tbuckley/cabot-search huggingface dataset:
Effect of concurrent beta-blocker (BB) use in patients receiving immune checkpoint inhibitors for metastatic urothelial (mUC) and renal cell carcinomas (mRCC).
Authors: Vaibhav G. Patel, William K. Oh, Matt D. Galsky, Bobby Chi-Hung Liaw, Che-Kai Tsao
Journal: Journal of Clinical Oncology (2019)

467 Background: Stress-induced adrenergic signaling suppresses the immune system. A pre-clinical mouse model has shown that pharmacologic beta-blockade can stimulate CD8+ T-cell activity, and as a result improve efficacy of checkpoint inhibitors (CPI) to inhibit growth in solid tumors. Herein, we investigate the effect of BB on outcomes of patients receiving immunotherapy in mUC and mRCC. Methods: Using the Mount Sinai Genitourinary (GU) Cancer Biorepository, an IRB approved database containing all consented GU cancer patients seen between 2010-2018, we identified patients with either UC or RCC that have received CTLA-4 and/or PD-1/PD-L1 blockade. Patients who received only 1 dose of CPI were excluded from this analysis. A descriptive analysis was performed to assess clinical characteristics and treatment response. Overall Survival (OS) was calculated with Kaplan-Meier curves and cox proportional hazard models. Results: We identified 34 evaluable patients with mUC and 14 with mRCC that received CPI (Table). The median age at initiation was 69 years (39–91 years) and 81.2% (39/48) received prior chemotherapy and/or molecular targeted therapies. The mean duration of therapy was longer in the BB group compared to non-BB group (10.6 vs. 4.0 mo). For patients with mUC, the overall response rate (ORR) was 62.5% vs. 12.5% in favor of the BB group. For the patients with mRCC, the ORR was 40.0% vs. 10.0% in favor of the BB group. There were more outstanding responders (&gt;1 year) in the BB group when compared with the non-BB group (41.2% vs. 6.5%). Patients with BB use had significantly improved median OS (NR vs. 11.6 mo, p = 0.004) when compared to those who did not receive BB. Conclusions: In this single-center cohort, the concurrent use of BB receiving CPI therapy is associated with an improved ORR, duration of therapy, and OS. Although this is hypothesis generating, the addition of BB is a promising strategy to improve response of immunotherapy, and prospective validation of this approach will be needed. [Table: see text]
Abstract 033: Directly Measured Triglyceride-Rich Lipoprotein Cholesterol and Small Dense LDL-Cholesterol Concentrations Associate With Incident Cardiovascular Disease: Prospective Data From the Women’s Health Study
Authors: Edward K Duran, Aaron W Aday, Nancy Cook, Julie E Buring, Paul M Ridker, Aruna D Pradhan
Journal: Circulation (2019)

Background: Elevated triglyceride rich lipoproteins (TRLs) and small dense LDL (sdLDL) levels are hallmarks of atherogenic dyslipidemia and the cholesterol content of these particles is hypothesized to drive atherosclerotic risk. However, laboratory quantitation has thus far been impractical with limited prospective clinical data utilizing directly measured levels of this cholesterol burden. Methods: We conducted a prospective case-cohort study within the Women’s Health Study. Randomly selected CVD case subjects (n=500) were compared to a reference subcohort (n=496). TRL-C and sdLDL-C (mg/dl) were directly measured in baseline blood specimens. Cox proportional hazards models were used to compute quartile-specific multivariable-adjusted HRs for total CVD and individual outcomes of coronary and cerebrovascular disease (CCVD) and peripheral artery disease (PAD). Clinical models also adjusted for LDL-C and hsCRP. Results: TRL-C and sdLDL-C were strongly correlated ( ρ =0.716, p&lt;0.001) and levels were higher in case subjects than in the reference risk set. The risk of each outcome increased across quartiles of TRL-C (HR adj Q4 vs Q1: total events 1.87, 95% CI 1.14 - 3.06, p=0.012; CCVD 1.81, 95% CI 1.05 - 3.09, p = 0.030; PAD 2.43, 95% CI 1.11 - 5.31, p=0.039). In contrast, elevated sdLDL-C associated with incident CCVD but not PAD (HR adj Q4 vs Q1: total events 1.85, 95% CI 1.04 - 3.31, p=0.014; CCVD 2.17, 95% CI 1.14 - 4.13, p = 0.006; PAD 1.34, 95% CI 0.54 - 3.33, p=0.389). Conclusion: Directly measured TRL-C and sdLDL-C concentrations are strongly linked to incident CVD with potentially differential effects for PAD. These findings may indicate a greater potential benefit of therapeutics targeting TRL-C rather than LDL in the prevention of PAD.
Abstract P307: Additional Prognostic Value of Toe-Brachial Index Beyond Ankle-Brachial Index in Hemodialysis Patients
Authors: Manabu Hishida, Takahiro Imaizumi, Masaki Okazaki, Shoichi Maruyama, Kunihiro Matsushita
Journal: Circulation (2019)

Background: Although ankle-brachial index (ABI) is considered the first-line diagnostic test for peripheral artery disease (PAD), ABI can be falsely elevated in some patients with uncompressible ankle arteries. In those patients, toe-brachial index (TBI) is recommended as an alternative test. However, whether TBI provides additional prognostic information beyond ABI is unknown. Methods: We examined data from 247 Japanese dialysis patients (mean age 66 years). ABI and TBI were measured bilaterally on the same day, and the lower values were used for analysis. We explored quartiles of ABI and TBI as well as three categories of low ABI (≤0.9), normal/high ABI (&gt;0.9) + low TBI (≤0.6), and normal/high ABI + normal TBI (&gt;0.6) (very few with low ABI and normal TBI). Multivariable Cox models were used to quantify the associations of ABI and TBI with all-cause mortality. Results: During a mean follow-up of 5.2 years, we observed 116 deaths. As anticipated, ABI showed a J-shaped association with mortality, with the higher risk seen in the lowest quartile (adjusted hazard ratio 2.70 [95% CI 1.38-5.30]) and the highest quartile (1.46 [0.73-2.90]) vs. the second highest quartile. In contrast, lower TBI showed a dose-response association with mortality (e.g., adjusted hazard ratios 2.41 [1.16-5.01] and 2.21 [1.04-4.71] in the lowest two quartiles vs. the highest quartile). When three categories by ABI and TBI were analyzed, low ABI showed worst prognosis, followed by normal/high ABI + low TBI and then normal/high ABI + normal TBI (Figure). Higher mortality risk in normal/high ABI + low TBI vs. normal/high ABI + normal TBI remained significant after accounting for potential confounders (adjusted hazard ratio 1.84 [1.04-3.25]). Conclusions: Lower TBI was independently associated with higher mortality risk in patients on dialysis and classified risk in patients with normal/high ABI. Our results support the importance of evaluating TBI in addition to ABI in dialysis patients.
Abstract P191: Birth Weight and Risk of Hypertension: A Mendelian Randomization Study of 183433 Individuals from 60 Studies
Authors: Yan Zheng, Tao Huang, Tiange Wang, Zhendong Mei, Xiang Li, Lu Qi
Journal: Circulation (2019)

Importance: Epidemiology studies suggested that low birth weight is associated with a higher risk of hypertension in later life. However, little is known about the causality of such associations. Objective: To evaluate the causality of the association between low birth weight and hypertension risk in later life. Design, Setting, and Participants: We collected data from 60 studies with 183,433 participants (CHARGE-BIG consortium), and each study analyzed the data following a standard analytic protocol. We applied a Mendelian randomization analysis using a genetic risk score of low birth weight from seven SNPs as the instrumental variable to explore the possible causal association between birth weight and adulthood hypertension. Main Outcomes and Measures: Hypertension was defined as systolic blood pressure of 140 mmHg or higher, diastolic blood pressure of 90 mmHg or higher, or current use of antihypertensive medication. Results: A total of 70,874 hypertensive participants and 61,933 normotensive controls provided study-level data. In the meta-analysis, each additional risk allele in the risk score was associated with a 0.02 SD decrease in birth weight (p &lt;0.05). Decreased birth weight was associated with a higher risk of hypertension in adults (odds ratio per 1 SD decrease in birth weight: 1.19, 95% confidence interval [CI]: 1.08 to 1.31), while no association was found between a genetic risk score of low birth weight and hypertension risk. The formal Mendelian randomization analysis suggested genetically instrumented birth weight was not associated with risk of hypertension (instrumental odds ratio for causal effect per 1 SD decrease in birth weight: 0.94, 95%CI 0.62 to 1.42). These findings were consistent across different strata of sex, body mass index, or race. Conclusions: Our findings suggest that the association of birth weight with hypertension from observational studies could be the result of confounding.
An HK2 Antisense Oligonucleotide Induces Synthetic Lethality in HK1−HK2+ Multiple Myeloma
Authors: Shili Xu, Tianyuan Zhou, Hanna M. Doh, K Ryan Trinh, Art Catapang, Jason T. Lee, Daniel Braas, Nicholas A. Bayley, Reiko E. Yamada, Alex Vasuthasawat, Joshua P. Sasine, John M. Timmerman, Sarah M. Larson, Youngsoo Kim, A. Robert MacLeod, Sherie L. Morrison, Harvey R. Herschman
Journal: Cancer Research (2019)

Although the majority of adult tissues express only hexokinase 1 (HK1) for glycolysis, most cancers express hexokinase 2 (HK2) and many coexpress HK1 and HK2. In contrast to HK1+HK2+ cancers, HK1-HK2+ cancer subsets are sensitive to cytostasis induced by HK2shRNA knockdown and are also sensitive to synthetic lethality in response to the combination of HK2shRNA knockdown, an oxidative phosphorylation (OXPHOS) inhibitor diphenyleneiodonium (DPI), and a fatty acid oxidation (FAO) inhibitor perhexiline (PER). The majority of human multiple myeloma cell lines are HK1-HK2+. Here we describe an antisense oligonucleotide (ASO) directed against human HK2 (HK2-ASO1), which suppressed HK2 expression in human multiple myeloma cell cultures and human multiple myeloma mouse xenograft models. The HK2-ASO1/DPI/PER triple-combination achieved synthetic lethality in multiple myeloma cells in culture and prevented HK1-HK2+ multiple myeloma tumor xenograft progression. DPI was replaceable by the FDA-approved OXPHOS inhibitor metformin (MET), both for synthetic lethality in culture and for inhibition of tumor xenograft progression. In addition, we used an ASO targeting murine HK2 (mHK2-ASO1) to validate the safety of mHK2-ASO1/MET/PER combination therapy in mice bearing murine multiple myeloma tumors. HK2-ASO1 is the first agent that shows selective HK2 inhibition and therapeutic efficacy in cell culture and in animal models, supporting clinical development of this synthetically lethal combination as a therapy for HK1-HK2+ multiple myeloma. SIGNIFICANCE: A first-in-class HK2 antisense oligonucleotide suppresses HK2 expression in cell culture and in in vivo, presenting an effective, tolerated combination therapy for preventing progression of HK1-HK2+ multiple myeloma tumors. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/79/10/2748/F1.large.jpg.
A Fifty‐Two–Week, Randomized, Placebo‐Controlled Trial of Certolizumab Pegol in Nonradiographic Axial Spondyloarthritis
Authors: Atul Deodhar, Lianne S. Gensler, Jonathan Kay, Walter P. Maksymowych, Nigil Haroon, Robert Landewé, Martin Rudwaleit, Stephen Hall, Lars Bauer, Bengt Hoepken, Natasha de Peyrecave, Brian Kilgallen, Désirée van der Heijde
Journal: Arthritis & Rheumatology (2019)

Objective The natural history of nonradiographic axial spondyloarthritis (SpA) is incompletely characterized, and there are concerns that nonsteroidal antiinflammatory drugs provide inadequate disease control in patients with active disease. This study was undertaken to investigate the effects of certolizumab pegol ( CZP ), an anti–tumor necrosis factor treatment, in patients with nonradiographic axial SpA with objective signs of inflammation. Methods In this ongoing parallel‐group double‐blind study, adults with active disease were recruited from 80 centers in Australia, Europe, North America, and Taiwan, and were randomized 1:1 to receive placebo or CZP (400 mg at weeks 0, 2, and 4, followed by 200 mg every 2 weeks) in addition to nonbiologic background medication ( NBBM ). Switching to open‐label CZP (or other biologic) or making background medication changes was permitted at any point during the trial, although changes before week 12 were discouraged. The primary end point was the proportion of patients achieving major improvement ( MI ) (i.e., a ≥2.0‐point decrease in the score from baseline or achievement of the lowest possible score [0.6]) in the Ankylosing Spondylitis Disease Activity Score ( ASDAS ) at week 52. Results A total of 317 patients were randomized to receive placebo plus NBBM (n = 158) or CZP plus NBBM (n = 159). ASDAS ‐ MI at week 52 was achieved in 47.2% (75 of 159) of CZP plus NBBM patients, which was significantly greater ( P &lt; 0.0001) than the 7.0% (11 of 158) of placebo plus NBBM patients in whom ASDAS‐MI was achieved. Of the placebo plus NBBM patients, 60.8% (96 of 158) switched to open‐label treatment before week 52 compared to 12.6% (20 of 159) of the CZP plus NBBM patients. Conclusion Adding CZP to background medication is superior to adding placebo in patients with active nonradiographic axial SpA. These results indicate that remission in nonradiographic axial SpA treated without biologics occurs infrequently, demonstrating the need for treatment beyond nonbiologic therapy.
Chemotherapy effectiveness in the treatment of non-medullary well-differentiated thyroid cancer: A systematic review.
Authors: Ana Alberto Tamarit, Esther MartÃÂn, Alberto Torres, Teresa GarcÃÂa Manrique, Maria Carmen Alamo de la Gala, Luis De La Cruz-Merino, TomÃÂ¡s MartÃÂn
Journal: Journal of Clinical Oncology (2015)

e17058 Background: Nowadays, the use of chemotherapy in the well-differentiated non medullary thyroid cancer, locally advanced stage and/or with radioiodine refractory metastases (Advanced CDT) is considered of scanty value. However, in the last 40 years was not published any phase III study nor a systematic review of its use in clinical setting. Methods: A systematic literature search was performed in databases such as Medline and Embase, among others. Two independent reviewers analyzed the articles selected full text, made a critical reading and extracted results using forms designed specifically. A qualitative synthesis of the results was performed and the accumulated data were calculated. Results: Of 509 references identified by searching the database, sixteen studies with 473 patients published in the last 40 years were included. Four studies included only patients with well-differentiated tumors. The overall response rate was 22.5% (between 0-57%) with a 2.5% complete responses and a clinical benefit (BC) in 51% (19-93 %) of cases. In addition, unlike modern studies a performance status > 2 was described in about 40% of patients. Five studies published individual survival data from 54 patients with advanced CDT: the median survival was estimated at 18 months (95% CI 0 to 37.5), with significant differences between patients treated before 2000 versus patients treated later (7 vs 41 months, P < 0.00) Overall survival time was unable to assess due to lack of data and the heterogeneity of the included studies. However, these data must be interpreted with caution because of the high risk of bias detected. Conclusions: Although it has not been able to find firm evidence on the effectiveness of chemotherapy, the results shown seems to have some efficacy, therefore, it could be necessary to be tested in well-designed studies versus or in combination with new therapies.
IMPACT OF HIGH-INTENSITY INTERVAL TRAINING ON CENTRAL OBESITY IN OUTPATIENT CARDIAC REHABILITATION PATIENTS WITH METABOLIC SYNDROME
Authors: Yaoshan Dun, Jose R. Medina-Inojosa, Amanda R. Bonikowske, Joshua R. Smith, Ray W. Squires, Randal J. Thomas, Suixin Liu, Maria Irene Barillas-Lara, Thomas P. Olson
Journal: Journal of the American College of Cardiology (2019)
Epidemiology and management of HIV-related non-Hodgkin lymphoma (NHL) in the United States (US): Analysis of the National Cancer Data Base (NCDB).
Authors: Adam J. Olszewski, Jaleh Fallah, Jorge J. Castillo
Journal: Journal of Clinical Oncology (2015)

1521 Background: Antiviral therapy has altered the incidence and prognosis of NHL associated with human immunodeficiency virus infection (HIV+NHL). We analyzed recent trends in HIV+NHL presentation, management and overall survival (OS) using data from the NCDB—a registry capturing about 70% of US cancer cases. Methods: We extracted from the NCDB records of 364,422 NHL cases diagnosed in 2004-2012. HIV status was recorded for 57% of cases, identifying 11,409 HIV+ and 197,343 HIV- patients (pts). Trends and relative risks (RR) were evaluated by robust Poisson regression. Results: HIV+NHL pts were on average younger than HIV- (median age, 47 versus [vs] 67 years), more often male (77 vs 52%), black (33 vs 8%) or Hispanic (14 vs 5%). The histologies of HIV+NHL were: diffuse large B-cell (DLBCL)—46%, Burkitt (BL)—15%, primary central nervous system (PCNSL)—9%, primary effusion (PEL)—1%, indolent B-cell—10%, T-cell—5%, other/unknown—14%. Between 2003 and 2012, the proportion of black pts increased from 28% to 39% (P< .0001). The proportion of BL cases doubled among white pts (from 11 to 22%, P< .0001), but not for other races (from 14 to 16%, P= .06). The rate of chemotherapy (Ct) use increased from 69% to 78% (P< .0001). Ct was given to 80% of DLBCL, 90% of BL, 61% of PEL but only 34% of PCNSL pts. In a multivariable model, Ct use was significantly less common in black vs white pts (RR, 0.90, P< .0001), in facilities reporting ≤ 2 HIV+NHL cases per year (RR 0.92, P< .0001), and varied by insurance type. OS improved between 2004 and 2011 (log-rank P= .0004 for trend). OS at 3 years was 47% for DLBCL, 48% for BL, 26% for PCNSL, and 28% for PEL. Among pts who received Ct, 3-year OS was 53, 51, 45 and 29%, respectively, which was significantly lower than for HIV- pts (67% for DLBCL, 61% for BL and 47% for PCNSL; stratified log-rank P< .0001). Conclusions: Changes in the HIV+NHL demographics mirror the high rate of HIV infections among US black and Hispanic men. More HIV+NHL pts receive Ct, and their survival is improving, but disparities in Ct delivery exist that are related to socioeconomic factors and facility expertise. HIV+ DLBCL and BL have similar OS if Ct is given. In contrast, Ct does not alter the poor prognosis of PEL.
PTH-091 Clinical outcomes of a personalised approach to the management of thiopurine drug therapy
Authors: R Powney, S Rajagopal, K Lithgo, T Price, D Housley, MW Johnson
Journal: Gut (2017)

Introduction  A significant number of patients with inflammatory bowel disease (IBD) are treated with thiopurine drugs. Typically target doses for Azathioprine (AZA) and 6-Mercaptopurine (6-MP) are 2.5 mg/kg and 1.25 mg/kg, respectively, provided these are tolerated. More personalised dosing can be achieved using thiopurine metabolites (TPM) assessments for 6-Thioguanine nucleotide (6-TGN) and 6-Methylmercaptopurine nucleotide (6-MMPN); improving therapeutic efficacy, whilst minimising unwanted side effects and identifying non-compliance. We were keen to assess whether the use of TPM assessments and standardised management guidelines could affect clinical outcomes.  Method  We reviewed our local patients (3462) on the National IBD Registry and identified 406 as being on TPMs. These patients were all offered TPM assessments, which 200 initially completed. Following a locally derived management algorithm, their management was standardised depending on their TPM results. This led to a change in management in 124 patients (62%). Using faecal calprotectin + CRP/ESR as objective markers of disease activity, and the HBI + mUCDAI as clinical outcome measures, we reviewed these patients before and after their TPM driven management changes. ALT, Amylase and neutrophil count were used as physiological markers to exclude thiopurine toxicity.  Results  Of the 124 whose management changed, drug doses were increased in 28, reduced in 73, stopped in 22 who were thought to be non-compliant in taking their medication, and 1 was changed from Azathioprine to 6-MP. Results from before and after the use of the thiopurine management algorithm were compared where available. Calprotectin was available for 55% of patients and showed an average decrease of 167 ug/g, with 47% decreasing and 32% increasing (by more than 38 ug/g), whilst 21% stayed the same. Improvements in ESR were not as impressive (average decrease of 0.45 mm/hr). The average HBI score decreased from 2.2 to 1.9, whilst the mUCDAI score dropped from 2.0 to 1.5. Classification of disease activity improved in 32%, stayed the same for 45% and deteriorated in 23%. Eight patients had raised ALTs, 3 had raised Amylase, and no patients suffered clinically significant neutropenia.  Conclusion  Personalising thiopurine management through TPM assessments and using a standardised management protocol enabled avoidance of any major complications. It didn’t, however,prevent minor fluctuations in ALT or amylase levels (11 patients - 9%). By optimising their dosage into appropriate therapeutic ranges, whilst avoiding toxic levels of 6-MMPN, a majority of patients saw an improvement in both their clinical disease activity scores and their objective markers of inflammation, with an average calprotectin reduction of 167 ug/g.  Disclosure of Interest  None Declared
Long-term follow-up of the RESONATE phase 3 trial of ibrutinib vs ofatumumab
Authors: John C. Byrd, Peter Hillmen, Susan O’Brien, Jacqueline C. Barrientos, Nishitha M. Reddy, Steven Coutre, Constantine S. Tam, Stephen P. Mulligan, Ulrich Jaeger, Paul M. Barr, Richard R. Furman, Thomas J. Kipps, Patrick Thornton, Carol Moreno, Marco Montillo, John M. Pagel, Jan A. Burger, Jennifer A. Woyach, Sandra Dai, Remus Vezan, Danelle F. James, Jennifer R. Brown
Journal: Blood (2019)