Identification of endothelin-1 in the pathophysiology of metastatic adenocarcinoma of the prostate.

Prostate cancer is the second most common cause of death from cancer in U.S. men, and advanced, hormone-refractory disease is characterized by painful osteoblastic bone metastases. Endothelin-1, more commonly known as a potent vasoconstrictor, is a normal ejaculate protein that also stimulates osteoblasts. We show here that plasma immunoreactive endothelin concentrations are significantly elevated in men with metastatic prostate cancer and that every human prostate cancer cell line tested produces endothelin-1 messenger RNA and secretes immunoreactive endothelin. Exogenous endothelin-1 is a prostate cancer mitogen in vitro and increases alkaline phosphatase activity in new bone formation, indicating that ectopic endothelin-1 may be a mediator of the osteoblastic response of bone to metastatic prostate cancer.

Gender-related differences in the risk factors for repeat stone surgery.

Our objective was to analyze and compare the associations between potential risk factors for nephrolithiasis and repeat stone surgery in male and female patients. We retrospectively analyzed 1970 patients who had stone surgery at our institution in the period from January 2009 to May 2017, were older than 18 years and had at least 12 months of postoperative follow-up. Our definition of surgical recurrence included repeat surgery on the same renal unit or on the opposite renal unit if the original imaging did not demonstrate significant stones on that side. Uni- and multivariate Cox regression models were built for each gender. We also explored the interactions between gender and other patient's characteristics in their effect on the risk of recurrence. Ureteroscopy was the most common treatment modality for both first (83%) and repeat (87%) procedures. Over a mean follow-up of 4.3 years (median 3.8, interquartile range 2.2-6.0), 413 (21.0%) patients had a surgical recurrence. In multivariate analyses, hypertension, diabetes, Caucasian race and younger age (less than 60 years) were significantly associated with the risk of surgical recurrence only in females. Interaction between these characteristics and gender was significant indicating a larger effect on the risk of surgical recurrence in females compared to males. Our study demonstrated a number of differences in the predictors of repeat surgery for nephrolithiasis between males and females. If confirmed by future studies these differences may be helpful for optimizing nephrolithiasis prevention efforts.

Viral vector delivery in solid-state vehicles: gene expression in a murine prostate cancer model.

BACKGROUND: Although there are increasingly more clinical trials involving gene therapy, efficient gene transfer remains a major hurdle to success. To enhance the efficiency of delivery of viral vectors in gene therapy protocols, we evaluated the effect of various matrices to act as a vehicle for recombinant virus during intratumoral injection. METHODS: The ability of several vehicles (catgut spacer, polyglycolic acid, chromic catgut, and gelatin sponge matrix) to deliver the canarypox virus ALVAC to the cells of the murine prostate cancer cell line RM-1 was studied in vitro and in vivo. ALVAC recombinants encoding the murine cytokines interleukin 2 (IL-2), interleukin 12 (IL-12), and tumor necrosis factor-alpha (TNF-alpha) were used to assess enhancement of antitumor activity after intratumoral inoculation. Confirmatory experiments were conducted by use of another mouse prostate cancer cell line, RM-11, and a mouse bladder cancer cell line, MB-49. All statistical tests were two-sided. RESULTS: The gelatin sponge matrix proved to be the most effective solid-state vehicle for delivering viral vectors to cells in culture. In addition, this matrix statistically significantly enhanced expression of ALVAC-delivered reporter genes in tumor models when compared with fluid-phase delivery of virus (P =.037 for the RM-1 model and P =.03 for the MB-49 model). Statistically significant growth inhibition of established tumors was observed when a combination of the three recombinant ALVAC viruses expressing IL-2, IL-12, and TNF-alpha was delivered with the matrix in comparison with 1) fluid-phase intratumoral injection of the ALVAC recombinants, 2) no treatment, or 3) treatment with parental ALVAC (all P<.05). CONCLUSIONS: Viral vector delivery in a solid-state vehicle resulted in improved recombinant gene expression in vivo and translated to greater inhibition of tumor growth in an immunotherapy protocol for heterotopic tumor nodules. The efficient delivery of reporter genes described herein may prove useful in many solid tumor gene therapy protocols.

Endothelin-1 production and decreased endothelin B receptor expression in advanced prostate cancer.

The potent vasoconstrictor endothelin-1 (ET-1) is at its highest concentration in the normal human ejaculate and is associated with the progression of metastatic prostate cancer. ET-1 protein expression is detected in situ in 14 of 14 primary cancers and 14 of 16 metastatic sites of human prostatic carcinoma. Exogenous ET-1 induces prostate cancer proliferation directly and enhances the mitogenic effects of insulin-like growth factor I, insulin-like growth factor II, platelet-derived growth factor, basic fibroblast growth factor, and epidermal growth factor in serum-free conditions in vitro. The ETA-selective receptor antagonist A-127722 inhibits ET-1-stimulated growth, but the ETB-selective receptor antagonist BQ-788 does not. ET-3, an ETB-selective agonist, also had no effect on prostate cancer growth. No specific ETB-binding sites could be demonstrated in any established human prostate cancer cell line tested, and ETB mRNA, detected by reverse transcription PCR, was reduced. The predominance of ETB binding on human benign prostatic epithelial tissue is not present in metastatic prostate cancer by autoradiography. In human prostate cancer progression to metastases, ET-1 and ETA expression are retained, whereas ETB receptor expression is reduced.

Percutaneous nephrolithotomy in infants and preschool age children: experience with a new technique.

OBJECTIVES: To develop a less invasive method for performing percutaneous nephrolithotomy (PCNL) with the intent of decreasing the morbidity of the procedure in young children. METHODS: A novel percutaneous renal access technique ("mini-perc") was developed using an 11F peel-away vascular access sheath. Tract dilation and insertion of the sheath into the collecting system was performed with a single pass over an access wire. PCNL was performed using pediatric instruments and electrohydraulic lithotripsy. Sheath design improvements were implemented that make it specific for pediatric PCNL. RESULTS: Eleven procedures have been performed with the 11F sheath. Patient age ranged from 2 to 6 years (mean 3.4) and weight from 5 to 24 kg (mean 12.5). The average stone burden was 1.2 cm2. Mean procedure time, estimated blood loss, and length of hospitalization were 203 minutes, 25 mL, and 6 days, respectively. Six (85%) of 7 patients are currently stone free with an average follow-up of 12 weeks. No patient required transfusion, developed urosepsis, or had a procedure-related complication. One procedure was performed in an outpatient setting with no postoperative nephrostomy tube. CONCLUSIONS: The 11F "mini-perc" technique was successful in rendering 85% of patients stone free with minimal morbidity. Its advantages over obtaining access with standard 24 to 34F access sheaths include a smaller skin incision, single-step dilation and sheath placement, good working access for pediatric instruments, variable length, and lower cost. In addition, the hypothesized decrease in renal and body wall trauma may result in less pain, reduced severity or risk of complications, and shorter hospital stays including the possibility of performing "tubeless" outpatient PCNLs. Further study is needed to confirm these possibilities.

Laparoscopy in urology.

Mention of all of the procedures in urology that have been attempted, or are being done, laparoscopically is beyond the scope of this article. The laparoscopic procedures outlined in this article are gaining increasing support as surgeons attempt to redefine gold standard minimally invasive therapies in the new millennium. Additional procedures, such as laparoscopic retroperitoneal lymph node dissections for low-stage, nonseminomatous germ cell testicular cancers and laparoscopic renal cryoablation of small renal cancers, are soon to be added to this list. As laparoscopic instrumentation and equipment continue to improve, it will become possible to explore even more procedures laparoscopically. Advances in imaging techniques, lasers, miniaturized robotics, and other areas may further define what is meant by the term minimal access surgery in the decades to follow.

Laparoscopic subcapsular nephrectomy.

A 26-year-old patient with end-stage renal disease secondary to vesicoureteral reflux and recurrent pyelonephritis was referred for bilateral native nephrectomy. A transperitoneal laparoscopic approach was used. Extremely dense fibrosis was encountered around the left kidney during the dissection. A left laparoscopic subcapsular nephrectomy and a right extracapsular nephrectomy were performed. The indications and surgical technique for laparoscopic subcapsular nephrectomy are discussed.

Laparoscopic renal surgery in patients at high risk for intra-abdominal or retroperitoneal scarring.

Prior open abdominal or renal surgery has been considered a relative contraindication to laparoscopic surgery because of the likelihood of adhesion formation and perinephric scarring, which results in difficulty obtaining access to the peritoneal cavity and during surgical dissection. The purpose of this study was to examine the feasibility and morbidity of laparoscopic renal surgery in patients at high risk for intra-abdominal or retroperitoneal scarring. Twenty-four patients who underwent laparoscopic renal surgery at our institution gave a history of significant open abdominal or renal surgery. Seven patients had undergone prior open extraperitoneal (N = 6) or percutaneous (N = 1) renal procedures, 10 patients had undergone prior open laparotomy for various reasons, and 7 patients had undergone open pelvic surgery. The mean interval from the prior operation to laparoscopic renal surgery was 16.5 years (range 0.3-44 years). Operative time, estimated blood loss, incidence of complications, perioperative parenteral narcotic use, length of hospitalization convalescence, and degree of intra-abdominal and retroperitoneal scarring were assessed. Patients who developed complications were compared with patients who did not. No difficulty was encountered while obtaining initial access to the peritoneal cavity or retroperitoneal space. No bowel or visceral injuries occurred during Veress needle or trocar placement. The laparoscopic procedure was completed successfully in all cases. The mean operative time was 4.3 (range 2.0-10.9) hours. The mean estimated blood loss was 266 mL (range 50-1200 mL). There were eight complications (overall complication 33%) including three major and five minor complications. Patients who developed complications had a higher total scarring score that those who did not (p = 0.01). For experienced laparoscopic surgeons, laparoscopic renal surgery in patients who have a history of open abdominal or renal surgery can be successful. Access via the transperitoneal or retroperitoneal route can be obtained safely, and the procedure usually can be performed in a timely fashion. However, a relatively high perioperative complication rate can be expected, particularly for those patients with significant intraperitoneal and retroperitoneal scarring.

Retroperitoneal access for transperitoneal laparoscopy in patients at high risk for intra-abdominal scarring.

BACKGROUND AND PURPOSE: Adhesions from prior extensive open abdominal surgery can make initial transperitoneal access for laparoscopy hazardous. An alternative to open port placement is a retroperitoneal approach to the peritoneal cavity. We describe our retroperitoneal access for transperitoneal laparoscopy and evaluate the success of the subsequent laparoscopic procedure. PATIENTS AND METHODS: Eight patients with a history of abdominal surgery have undergone retroperitoneal access to the peritoneum prior to a laparoscopic urologic procedure. With the patient in a lateral decubitus position, the retroperitoneum is entered with a 10-mm Visiport device (US Surgical Corp., Norwalk, CT) along the posterior axillary line. A working space is bluntly created, the peritoneum identified anterior to the colon, and the endoscope passed through a peritoneotomy. The abdomen is then inspected, transperitoneal ports are strategically placed under direct vision, and the intended procedure is commenced. RESULTS: In all cases, retroperitoneal access to the peritoneum and subsequent trocar placement was successful. In five cases, the intended procedure was completed laparoscopically. In a case of bilateral ureterolysis, one side was completed laparoscopically; however, the other required open conversion. In two nephrectomies for xanthogranulomatous pyelonephritis (XGP), open conversion was necessary because of fibrosis. CONCLUSION: Retroperitoneal access to the peritoneal cavity permits safe and effective port placement when previous abdominal surgery makes initial transabdominal access difficult. However, despite successful access, in patients at risk for extensive perinephric fibrosis (e.g., XGP), a high incidence of open conversion may be expected.

Postoperative bleeding following radical retropubic prostatectomy.

Bleeding following radical prostatectomy is defined as significant postoperative hemorrhage requiring the acute transfusion of blood to support blood pressure. Of 1,350 consecutive radical prostatectomies 7 cases (0.5%) met this criterion. Of these patients 4 were explored for bleeding and 3 were managed expectantly. Mean blood product requirements for explored patients were comparable to those managed conservatively (13.8 versus 14.7). Total hospitalization days were less in patients who underwent a secondary operation (14.5 versus 21 days). In the 3 patients managed nonoperatively the pelvic hematoma drained through the anastomosis, resulting in symptomatic bladder neck contractures in all 3 and long-term incontinence in 2. Only 1 of the 4 patients explored (25%) experienced prolonged mild incontinence. These results suggest that patients requiring acute transfusions for hypotension following radical prostatectomy should be explored to evacuate the pelvic hematoma, and decrease the likelihood of bladder neck contracture and incontinence.

Adrenocortical carcinoma with intracaval extension.

PURPOSE: We describe the presenting features, treatment approach and prognosis of adrenocortical carcinoma with intracaval extension of tumor thrombus. MATERIALS AND METHODS: In addition to 3 patients with adrenocortical carcinoma associated tumor thrombus treated at our institution, we reviewed an additional 26 patients described in the literature from 1972 to 1997 with regard to presentation, management and outcome. RESULTS: We identified 23 female and 6 male patients 6 to 77 years old (mean age 41.3). Of the lesions 24 originated in the right adrenal gland. Mean tumor size was 10.1 cm. and 89% of lesions were at least 9 cm. in greatest dimension. Tumor thrombus extended to the atrium in 15 patients, retrohepatic cava in 7 and subhepatic cava in 7. Flank or abdominal discomfort was the most common presenting complaint and abnormal steroid metabolism was documented in 76% of patients. Cardiac bypass techniques were used in 14 patients and none of the 3 intraoperative mortalities, 2 thromboemboli and 1 exsanguination, occurred using this approach. Eight patients received postoperative mitotane, 6 of whom had no evidence of residual disease at the time of case description. CONCLUSIONS: All patients with large adrenal tumors, especially those arising from the right gland, should undergo careful evaluation of the vena cava for thrombus. The best chance for survival is via complete surgical extirpation which is facilitated by the use of cardiac bypass techniques. There is evidence to support the early use of postoperative mitotane if there is a suspicion of residual or recurrent disease.

Reassessing the efficacy of the Dornier MFL-5000 lithotriptor.

PURPOSE: The Dornier MFL-5000* is a multifunctional lithotriptor unit that has been purported to be highly efficacious for treating stones. Our experience led us to believe that the actual success rates are not as high as those reported by others. We objectively reexamined the efficacy of this device and factors contributing to treatment success or failure. MATERIALS AND METHODS: We retrospectively reviewed the records and x-rays of 105 consecutive patients treated with extracorporeal shock wave lithotripsy (ESWL*) using the MFL-5000 during an 18-month period from September 1997 to March 1999. One patient was excluded from study due to a stone within a caliceal diverticulum. Patients were divided evenly by gender and stone laterality. In 70% of cases a stent was placed preoperatively to relieve obstruction and/or facilitate the passage of calculous fragments. The majority of stones (70%) were 10 mm. or less. Treatment success was determined by examining x-rays done preoperatively and at a median of 4 weeks postoperatively. RESULTS: ESWL was successful in only 47% of our patients, defined as residual stone fragments 2 mm. or less. A secondary procedure was required in 27% of the patients, including repeat ESWL in 6, ureteroscopic stone manipulation in 14, percutaneous tube placement in 1 and percutaneous nephrolithotripsy in 7. Factors contributing to secondary procedures and poor stone clearance were a stone burden of greater than 100 mm.2 and mid pole location (p = 0.0242 and 0.016, respectively). Poor stone fragmentation and clearance were noted despite significantly more shocks delivered (p = 0.0122). Only a small stone burden of 50 mm.2 or less responded well to ESWL (p = 0. 0142). CONCLUSIONS: These results compel us to reconsider the effectiveness of the Dornier MFL-5000 lithotriptor. We encourage groups at other institutions to reexamine and report their success rates. We recommend the use of this lithotriptor only for a stone burden of 50 mm.2 or less.

Radially dilating trocar system for open laparoscopic access.

Laparoscopic access can be obtained quickly and without complication by placing a radially dilating trocar sleeve into the peritoneum through a 3-mm umbilical incision and dilating to 5 or 10 mm. This provides a tight seal without purse-string sutures. This is our preferred method of open laparoscopic access.

Laparoscopic assisted reconstructive surgery.

PURPOSE: We describe the use of laparoscopy to assist in performing complex pediatric reconstructive cases with the goals of improved cosmesis, and limited postoperative morbidity and adhesion formation. MATERIALS AND METHODS: Eight patients a mean age of 13.4 years underwent 8 laparoscopic assisted reconstructive procedures at our institution from June 1995 to February 1998. The group consisted of 5 patients with spina bifida, 1 with sacral agenesis, 1 with classic bladder exstrophy and 1 with bladder dysfunction secondary to posterior urethral valves. Information was obtained via personal communication and review of the hospital records. RESULTS: Eight successful laparoscopic assisted procedures were performed, including bladder augmentation and an appendiceal Mitrofanoff procedure in 4 cases as well as tapered ileal Mitrofanoff and Malone antegrade continence enema procedures in 1, and bladder augmentation, appendiceal Mitrofanoff and antegrade continence enema procedure, gastrocystoplasty removal, ileal augmentation and an appendiceal Mitrofanoff procedure, and an antegrade continence enema procedure in 1 each. The laparoscopic component of these operations included extensive mobilization of the right colon in all patients and complete appendiceal harvesting in 2. Reconstruction was then completed through a Pfannenstiel incision in 4 patients, previous low midline scar in 2 and a small midline incision in 2. Drains were placed via existing trocar sites and open incisions were carried through other sites whenever possible. Continent stomas were matured through a trocar site in all 8 cases. Final cosmesis was excellent. Operative time was comparable to that of similar open procedures and intraoperative blood loss was minimal. CONCLUSIONS: Laparoscopy may be used as a successful adjunct in complex pediatric reconstructive procedures to minimize disfiguring and morbid upper abdominal incisions, and decrease the risk of future adhesions.

Biomarker distribution after injection into the canine prostate: implications for gene therapy.

OBJECTIVE: To evaluate the distribution of biomarkers after transrectal injection into the canine prostate and to report a method for enhancing the distribution of gene expression. MATERIALS AND METHODS: Carbon black was first used to evaluate the histopathological distribution in canine prostate of single or multiple injections via the transurethral, transperineal and transrectal routes. The distribution of canarypox virus (ALVAC) vector-delivered gene expression was then compared using both fluid-phase injection techniques and delivery in a solid carrier composed of a gelatine sponge matrix. RESULTS: After transurethral administration, carbon black was detected as scattered particles in ducts and acini, mostly in the periphery of the gland. Direct transrectal injection of carbon black resulted in a localized collection at the site of injection, with only a minimal peri-acinar distribution. Transrectal injection of the fluid-phase (virus suspended in diluent) ALVAC vector encoding the beta-galactosidase gene resulted in a similar distribution, with limited gene expression at the site of injection and in the needle track. Delivery of the same number of virus particles in the gelatine sponge matrix resulted in qualitatively greater gene expression. CONCLUSIONS: Direct injection of the canine prostate with biomarkers, including viral vectors, in the fluid-phase results in very localized gene expression, while the distribution was more widespread after delivery in a gelatine sponge matrix.