Rie von Eyben

Day and Night Closed-Loop Control Using the Integrated Medtronic Hybrid Closed-Loop System in Type 1 Diabetes at Diabetes Camp

OBJECTIVE To evaluate the feasibility and efficacy of a fully integrated hybrid closed-loop (HCL) system (Medtronic MiniMed Inc., Northridge, CA), in day and night closed-loop control in subjects with type 1 diabetes, both in an inpatient setting and during 6 days at diabetes camp. RESEARCH DESIGN AND METHODS The Medtronic MiniMed HCL system consists of a fourth generation (4S) glucose sensor, a sensor transmitter, and an insulin pump using a modified proportional-integral-derivative (PID) insulin feedback algorithm with safety constraints. Eight subjects were studied over 48 h in an inpatient setting. This was followed by a study of 21 subjects for 6 days at diabetes camp, randomized to either the closed-loop control group using the HCL system or to the group using the Medtronic MiniMed 530G with threshold suspend (control group). RESULTS The overall mean sensor glucose percent time in range 70–180 mg/dL was similar between the groups (73.1% vs. 69.9%, control vs. HCL, respectively) (P = 0.580). Meter glucose values between 70 and 180 mg/dL were also similar between the groups (73.6% vs. 63.2%, control vs. HCL, respectively) (P = 0.086). The mean absolute relative difference of the 4S sensor was 10.8 ± 10.2%, when compared with plasma glucose values in the inpatient setting, and 12.6 ± 11.0% compared with capillary Bayer CONTOUR NEXT LINK glucose meter values during 6 days at camp. CONCLUSIONS In the first clinical study of this fully integrated system using an investigational PID algorithm, the system did not demonstrate improved glucose control compared with sensor-augmented pump therapy alone. The system demonstrated good connectivity and improved sensor performance.

Suppression of PGC-1α Is Critical for Reprogramming Oxidative Metabolism in Renal Cell Carcinoma

Long believed to be a byproduct of malignant transformation, reprogramming of cellular metabolism is now recognized as a driving force in tumorigenesis. In clear cell renal cell carcinoma (ccRCC), frequent activation of HIF signaling induces a metabolic switch that promotes tumorigenesis. Here, we demonstrate that PGC-1α, a central regulator of energy metabolism, is suppressed in VHL-deficient ccRCC by a HIF/Dec1-dependent mechanism. In VHL wild-type cells, PGC-1α suppression leads to decreased expression of the mitochondrial transcription factor Tfam and impaired mitochondrial respiration. Conversely, PGC-1α expression in VHL-deficient cells restores mitochondrial function and induces oxidative stress. ccRCC cells expressing PGC-1α exhibit impaired tumor growth and enhanced sensitivity to cytotoxic therapies. In patients, low levels of PGC-1α expression are associated with poor outcome. These studies demonstrate that suppression of PGC-1α recapitulates key metabolic phenotypes of ccRCC and highlight the potential of targeting PGC-1α expression as a therapeutic modality for the treatment of ccRCC.

Clinical evaluation of the iterative metal artifact reduction algorithm for CT simulation in radiotherapy

PURPOSE To clinically evaluate an iterative metal artifact reduction (IMAR) algorithm prototype in the radiation oncology clinic setting by testing for accuracy in CT number retrieval, relative dosimetric changes in regions affected by artifacts, and improvements in anatomical and shape conspicuity of corrected images. METHODS A phantom with known material inserts was scanned in the presence/absence of metal with different configurations of placement and sizes. The relative change in CT numbers from the reference data (CT with no metal) was analyzed. The CT studies were also used for dosimetric tests where dose distributions from both photon and proton beams were calculated. Dose differences and gamma analysis were calculated to quantify the relative changes between doses calculated on the different CT studies. Data from eight patients (all different treatment sites) were also used to quantify the differences between dose distributions before and after correction with IMAR, with no reference standard. A ranking experiment was also conducted to analyze the relative confidence of physicians delineating anatomy in the near vicinity of the metal implants. RESULTS IMAR corrected images proved to accurately retrieve CT numbers in the phantom study, independent of metal insert configuration, size of the metal, and acquisition energy. For plastic water, the mean difference between corrected images and reference images was -1.3 HU across all scenarios (N = 37) with a 90% confidence interval of [-2.4, -0.2] HU. While deviations were relatively higher in images with more metal content, IMAR was able to effectively correct the CT numbers independent of the quantity of metal. Residual errors in the CT numbers as well as some induced by the correction algorithm were found in the IMAR corrected images. However, the dose distributions calculated on IMAR corrected images were closer to the reference data in phantom studies. Relative spatial difference in the dose distributions in the regions affected by the metal artifacts was also observed in patient data. However, in absence of a reference ground truth (CT set without metal inserts), these differences should not be interpreted as improvement/deterioration of the accuracy of calculated dose. With limited data presented, it was observed that proton dosimetry was affected more than photons as expected. Physicians were significantly more confident contouring anatomy in the regions affected by artifacts. While site specific preferences were detected, all indicated that they would consistently use IMAR corrected images. CONCLUSIONS IMAR correction algorithm could be readily implemented in an existing clinical workflow upon commercial release. While residual errors still exist in IMAR corrected images, these images present with better overall conspicuity of the patient/phantom geometry and offer more accurate CT numbers for improved local dosimetry. The variety of different scenarios included herein attest to the utility of the evaluated IMAR for a wide range of radiotherapy clinical scenarios.

Safety Report of Ferumoxytol for Magnetic Resonance Imaging in Children and Young Adults.

ObjectiveThe aim of this study was to assess the safety profile of ferumoxytol as an intravenous magnetic resonance imaging contrast agent in children. Materials and MethodsWe prospectively evaluated the safety of ferumoxytol administrations as an “off-label” contrast agent for magnetic resonance imaging in nonrandomized phase 4 clinical trials at 2 centers. From September 2009 to February 2015, 49 pediatric patients (21 female and 28 male, 5–18 years) and 19 young adults (8 female and 11 male, 18–25 years) were reported under an investigator-initiated investigational new drug investigation with institutional review board approval, in health insurance portability and accountability act compliance, and after written informed consent of the childs legal representative or the competent adult patient was obtained. Patients received either a single dose (5 mg Fe/kg) or up to 4 doses of ferumoxytol (0.7–4 mg Fe/kg) intravenously, which were approximately equivalent to one third of the dose for anemia treatment. We monitored vital signs and adverse events directly for up to 1 hour after injection. In addition, we examined weekly vitals, hematologic, renal, and liver serum panels for 1 month after injection in over 20 pediatric patients. At fixed time points before and after ferumoxytol injection, data were evaluated for significant differences by a repeated measures linear mixed model. ResultsFour mild adverse events, thought to be related to ferumoxytol, were observed within 1 hour of 85 ferumoxytol injections: 2 episodes of mild hypotension and 1 case of nausea in 65 injections in pediatric patients without related clinical symptoms. One young adult patient developed warmness and erythema at the injection site. All adverse events were self-resolving. No spontaneous serious adverse events were reported. At a dose of 5 mg Fe/kg or lower, intravenous ferumoxytol injection had no clinical relevance or statistically significant effect (P > 0.05) on vital signs, hematological parameters, kidney function, or liver enzymes within 1 month of the injection. ConclusionsFerumoxytol was overall well tolerated among 49 pediatric and 19 young adult patients experiencing various tumors or kidney transplants without major adverse events or signs of hematologic and kidney impairment or liver toxicity. Larger studies are needed to determine the incidence of anaphylactic reactions.

68Ga-Labeled Prostate-specific Membrane Antigen Ligand Positron Emission Tomography/Computed Tomography for Prostate Cancer: A Systematic Review and Meta-analysis

CONTEXT 68Gallium prostate-specific membrane antigen (PSMA) ligand 68Ga-HBED-CC-PSMA (68Ga-PSMA) is a promising radiotracer for positron emission tomography (PET)/computed tomography (CT) of prostate cancer. OBJECTIVE To conduct a meta-analysis to evaluate detection rate, diagnostic test accuracy, and adverse effects of 68Ga-PSMA PET/CT or PET/magnetic resonance imaging (MRI) for staging of prostate cancer and for restaging of rising prostate-specific antigen (PSA) after initial treatment. EVIDENCE ACQUISITION Following the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) guidelines, our systematic review searched for articles in PubMed and EMBASE databases from 2012 to July 2016. The reference standard was pathology after biopsy or surgery. The analyses used a random effect model and a hierarchical summary receiver operating characteristic model. EVIDENCE SYNTHESIS Fifteen 68Ga-PSMA PET/CT studies with 1256 patients met the inclusion criteria. Seven studies of staging PET/CT or PET/MRI detected a regional site of cancer for 203 of 273 patients (74%). Nine studies of restaging PET/CT detected sites of recurrence in 799 of 983 patients (81%) with a 50% detection rate (74 of 147 patients) for restaging PSA of 0.2-0.49 ng/ml and a 53% detection rate (56 of 195 patients) for restaging PSA of 0.50-0.99 ng/ml. Staging 68Ga-PSMA PET/CT in the studies had higher detection rates of sites in the prostate bed than restaging 68Ga-PSMA PET/CT (mean 57% vs 14%, p=0.031, t test). Both staging and restaging 68Ga-PSMA PET/CT found that a subgroup of the patients had metastatic sites in pelvic lymph nodes or distant organs. Eight studies of staging PET/CT undertook histologic correlations. We performed prostate-segment-based analysis specifically regarding the primary cancer lesion for four of these studies, and patient-based analysis specifically regarding pelvic lymph node metastases for four other studies. The pooled sensitivities for staging in the two groups of studies were 70% and 61%, and the pooled specificities were 84% and 97%. None of the studies reported complications from the PET/CT imaging. CONCLUSIONS 68Ga-PSMA PET/CT has clinical relevance to detect sites of recurrence for patients with PSA recurrence after radical prostatectomy (RP) with PSA levels less than 1.0 ng/ml. PATIENT SUMMARY Choline positron emission tomography (PET)/computed tomography (CT) can detect sites of recurrent prostate cancer in an earlier phase of prostate-specific antigen (PSA) recurrence than bone scans and CT scans, but choline PET/CT is rarely positive for patients with restaging PSA levels under 1 ng/ml. A new radiotracer called 68Ga-PSMA for PET/CT was able to detect sites of recurring cancer in up to 50% of patients who had an early rise in PSA exceeding 0.5 ng/ml after initial radical prostatectomy. The published studies did not report adverse effects of 68Ga-PSMA PET/CT imaging.

Galectin-1 mediates radiation-related lymphopenia and attenuates NSCLC radiation response.

Purpose: Radiotherapy can result in lymphopenia, which has been linked to poorer survival. Here, we test the hypothesis that radiotherapy-induced lymphopenia is mediated by a tumor-secreted factor, Galectin-1 (Gal-1), which possesses T-cell proapoptotic activities. Experimental Design: Matched Gal-1 wild-type (WT) or null mice were implanted with Lewis lung carcinoma (LLC-1) that either expressed Gal-1 or had Gal-1 stably downregulated. Tumors were irradiated locally and circulating Gal-1 and T cells were measured. Tumor growth, lung metastasis, intratumoral T-cell apoptosis, and microvessel density count were quantified. Thiodigalactoside (TDG), a Gal-1 inhibitor, was used to inhibit Gal-1 function in another group of mice to validate the observations noted with Gal-1 downregulation. Lymphocyte counts, survival, and plasma Gal-1 were analyzed in cohorts of radiotherapy-treated lung [non–small cell lung cancer (NSCLC)] and head and neck cancer patients. Results: LLC irradiation increased Gal-1 secretion and decreased circulating T cells in mice, regardless of host Gal-1 expression. Inhibition of tumor Gal-1 with either shRNA or thiodigalactoside ablated radiotherapy-induced lymphopenia. Irradiated shGal-1 tumors showed significantly less intratumoral CD8+ T-cell apoptosis and microvessel density, which led to marked tumor growth delay and reduced lung metastasis compared with controls. Similar observations were made after thiodigalactoside treatment. Radiotherapy-induced lymphopenia was associated with poorer overall survival in patients with NSCLC treated with hypofractionated radiotherapy. Plasma Gal-1 increased whereas T-cell decreased after radiation in another group of patients. Conclusions: Radiotherapy-related systemic lymphopenia appeared to be mediated by radiotherapy-induced tumor Gal-1 secretion that could lead to tumor progression through intratumoral immune suppression and enhanced angiogenesis. Clin Cancer Res; 20(21); 5558–69. ©2014 AACR.

Concurrent cetuximab versus platinum-based chemoradiation for the definitive treatment of locoregionally advanced head and neck cancer.

The purpose of this study was to present our experience utilizing cetuximab and platinum‐based concurrent chemoradiotherapy for the definitive treatment of head and neck squamous cell carcinoma (HNSCC).

Automated hybrid closed-loop control with a proportional-integral-derivative based system in adolescents and adults with type 1 diabetes: individualizing settings for optimal performance

Automated insulin delivery systems, utilizing a control algorithm to dose insulin based upon subcutaneous continuous glucose sensor values and insulin pump therapy, will soon be available for commercial use. The objective of this study was to determine the preliminary safety and efficacy of initialization parameters with the Medtronic hybrid closed‐loop controller by comparing percentage of time in range, 70–180 mg/dL (3.9–10 mmol/L), mean glucose values, as well as percentage of time above and below target range between sensor‐augmented pump therapy and hybrid closed‐loop, in adults and adolescents with type 1 diabetes.

Reprogramming the immunological microenvironment through radiation and targeting Axl

Increasing evidence suggests that ionizing radiation therapy (RT) in combination with checkpoint immunotherapy is highly effective in treating a subset of cancers. To better understand the limited responses to this combination we analysed the genetic, microenvironmental, and immune factors in tumours derived from a transgenic breast cancer model. We identified two tumours with similar growth characteristics but different RT responses primarily due to an antitumour immune response. The combination of RT and checkpoint immunotherapy resulted in cures in the responsive but not the unresponsive tumours. Profiling the tumours revealed that the Axl receptor tyrosine kinase is overexpressed in the unresponsive tumours, and Axl knockout resulted in slower growth and increased radiosensitivity. These changes were associated with a CD8+ T-cell response, which was improved in combination with checkpoint immunotherapy. These results suggest a novel role for Axl in suppressing antigen presentation through MHCI, and enhancing cytokine release, which promotes a suppressive myeloid microenvironment.

Central liver toxicity after SBRT: An expanded analysis and predictive nomogram

PURPOSE To further explore the correlation of central biliary tract (cHBT) radiation doses with hepatobiliary toxicity (HBT) after stereotactic body radiation therapy (SBRT) in a larger patient dataset. METHODS We reviewed the treatment and outcomes of all patients who received SBRT for primary liver cancer (PLC) and metastatic liver tumors between July 2004 and November 2015 at our institution. The cHBT was defined as isotropic expansions (5, 10, 15, 20 and 25mm) from the portal vein (PV). Doses were converted to biologically effective doses by using the standard linear quadratic model with α/β of 10 (BED10). HBT was graded according to the Common Terminology Criteria for Adverse Events v4.03. RESULTS Median follow-up was 13months. Out of the 130 patients with complete follow-up records analyzed, 60 (46.1%) had liver metastases, 40 (30.8%) had hepatocellular carcinoma (HCC), 26 (20%) had cholangiocarcinoma (CCA) and 4 (3.1%) patients other PLC histologies. Thirty-three (25.4%) grade 2+ and 28 (21.5%) grade 3+ HBT were observed. Grade 3+ HBT was seen in 13 patients (50%) with CCA, 7 patients (17.5%) with HCC and 7 (11.7%) patients with liver metastases. SBRT doses to the cHBT were highly associated with HBT, but only for PLC patients when analyzed by histological subtype. The 15mm expansion from the PV (cHBT15) proved to be an appropriate surrogate for the cHBT. The strongest cHBT15 dose predictors for G3+ HBT for PLC were the VBED1040⩾37cc (p<0.0001) and the VBED1030⩾45cc (p<0.0001). CONCLUSION SBRT doses to the cHBT are associated with occurrence of HBT only in PLC patients. Limiting the dose to the cHBT to VBED1040<37cc and VBED1030<45cc when treating PLC patients with SBRT may reduce the risk of HBT.