tbuckley/cabot-search huggingface dataset:
A randomized phase III trial between adjuvant docetaxel and surveillance after radical radiotherapy (RT) for intermediate and high-risk prostate cancer (PC): Quality-of-life results (QoL) in SPCG-13 trial.
Authors: Pirkko-Liisa Kellokumpu-Lehtinen, Marie Hjälm-Eriksson, Camilla Thellenberg-Karlsson, Lennart Astrom, Lars Franzen, Ann-Sofie Fransson, Markku J. Leskinen, Teppo Huttunen, Claes Ginman
Journal: Journal of Clinical Oncology (2020)

313 Background: Six docetaxel cycles did not improve PSA relapse free survival as an adjuvant treatment after radical RT (Kellokumpu-Lehtinen EURURO-8532). Here we report SPCG-13 trials QoL results. Methods: A total of 376 PC patients (T2 with Gleason score (GS) 4+3, PSA&gt;10; T2, GS 8-10 any PSA; or any T3) were randomised to receive either 6 cycles of docetaxel 75mg/m 2 every 3 weeks (Arm A, n=188) or surveillance (Arm B, n=188) after radical RT NTC006653848. Neoadjuvant/adjuvant ADT was mandatory. Primary end-point was a rising PSA &gt; 2 ng/ml above the nadir. Patients were followed for 5 years with PSA every 3 months for two years and thereafter every 6 month. FACT-P QoL questionnaires were used at baseline, during and after docetaxel treatment and in the follow-ups (at 1 year, 2 years and 4 years after treatment) in both groups, and analysed using analysis of variance (ANOVA) models. Results: Median follow-up was 59.4 months (range 1 to 111 months). 147 (78.2%) patients completed all six cycles in arm A. Mean age was 66.2 years in Arm A and 66.4 years in Arm B. The total QoL scores at baseline did not differ between the Arms (mean 119.0, SD±18.9, n=177 vs 118.2, SD±18.1, n=180). In Arm A the total score declined to 116.3 (SD+15.2), at 24 weeks and was 118.5 (SD±21.3) after chemotherapy. In Arm B at 24 weeks the QoL score had increased to 123.3 (SD±19.2) and was significantly higher than in Arm A (estimated difference of 8.2 with p&lt;0.0001, ANOVA model adjusted for baseline). However, in the first follow-up (1 year) the QoL score was same in both Arms (123.7 vs 123.6, respectively, p=0.344, ANOVA model adjusted for baseline) and remained at the same level during further follow-ups. The decline in QoL scores during the docetaxel treatment were seen only in two sub-scores; functional and physical. Conclusions: Adjuvant docetaxel did decrease the QoL of patients during the treatment. However, in the later follow-ups it increased to the same level as those patients without docetaxel treatment. These results further support our conclusions of showing no benefit from docetaxel as adjuvant treatment in this patient group after radical curative treatment. Clinical trial information: RT NTC006653848.
Pathobiology of pulmonary artery hypertension: role of long non-coding RNAs
Authors: Kashif Rafiq Zahid, Umar Raza, Jidong Chen, Usha J Raj, Deming Gou
Journal: Cardiovascular Research (2020)

Pulmonary arterial hypertension (PAH) is a disease with complex pathobiology, significant morbidity and mortality, and remains without a cure. It is characterized by vascular remodelling associated with uncontrolled proliferation of pulmonary artery smooth muscle cells, endothelial cell proliferation and dysfunction, and endothelial-to-mesenchymal transition, leading to narrowing of the vascular lumen, increased vascular resistance and pulmonary arterial pressure, which inevitably results in right heart failure and death. There are multiple molecules and signalling pathways that are involved in the vascular remodelling, including non-coding RNAs, i.e. microRNAs and long non-coding RNAs (lncRNAs). It is only in recent years that the role of lncRNAs in the pathobiology of pulmonary vascular remodelling and right ventricular dysfunction is being vigorously investigated. In this review, we have summarized the current state of knowledge about the role of lncRNAs as key drivers and gatekeepers in regulating major cellular and molecular trafficking involved in the pathogenesis of PAH. In addition, we have discussed the limitations and challenges in translating lncRNA research in vivo and in therapeutic applications of lncRNAs in PAH.
Chlamydia pneumoniae decreases CD4+ and CD8+ T effector memory IL-2 responses in stimulated peripheral blood mononuclear cells in non-asthmatic subjects
Authors: Sarah Shidid, Stephan Kohlhoff, Yitzchok Norowitz, Margaret Hammerschlag, Tamar Smith-Norowitz
Journal: Journal of Allergy and Clinical Immunology (2020)
Effectiveness of Implanted Cardiac Rhythm Recorders With Electrocardiographic Monitoring for Detecting Arrhythmias in Pregnant Women With Symptomatic Arrhythmia and/or Structural Heart Disease
Authors: Karen Sliwa, Feriel Azibani, Mark R. Johnson, Charle Viljoen, Johann Baard, Ayesha Osman, Olivia Briton, Mpiko Ntsekhe, Ashley Chin
Journal: JAMA Cardiology (2020)

Arrhythmias are an important cause of maternal morbidity and mortality but remain difficult to diagnose.To compare implantable loop recorder (ILR) plus 24-hour Holter electrocardiographic (ECG) monitoring with standard 24-hour Holter ECG monitoring alone in terms of acceptability, ability to identify significant arrythmias, and effect on management and pregnancy outcome in women who were symptomatic or at high risk of arrythmia because of underlying structural heart disease.This single-center, prospective randomized clinical trial recruited 40 consecutive patients from the Cardiac Disease and Maternity Clinic at Groote Schuur Hospital in Cape Town, South Africa. Pregnant patients with symptoms of arrhythmia and/or structural heart disease at risk of arrhythmia were included.Patients were randomized to standard care (SC; 24-hour Holter ECG monitoring [n = 20]) or standard care plus ILR (SC-ILR; 24-hour Holter ECG monitoring plus ILR [n = 20]). Only 17 consented to ILR insertion, and the 3 who declined ILR were allocated to the SC group.Arrhythmias considered included atrial fibrillation, atrial flutter, premature ventricular complexes, supraventricular tachycardia, ventricular tachycardia, or ventricular fibrillation.Among the 40 women in this trial, the mean (SD) age was 28.4 (5.5) years. Holter monitoring detected arrhythmias in 3 of 23 patients (13%) in the SC group and 4 of 17 patients (24%) in the SC-ILR group compared with 9 of 17 patients (53%) patients who had arrhythmias detected by ILR. Seven patients (4 with supraventricular tachycardia, 1 with premature ventricular complexes, and 2 with paroxysmal atrial fibrillation recorded by ILR) did not have arrhythmias detected by 24-hour Holter monitoring. Three of these 7 patients (43%) had a change in management as a result of their ILR recordings. There were no maternal deaths. However, the SC group had a significantly lower mean (SD) gestational stage at delivery (35 [5] weeks vs 38 [2], P = .04).The ILR was better than 24-hour Holter monitoring in detecting arrhythmias, which led to a change in management for a significant proportion of patients. Our findings suggest that ILR may be beneficial for pregnant women at risk of arrhythmia.ClinicalTrials.gov Identifier: NCT02249195.
Influence of caseload on survival of patients (pts) with localized prostate cancer (PC) after definitive radiation therapy (DRT).
Authors: Sarmad Sadeghi, Primo Lara, Denice D. Tsao-Wei, Monish Aron, Jacek K. Pinski, David I. Quinn, Inderbir Gill, Afsaneh Barzi
Journal: Journal of Clinical Oncology (2020)

357 Background: We recently reported a significant all-cause mortality risk reduction associated with higher annual caseload for radical prostatectomy (RP)- (PMID 31398279). Here we explore this relationship in DRT. Methods: National Cancer Database (NCDB) was used to investigate outcomes of DRT in the United States. Beam radiation (BR), radioactive implant (RI) and both (BRRI) were included in analysis. Using overall survival (OS) as primary outcome, the relationship between facility annual caseload (FAC) for all PC pts and facility annual caseload (FARC) for those requiring DRT were examined using Cox model. Four volume groups (VG) were defined as VG1: &lt;50th, VG2: 50th-74th, VG3: 75th-89th and VG4: top 10 percentile of caseload. Results: Between 2004 and 2014, 355,247 pts underwent DRT. At a median follow up of 70.1 (95% CI: 1.0 - 143.1) months (mo), the median OS was 137.3 mo (136.9, 138.1). Using FAC/FARC, 19/14, 27/24, 24/26, and 30/37 % of pts were treated at VG 1 through 4, respectively. For FARC, median OS was 136.8 mo (134.9, 142.2+) for VG1 and 139.7 (137.7, 141.8+) mo for VG4, adjusted hazard ratio (aHR) 1.06 (1.03-1.09), p &lt;0.001. For FAC, median OS was 135.4 (134.1, 138.7) mo for VG1 and not reached for VG4, aHR 1.13 (1.09, 1.16), p &lt;0.001. In subgroups, FARC aHR for VG1 vs VG4 were 1.20 (1.16-1.25) for BR, 0.99 (0.93-1.05) for RI, and 1.15 (1.02-1.31) for BRRI. These numbers for FAC were 1.10 (1.06, 1.14), 1.12 (1.05, 1.19), and 1.24 (1.12, 1.39), respectively. Conclusions: There is a statistically significant OS advantage to DRT at a high annual caseload facility. This effect is more pronounced for BR and is influenced more noticeably by facility all PC caseload rather than DRT.[Table: see text]
A risk scoring system for African-American (AA) patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) treated with first-line abiraterone (ABA) or enzalutamide (ENZ).
Authors: Jacqueline T Brown, Yuan Liu, Jennifer Ann LaFollette, Omer Kucuk, Melvin R. Moore, Mehmet Asim Bilen
Journal: Journal of Clinical Oncology (2020)

51 Background: AA pts represented &lt; 3% of the COU-AA-302 and PREVAIL trial cohorts that led to the approval of ABA and ENZ in the 1st line treatment of mCRPC. We characterized the clinical outcomes (CO) and developed a risk score for AA pts with mCRPC on these agents. Methods: We retrospectively reviewed 77 AA pts with mCRPC treated with 1st line ABA or ENZ at Grady Memorial Hospital from 2015-2018. The CO included median overall survival (mOS), progression-free survival (mPFS) and PSA response (PSAr) as defined by a ≥ 50% drop in PSA over the 1st 12 weeks of treatment. Cox proportional hazard model and Kaplan-Meier method were used for association with OS and PFS and logistic regression model for PSAr. The risk score was built by regression coefficient-based scoring system using OS as the 1° outcome. Covariates included grade group (GG), baseline (bl) PSA, albumin, and BMI, ECOG status, and age. Results: Median age was 60 years with median follow-up of 11.5 months (mos). 50 pts received ABA; 27 received ENZ. The overall mOS was 45.7 mos, mPFS was 12.9 mos, and PSAr was 84.4%. CO did not differ significantly for ABA vs. ENZ with a 24-month OS of 66.6% vs. 57.7% and PFS of 34.3% vs. 45%. 1 point was assigned for each of the following: GG &gt; 3, bl PSA ≥ 108, or bl albumin ≤ 4.2. The total was classified into low (0-1), intermediate (2), and high (3) risk and associated with CO via univariate (UVA) and multivariate (MVA) analyses (Table). Conclusions: We present the efficacy of ABA and ENZ in a cohort of AA pts with mCRPC. Risk grouping using bl PSA, bl albumin and GG may predict CO in this population. These results should be validated in a larger, prospective study.[Table: see text]
Prevalence and adherence trends of inhaled corticosteroid/long-acting bronchodilator (ICS/LABA) and ICS monotherapy by age group using electronic medication monitoring (EMM) data from 2017-2019
Authors: William Anderson, Rahul Gondalia, Heather Hoch, Stanley Szefler, David Stempel
Journal: Journal of Allergy and Clinical Immunology (2020)
Impact of molecular weight on the mechanism of cellular uptake of polyethylene glycols (PEGs) with particular reference to P-glycoprotein
Authors: Tingting Wang, Yingjie Guo, Yang He, Tianming Ren, Lei Yin, John Paul Fawcett, Jingkai Gu, Huimin Sun
Journal: Acta Pharmaceutica Sinica B (2020)

Polyethylene glycols (PEGs) in general use are polydisperse molecules with molecular weight (MW) distributed around an average value applied in their designation e.g., PEG 4000. Previous research has shown that PEGs can act as P-glycoprotein (P-gp) inhibitors with the potential to affect the absorption and efflux of concomitantly administered drugs. However, questions related to the mechanism of cellular uptake of PEGs and the exact role played by P-gp has not been addressed. In this study, we examined the mechanism of uptake of PEGs by MDCK-mock cells, in particular, the effect of MW and interaction with P-gp by MDCK-hMDR1 and A549 cells. The results show that: (a) the uptake of PEGs by MDCK-hMDR1 cells is enhanced by P-gp inhibitors; (b) PEGs stimulate P-gp ATPase activity but to a much lesser extent than verapamil; and (c) uptake of PEGs of low MW (<2000 Da) occurs by passive diffusion whereas uptake of PEGs of high MW (>5000 Da) occurs by a combination of passive diffusion and caveolae-mediated endocytosis. These findings suggest that PEGs can engage in P-gp-based drug interactions which we believe should be taken into account when using PEGs as excipients and in PEGylated drugs and drug delivery systems.
Glial TIM-3 Modulates Immune Responses in the Brain Tumor Microenvironment
Authors: Hyung-Seok Kim, Chi Young Chang, Hee Jung Yoon, Ki Sun Kim, Han Seok Koh, Sang Soo Kim, Sang-Jin Lee, Lawrence P. Kane, Eun Jung Park
Journal: Cancer Research (2020)

Abstract T-cell immunoglobulin and mucin domain–containing molecule 3 (TIM-3), a potential immunotherapeutic target for cancer, has been shown to display diverse characteristics in a context-dependent manner. Thus, it would be useful to delineate the precise functional features of TIM-3 in a given situation. Here, we report that glial TIM-3 shows distinctive properties in the brain tumor microenvironment. TIM-3 was expressed on both growing tumor cells and their surrounding cells including glia and T cells in an orthotopic mouse glioma model. The expression pattern of TIM-3 was distinct from those of other immune checkpoint molecules in tumor-exposed and tumor-infiltrating glia. Comparison of cells from tumor-bearing and contralateral hemispheres of a glioma model showed that TIM-3 expression was lower in tumor-infiltrating CD11b+CD45mid glial cells but higher in tumor-infiltrating CD8+ T cells. In TIM-3 mutant mice with intracellular signaling defects and Cre-inducible TIM-3 mice, TIM-3 affected the expression of several immune-associated molecules including iNOS and PD-L1 in primary glia-exposed conditioned media (CM) from brain tumors. Further, TIM-3 was cross-regulated by TLR2, but not by TLR4, in brain tumor CM- or Pam3CSK4-exposed glia. In addition, following exposure to tumor CM, IFNγ production was lower in T cells cocultured with TIM-3–defective glia than with normal glia. Collectively, these findings suggest that glial TIM-3 actively and distinctively responds to brain tumor, and plays specific intracellular and intercellular immunoregulatory roles that might be different from TIM-3 on T cells in the brain tumor microenvironment. Significance: TIM-3 is typically thought of as a T-cell checkpoint receptor. This study demonstrates a role for TIM-3 in mediating myeloid cell responses in glioblastoma.
Differences in food allergens and atopy between African American and Caucasian children with food allergy in the FORWARD study
Authors: Aame Andy-Nweye, Susan Fox, Mahboobeh Mahdavinia, Mary Tobin, Perry Catlin, Annika Chura, Amal Assa'ad, Adam Robinson, Iman Abdikarim, Hemant Sharma, Amaziah Coleman, Jialing Jiang, Lucy Bilaver, Christopher Warren, Jamie Fierstein, Pamela Newmark, Alexandria Bozen, Avneet Chadha, Jacqueline Pongracic, Ruchi Gupta
Journal: Journal of Allergy and Clinical Immunology (2020)
Real-world analysis of prostate-specific antigen (PSA) outcomes among patients with metastatic castration-resistant prostate cancer (mCRPC) treated with enzalutamide (ENZA).
Authors: Stephen J. Freedland, Neil M. Schultz, Anna D. Coutinho, Rupali Fuldeore, Nancy Hedlund, Qi Feng, Krishnan Ramaswamy, Agnes Hong
Journal: Journal of Clinical Oncology (2020)

33 Background: ENZA showed efficacy in chemotherapy-naïve men with mCRPC in a clinical trial setting (PREVAIL). We report real-world outcomes with ENZA for this population in a urology practice setting. Methods: This retrospective cohort study included men with prostate cancer newly initiating ENZA in the IntrinsiQ Specialty Solutions™ urology electronic medical records database between September 1, 2014 and February 28, 2018. Due to the approved indication in the study time frame, prescription of ENZA (first claim date = index date) was used as a proxy for mCRPC. Patients with evidence of prior chemotherapy and/or abiraterone were excluded. PSA value closest to index date (±30 days) was used as baseline. Men were followed until the earliest of: discontinuing ENZA, leaving practice, death, or study end. Best PSA response (largest decline or smallest increase in absence of decline from baseline), PSA declines of ≥50% and ≥90%, undetectable PSA, and time to PSA progression were analyzed. Results: We identified 931 eligible men. Most (&gt;95%) were ≥60 years old; hypertension (54.6%) and diabetes (17.0%) were the most common comorbidities. Median (interquartile range [IQR]) baseline PSA was 9.0 (2, 37) ng/dL. Median (IQR) follow-up time was 12.5 (7.6, 19.4) months, during which a median (IQR) of 4 (3, 6) PSA tests were observed. Median time between two adjacent PSA tests was 2.0 months. A ≥50% and ≥90% PSA decline was observed in 55.0% and 23.8%, respectively. Best PSA response was a median (IQR) PSA decline of 58% (-89%, 1%), with 14.2% reaching an undetectable PSA value. Median time to PSA progression was 18.5 months (95% confidence interval 15.6, 23.7). Conclusions: This real-world study supports the effectiveness of ENZA in patients with mCRPC. The median PSA at treatment was much lower than PREVAIL, potentially explaining the longer time to PSA progression vs. PREVAIL. However, a lower proportion had PSA declines of ≥50% and ≥90% vs. PREVAIL, which may be attributed to more frequent PSA monitoring within a clinical trial setting and thus more opportunity to capture the true best PSA response.
Abstract 13317: The Circulating Soluble LR11 Levels Predict the Severity of Pulmonary Hypertension Due to Left Heart Disease
Authors: Kiyoshi Takasu, Hakuoh Konishi, Yusuke Joki, Hiroyuki Daida
Journal: Circulation (2018)

Introduction: Pulmonary hypertension due to left heart disease (PH-LHD) progresses to combined post- and pre-capillary PH (Cpc-PH) which is associated with pulmonary vascular remodeling. LR11 (low-...
Neoplasic Disease and Chronic Kidney Disease: Does the Association Worsen Prognosis?
Authors: D. Romeira, C.T. Carvalho, M. Proença, M. Alface, R. Cardiga, R. Ferreira, A. Leitão, C. Fonseca, F. Ceia, A.M. Martins
Journal: Annals of Oncology (2012)
Perioperative chemotherapy for upper tract urothelial carcinoma: A microsimulation Markov model.
Authors: Diana E. Magee, Amanda Elizabeth Hird, Douglas Cheung, Beate Sander, Robert Nam, Srikala S. Sridhar, Girish S. Kulkarni
Journal: Journal of Clinical Oncology (2020)

508 Background: Upper tract urothelial carcinoma (UTUC) accounts for less than 5% of all urothelial cancers. As a result, this disease is clinically understudied and there are no definitive recommendations regarding use and timing of peri-operative chemotherapy. The objective of this study was to create a decision model comparing three treatment pathways in UTUC: nephroureterectomy (NU) alone, neoadjuvant chemotherapy (NAC), and adjuvant chemotherapy (AC). Methods: A Markov microsimulation model was constructed using TreeAge Pro to compare treatment strategies for patients with newly diagnosed UTUC. Our primary outcome was quality adjusted life expectancy (QALE). Secondary outcomes included rates of adverse chemotherapy events, bladder cancer diagnoses, and crude survival. Markov cycle length was 3 months to mimic the follow up interval used in clinical practice for patients with UTUC. A systematic literature review was used to generate probabilities to populate the model. The base case was a 70-year-old patient with a radiographically localized upper tract tumor. Patients could have evidence of nodal disease, but no distant metastasis. Results: A total of 100,000 microsimulations were generated. NAC was preferred with an estimated QALE of 7.52 years versus 6.80 years with NU alone and 7.20 years with AC. Overall, 39.6% of patients in the AC group with invasive pathology received and were able to complete chemotherapy. A total of 37.5% of patients in the NAC group experienced an adverse chemotherapy event compared to 15.1% of patients in the AC group. Bladder cancer recurrence rates were 64.9%, 66.0%, and 67.1% over the patient’s lifetime in the NU, NAC, and AC groups, respectively. Conclusions: This study provides evidence to support the increased use of NAC in UTUC until robust randomized trials can be completed. While the use of NAC in this population appears favourable, the ultimate choice rests with the clinician and should be based on patient and tumor factors.
Treatment outcomes for metastatic castrate-resistant prostate cancer (mCRPC) patients (pts) following docetaxel (D) for hormone sensitive disease.
Authors: Andrew Lachlan Schmidt, Angelyn Anton, Shirley S. Wong, Arun Azad, Edmond Michael Kwan, Lavinia Anne Spain, Javier Torres, Arunbalaji Muthusamy, Phillip Parente, Francis Parnis, Jeffrey C. Goh, Anthony M. Joshua, David William Pook, Peter Gibbs, Ben Tran, Andrew James Weickhardt
Journal: Journal of Clinical Oncology (2020)

78 Background: There is no prospective data to guide optimal selection of treatment for first line (1L) mCRPC after D and androgen deprivation therapy (ADT) is given in the hormone sensitive setting. We explored efficacy of 1L treatment in this group. Methods: Pts with mCRPC treated with D for hormone sensitive disease were identified from a prospectively maintained multi-site mCRPC database (ePAD) of patients treated in a community and academic setting in Australia. 1L treatment, clinicopathologic and outcome data were extracted. Results: We identified 93 pts, median age 65y (range 43–85), who received median 6 cycles of D-ADT and developed mCRPC between May 2013 and Jun 2019. 58% had Gleason ≥ 8, median PSA at diagnosis was 53 ng/mL (range 0.67–7086), 65% had de-novo metastatic disease. Median time to mCRPC was 14.8mo (range 1.3 to 56.9) with median time to 1L 16.3mo (range 2.1–57.2). Eighty-five patients (91%) received at least one further active treatment for mCRPC with outcomes below. Conclusions: Abiraterone, enzalutamide, and cabazitaxel all demonstrate activity for 1L mCRPC following progression on D-ADT. Compared to historical controls, PSA responses appear less than pre-docetaxel, but greater than the post-docetaxel setting.[Table: see text]