Combination GLP-1 and Insulin Treatment Fails to Alter Myocardial Fuel Selection Versus Insulin Alone in Type 2 Diabetes

Context Glucagon-like peptide-1 (GLP-1) and the clinically available GLP-1 agonists have been shown to exert effects on the heart. It is unclear whether these effects occur at clinically used doses in vivo in humans, possibly contributing to CVD risk reduction. Objective To determine whether liraglutide at clinical dosing augments myocardial glucose uptake alone or in combination with insulin compared to insulin alone in metformin-treated Type 2 diabetes mellitus. Design Comparison of myocardial fuel utilization after 3 months of treatment with insulin detemir, liraglutide, or combination detemir+liraglutide. Setting Academic hospital Participants Type 2 diabetes treated with metformin plus oral agents or basal insulin. Interventions Insulin detemir, liraglutide, or combination added to background metformin Main Outcome Measures Myocardial blood flow, fuel selection and rates of fuel utilization evaluated using positron emission tomography, powered to demonstrate large effects. Results We observed greater myocardial blood flow in the insulin-treated groups (median[25th, 75th percentile]: detemir 0.64[0.50, 0.69], liraglutide 0.52[0.46, 0.58] and detemir+liraglutide 0.75[0.55, 0.77] mL/g/min, p=0.035 comparing 3 groups and p=0.01 comparing detemir groups to liraglutide alone). There were no evident differences between groups in myocardial glucose uptake (detemir 0.040[0.013, 0.049], liraglutide 0.055[0.019, 0.105], detemir+liraglutide 0.037[0.009, 0.046] µmol/g/min, p=0.68 comparing 3 groups). Similarly there were no treatment group differences in measures of myocardial fatty acid uptake or handling, and no differences in total oxidation rate. Conclusions These observations argue against large effects of GLP-1 agonists on myocardial fuel metabolism as mediators of beneficial treatment effects on myocardial function and ischemia protection

Characterization of A Type 1 Collagen Targeted PET Tracer

poster abstractRenal fibrosis occurs in many diseases of the kidney, including chronic kidney disease (CKD). Renal fibrosis is characterized by an excessive accumulation and deposition of extracellular matrix components, mainly type I collagen. Determination of the presence and extent of renal fibrosis may aid in the prediction of the long-term outcome of renal function in CKD. Biopsy is considered the gold standard in the diagnosis of renal fibrosis; however biopsy is inherently invasive and does not easily lend itself to following the disease thru time. A noninvasive technique such as PET would both allow the detection and monitoring of renal fibrosis progression. A type I collagen-specific cyclic peptide, EP-3533, has been identified and used as a contrast agent in MRI after conjugation with three Gd-DOTA chelates (Caravan et al 2007). To explore the potential for imaging with PET, which can provide a quantitative assessment of regional peptide localization, we have prepared an EP-3533 conjugate incorporating the NODAGA chelating agent at its amine terminus, and radiolabeled that conjugate with generator-produced positron-emitting 68Ga (68-minute half-life). In vitro association kinetics binding of the labeled peptide was performed in collagen type 1 coated plates, where 68GaDOTA-EP-3533 exhibited a Kd of 0.2 M for type I collagen. To better characterize the tracer in an animal model, renal fibrosis was induced in male Wistar rats by clamping the renal artery and vein of the left kidney for 50 minutes. Thus providing both a diseased and control kidney in each animal. Approximately 10 weeks after surgery both left (fibrotic) and right (normal) kidneys were resected and frozen and mounted in OTC for cryotomy. Longitudinal sections obtained from each kidney were used for autoradiography. ROI analysis found an approximate two- to four-fold region-dependent increase in binding in fibrotic tissue compared to normal. Collagen and non-collagen protein levels were determined in the same kidney sections that had been used for autoradiography using a commercially available staining assay. This assay yielded a 1.7-fold difference in collagen levels between normal and fibrotic tissue. Additionally, representative slices were stained with Sirius Red for histological evaluation. Preliminary data indicates that 68Ga-NODAGA-EP-3533 binds to collagen-rich tissue, consistent with the literature for Gd-DOTA-EP-3533. In vivo studies in an animal model of fibrosis are needed to further characterize this tracer and its potential for PET tracer detection and monitoring of Renal Fibrosis

Manometric evaluation of internal anal sphincter after fissurectomy and anoplasty for chronic anal fissure: a prospective study

Chronic anal fissure (CAF) is a common painful clinical disease and its pathogenesis remains poorly understood. After failure of pharmacological therapy, that is the first-line treatment, sur- gical sphincterotomy remains the treatment of choice although it is followed by a high rate of anal incontinence resulting from the sphincter damage; therefore, the research of a sphincter-saving surgical option has become an important goal. The aim of this study was to evaluate the mano- metric modifications and the incidence of anal incontinence after fissurectomy and anoplasty with advancement skin flap in patients affected by CAF with hypertonia of the internal anal sphincter (IAS). Fifteen patients affected by CAF with hypertonia of IAS, unresponsive to medical therapy, were enrolled. All subjects underwent fissurectomy and anoplasty with advancement skin flap. Anorectal manometry was performed preoperatively and after 6 and 12 months from surgery. Maximum resting pressure (MRP), maximum squeeze pressure (MSP), ultraslow wave activity (USWA), fissure healing, anal continence, and postoperative complications were recorded. All patients healed within 30 days from surgery. No intra- or postoperative complications were recorded except for a case of partial donor site break. No significant modifications of MSP were detected. Six months after surgery, MRP was higher with respect to healthy subjects but signif- icantly reduced in comparison to baseline levels. At 12 months, it was higher have versus 6-month values but significantly lower versus preoperative values. USWA was significantly represented in patients with CAF versus healthy subject. Both at 6 and 12 months, they decreased significantly with respect to preoperative values without significant differences versus healthy subjects. Both at 6 and 12 months, anal continence did not differ with respect to preoperative time. The fissurectomy with anoplasty resulted in a high healing rate without surgical sequelae or anal incontinence. Also, it was able to reduce IAS pressure in the same manner as surgical sphincterotomy or forceful dilatation

Advancement flap in the management of chronic anal fissure: A prospective study

Lateral internal sphincterotomy is the surgical treatment of choice of chronic anal fissure after failure of conservative measures. Several randomized trials identified an overall risk of incontinence of 10 % mostly for flatus. Fissurectomy is the most commonly used procedure to preserve the integrity of the anal sphincters. However, a possible complication is keyhole defect that may lead to faecal soiling. In this study, chronic anal fissure (CAF) was treated by fissurectomy and anal advancement flap to preserve the anatomo-functional integrity of sphincters and to reduce healing time and the risk of anal stenosis. In patients with hypertonia, surgical treatment was combined with chemical sphincterotomy by injection of botulinum toxin to enhance tissue perfusion. Forty eight patients with CAF underwent fissurectomy and anal advancement flap. In 22 subjects with hypertonia of the internal anal sphincter, intrasphincter injection of 30 UI of botulinum toxin at the completion of the surgical operation was used. All patients were followed up to 24 months. Since the first defecation, the intensity and duration of pain were significantly reduced. Two patients had urinary retention, five had infections and three had partial breakdowns. No anal stenosis, keyhole deformity or necrosis flap was recorded. At the 24 months follow-up visit, anal incontinence was similar to those detected preoperatively. Only four recurrences were detected at 18 and 20 months. After medical treatment failure, fissurectomy with advancement flap is a valid sphincter-conserving procedure for treatment of anterior or posterior CAF, regardless of hypertonia of the internal anal sphincter. © 2011 Springer-Verlag

Robot-assisted kidney transplantation with regional hypothermia using grafts with Multiple Vessels After Extracorporeal Vascular Reconstruction: results from the European Association of Urology Robotic Urology Section Working Group

Background: Kidney transplantation using grafts with multiple vessels (GMVs) is technically demanding and may be associated with increased risk of complications or suboptimal graft function. To date, no studies have reported on robot-assisted kidney transplantation (RAKT) using GMVs. Objective: To report our experience with RAKT using GMVs from living donors, focusing on technical feasibility and early postoperative outcomes. Design, setting, and participants: We reviewed the multi-institutional, prospectively collected European Association of Urology (EAU) Robotic Urology Section (ERUS)-RAKT database to select consecutive patients undergoing RAKT from living donors using GMVs between July 2015 and January 2018. Patients undergoing RAKT using grafts with single vessels (GSVs) served as controls. In case of GMVs, ex vivo vascular reconstruction techniques were performed during bench surgery according to the case-specific anatomy. Intervention: RAKT with regional hypothermia. Outcome measurements and statistical analysis: Intraoperative outcomes and early (30 d) postoperative complications and functional results were the main study endpoints. Multivariable logistic regression analysis evaluated potential predictors of suboptimal renal function at 1 mo. Results and limitations: Overall, 148 RAKTs were performed during the study period. Of these, 21/148 (14.2%) used GMVs; in all cases, single arterial and venous anastomoses could be performed after vascular reconstruction. Median anastomoses and rewarming times did not differ significantly between the GMV and GSV groups. Total and cold ischemia times were significantly higher in the GMV cohort (112 vs 88 min, p = 0.004 and 50 vs 34 min, p = 0.003, respectively). Overall complication rate and early functional outcomes were similar among the two groups. No major intra-or postoperative complications were recorded in the GMV cohort. At multivariable analysis, use of GMVs was not significantly associated with suboptimal renal function at 1 mo. Small sample size and short follow-up represent the main study limitations. Conclusions: RAKT using GMVs from living donors is technically feasible and achieved favorable perioperative and short-term functional outcomes. Larger studies with longer follow-up are needed to confirm our findings. Patient summary: In this study, we evaluated for the first time in literature the results of RAKT from living donors using kidneys with multiple arteries and veins. We found that, in experienced centers, RAKT using kidneys with multiple vessels is feasible and achieves optimal results in terms of postoperative kidney function with a low number of postoperative complications. (C) 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved

Double localization and multiple recurrences of dermatofibrosarcoma protuberans of the female breast: A rare clinical case

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Concomitant Small Cell Neuroendocrine Carcinoma of Gallbladder and Breast Cancer

The neuroendocrine carcinoma is defined as a high-grade malignant neuroendocrine neoplasm arising from enterochromaffin cells, usually disposed in the mucosa of gastric and respiratory tracts. The localization in the gallbladder is rare. Knowledge of these gallbladder tumors is limited and based on isolated case reports. We describe a case of an incidental finding of small cell neuroendocrine carcinoma of the gallbladder, observed after cholecystectomy for cholelithiasis, in a 55-year-old female, who already underwent quadrantectomy and sentinel lymph-node biopsy for breast cancer. The patient underwent radiotherapy for breast cancer and six cycles of chemotherapy with cisplatin and etoposide. Eighteen months after surgery, the patient was free from disease. Small cell neuroendocrine carcinoma of the gallbladder has poor prognosis. Because of the rarity of the reported cases, specific prognostic factors have not been identified. The coexistence of small cell neuroendocrine carcinoma of the gallbladder with another malignancy has been reported only once.The contemporary presence of the two neoplasms could reflect that bioactive agents secreted by carcinoid can promote phenotypic changes in susceptible cells and induce neoplastic transformation

Sodium iodide symporter (NIS) in extrathyroidal malignancies: Focus on breast and urological cancer

BACKGROUND: Expression and function of sodium iodide symporter (NIS) is requisite for efficient iodide transport in thyrocytes, and its presence in cancer cells allows the use of radioiodine as a diagnostic and therapeutic tool in thyroid neoplasia. Discovery of NIS expression in extrathyroidal tissues, including transformed cells, has opened a novel field of research regarding NIS-expressing extrathyroidal neoplasia. Indeed, expression of NIS may be used as a biomarker for diagnostic, prognostic, and therapeutic purposes. Moreover, stimulation of endogenous NIS expression may permit the radioiodine treatment of extrathyroidal lesions by concentrating this radioisotope. RESULTS: This review describes recent findings in NIS research in extrathyroidal malignancies, focusing on breast and urological cancer, emphasizing the most relevant developments that may have clinical impact. CONCLUSIONS: Given the recent progress in the study of NIS regulation as molecular basis for new therapeutic approaches in extrathyroidal cancers, particular attention is given to studies regarding the relationship between NIS and clinical-pathological aspects of the tumors and the regulation of NIS expression in the experimental models

Bilateral spermatic cord en bloc ligation by laparoendoscopic single-site surgery: preliminary experience compared to conventional laparoscopy

BACKGROUND: Laparo Endoscopic Single-site Surgery (LESS) represents an evolution of minimally invasive surgery and aims to improve cosmetic outcome and reduce surgical trauma and complications associated with traditional laparoscopy. This study was performed to present our preliminary experience in bilateral spermatic cord ligation with the LESS technique and compare the results with the outcomes of conventional laparoscopic surgery. METHODS: Between June 2007 and May 2013, 24 patients were referred to our institute for bilateral varicocelectomy. The indications for this type of procedure were bilateral varicocele with impairment of semen parameters or chronic bilateral testicular pain. All procedures were performed via the same surgeon. The patients were divided into two groups according to the type of laparoscopic surgery. Group A included 10 patients underwent LESS technique while group B included the remaining 14 patients that underwent conventional laparoscopy. RESULTS: The comparison between the two techniques showed some important advantages for LESS: shorter operating time (45.4 min vs. 88.3 (P\u2009<\u2009.001), shorter hospital stay (16.6 hours vs. 51.4 hours) (P\u2009<\u2009.001), early return to the normal activity (2.3 days vs. 4.7 days) and better cosmetic outcomes. No conversions from LESS to conventional laparoscopy were necessary and blood loss was insignificant in all patients.All patients in the LESS group reported full satisfaction with the cosmetic outcome, whereas 85.7% of patients after conventional laparoscopy were fully satisfied with cosmesis. CONCLUSIONS: Bilateral spermatic cord ligation with LESS is an alternative to conventional laparoscopy. The procedure was successfully performed in all patients. The trans-umbilical approach offers the advantage of a better cosmetic result, shorter hospital stay and less postoperative pain

Synthesis and preliminary biological evaluation of radiolabeled 5-BDBD analogs as new candidate PET radioligands for P2X4 receptor

P2X4 receptor has become an interesting molecular target for treatment and PET imaging of neuroinflammation and associated brain diseases such as Alzheimer’s disease. This study reports the first design, synthesis, radiolabeling and biological evaluation of new candidate PET P2X4 receptor radioligands using 5-BDBD, a specific P2X4 receptor antagonist, as a scaffold. 5-(3-Hydroxyphenyl)-1-[11C]methyl-1,3-dihydro-2H-benzofuro[3,2-e][1,4]diazepin-2-one (N-[11C]Me-5-BDBD analog, [11C]9) and 5-(3-Bromophenyl)-1-[11C]methyl-1,3-dihydro-2H-benzofuro[3,2-e][1,4]diazepin-2-one (N-[11C]Me-5-BDBD, [11C]8c) were prepared from their corresponding desmethylated precursors with [11C]CH3OTf through N-[11C]methylation and isolated by HPLC combined with SPE in 30–50% decay corrected radiochemical yields with 370–1110 GBq/µmol specific activity at EOB. 5-(3-[18F]Fluorophenyl)-1,3-dihydro-2H-benzofuro[3,2-e][1,4]diazepin-2-one ([18F]F-5-BDBD, [18F]5a) and 5-(3-(2-[18F]fluoroethoxy)phenyl)-1,3-dihydro-2H-benzofuro[3,2-e][1,4]diazepin-2-one ([18F]FE-5-BDBD, [18F]11) were prepared from their corresponding nitro- and tosylated precursors by nucleophilic substitution with K[18F]F/Kryptofix 2.2.2 and isolated by HPLC-SPE in 5–25% decay corrected radiochemical yields with 111–740 GBq/µmol specific activity at EOB. The preliminary biological evaluation of radiolabeled 5-BDBD analogs indicated these new radioligands have similar biological activity with their parent compound 5-BDBD