Shadi Abdar Esfahani

Diagnostic Accuracy and Clinical Utility of Noninvasive Testing for Coronary Artery Disease

BACKGROUND Computed tomography coronary angiography (CTCA) has become a popular noninvasive test for diagnosing coronary artery disease. OBJECTIVE To compare the accuracy and clinical utility of stress testing and CTCA for identifying patients who require invasive coronary angiography (ICA). DESIGN Observational study. SETTING University medical center in Rotterdam, the Netherlands. PATIENTS 517 patients referred by their treating physicians for evaluation of chest symptoms by using stress testing or ICA. INTERVENTION Stress testing and CTCA in all patients. MEASUREMENTS Diagnostic accuracy of stress testing and CTCA compared with ICA; pretest probabilities of disease by Duke clinical score; and clinical utility of noninvasive testing, defined as a pretest or posttest probability that suggests how to proceed with testing (no further testing if < or =5%, proceed with ICA if between 5% and 90%, and refer directly for ICA if > or =90%). RESULTS Stress testing was not as accurate as CTCA; CTCA sensitivity approached 100%. In patients with a low (<20%) pretest probability of disease, negative stress test or CTCA results suggested no need for ICA. In patients with an intermediate (20% to 80%) pretest probability, a positive CTCA result suggested need to proceed with ICA (posttest probability, 93% [95% CI, 92% to 93%]) and a negative result suggested no need for further testing (posttest probability, 1% [CI, 1% to 1%]). Physicians could proceed directly with ICA in patients with a high (>80%) pretest probability (91% [CI, 90% to 92%]). LIMITATIONS Referral and verification bias might have influenced findings. Stress testing provides functional information that may add value to that from anatomical (CTCA or ICA) imaging. CONCLUSION Computed tomography coronary angiography seems most valuable in patients with intermediate pretest probability of disease, because the test can distinguish which of these patients need invasive angiography. These findings need to be confirmed before CTCA can be routinely recommended for these patients.The role of computed tomography coronary angiography (CTCA) for diagnosing coronary artery disease is uncertain. Weustink and colleagues compared the accuracy of stress testing and CTCA with that o...

Functional external anal sphincter reconstruction for treatment of anal incontinence using muscle progenitor cell auto grafting.

PURPOSE: This study aimed to investigate the feasibility of autologous muscle progenitor cell transplantation for anal sphincter regeneration in a rabbit model of anal incontinence. We examined the serial changes in structure, with particular emphasis on histology and functional properties of the anal sphincter. METHODS: External anal sphincterotomy was performed in 21 rabbits; these rabbits were randomly assigned to 2 groups. In group I (n = 9), autologous muscle progenitor cells were isolated from quadriceps myofiber explants, labeled with PKH-26, and injected into sphincter 3 weeks after sphincterotomy. In group II (n = 12), saline buffer was injected at the site of damage. Sphincter electromyography and manometry were performed immediately before sphincterotomy and 14, 28, and 60 days after injection in 3 animals in each group at every interval and the findings were correlated with histomorphological studies. In addition, electromyography and manometry were performed in the remaining 3 rabbits in group II after 6 months. RESULTS: In group II, a flaccid sphincter persisted during the 6 months of follow-up. In group I, muscle progenitor autografting accelerated sphincter myofiber repair and improvement in functional capacity of the damaged sphincter. Fluorescently labeled cells were detected in all of the grafted sphincters; regenerated myotubes were detectable at the injection site as evidenced by the presence of desmin. We also observed a significant decrease in interstitial fibrosis in the 4th week and strikingly higher amounts of Ki-67-positive cells in group I. Manometry and electromyography showed a significant improvement in the mean resting anal canal pressure and sphincteric electrical activity 4 weeks after cell injection, respectively. CONCLUSION: Transplanting muscle progenitor cells showed the potential for recapitulation of a myogenic program when injected into deficient rabbit anal sphincter. Objective anal measures of resting and stimulated pressures and electromyographic profile improved. Stem cell-mediated anal myoplasty warrants additional investigation as a new method to treat anal incontinence before attempting this modality in the clinical setting.

Genetic susceptibility to Graves’ ophthalmopathy: the role of polymorphisms in proinflammatory cytokine genes

PurposeIn order to investigate the underlying genetic mechanisms of Graves’ ophthalmopathy (GO), we examined the association between single-nucleotide polymorphisms in five important proinflammatory cytokines, namely IL-12, TNF-α, IFN-γ, IL-2, and IL-6, with GO in a sample of Iranian adults.MethodsA total of 57 patients with Graves’ disease without GO, 50 patients with GO, and 140 healthy controls were enrolled. Patients were recruited consecutively from the outpatient endocrine clinic of a large university general hospital. Genotype and allele frequencies of the following proinflammatory cytokines were compared between the groups: IL-12 (−1188A/C), TNF-α(−308A/G, −238A/G), INF-γ(UTR 5644A/T), IL-2 (-330T/G, 166G/T), and IL-6 (−174C/G, nt565A/G). A corrected (for multiple testing) P-value (P c) less than 0.05 was considered statistically significant.ResultsThe IL-12 −1188C allele (odds ratio (OR)=2.65, P c<0.01) and CC genotype (OR=7.58, P c<0.01) were significantly more common in patients with GO than in patients without GO. The TNF-α−238A allele was more frequent in patients with GO than in patients without GO (OR=2.99, P c<0.05). The frequency of the IFN-γUTR 5644T allele (OR=2.67, P c<0.05), AT genotype (OR=13.33, P c<0.05), and TT genotype (OR=18.46, P c<0.01) was significantly higher among patients with GO than patients without GO. No significant association was found for other polymorphisms.ConclusionsWe demonstrated that specific polymorphisms in IL-12, IFN- γ, and TNF-αgenes are associated with susceptibility to GO in the Iranian population. Our results open a new perspective to genetic correlates of GO.

Urinary and Serum Carbohydrate Antigen 19-9 as a Biomarker in Ureteropelvic Junction Obstruction in Children

PURPOSE We evaluated the predictive role of serum and urinary carbohydrate antigen 19-9 in the diagnosis and followup of pediatric ureteropelvic junction obstruction. MATERIALS AND METHODS The study included 27 children with ureteropelvic junction obstruction who underwent pyeloplasty (group 1), and 41 controls consisting of 27 healthy children (group 2) and 14 children with hydrocele/renal cyst (group 3). Serum and voided urine were evaluated for carbohydrate antigen 19-9 in each group. Additionally urine from the affected pelvis and fluid in hydrocele/renal cyst were collected at surgery in groups 1 and 3. Serum and voided urine samples were obtained at 3, 6 and 9 months after pyeloplasty for carbohydrate antigen 19-9 assessment, and were correlated with clinical factors. RESULTS Preoperative carbohydrate antigen 19-9 level was significantly greater in group 1 than in controls. The best cutoff values for serum and urinary carbohydrate antigen 19-9 were 13.21 U/ml and 30.6 U/ml, respectively, with significantly higher sensitivity and specificity for urinary values. Obstruction release was followed by improvement of renal function together with significant reduction in urinary and serum carbohydrate antigen 19-9 at 3 months. Initial pelvis diameter and renographic function significantly correlated with urinary carbohydrate antigen 19-9. No significant correlation was found regarding serum carbohydrate antigen 19-9. CONCLUSIONS Voided urine carbohydrate antigen 19-9 is a noninvasive, clinically applicable marker in congenital obstructive nephropathy. The practical implications of these data for diagnosis and long-term followup in ureteropelvic junction obstruction are significant. Our findings suggest that proper decrease in urinary carbohydrate antigen 19-9 after pyeloplasty is predictive of excellent surgical outcomes and resolution of renal damage.

Safety, Efficacy and Health Related Quality of Life of Autologous Myoblast Transplantation for Treatment of Urinary Incontinence in Children With Bladder Exstrophy-Epispadias Complex

PURPOSE Children with bladder exstrophy-epispadias complex undergoing endourethral autologous myoblast transplantation to treat urinary incontinence were evaluated at 4 years of followup regarding the safety, efficacy and durability of the procedure, and health related quality of life. MATERIALS AND METHODS Seven boys underwent autologous myoblast transplantation between May and December 2006. All patients had persistent urinary incontinence after bladder neck reconstruction and bulking agent injection. Patients were followed for 4 years after autologous myoblast transplantation regarding clinical outcomes and cystometric, urodynamic, uroflowmetric and urethrocystoscopic evaluations. Health related quality of life was also measured before treatment and at final followup. RESULTS No evidence of urinary obstruction was observed. Five children (71%) were completely continent and 2 (29%) were socially dry with complete daytime dryness at final followup. Health related quality of life was improved significantly. Urodynamic studies revealed a progressive increase in bladder capacity (p <0.001). Mean detrusor leak point pressure showed a 27 cm H(2)O (158%) increase during 4-year followup. Uroflowmetry parameters of voided volume and average maximum flow rate were improved significantly (p <0.001). CONCLUSIONS The 4-year outcomes demonstrate that autologous myoblast transplantation for urinary incontinence in children with bladder exstrophy-epispadias complex is relatively reliable, reproducible, safe and effective with minimal morbidity. This novel treatment represents a promising therapeutic approach in patients with urinary incontinence. Further randomized trials with larger numbers of patients and longer followup are needed.

In-vivo autologous bladder muscular wall regeneration: Application of tissue-engineered pericardium in a model of bladder as a bioreactor

PURPOSE Tissue-engineered pericardium (TEP) is a collagen-rich matrix that has previously been shown to promote in vivo and in vitro tissue regeneration. We evaluated the potential of TEP as a source for the in-vivo creation of bladder muscular wall grafts. We used bladder wall as a bioreactor to create a natural environment for cellular growth and differentiation. MATERIALS AND METHODS Sixteen rabbits were divided into four groups. A control group underwent classical bladder autoaugmentation. Other groups underwent insertion of TEP between bladder mucosa and muscular layer: group 2 with insertion of TEP, group 3 with TEP over autologous bladder muscular wall fragments, and group 4 with autologous bladder smooth muscle cells (SMCs) seeded on TEP. After 4 and 8 weeks, grafts were biopsied for histopathological evaluations. RESULTS Frames from groups 3 and 4 demonstrated more organized muscular wall generation with a significantly higher number of CD34 + endothelial progenitor cells and CD31 + microvessels, and maintenance of α-smooth muscle actin expression through immunohistochemistry. Group 4 showed significant enhancement of SMC penetration to TEP. Although the fragment-seeded group required a simpler procedure, the cell-seeded group showed superior organization of the muscular layer on histopathology. We found a semi-organized muscular layer and new vessels in the margins of TEP in group 3, while there was a homogeneous pattern of SMCs and new vessels in both the margins and center of TEP in group 4. CONCLUSIONS This preliminary work has important functional and clinical implications, as it indicates that use of the autologous SMC seeding method may enhance the properties of TEP in terms of bladder wall regeneration.

Analysis of the trajectory of osteoarthritis development in a mouse model by serial near-infrared fluorescence imaging of matrix metalloproteinase activities.

A major hurdle in osteoarthritis (OA) research is the lack of sensitive detection and monitoring methods. It is hypothesized that proteases, such as matrix metalloproteinases (MMPs), are up‐regulated in the early stages of OA development. This study was undertaken to investigate if a near‐infrared (NIR) fluorescent probe activated by MMPs could visualize in vivo OA progression beginning in the early stages of the disease.

Interventional Optical Molecular Imaging Guidance during Percutaneous Biopsy

PURPOSE To investigate indocyanine green (ICG) as a molecular beacon for malignant lesions within the liver and evaluate the ability of a developed handheld imaging system to allow measurement of ICG fluorescence within focal hepatic lesions with high target-to-background ratios in a mouse model. MATERIALS AND METHODS All animal experiments were approved by the institutional animal care committee. A handheld optical molecular imaging device was constructed to pass through the introducer needle of a standard percutaneous biopsy kit. An ex vivo phantom system was constructed to quantify tissue attenuation properties of ICG in liver parenchyma. Subsequently, intrahepatic colorectal cancer metastases were generated in nude mice, and epifluorescence imaging of ICG, as well as histologic analysis of the explanted livers, was performed at 3 weeks after implantation (n = 6). Epifluorescence imaging with the handheld imaging device was then performed on intrahepatic colorectal metastases after the administration of ICG (n = 15) at 3, 6, and 24 hours after injection. Target-to-background ratios were calculated for each time point. Subsequently, a core biopsy of intrahepatic colorectal metastases was performed by using a standard clinical 18-gauge biopsy needle. RESULTS There was avid localization of ICG to the focal lesions at all time points. Similarly, fluorescence within the tumors was greater than that within normal liver, as detected with the handheld imaging system (mean target-to-background ratio ± standard deviation, 3.9 ± 0.2 at 24 hours). A core biopsy of tumor and normal adjacent liver by using a standard biopsy needle demonstrated a sharp margin of fluorescence intensity at the tumor-liver interface. CONCLUSION The custom-designed molecular imaging device, in combination with ICG, readily allowed differentiation between normal and malignant tissue in a murine model of intrahepatic colorectal metastasis.

Pharmacodynamic Imaging Guides Dosing of a Selective Estrogen Receptor Degrader

Purpose: Estrogen receptor (ER) targeting is key in management of receptor-positive breast cancer. Currently, there are no methods to optimize anti-ER therapy dosing. This study assesses the use of 16α-18F-fluoroestradiol (18F-FES) PET for fulvestrant dose optimization in a preclinical ER+ breast cancer model. Experimental Design: In vitro, 18F-FES retention was compared with ERα protein expression (ELISA) and ESR1 mRNA transcription (qPCR) in MCF7 cells (ER+) after treatment with different fulvestrant doses. MCF7 xenografts were grown in ovariectomized nude mice and assigned to vehicle, low- (0.05 mg), medium- (0.5 mg), or high-dose (5 mg) fulvestrant treatment groups (5–7 per group). Two and 3 days after fulvestrant treatment, PET/CT was performed using 18F-FES and 18F-FDG, respectively. ER expression was assessed by immunohistochemistry, ELISA, and qPCR on xenografts. Tumor proliferation was assessed using Ki67 immunohistochemistry. Results: In vitro, we observed a parallel graded reduction in 18F-FES uptake and ER expression with increased fulvestrant doses, despite enhancement of ER mRNA transcription. In xenografts, ER expression significantly decreased with increased fulvestrant dose, despite similar mRNA expression and Ki67 staining among the treatment groups. We observed a significant dose-dependent reduction of 18F-FES PET mean standardized uptake value (SUVmean) with fulvestrant treatment but no significant difference among the treatment groups in 18F-FDG PET SUVmean. Conclusions: We demonstrated that 18F-FES uptake mirrors the dose-dependent changes in functional ER expression with fulvestrant resulting in ER degradation and/or blockade; these precede changes in tumor metabolism and proliferation. Quantitative 18F-FES PET may be useful for tracking early efficacy of ER blockade/degradation and guiding ER-targeted therapy dosing in patients with breast cancer. Clin Cancer Res; 21(6); 1340–7. ©2015 AACR.

Modified Scrotal Approach for Correction of Abdominoscrotal Hydrocele in Children: Clinical Presentation and Description of Technique

OBJECTIVES To introduce a modified trans-scrotal approach for treatment of abdominoscrotal hydrocele (ASH) in children. The postoperative outcomes are reviewed with long-term follow-up. METHODS We described a series of 7 boys (mean age, 23.4 months) who underwent surgical repair of ASH. The diagnosis was made based on physical examination, which revealed a tense hydrocele in association with ipsilateral cystic abdominal mass, confirmed by ultrasonography. After exposing the hydrocele sac through a scrotal incision, tunica vaginalis was opened and marsupialization of the hydrocele along with undermined dartos muscle layer was performed. Follow-up ranged from 9-12 months (average, 10.7 months). RESULTS Overall, 10 ASH units (including 3 bilateral) were repaired. All of the affected testicles except one showed some degree of dysmorphism, according to ultrasonography or intraoperative findings, which resolved in all patients 3 months after surgery. There were no early postoperative complications except a mild scrotal edema. Neither recurrences of ASH nor testicular atrophy was observed. CONCLUSIONS The diagnosis of ASH should be considered in a boy with hydrocele and concomitant abdominal mass, and can be established by ultrasonographic evaluation. Our experiment suggests that the modified trans-scrotal surgical method for management of ASH is reliable and effective with definite advantages. The high success rate, no extensive dissection of the inguinal canal, or complete excision of the sac, along with safety and simplicity of the procedure and short hospital stay, are important preconditions for the introduction of this method as a valid option for treatment of ASH.