Multimodality PET and Near-Infrared Fluorescence Intraoperative Imaging of CEA-Positive Colorectal Cancer.

PURPOSE: Molecular imaging is a major diagnostic component for cancer management, enabling detection, staging of disease, targeting therapy, and monitoring the therapeutic response. The coordination of multimodality imaging techniques further enhances tumor localization. The development of a single agent for real-time non-invasive targeted positron emission tomography (PET) imaging and fluorescence guided surgery (FGS) will provide the next generation tool in the surgical management of cancer. PROCEDURES: The humanized anti-CEA M5A-IR800 "sidewinder" (M5A-IR800-SW) antibody-dye conjugate was designed with a NIR 800 nm dye incorporated into a PEGylated linker and conjugated with the metal chelate p-SCN-Bn-deferoxamine (DFO) for zirconium-89 PET imaging (89Zr, half-life 78.4 h). The dual-labeled 89Zr-DFO-M5A-SW-IR800 was evaluated for near infrared (NIR) fluorescence imaging, PET/MRI imaging, terminal tissue biodistribution, and blood clearance in a human colorectal cancer LS174T xenograft mouse model. RESULTS: The 89Zr-DFO-M5A-SW-IR800 NIR fluorescence imaging showed high tumor targeting with normal liver uptake. Serial PET/MRI imaging was performed at 24 h, 48 h, and 72 h and showed tumor localization visible at 24 h that persisted throughout the experiment. However, the PET scans showed higher activity for the liver than the tumor, compared to the NIR fluorescence imaging. This difference is an important finding as it quantifies the expected difference due to the sensitivity and depth of penetration between the 2 modalities. CONCLUSIONS: This study demonstrates the potential of a pegylated anti-CEA M5A-IR800-Sidewinder for NIR fluorescence/PET/MR multimodality imaging for intraoperative fluorescence guided surgery.

Long-term follow-up of patients with poor-risk acute leukemia treated on a phase 2 trial undergoing intensified conditioning regimen prior to allogeneic hematopoietic cell transplantation.

Patients with acute leukemia who undergo allogenic hematopoietic cell transplantation with active disease have high rates of relapse and poor overall survival (OS) post-transplant compared to patients undergoing HCT in remission. Here, we report the long-term outcomes in 32 patients who received a high-intensity conditioning regimen comprising fractionated total body irradiation (FTBI; 1200 cGy) with pharmacokinetic (PK) dosing of intravenous Busulfan (IV BU) targeted to first dose area under curve (AUC) of 700-900 µM/min and etoposide (30 mg/kg) in a prospective phase 2 clinical trial. The median age of the patients at the time of HCT was 37 years (range: 18-50) presenting with high-risk (n = 6) and relapsed/refractory(r/r) acute leukemias (n = 26). All but one patient underwent HCT using peripheral blood stem cells from matched sibling donors. At a median follow-up of 17.3 years (range 14.4-19.0), 11 patients remained alive. The disease-free survival and OS at 15 years was 34% (versus 40% at 5-years post-HCT). The 15-year cumulative incidence of relapse was 26% and non-relapse mortality (NRM) was 38% (95% CI: 21-54%) and the cumulative incidence of chronic GVHD at 15 years was 33% using a prophylactic regimen of cyclosporine A and mycophenolate mofetil. The most common life-threatening late effects were secondary malignancies, metabolic, or cardiac complications with a cumulative incidence of 6.6%, 6.6%, and 13.3%, respectively. No unusual late effects or patterns of relapse were noted on longer followed on patients treated with intensified myeloablative condition regimen. Results from this study supports continued development of intensive conditioning regimens in patients with r/r acute leukemias to improve leukemia free (LFS) and OS in this high-risk population.

High Prevalence of Late-Onset Fabry Cardiomyopathy in a Cohort of 499 Non-Selective Patients with Left Ventricular Hypertrophy: The Asian Fabry Cardiomyopathy High-Risk Screening Study (ASIAN-FAME).

Left ventricular hypertrophy (LVH) caused by cardiac variant Fabry disease (FD) is typically late-onset and may mimic LVH caused by abnormal loading conditions. We aimed to determine the prevalence of FD in a non-selective patient population of everyday practice presenting with LVH, including those with hypertension and valve disease. We measured plasma alpha-galactosidase A activity using dried blood spot tests in 499 (age = 66 ± 13 years; 336 men) Hong Kong Chinese patients with LVH defined as maximal LV septal/posterior wall thickness ≥13 mm on echocardiography. Patients with low enzyme activity underwent mutation analysis of the GLA gene. Eight (age = 53-74 years; all men) unrelated patients (1.6%) had low plasma alpha-galactosidase A activity (0.57 ± 0.27 µmol/L wb/hr) and all were confirmed to have the GLA IVS4 + 919G > A mutation. FD patients presented with heart failure (n = 5), heart block (n = 2), ventricular tachycardia (n = 1), chest pain (n = 3), and/or murmur (n = 1). Uncontrolled hypertension (n = 4) and/or severe mitral/aortic valve pathology (n = 2) were frequent. Ethnic subgroups included Teochew (n = 5), Canton (n = 2), and Wenzhou (n = 1). Endomyocardial biopsy (n = 6) revealed hypertrophic myocytes with vacuolization and dense lamellar bodies. Late-onset IVS4 + 919G > A FD is prevalent among Chinese LVH patients, and should be considered as a cause of LVH in adult patients even when hypertension and/or valve pathology are present.

Impact of Previous Tunneled Vascular Catheters and their Location on Upper Limb Arteriovenous Fistula Function.

Background: Long-term arteriovenous fistula (AVF) survival has been shown to be adversely affected by the presence of previous tunneled vascular catheters (TVC). We analyzed the effect of previous TVCs and their location (ipsilateral versus contralateral) on the successful function of upper-limb AVFs in the first 12 months after creation. Methods: We retrospectively reviewed clinical data on patients' first upper-limb AVFs, created between January 2013 and December 2017. We analyzed the rates of successful AVF function (successful cannulation using two needles for ≥50% sessions over a 2-week period) at 6 and 12 months after creation, time to AVF maturation, and rates of assisted maturation. Results: In total, 287 patients with first AVFs were identified, of which 142 patients had a previous TVC (102 contralateral, 40 ipsilateral) and 145 had no previous TVC. The no TVC group had higher rates of AVF function at both 6 months (69% versus 54%, OR, 1.84; 95% CI, 1.00 to 3.39, P=0.05) and 12 months (84% versus 64%, OR, 3.10; 95% CI, 1.53 to 6.26, P=0.002) compared with the TVC group. The contralateral TVC group had higher rates of AVF function at 6 months (60% versus 40%, OR, 2.21; 95% CI, 1.01 to 4.88, P=0.05), but not at 12 months (66% versus 58%, OR, 1.42; 95% CI, 0.62 to 3.25, P=0.40) compared with the ipsilateral TVC group. The median time to AVF maturation in the contralateral and ipsilateral TVC groups were 121.5 and 146 days respectively (P=0.07). Assisted maturation rates were lower in no TVC group compared with the TVC group (12% versus 28%, P=0.007), but similar between the contralateral and ipsilateral TVC groups (29% versus 26%, P=0.74). Conclusions: Previous TVC use was associated with poorer AVF function at 6 and 12 months, with a higher rate of assisted maturation. The presence of an ipsilateral TVC was associated with lower successful AVF use at 6 months, compared with contralateral TVC.

Terminal Sterilization of Anterior Cruciate Ligament (ACL) Allografts: A Systematic Review of Outcomes.

INTRODUCTION: Anterior cruciate ligament (ACL) injuries are common and reconstruction can be completed with either autograft or allograft tissue. However, there is concern about an increased failure rate with allograft tissue. The purpose of this study was to systematically review the available evidence to determine the effect of irradiation and level of dose on the failure rates of allograft in ACL reconstruction. METHODS: A literature search was performed using PubMed, Scopus, and Web of Science from January 2000 to September 2013. Inclusion criteria consisted of the following: (1) primary, unilateral, single-bundle allograft ACL procedure, (2) studies with data documenting graft type and terminal sterilization technique, (3) subjective assessments of outcome, and (4) objective assessments of outcome. Studies without reported subjective and objective outcomes and those pertaining to revision ACL reconstruction were excluded. Failures were defined and compared between irradiated and non-irradiated grafts, as well as between grafts irradiated with 1.2 - 1.8 Mrad and those with 2.0 - 2.5 Mrad. RESULTS: Of the 242 articles identified via initial search, 17 studies met the final inclusion criteria. A total of 1,090 patients were evaluated in this study, all having undergone unilateral primary ACL reconstruction with allograft tissue with 155 failures. The failure rate between non-irradiated (98/687, 14.7%) and irradiated (57/408, 14.0%) was not statistically significant (p = 0.86). Grafts in the high-dose irradiation group (27/135, 20.0%) had a statistically significant higher (p < 0.001) rate of failure than those in the low-dose irradiation group (30/273, 10.6%). CONCLUSION: The irradiation of an allograft increases the risk of failure after an ACL reconstruction but the use of lower doses of radiation decreases that risk.

Role of a high throughput biodosimetry test in treatment prioritization after a nuclear incident.

PURPOSE: We introduce and evaluate a high throughput biodosimetry test system (REDI-Dx) suitable for testing of thousands of potential radiation victims following a mass scale nuclear event caused by detonation of a nuclear device or a nuclear accident, as part of an overall strategy for effective medical management of the crisis. MATERIALS AND METHODS: The performance of a high throughput biodosimetry test was evaluated by collecting samples of both non-irradiated presumed healthy donors as well as irradiated subjects collected as part of either cancer treatment regimens or banked from previous studies. The test measures the gene expression of a set of radiation responsive genes based on the DxDirect® genomic platform. The potential diagnostic accuracy of REDI-Dx was evaluated as a predictor of actual dose of radiation. While the REDI-Dx test has been calibrated to provide a quantitative measure of actual absorbed dose, we compared the performance of the REDI-Dx test (sensitivity and specificity) as a qualitative result at the most commonly applied thresholds 2.0 Gy and 6.0 Gy. RESULTS: The test demonstrated high specificity and lack of effect of medical conditions. Using receiver operating characteristic (ROC) curve analysis, REDI-Dx was shown to be a good predictor of actual dose for determining treatment category based on either 2.0 or 6.0 Gy, with a 98.5% sensitivity and 90% specificity for 2.0 Gy, and 92% sensitivity and 84% specificity for 6.0 Gy. Results were reproducible between clinical laboratories with an SD of 0.2 Gy for samples ≤2.0 Gy and a CV of 10.3% for samples from 2.0 to 10.0 Gy. CONCLUSIONS: Use of a biodosimetry test, like REDI-Dx test system would provide valuable information that would improve the ability to assign patients to the correct treatment category when combined with currently available biodosimetry tools, as compared to the use of existing tools alone. The REDI-Dx biodosimetry test system is for investigational use only in the U.S.A. The performance characteristics of this product have not been established.

Why do students participate in medical education?

BACKGROUND: Medical student involvement in curriculum development is important; however, little is known about why medical students become engaged in this activity. The aim of this study was to understand what motivates medical students at one university to participate in the process of curriculum development and gain a wider perspective on student engagement in medical education. METHODS: Grounded theory methodology was the foundation of this study. We conducted semi-structured interviews with seven medical students from the University of Tokyo who developed and participated in a group whose aim was to actively contribute towards improving their medical education. The data from the interviews were analysed by thematic synthesis, with triangulation. RESULTS: Three themes emerged as potential explanations for motivating student behaviour: (1) extracurricular interaction with faculty members; (2) engaging with highly motivated peers; and (3) student values for serving the public. CONCLUSIONS: Students working to improve educational processes at their medical schools had the opportunity to communicate more with faculty members, enjoyed opportunities for networking with other highly motivated peers and enhanced aspects of their developing professionalism.

Expression of ErbB2 enhances radiation-induced NF-kappaB activation.

Her-2/neu (ErbB2) oncogene, the second member of the epidermal growth factor receptor (EGFR) family, encodes a transmembrane tyrosine kinase receptor in Her-2-positive tumors. Accumulating evidences demonstrate that signaling networks activated by EGFR and transcription factor NF-kappaB are associated with cell response to ionizing radiation (IR). The present study shows that overexpression of ErbB2 enhanced NF-kappaB activation induced by IR in human breast carcinoma MCF-7 cells transfected with ErbB2 genes (MCF-7/ErbB2). Stable transfection of dominant-negative mutant IkappaB (MCF-7/ErbB2/mIkappaB) or treatment with anti-ErbB2 antibody, Herceptin, inhibited NF-kappaB activation and radiosensitized MCF-7/ErbB2 cells. Consistent with NF-kappaB regulation, basal and IR-induced Akt, a kinase downstream of ErbB2, was activated in MCF-7/ErbB2 cells and inhibited by Herceptin. To identify specific genes affected by ErbB2-mediated NF-kappaB activation, a group of IR-responsive elements Cyclin B1, Cyclin D1, Bcl-2, Bcl/XL, BAD and BAX were evaluated. Basal levels of prosurvival elements Cyclin B1, Cyclin D1, Bcl-2 and Bcl/XL but not apoptotic BAD and BAX were upregulated in MCF-7/ErbB2 cells with striking enhancements in Bcl-2 and Bcl/XL. IR further induced Cyclin B1 and Cyclin D1 expression that was reduced by Herceptin. Bcl-2 kept a high steady level after Herceptin+IR treatment and, in contrast to control MCF-7/Vector cells, Bcl/XL was inhibited in MCF-7/ErbB2 cells by Herceptin+IR treatment. However, all four prosurvival proteins were downregulated by inhibition of NF-kappaB in MCF-7/ErbB2/mIkappaB cells. These results thus provide evidence suggesting that overexpression of ErbB2 is able to enhance NF-kappaB response to IR, and that a specific prosurvival network downstream of NF-kappaB is triggered by treatments using anti-ErbB2 antibody combined with radiation.