Citations

Abstract Purpose: It has been demonstrated that large numbers of tumor-specific T cells for adoptive cell transfer (ACT) can be manufactured by retroviral genetic engineering of autologous peripheral blood lymphocytes and expanding them over several weeks. In mouse models, this therapy is optimized when administered with dendritic cell (DC) vaccination. We developed a short 1-week manufacture protocol to determine the feasibility, safety, and antitumor efficacy of this double cell therapy. Experimental Design: A clinical trial (NCT00910650) adoptively transferring MART-1 T-cell receptor (TCR) transgenic lymphocytes together with MART-1 peptide-pulsed DC vaccination in HLA-A2.1 patients with metastatic melanoma. Autologous TCR transgenic cells were manufactured in 6 to 7 days using retroviral vector gene transfer, and reinfused with (n = 10) or without (n = 3) prior cryopreservation. Results: A total of 14 patients with metastatic melanoma were enrolled and 9 of 13 treated patients (69%) showed evidence of tumor regression. Peripheral blood reconstitution with MART-1–specific T cells peaked within 2 weeks of ACT, indicating rapid in vivo expansion. Administration of freshly manufactured TCR transgenic T cells resulted in a higher persistence of MART-1–specific T cells in the blood as compared with cryopreserved. Evidence that DC vaccination could cause further in vivo expansion was only observed with ACT using noncryopreserved T cells. Conclusion: Double cell therapy with ACT of TCR-engineered T cells with a very short ex vivo manipulation and DC vaccines is feasible and results in antitumor activity, but improvements are needed to maintain tumor responses. Clin Cancer Res; 20(9); 2457–65. ©2014 AACR.

Objective: A prototype tear glucose (TG) sensor was tested in New Zealand white rabbits to assess eye irritation, blood glucose (BG) and TG lag time, and correlation with BG. Methods: A total of 4 animals were used. Eye irritation was monitored by Lissamine green dye and analyzed using image analysis software. Lag time was correlated with an oral glucose load while recording TG and BG readings. Correlation between TG and BG were plotted against one another to form a correlation diagram, using a Yellow Springs Instrument (YSI) and self-monitoring of blood glucose as the reference measurements. Finally, TG levels were calculated using analytically derived expressions. Results: From repeated testing carried over the course of 12 months, little to no eye irritation was detected. TG fluctuations over time visually appeared to trace the same pattern as BG with an average lag times of 13 minutes. TG levels calculated from the device current measurements ranged from 4 to 20 mg/dL and correlated linearly with BG levels of 75-160 mg/dL (TG = 0.1723 BG = 7.9448 mg/dL; R 2 = .7544). Conclusion: The first steps were taken toward preliminary development of a sensor for self-monitoring of tear glucose (SMTG). No conjunctival irritation in any of the animals was noted. Lag time between TG and BG was found to be noticeable, but a quantitative modeling to correlate lag time in this study is unnecessary. Measured currents from the sensors and the calculated TG showed promising correlation to BG levels. Previous analytical bench marking showed BG and TG levels consistent with other literature.

Angiosarcoma of the seminal vesicle is an extremely rare malignancy, with few published case reports in the literature. We present a case of primary angiosarcoma of the seminal vesicle in a 45-year-old male who was treated with multimodality therapy, consisting of neoadjuvant chemotherapy and chemoradiation followed by surgical resection and intraoperative radiation therapy. He has been free of cancer recurrence for more than six years after completion of therapy. To our knowledge, this represents the longest reported survival of a patient with this rare tumor, and one of the few cases reported using a multimodality therapy approach.

New Findings What is the central question of this study? The aim of the study was to evaluate the effect of acute induced systemic inflammation on endothelial function, wave reflection and arterial function in older adults. What is the main finding and its importance? Acute inflammation induced by influenza vaccination did not affect endothelial function in older adults. These findings have never been shown in older adults, and they emphasize the importance of vascular function during systemic arterial inflammation. Acute inflammation reduces flow‐mediated vasodilatation and increases arterial stiffness in young healthy individuals. However, this response has not been studied in older adults. The aim of this study, therefore, was to evaluate the effect of acute induced systemic inflammation on endothelial function and wave reflection in older adults. Furthermore, an acute bout of moderate‐intensity aerobic exercise can be anti‐inflammatory. Taken together, we tested the hypothesis that acute moderate‐intensity endurance exercise, immediately preceding induced inflammation, would be protective against the negative effects of acute systemic inflammation on vascular function. Fifty‐nine healthy volunteers between 55 and 75 years of age were randomized to an exercise or a control group. Both groups received a vaccine (induced inflammation) and sham (saline) injection in a counterbalanced crossover design. Inflammatory markers, endothelial function (flow‐mediated vasodilatation) and measures of wave reflection and arterial stiffness were evaluated at baseline and at 24 and 48 h after injections. There were no significant differences in endothelial function and arterial stiffness between the exercise and control group after induced inflammation. The groups were then analysed together, and we found significant differences in the inflammatory markers 24 and 48 h after induction of acute inflammation compared with sham injection. However, flow‐mediated vasodilatation, augmentation index normalized for heart rate (AIx75) and β‐stiffness did not change significantly. Our results suggest that acute inflammation induced by influenza vaccination did not affect endothelial function in older adults.

Abstract Background: In patients with Barrett's esophagus, chronic reflux injury and inflammation are associated with esophageal adenocarcinoma, one of the most rapidly increasing lethal cancers. Epidemiological and preclinical studies support decreased risk of esophageal adenocarcinoma with NSAID use. Gastroesophageal refluxate contents can promote carcinogenesis in Barrett's metaplasia by activating AKT, which up regulates COX-2 expression and prostaglandin biosynthesis. We recently noted that neoplastic transformation in Barrett's esophagus is associated with increased AKT expression, particularly isoform AKT1. The AIM of this study is to investigate the effect of NSAID (Aspirin) use in patients with Barrett's esophagus on AKT1 expression using frozen tissue from the randomized, phase II trial of aspirin and esomeprazole for esophageal cancer chemoprevention in Barrett's esophagus patients and to assess the functional consequences of AKT1 expression in-vitro. Methods and Results: In a subset of patients (12 of 120 patients) with Barrett's esophagus who were randomized to placebo, lower dose (81 mg) or higher dose (325 mg) Aspirin for 4 weeks, both PCR and Western blot revealed marked reduction in AKT1 expression in patients who received 325 mg of Aspirin daily compared to patients who received placebo. Our in-vitro experiments support that AKT1 expression is functionally relevant to the process of carcinogenesis in Barrett's epithelial cells. Using adenovirus to induce AKT1 expression, we show that increased AKT1 expression increases Barrett's epithelial cell growth, facilitates RAS-mediated transformation of pre-neoplastic epithelial cells and promotes colony formation. Since AKT1 is known as Warburg kinase and regulates cellular glucose uptake to support aerobic glycolysis during growth de-regulation and neoplasia, we examined the uptake of fluorescent deoxyglucose analog (2-NBDG) in Barrett's epithelial cells transduced with AKT1 adenovirus. At 48 hrs, compared to control, AKT1 overexpression resulted in increased glucose uptake both by metaplastic and neoplastic Barrett's epithelial cells. Transcriptional repression of AKT1 abrogated the 2-NBDG uptake by these cells. Finally, we did pathway specific qPCRs and noted that use of Aspirin is associated with altered expression of chromatin remodelers that could down-regulate AKT1 expression. Conclusion: Collectively, our results demonstrate that Aspirin mediated down-regulation of Warburg kinase AKT1 in patients with Barrett?s esophagus is a novel mechanism for the regulation of Barrett?s epithelial cell growth. The in-depth characterization of molecular mechanisms is currently underway. This abstract is also presented as Poster A82. Citation Format: Navtej S. Buttar, Gary W. Falk, Cathrine J. DeMars, Sonia Chowdhury, Ahmed Elebiary, Anamay Sharma, Sidhartha Chaudhry, Nathan R. Foster, Katie L. Allen Ziegler, Yvonne Romero, Norman E. Marcon, Thomas Schnell, Douglas A. Corley, Prateek Sharma, Marcia R. Cruz-Correa, Chin Hur, David E. Fleischer, Amitabh Chak, Kenneth R. DeVault, David S. Weinberg, Gary Della’Zanna, Ellen Richmond, Thomas C. Smyrk, Sumithra Mandrekar, Paul J. Limburg. Aspirin mediated downregulation of Warburg kinase AKT1 in patients with Barrett's esophagus: Implications in neoplastic transformation. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr PR-03.

Purpose To provide an update on recent advances in the management of patients with multiple myeloma who are not eligible for autologous stem-cell transplantation. Methods A comprehensive review of the literature on diagnostic criteria is provided, and treatment options and management of adverse events are summarized. Results Patients with symptomatic disease and organ damage (ie, hypercalcemia, renal failure, anemia, or bone lesions) require immediate treatment. The International Staging System and chromosomal abnormalities identify high- and standard-risk patients. Proteasome inhibitors, immunomodulatory drugs, corticosteroids, and alkylating agents are the most active agents. The presence of concomitant diseases, frailty, or disability should be assessed and, if present, treated with reduced-dose approaches. Bone disease, renal damage, hematologic toxicities, infections, thromboembolism, and peripheral neuropathy are the most frequent disabling events requiring prompt and active supportive care. Conclusion These recommendations will help clinicians ensure the most appropriate care for patients with myeloma in everyday clinical practice.

Key Points Pomalidomide plus low-dose dexamethasone significantly improved PFS vs pomalidomide alone in relapsed and refractory multiple myeloma. Pomalidomide plus low-dose dexamethasone is an important new treatment option for RRMM patients who have received multiple prior therapies.

Background: A concept for a tear glucose sensor based on amperometric measurement of enzymatic oxidation of glucose was previously presented, using glucose dehydrogenase flavin adenine dinucleotide (GDH-FAD) as the enzyme. Glucose dehydrogenase flavin adenine dinucleotide is further characterized in this article and evaluated for suitability in glucose-sensing applications in purified tear-like saline, with specific attention to the effect of interfering substances only. These interferents are specifically saccharides that could interact with the enzymatic activity seen in the sensor's performance. Methods: Bench top amperometric glucose assays were performed using an assay solution of GDH-FAD and ferricyanide redox mediator with samples of glucose, mannose, lactose, maltose, galactose, fructose, sucrose, and xylose at varying concentrations to evaluate specificity, linear dynamic range, signal size, and signal-to-noise ratio. A comparison study was done by substituting an equivalent activity unit concentration of glucose oxidase (GOx) for GDH-FAD. Results: Glucose dehydrogenase flavin adenine dinucleotide was found to be more sensitive than GOx, producing larger oxidation currents than GOx on an identical glucose concentration gradient, and GDH-FAD exhibited larger slope response (-5.65 × 10 −7 versus −3.11 × 10 −7 A/mM), signal-to-noise ratio (18.04 versus 2.62), and linear dynamic range (0–30 versus 0–10 mM), and lower background signal (−7.12 versus −261.63 nA) than GOx under the same assay conditions. GDH-FAD responds equally to glucose and xylose but is otherwise specific for glucose. Conclusion: Glucose dehydrogenase flavin adenine dinucleotide compares favorably with GOx in many sensor-relevant attributes and may enable measurement of glucose concentrations both higher and lower than those measurable by GOx. GDH-FAD is a viable enzyme to use in the proposed amperometric tear glucose sensor system and perhaps also in detecting extreme hypoglycemia or hyperglycemia in blood.