch, Jane Estell, E. Van Den Este, Reda Bouabdallah, Andrew L Feldman, Joan Bargay, Alain Jacques Delmer, Susan L Slager, Maria Gomes Silva, Olivier Fitoussi, David Belada, Herve Maisonneuve, Tanin Intragumtornchai, Stephen M Ansell, Thierry Lamy, Peggy Dartigues-Cuillères, Brian K Link, John F Seymour, James R. Cerhan, Gilles Salles
Journal: Blood (2017)
A comprehensive assessment of postoperative complications in female patients undergoing robot versus open radical cystectomy.
Authors: Vikram M Narayan, Mohamed Seif, Amy Lim, Roger Li, Wei Qiao, Hyunsoo Hwang, Colin P.N. Dinney, Neema Navai
Journal: Journal of Clinical Oncology (2019)

490 Background: Radical cystectomy (RC) is the standard of care for non-metastatic, muscle invasive bladder cancer. Studies comparing robotic to open RC have found that the robotic approach confers non-inferior oncologic outcomes while potentially decreasing morbidity, but to date there have been no comparisons performed exclusively within female patients, who have unique anatomic considerations. Women undergoing RC may be at higher risk for urethral margin positivity, wound complications, and bleeding. Methods: Female patients who underwent either open or robot-assisted RC at the MD Anderson Cancer Center from 1/2014-6/2018 were identified. We assessed co-morbidities, pathologic data, and outcomes including complications. Descriptive statistics, along with uni- and multivariable logistic regression, were performed. Results: 122 female patients underwent either open (n=76) or robotic (n=46) RC. There were no statistically significant differences in age, BMI, smoking history, exposure to neoadjuvant chemotherapy, Charlson comorbidity index, or cTNM stages between the groups. In both uni- and multivariable models, open RC in females was associated with greater blood loss (median EBL 775 mL, IQR 600 mL) compared with robotic RC (median EBL 300 mL, IQR 350 mL), p&lt;0.001. Female open RC was also associated with greater risk of transfusion compared to robotic RC (OR 6.2, 95% CI 2.7-14.3, p&lt;0.001). Robotic RC conferred a higher median lymph node yield (27 nodes (range 7,57) vs 20 nodes (0,57), p, &lt;0.001). Operative times were longer in the robotic cohort (median 507 min vs 388 min, p&lt;0.001). There were no differences between robotic vs open groups in margin positivity (5.3% vs 4.4%, p≥0.99), length of stay (6.3 vs 6.9 days, p=0.32), or readmission rates at 30 (26.1% vs 22.7%, p=0.67) and 90 days (32.6% vs 28%, p=0.68). Conclusions: In this cohort of women undergoing RC, the robotic approach was associated with a lower risk of transfusion and EBL, and a higher median lymph node yield and operative time. Unique anatomic considerations in female patients and the improved visualization conferred by the robotic approach may be responsible for these findings, particularly with respect to blood loss.
Tissue factor as an anti-cancer target: inhibition of tumor growth and metastasis by anti-tissue factor monoclonal antibodies blocking factor X activation
Authors: Jinghai Wen, Jin-An Jiao, Kaiping Han, Julie Zaias, Hing C. Wong
Journal: Cancer Research (2005)

699  We report the inhibitory effects of an anti-human tissue factor (TF) monoclonal antibody (mAb, H36, a murine mAb, and hOAT, the humanized form of H36) on primary tumor growth and metastasis in animal models of human cancer. H36/hOAT inhibit TF/FVIIa-dependent activation of Factor X (FX) or FIX by blocking the binding of FX (or IX) to TF or TF/FVIIa complex. The cell lines used in the studies (MDA-MB-435/TF, MCF-7/TF, DU145L1, HT29Lu3 and A375) all express functional human TF. Subcutaneous injection of MCF-7/TF cells resulted in larger primary tumors with extensive blood vessels when compared with MCF-7 parental cells. Matrigel plug assay demonstrated that rhuTF promoted neovascularization and treatment with anti-TF mAb inhibited the process. Complete inhibition or a significant reduction (P
Molecular targets for modulating the protein translation vital to proteostasis and neuron degeneration in Parkinson’s disease
Authors: Zhi Dong Zhou, Thevapriya Selvaratnam, Ji Chao Tristan Lee, Yin Xia Chao, Eng-King Tan
Journal: Translational Neurodegeneration (2019)

Parkinson's disease (PD) is the most common neurodegenerative movement disorder, which is characterized by the progressive loss of dopaminergic neurons in the Substantia Nigra pars compacta concomitant with Lewy body formation in affected brain areas. The detailed pathogenic mechanisms underlying the selective loss of dopaminergic neurons in PD are unclear, and no drugs or treatments have been developed to alleviate progressive dopaminergic neuron degeneration in PD. However, the formation of α-synuclein-positive protein aggregates in Lewy body has been identified as a common pathological feature of PD, possibly stemming from the consequence of protein misfolding and dysfunctional proteostasis. Proteostasis is the mechanism for maintaining protein homeostasis via modulation of protein translation, enhancement of chaperone capacity and the prompt clearance of misfolded protein by the ubiquitin proteasome system and autophagy. Deregulated protein translation and impaired capacities of chaperone or protein degradation can disturb proteostasis processes, leading to pathological protein aggregation and neurodegeneration in PD. In recent years, multiple molecular targets in the modulation of protein translation vital to proteostasis and dopaminergic neuron degeneration have been identified. The potential pathophysiological and therapeutic significance of these molecular targets to neurodegeneration in PD is highlighted.
LRG1 Promotes Diabetic Kidney Disease Progression by Enhancing TGF-β–Induced Angiogenesis
Authors: Quan Hong, Lu Zhang, Jia Fu, Divya A. Verghese, Kinsuk Chauhan, Girish N. Nadkarni, Zhengzhe Li, Wenjun Ju, Matthias Kretzler, Guang-Yan Cai, Xiang-Mei Chen, Vivette D. D’Agati, Steven G. Coca, Detlef Schlondorff, John C. He, Kyung Lee
Journal: Journal of the American Society of Nephrology (2019)

Glomerular endothelial dysfunction and neoangiogenesis have long been implicated in the pathogenesis of diabetic kidney disease (DKD). However, the specific molecular pathways contributing to these processes in the early stages of DKD are not well understood. Our recent transcriptomic profiling of glomerular endothelial cells identified a number of proangiogenic genes that were upregulated in diabetic mice, including leucine-rich α-2-glycoprotein 1 (LRG1). LRG1 was previously shown to promote neovascularization in mouse models of ocular disease by potentiating endothelial TGF-β/activin receptor-like kinase 1 (ALK1) signaling. However, LRG1's role in the kidney, particularly in the setting of DKD, has been unclear.We analyzed expression of LRG1 mRNA in glomeruli of diabetic kidneys and assessed its localization by RNA in situ hybridization. We examined the effects of genetic ablation of Lrg1 on DKD progression in unilaterally nephrectomized, streptozotocin-induced diabetic mice at 12 and 20 weeks after diabetes induction. We also assessed whether plasma LRG1 was associated with renal outcome in patients with type 2 diabetes.LRG1 localized predominantly to glomerular endothelial cells, and its expression was elevated in the diabetic kidneys. LRG1 ablation markedly attenuated diabetes-induced glomerular angiogenesis, podocyte loss, and the development of diabetic glomerulopathy. These improvements were associated with reduced ALK1-Smad1/5/8 activation in glomeruli of diabetic mice. Moreover, increased plasma LRG1 was associated with worse renal outcome in patients with type 2 diabetes.These findings identify LRG1 as a potential novel pathogenic mediator of diabetic glomerular neoangiogenesis and a risk factor in DKD progression.
The role of salvage radiation in recurrent glioblastoma after bevacizumab failure.
Authors: Nehaw Sarmey, Samuel T. Chao, Erin Sennett Murphy, Jennifer S. Yu, David M. Peereboom, Glen Stevens, John H. Suh, Manmeet Singh Ahluwalia
Journal: Journal of Clinical Oncology (2015)

2048 Background: Bevacizumab is FDA-approved for patients with recurrent glioblastoma (GBM). Despite bevacizumab treatment most patients progress, and there are limited therapeutic options for them. We evaluated the role of radiation therapy (RT) after bevacizumab failure in recurrent GBM. Methods: With IRB approval, the Cleveland Clinic’s database was used to identify all recurrent GBM patients who received salvage treatment after initial bevacizumab failure. Patients were stratified by whether or not they received a RT-containing regimen. Kaplan-Meier analysis and log-rank method were used to compare overall survival (OS) and progression-free survival (PFS) from time of initial bevacizumab failure. Univariable and multivariable Cox proportional hazards models were used to assess the association between patient and treatment characteristics and OS. Results: We identified 108 recurrent GBM patients treated after initial bevacizumab failure. Seventeen patients received a RT-based regimen and 91 patients received a non-RT regimen. Of the 17 patients who underwent some form of RT, 5 received RT alone and 12 received RT in combination with other chemo/targeted therapy (11 received RT with bevacizumab). Six patients underwent stereotactic radiosurgery, and 11 patients received fractionated radiation ranging 20 to 60 Gy (4 patients received standard fractionation of 2 Gy per fraction, 6 patients received a hypo-fractionated regimen of > 2 Gy per fraction, and 1 patient’s regimen was unknown). At time of initial bevacizumab failure, both the RT and non-RT groups were similar in age, performance status, and extent of resection. Median OS and PFS for the entire cohort was 6.0 months (95% CI: 5.2, 6.6) and 2.6 months (95% CI: 2.3, 3.1) respectively. The group that received subsequent RT had a statistically significant increase in both OS (8.8 vs 5.4 mos; p = 0.05) and PFS (4.1 vs 2.3 mos; p = 0.006) when compared to the group that did not receive RT. In both univariate and multivariate analyses, only RT use after bevacizumab failure was predictive of OS. Conclusions: In this small cohort, use of salvage RT after bevacizumab failure in recurrent GBM was associated with improved survival. A prospective trial is warranted to confirm this finding.
Early ctDNA dynamics as a surrogate for progression-free survival in advanced breast cancer in the BEECH trial
Authors: S. Hrebien, V. Citi, I. Garcia-Murillas, R. Cutts, K. Fenwick, I. Kozarewa, R. McEwen, J. Ratnayake, R. Maudsley, T.H. Carr, E.C. de Bruin, G. Schiavon, M. Oliveira, N. Turner
Journal: Annals of Oncology (2019)

BackgroundDynamic changes in circulating tumour DNA (ctDNA) levels may predict long-term outcome. We utilised samples from a phase I/II randomised trial (BEECH) to assess ctDNA dynamics as a surrogate for progression-free survival (PFS) and early predictor of drug efficacy.Patients and methodsPatients with estrogen receptor-positive advanced metastatic breast cancer (ER+ mBC) in the BEECH study, paclitaxel plus placebo versus paclitaxel plus AKT inhibitor capivasertib, had plasma samples collected for ctDNA analysis at baseline and at multiple time points in the development cohort (safety run-in, part A) and validation cohort (randomised, part B). Baseline sample ctDNA sequencing identified mutations for longitudinal analysis and mutation-specific digital droplet PCR (ddPCR) assays were utilised to assess change in ctDNA abundance (allele fraction) between baseline and 872 on-treatment samples. Primary objective was to assess whether early suppression of ctDNA, based on pre-defined criteria from the development cohort, independently predicted outcome in the validation cohort.ResultsIn the development cohort, suppression of ctDNA was apparent after 8 days of treatment (P= 0.014), with cycle 2 day 1 (4 weeks) identified as the optimal time point to predict PFS from early ctDNA dynamics. In the validation cohort, median PFS was 11.1 months in patients with suppressed ctDNA at 4 weeks and 6.4 months in patients with high ctDNA (hazard ratio = 0.20, 95% confidence interval 0.083–0.50, P< 0.0001). There was no difference in the level of ctDNA suppression between patients randomised to capivasertib or placebo overall (P= 0.904) nor in the PIK3CA mutant subpopulation (P= 0.071). Clonal haematopoiesis of indeterminate potential (CHIP) was evident in 30% (18/59) baseline samples, although CHIP had no effect on tolerance of chemotherapy nor on PFS.ConclusionEarly on-treatment ctDNA dynamics are a surrogate for PFS. Dynamic ctDNA assessment has the potential to substantially enhance early drug development.Clinical registration numberNCT01625286.
Abstract MP08: Higher Fitness Level and Favorable Hemodynamic Responses to Submaximal Exercise Test in Young Adults are Associated With Lower Risk of Chronic Kidney Disease in Later Life: The Framingham Heart Study
Authors: Joowon Lee, Vanessa Xanthikis, Rebecca Song, Ramachandran S Vasan
Journal: Circulation (2019)

Introduction: Studies have demonstrated that higher cardiorespiratory fitness (CRF) and a favorable heart rate (HR) and blood pressure (BP) response to submaximal exercise, including during the recovery period, are associated with lower cardiovascular disease (CVD) risk. However, there are limited studies examining the association of CRF and hemodynamic response to exercise test with incidence of chronic kidney disease (CKD). Hypothesis: We hypothesized that high CRF and a favorable HR and BP response to submaximal exercise test and during recovery will be associated with lower risk of CKD prospectively. Methods: We evaluated 3,535 Framingham Offspring Study participants (mean age 43.5 yrs, 52.1% women) without CKD, who completed a submaximal exercise test between 1979-1983. CKD incidence was defined as eGFR &lt;60ml/min/1.73m 2 on follow-up. Multivariable-adjusted Cox regression models with discrete time intervals were used to relate CRF and hemodynamic responses to exercise test at baseline with the incidence of CKD on follow-up. Results: At baseline, 23% of participants had chronotropic incompetence and 19.6% had impaired HR recovery after exercise (Δ HR 1 &lt; 12 bpm). On follow-up (median 25.7 years), 801 individuals (22.8%; 434 women) developed CKD. Participants in the second and third tertile of CRF (defined based on age and sex-specific treadmill exercise duration) had lower risk of CKD compared to those in the first tertile of CRF ( Table ). Participants with chronotropic incompetence, higher peak SBP during exercise and impaired HR recovery had higher risk of CKD, compared to those with chronotropic competence, lower peak SBP during exercise, and normal HR recovery post-exercise ( Table ). Conclusions: Higher CRF and favorable HR and BP responses to exercise test in young adulthood may be a marker of lower risk of CKD in later life. The biological mechanisms underlying the observed association warrant further investigation.
Indoleamine 2,3-dioxygenase-1 expression in acute myeloid leukemia.
Authors: Abhishek Avinash Mangaonkar, Ashis Mondal, Kimya Jones, Vamsi Kota, Natasha Savage, Ravindra Kolhe
Journal: Journal of Clinical Oncology (2015)

e18054 Background: Indoleamine 2,3-dioxygenase (IDO) is an enzyme involved in the kynurenine pathway and plays a significant role in tumor-mediated immune tolerance. IDO-1 is the initial isoform of the enzyme and IDO-2 is a splice variant. As with other solid tumors, previous studies with Acute Myeloid Leukemia (AML) have shown a negative correlation of IDO mRNA expression in blast cells and survival; however, IDO-1 protein expression has not been studied before. Methods: We collected formalin-fixed, paraffin-embedded (FFPE) bone marrow specimens at the time of initial diagnosis from 40 AML patients (under an approved institutional review board protocol). Total RNA extraction was done in 29 specimens using a commercial kit. IDO-1 gene expression was evaluated by real-time polymerase chain reaction (PCR) after running the samples in triplicates. IDO-1 protein expression was checked by immunohistochemistry of 40 samples. Two pathologists analyzed the slides and percentage of mononuclear blast cells stained with IDO-1 antibody was documented. Intensity of staining was graded as weak (1), moderate (2) and strong (3). Product of the two scores was calculated as a composite IDO-1 score. Results: Samples were divided into four survival groups: > 5 years (n = 8, group 1), 1-5 years (n = 11, group 2), 6 months to 1 year (n = 8, group 3) and < 6 months (n = 13, group 4). IDO-1 mRNA expression had a positive correlation with decreasing survival but it did not reach statistical significance (n = 29). Average composite IDO-1 score was 0.351 in group 1, 0.386 in group 2, 0.588 in group 3, and 1.696 in group 4 (n = 40). There was statistically significant difference between group 4 when compared to group 1 (p = 0.0004). Conclusions: Higher mRNA IDO-1 expression showed a statistically non-significant positive trend with decreased overall survival. IDO-1 protein expression by immunohistochemistry showed a significant correlation with decreased survival. Our data suggests that in AML, IDO-1 plays a role in tumor-induced immune tolerance and IDO inhibitors such as 1-methyl tryptophan could potentially have an immunotherapeutic benefit.
Clinical drivers for imaging testing in nonmetastatic castration-resistant prostate cancer: May they be optimized?—Data of “IDENTIFICA” study.
Authors: Eduardo Useros RodrÃguez, Álvaro Juárez, Joaquín Carballido Rodríguez, Jose Rubio, Alfredo Rodríguez Antolín, Francisco Javier Amores Bermúdez, Antonio Medina González, Miguel Rodrigo, Juan Moreno Jiménez, Fernando Vázquez, Jacobo Muñoz del Toro, Angela Garcia, José Manuel Cózar Olmo
Journal: Journal of Clinical Oncology (2019)

318 Background: Metastases (M+) detection is a critical event in non-metastatic castration-resistant prostate cancer (nmCRPC), as it entails a change in PC management and is a potential surrogate for survival at this stage. PSA doubling time (PSA-DT) has been described as a prognostic factor to develop M+. However, there could be other relevant factors to raise suspicion of progression in nmCRPC patients. The “IDENTIFICA” study tries to describe disease characteristics and clinical drivers that make physicians suspect the presence of M+ in nmCRPC patients in clinical practice in Spain. Methods: Observational, transversal, multicenter study. nmCRPC patients with physician’s suspiction of M+ were selected. Imaging tests to rule out metastases were requested; clinical drivers were described, along with clinical data related to prostate cancer (PC). Results: 197 nmCRPC patients were recruited (Jan-Jun 2018). Median age was 81.3 years. Median time from the onset of androgen deprivation therapy (ADT) to CRPC was 5.1 years (IQR: 2.5-8.2). ADT was the first PC treatment for 64.4% of , while 41.2% went through a curative-intent treatment. Median PSA-DT at CRPC diagnosis was 7.5 months. Time from PC diagnosis to CRPC was influenced by Gleason score at diagnosis ( p=0.001), primary curative intent treatment ( p&lt;0.001), and PSA-DT at CRPC diagnosis ( p=0.04). Most important clinical drivers leading physicians to request imaging were PSA value, PSA-DT and PC guidelines recommendations. M+ were detected in 23 patients (16.5%). In the multivariate analysis, there was a statistically significant relation between positive imaging and time on ADT (OR 1.16; 95% CI 1.018-1.325; p=0.026) and time on CRPC status (OR 1.55; 95% CI 1.038-2.302; p=0.032). In this interim analysis, PSA and PSA-DT seemed not to be statistically related to M+ appearance. Conclusions: PSA and PSA-DT seem to be the most influential drivers to request imaging tests during follow-up of nmCRPC patients. Time on ADT and time on CRPC status could be relevant factors for M+ detection and phycisians should be aware of them and not just PSA or PSADT to properly ask for imaging tests.