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ABSTRACT: PURPOSE: We investigated oncological outcomes in patients who underwent robot-assisted radical prostatectomy more than 5 years previously. MATERIALS AND METHODS: Between June 2002 and August 2006 we prospectively followed 435 consecutive patients who underwent robot-assisted radical prostatectomy. Six patients were excluded from analysis, including 4 lost to followup and 2 with prior therapy. Biochemical recurrence was denoted as 1) adjuvant therapy or 2) 2 prostate specific antigen values above 0.2 ng/ml. Biochemical recurrence-free survival, and patient and tumor characteristics were investigated. RESULTS: Mean ± SD patient age was 61.4 ± 7.1 years. A total of 289 patients (63%) had 5 or more years of followup and 4 (1%) were lost to followup. Median time to biochemical recurrence was 18 months (range 1 month to 9.1 years). Four patients (0.93%) died of prostate cancer. The 5-year biochemical recurrence-free survival rate was 84.9% (95% CI 81.4-88.4). Five-year biochemical recurrence-free survival was 94.4% (95% CI 91.7-97.1) for pT2 disease compared to 63.8% (95% CI 53.4-74.1) and 47.1% (95% CI 27.3-67.0) for pT3a and pT3b, respectively (p <0.001). Patients with a Gleason score of 3 or less + 3, 3 + 4, 4 + 3 and 4 or greater + 4 experienced a 5-year biochemical recurrence-free survival of 97%, 86%, 62% and 43%, respectively (p <0.001). Patients with positive margins had a 5-year biochemical recurrence-free survival of 60.7% (95% CI 48.7-72.7) compared to 89.6% (95% CI 86.3-92.9) in those with negative margins (p <0.001). CONCLUSIONS: This represents the third report of the oncological outcomes of robot-assisted radical prostatectomy, demonstrating a 5-year biochemical recurrence rate of approximately 14% and just below 1% prostate cancer specific mortality.
The Journal of urology 10/2012; · 4.02 Impact Factor
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Jennifer Lee Young,
Elham Khanifar, Navneet Narula,
Cervando Gerardo Ortiz-Vanderdys,
Surendra Babu Kolla,
Donald Lowell Pick,
Petros George Sountoulides,
Oskar Grau Kaufmann,
Kathryn Elizabeth Osann,
Victor Buu Huynh,
Adam Geoffrey Kaplan,
Lorena Aurora Andrade,
Michael Ken Louie,
Elspeth Marguerita McDougall,
Ralph Victor Clayman
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ABSTRACT: To our knowledge the optimal freeze cycle length in renal cryotherapy is unknown. Ten-minute time based freeze cycles were compared to temperature based freeze cycles to -20C.
Laparoscopic renal cryotherapy was performed on 16 swine. Time based trials consisted of a double 10-minute freeze separated by a 5-minute thaw. Temperature based trials were double cycles of 1, 5 or 10-minute freeze initiated after 1 of 4 sensors indicated -20C. A 5-minute active thaw was used between freeze cycles. Control trials consisted of cryoneedle placement for 25 minutes without freeze or thaw. Viability staining and histological analysis were done.
There was no difference in cellular necrosis between any of the temperature based freeze cycles (p = 0.1). Time based freeze cycles showed more nuclear pyknosis, indicative of necrosis, than the 3 experimental freeze cycles for the renal cortex (p = 0.05) but not for the renal medulla (p = 0.61). Mean time to -20C for freeze cycle 1 was 19 minutes 10 seconds (range 9 to 46 minutes). In 4 of 21 trials (19%) -20C was never attained despite freezing for 25 to 63 minutes.
There was no difference in immediate cellular necrosis among double 1, 5 or 10-minute freeze cycles. Cellular necrosis was evident on histological analysis for trials in which -20C was attained and in freeze cycles based on time alone. With a standard 10-minute cryoablation period most treated parenchyma 1 cm from the probe never attained -20C. Cell death appeared to occur at temperatures warmer than -20C during renal cryotherapy.
The Journal of urology 07/2011; 186(1):283-8. · 4.02 Impact Factor
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ABSTRACT: To demonstrate coronary sinus-left atrium connections and evaluate coronary sinus function and anatomy in detail by using multidetector computed tomography (CT).
In this institutional review board-approved retrospective study, the authors evaluated coronary CT angiograms obtained in 65 patients with normal sinus rhythm (normal group) and seven with atrial fibrillation at CT (atrial fibrillation group). Coronary sinus-right atrium muscle continuity was indirectly evaluated by measuring the length of the coronary sinus contraction during atrial systole. The length, number, and extent of coronary sinus-left atrium connections were recorded. The accuracy of CT was validated by comparing microscopic images of autopsied hearts with corresponding CT images. Comparisons were performed by using Student t tests for continuous variables. P ≤ .05 was considered indicative of a statistically significant difference.
In the normal group, coronary sinus contraction was seen in 60 of the 65 patients (92%, mean length ± standard deviation, 25.7 mm ± 8.0). The coronary sinus narrowed 26% from middiastole to atrial systole (P < .0001). Coronary sinus-left atrium muscle connections were seen in 58 of the 65 patients (89%). A single connection was seen in 43 of the 65 patients (66%), with a mean length of 21.0 mm ± 14.0 within 12.0 mm ± 11.0 of the coronary sinus ostium. In 10 of the 43 patients (26%) with single connections, the connection extended to the coronary sinus ostium. In 10 of the 65 patients (15%), the entire coronary sinus was attached to the left atrial wall. Fifteen patients (23%) had two connections; distal connections measured 9 mm ± 2.4 in length within 2.2 mm ± 3.8 of the coronary sinus ostium, and proximal connections measured 15.4 mm ± 10.0 in length within 24.0 mm ± 8.0 of the coronary sinus ostium. In seven patients (11%), no coronary sinus-left atrium connection was seen; however, all showed a coronary sinus constriction during atrial systole, indicating that coronary sinus-right atrium muscle continuity is likely the primary cause for coronary sinus contractions. In the atrial fibrillation group, no coronary sinus contraction was seen. All images in the atrial fibrillation group showed a coronary sinus-left atrium connection, which was single in five patients and double in two. The area of the coronary sinus during diastole was larger in the atrial fibrillation group than in the normal group (114 mm(2) ± 37 vs 77 mm(2) ± 40, respectively; P = .02).
CT can provide excellent information about coronary sinus function and coronary sinus-left atrium muscle connections.
Radiology 05/2011; 260(3):671-9. · 5.73 Impact Factor
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ABSTRACT: • To evaluate associations between baseline characteristics, nerve-sparing (NS) status and return of continence, as a relationship may exist between return to continence and preservation of the neurovascular bundles for potency during radical prostatectomy (RP).
• The study included 592 consecutive robotic RPs completed between 2002 and 2007. • All data were entered prospectively into an electronic database. • Continence data (defined as zero pads) was collected using self-administered validated questionnaires. • Baseline characteristics (age, International Index of Erectile Function [IIEF-5] score, American Urological Association symptom score, body mass index [BMI], clinical T-stage, Gleason score, and prostate-specific antigen level), NS status and learning curve were retrospectively evaluated for association with overall continence at 1, 3 and 12 months after RP using univariate and multivariable methods. • Any patient taking preoperative phosphodiesterase inhibitors was excluded from the postoperative analysis.
• Complete data were available for 537 of 592 patients (91%). • Continence rates at 12 months after RP were 89.2%, 88.9% and 84.8% for bilateral NS, unilateral NS and non-NS respectively (P= 0.56). • In multivariable analysis age, IIEF-5 score and BMI were significant independent predictors of continence. • CavernosalNS status did not significantly affect continence after adjusting for other co-variables.
• After careful multivariable analysis of baseline characteristics age, IIEF-5 score and BMI affected continence in a statistically significant fashion. This suggests that baseline factors and not the physical preservation of the cavernosal nerves predict overall return to continence.
BJU International 01/2011; 108(9):1492-6. · 2.84 Impact Factor
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Satoru Ohshima,
Shinichiro Fujimoto,
Artiom Petrov,
Hironori Nakagami,
Nezam Haider,
Jun Zhou,
Nobuhiro Tahara,
Mariana Kiomy Osako,
Ai Fujimoto,
Jie Zhu,
Toyoaki Murohara,
D Scott Edwards, Navneet Narula,
Nathan D Wong,
Y Chandrashekhar,
Ryuichi Morishita,
Jagat Narula
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ABSTRACT: Technetium-99m-labeled matrix metalloproteinase inhibitor (MPI) was used for the noninvasive assessment of matrix metalloproteinase (MMP) activity in atherosclerotic plaques after minocycline (MC) intervention.
MMP activity in atherosclerosis contributes to plaque instability. Some antimicrobial agents may attenuate MMP activity.
Atherosclerotic lesions were produced in 38 rabbits with a high cholesterol diet for 4 months; 5 groups of rabbits, in the fourth month, received fluvastatin (FS) (n = 6), low-dose MC (n = 7), high-dose MC (n = 7), a combination of low-dose MC and FS (n = 6), or no intervention (n = 12); 8 unmanipulated rabbits were used as disease controls. Micro-single-photon emission computed tomography imaging was performed in all animals after intravenous MPI administration, followed by pathologic characterization of the aorta. A cell culture study evaluated the effect of MC on MMP production by activated human monocytes.
MPI uptake was visualized best in untreated atherosclerotic animals (percent injected dose per gram MPI uptake, 0.11 +/- 0.04%). MPI uptake was reduced in the FS (0.06 +/- 0.01%; p < 0.0001), high-dose MC (0.05 +/- 0.01%; p < 0.0001), and MC-FS (0.05 +/- 0.005%; p < 0.0001) groups. Low-dose MC did not resolve MPI uptake significantly (0.08 +/- 0.02; p = 0.167). There was no incremental benefit of the combination of MC and FS. MPI uptake showed a significant correlation with plaque MMP-2, and MMP-9 activity. MMP-9 release from tumor necrosis factor-alpha-activated macrophages was abrogated by incubation with MC.
Molecular imaging of MMP activity in atherosclerotic plaque allows for the study of the efficacy of therapeutic interventions. MC administration resulted in substantial reduction in plaque MMP activity and histologically verified plaque stabilization. MC was found to be equally effective as FS.
Journal of the American College of Cardiology 03/2010; 55(12):1240-9. · 14.16 Impact Factor
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Heidi Kenis,
Harmen Reinier Zandbergen,
Leonard Hofstra,
Artiom D Petrov,
Ewald A Dumont,
Francis D Blankenberg,
Nezam Haider,
Nicole Bitsch,
Marion Gijbels,
Johan W H Verjans, Navneet Narula,
Jagat Narula,
Chris P M Reutelingsperger
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ABSTRACT: Ischemic insult to the myocardium is associated with cardiomyocyte apoptosis. Because apoptotic cell death is characterized by phosphatidylserine externalization on cell membrane and annexin-A5 (AA5) avidly binds to phosphatidylserine, we hypothesized that radiolabeled AA5 should be able to identify the regions of myocardial ischemia.
Models of brief myocardial ischemia by the occlusion of the coronary artery for 10 min (I-10) and reperfusion for 180 min (R-180) for the detection of phosphatidylserine exteriorization using (99m)Tc-labeled AA5 and gamma-imaging were produced in rabbits. (99m)Tc-AA5 uptake after brief ischemia was compared with an I-40/R-180 infarct model. Histologic characterization of both myocardial necrosis and apoptosis was performed in ischemia and infarct models. Phosphatidylserine exteriorization was also studied in a mouse model, and the dynamics and kinetics of phosphatidylserine exposure were assessed using unlabeled recombinant AA5 and AA5 labeled with biotin, Oregon Green, or Alexa 568. Appropriate controls were established.
Phosphatidylserine exposure after ischemia in the rabbit heart could be detected by radionuclide imaging with (99m)Tc-AA5. Pathologic characterization of the explanted rabbit hearts did not show apoptosis or necrosis. Homogenization and ultracentrifugation of the ischemic myocardial tissue from rabbit hearts recovered two thirds of the radiolabeled AA5 from the cytoplasmic compartment. Murine experiments demonstrated that the cardiomyocytes expressed phosphatidylserine on their cell surface after an ischemic insult of 5 min. Phosphatidylserine exposure occurred continuously for at least 6 h after solitary ischemic insult. AA5 targeted the exposed phosphatidylserine on cardiomyocytes; AA5 was internalized into cytoplasmic vesicles within 10-30 min. Twenty-four hours after ischemia, cardiomyocytes with internalized AA5 had restored phosphatidylserine asymmetry of the sarcolemma, and no detectable phosphatidylserine remained on the cell surface. The preadministration of a pan-caspase inhibitor, zVAD-fmk, prevented phosphatidylserine exposure after ischemia.
After a single episode of ischemia, cardiomyocytes express phosphatidylserine, which is amenable to targeting by AA5, for at least 6 h. Phosphatidylserine exposure is transient and internalized in cytoplasmic vesicles after AA5 binding, indicating the reversibility of the apoptotic process.
Journal of Nuclear Medicine 02/2010; 51(2):259-67. · 6.38 Impact Factor
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ABSTRACT: Adipose tissue has been suggested to contribute to the pathogenesis of various disease states, including prostate cancer. We investigated the association of cytokines and growth factors secreted by periprostatic adipose tissue with pathological features of aggressive prostate cancer.
Periprostatic adipose tissue was harvested from patients undergoing radical prostatectomy and cultured for 24 hours to generate conditioned medium or snap frozen immediately for functional signaling profiling. Multiplex analysis of the periprostatic adipose tissue conditioned medium was used to detect cytokine levels and compared to patient matched serum from 7 patients. Interleukin-6 in serum and periprostatic adipose tissue conditioned medium was further analyzed by enzyme-linked immunosorbent assay and correlated with clinical variables, such as age, body mass index and Gleason score, in 45 patients. Interleukin-6 expression in periprostatic adipose tissue was determined by immunohistochemistry. Reverse phase protein microarray technology was used to analyze cell signaling networks in periprostatic adipose tissue.
Interleukin-6 in periprostatic adipose tissue conditioned medium was approximately 375 times greater than that in patient matched serum and levels correlated with pathological grade. This finding was further extended by cell signaling analysis of periprostatic adipose tissue, which showed greater phosphorylation on Stat3 with high grade tumors (any component of Gleason score 4 or 5).
Higher Gleason score correlated with high levels of conditioned medium derived interleukin-6. Moreover, cell signaling analysis of periprostatic adipose tissue identified activated signaling molecules, including STAT3, that correlated with Gleason score. Since STAT3 is interleukin-6 regulated, these findings suggest that periprostatic adipose tissue may have a role in modulating prostate cancer aggressiveness by serving as a source of interleukin-6. Also, we found low numbers of inflammatory cells in the fat, suggesting that adipocytes are the major secretors of interleukin-6.
The Journal of urology 09/2009; 182(4):1621-7. · 4.02 Impact Factor
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ABSTRACT: Concern exists over a lack of tactile sensation and positive surgical margins (PSMs) in patients undergoing robot-assisted radical prostatectomy. We report our PSM rates in our most current 500 cases and particularly in clinically high-risk disease.
After implementation of our present technique at case #251, we report PSM rates according to pathologic stage and D'Amico's risk stratification: low risk (prostate-specific antigen [PSA] <10, Gleason score [GS] 5-6, cT1-T2A), intermediate risk (PSA 10-20, GS 7, cT2B), and high risk (PSA >20, GS 8-10, cT3). Patients with cT2b/T3 disease or GS 8 to 10 and multiple cores with >30% involvement underwent wide excision of the neurovascular bundle. PSM was defined as ink on tumor.
The overall PSM rate was 7.4%: pT2 = 3.1%, pT3 = 15.9%, and pT4 = 55.6%. PSMs occurred in 13 (4.9%) low, 10 (5.8%) intermediate, and 14 (22.6%) high D'Amico risk patients. Of the 62 high-risk patients, the median PSA was 6.9 (range 2.2-97.9); biopsy GS was 6 to 7 (26%) and 8 to 10 (74%). For preoperatively palpable disease, the PSM rate was 9.9%: cT1 = 6.0%, cT2 = 7.7%, and cT3 = 26.3%. No PSMs occurred along the neurovascular bundle.
Since 2005, 500 men with clinically low-, intermediate-, and high-risk prostate cancer have undergone robot-assisted radical prostatectomy with acceptable surgical margin rates. In patients with high-risk and usually palpable disease, PSM rates were also acceptable despite the lack of tactile sensation with the robot.
Journal of endourology / Endourological Society 08/2009; 23(9):1461-5. · 1.75 Impact Factor
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Nezam Haider,
Dagmar Hartung,
Shinichiro Fujimoto,
Artiom Petrov,
Frank D Kolodgie,
Renu Virmani,
Satoru Ohshima,
Han Liu,
Jun Zhou,
Ai Fujimoto,
Atsuko Tahara,
Leo Hofstra, Navneet Narula,
Chris Reutelingsperger,
Jagat Narula
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ABSTRACT: Macrophage apoptosis and MMP activity contribute to vulnerability of atherosclerotic plaques to rupture. By employing molecular imaging techniques, we investigated if apoptosis and MMP release are interlinked.
Atherosclerosis was produced in rabbits receiving high-cholesterol diet (HC), who underwent dual radionuclide imaging with (99m)Tc-labeled matrix metalloproteinase inhibitor (MPI) and (111)In-labeled annexin A5 (AA5) using micro-SPECT/CT. %ID/g MPI and AA5 uptake was measured, followed by histological characterization. Unmanipulated animals were used as disease controls. Correlation between MPI and AA5 uptake was undertaken and relationship confirmed in culture study of activated THP-1 monocytes.
MPI and AA5 uptake was best visualized in HC diet animals (n = 6) and reduced significantly after fluvastatin treatment (n = 4) or diet withdrawal (n = 3). %ID/g MPI (.087 +/- .018%) and AA5 (.03 +/- .01%) uptake was higher in HC than control (n = 6) animals (.014 +/- .004%, P < .0001; .0007 +/- .0002%, P < .0001), and reduced substantially after diet or statin intervention. There was a significant correlation between MPI and AA5 uptake (r = .62, P < .0001), both correlated with pathologically verified MMP-9 activity, macrophage content, and TUNEL staining. In vitro studies demonstrated MMP-9 release in culture medium from apoptotic THP-1 monocytes.
The present study suggests that apoptosis and MMP are interrelated in atherosclerotic lesions and the targeting of more than one molecular candidate is feasible by molecular imaging.
Journal of Nuclear Cardiology 08/2009; 16(5):753-62. · 2.67 Impact Factor
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ABSTRACT: Matrix metalloproteinases (MMPs) are expressed in atherosclerotic plaques and play an important role in plaque instability.
Using (99m)Tc-labeled broad-spectrum MMP inhibitor (MPI), we performed noninvasive imaging of MMP expression with micro-SPECT/micro-CT in mice deficient in apolipoprotein E (ApoE(-/-), n = 14), mice deficient in low-density-lipoprotein receptor (LDLR(-/-), n = 14), and C57/BL6 mice as controls (n = 7). Seven ApoE(-/-) and 7 LDLR(-/-) received a high-cholesterol diet. After in vivo imaging, aortas were explanted, ex vivo images acquired, and the percent injected dose of MPI per gram (%ID/g) determined, followed by histologic characterization of atherosclerotic lesions.
MPI uptake was noninvasively visualized in atherosclerotic lesions by micro-SPECT, with confirmation by micro-CT of anatomic location and aortic calcification. %ID/g in each part of the aorta was highest in ApoE(-/-) that were fed a high-cholesterol diet, followed by LDLR(-/-) that were fed a high-cholesterol diet, ApoE(-/-) that were fed normal chow, and LDLR(-/-) that were fed normal chow. The control mice had minimal MPI uptake. A significant correlation was noted between %ID/g and % area positive for macrophages (r = 0.81, P = 0.009), MMP-2 (r = 0.65, P = 0.013), and MMP-9 (r = 0.62, P = 0.008).
This study demonstrates the usefulness of molecular imaging for noninvasive assessment of the extent of MMP expression in various transgenic mouse models of atherosclerosis receiving a normal or hyperlipidemic diet. It is conceivable that such a strategy may be translationally developed for identification of unstable atherosclerotic plaques.
Journal of Nuclear Medicine 05/2009; 50(4):612-7. · 6.38 Impact Factor
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ABSTRACT: Cardiomyocyte apoptosis has been implicated in the pathogenesis of heart failure (HF). This study was performed in patients with left ventricular (LV) volume overload at different stages in the development of HF to correlate apoptotic gene expression with LV echocardiographic phenotype. LV biopsies were procured from 24 cardiac surgical patients selected from 4 distinct clinical groups (n = 6) in the progression from preserved LV function to HF. Group I consisted of control patients with normal LV function (e.g., with atrial myxoma), group II had aortic regurgitation with LV hypertrophy and preserved systolic function (ejection fraction >50%), group III had aortic regurgitation with LV dysfunction (ejection fraction 30% to 40%), and group IV had end-stage HF (ejection fraction <20%). Biopsies were used to measure mRNA expression of the genetic regulators of mitochondrial (Bad, Bax, Bcl-2, Bcl-xL, and p53) and death-receptor- (Fas and tumor necrosis factor receptor 1 [TNFR1]) mediated apoptotic pathways by reverse transcription-polymerase chain reaction. Caspase activity was determined using specific fluorogenic peptide substrates and immunohistochemistry. Evidence for apoptosis was obtained using terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling and in situ oligo ligation assays. Expression of proapoptotic factors (Bax, p53, TNFR1), antiapoptotic mitochondrial factor (Bcl-xL), and caspases 3, 8, and 9 increased progressively during the transition from preserved LV function to HF (p <0.05, analysis of variance). No significant difference was found for Bad, Bcl-2, or Fas. No evidence of DNA fragmentation was identified. In conclusion, activation of the cardiomyocyte apoptotic cascade occurs during the development of volume overload-induced HF. Mitochondrial (Bax, p53, caspase 9) and death-receptor mediated (TNFR1, caspase 8) pathways are upregulated but without completion of DNA fragmentation.
The American journal of cardiology 05/2009; 103(9):1261-8. · 3.58 Impact Factor
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Nezam Haider,
Eloisa Arbustini,
Sudhir Gupta,
Han Liu, Navneet Narula,
Roger Hajjar,
Narain Moorjani,
Stephen Westaby,
Marc J Semigran,
G William Dec,
Y Chandrashekhar,
Jagat Narula
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ABSTRACT: Despite widespread activation of proapoptotic stimuli and mediators, the degree of apoptosis in failing hearts is not very high. Endogenous antiapoptotic mechanisms are thought to be triggered by the heart-failure process. We investigated whether activation of endogenous apoptosis inhibitors plays a part when death receptor and mitochondrial apoptotic pathways have been triggered.
We evaluated various proapoptotic and antiapoptotic factors in myocardial tissue specimens obtained from normal and explanted end-stage ischemic and dilated cardiomyopathic hearts. Caspases (CASPs) 3, 8 and 9, total and activated Bcl-2 homology domain 3-interacting domain death agonist, the X-linked inhibitor of apoptosis (XIAP), and DNA fragmentation factor (DFF) proteins were analyzed by western blotting. Expression of messenger RNA was measured by reverse-transcription polymerase chain reaction for the XIAP, DIABLO, CFLAR and DFF genes. We also assessed CASP3, CASP8 and CASP9 and DFF activity. Cytochrome c1 localization in myocytes was analyzed by immunohistochemistry and immunoelectron microscopy.
We collected myocardial tissue from eight cardiomyopathic hearts and five normal hearts. Cytochrome c1 was released from mitochondria into the cytosol in the cardiomyopathic hearts but CASP9 was not activated. CASP8 activity was increased compared with that in normal myocardium. Although CASP3 was cleaved, activity was not greatly increased because of an increase in XIAP and decrease in DIABLO expression. DFF proteins were conspicuously absent.
Concurrent upregulation of endogenous antiapoptotic mechanisms can interrupt the apoptotic cascade and prevents cell loss despite the presence of multiple proapoptotic factors. This period might offer a therapeutic window for restoration of myocardial function in heart failure.
Nature Clinical Practice Cardiovascular Medicine 04/2009; 6(3):250-61. · 7.04 Impact Factor
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Susanne W M van den Borne,
Satoshi Isobe,
H Reinier Zandbergen,
Peng Li,
Artiom Petrov,
Nathan D Wong,
Shinichiro Fujimoto,
Ai Fujimoto,
Dagfinn Lovhaug,
Jos F M Smits,
Mat J A P Daemen,
W Matthijs Blankesteijn,
Chris Reutelingsperger,
Faiez Zannad, Navneet Narula,
Mani A Vannan,
Bertram Pitt,
Leonard Hofstra,
Jagat Narula
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ABSTRACT: Using molecular imaging techniques, we examined interstitial alterations during postmyocardial infarction (MI) remodeling and assessed the efficacy of antiangiotensin and antimineralocorticoid intervention, alone and in combination.
The antagonists of the renin-angiotensin-aldosterone axis restrict myocardial fibrosis and cardiac remodeling after MI and contribute to improved survival. Radionuclide imaging with technetium-99m-labeled Cy5.5 RGD imaging peptide (CRIP) targets myofibroblasts and indirectly allows monitoring of the extent of collagen deposition post-MI.
CRIP was intravenously administered for gamma imaging after 4 weeks of MI in 63 Swiss-Webster mice and in 6 unmanipulated mice. Of 63 animals, 50 were treated with captopril (C), losartan (L), spironolactone (S) alone, or in combination (CL, SC, SL, and SCL), 8 mice received no treatment. Echocardiography was performed for assessment of cardiac remodeling. Hearts were characterized histopathologically for the presence of myofibroblasts and thick and thin collagen fiber deposition.
Acute MI size was similar in all groups. The quantitative CRIP percent injected dose per gram uptake was greatest in the infarct area of untreated control mice (2.30 +/- 0.14%) and decreased significantly in animals treated with 1 agent (C, L, or S; 1.71 +/- 0.35%; p = 0.0002). The addition of 2 (CL, SC, or SL 1.31 +/- 0.40%; p < 0.0001) or 3 agents (SCL; 1.16 +/- 0.26%; p < 0.0001) demonstrated further reduction in tracer uptake. The decrease in echocardiographic left ventricular function, strain and rotation parameters, as well as histologically verified deposition of thin collagen fibers, was significantly reduced in treatment groups and correlated with CRIP uptake.
Radiolabeled CRIP allows for the evaluation of the efficacy of neurohumoral antagonists after MI and reconfirms superiority of combination therapy. If proven clinically, molecular imaging of the myocardial healing process may help plan an optimal treatment for patients susceptible to heart failure.
JACC. Cardiovascular imaging 03/2009; 2(2):187-98. · 14.29 Impact Factor
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Shinichiro Fujimoto,
Dagmar Hartung,
Satoru Ohshima,
D Scott Edwards,
Jun Zhou,
Padmaja Yalamanchili,
Michael Azure,
Ai Fujimoto,
Satoshi Isobe,
Yuji Matsumoto,
Hendricus Boersma,
Nathan Wong,
Junichi Yamazaki, Navneet Narula,
Artiom Petrov,
Jagat Narula
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ABSTRACT: This study sought to evaluate the feasibility of noninvasive detection of matrix metalloproteinase (MMP) activity in experimental atherosclerosis using technetium-99m-labeled broad matrix metalloproteinase inhibitor (MPI) and to determine the effect of dietary modification and statin treatment on MMP activity.
The MMP activity in atherosclerotic lesions contributes to the vulnerability of atherosclerotic plaques to rupture.
Atherosclerosis was produced in 34 New Zealand White rabbits by balloon de-endotheliazation of the abdominal aorta and a high-cholesterol diet. In addition, 12 unmanipulated rabbits were used as controls and 3 for blood clearance characteristics. In vivo micro-single-photon emission computed tomography (SPECT) imaging was performed after radiolabeled MPI administration. Subsequently, aortas were explanted to quantitatively measure percent injected dose per gram (%ID/g) MPI uptake. Histological and immunohistochemical characterization was performed and the extent of MMP activity was determined by gel zymography or enzyme-linked immunosorbent assays.
The MPI uptake in atherosclerotic lesions (n = 18) was clearly visualized by micro-SPECT imaging; MPI uptake was markedly reduced by administration of unlabeled MPI before the radiotracer (n = 4). The MPI uptake was also significantly reduced after diet withdrawal (n = 6) and fluvastatin treatment (n = 6); no uptake was observed in normal control rabbits (n = 12). The %ID/g MPI uptake (0.10 +/- 0.03%) in the atherosclerotic lesions was significantly higher than the uptake in control aorta (0.016 +/- 0.004%, p < 0.0001). Uptake in fluvastatin (0.056 +/- 0.011%, p < 0.0005) and diet withdrawal groups (0.043 +/- 0.011%, p < 0.0001) was lower than the untreated group. The MPI uptake correlated with immunohistochemically verified macrophage infiltration (r = 0.643, p < 0.0001), and MMP-2 (r = 0.542, p < 0.0001) or MMP-9 (r = 0.578, p < 0.0001) expression in plaques.
The present data show the feasibility of noninvasive detection of MMP activity in atherosclerotic plaques, and confirm that dietary modification and statin therapy reduce MMP activity.
Journal of the American College of Cardiology 01/2009; 52(23):1847-57. · 14.16 Impact Factor
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ABSTRACT: To evaluate the immunohistochemical profile of a carcinoid (low grade neuroendocrine tumor of the kidney) from a patient with lymph node positive disease who remains disease free for 31 months after radical nephrectomy, lymph node dissection, and adjuvant therapy with sunitinib malate.
Immunohistochemical staining was performed for chromogranin, synaptophysin, CD31, VEGF, HIF-1α, HIF-2, and Glut-1. Staining was evaluated in 3 high-power fields and samples scored as strongly positive (3+), moderately positive (2+), weakly positive (1+), or negative (0). A clear cell renal cell carcinoma was used as positive control.
Immunohistochemical staining was strongly positive VEGF, weak to moderately positive for HIF-2, and negative for HIF-1α and Glut-1.
Our case of primary renal carcinoid stained intensely for VEGF and HIF-2, consistent with a VHL-HIF1-HIF2-Glut1 independent pathway for VEGF activation. These data suggest that like other neuroendocrine tumors, primary renal carcinoid is a potential target for anti-angiogenic therapy with sunitinib.
Urologic Oncology 01/2009; 29(1):85-9. · 3.22 Impact Factor
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Susanne W M van den Borne,
Satoshi Isobe,
Johan W Verjans,
Artiom Petrov,
Dagfinn Lovhaug,
Peng Li,
H Reinier Zandbergen,
Youping Ni,
Peter Frederik,
Jun Zhou, [......],
Chris Reutelingsperger,
W Matthijs Blankesteijn,
Jos F M Smits,
Mat J A P Daemen,
Faiez Zannad,
Mani A Vannan, Navneet Narula,
Bertram Pitt,
Leonard Hofstra,
Jagat Narula
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[hide abstract]
ABSTRACT: The purpose of this study was to evaluate interstitial alterations in myocardial remodeling using a radiolabeled Cy5.5-RGD imaging peptide (CRIP) that targets myofibroblasts.
Collagen deposition and interstitial fibrosis contribute to cardiac remodeling and heart failure after myocardial infarction (MI). Evaluation of myofibroblastic proliferation should provide indirect evidence of the extent of fibrosis.
Of 46 Swiss-Webster mice, MI was induced in 41 by coronary artery occlusion, and 5 were unmanipulated. Of the 41 mice, 6, 6, and 5 received intravenous technetium-99m labeled CRIP for micro-single-photon emission computed tomography imaging 2, 4, and 12 weeks after MI, respectively; 8 received captopril or captopril with losartan up to 4 weeks after MI. Scrambled CRIP was used 4 weeks after MI in 6 mice; the remaining 10 of 46 mice received unradiolabeled CRIP for histologic characterization.
Maximum CRIP uptake was observed in the infarct area; quantitative uptake (percent injected dose/g) was highest at 2 weeks (2.75 +/- 0.46%), followed by 4 (2.26 +/- 0.09%) and 12 (1.74 +/- 0.24%) weeks compared with that in unmanipulated mice (0.59 +/- 0.19%). Uptake was higher at 12 weeks in the remote areas. CRIP uptake was histologically traced to myofibroblasts. Captopril alone (1.78 +/- 0.31%) and with losartan (1.13 +/- 0.28%) significantly reduced tracer uptake; scrambled CRIP uptake in infarct area (0.74 +/- 0.17%) was similar to CRIP uptake in normal myocardium.
Radiolabeled CRIP allows for noninvasive visualization of interstitial alterations during cardiac remodeling, and is responsive to antiangiotensin treatment. If proven clinically feasible, such a strategy would help identify post-MI patients likely to develop heart failure.
Journal of the American College of Cardiology 01/2009; 52(24):2017-28. · 14.16 Impact Factor
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ABSTRACT: Positive surgical margins represents incomplete resection by the surgeon, and the elimination of positive margins represents the only clinical feature during radical prostatectomy that can lead directly to improved cancer outcomes. The introduction of new robot-assisted technology and technical refinements has led to declines of positive surgical margins. Although margins induced by incomplete cancer resection by the surgeon have been reduced for organ-confined disease, the 'Holy Grail' of zero margins is not yet attainable in prostatectomy, and is more problematic in cancer that has penetrated beyond the prostate. Intraoperative frozen biopsies are imprecise. The union of real-time optical coherence tomography technology of the da Vinci robotic platform for identification of positive margin sites, and technical advances with wider excisions during surgery may provide promise for further reduction of surgical margins to zero.
Expert Review of Medical Devices 12/2008; 5(6):709-17. · 2.63 Impact Factor
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ABSTRACT: Several groups, including ours, have reported that annexin A2 (ANXA2) expression is reduced in most prostate cancer (CaP). More recently, however, we reported that ANXA2 is expressed in some high-grade tumors, but the biologic consequence of this is currently unknown. To elucidate the function of ANXA2 in CaP, we reduced its expression in DU145 cells using shRNA and tested the impact on characteristics of malignancy. Reduction of ANXA2 suppressed anchorage-dependent and -independent cell growth without affecting invasiveness. Interestingly, interleukin-6 (IL-6) secretion was reduced concomitantly with the reduction of ANXA2 but independently of S100A10. IL-6 expression was restored when wild type but not mutant ANXA2 was reexpressed in these cells. In a retrospective study of radical prostatectomy specimens from patients with nonmetastatic CaP, 100% of patients with ANXA2-positive tumors (n = 4) had a biochemical relapse while only 50% of patients with ANXA2 negative tumors (n = 20) relapsed, suggesting that ANXA2 expression in prostate tumors may be predictive of biochemical relapse. Significant cytoplasmic staining of ANXA2 was detected in 3 of 4 ANXA2-positive tumors, whereas ANXA2 is localized to the plasma membrane in benign prostatic glands. These finding, taken together, suggests a possible mechanism whereby ANXA2 expression positively contributes to an aggressive phenotype in a subset of CaP and suggest that ANXA2 has markedly different functions depending on its cellular context. Finally, this is the first description of a role for ANXA2 in IL-6 expression, and ANXA2 represents a new therapeutic target for reducing IL-6 in high-grade prostate cancer.
International Journal of Cancer 11/2008; 124(1):68-74. · 5.44 Impact Factor
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ABSTRACT: Several groups, including ours, have reported that annexin A2 (ANXA2) expression is reduced in most prostate cancer (CaP). More recently, however, we reported that ANXA2 is expressed in some high-grade tumors, but the biologic consequence of this is currently unknown. To elucidate the function of ANXA2 in CaP, we reduced its expression in DU145 cells using shRNA and tested the impact on characteristics of malignancy. Reduction of ANXA2 suppressed anchorage-dependent and -independent cell growth without affecting invasiveness. Interestingly, interleukin-6 (IL-6) secretion was reduced concomitantly with the reduction of ANXA2 but independently of S100A10. IL-6 expression was restored when wild type but not mutant ANXA2 was reexpressed in these cells. In a retrospective study of radical prostatectomy specimens from patients with nonmetastatic CaP, 100% of patients with ANXA2-positive tumors (n = 4) had a biochemical relapse while only 50% of patients with ANXA2 negative tumors (n = 20) relapsed, suggesting that ANXA2 expression in prostate tumors may be predictive of biochemical relapse. Significant cytoplasmic staining of ANXA2 was detected in 3 of 4 ANXA2-positive tumors, whereas ANXA2 is localized to the plasma membrane in benign prostatic glands. These finding, taken together, suggests a possible mechanism whereby ANXA2 expression positively contributes to an aggressive phenotype in a subset of CaP and suggest that ANXA2 has markedly different functions depending on its cellular context. Finally, this is the first description of a role for ANXA2 in IL-6 expression, and ANXA2 represents a new therapeutic target for reducing IL-6 in high-grade prostate cancer. © 2008 Wiley-Liss, Inc.
International Journal of Cancer 10/2008; 124(1):68 - 74. · 5.44 Impact Factor
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ABSTRACT: While most laparoscopic nephron sparing surgery is performed using cold scissors, energy based devices may also be used. A criticism of this approach has been the potential thermal destruction of the cellular architecture at the tumor margin, precluding the ability to accurately determine whether tumor cells are present. We clinically characterized the histological appearance of tumor margins excised with cold scissors, and bipolar and ultrasonic shears.
We evaluated 40 renal mass excisions performed by a total of 3 urologists at our institution between February 2003 and March 2007. There were 10 bipolar (5 mm LigaSure), 20 ultrasonic (Harmonic Scalpel) and 10 cold excisions. All slides were randomly evaluated twice by a single pathologist blinded to surgeon and excision method. Histological interpretation of the margin was scored as clear vs indeterminate. Variables, including margin fragmentation, artifact, extravascular blood clot, parenchymal hemorrhage, capillary congestion and vessel sealing, were assessed and scored on a scale of 0 to 3, that is 0--none, 1-1% to 25%, 2-26% to 50% and 3--greater than 50%.
The pathologist was able to confidently identify cells at the margin as being malignant or benign in all cases. Histologically the ultrasonic scalpel demonstrated increased fragmentation and extravascular blood clotting compared with those of the other cutting methods (p <0.025 and <0.026, respectively). The ultrasonic scalpel also showed increased artifact depth compared to that of cold cutting (p <0.001). There were no statistical differences between the groups regarding margin artifact, parenchymal hemorrhage or capillary congestion. No statistical significance was observed in any variables between bipolar and cold cutting.
Despite some degree of cellular damage the ability to determine whether cells at the margin were benign or malignant was not affected by using an energy based bipolar or ultrasonic device.
The Journal of urology 10/2008; 180(6):2348-52. · 4.02 Impact Factor
