Multi-institutional assessment of ureteroscopic laser papillotomy for chronic flank pain associated with papillary calcifications.

PURPOSE: We evaluated the long-term safety, efficacy and durability of ureteroscopic laser papillotomy for chronic flank pain associated with renal papillary calcifications. MATERIALS AND METHODS: We reviewed the medical records of all patients who underwent ureteroscopic laser papillotomy in the absence of free urinary calculi at our institutions from 1998 through 2008. Success was defined as patient report of significant pain relief. The duration of response was considered the time from papillotomy to repeat papillotomy in the same renal unit, patient report of recurrent pain or final followup. RESULTS: Ureteroscopic Ho:YAG laser papillotomy was done a total of 176 times in 65 patients, including 147 unilateral and 29 bilateral procedures. Of the patients 39 underwent multiple procedures (2 to 12). Symptomatic followup was available in 50 patients (146 procedures) during a mean of 38 months. Significantly less pain was reported after 121 procedures (83%). The mean duration of response per procedure was 26 months and 30 patients (60%) had a mean remission duration of greater than 1 year. Postoperatively hospital admission was required after 14 procedures (8%). There was no significant change in the mean estimated glomerular filtration rate during a mean 41.3-month followup. Seven of the 65 patients (11%) had hypertension before papillotomy. In 3 of the 49 patients (6.1%) with adequate followup new hypertension developed during a mean of 38 months. CONCLUSIONS: Ureteroscopic laser papillotomy is safe and effective. In patients with papillary calcifications and characteristic chronic, noncolicky pain this procedure provides significant, moderately durable symptom relief.

Patient and pathologic correlates with perioperative and long-term outcomes of laparoscopic radical nephrectomy.

OBJECTIVES: To comprehensively analyze and compare patient and pathologic correlates with perioperative events and with the long-term results of laparoscopic radical nephrectomy. METHODS: Laparoscopic radical nephrectomy was performed in 255 patients with renal cell carcinoma. Mean follow-up time was 35.2 months; for 39 patients, it was 5 or more years. RESULTS: Multivariate analysis revealed that major intraoperative complications were associated with increased body mass index and that major postoperative complications were associated with a higher American Society of Anesthesiologists (ASA) score. Older age and higher ASA score were associated with longer hospitalization. Patients were classified using a risk group stratification that incorporated grade and stage; 118 patients were low risk, 93 were intermediate risk, and 44 patients were high risk. No pathologic features were associated with perioperative outcomes. Kaplan-Meier recurrence-free, cancer-specific, and overall survival at 5 years were 79.2%, 88%, and 76.2%, respectively. Multivariate analysis revealed that pathologic risk group, mass size, and high-risk histologic subtype were associated with recurrence-free survival, and cancer-specific survival was associated with pathologic risk group and mass size. Age, high-risk pathologic risk group, and a high-risk histologic subtype were associated with overall survival. CONCLUSIONS: Our results indicate that perioperative outcomes of laparoscopic radical nephrectomy are associated with body mass index, ASA score, and age, but not with tumor characteristics. Recurrence-free and cancer-specific survival rates were associated with the expected pathologic parameters, confirming the oncologic efficacy of the procedure. Overall survival is associated not only with tumor pathology but also with age, suggesting that competing-cause mortality is important in this setting.

Approach and specimen handling do not influence oncological perioperative and long-term outcomes after laparoscopic radical nephrectomy.

PURPOSE: We assessed the impact of approach (standard vs hand assisted) and specimen handling (morcellation vs intact extraction) on laparoscopic radical nephrectomy short-term recovery and long-term oncological outcome. MATERIALS AND METHODS: Of 255 patients with pathologically confirmed and presumed localized renal cell carcinoma 147 underwent standard and 108 underwent hand assisted laparoscopic radical nephrectomy. Specimen handling was done by intact extraction in 132 cases and morcellation in 123. Perioperative data were recorded prospectively and oncological surveillance was reviewed retrospectively. RESULTS: Despite significant differences in body mass index, mass size, T stage and pathological risk between the groups there were no statistically significant differences in perioperative outcome by approach or specimen handling except greater estimated blood loss (mean 406 vs 283 ml), longer hospital stay (mean 2.8 vs 2.4 days) and greater time to recovery (mean 13 vs 9.9 days) in the hand assisted vs the standard group. Discovery of pT3 disease was not significantly different between the specimen handling groups after controlling for mass size. Multivariate analysis of 5-year Kaplan-Meier survival curves revealed that neither approach nor specimen handling impacted recurrence-free, cancer specific or overall survival. CONCLUSIONS: Differences in perioperative outcomes attributable to the specific approach (standard vs hand assisted) and the method of specimen handling (morcellation vs intact extraction) at laparoscopic radical nephrectomy have minimal clinical significance. There are no discernible differences in long-term oncological efficacy. The choice of approach and specimen handling for laparoscopic radical nephrectomy can be based on surgeon and patient preference, cosmetic considerations and other factors.

Radiographic surveillance of minimally and moderately complex renal cysts.

OBJECTIVE: To assess the effectiveness of radiographic surveillance for managing minimally and moderately complex renal cysts. PATIENTS AND METHODS: Forty-three patients with 50 minimally or moderately complex renal cysts underwent radiographic surveillance at our institution. Study inclusion criteria were surveillance for >2 years (36 patients, mean follow-up 3.0 years) or surveillance for >6 months with subsequent surgical excision (seven patients, mean follow-up 3.3 years). RESULTS: The complexity of the renal cysts was in the form of high attenuation before contrast-enhanced imaging ('hyperdense') in 29 patients, thin septations in nine, borderline enhancement in six, thin calcifications in five, and a thick wall in one. The mean initial largest dimension was 2.9 cm and the mean final dimension was 3.0 cm, with the size increased in 29 cysts, decreased in 14 and with no change in seven. The cyst character worsened in seven patients, improved in four and did not change in 39. Eventually seven patients had surgery (laparoscopic partial nephrectomy in five and laparoscopic radical nephrectomy in two), which revealed renal cancer in five. Surgical intervention was prompted by growth alone in two patients, growth and worsening of cyst characteristics in two, new onset of flank pain in one, and appearance of an enhancing nodule in the wall or septa in two. CONCLUSION: Radiographic surveillance is an effective method for managing patients with minimally or moderately complex renal cysts. Malignant lesions can be identified and removed while still of low grade and contained, and surgery can be avoided in most patients.

Success of laser endoureterotomy of ureteral strictures associated with ureteral stones is related to stone impaction.

PURPOSE: Since the holmium:yttrium-aluminum-garnet (Ho:YAG) laser is the flexible lithotrite of choice for ureteral stones, its application to ureteral strictures associated with ureteral calculi is convenient. The results of Ho:YAG laser endoureterotomy in this specific setting have not been defined. We report our experience with Ho:YAG laser endoureterotomy of ureteral strictures associated with ureteral stone treatment, with or without a history of stone impaction. METHODS: We reviewed the medical records of 13 patients with ureteral stricture related to stone treatment, with (n = 9) or without (n = 4) a history of impacted ureteral stones, who were managed with Ho:YAG laser endoureterotomy. Follow-up was obtained with radiographic imaging and renal scans. RESULTS: The overall success rate was 62%, with a mean follow-up of 21 months in successful cases and a mean recurrence time of 1.6 months in failures. Outcome was not associated with length or location of the stricture. Among the nine strictures associated with impacted stones, treatment was successful in only 5 (56%). Of the four strictures that occurred after stone removal but without history of impaction, the success rate was 75%. Success was also greater for strictures managed with post-procedure stents >or=8 Fr (75%), compared to stents

Obesity and morbid obesity are associated with a greater conversion rate to open surgery for standard but not hand assisted laparoscopic radical nephrectomy.

PURPOSE: We noted that the impact of obesity on renal laparoscopy may vary with the specific surgical approach. MATERIALS AND METHODS: Patients who underwent standard and hand assisted laparoscopic radical nephrectomy at our institution were categorized by body mass index as nonobese--body mass index less than 30, obese--30 to 39.9 and morbidly obese--40 kg/m(2) or greater. We assessed the association of intraoperative and postoperative outcomes with body mass index for standard and hand assisted laparoscopic radical nephrectomy. RESULTS: Of 350 patients who underwent standard (196) or hand assisted (154) laparoscopic radical nephrectomy 36% were obese and 12% were morbidly obese. Patients who underwent hand assisted laparoscopic radical nephrectomy had a greater body mass index, more frequent assignment of American Society of Anesthesiologists score 3 or 4 and larger masses than those who underwent standard laparoscopic radical nephrectomy. Despite this fact conversion to open surgery from hand assisted laparoscopic radical nephrectomy did not occur, while such conversion occurred in the standard laparoscopic radical nephrectomy group in 0.8% of nonobese, 3.0% of obese and 17% of morbidly obese patients (association with body mass index p = 0.003). Operative time, intraoperative and postoperative complications, and hospitalization duration did not vary with body mass index. On multivariate analysis only body mass index and not age, gender, American Society of Anesthesiologists score, prior abdominal surgery or tumor size was associated with an increasing likelihood of conversion to open surgery (p = 0.04), and only in the standard laparoscopic radical nephrectomy group. CONCLUSIONS: Although obesity and morbid obesity are associated with more frequent conversion to open surgery during standard laparoscopic radical nephrectomy, such conversion did not occur during hand assisted laparoscopic radical nephrectomy. This advantage of hand assisted laparoscopic radical nephrectomy should be considered when planning laparoscopic radical nephrectomy in obese and morbidly obese patients.

Holmium:yttrium-aluminum-garnet laser endoureterotomy for the treatment of transplant kidney ureteral strictures.

BACKGROUND: The management of ureteral strictures in transplanted kidney is challenging. Open surgical treatment is effective but entails significant convalescence. Holmium:yttrium-aluminum-garnet (Ho:YAG) laser endoureterotomy is useful for other types of ureteral obstruction, and we aimed to assess its long-term success for strictures of transplant kidney ureters. METHODS: We reviewed the course of 12 kidney transplant patients managed with Ho:YAG laser endoureterotomy and/or percutaneous ureteroscopic balloon dilatation for ureterovesical anastomotic strictures or ureteropelvic junction obstruction. Success was defined as stable serum creatinine and no hydronephrosis on follow-up. RESULTS: Of the patients, nine had ureterovesical anastomotic strictures. Of the six treated with balloon dilatation and Ho:YAG laser endoureterotomy, the success rate was 67% (58 months mean follow-up). Both strictures with failure were longer than 10 mm. Of the three patients treated with balloon dilatation only, there was success in only one (14 months follow-up) and both strictures with failure were shorter than 10 mm. There were three patients treated for ureteropelvic junction obstruction, one with balloon dilatation and two with balloon dilatation plus Ho:YAG laser endoureterotomy, all successfully (57 months mean follow-up). Overall, of the eight strictures 10 mm or shorter, there was success rate in six (75%), with 52 months mean follow-up, including five of five (100%) treated with laser endoureterotomy and one of three (33%) treated with only balloon dilation. CONCLUSIONS: Our results suggest that Ho:YAG laser endoureterotomy should be a first line treatment for ureteral strictures of length 10 mm or shorter in kidney transplant patients.

Biological response determinants in HSV-tk + ganciclovir gene therapy for prostate cancer.

The limitations of current forms of prostate cancer therapy have driven researchers to search for new alternatives. Previously we showed cytopathic effect related to HSV-tk in prostate cancer. In this study we present initial results of a neoadjuvant HSV-tk gene therapy trial and address some of the potential mechanistic aspects of its effect in human tissues. We enrolled 23 men with clinically localized prostate cancer but high risk for recurrence in this Phase I-II trial. Intraprostatic viral injections (one to four) were followed by 2 weeks of ganciclovir and prostatectomy 2-4 weeks later. Toxicity was modest. Surgical specimens were embedded fully and whole-mount slides were imaged and analyzed for areas of cytopathic effect. The larger the tumor the greater the cytopathic effect. The effect also seems to be related to areas of high CAR expression. However, the number of injection sites did not influence effect. Local (CD8+ cells and macrophages) and systemic immune response (CD8+ and activated CD8+, IL-12) was increased in patients treated with HSV-tk. Increased apoptosis and decreased microvessel density were also noted in these patients. The results suggest a tumor-specific effect mediated by systemic and local immune response, antiangiogenic effect, and modulation of apoptosis.

Anastomotic urethroplasty for failed previously treated membranous urethral rupture.

OBJECTIVES: To determine whether delayed excision and primary anastomosis is appropriate after failed previous therapeutic attempts for post-traumatic membranous urethral strictures. Delayed excision and primary anastomosis is widely accepted as the first-line treatment of post-traumatic membranous urethral strictures. METHODS: A review of the medical records identified 13 patients who had undergone anastomotic urethroplasty as a second procedure for traumatic membranous urethral strictures. The previous treatments in these patients included anastomotic urethroplasty in four, staged urethroplasty in four, and endoscopic urethrotomy or primary catheter realignment in five. The mean stricture length was 2.8 cm. All patients underwent excision and primary bulboprostatic anastomosis using the perineal approach. RESULTS: Four patients required partial pubectomy and one required corporal rerouting to achieve anastomosis. The mean follow-up was 27 months. Urethrography performed 1 month postoperatively demonstrated a widely patent anastomosis in all cases. Flexible urethroscopy performed 1 year after surgery revealed a widely patent anastomosis with normal urethral mucosa in all patients but one. The mean maximal flow rate at the last follow-up visit was 23.5 mL/s compared with 3.9 mL/s preoperatively. No statistically significant postvoid residual urine volume was found in any patient. One patient developed an anastomotic stricture 3 months after surgery that was treated successfully by internal urethrotomy. Thus, the objective success rate was 92%. Subjectively, all patients but one reported satisfactory voiding. Complications were mild and included urinary tract infection, bladder stone formation, and decreased erectile function in 1 patient each. CONCLUSIONS: Even in patients with failed previous surgical attempts, excision and primary anastomosis is feasible and provides good surgical results in post-traumatic posterior urethral strictures. The complications were mild and easily treated.

Enhanced systemic T-cell activation after in situ gene therapy with radiotherapy in prostate cancer patients.

PURPOSE: In situ cytotoxic gene therapy can potentially trigger a systemic immune response, which could impact occult metastatic disease. We are currently conducting three clinical trials using in situ adenoviral vector mediated herpes simplex virus-thymidine kinase (HSV-tk) gene delivery followed by the HSV-tk prodrug ganciclovir (GCV) or valacyclovir (VCV). This study evaluates the systemic T-cell response after gene therapy in each trial. METHODS AND MATERIALS: The study protocol included three separate clinical trials in the Baylor Prostate Cancer SPORE Program: Trial A gene therapy in prostate cancer patients failing radiotherapy (36 patients), Trial B neoadjuvant gene therapy in pre-radical prostatectomy patients (22 patients), and Trial C gene therapy in combination with radiotherapy for prostate cancer (27 patients). Heparinized blood was collected at the time of vector injection and at selected intervals afterward. A complete blood count was performed, and peripheral blood lymphocytes were analyzed by fluorescent antibody cell sorting after labeling with dual color-labeled antibody pairs. RESULTS: The pretreatment mean percentage of activated CD8+ T cells (DR+CD8+ T cells) was 12.23%, 16.72%, and 14.09% (Trials A, B, and C, respectively). Two weeks posttreatment, this increased to 22.87%, 26.15%, and 39.04% (Trials A, B, and C, respectively), and these increases were statistically significant (p = 0.0188, p = 0.0010, p < 0.0001, respectively). The increase of DR+CD8+ T cells was significantly larger in Trial C than in Trial A (p = 0.0044) or Trial B (p = 0.0288). Total CD8+ T cells significantly increased at 2 weeks posttreatment in Trial B and C (p = 0.0013, p = 0.0004, respectively). Interestingly, only in Trial C were significant increases in activated CD4+ T cells seen at 2 weeks (p = 0.0035). CONCLUSIONS: This is the first report of systemic T-cell responses after HSV-tk+GCV/VCV gene therapy under three clinical trial conditions. There was an increase in activated CD8+ T cells in the peripheral blood after vector injection, suggesting the potential for activation of components of cell-mediated immune response in all trial conditions. The addition of radiotherapy to in situ gene therapy seems to further increase the total CD8+ T cells and activated CD4+ T cells.

Development of an immunoassay for serum caveolin-1: a novel biomarker for prostate cancer.

PURPOSE: Caveolin-1 (cav-1), the major protein component of caveolae, plays an important role in multiple signaling pathways, molecular transport, and cellular proliferation and differentiation. The specific functions of cav-1/caveolae are highly cell and context dependent. We have previously shown that cav-1 expression is increased in metastatic human prostate cancer and that cav-1 cellular protein expression is predictive of recurrence of the disease after radical prostatectomy. Recently, we reported that cav-1 is secreted by androgen-insensitive prostate cancer cells, and we detected, by Western blotting, cav-1 in the high-density lipoprotein(3) fraction of serum specimens from patients with prostate cancer. EXPERIMENTAL DESIGN: Using rabbit polyclonal antibodies with specificity for cav-1, we developed a direct sandwich immunoassay for the determination of cav-1 in serum. A recombinant human cav-1 fusion protein was overexpressed and purified from 293 PE cells and used as a calibrator. RESULTS: The assay was highly specific and had a minimum detection limit of 0.017 ng/ml (mean + 3 SD of zero calibrator) and measuring range of up to 200 ng/ml. Intra-assay coefficient of variation was 2.29-6.74% and inter-assay coefficient of variation was 2.81-6.43% over the serum concentration tested 0.04-31.89 ng/ml. The recovery limit of cav-1 by the assay was 89.55-100.28%. The median serum cav-1 level in 102 prostate cancer patients with clinically localized disease (0.463 ng/ml) was significantly higher than 81 healthy control men (0.324 ng/ml; P = 0.0446, Mann-Whitney test) or 107 men with benign prostatic hyperplasia (0.172 ng/ml; P = 0.0317, Mann-Whitney test). CONCLUSIONS: Our results indicate that serum cav-1 has the power to differentiate between prostate cancer and benign prostatic hyperplasia patients and the potential to be an important biomarker for prostate cancer. Additional studies to test the potential of serum cav-1 as a diagnostic and/or prognostic marker in prostate cancer are warranted.

Gene therapy for prostate cancer.

Prostate cancer is the most common noncutaneous cancer in man. When confined to the prostate it can be cured by radical prostatectomy or irradiation therapy. However, there are no curative therapies for locally advanced, recurrent or metastatic disease. Prostate cancer gene therapy has recently transition from preclinical studies to clinical trials with the goal of developing novel treatments for prostate cancer. The greatest challenge in treating advanced prostate cancer is therapeutic access to and the elimination of metastases. This review details two aspects of prostate cancer gene therapy, the types of delivery systems under development and specific categories of therapeutic genes available with an emphasis on the mechanism of action of specific gene therapy strategies.