tbuckley/cabot-search huggingface dataset:
Abstract MP09: Indices of Kidney Tubular Health Improve Cardiovascular Disease Risk Prediction in Adults With Hypertension and Chronic Kidney Disease in SPRINT
Authors: Alexandra K Lee, Ronit Katz, Walter T Ambrosius, Alfred K Cheung, Pranav Garimella, Lisa H Gren, Vasantha Jotwani, Javier A Neyra, Henry Punzi, Kalani Raphael, Joachim H Ix, Michael Shlipak
Journal: Circulation (2019)

Introduction: While chronic kidney disease (CKD) is a strong risk factor for cardiovascular disease (CVD), traditional metrics of kidney function (eGFR and albuminuria) have not improved CVD risk prediction equations. We hypothesize that new measures of kidney tubular function and injury can improve CVD risk prediction. Methods: Of 1971 SPRINT participants with eGFR &lt;60mL/min/1.73m 2 and without CVD at baseline, we analyzed 1858 with urine and serum biomarkers. We conducted factor analysis on 10 kidney tubule biomarkers using principal-component factor estimation and promax rotation. To examine the association between the factor scores and risk of subsequent cardiovascular events, we used adjusted Cox models. Using Harrell’s C-statistic, we compared a standard CVD risk prediction model to models adding 1) factor scores of kidney tubular health, 2) eGFR and albumin-to-creatinine ratio (ACR), and 3) factor scores, eGFR and ACR. We also conducted these comparisons using ASCVD predicted risk in place of CVD risk factors among those &lt;80 years. Results: Mean age was 73, 44% female, 29% black, and mean±SD eGFR was 45±12 mL/min/1.73m 2 . Factor analysis identified 4 unique dimensions of kidney tubular health that correspond to hypothesized physiologic processes ( Table ). Three of four factors were associated with CVD in demographic models, and Factors 3 and 4 remained associated in the full model. The C-statistic of the base CVD risk equation was 0.670, and with inclusion of the four kidney tubule factors the C-statistic improved to 0.727 (p for difference &lt;0.0001), a larger increase than addition of eGFR and ACR to the base model (c=0.711, p for difference=0.0007). Addition of eGFR and ACR to the kidney tubule model did not improve discrimination (c=0.730, p for difference=0.17). Results were similar with ASCVD predicted risk. Conclusion: Indices of kidney tubular health based on urine and serum biomarkers may improve CVD risk prediction in adults with hypertensive CKD. Further studies are needed in the general, non-CKD population.
Patient perspectives on cytoreductive nephrectomy after CARMENA.
Authors: Dena Battle, Daniel J. George, Axel Bex, Michael D. Staehler
Journal: Journal of Clinical Oncology (2019)

658 Background: Conducted over eight years, enrolling 450 patients at multiple centers in Europe, the CARMENA (Cancer du Rein Metastatique Nephrectomie et Antiangiongeniques) trial demonstrated that systemic therapy using sunitinib alone is not worse than cytoreductive nephrectomy (CN) plus sunitinib in metastatic RCC in an intention to treat analysis (hazard ratio HR): 0.89, 95% confidence interval (CI), 0.71-1.10) (Mejean, NEJM, 2018). We wanted to assess patient views related to CN following the publication of these results. Methods: The Kidney Cancer Research Alliance (KCCure) conducted a survey among kidney cancer patients. The short survey was created via SurveyMonkey and was disseminated in various patient communities using social media and was posted to the KCCure website in June 2018 after the presentation of the CARMENA trial. Patients were asked “The CARMENA trial presented recently at ASCO found that for kidney cancer patients diagnosed with metastatic disease, there is no overall survival benefit of having a nephrectomy prior to starting systemic therapy. Knowing that information, would you still want to have a nephrectomy at diagnosis if you were metastatic?” Patients were also asked whether they had already had a nephrectomy and their stage at diagnosis, whether they were on systemic therapy, gender and age. Results: 186 patients responded with 60.5% being female. Median age 56.5 years (range 26-84). On the question of whether they would want CN. 75.2% of the patients indicated they would still prefer nephrectomy. Of the patients with primary metastatic disease and the tumor in place treated with systemic therapy, 20.1% wanted their kidney tumor to be removed. There was no statistically significant difference between patients who had experience with systemic therapy and those who hadn’t, answers were also consistent regardless of gender and age. Conclusions: Overall survival should not be overestimated as the most important aim in an end-stage patient population. Patients might think differently about benefits, risks and value of surgical procedures then physicians.
Cariprazine Treatment of Bipolar Depression: A Randomized Double-Blind Placebo-Controlled Phase 3 Study
Authors: Willie Earley, Maria Victoria Burgess, Ludmyla Rekeda, Regan Dickinson, Balázs Szatmári, György Németh, Roger S. McIntyre, Gary S. Sachs, Lakshmi N. Yatham
Journal: American Journal of Psychiatry (2019)

Cariprazine, a dopamine D3/D2 and 5-HT1A receptor partial agonist, was found to be effective in treating bipolar I depression in a previous phase 2 study. This phase 3 study further assessed the efficacy, safety, and tolerability of cariprazine in bipolar I depression.In a double-blind placebo-controlled study, adult participants (18-65 years old) who met DSM-5 criteria for bipolar I disorder and a current depressive episode were randomly assigned to receive placebo (N=158) or cariprazine at 1.5 mg/day (N=157) or 3.0 mg/day (N=165). The primary and secondary efficacy parameters were changes from baseline to week 6 in Montgomery-Åsberg Depression Rating Scale (MADRS) score and Clinical Global Impressions severity (CGI-S) score, respectively. Least squares mean differences were estimated using a mixed model for repeated measures, and p values were adjusted for multiplicity.Both dosages of cariprazine were significantly more effective than placebo in improving depressive symptoms (reducing MADRS total score); the least squares mean differences were -2.5 (95% CI=-4.6, -0.4) for cariprazine at 1.5 mg/day and -3.0 (95% CI=-5.1, -0.9) for cariprazine at 3.0 mg/day. Both cariprazine dosages were associated with lower CGI-S scores compared with placebo, but the differences did not reach statistical significance after adjustment for multiplicity (least squares mean difference, -0.2 [95% CI=-0.5, 0.0] for the 1.5 mg/day group and -0.3 [95% CI=-0.5, 0.0] for the 3.0 mg/day group). Common treatment-emergent adverse events (in at least 5% of participants in either cariprazine treatment group and twice the rate of the placebo group) were nausea, akathisia, dizziness, and sedation. Mean changes in weight and metabolic parameters were relatively small and comparable across groups.Cariprazine, at both 1.5 mg/day and 3.0 mg/day, was effective, generally well tolerated, and relatively safe in reducing depressive symptoms in adults with bipolar I depression.
Abstract P213: Serum Metabolomic Profile of Dietary Acid Load in Two Chronic Kidney Disease Studies
Authors: Casey M Rebholz, Aditya Surapaneni, Andrew S Levey, Mark J Sarnak, Lesley A Inker, Lawrence J Appel, Josef Coresh, Morgan E Grams
Journal: Circulation (2019)

Background: Dietary acid load reflects the balance between acid-producing foods (meat, cheese) and base-producing foods (fruits, vegetables), and is clinically important due to its association with risk of cardiovascular disease, diabetes, kidney disease, and mortality. Methods: We used untargeted metabolomics to identify blood biomarkers of dietary acid load in two independent studies of chronic kidney disease patients: the African American Study of Kidney Disease and Hypertension (AASK, n=689) and the Modification of Diet in Renal Disease (MDRD, n=356) study. Multivariable linear regression was used to assess the cross-sectional association between serum metabolites whose identity was known (outcome) and dietary acid load (exposure), estimated with net endogenous acid production based on 24-hour urine levels of urea nitrogen and potassium, and adjusted for age, sex, race, randomization group, mGFR, log-transformed urine protein-to-creatinine ratio, history of cardiovascular disease, body mass index, and smoking status. Results: Out of the 757 known, non-drug metabolites identified in AASK, 26 were significantly associated with net endogenous acid production at the Bonferroni threshold for significance (p&lt;6.6 х 10 -5 ). Twenty-three of the 26 metabolites were also identified in the MDRD study, and 13 of the 23 (57%) were significantly associated with net endogenous acid production (p&lt;2.2 х 10 -3 ), including 5 amino acids, 2 cofactors and vitamins, 1 lipid, and 5 xenobiotics ( Table ). Higher levels of all 13 replicated metabolites were associated with lower levels of net endogenous acid production in both AASK and the MDRD study. Conclusion: Untargeted metabolomics of serum specimens from kidney disease patients in two study populations identified 13 replicated metabolites associated with dietary acid load. Additional studies are needed to validate these compounds in healthy populations. These 13 compounds may potentially be used as objective markers of dietary acid load in future nutrition research studies.
An exercise intervention during acute hospitalization improved function and cognition at discharge in older adults
Authors: Dinesh Kumbhare
Journal: Annals of Internal Medicine (2019)

Source Citation Martínez-Velilla N, Casas-Herrero A, Zambom-Ferraresi F, et al. Effect of exercise intervention on functional decline in very elderly patients during acute hospitalization: a randomized clinical trial. JAMA Intern Med. 2018. [Epub ahead of print]. 30419096
Suppression of human colorectal cancer cell proliferation by noncanonical Wnt 9A ligand induction.
Authors: Donald Peter Braun, Irshad Ali
Journal: Journal of Clinical Oncology (2015)

e14621 Background: Malignant tissues are often characterized by dysfunctional Wnt signaling with the predominant feature involving the regulation of β-catenin. β-catenin is utilized by the canonical pathway (CP) for stimulation of proliferation and its activity is countered by the noncanonical pathway (NCP) involved with differentiation. The possibility that the NCP components in malignant tissues facilitate uncontrolled proliferation has not been studied comprehensively. This study was performed to determine the capacity of NCP components to modulate proliferation of human colorectal cancer (CRC) cells. Methods: Short term, primary CRC lines (n = 5) were established from resected tumors from patients with metastatic and/or recurrent disease. CRC were treated with LiCl, an activator of CP in the presence and absence of various Wnt pathway modulators including: IWP-2, a pan inhibitor of CP and NCP Wnt ligand secretion; conditioned media (CM) from LiCl + IWP-2 treated cells; a specific antibody against NCP ligand, Wnt 9A; and recombinant Wnt 9A protein. CRC proliferation assay and Wnt pathway gene expression analysis was performed. Results: CRC proliferation was inhibited by LiCl (p < 0.001) and this effect was partially reversed by IWP-2 (p < 0.05). Expression of the gene for the NCP ligand Wnt 9A was increased 17 fold by LiCl (p < 0.03). CM from cells treated with LiCl inhibited proliferation (p < 0.05) and this inhibition was absent in CM from LiCl+IWP-2 treated cells. Wnt 9A antibody partially but significantly reversed the LiCl-mediated suppression of proliferation (p < 0.05). Recombinant Wnt 9A protein inhibited CRC proliferation (p < 0.002). Conclusions: The correlation of increased Wnt 9A expression with suppression of CRC proliferation and reversal of this effect by specific Wnt 9A antibody demonstrate that this NCP ligand is capable of suppressing proliferation of human CRC. This contention is supported by the capacity of recombinant Wnt 9A protein to inhibit CRC proliferation. This study demonstrates a novel mechanism for suppression of CRC proliferation by induction of a NCP ligand and suggests that development of therapeutic interventions that activate NCP may be beneficial for controlling human CRC proliferation.
A prospective multicenter study assessing effectiveness and safety of secukinumab in a real-life setting in 158 patients
Authors: José-María Ortiz-Salvador, Martina Saneleuterio-Temporal, Jorge Magdaleno-Tapial, Manel Velasco-Pastor, Conrad Pujol-Marco, Antonio Sahuquillo-Torralba, Almudena Mateu-Puchades, Gerard Pitarch-Bort, Juan-Ignacio Marí-Ruiz, Javier Mataix-Díaz, Encarna Montesinos-Villaescusa, Julia Miralles-Botella, Laura García-Fernández, Antonio Martorell-Calatayud, Isabel Belinchón-Romero, José-Luis Sánchez-Carazo, Amparo Pérez-Ferriols
Journal: Journal of the American Academy of Dermatology (2019)

Secukinumab is a first-in-class interleukin 17A monoclonal antibody that has demonstrated an excellent safety and efficacy profile in phase 3 studies.To evaluate the effectiveness of secukinumab in daily clinical practice and to understand the clinical and epidemiologic characteristics of patients treated with secukinumab in clinical settings.In this multicenter prospective observational study, we recruited adult patients with moderate-to-severe plaque psoriasis from 12 hospitals in Spain during January-December 2016. These patients were treated with secukinumab and prospectively followed at 12-week intervals for 52 weeks.In total, 158 patients were recruited to the study. A Psoriasis Area and Severity Index (PASI) score improvement ≥75% over baseline (PASI-75) was achieved by 57%, 83.5%, 89%, and 78.5% of patients at weeks 4, 12, 24, and 52, respectively. PASI-90 was achieved in 27.8%, 62%, 64.6%, and 63.2% of patients at weeks 4, 12, 24, and 52, respectively; PASI-75 and PASI-90 responders were significantly more common among patients with a body mass index <30 kg/cm2 and patients without previous biologic therapy failures.Observational study. Time from onset of psoriasis was not evaluated.Secukinumab is a safe treatment with effectiveness rates similar to those found in its phase 3 studies. These rates endure up to a year from start of treatment.
Cost-effectiveness for extended RAS/RAF testing in metastatic colorectal cancer.
Authors: Marwan R. Al-hajeili, Faris Elkhider, M. Hakam Tiba
Journal: Journal of Clinical Oncology (2015)

3572 Background: Epithelial growth factor receptors (EGFR) inhibitors (Cetuximab and panitumumab) are monoclonal antibodies directed against EGFR and promote apoptosis. Douillard et al demonstrated the benefit of using EGFR inhibitors agents in wild type (WT) KRAS metastatic colorectal cancer (mCRC) and lack of benefit in mutated KRAS mCRC patients. Only WT KRAS mCRC are candidate for EGFR inhibitors, they constitute 57.6% of all mCRC patients, 27.3% of them carry other RAS/RAF mutations that preclude them from EGFR inhibitors benefits. Insurance companies are willing to pay the cost of KRAS testing and EGFR inhibitors treatment for all WT KRAS mCRC. We conducted this analysis to assess the cost-effectiveness of the extended testing for other RAS/RAF mutations for WT KRAS mCRC patients. Methods: A decision analysis model using (Treeage pro Software, Williamstown, MA) was developed to assess and compare treatment costs and disease outcomes associated with presence or absence of additional mutations (RAS/RAF) in a WT KRAS mCRC. . For utility estimate, Quality of life (QoL) assessment based on Skindex-16 for EGFR inhibitors side effects. The difference in median survival time was used to calculate incremental effectiveness of using EGFR inhibitors based on the extended testing or not. Costs were determined through Medicare records and direct hospital charges for extended testing, and treatment with EGFR inhibitors. For sensitivity analysis, we modify mutations probability and the extended testing cost, in both 1-way and combined 2-way sensitivity analyses. Results: The total expected cost was $56,306.06 vs. $42,683.75 favoring additional testing. The median overall survival was 15.8 vs.14.5 months favoring additional testing. In order to conclude extended testing is not worth it, mutation probability has to be less than 1.8%, or extended testing cost of more than 14000 $ in one way sensitivity testing. However, for two-way analysis, the mutation probability needs to be less than 17% and test cost needs to be more than $8,200. Conclusions: Our analysis shows that extended testing for other RAS/RAF mutations is cost-effective in WT KRAS mCRC patients before treating with EGFR inhibitors.
The predictive value of DRE in the modern era of prostate cancer diagnostics.
Authors: Joel Marcus Andersson, Tobias Nordström, Martin Eklund, Henrik Gronberg
Journal: Journal of Clinical Oncology (2019)

48 Background: DRE (digital rectal examination) suspicious for prostate cancer is still used as a clinical tool to diagnose prostate cancer. We aim to analyse the predictive value of DRE to diagnose prostate cancer ISUP grade group ≥2 (GG≥2) prostate cancer including the setting of STHLM3 test as a variable. Methods: The previously described STHLM3 screening-cohort included men between 50 to 70 years with ≥10% risk of prostate cancer as assessed by PSA or the Stockholm3 test and invited for transrectal biopsy (TRUSbx). All 7415 biopsied men was included for analysis. DRE status was categorized as T1-T4. We analysed sensitivity (Sn), specificity (Sp), positive predictive value (PPV) and negative predictive value (NPV) for DRE status of T2-4 to predict GG≥2 and GG≥3 in biopsies. In a multivariate logistic regression analysis; we adjusted for PSA, age, PVol, earlier biopsy (EB) and adjusted STHLM3 model risk set to exclude DRE and prostate volume (PVol). We calculated adjusted odds ratio (OR) for different strata of adjusted STHLM3 risk. Results: Prevalence of ISUP≥2 was 16.8% (1,243/7415). 9.7% (716/7415) men had DRE suspicious for cancer (T2-4) with a Sn to detect GG≥2 of 25.2%. Sp, PPV and NPV was 93.5%, 43.7% and 86.1%, respectively. In univariate model the OR for DRE T2-4 vs. T1 to predict GG≥2 was 4.28 (95% CI 4.09–5.67). Logistic regression analysis including also age, PVol, PSA, earlier biopsies and adjusted STHLM3 risk (%) gave an OR for DRE T2-4 of 2.87 (95% CI 2.36–3.49). In the same analysis stratified PSA group 5-10 ng/ml with PSA &lt; 3 ng/ml as baseline gave OR = 3.21. Using the same univariate model, OR for DRE T2-4 vs. T1 to predict GG≥3 was 6.68 (95% CI 5.44–8.21) and in the multivariate model OR was 3.25 (95% CI 2.54–4.17). Conclusions: As a diagnostic test DRE holds little merit on its own but in combination with other clinical factors and biomarkers in this study we could show that it contributes with value. Just under half of men with DRE suspicious for cancer has GG≥2 cancer. This study does not establish evidence to rule out DRE as a clinically valuable adjunct to PSA, other clinical parameters and new biomarkers like STHLM3.
Synchronous and metachronous cases of renal cell carcinoma and hematologic malignancies in a state cancer registry.
Authors: John Clark Henegan, Katelyn Mitchell, Joseph Maher
Journal: Journal of Clinical Oncology (2019)

593 Background: A Swedish national family-cancer database reported an association between renal cell carcinoma (RCC) and hematologic malignancies within families. Our hypothesis was that a search of a state cancer registry would detect an increased incidence of observed (versus expected) synchronous and metachronous cases of RCC and select hematologic malignancies. Methods: A query of the Mississippi Cancer Registry was performed for synchronous ( &lt; 6 months between diagnoses) and metachronous ( &gt; 6 months) cases of RCC and select hematologic malignancies (non-Hodgkin lymphoma (NHL), multiple myeloma (MM), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia, and Hodgkin lymphoma) in the state from 2003 to 2013. The expected number of cases was calculated based on crude case numbers available from https://www.cancer-rates.info/ms/. The percentage of the population &lt; 18 years of age was removed from the eligible population. 2x2 tables were constructed to calculate a chi-square score of expected versus observed cases. Using one degree of freedom, a p-value was calculated from this statistic. Due to privacy issues, the registry was unable to provide an exact number of observed combined cases if there were &lt; 5 in the time period. Results: Conclusions: There is a statistically significantly increased incidence of observed (versus expected) synchronous and metachronous cases of RCC with the B-cell malignancies NHL, MM, and CLL in Mississippi between 2003 and 2013. Future research will focus on clinical characteristics of patients with synchronous or metachronous cases of RCC and these hematologic malignancies.[Table: see text]
Validation of a two-gene mRNA urine test for detection of high-grade prostate cancer in German men.
Authors: Derya Tilki, Daphne Hessels, Geert Trooskens, Susan Mulders, Michael Brawer, Wim Van Criekinge, Jack Groskopf, Alexander Haese
Journal: Journal of Clinical Oncology (2019)

96 Background: There is an unmet need for non-invasive methods that can accurately identify patients at increased risk for clinically significant prostate cancer (PCa). SelectMDx is a urine-based molecular test that has been clinically validated for the detection of high-grade PCa. We evaluated SelectMDx clinical performance in a cohort of German men undergoing initial prostate biopsy. Methods: The study population consisted of 443 men sequentially enrolled men who underwent initial prostate biopsy between July 2009 and December 2014 due to suspected PCa. Post-DRE urine was collected from all subjects prior to biopsy, and samples stored at -70C. Urinary HOXC6 and DLX-1 mRNAs were quantified by PCR in May 2018, and RNA results combined with clinical risk factors to determine the likelihood that biopsy would identify ISUP grade group (GG) ≥ 2 (Gleason Score ≥ 7) PCa. We assessed SelectMDx performance for detection of GG ≥ 2 PCa, compared to the PCPT Risk Calculator Version 2.0 (PCPTRC, http://myprostatecancerrisk.com , accessed Oct 7, 2018). Results: For the 443 subjects enrolled, average age was 66 years (median 66, interquartile range 61 to 71), and average serum PSA level 8.8 ng/mL (6.4, 4.8 to 9.7). Cancer was detected in 243/443 (55%) men biopsied (43% GG1, 36% GG2, 9% GG3 and 12% GG4-5). The prevalence of GG2-5 PCa in this population was 31.4% (139/443). For detection of GG2 or higher PCa versus GG1 or no PCa at biopsy, SelectMDx AUC was 0.82 (95% C.I. 0.78-0.86) and the PCPTRC yielded AUC 0.75 (0.70-0.80), P &lt; 0.001. SelectMDx sensitivity was 94% (89-98%), specificity 46% (40-52%), positive predictive value 45% (42-47%) and negative predictive value (NPV) 95% (90-97%). If the initial biopsy had been performed based on SelectMDx results alone, 46% of potentially unnecessary biopsies and 34% of all biopsies would have been avoided, while 5.8% of men with biopsy-detectable high-grade PCa (seven GG2, one GG3) may have had their diagnosis delayed. Conclusions: In this first validation study of SelectMDx in German men, the test’s clinical performance was comparable to the published EU validation study, showing a high NPV for detection of GG2 or higher PCa. These results provide further evidence for the clinical validity of SelectMDx.