Dragan Golijanin

Selective ablation of immature blood vessels in established human tumors follows vascular endothelial growth factor withdrawal

Features that distinguish tumor vasculatures from normal blood vessels are sought to enable the destruction of preformed tumor vessels. We show that blood vessels in both a xenografted tumor and primary human tumors contain a sizable fraction of immature blood vessels that have not yet recruited periendothelial cells. These immature vessels are selectively obliterated as a consequence of vascular endothelial growth factor (VEGF) withdrawal. In a xenografted glioma, the selective vulnerability of immature vessels to VEGF loss was demonstrated by downregulating VEGF transgene expression using a tetracycline-regulated expression system. In human prostate cancer, the constitutive production of VEGF by the glandular epithelium was suppressed as a consequence of androgen-ablation therapy. VEGF loss led, in turn, to selective apoptosis of endothelial cells in vessels devoid of periendothelial cells. These results suggest that the unique dependence on VEGF of blood vessels lacking periendothelial cells can be exploited to reduce an existing tumor vasculature.

Microsomal Prostaglandin E Synthase-1 Is Overexpressed in Inflammatory Bowel Disease EVIDENCE FOR INVOLVEMENT OF THE TRANSCRIPTION FACTOR Egr-1

Microsomal prostaglandin E synthase-1 (mPGES-1) catalyzes the conversion of cyclooxygenase-derived prostaglandin (PG) H2 to PGE2. Increased amounts of mPGES-1 were detected in inflamed intestinal mucosa from patients with inflammatory bowel disease (IBD). Treatment with tumor necrosis factor (TNF)-α stimulated mPGES-1 transcription in human colonocytes, resulting in increased amounts of mPGES-1 mRNA and protein. The inductive effect of TNF-α localized to the GC box region of the mPGES-1 promoter. Binding of Egr-1 to the GC box region of the mPGES-1 promoter was enhanced by treatment with TNF-α. Notably, increased Egr-1 expression and binding activity were also detected in inflamed mucosa from IBD patients. Treatment with TNF-α induced the activities of phosphatidylcholine-phospholipase C (PC-PLC) and protein kinase (PK) C and enhanced NO production. A pharmacological approach was used to implicate PC-PLC → PKC → NO signaling as being important for the induction of mPGES-1 by TNF-α. TNF-α also enhanced guanylate cyclase activity and inhibitors of guanylate cyclase activity blocked the induction of mPGES-1 by TNF-α. YC-1, an activator of guanylate cyclase, induced mPGES-1. Overexpressing a dominant negative form of PKG blocked TNF-α-mediated stimulation of the mPGES-1 promoter. Taken together, these results suggest that overexpression of mPGES-1 in IBD is the result of Egr-1-mediated activation of transcription. Moreover, TNF-α induced mPGES-1 by stimulating PC-PLC → PKC → NO → cGMP → PKG signal transduction pathway.

Prostate cancer in the elderly: frequency of advanced disease at presentation and disease-specific mortality.

The objectives of this study were to determine the frequency of metastatic (M1) prostate cancer (PC) at presentation in different age groups, to examine the association of age with PC‐specific mortality, and to calculate the relative contribution of different age groups to the pool of M1 cases and PC deaths.

Prostate cancer in the elderly

The objectives of this study were to determine the frequency of metastatic (M1) prostate cancer (PC) at presentation in different age groups, to examine the association of age with PC‐specific mortality, and to calculate the relative contribution of different age groups to the pool of M1 cases and PC deaths.

IS THE PEDIATRIC URETER AS EFFICIENT AS THE ADULT URETER IN TRANSPORTING FRAGMENTS FOLLOWING EXTRACORPOREAL SHOCK WAVE LITHOTRIPSY FOR RENAL CALCULI LARGER THAN 10 MM.

PURPOSE We determined whether the thin ureter of the young child transports stone fragments after extracorporeal shockwave lithotripsy (ESWL) as efficiently as the adult ureter does. This determination was done by comparing the outcome after lithotripsy of renal stones greater than 10 mm. between young children and adults. MATERIALS AND METHODS Our study group consisted of 38 children 6 months to 6 years old (median 3 years) with renal stones greater than 10 mm. in diameter. This group was further divided into 3 subgroups according to the longest stone diameter on plain abdominal film. There were 21 children with a renal stone diameter of 10 to 15 mm. (subgroup 1), 8, 16 to 20 mm. (subgroup 2) and 9 greater than 20 mm. (subgroup 3). The control group consisted of 38 adults older than 20 years randomly selected from the local ESWL registry. Each adult was matched with a child regarding stone diameter and localization. The control group was similarly divided into subgroups 1a, 2a and 3a. ESWL was performed with the unmodified Dornier HM-3 lithotriptor (Dornier Medical Systems, Inc., Marietta, Georgia). The stone-free rate, complication rate, and need for tubes, including stent or nephrostomy, and greater than 1 ESWL session were compared. RESULTS The stone-free rate was 95% in the study and 78.9% in the control group (p = 0.086). Stone-free rates were 95%, 100% and 89% in subgroups 1, 2 and 3, and 95%, 65% and 56% in subgroups 1a, 2a and 3a, respectively. There were 10 children and 4 adults who underwent greater than 1 ESWL session (p = 0.14). Then there were 10 children and 6 adults who required a tube before ESWL (p = 0.04), and almost all of them were included in subgroups 3 and 3a. Early complications were rare in both the study and control groups. Late complications had included 2 cases of Steinstrasse in the control and none in the study group. CONCLUSIONS The stone-free rate after ESWL for large renal stones is higher in young children compared to adults with matching stone size. Renal stones greater than 20 mm. often require more than 1 ESWL session. The pediatric ureter is at least as efficient as the adult for transporting stone fragments after ESWL.

Near infrared fluorescence imaging with robotic assisted laparoscopic partial nephrectomy: initial clinical experience for renal cortical tumors.

PURPOSE We evaluated the utility of near infrared fluorescence of intravenously injected indocyanine green in performing robotic assisted laparoscopic partial nephrectomy. In addition, we evaluated the initial performance of a novel near infrared fluorescence imaging system integrated into the da Vinci® Si Surgical System during robotic assisted laparoscopic nephrectomy. MATERIALS AND METHODS Fluorescence imaging for the da Vinci Si Surgical System was used for all cases. Indocyanine green was injected before near infrared imaging. Immediate imaging assessed the renal vasculature while delayed imaging differentiated renal cortical tumors from normal parenchyma. The intraoperative performance of near infrared fluorescence of intravenous indocyanine green was evaluated for tumor appearance relative to surrounding renal parenchyma as well as identification of the renal vasculature. RESULTS A total of 11 patients underwent robotic assisted laparoscopic nephrectomy with 2 converted to robotic assisted laparoscopic radical nephrectomy. Indocyanine green injections were repeated up to a total of 5 times depending on the goal of visualization. Of the 11 patients 10 demonstrated malignancy on final pathology. Of the malignant tumors 7 were hypofluorescent and 3 were isofluorescent compared to the surrounding renal parenchyma. Near infrared fluorescence imaging delineated the vascular anatomy in all cases. All surgical margins were negative on final pathology. CONCLUSIONS Intraoperative imaging of indocyanine green with near infrared fluorescence is a safe and effective method to accurately identify the renal vasculature and to differentiate renal tumors from surrounding normal parenchyma. The capacity for multimodal imaging within the surgical console further facilitates this imaging. Further study is needed to determine if this technique will help improve outcomes of robotic assisted laparoscopic nephrectomy.

Laparoscopic cholecystectomy in octogenarians

Background: This study aimed to assess the outcome of laparoscopic cholecystectomy (LC) in patients 80 years old or older. Methods: All consecutive patients 80 years old or older who underwent LC for symptomatic gallstone disease were evaluated. Data analysis included patients’ age, gender, indication for surgery, comorbid condition, American Society of Anesthesiology (ASA) score, preoperative endoscopic retrograde cholangio pancreatography (ERCP), intraoperative cholangiogram, operative time, conversion to open surgery, morbidity, mortality, and length of stay. Results: In this study, 67 patients (31 men and 36 women) with a mean age of 84 years (range, 80–90 years) were evaluated. Of these 67 patients, 38 (57%) underwent surgery for complicated diseases including acute cholecystitis in 15 patients (22%), gallstone pancreatitis in 17 patients (25%), cholangitis in 3 patients (4.5%), and obstructive jaundice in 3 patients (4.5%). A total of 38 patients (57%) had a preoperative ASA of 3 or 4; 23 (34%) had a preoperative ERCP; and 6 (9%) had intraoperative cholangiogram. The mean operative time was 94 ± 20 min. Five patients (7.4%) underwent conversion to open surgery because of unclear anatomy. Complications occurred in 12 patients (18%) including pulmonary edema in 3 patients, myocardial infarction in 1 patient, atelectasis in 2 patients, common bile duct injury in 1 patient, urinary tract infection in 2 patients, wound infection in 2 patients, and intraabdominal infected hematoma in 1 patient. The mean length of stay was 5.3 days. There was no mortality. Conclusions: In octogenarians LC is safe and associated with acceptable morbidity and mortality. Therefore, it should be considered for this age group. The relatively high incidence of complicated gallstone disease in this age group may be decreased if surgery is offered to them at earlier stage of the disease, leading to further decrease in perioperative morbidity.

Extracorporeal shock wave lithotripsy is highly effective for ureteral calculi in children.

PURPOSE Treatment of ureteral calculi in the pediatric population represents a unique challenge. Extracorporeal shock wave lithotripsy (ESWL*) and ureteroscopy have been advocated for the treatment of such stones. We present our experience with ESWL monotherapy for ureteral stones in children in the last decade. MATERIALS AND METHODS Between 1989 and 1999 we treated 21 boys and 17 girls with a mean age of 8 years (range 8 months to 14 years) with ureteral stones at our institution. Records were reviewed and analyzed for presentation, metabolic and anatomical anomalies, stone size and location, outcome and complications. Average stone size was 9.5 x 6.5 mm. (range 3 to 32). Stones were in the upper ureter in 17 cases, mid ureter in 2 and lower ureter in 19. All patients underwent ESWL with a Dornier HM3 lithotriptor under general anesthesia. Nephrostomies were placed in an anuric infant with bilateral ureteral obstruction and in 2 patients with nonfunctioning kidneys (4 renal units). Ureteral catheters were used in 15 patients for better identification and localization of the stone during ESWL. The catheters were removed immediately postoperatively. RESULTS Of the patients 31 (81.5%) were free of stones after 1 session of ESWL, 5 (13.1%) after 2 and 1 after 3. One patient underwent ureteroscopy for residual fragments after 2 ESWL sessions. The stone-free rate following 1 ESWL session was 100% for ureteral calculi 10 mm. or smaller regardless of location. Of the 12 patients with stones larger than 10 mm. 8 (67%) were free of stones following 1 ESWL session. The overall success rate of ESWL was 97.3%. No child had postoperative urinary infection or ureteral obstruction. CONCLUSIONS ESWL is an efficient and safe modality for the treatment of pediatric ureteral stones.

ORTHOTOPIC URINARY DIVERSION AFTER CYSTECTOMY FOR BLADDER CANCER: IMPLICATIONS FOR CANCER CONTROL AND PATTERNS OF DISEASE RECURRENCE

PURPOSE The impact of orthotopic urinary diversion on the quality of cystectomy and ensuing cancer control has not been adequately studied. We analyzed our experience with this clinical problem. MATERIALS AND METHODS The records of 214 patients who underwent cystectomy and orthotopic diversion for bladder cancer were retrospectively evaluated and compared with those of 269 treated with an ileal conduit. Analyzed end points included overall and cancer specific survival. We specifically assessed the patterns of relapse and their association with pathological findings at cystectomy in the neobladder group. RESULTS No cancer specific survival difference was identified in the neobladder and ileal conduit cohorts when adjusting for pathological stage. Patterns of relapse in 62 of the 214 patients with a neobladder (29%) included local recurrence in 23 (11%), distant recurrence in 19 (9%), and combined local and distant recurrence in 18 (8%). Urethral recurrence was rare (2%). Of 10 patients (4.6%) diagnosed with upper tract recurrence 6 and 4 initially had relapse in the ureteroenteric anastomosis and renal pelvis, respectively. Five of the 6 patients with anastomotic relapse had evidence of disease in the intramural or juxtavesical ureter that was removed en bloc with the cystectomy specimen. Only 1 patient required neobladder takedown after such anastomotic recurrence. CONCLUSIONS These results indicate that neobladders do not compromise the quality of preceding cystectomy or interfere with management in the presence of local or distant disease relapse. Our data suggest that involvement of the intramural or juxtavesical ureteral segment at cystectomy irrespective of surgical margin status may identify patients at higher risk for anastomotic recurrence, which is associated with an ominous prognosis.

Cyclooxygenase-2 and Microsomal Prostaglandin E Synthase-1 Are Overexpressed in Squamous Cell Carcinoma of the Penis

Purpose: Prostaglandin E2 (PGE2) promotes malignant growth. Cyclooxygenase (COX) catalyzes the synthesis of PGH2, which is converted, in turn, by microsomal prostaglandin E synthase (mPGES-1) to PGE2. One strategy for inhibiting carcinogenesis is to prevent PGE2 production in premalignant and malignant tissues. It is important, therefore, to determine whether enzymes involved in PGE2 biosynthesis are deregulated in neoplasia. The main purpose of this study was to determine whether amounts of COX-2 or mPGES-1 were increased in intraepithelial neoplasia or squamous cell carcinoma (SCC) of the penis. Because human papillomavirus (HPV) has been linked to the development of penile SCC, a secondary objective was to determine whether COX-2 was overexpressed in SCC arising in an HPV16 transgenic mouse. Experimental Design: Immunohistochemistry and immunoblotting were used to evaluate the expression of COX-2 and mPGES-1 in benign and malignant lesions including metastases to lymph nodes. Amounts of intratumoral PGE2 were quantified by enzyme immunoassay. Reverse transcription-PCR was used to determine the expression of each of the four known receptors (EP1–4) for PGE2. Results: Immunohistochemistry demonstrated increased expression of COX-2 and mPGES-1 in dysplasia, carcinoma in situ, invasive SCC, and metastases to lymph nodes. Immunoblot analysis confirmed that COX-2 and mPGES-1 were consistently overexpressed in SCC. PGE2 and all four of the PGE2 receptor subtypes were detected in each of the tumor samples. Elevated levels of COX-2 were also detected in SCC arising in an HPV16 transgenic mouse. Conclusions: Increased amounts of COX-2 and mPGES-1 were detected in penile intraepithelial neoplasia and carcinoma. These findings provide the basis for evaluating whether inhibiting COX-2 will be useful in the prevention or treatment of penile SCC.