tbuckley/cabot-search huggingface dataset:
Sodium–Glucose Cotransporter 2 Inhibitors and the Risk of Fractures Among Patients With Type 2 Diabetes
Authors: Devin Abrahami, Antonios Douros, Hui Yin, Oriana H.Y. Yu, Laurent Azoulay
Journal: Diabetes Care (2019)

The association between sodium–glucose cotransporter 2 (SGLT2) inhibitors and the risk of fractures is controversial. In the Canagliflozin Cardiovascular Assessment Study (CANVAS), canagliflozin was associated with a significant increased risk of fractures compared with placebo (hazard ratio [HR] 1.26, 95% CI 1.04–1.52) (1). Possible mechanisms may involve elevated serum phosphate levels or reductions in bone mineral density (2). To date, three recent observational studies investigated this association, but these did not observe an increased risk of fractures (3–5). However, these studies had some limitations, including residual confounding, a limited outcome definition, or restriction to a single SGLT2 inhibitor.

To address these limitations, we conducted a population-based cohort study using the U.K. Clinical Practice Research Datalink (CPRD). We first assembled a base cohort of all individuals, at least 40 years old, newly treated with antidiabetic drugs between 1 January 1988 and 31 December 2017. We excluded individuals with <1 year of medical history, those initially prescribed insulin in monotherapy, and women with polycystic ovary syndrome (alternate metformin indication) at the time of the first-ever prescription of an antidiabetic drug. Using this base cohort, we then assembled a study cohort of individuals who initiated a new antidiabetic drug class as of 2013 (year the first SGLT2 inhibitor was introduced …
Durvalumab With or Without Tremelimumab for Patients With Metastatic Pancreatic Ductal Adenocarcinoma
Authors: Eileen M. O’Reilly, Do-Youn Oh, Neesha Dhani, Daniel J. Renouf, Myung Ah Lee, Weijing Sun, George Fisher, Aram Hezel, Shao-Chun Chang, Gordana Vlahovic, Osamu Takahashi, Yin Yang, David Fitts, Philip Agop Philip
Journal: JAMA Oncology (2019)

New therapeutic options for patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) are needed. This study evaluated dual checkpoint combination therapy in patients with mPDAC.To evaluate the safety and efficacy of the anti-PD-L1 (programmed death-ligand 1) antibody using either durvalumab monotherapy or in combination with the anticytotoxic T-lymphocyte antigen 4 antibody using durvalumab plus tremelimumab therapy in patients with mPDAC.Part A of this multicenter, 2-part, phase 2 randomized clinical trial was a lead-in safety, open-label study with planned expansion to part B pending an efficacy signal from part A. Between November 26, 2015, and March 23, 2017, 65 patients with mPDAC who had previously received only 1 first-line fluorouracil-based or gemcitabine-based treatment were enrolled at 21 sites in 6 countries. Efficacy analysis included the intent-to-treat population; safety analysis included patients who received at least 1 dose of study treatment and for whom any postdose data were available.Patients received durvalumab (1500 mg every 4 weeks) plus tremelimumab (75 mg every 4 weeks) combination therapy for 4 cycles followed by durvalumab therapy (1500 mg every 4 weeks) or durvalumab monotherapy (1500 mg every 4 weeks) for up to 12 months or until the onset of progressive disease or unacceptable toxic effects.Safety and efficacy were measured by objective response rate, which was used to determine study expansion to part B. The threshold for expansion was an objective response rate of 10% for either treatment arm.Among 65 randomized patients, 34 (52%) were men and median age was 61 (95% CI, 37-81) years. Grade 3 or higher treatment-related adverse events occurred in 7 of 32 patients (22%) receiving combination therapy and in 2 of 32 patients (6%) receiving monotherapy; 1 patient randomized to the monotherapy arm did not receive treatment owing to worsened disease. Fatigue, diarrhea, and pruritus were the most common adverse events in both arms. Overall, 4 of 64 patients (6%) discontinued treatment owing to treatment-related adverse events. Objective response rate was 3.1% (95% CI, 0.08-16.22) for patients receiving combination therapy and 0% (95% CI, 0.00-10.58) for patients receiving monotherapy. Low patient numbers limited observation of the associations between treatment response and PD-L1 expression or microsatellite instability status.Treatment was well tolerated, and the efficacy of durvalumab plus tremelimumab therapy and durvalumab monotherapy reflected a population of patients with mPDAC who had poor prognoses and rapidly progressing disease. Patients were not enrolled in part B because the threshold for efficacy was not met in part A.ClinicalTrials.gov identifier: NCT02558894.
Computer-Assisted Techniques in Corrective Distal Radius Osteotomy Procedures
Authors: Giuliana Caiti, Johannes G. G. Dobbe, Simon D. Strackee, Gustav J. Strijkers, Geert J. Streekstra
Journal: IEEE Reviews in Biomedical Engineering (2019)

Malunion of the distal radius is a common complication following a distal radius fracture. The surgical treatment of a symptomatic distal radius malunion is a corrective osteotomy (CO) procedure aimed at the restoration of the anatomical alignment of the distal radius articular surface in the wrist joint. Traditional two-dimensional imaging techniques in the management of malunion have demonstrated to be limited in pre-, intra-, and postoperative imaging and visualization of the bone architecture. Over the past decades, with the advent of three-dimensional (3-D) imaging techniques, innovations have emerged in the field of preoperative planning, navigation, and 3-D printing. The aim of this paper is to review the existing literature and inform clinicians and biomedical engineers approaching the field about advantages, disadvantages, and future perspectives of existing computer-assisted technology for CO. Collected studies agree on showing the efficacy of the computed-tomography-based 3-D virtual planning. Currently, patient-specific 3-D printed guides and implants are the most promising technology to transfer the preoperative plan to the patient. However, further biomechanical studies, larger clinical trials, and a major exposure of clinicians to 3-D planning are needed to augment the feasibility of using these technologies in standard practice.
Is successful HIV therapy a Pyrrhic victory for the brain?
Authors: David B. Clifford
Journal: Journal of Clinical Investigation (2019)

Neurologic involvement of HIV remains an important concern for patients, physicians, and investigators. Catastrophic decline is rarely seen in patients on combination antiretroviral therapy (cART); however, neurological decline remains a critical clinical challenge. In this issue of the JCI, Spudich and associates investigated the status of HIV in the cerebral spinal fluid (CSF) and revealed ongoing presence of HIV in the nervous system. Surprisingly, even in the face of optimal treatment, including suppressed HIV RNA, almost half of the patients investigated showed cell-associated HIV (CA-HIV) DNA in the CSF. Spudich et al. find that persistence of HIV in CSF cells is associated with lower performance on neurocognitive testing. These findings emphasize the need to consider a viral-associated mechanism as playing a significant and potentially ongoing role in HIV-associated neurocognitive disorder (HAND).
Early imaging biomarker assessment to predict long-term responses for large B-cell lymphoma (LBCL) after CAR-T therapy.
Authors: Reza Sirous, Ali Abbas Bukhari, Firas El Chaer, Jean Yared, Nancy Maureen Hardy, Mehmet Hakan Kocoglu, Ashraf Z. Badros, Azra Borogovac, Elizabeth Hutnick, Natalie Gahres, Kathleen Ruehle, Aaron Rapoport, Babak Saboury, Saurabh Dahiya
Journal: Journal of Clinical Oncology (2019)

7560 Background: Axicabtagene Ciloleucel (Axi-cel), an anti-CD19 CART cell therapy, achieved 58% complete response (CR) rate, in patients with relapsed refractory (r/r) LBCL on the ZUMA-1 study (Neelapu, NEJM 2017). Early response assessment (PET-CT) at day 30 is a common clinical practice. Patients with partial response (PR) at day 30 pose a therapeutic dilemma. ZUMA-1 analysis showed 1/3rd PR patients would convert to a CR. No biomarkers exist to predict eventual response. We report comprehensive PET-CT biomarker analysis on patients with PR at day 30 treated with Axi-cel for r/r LBCL. Methods: Ten patients with PR based on PET-CT imaging at day 30 were retrospectively assessed. Day 30 PET-CT was compared to baseline and a day 90 PET-CT. Global burden of disease of each patient at every time-point were quantified using Total Tumor Glycolysis (TTG) methodology as the imaging biomarker. Using adaptive-thresholding method, each lesion on FDG PET image was segmented and the following parameters were quantified: metabolic-volume (MV), SUVmax, SUVpeak, Partial-Volume-Corrected SUVmean and five other imaging biomarkers. To evaluate the effect of baseline and early imaging biomarkers to predict the subsequent burden of disease multiple regression analysis was performed (STATA 15). Results: Day 90 PET-CT assessment revealed, 4 patients had progressive disease (PD), 4 had CR, and 2 had PR. TTG of patients with PD at day 90 was 900 vs. 29 in patients with non-PD (CR, PR). The Global-SUVmean of the patients with PD at day 90 was 725 vs. 86 in patient with non-PD. Regression analysis showed early-TTG as a significant predictor of subsequent-TTG (beta-coefficient = 1.26 (0.39-2.13); P-value = 0.02; adjusted-R-squared = 0.97), while the baseline-TTG didn’t have any effect on subsequent-TTG (P-value = 0.3). Additionally, the regression analysis didn’t show any significant predictive value in SUVmean and SUVmax of baseline and day 30 scans to predict subsequent burden of disease (TTG or Global-SUVmean) with P-values &gt; 0.8. Conclusions: Early post-axi-cel TTG, rather than baseline, can predict subsequent response to treatment. None of the SUV indices, commonly used in daily practice, were predictive of eventual response.
Assessment of Self-reported Prognostic Expectations of People Undergoing Dialysis
Authors: Ann M. O’Hare, Manjula Kurella Tamura, Danielle C. Lavallee, Elizabeth K. Vig, Janelle S. Taylor, Yoshio N. Hall, Ronit Katz, J. Randall Curtis, Ruth A. Engelberg
Journal: JAMA Internal Medicine (2019)

Prognostic understanding can shape patients' treatment goals and preferences. Patients undergoing dialysis in the United States have limited life expectancy and may receive end-of-life care directed at life extension. Little is known about their prognostic expectations.To understand the prognostic expectations of patients undergoing dialysis and how these relate to care planning, goals, and preferences.Cross-sectional survey study of 996 eligible patients treated with regular dialysis at 31 nonprofit dialysis facilities in 2 metropolitan areas (Seattle, Washington, and Nashville, Tennessee) between April 2015 and October 2018. After a pilot phase, 1434 eligible patients were invited to participate (response rate, 69.5%). To provide a context for interpreting survey participants' prognostic estimates, United States Renal Data System standard analysis files were used to construct a comparison cohort of 307 602 patients undergoing in-center hemodialysis on January 1, 2006, and followed for death through July 31, 2017. Final analyses for this study were conducted between November 2018 and March 2019.Responses to the question "How long would you guess people your age with similar health conditions usually live?" (<5 years, 5-10 years, >10 years, or not sure).Self-reported (1) documentation of a surrogate decision-maker, (2) documentation of treatment preferences, (3) values around life prolongation, (4) preferences for receipt of cardiopulmonary resuscitation and mechanical ventilation, and (5) desired place of death.Of the 996 survey respondents, the mean (SD) age was 62.7 (13.9) years, and 438 (44.0%) were women. Overall, 112 (11.2%) survey respondents selected a prognosis of fewer than 5 years, 150 (15.1%) respondents selected 5 to 10 years, 330 (33.1%) respondents selected more than 10 years, and 404 (40.6%) were not sure. By comparison, 185 427 (60.3%) prevalent US in-center patients undergoing hemodialysis died within 5 years, 58 437 (19.0%) died within 5 to 10 years, and 63 738 (20.7%) lived more than 10 years. In analyses adjusted for participant characteristics, survey respondents with a prognostic expectation of more than 10 years (vs <5 years) were less likely to report documentation of a surrogate decision-maker (adjusted odds ratio [aOR], 0.6; 95% CI, 0.4-0.9) and treatment preferences (aOR, 0.4; 95% CI, 0.2-0.6) and to value comfort over life extension (aOR, 0.1; 95% CI, 0.04-0.3), and were more likely to want cardiopulmonary resuscitation (aOR, 5.3; 95% CI, 3.2-8.7) and mechanical ventilation (aOR, 2.2; 95% CI, 1.2-3.7). The respondents who reported that they were not sure about prognosis had similar associations.Uncertain and overly optimistic prognostic expectations may limit the benefit of advance care planning and contribute to high-intensity end-of-life care in patients undergoing dialysis.
Abstract 61: Ablation of BK <sub>Ca</sub> Channels Results in Cardiac Hypertrophy
Authors: Harpreet Singh, Kajol Shah, Devsena Ponnalagu, Sanjay Chandrasekhar, Andrew R Kohut, Andrea L Meredith, Shubha Gururaja Rao
Journal: Circulation Research (2016)

Expression and activation of the large conductance calcium and voltage-gated potassium (BK Ca ) channels encoded by Kcnma1 gene is shown to be vital in cardioprotection from ischemia-reperfusion injury. BK Ca channels present in SA node cells regulate the heart rate, and in blood vessels play an active role in vascular relaxation. However, the role of BK Ca in regulation of structure and function of the heart is not fully-established. Using Kcnma1 -/- mice, we have observed structural changes in cardiomyocytes and compromised cardiac function as compared to wild type mice. Absence of BK Ca resulted in significant increase in size of adult cardiomyocytes (from 7.95 + 0.1 um 2 to 9.68 + 0.1 um 2 , p &lt; 0.01, n=480 cells each) and also increased cardiac fibrosis. Further to determine underlying signaling mechanisms in cardiac hypertrophy, we performed microarray analysis of RNAs isolated from wild type and Kcnma1 -/- mice (n=3) hearts. We found up regulation of a class of cardiac hypertrophy markers (myosin variants) and changes in the expression of several mitochondrial genes (such as ND4) directly associated with heart diseases in Kcnma1 -/- mice. To evaluate the functional consequence of absence of BK Ca , we performed high-resolution echocardiography on wild type and Kcnma1 -/- mice. Under anesthesia (1.5% isoflurane), left ventricle of Kcnma1 -/- mice showed significant reduction (p &lt; 0.05) in ejection fraction (56 + 2 %, n=7) as compared to wild type (74 + 3 %, n=6) as well as fractional shortening (23 + 3 %, n=7, and 39 + 3 %, n=6, respectively). Similarly, right ventricle had a lower ejection fraction (35.7 + 4% vs 56.9 + 5 %, n &gt; 5) in Kcnma1 -/- as compared to wild type mice. In agreement with our histopathology and microarray data, Kcnma1 -/- mice showed increased posterior wall thickness (0.75 + 0.3 mm vs 0.62 + 0.1 mm) and interventricular septum thickness (0.83 + 0.4 mm, n=7 vs 0.68 + 0.3 mm, n=6) . Together, these data imply that BK Ca plays a direct role in cardiac hypertrophy and cardiac function.
Mammographic Density Change and Risk of Breast Cancer
Authors: Shadi Azam, Mikael Eriksson, Arvid Sjölander, Roxanna Hellgren, Marike Gabrielson, Kamila Czene, Per Hall
Journal: JNCI Journal of the National Cancer Institute (2019)

Abstract Background We examined the association between annual mammographic density change (MDC) and breast cancer (BC) risk, and how annual MDC influences the association between baseline mammographic density (MD) and BC risk. Methods We used the Karolinska Mammography Project for Risk Prediction of Breast Cancer cohort of Swedish women (N = 43 810) aged 30–79 years with full access to BC risk factors and mammograms. MD was measured as dense area (cm2) and percent MD using the STRATUS method. We used the contralateral mammogram for women with BC and randomly selected a mammogram from either left or right breast for healthy women. We calculated relative area MDC between repeated examinations. Relative area MDC was categorized as decreased (&amp;gt;10% decrease per year), stable (no change), or increased (&amp;gt;10% increase per year). We used Cox proportional hazards regression to estimate the association of BC with MDC and interaction analysis to investigate how MDC modified the association between baseline MD and BC risk. All tests of statistical significance were two-sided. Results In all, 563 women were diagnosed with BC. Compared with women with a decreased MD over time, no statistically significant difference in BC risk was seen for women with either stable MD or increasing MD (hazard ratio = 1.01, 95% confidence interval = 0.82 to 1.23, P = .90; and hazard ratio = 0.98, 95% confidence interval = 0.80 to 1.22, P = .90, respectively). Categorizing baseline MD and subsequently adding MDC did not seem to influence the association between baseline MD and BC risk. Conclusions Our results suggest that annual MDC does not influence BC risk. Furthermore, MDC does not seem to influence the association between baseline MD and BC risk.
Gal9/Tim-3 expression level is higher in AML patients who fail chemotherapy
Authors: Paola Dama, Marshall Tang, Noreen Fulton, Justin Kline, Hongtao Liu
Journal: Journal for ImmunoTherapy of Cancer (2019)

Immune checkpoint pathways active in Acute Myeloid Leukemia (AML) patients, especially during the course of remission induction chemotherapy, have not been well studied. Although dominant in mediating T cell dysfunction in cancer, it is now well-accepted that interruption of PD-1/PD-L1 axes alone does not always completely restore T cell function, indicating the involvement of additional negative regulatory pathways, such as TIM-3/Gal-9, in promoting T cell exhaustion.Here, we characterized these pathways in AML patients enrolled in a phase I dose escalation trial that combined Selinexor, a Selective Inhibitor of Nuclear Export (SINE), with high-dose cytarabine (HiDAC) and mitoxantrone (Mito) (NCT02573363) as induction therapy.To monitor changes in expression of immune checkpoint receptors, multi-parameter flow cytometry was performed on peripheral blood and bone marrow biopsy specimens at diagnosis and following induction therapy in 26 AML patients. Expression of CD47, PD-L1, PD-L2 and Gal9 was assessed on CD34+ AML blasts, as well as on CD34- cell populations. In parallel, we evaluated expression of inhibitory (PD1, CTLA4, LAG3, TIM-3) and stimulatory (CD28, ICOS, CD137, OX40, CD40L, HLA-DR) co-receptors on CD4+ and CD8+ T cell subsets.Compared to baseline, the frequency of Gal9+ CD34- cells was significantly higher in patients with treatment failure (TF) than in those in complete remission (CR), and this finding correlated with increased TIM-3 expression on marrow-resident T cells in TF patients. Moreover, when we measured the expression level of PD-1 and TIM-3 in bone marrow samples compared to peripheral blood, TIM-3 was significantly higher in BM specimens.Our results suggest that targeting the Gal9/Tim-3 axis could be effective in combination with induction chemotherapy to increase the likelihood of complete remission in AML patients.
Pembrolizumab (Pembro) therapy vs best supportive care (BSC) in advanced hepatocellular carcinoma (HCC): KEYNOTE-240
Authors: R.S. Finn, B.-Y. Ryoo, P. Merle, M. Kudo, M. Bouattour, H.-Y. Lim, V. Breder, J. Edeline, Y. Chao, S. Ogasawara, T. Yau, M. Garrido, S.L. Chan, J. Knox, B. Daniele, S.W. Ebbinghaus, E. Chen, A.B. Siegel, A.X. Zhu, A.-L. Cheng
Journal: Annals of Oncology (2019)
Use of miRNA profiling in metastatic renal cell carcinoma to reveal a tumor suppressor effect for mir-215.
Authors: George M. Yousef, Susanne M. Chan, Nicole MA White, Heba WZ Khella, Joerg Grigull, Sonja Adzovic, Youssef M. Youssef, R. John Honey, Robert Stewart, Kenneth T Pace, Michael A. S. Jewett, Andrew Evans, Manal Y. Gabril, Georg A. Bjarnason
Journal: Journal of Clinical Oncology (2012)

4633 Background: Renal cell carcinoma (RCC) is the most common neoplasm of the adult kidney. Metastatic RCC is difficult to treat. The five-year survival rate for metastatic RCC is &lt;10%. Recently, microRNAs (miRNAs) have been shown to have a role in cancer metastasis and potential as prognostic biomarkers in cancer. Methods: We performed a miRNA microarray to identify a miRNA signature characteristic of metastatic compared to primary RCC. Results were validated by quantitative real time PCR. Target prediction analysis and gene expression profiling identified many of the dysregulated miRNAs could target genes involved in tumor metastasis. The effect of miR-215 on cellular migration and invasion was shown in a RCC cell line model. Results: We identified 65 miRNAs that were significantly altered in metastatic when compared to primary RCC. Nine (14%) miRNAs had increased expression while 56 (86%) miRNAs showed decreased expression. miR-10b, miR-196a, and miR-27b were the most downregulated while miR-638, miR-1915, and miR-149* were the most upregulated. A non-supervised 2D-cluster analysis showed that a sub-group of the primary tumors clustered under the metastatic arm with a group of miRNAs that follow the same pattern of expression suggesting they have an inherited aggressive signature. We validated our results by examining the expressions of miR-10b, miR-126, miR-196a, miR-204, and miR-215, in two independent cohorts of patients. We also showed that overexpression of miR-215 decreased cellular migration and invasion in a RCC cell line model. In addition, through gene expression profiling, we identified direct and indirect targets of miR-215 that can contribute to tumor metastasis. Conclusions: Our analysis showed that miRNAs are altered in metastatic RCC and can contribute to kidney cancer metastasis through different biological processes. Dysregulated miRNAs represent potential prognostic biomarkers and may have therapeutic applications in kidney cancer.