Citations

Higher levels of tumor-derived extracellular vesicles are detected in metastatic prostate cancer compared to localized prostate cancer by standardized and calibrated flow cytometry.

Objective Investigation of onabotulinumtoxinA in a murine model of acute and persistent post-traumatic headache. Methods Mild traumatic brain injury was induced with a weight drop method. Periorbital and hindpaw cutaneous allodynia were measured for 14 days. Mice were then exposed to bright light stress and allodynia was reassessed. OnabotulinumtoxinA (0.5 U) was injected subcutaneously over the cranial sutures at different post-injury time points. Results After milt traumatic brain injury, mice exhibited periorbital and hindpaw allodynia that lasted for approximately 14 days. Allodynia could be reinstated on days 14–67 by exposure to stress only in previously injured mice. OnabotulinumtoxinA administration at 2 h after mild traumatic brain injury fully blocked both transient acute and stress-induced allodynia up to day 67. When administered 72 h post-mild traumatic brain injury, onabotulinumtoxinA reversed acute allodynia, but only partially prevented stress-induced allodynia. OnabotulinumtoxinA administration at day 12, when initial allodynia was largely resolved, produced incomplete and transient prevention of stress-induced allodynia. The degree of acute allodynia correlated positively with subsequent stress-induced allodynia. Conclusion Mild traumatic brain injury induced transient headache-like pain followed by long lasting sensitization and persistent vulnerability to a normally innocuous stress stimulus, respectively modeling acute and persistent post-traumatic headache.. Administration of onabotulinumtoxinA following the resolution of acute post-traumatic headache diminished persistent post-traumatic headache but the effects were transient, suggesting that underlying persistent mild traumatic brain injury-induced maladaptations were not reversed. In contrast, early onabotulinumtoxinA administration fully blocked both acute post-traumatic headache as well as the transition to persistent post-traumatic headache suggesting prevention of neural adaptations that promote vulnerability to headache-like pain. Additionally, the degree of acute post-traumatic headache was predictive of risk of persistent post-traumatic headache.

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non–Small Cell Lung Cancer (NSCLC) provide recommended management for patients with NSCLC, including diagnosis, primary treatment, surveillance for relapse, and subsequent treatment. Patients with metastatic lung cancer who are eligible for targeted therapies or immunotherapies are now surviving longer. This selection from the NCCN Guidelines for NSCLC focuses on targeted therapies for patients with metastatic NSCLC and actionable mutations.

Objective The objective of this study was to determine whether a triple therapy regimen incorporating twice-daily saquinavir is as effective as a three-times daily regimen. Methods This was an open-label, Phase III, multicentre, 48-week study involving 837 HIV-1-infected patients randomised to one of the following: saquinavir soft gel capsule (SGC) 1200 mg three-times daily, plus two nucleoside reverse transcriptase inhibitors (NRTIs) (arm A); saquinavir SGC 1600 mg twice-daily, plus two NRTIs (arm B); saquinavir SGC 1200 mg twice-daily and nelfinavir 1250 mg twice-daily, plus a single NRTI (arm C). The primary outcome measure was the virological response in arm A versus B and in arm A versus C with respect to the percentage of patients whose plasma HIV-1 RNA levels fell below the level of quantification for the Amplicor assay (<400 copies/ml) at weeks 24 and 48. Results At 48 weeks, the percentage of patients with plasma HIV-1 RNA levels <400 copies/ml was 47.1% (arm A), 45.3% (arm B) and 42.7% (arm C) in the intention-to-treat analysis. The treatment difference between arm B–arm A was -1.8% (95% confidence intervals -10.1, 6.5) and for arm C–arm A was -4.5% (95% confidence intervals -12.7, 3.7) in the intention-to-treat analysis. These differences fell within the maximum allowable difference (±12%) for arm B compared with arm A. At week 24, the percentage of patients with HIV-1 RNA levels <400 copies/ml was 59.6% (arm A), 57.6% (arm B) and 51.3% (arm C). Conclusions A twice-daily triple therapy regimen incorporating saquinavir SGC plus two NRTIs was of equivalent efficacy to the three-times daily regimen studied. All regimens were generally well tolerated.

Human genetic studies support an inverse causal relationship between leukocyte telomere length (LTL) and coronary artery disease (CAD), but directionally mixed effects for LTL and diverse malignancies. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by expansion of hematopoietic cells bearing leukemogenic mutations, predisposes both hematologic malignancy and CAD. TERT (which encodes telomerase reverse transcriptase) is the most significantly associated germline locus for CHIP in genome-wide association studies. Here, we investigated the relationship between CHIP, LTL, and CAD in the Trans-Omics for Precision Medicine (TOPMed) program ( n = 63,302) and UK Biobank ( n = 47,080). Bidirectional Mendelian randomization studies were consistent with longer genetically imputed LTL increasing propensity to develop CHIP, but CHIP then, in turn, hastens to shorten measured LTL (mLTL). We also demonstrated evidence of modest mediation between CHIP and CAD by mLTL. Our data promote an understanding of potential causal relationships across CHIP and LTL toward prevention of CAD.

BACKGROUND: Opioid-induced respiratory depression (OIRD) is common on the medical and surgical wards and is associated with increased morbidity and health care costs. While previous studies have investigated risk factors for OIRD, the role of race remains unclear. We aim to investigate the association between race and OIRD occurrence on the medical/surgical ward. METHODS: This is a post hoc analysis of the PRediction of Opioid-induced respiratory Depression In patients monitored by capnoGraphY (PRODIGY) trial; a prospective multinational observational blinded study of 1335 general ward patients who received parenteral opioids and underwent blinded capnography and oximetry monitoring to identify OIRD episodes. For this study, demographic and perioperative data, including race and comorbidities, were analyzed and assessed for potential associations with OIRD. Univariable χ 2 and Mann-Whitney U tests were used. Stepwise selection of all baseline and demographic characteristics was used in the multivariable logistic regression analysis. RESULTS: A total of 1253 patients had sufficient racial data (317 Asian, 158 Black, 736 White, and 42 other races) for inclusion. The incidence of OIRD was 60% in Asians (N = 190/317), 25% in Blacks (N = 40/158), 43% in Whites (N = 316/736), and 45% (N = 19/42) in other races. Baseline characteristics varied significantly: Asians were older, more opioid naïve, and had higher opioid requirements, while Blacks had higher incidences of heart failure, obesity, and smoking. Stepwise multivariable logistic regression revealed that Asians had increased risk of OIRD compared to Blacks (odds ratio [OR], 2.49; 95% confidence interval [CI], 1.54–4.04; P = .0002) and Whites (OR, 1.38; 95% CI, 1.01–1.87; P = .0432). Whites had a higher risk of OIRD compared to Blacks (OR, 1.81; 95% CI, 1.18–2.78; P = .0067). The model’s area under the curve was 0.760 (95% CI, 0.733–0.787), with a Hosmer-Lemeshow goodness-of-fit test P value of .23. CONCLUSIONS: This post hoc analysis of PRODIGY found a novel association between Asian race and increased OIRD incidence. Further study is required to elucidate its underlying mechanisms and develop targeted care pathways to reduce OIRD in susceptible populations.

Abstract Type 2 diabetes has reached endemic proportions and is a substantial burden for the affected patients and the society. Along with lifestyle factors, a number of genetic loci predisposing to type 2 diabetes have been identified, including SORCS1 that encodes the transmembrane receptor SorCS1. The ectodomain of SorCS1 (sol-SorCS1) is shed from plasma membranes but the biological function of this fragment is unknown. Here we show that sol-SorCS1 acts as a high-affinity binding partner for the insulin receptor to stabilize the receptor and increase insulin affinity, protein kinase B activation, and glucose uptake in myocytes. Sol-SorCS1 is liberated from adipocytes, and in diabetic patients the plasma concentration positively correlates with body mass index, but inversely with plasma glucose. In mouse models of insulin resistance, exogenous sol-SorCS1 restored insulin sensitivity. We conclude that sol-SorCS1 increases peripheral insulin sensitivity and propose sol-SorCS1 as a novel insulin sensitizing adipokine and potential antidiabetic agent.

Background. This single-arm, multicenter, phase 2 study evaluated the safety and antitumor activity of pazopanib in patients with unresectable, pulmonary metastatic osteosarcoma. Patients and Methods. Patients with pulmonary metastatic osteosarcoma unresponsive to chemotherapy were eligible. Patients who received prior tyrosine kinase inhibitor therapy were excluded. Pazopanib at 800 mg once daily was administered for 28-day cycles. Tumor responses were evaluated by local radiology assessment 1 month prior to and after initiation of treatment to calculate tumor doubling time and after every even numbered cycle. The primary endpoints were progression-free survival at 4 months, concomitant with a demonstrated 30% increase in tumor doubling time relative to the pretreatment growth rate. Results. 12 patients (7 female) were enrolled. The study was terminated prematurely due to withdrawal of financial support by the sponsor. 8 subjects were eligible for the primary analysis, whereas 4 patients were in a predefined exploratory “slow-growing” cohort. In the “fast-growing” cohort, 3 of the 8 patients (37.5%) eligible for first-stage analysis were deemed “success” by the preplanned criteria, adequate to proceed to second-stage accrual. In addition, 1 of the 4 patients in the “slow-growing” cohort experienced a partial remission. Grade 1-2 diarrhea was the most common adverse event, and grade 3 events were infrequent. Conclusion. This study illustrates a novel method of demonstrating positive drug activity in osteosarcoma by increasing tumor doubling time, and this is further supported by a partial response in a patient with “slow-growing” disease. This trial is registered with NCT01759303.

AbstractPurposeWe have used a hematopoietic progenitor cell (HPC) algorithm (standard [STD]) that restricted the inlet flow rate to 65 mL/min for peripheral white blood cell count (PWBC) >35 × 109/L (STD). In this study, we evaluated a technique that allows 85 mL/min, regardless of the PWBC count (high). For patients with PWBC >35 × 109/L, a prospective, randomized comparison of the high flow rate vs the STD PWBC‐based flow rate (65 mL/min) was performed, comparing CD34+ and lymphocyte yields, collection efficiencies (CE1), mononuclear cells (MNC), and granulocytes, red blood cell (RBC), and platelet content.MethodsThe Fenwal Amicus version 4.5 with a heparinized ACD‐A anticoagulant (AC) delivered at a 26:1 AC ratio was used. Paired comparisons between high and STD techniques were assessed with Wilcoxon signed rank tests, with P < .05 considered significant. Data are summarized as medians.ResultsForty patient pairs (autologous) were compared. Diagnoses included primarily multiple myeloma (60%) and lymphoma (37.5%). High had significantly higher median average inlet rates (69 vs 55 mL/min), whole blood processed (20 vs 16 L), and cycles (15 vs 14) than STD. There were no significant differences in pre‐procedure counts. Collection contents were (high/STD): 306/328 × 106 CD34+ cells, 48/59% CD34+ CE1 (significant), 0.2/0.2 × 109/kg lymphocytes, 45/57% lymphocyte CE1, 63/59 × 109 WBC, 15/16 × 109 granulocytes, and 1.9/1.7 × 1011 platelets.ConclusionsThe simpler, standardized high flow technique did not significantly increase or decrease CD34+ cells or lymphocyte yields, but did significantly decrease CD34+ CE1. The effects on cross‐cellular content were minimal and not clinically significant.