Dov Pode

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.

Determination of Renal Stone Composition with Dual-Energy CT: In Vivo Analysis and Comparison with X-ray Diffraction

PURPOSE To preoperatively assess the composition of urinary stones by using dual-energy computed tomography (CT), with postoperative in vitro x-ray diffraction analysis as the reference standard. MATERIALS AND METHODS Institutional review board approval was obtained, and all participants provided written informed consent. Twenty-seven patients aged 50-64 years with renal stones, who were scheduled for stone extraction with percutaneous nephrolithotomy (PCNL), preoperatively underwent nonenhanced single-source dual-energy multidetector CT with 2-mm section thickness, 1-mm increments, 140 kVp, and 250 mAs. Regions of interest were drawn on low- and high-energy images, and low- and high-energy attenuation ratios were calculated for each stone scanned in vivo. The attenuation ratios for the patients were compared with those for an in vitro stone library phantom model of 37 stones with known chemical compositions. After surgery, the extracted stones were analyzed by using x-ray diffraction. The results of in vivo multidetector CT and ex vivo chemical analysis were compared. RESULTS Dual-energy low- and high-energy attenuation ratios measured with the phantom were less than 1.1 for uric acid, 1.1-1.24 for cystine, and greater than 1.24 for calcified stones. Struvite stones had attenuation ratios that overlapped with calcified stone ratios and thus could not be assessed reliably. Four patients had mixed stones (<75% of a single component), and one patient had a struvite stone. Of 27 patients, 22 (82%) (exact confidence interval [CI]: 68%, 92%) received a correct diagnosis with dual-energy CT: all six (100%; exact CI: 54%, 100%) patients with uric acid stones, 15 (79%; exact CI: 62%, 95%) of the 19 patients with calcium stones, and the one (100%) patient with a cystine stone. The patient with a struvite stone did not receive a correct dual-energy CT-based diagnosis. CONCLUSION Dual-energy multidetector CT may enable accurate in vivo characterization of kidney stone composition.

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.

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.

Complete Staghorn Calculi: Random Prospective Comparison Between Extracorporeal Shock Wave Lithotripsy Monotherapy and Combined With Percutaneous Nephrostolithotomy

PURPOSE We determined the preferred treatment of staghorn calculi. MATERIALS AND METHODS Between January 1992 and December 1994 we performed a prospective, randomized, single center study involving 50 kidneys with complete staghorn calculi: 27 renal units were treated with extracorporeal shock wave lithotripsy (ESWL) monotherapy (group 1) and 23 were treated with combined (initial) percutaneous nephrostolithotomy with ESWL (group 2). The 2 treatment groups were compared regarding stone size, grade of collecting system dilatation and urine culture at presentation. The number of treatment sessions, narcotic doses, renal colic episodes, septic complications, unplanned ancillary procedures, length of hospitalization, total treatment duration and stone-free rate at 6 months were recorded and compared. RESULTS At the conclusion of therapy the stone-free rate was significantly greater in group 2 than in group 1 (74 versus 22%, respectively, p = 0.0005). The complication rate was significantly greater in group 1, with 15 septic complications (fever greater than 38.5C for longer than 3 days) in 10 patients compared to only 2 episodes in group 2 (p = 0.007). The unplanned ancillary procedure rate was significantly greater in group 1 (8 procedures in 7 patients versus 1 procedure in group 2, p = 0.03). The overall treatment length was significantly shorter in group 2 (1 versus 6 months, p = 0.0006). There was no significant difference in the number of procedures performed with anesthesia or in the number of hospitalization days between the 2 treatment groups. CONCLUSIONS Combined percutaneous nephrostolithotomy and ESWL should be recommended as the first line treatment choice for most patients with staghorn stones.

Lateral Decubitus Position for Percutaneous Nephrolithotripsy in the Morbidly Obese or Kyphotic Patient

BACKGROUND AND PURPOSE Morbidly obese or debilitated patients do not tolerate the prone position used for percutaneous nephrolithotripsy (PCNL) well and may suffer from severe cardiorespiratory compromise in this position. The purpose of this study is to demonstrate a simple way to overcome this difficulty. PATIENTS AND METHODS Two morbidly obese patients, ages 48 and 32 years, with Body Mass Indices of 47.5 and 43.2 and a 68-year old patient severely debilitated by multiple cerebral infarctions, ischemic heart disease, and kyphosis suffered from relatively high renal stone burdens. For PCNL, the patients were placed in the lateral decubitus position. To obtain an anteroposterior projection in this position, the C-arm fluoroscopy unit was tilted to one side and the operating table to the other. Tract dilation, stone fragmentation, and fragment extraction were performed with the patient in this position. RESULTS An attempt to perform PCNL in the prone position in the first patient was aborted because of severe hypoxemia and hypercarbia. In the lateral decubitus position, the procedures were easily performed in all patients without any complications. It was noted that by rotating the C-arm to a perpendicular position, it was possible to perform nephroscopy and use fluoroscopy simultaneously. CONCLUSION We highly recommend using the lateral position for PCNL in morbidly obese patients and in patients suffering from kyphosis. This position is safe and convenient.

The Mechanism of Human Bladder Tumor Implantation in an in Vitro Model

Implantation of tumor cells in the bladder following transurethral resection of superficial bladder tumors is believed to be one factor in the etiology of bladder tumor recurrences. Using an in vitro model system we have studied the initial interaction between bladder carcinoma cells and a naturally produced basement membrane-like substrate. Minced explants of superficial low grade human bladder tumors from 10 patients were plated into culture dishes coated with a naturally produced extracellular matrix (ECM). This ECM has been shown to resemble the human urothelial basement membrane and submucosa in its macromolecular composition and ultrastructural appearance. It was found that a firm attachment of the human bladder tumor cells occurred within one hour, reached a maximal value within 24 hours and was followed by flattening and proliferation of the plated cells. These results indicate that prevention of tumor implantation should be initiated in the first hour after transurethral resection of the bladder tumors. This assay can be used for the investigation of various treatments to prevent tumor implantation.

Detection of bladder tumors by immunostaininc of the lewis x antigen in cells from voided urine

OBJECTIVES A study was made to determine the sensitivity and specificity of immunostaining of the Lewis X antigen in exfoliated urothelial cells from voided urine, for the detection and surveillance of bladder tumors. METHODS Three consecutive voided urine specimens were obtained from 101 patients, 78 of whom were under surveillance because of a history of bladder tumors, and 23 were being evaluated because of hematuria or irritative urinary symptoms. Indirect immunoperoxidase staining of two urine samples was done on cytocentrifuge slides, using the P12 monoclonal antibody against the Lewis X antigen. The diagnosis of the presence of urothelial tumor was made if more than 5% of the cells showed a typical red-brown staining. Cytopathologic examination of the third urine specimen was done according to Papanicolaou. Each patient underwent cystoscopy, and biopsies were obtained whenever there was endoscopic evidence of bladder tumors or carcinoma in situ. RESULTS Cystoscopy and biopsies revealed transitional cell carcinoma in 32 patients, whereas 69 patients had no evidence of bladder tumors. Immunocytology of one urine sample showed true-positive results in 26 of the 32 patients with bladder tumors, corresponding to a sensitivity of 81.25%. When two samples were examined, a sensitivity of 97% and a specificity of 85.5% were obtained. When the results of cytology and immunocytology were combined, sensitivity reached 100%. High-grade and low-grade transitional cell tumors were detected with equal efficiency. CONCLUSIONS The use of P12 monoclonal antibody for evaluation of Lewis X reactivity in cytologic preparations from multiple voided urine specimens can improve the sensitivity of noninvasive detection of bladder cancer. The technique may ultimately replace cystoscopy in monitoring therapeutic response and tumor recurrence.

Vesicouterine Fistula: A Rare Complication of Cesarean Section

Vesicouterine fistula is a rare complication of cesarean section. Most patients present early postoperatively, while others are seen months later with urinary incontinence. Recurrent urinary infections, menstruation through the bladder (menouria), secondary infertility and amenorrhea are less common reasons for consultation. Although more than 100 such cases have been described, there have been few reports on fertility after surgical cure of the fistula. We report 4 cases of a vesicouterine fistula after cesarean section. The first patient was treated nonoperatively and the other 3 patients were treated surgically. Three patients had normal pregnancies after resolution of the problem. The clinical features, etiological factors and treatment modalities are discussed.

IMMUNOSTAINING OF LEWIS X IN CELLS FROM VOIDED URINE, CYTOPATHOLOGY AND ULTRASOUND FOR NONINVASIVE DETECTION OF BLADDER TUMORS

PURPOSE We examined the use of immunostaining of the Lewis X antigen in exfoliated cells from voided urine samples, cytopathology and bladder ultrasound for noninvasive detection of bladder tumors as a potential substitute for cystoscopy. MATERIALS AND METHODS A total of 260 patients were included, of whom 80 were evaluated because of irritative symptoms or hematuria and 180 were examined during followup visits after resection of bladder tumors. Voided urine samples were obtained from each patient for immunocytology and cytopathology. Bladder ultrasound and cystoscopy were performed. Biopsies were obtained whenever a bladder tumor was seen or if carcinoma in situ was suspected. Indirect immunoperoxidase staining was done on cytocentrifuge slides, using the P12 monoclonal antibody against the Lewis X antigen. RESULTS Cystoscopy and biopsies revealed bladder tumors in 84 patients. Immunocytology of 1 urine sample resulted in a sensitivity of 79.8% and a specificity of 86.4%. The diagnosis of primary carcinoma in situ by immunocytology was correct in 100% of the cases. The examination of 2 consecutive urine samples detected 95.1% of the tumors. False-negative results occurred in a few cases with small, superficial, low grade tumors. Cytopathology and bladder ultrasound resulted in a sensitivity of 47.6 and 66.7%, and a specificity of 97.7 and 97.2%, respectively. The results of immunocytology of 2 urine samples were equivalent to the combination of immunocytology of a single urine sample, cytology and ultrasound. CONCLUSIONS Immunostaining of the Lewis X antigen is significantly more sensitive than cytopathology for the detection of low grade as well as high grade tumor cells in voided urine. Immunocytological evaluation of 2 consecutive voided urine specimens for the Lewis X antigen is the most sensitive method currently available for noninvasive detection of transitional cell tumors. This assay may replace cystoscopy for detection of bladder cancer.