tbuckley/cabot-search huggingface dataset:
Abstract 15973: The Association Between Blood Pressure Control and Outcomes Among Black Participants in the Jackson Heart Study
Authors: Tiffany C Randolph, Melissa A Greiner, Chidiebube Egwim, Adrian F Hernandez, Kevin L Thomas, Lesley H Curtis, Paul Muntner, Wei Wang, Robert J Mentz, Emily C O'Brien
Journal: Circulation (2015)

Introduction: The 2014 hypertension (HTN) guidelines liberalized blood pressure (BP) goals for people ≥60 years. Hypothesis: Increased systolic and diastolic blood pressure (SBP/DBP) will be associated with a higher risk of mortality and heart failure hospitalization (HFH) across all age groups. Methods: We used age-adjusted Kaplan-Meier estimates to calculate the cumulative incidence of mortality and HFH across SBP/DBP categories (Figure) among 5280 participants of the Jackson Heart Study (JHS), an exclusively black population. We used Cox proportional hazards models to investigate associations between baseline visit SBP/DBP and both mortality and HFH. Linearity of associations and differential effects by age were assessed. Results: Median age was 56 years (IQR: 46-65); 63% were female; median SBP was 125 mmHg (IQR: 114-137); and median DBP was 79 mmHg (IQR: 72-86). There were 520 deaths over 9 years and 340 HFHs over 7 years. The age-adjusted cumulative incidence of both mortality and HFH increased with SBP, while rates of both outcomes were similar by DBP (Figure). After multivariable adjustment, every 10 mmHg increase in SBP was associated with increased mortality (HR 1.12 95% CI [1.06, 1.17]; p&lt;.001) and HFH (HR 1.07 95% CI [1.00, 1.14]; p=0.05). The mortality risk per 10mmHg increase in SBP was greater in participants &lt;60 years (HR 1.26 95% CI [1.13, 1.42]; p&lt;.001) than ≥ 60 years (HR 1.09 95% CI [1.03, 1.15]; p=.004). DBP was inversely associated with risk of mortality (HR 0.85 95% CI [0.77, 0.94]; p= .002) and not associated with HFH (p=.20). Conclusions: In this JHS cohort, SBP was associated with both mortality and HFH, while DBP was inversely associated with mortality. Adults across all age groups were at increased risk of mortality as SBP increased. In the context of new HTN guidelines, these findings have important implications and should be considered when determining BP treatment goals in Black patients.
TCT-634 Percutaneous Coronary Intervention with Drug-Eluting Stents for the Treatment of Cardiac Allograft Vasculopathy and the Impact of Intravascular Ultrasound and Stent Characteristics on Lesion Patency: 4-Year Outcomes
Authors: Richard Cheng, Dael Geft, Evan Kransdorf, Jignesh Patel, Jon Kobashigawa, Babak Azarbal
Journal: Journal of the American College of Cardiology (2018)
Comprehensive genomic profiling in Chinese patients with clear cell renal cell carcinoma.
Authors: Baiye Jin, Yimin Wang, Jindan Luo, Yu Wang, Shuang Ren, Chin-Lee Wu, Peng Zhang, Lei Mei, Kai Wang, Shuang Wang
Journal: Journal of Clinical Oncology (2018)

e13517 Background: Clear cell renal cell carcinoma (ccRCC) represents the most common histological subtype of RCC, with poor response to chemotherapy and radiotherapy. Immunotherapy and novel therapies targeting angiogenesis signaling pathways have proved to be effective for RCC patients (pts). However, the comprehensive genomic features of ccRCC in Chinese pts have not been well understood. Methods: Deep sequencing targeting 450 cancer genes was performed on FFPE and matched blood samples collected from 39 Chinese ccRCC pts with a median age of 54 years (range 31-75) and a male-to-female ratio of 3.3. Genomic alterations (GAs) including single nucleotide variations, short and long insertions and deletions, copy number variations, and gene rearrangements were analyzed. Tumor mutation burden (TMB) and microsatellite instability (MSI) status were assessed by standard NGS algorithms. Results: In the Chinese cohort, the most common genomic alterations were detected in VHL (82.1%), PBRM1 (53.8%), SETD2 (20.5%), PTEN (15.4%), BAP1 (17.9%), TSC1/2 (15.4%), TP53 (10.3%), TERT (7.7%), MTOR (7.7%), KMT2C (7.7%), and CHD2 (7.7%). In total, 80% of the pts had one or more actionable GAs. The chromosome 3p tumor suppressors (VHL, PBRM1, and SETD2) were identified in 87% of the pts. PI3K/mTOR pathway alterations including PTEN, MTOR, TSC1/2 and PIK3CA mutations were detected in 30% of the pts. Compared with TCGA data (501 pts), we found higher mutation frequency of VHL, PBRM1, and PTEN in the current Chinese cohort. The median TMB value of our ccRCC pts was 5.6 muts/Mb (range: 0-58); 8.3% of the pts had TMB greater than or equal to 20 muts/Mb. Three ccRCC pts were identified as MSI-H. One pt with a novel MET fusion responded well to cabozantinib. Conclusions: Compared with the TCGA data set mostly based on Western population, our Chinese cohort revealed that the genomic alteration frequencies of chromosome 3p tumor suppressors (VHL, PBRM1, and SETD2) were higher compared with TCGA (VHL: 82.1% vs 49.3%; PBRM1: 53.8% vs 30.1%; SETD2: 20.5% vs 12.4%). The NGS-based comprehensive genomic profiling assay could detect all GAs, TMB, and MSI status simultaneously, and suggest personalized treatment options of targeted therapy and immunotherapy for ccRCC pts.
Combating herpesvirus encephalitis by potentiating a TLR3–mTORC2 axis
Authors: Ryota Sato, Akihisa Kato, Takahiko Chimura, Shin-Ichiroh Saitoh, Takuma Shibata, Yusuke Murakami, Ryutaro Fukui, Kaiwen Liu, Yun Zhang, Jun Arii, Ge-Hong Sun-Wada, Yoh Wada, Tsuneo Ikenoue, Glen N. Barber, Toshiya Manabe, Yasushi Kawaguchi, Kensuke Miyake
Journal: Nature Immunology (2018)
Efficacy and safety of tamibarotene or placebo added to paclitaxel/carboplatin for advanced non-small cell lung cancer.
Authors: Daniel J. Levitt, Scott Wieland, David Haen, Shanta Chawla
Journal: Journal of Clinical Oncology (2016)

e20560 Background: The results of studies to evaluate adding retinoids to chemotherapy for patients with advanced non-small cell lung cancer (NSCLC) have been mixed. The retinoid all-trans retinoid acid (ATRA) appears to improve efficacy in NSCLC patients, while bexarotene, a rexinoid, does not. Tamibarotene (T) is a potent retinoid with fewer side effects than ATRA. We evaluated the efficacy and safety of adding T or placebo (Pb) to paclitaxel (P) and carboplatin (C) in patients with stage IIIb (+ pleural effusion) or IV non-small cell lung cancer. Methods: Patients with either stage IIIb (with pleural effusion) or stage IV NSCLC (both adeno- and squamous carcinomas), no prior chemotherpy, satisfactory neutrophil, platelet and red cell numbers, ECOG < / = 2, satisfactory liver, cardiac and renal function, peripheral neuropathy < grade 2, triglycerides < 1000 mg/dL, Hb1Ac < 5.7 and no active CNS metastases were eligible. Patients were randomized to receive P (200 mg/m2 ) and C (AUC = 6) every 3 weeks, and either T (6 mg/m2 ) or matching Pb daily for up to 6 cycles. Patients with stable disease or an objective response could continue to receive either T or Pb until progression. CT scans were obtained on Days 50, 113 and every 2 months to progression or death. Scans were read by a blinded radiology review organization (RECIST 1.1) . Results: 127 randomized patients were analyzed by intent-to-treat criteria (59 Pb/P/C; 68 T/P/C). Median PFS for Pb/P/C was 9.2 months (95% CI 6.8-12.7) and for T/P/C it was 5.7 months (95% CI 2.8-7.9), p = 0.088; HR 1.54 (0.85- ). At the time of analysis median OS for Pb/P/C was 13.8 months (9.7- ) and for T/P/C it was 13.7 months (8.9-15.8), p = 0.24; HR = 1.48 (0.68- ). The ORR for Pb/P/C was 27.0% and for T/P/C it was 19.1% (p = 0.28). Grades 3&4 adverse events were generally greater in the T/P/C cohort and included anemia (8.2 vs 3.2%); hypertrigyceridemia (17.8 vs 1.6%); thromboembolism (8.2 vs 1.6%); febrile neutropenia (4.2 vs 0%). Grades 3&4 neutropenia were similar in both arms (12.3 vs 12.7%). Conclusions: The potent retinoid tamibarotene does not improve the outcome in NSCLC patients receiving paclitaxel/carboplatin chemotherapy and is associated with increased toxicity. Clinical trial information: NCT01337154.
TCT-308 Comparison between fractional flow reserve (FFR) and Computational fractional flow reserve derived from three-dimensional intravascular ultrasound (FFR-IVUS), percentage of diameter stenosis by visual estimation and bi-dimensional quantitative coronary angiography.
Authors: Alexandre Hideo-Kajita, Hector Garcia-Garcia, Cristiano Bezerra, Fábio A. Pinton, Breno Falcão, Jose Mariani, Carlos Bulant, Gonzalo Maso Talou, Antonio Esteves Filh Esteves, Pablo Blanco, Pedro A. Lemos
Journal: Journal of the American College of Cardiology (2018)
Pioglitazone and the risk of prostate cancer.
Authors: Adi Joseph Klil-Drori, Hui Yin, Oriana Yu, Michael N. Pollak, Laurent Azoulay
Journal: Journal of Clinical Oncology (2016)

e16574 Background: Data from recent studies have associated the use of pioglitazone, an antidiabetic drug of the thiazolidinedione (TZD) class, with an increased risk of prostate cancer (PCa), but the evidence remains limited. Additional studies are needed to examine this possible association. Methods: Using the UK Clinical Practice Research Datalink, we identified all male patients initiating an antidiabetic drug between 2000 and 2013; patients were followed through 2014. The use of pioglitazone was treated as a time-varying variable, lagged by one year for latency purposes. Time-dependent Cox proportional hazards models were used to estimate adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) of PCa associated with the use of pioglitazone, compared with non-TZD use. Secondary analyses were conducted to assess the association by tertile categories of cumulative duration and cumulative dose. Results: The cohort included 81,206 patients, of whom 1344 were newly-diagnosed with PCa (rate: 332/100,000 person-years). The use of pioglitazone was not associated with an overall increased risk of PCa (HR: 1.10, 95% CI: 0.90-1.34). In secondary analyses, non-linear trends were observed with cumulative duration and cumulative dose (Table). In the latter, the second tertile was associated with a significant increased risk of PCa (HR: 1.62, 95% CI: 1.18-2.22), whereas the third tertile was associated with a decreased risk (HR: 0.45, 95% CI: 0.26-0.81). Conclusions: The use of pioglitazone was not associated with an overall increased risk of PCa, and the inconsistent duration- and dose-response relationships suggest a non-causal relationship. Hazard ratios for pioglitazone and prostate cancer risk by cumulative duration and dose. Pioglitazone use category Cumulative dura tion (days) Adjusted HR (95% CI) Cumulative dose (mg) Adjusted HR (95% CI) Tertile 1 1-480 1.24 (0.87- 1.77) 1-11,220 1.17 (0.82- 1.68) Tertile 2 481-1035 1.36 (0.96- 1.92) 11,221- 27,945 1.62 (1.18- 2.22) Tertile 3 ≥ 1036 0.65 (0.40- 1.04) ≥ 27,946 0.45 (0.26- 0.81)
Predictive biomarkers of ipilimumab toxicity in metastatic melanoma.
Authors: Michael Gowen, Jeremy Tchack, Hua Zhou, Keith Michael Giles, Scott Paschke, Una Moran, David Fenyo, Aristotelis Tsirigos, Michael Pacold, Anna C. Pavlick, Michelle Krogsgaard, Iman Osman
Journal: Journal of Clinical Oncology (2017)

9559 Background: There are no predictive biomarkers of ipilimumab (IPI) toxicity. Of metastatic melanoma (MM) patients (pts) receiving IPI (3mg/kg), 35% require systemic therapies to treat immune-related adverse events (irAEs) and 20% must terminate treatment (Horvat et al., JCO 2015). Here we tested the hypothesis that a pre-existing autoantibody (autoAb) profile is predictive of IPI irAEs. Methods: We measured autoAb levels in pre- and post-treatment sera from mm pts who received IPI (3mg/kg) monotherapy on a proteome microarray containing ~20,000 unique full-length human proteins (HuProt array, CDI Laboratories). Clinical data were prospectively collected with protocol-driven follow-up. IrAEs were categorized by CTCAE guidelines as none (grade 0), mild (grade 1-2), or severe (grade 3-4). AutoAb levels were standardized using median quantile normalization and considered positive hits if &gt; 2-SD above the peak array signal and differed by ≥2 fold with p &lt; 0.05 between toxicity groups (Non-parametric Analysis/Wilcox test). Results: Seventy-eight sera from 37 mm pts were analyzed. Antibodies against CTLA-4 were significantly elevated post IPI treatment (p &lt; 0.0001), validating the assay. The pre-treatment levels of 190 IgG autoAbs were significantly different in pts who experienced irAEs (n = 28) compared to those with no irAEs (n = 9). Comparison of severe irAE (n = 9) and no irAE (n = 9) groups revealed 129 IgG autoAbs that significantly differed in pre-treatment sera. Localization and pathway analysis (UniProt, KEGG, Reactome) showed 81/190 (43%) of the autoAbs targeted nuclear and mitochondrial antigens and were enriched in metabolic pathways (p = 0.015). AutoAbs associated with irAEs did not correlate with treatment response. Conclusions: AutoAbs to antigens enriched in metabolic pathways prior to treatment may predict IPI-induced toxicity in MM. The subcellular localization of targeted antigens could explain the autoimmune toxicities associated with IPI. Studies in larger cohorts and in pts receiving other checkpoint inhibitors and/or combination therapies are essential to determine the validity of the data. If validated, our results would support the discovery of the first toxicity predictor in cancer immunotherapy.
Characterizing tumor immune microenvironment (TME) and outcomes for 409 patients (pts) treated on COMPARZ: Distinct clusters emphasize immune infiltration vs. angiogenesis.
Authors: Martin Henner Voss, Fengshen Kuo, Alejandro Sanchez, Irina Ostrovnaya, Yuan Cheng, Parul Patel, Mahtab Marker, Albert Reising, Timothy An-thy Chan, Robert J. Motzer, A. Ari Hakimi
Journal: Journal of Clinical Oncology (2018)

4515 Background: Growing evidence highlights the critical role of the TME for RCC biology and response to systemic therapy. We used integrated molecular profiling to characterize immune & stromal TME across a large cohort of pts treated on the phase 3 COMPARZ trial. Methods: We performed mRNA expression profiling (Affymetrix GeneChip HTA 2.0) and unsupervised consensus clustering from archival paraffin specimens. Clusters were characterized by gene set enrichment analyses (GSEA); transcriptional deconvolution; a 43 gene angiogenesis expression score; immunohistochemistry (IHC) for PD-L1 expression on tumor cells and macrophages; and mutation status for a defined list of genes. Findings were correlated with clinical outcomes using parametric and non-parametric tests. Results: mRNA clustering was done for 409 patients (212 sunitinib, 197 pazopanib treated) and revealed 4 biologically distinct clusters (C1-4) with significant differences in median overall survival (OS;P= 2.00E-4) and progression free survival (PFS;P= 0.03). C4 displayed the worst outcomes and highest rate of IMDC poor risk features (45.7% pts); GSEA showed enrichment for inflammation signatures, e.g. IFN-γ responses. Immune deconvolution demonstrated the most immune-infiltrated TME for C4 with enrichment of many immune subsets, especially macrophages (compared to C1-3, P= 0.0015); C4 also had the highest rate of PD-L1 expression on tumor cells and macrophages (P= 3.50E-7). Pts in C3 had the most favorable outcomes and displayed the highest angiogenesis gene expression levels (P= 2.20E-16). An integrated model of molecular and IMDC variables compared to IMDC risk stratification alone improved the c-index for OS from 0.63 to 0.69 and PFS from 0.60 to 0.65. Conclusions: mRNA-based analyses revealed four distinct molecular subgroups of RCC associated with varying outcomes on TKI therapy. These data highlight stromal and immune TME, specifically angiogenesis and macrophage infiltration programs, as powerful determinants of clinical course. Further study of these differences will be critical in advancing the field of advanced RCC towards precision-medicine. Clinical trial information: NCT00720941.
Profiling analysis reveals potential prognostic biomarkers for esophageal cancer patients treated with radiotherapy.
Authors: Yu Fan, Tao Li, Qifeng Wang, Jiahua Lv, Qi Li, Yi Wang, Junchao Wang
Journal: Journal of Clinical Oncology (2017)

e23190 Background: Survival time among esophageal cancer patients undergoing radiotherapy varies considerably. Treatment failure resulting from local recurrence and metastasis reflects varying biological features such as radiosensitivity, invasion, and metastasis. This study aims to explore the genetic characterizations that are associated with prognosis of esophageal cancer patients who have undergone radiotherapy. Methods: We retrospectively reviewed specimens of 21 patients who were treated with radiotherapy. Based on the progression-free-survival (PFS), these patients were divided in to two groups: short PFS group with an average PFS of 6.9 months and long PFS group with an average PFS of 31.9 months. We extracted DNA from paraffin specimens for next generation sequencing. Mutation burden (the sum of mutation frequencies of targeted genes) and copy number aberrance were analyzed by targeted sequencing that covers 1086 genes. Results: We excluded six samples in the mutation burden analysis because of the shortage of coverage of the targeted genes. The mutation burden of 15 genes panel, which included ARID1A, BCL2, BRAF, CDH1, ERBB2, FAT1, LRP1B, MET, MTOR, NOTCH1,NOTCH2, PDGFRA, PTCH1, RB1, STK11, showed a statistically significant difference between the long PFS group and the short PFS group (p value = 0.001408). We then used copy number variation (CNV) kit to detect genes copy number variation between these two groups. The CNV of 9 genes panel, which include ASH1L, CD55, CDK4, CREBBP, FGFR1, MYC, TP53 , TYMS, XRCC3, showed a statistically significant difference between the long PFS group and the short PFS group (p value = 0.03147). Conclusions: Our results suggested that the gene mutation burden and CNV detected by targeted sequencing have a relationship with the prognosis of esophageal cancer patients who had undergone radiotherapy. In this exploratory study, we involved patients with extreme PFS ( &lt; 1 year and &gt; 2 years), which can be expanded in the future. To construct a predictive genetic model of prognosis in esophageal cancer patients, one may also consider analyzing circulating tumor DNA (ctDNA) in serum.
Comparison of IHC testing for HER-2 in breast cancer specimens before and after adoption of new 2013 ASCO/CAP guidelines in a single institution: Impact on outcome and cost.
Authors: Anurag Sharma, Poornima Hegde, Deepak Vadehra, Talal Kaiser, Susan Tannenbaum
Journal: Journal of Clinical Oncology (2017)

e18294 Background: Revised guidelines for HER-2 testing in Breast Cancer Specimens occurred in 2007 and again in 2013 with an intention to capture more patients who could benefit from HER-2 directed therapy. Methods: The purpose of this study was to compare the HER 2 + cases outright and the equivocal cases that resulted in a reflex FISH test that was ultimately positive utilizing both guidelines. The number of equivocal tests results and those that ultimately were positive, negative or remained equivocal were quantitated. A retrospective analysis on specimens from 2003-2008 and 2013-2016 was performed. Results: see table. Conclusions: An expansion of 8.8% is seen in the equivocal category after adoption of the 2013 guidelines. Despite an increased number of reflex FISH testing there was no significant increase in the number of FISH positive patients. The end result was a greater delay in time to treat patients appropriately for send-out FISH tests and significant increase in costs for testing that did not result in management change. If the additional costs are multiplied by the number of patients with breast cancer each year and resultant equivocal results calculated for the almost 9% increase, that extra cost is close to 12 million dollars. Based on our small institution study, reconsideration of guideline criteria is important in this era of value-based medicine. [Table: see text]
Abstract 17410: Catheter-based Radiofrequency Renal Denervation Decreases Renal Norepinephrine Spillover and Improves Cardiac Contractile Function in a Porcine Model of Ischemic Heart Failure
Authors: Hung-Fat Tse, Song-Yan Liao, Ziyi Zhu, Zhe Zhen, Rita DeRama, Cary Hata, Peter Chen
Journal: Circulation (2015)

Background: Catheter-based radiofrequency (RF) renal denervation (RD) has been shown to decrease renal norepinephrine (NE) spillover in animal models and humans with hypertension. Nevertheless, the effect of RD on renal NE spillover in systolic heart failure (HF) is unknown. Methods: Ischemic HF model was created in 16 porcine by inducing myocardial infarction (MI) via coronary embolization of the left circumflex artery followed by rapid ventricular pacing for 4 weeks (MI+HF). Of these, 8 porcine underwent bilateral RD using the EnligHTN System (St. Jude Medical) and the remaining 8 served as control. All animals were given daily oral metoprolol ZOK (50 mg) plus ramipril (2.5 mg). Serum NE levels at different sites and index of cardiac contractility (dP/dt max /IP) were measured at baseline, immediately after MI (post-MI), at MI+HF and at 10 weeks follow-up. Renal arteries were then prepared for histological analysis. Results: RD significantly increased the dP/dt max /IP as compared with the control group (P&lt;0.05, Figure 1a). RD also decreased the arterial and coronary sinus NE (P&lt;0.05), and renal NE spillover (-54%, P=0.06) at 10 weeks as compared with MI+HF (Figures 1b &amp; 1c). Histological examination showed significant reduction of renal sympathetic efferent nerves (tyrosine hydroxylase+) at proximal, middle and distal portions of the renal artery after RD as compared with the control group (-65%, P&lt;0.05, Figure 1d). Conclusions: In a porcine model of ischemic HF, bilateral RD using catheter-based RF effectively destroys renal nerves to decrease renal NE spillover, and improves LV contractile function compared with medical therapy alone.