tbuckley/cabot-search huggingface dataset:
Next-generation sequencing (NGS) of tissue and cell free DNA (cfDNA) to identify somatic and germline alterations in advanced prostate cancer.
Authors: Michael L. Cheng, Wassim Abida, Dana E. Rathkopf, Maria E. Arcila, David Barron, Karen A. Autio, Ahmet Zehir, Daniel Costin Danila, Michael J. Morris, Anuradha Gopalan, Victor E. Reuter, Philip W. Kantoff, Susan F. Slovin, Mark E. Robson, Liying Zhang, Diana Mandelker, Dana Tsui, Barry S. Taylor, David B. Solit, Howard I. Scher
Journal: Journal of Clinical Oncology (2017)

5010 Background: With the goal of accelerating enrollment onto appropriate clinical trials, we performed prospective genomic characterization of pts with advanced prostate cancer. Given the long natural history and osseous disease predominance, we also analyzed plasma cfDNA to assess the feasibility of identifying targetable alterations in pts for whom adequate tumor tissue was unavailable. Methods: 1038 tumors from 896 pts along with matched normal DNA were analyzed with a capture-based NGS assay (MSK-IMPACT) targeting 341–468 genes. In 5/2015, the protocol was amended to allow pts to opt-in for a formal germline analysis of 76 genes associated with heritable cancer risk. In select pts, plasma cfDNA was collected and analyzed using the same assay. Results: Between 2/2014 and 2/2017, 576 primary tumors and 462 metastases were sequenced. The most notable finding was the high frequency of known or likely pathogenic germline and somatic mutations in genes that regulate DNA damage response (DDR). In the subset with both tumor and germline analysis, 28.84% (169/586) had a DDR mutation identified compared to only 10.65% (33/310) of pts with somatic only analysis. In the subset with tumor and germline analysis, 9.39% (55/586) had somatic only DDR mutations and 16.38% (96/586) had germline only DDR mutations, including 8 pts with two germline mutations. 3.07% (18/586) had co-occurring somatic and germline DDR mutations, with only 0.68% (4/586) involving the same DDR gene (all BRCA2). Prostate cancer had the highest tissue failure rate among the overall MSK-IMPACT solid tumor cohort, and bone biopsy-derived tissue was successfully sequenced in only 42% of pts. Profiling of cfDNA did identify somatic DDR or AR mutations in 12.5% (4/32) of pts without adequate tumor for analysis. Conclusions: This prospective genomic profiling effort identified frequent somatic and germline DDR mutations that may guide PARPi or platinum therapy. Both somatic and germline analyses were required to identify all pts with likely pathogenic DDR alterations. NGS-based cfDNA analysis is feasible in advanced prostate cancer and may identify mutations missed by tumor only sequencing.
Could neutrophil to lymphocyte ratio (NLR), derived neutrophil to lymphocyte ratio (dNLR), platelet to lymphocyte ratio (PLT), and lymphocyte to monocyte ratio be common independent prognostic factors in head and neck squamous cell carcinoma?
Authors: Georgy M. Manikhas, Svetlana I. Kutukova, Natalia P. Beliak, Natalia V. Popova, Natalia V. Zhukova, Julia V. Ivaskova, Sanal Erdniev
Journal: Journal of Clinical Oncology (2017)

e17519 Background: The purpose of our study was to investigate prognostic role of neutrophil to lymphocyte ratio (NLR), derived neutrophil to lymphocyte ratio (dNLR), platelet to lymphocyte ratio (PLR), and lymphocyte to monocyte ratio in PFS and OS, and immunological tumor’s microenvironment in patient with HNSCC. Methods: We analysed medical records an tumor samples of 60 patients with HNSCC with stage I - IVB (37 men, 23 women; median age 59). All patients were under standard clinical complex protocol. All patients were under our supervision from 2010 to 2015. We examined demographic data, clinical stage, tumor morphological characteristics and specific level of expression of CD8(+) T-cells, in the tumor and microenvironment, and baseline level of WBC, neutrophil, lymphocyte, monocyte and PLT . Also we analysed calculated value of NLR, dNLR, PLR, and LMR. Results: The median value of NLR was 2.03 (95% CI: 1.66-2.59), dNLR - 1.44 (95% CI: 1.23-1.70), PLR - 144.58 (95% CI: 107.59-179.32) and LMR - 6.79 (95% CI: 5.34-8.17). Median of 1-year OS and PFS was non significantly lower in pts with NLR &lt; 2.03 (16.0 vs 18.0 month, p = 0.6020 and 5.00 vs 7.00 month, p = 0.5383). But NLR correlate with expression of CD8(+) T-cell in tumor (p = 0.05). Median of 1-year OS was the same in both group (16.0 vs 17.0 month, p = 0.5453), PFS was non significantly lower in pts with dNLR &lt; 1.44 (16.0 vs 18.0 month, p = 0.6020 and (5.00 vs 7.00 month, p = 0.7435). NLR correlate with expression of CD8(+) T-cell in tumor (p = 0.0337). Analyse of LMR showed trend of best 1-year OS in pts with LMR &lt; 6.79 (18.0 vs 15.0 month, p = 0.4674) and equal PFS (6.00 vs 7.00 month, p = 0.4914). PFS and 1-year OS were better (nonsignificant) in pts with PLT &gt; 144.58 (9.0 vs 5.0 month, p = 0.5854) and (18.0 vs 16.0 month, p = 0.5836). Conclusions: Important role of indicators of systemic inflammation is obvious for patient with HNSCC, but our study showed that only baseline characteristics couldn’t be strong prognostic factors by different degree of intratumor inflammation.
Evaluation of the spectrum selective RTK inhibitor sitravatinib in clear cell renal cell carcinoma (ccRCC) refractory to anti-angiogenic therapy (AAT).
Authors: Shubham Pant, Alexander I. Spira, Byoung Chul Cho, Sanjay Goel, Christopher J. Hoimes, Ajjai Shivaram Alva, Rama Balaraman, Todd Michael Bauer, Philip A. Lowry, Ryan C. Ramaekers, Robert D. Siegel, Theresa Louise Werner, Nizar M. Tannir, Demiana Faltaos, Diane Potvin, Saskia T.C. Neuteboom, James Christensen, Richard C. Chao, Christos Kyriakopoulos
Journal: Journal of Clinical Oncology (2018)

4568 Background: Sitravatinib (MGCD516) is an oral, potent small molecule inhibitor of a closely related spectrum of receptor tyrosine kinases (RTKs) including the TAM family (AXL, MER), split RTKs (VEGFR2, PDGFR, KIT), RET and MET. Because of the importance of sitravatinib targets in the pathogenesis of ccRCC and putative roles for MET and AXL in intrinsic and acquired resistance to anti-angiogenic agents, sitravatinib was evaluated in patients (pts) with ccRCC after failure of AAT. Methods: Study 516-001 is a Phase 1/1b study of sitravatinib in pts with advanced solid tumors. After determination of the MTD in Phase 1, pts with ccRCC after failure of AAT and pts with qualifying genetic alterations in sitravatinib targets were enrolled into distinct Phase1b cohorts using respective multi-stage designs. Pts received 150mg sitravatinib once daily in continuous 21-day cycles and were evaluated for safety, PK and clinical activity. Here we report on the completion of Stage 2 enrollment of the Phase1b ccRCC cohort. Results: 89 pts (50 men/39 women; median age 67 years; range 36-84) with advanced solid tumors were enrolled in Phase1b cohorts, including 28 pts (20 men/8 women; median age 67.5 years; range 47-77) in the ccRCC cohort who received a median of 3 prior treatment regimens. Prior AAT included sunitinib (n=17), pazopanib (n=13) and axitinib (n=9); 12 pts received ≥2 prior angiogenesis inhibitors. One partial response (PR) among the first 10 evaluable ccRCC pts in Stage 1 met criteria for enrollment of a total of 20 evaluable pts for Stage 2, where 4 confirmed PRs were observed and an unconfirmed PR in a pt who had received 4 prior AATs. Prolonged stable disease for at least 24 weeks was observed in an additional 5 pts. Treatment-related AEs (>20% of pts; Grades 1-3) included diarrhea, hypertension, nausea, vomiting, fatigue and decreased appetite. Conclusions: Stage 2 enrollment of the Study 516-001 Phase1b cohort of ccRCC refractory to AAT was completed. Sitravatinib treatment resulted in 4 confirmed PRs in a heavily pre-treated patient population and demonstrated a manageable safety profile. Further evaluation of sitravatinib in ccRCC is warranted. Clinical trial information: NCT02219711.
Evaluation of retinal microvascular density in patients affected by systemic lupus erythematosus: an optical coherence tomography angiography study
Authors: Paola Conigliaro, Massimo Cesareo, Maria Sole Chimenti, Paola Triggianese, Claudia Canofari, Gianluca Aloe, Carlo Nucci, Roberto Perricone
Journal: Annals of the Rheumatic Diseases (2018)

Retinopathy in systemic lupus erythematosus (SLE) has an incidence of 7%–29% and is suggestive of high disease activity being a marker of poor visual outcome and prognosis for survival.1 Recently, we demonstrated a subclinical retinal involvement in patients with SLE that seems to be related to kidney involvement where hydroxychloroquine had a protective role.2 The pathogenesis of lupus retinopathy is attributed to a vasculopathy most commonly immune complex-mediated microangiopathy.1 Optical coherence tomography angiography (OCTA) is a non-invasive technique for imaging the microvasculature of the retina and choroid that may quantify foveal avascular zone, non-perfused or low-perfused areas. Quantitative measurements based on OCTA may have value in managing retinopathy but also correlate with visual outcome and mirror vascular involvement in systemic diseases.3 The aim of this study was to evaluate retinal microvasculature using OCTA in patients with SLE without signs of retinopathy according to standard lupus retinopathy classification4 and correlate abnormal vascular density with disease activity, damage …
Prognostic impact of age at diagnosis in triple negative breast cancer: Analysis of 204 patients from single institution registry.
Authors: Salman Otoukesh, Alok kumar Dwivedi, Anthony L. Nguyen, Andres Alvarado, Gayathri Nagaraj
Journal: Journal of Clinical Oncology (2018)

e13130 Background: Age at diagnosis is an important prognostic factor for breast cancer in general however its specific significance in triple negative breast cancer (TNBC) is unclear. Few existing data on the prognostic value of age in TNBC are inconclusive. In this study, we evaluate the prognostic value of age at presentation in TNBC patients diagnosed at Loma Linda University Cancer Center. Methods: This is a retrospective analysis of 204 patients diagnosed with TNBC between January 2005 and December 2015. Survival was defined on the date of last visit or death. Kaplan Meier method was used to calculated survival as well as to calculate it with respect to age. Age was categorized into ≤ 40 and > 40. Chi-square test was used to correlate the age with other prognostic factors. The log rank test and Fisher’s exact test were used to calculate significance. All statistical analysis was carried out using STATA 13. P-values less than 5% were considered as significant. Results: 24% of patients in our cohort were diagnosed at or below the age of 40. Age was found to be significantly associated with Race and receipt of chemotherapy in our analysis. Specifically, there were proportionally larger number of Hispanic patients younger than 40 years compared to Non-Hispanics (P = 0.002). Of the patients who were ≤ 40 years of age, 88% of them received chemotherapy as compared to only 66.67 % who were > 40 years of age (P = 0.036). There was however no correlation with age and cancer stage, histology, lymph node status, type of surgery or receipt of radiation. Our analysis also found no survival association between Race, Age, Chemotherapy, or Radiation treatment. Conclusions: In our study, young age was not statistically associated with poorer 5-years overall survival nor was it associated with other clinico-pathologic factors at presentation. Hispanic women were noted to be specifically predisposed to TNBC at a younger age (≤ 40 years). Further studies are needed to understand the underlying pathophysiology and define new prognostic factors, e.g. molecular markers, in this subgroup.
Quality-adjusted time without symptoms or toxicity (Q-TWiST) of patients with metastatic colorectal cancer (mCRC) treated with fruquintinib in the randomized phase III FRESCO trial.
Authors: Yu-Xian Bai, Shukui Qin, Jin Li, Yanhong Deng, Lei Yang, Rui-hua Xu, Haijun Zhong, Zhendong Chen, Hongming Pan, Weijian Guo, Yongqian Shu, Cike Peng, Yun Chen, Hongyan Li, Ning Wang, Xiaojun Guo, Wei Wang, Songhua Fan, Jian-Ming Xu, Lin Shen
Journal: Journal of Clinical Oncology (2018)

3544 Background: The FRESCO Study is a randomized, double-blind, phase III trial comparing fruquintinib + best supportive care (BSC), to placebo + BSC in the treatment of metastatic colorectal cancer (mCRC). This ad-hoc analysis aims to compare the quality-adjusted survival between the two arms using quality-adjusted time without symptoms or toxicity (Q-TWiST) methodology, and to investigate the Q-TWiST benefit of fruquintinib treatment among sub-groups. Methods: The survival time for each patient was divided into 3 portions: TOX (time with ≥ grade 3 toxicity before progression), TWiST (time without symptoms or ≥ grade 3 toxicity), and REL (time from progression or relapse until death or end of follow-up). Q-TWiST was calculated as the sum of the utility-weighted mean durations for each health state. Threshold analyses were conducted to understand Q-TWiST gains associated with utility weight and subgroup analyses were performed according to baseline clinical characteristics. Results: Of 416 patients randomized, 278 received fruquintinib treatment. Survival benefit was seen in Q-TWiST in patients in the fruquintinib arm when compared to those in the placebo arm (mean: 7.0 vs. 4.8 months, difference [95% CI]: 2.2[1.4, 3.0]) in the base case scenario (TOX = 0.5 and REL = 0.5). Threshold analyses suggested that Q-TWiST gains ranged from 16.7% to 39.9% and favored fruquintinib across all possible utility weight combinations. The differences in Q-TWiST favored patients in the fruquintinib arm across pre-specified subgroups. Patients benefited from fruquintinib treatment in terms of Q-TWiST gain regardless of prior targeted treatment (32.3% and 22.9% of those with and without prior targeted treatment, respectively). Conclusions: In mCRC patients who failed 2 lines of standard therapy, fruquintinib treatment resulted in more quality-adjusted survival benefits when compared to placebo arm. The benefits seen may have been achieved by good disease control and safety profile. Both patients with and without prior targeted therapy can benefit from fruquintinib treatment.
Early TKI-pharmokinetics and circulating tumor DNA (ctDNA) to predict outcome in patients with EGFR-mutated non-small cell lung cancer (NSCLC).
Authors: Frederic Bigot, Nicolas Pecuchet, Benoit Blanchet, Pierre Laurent-Puig, Helene Blons, Francois Goldwasser, Pascaline Boudou-Rouquette, Edouard Auclin, Stephane Oudard, Elizabeth Fabre
Journal: Journal of Clinical Oncology (2017)

11544 Background: Erlotinib (E) and gefitinib (G) are indicated as first-line therapy of EGFR-mutated NSCLC patients (pts). Many studies highlighted TKI pharmacokinetic (PK) impact on toxicities. However, data about the relationship between PK and efficacy are sparse. Recently, ctDNA has been shown to be a strong prognostic factor for metastatic NSCLC pts undergoing specific treatment. Thus, we underwent an observational study to determine plasma drug concentration and ctDNA impact on outcomes in NSCLC pts treated with E or G. Then, we explored the correlation between PK and ctDNA in order to improve management of pts treated with EGFR-TKI. Methods: We analyzed consecutive pts with EGFR-mutated NSCLC treated with TKI in Cochin and European Georges Pompidou hospitals (APHP, Paris) from April 2010 to March 2016. Plasma samples were collected 2 to 6 weeks after TKI initiation. Steady state trough concentration (Cssmin) was assessed by high performance chromatography. CtDNA was analyzed using Next-Generation Sequencing (Ampliseq ColonLungV2 panel, BPER method). Therapeutic ranges obtained from previous studies were between 1200 to 2000 ng/mL and &gt; 200 ng/mL for E and G, respectively. Results: Out of 77 pts, 56 had Cssmin analysis, 40 ctDNA analysis and 31 both. Median age was 70 years (range: 31-90), 49 were treated with E, 24 with G. Median follow-up was 19 months. Whatever EGFR TKI, pts with Cssmin into therapeutic ranges had longer PFS than pts over or under-exposed (median: 17.5 vs 7.5 months, p = 0.002). Those with early indetectable ctDNA had significantly better PFS (median 13 vs 5.8 months, p = 0.01) and OS (median: 21.4 vs 14.3 months, p = 0.02). No correlation was found between ctDNA and Cssmin. Occurrence of toxicity &gt; grade 2 in pts treated with E was associated with higher plasma concentration (mean 1991 vs 1184 ng/mL, p &lt; 0.01). Conclusions: Early Cssmin and ctDNA assessment appear as markers to predict outcomes. Our observational study is the proof of concept that pts undergoing EGFR-TKI therapy could be monitored with Cssmin and ctDNA to define optimal personalized treatment strategies. A prospective study is planned to evaluate dose adaptation of TKI based on those 2 tools.
Acute, local infusion of angiotensin II impairs microvascular and metabolic insulin sensitivity in skeletal muscle
Authors: Dino Premilovac, Emily Attrill, Stephen Rattigan, Stephen M Richards, Jeonga Kim, Michelle A Keske
Journal: Cardiovascular Research (2018)

Angiotensin II (AngII) is a potent vasoconstrictor implicated in both hypertension and insulin resistance. Insulin dilates the vasculature in skeletal muscle to increase microvascular blood flow and enhance glucose disposal. In the present study, we investigated whether acute AngII infusion interferes with insulin's microvascular and metabolic actions in skeletal muscle.Adult, male Sprague-Dawley rats received a systemic infusion of either saline, AngII, insulin (hyperinsulinaemic euglycaemic clamp), or insulin (hyperinsulinaemic euglycaemic clamp) plus AngII. A final, separate group of rats received an acute local infusion of AngII into a single hindleg during systemic insulin (hyperinsulinaemic euglycaemic clamp) infusion. In all animals' systemic metabolic effects, central haemodynamics, femoral artery blood flow, microvascular blood flow, and skeletal muscle glucose uptake (isotopic glucose) were monitored. Systemic AngII infusion increased blood pressure, decreased heart rate, and markedly increased circulating glucose and insulin concentrations. Systemic infusion of AngII during hyperinsulinaemic euglycaemic clamp inhibited insulin-mediated suppression of hepatic glucose output and insulin-stimulated microvascular blood flow in skeletal muscle but did not alter insulin's effects on the femoral artery or muscle glucose uptake. Local AngII infusion did not alter blood pressure, heart rate, or circulating glucose and insulin. However, local AngII inhibited insulin-stimulated microvascular blood flow, and this was accompanied by reduced skeletal muscle glucose uptake.Acute infusion of AngII significantly alters basal haemodynamic and metabolic homeostasis in rats. Both local and systemic AngII infusion attenuated insulin's microvascular actions in skeletal muscle, but only local AngII infusion led to reduced insulin-stimulated muscle glucose uptake. While increased local, tissue production of AngII may be a factor that couples microvascular insulin resistance and hypertension, additional studies are needed to determine the molecular mechanisms responsible for these vascular defects.
Abstract 12630: Comparison of Clinical and Imaging Characteristics and Outcome Between Provoked and Unprovoked Acute Pulmonary Thromboembolism
Authors: Hae Ok Jung, Jae-Sun Uhm, Chan Joon Kim, Seo Hee Ahn, Ho-Joong Youn
Journal: Circulation (2011)

Objective: Pulmonary thromboembolism (PTE) in the absence of risk factors is classified as unprovoked or spontaneous PTE. We compared the clinical and imaging characteristics and prognosis of unpro...
A Growth Reference for Mid Upper Arm Circumference for Age among School Age Children and Adolescents, with Validation for Mortality in Two Cohorts
Authors: L Mramba, M Ngari, M Mwangome, L Muchai, E Bauni, AS Walker, DM Gibb, G Fegan, JA Berkley
Journal: BMJ (2017)

OBJECTIVES: To construct growth curves for mid-upper-arm circumference (MUAC)-for-age z score for 5-19 year olds that accord with the World Health Organization growth standards, and to evaluate their discriminatory performance for subsequent mortality.

DESIGN: Growth curve construction and longitudinal cohort study.

SETTING: United States and international growth data, and cohorts in Kenya, Uganda, and Zimbabwe.

PARTICIPANTS The Health Examination Survey (HES)/National Health and Nutrition Examination Survey (NHANES) US population datasets (age 5-25 years), which were used to construct the 2007 WHO growth reference for body mass index in this age group, were merged with an imputed dataset matching the distribution of the WHO 2006 growth standards age 2-6 years. Validation data were from 685 HIV infected children aged 5-17 years participating in the Antiretroviral Research for Watoto (ARROW) trial in Uganda and Zimbabwe; and 1741 children aged 5-13 years discharged from a rural Kenyan hospital (3.8% HIV infected). Both cohorts were followed-up for survival during one year.

MAIN OUTCOME MEASURES: Concordance with WHO 2006 growth standards at age 60 months and survival during one year according to MUAC-for-age and body mass index-for-age z scores.

RESULTS: The new growth curves transitioned smoothly with WHO growth standards at age 5 years. MUAC-for-age z scores of −2 to −3 and less than−3, compared with −2 or more, was associated with hazard ratios for death within one year of 3.63 (95% confidence interval 0.90 to 14.7; P=0.07) and 11.1 (3.40 to 36.0; P<0.001), respectively, among ARROW trial participants; and 2.22 (1.01 to 4.9; P=0.04) and 5.15 (2.49 to 10.7; P<0.001), respectively, among Kenyan children after discharge from hospital. The AUCs for MUAC-for-age and body mass index-for-age z scores for discriminating subsequent mortality were 0.81 (95% confidence interval 0.70 to 0.92) and 0.75 (0.63 to 0.86) in the ARROW trial (absolute difference 0.06, 95% confidence interval −0.032 to 0.16; P=0.2) and 0.73 (0.65 to 0.80) and 0.58 (0.49 to 0.67), respectively, in Kenya (absolute difference in AUC 0.15, 0.07 to 0.23; P=0.0002).

CONCLUSIONS: The MUAC-for-age z score is at least as effective as the body mass index-for-age z score for assessing mortality risks associated with undernutrition among African school aged children and adolescents. MUAC can provide simplified screening and diagnosis within nutrition and HIV programmes, and in research.