Pelvic lymph node dissection is associated with symptomatic venous thromboembolism risk during laparoscopic radical prostatectomy.

PURPOSE: Venous thromboembolism is a potentially catastrophic complication of radical prostatectomy. It is unknown whether pelvic lymph node dissection is related to the development of venous thromboembolism. We hypothesized that omitting pelvic lymph node dissection may be associated with a decreased incidence of venous thromboembolism. MATERIALS AND METHODS: The records of 773 consecutive patients who underwent laparoscopic radical prostatectomy by a single surgeon from 2001 to 2009 were reviewed for postoperative venous thromboembolism. All patients underwent laparoscopic radical prostatectomy with or without pelvic lymph node dissection and had at least 3 months of followup. Generally only patients at increased risk for lymph node metastasis received pelvic lymph node dissection. Diagnostic studies were not routinely performed but were initiated for clinical symptoms of venous thromboembolism. Separately a meta-analysis of radical prostatectomy studies with or without pelvic lymph node dissection was performed to evaluate associations with venous thromboembolism. RESULTS: Of the 773 patients 468 (60.8%) underwent laparoscopic radical prostatectomy plus pelvic lymph node dissection, 302 (39.2%) underwent laparoscopic radical prostatectomy without pelvic lymph node dissection, and 3 were missing preoperative data and were excluded from study. Patients in the laparoscopic radical prostatectomy plus pelvic lymph node dissection and laparoscopic radical prostatectomy only groups were similar in age, body mass index and prostate volume, although they differed in pathological characteristics and operative time. Venous thromboembolism occurred in 7 of 468 (1.5%) patients who underwent laparoscopic radical prostatectomy plus pelvic lymph node dissection and in 0 of 302 (0%) who underwent laparoscopic radical prostatectomy only (p = 0.047). Patients in whom venous thromboembolism developed had greater body mass index (30.8 vs 27.1 kg/m(2), p = 0.015) than those in whom venous thromboembolism did not develop. No patient had a symptomatic lymphocele. Meta-analysis of the literature demonstrated a significant association between venous thromboembolism and radical prostatectomy plus pelvic lymph node dissection compared to radical prostatectomy only (RR 2.15, CI 1.14-4.04, p = 0.018). CONCLUSIONS: Pelvic lymph node dissection during radical prostatectomy increases the risk of venous thromboembolism. In carefully selected low risk patients omitting pelvic lymph node dissection may decrease the incidence of venous thromboembolism.

A multi-institutional randomized controlled trial comparing first-generation transrectal high-resolution micro-ultrasound with conventional frequency transrectal ultrasound for prostate biopsy.

Objectives: To study high-frequency 29 MHz transrectal side-fire micro-ultrasound (micro-US) for the detection of clinically significant prostate cancer (csPCa) on prostate biopsy, and validate an image interpretation protocol for micro-US imaging of the prostate. Materials and methods: A prospective randomized clinical trial was performed where 1676 men with indications for prostate biopsy and without known prostate cancer were randomized 1:1 to micro-US vs conventional end-fire ultrasound (conv-US) transrectal-guided prostate biopsy across five sites in North America. The trial was split into two phases, before and after training on a micro-US image interpretation protocol that was developed during the trial using data from the pre-training micro-US arm. Investigators received a standardized training program mid-trial, and the post-training micro-US data were used to examine the training effect. Results: Detection of csPCa (the primary outcome) was no better with the first-generation micro-US system than with conv-US in the overall population (34.6% vs 36.6%, respectively, P = .21). Data from the first portion of the trial were, however, used to develop an image interpretation protocol termed PRI-MUS in order to address the lack of understanding of the appearance of cancer under micro-US. Micro-US sensitivity in the post-training group improved to 60.8% from 24.6% (P < .01), while specificity decreased (from 84.2% to 63.2%). Detection of csPCa in the micro-US arm increased by 7% after training (32% to 39%, P < .03), but training instituted mid-trial did not affect the overall results of the comparison between arms. Conclusion: Micro-US provided no clear benefit over conv-US for the detection of csPCa at biopsy. However, it became evident during the trial that training and increasing experience with this novel technology improved the performance of this first-generation system.

Premature expression of T cell receptor (TCR)alphabeta suppresses TCRgammadelta gene rearrangement but permits development of gammadelta lineage T cells.

The T cell receptor (TCR)gammadelta and the pre-TCR promote survival and maturation of early thymocyte precursors. Whether these receptors also influence gammadelta versus alphabeta lineage determination is less clear. We show here that TCRgammadelta gene rearrangements are suppressed in TCRalphabeta transgenic mice when the TCRalphabeta is expressed early in T cell development. This situation offers the opportunity to examine the outcome of gammadelta versus alphabeta T lineage commitment when only the TCRalphabeta is expressed. We find that precursor thymocytes expressing TCRalphabeta not only mature in the alphabeta pathway as expected, but also as CD4(-)CD8(-) T cells with properties of gammadelta lineage cells. In TCRalphabeta transgenic mice, in which the transgenic receptor is expressed relatively late, TCRgammadelta rearrangements occur normally such that TCRalphabeta(+)CD4(-)CD8(-) cells co-express TCRgammadelta. The results support the notion that TCRalphabeta can substitute for TCRgammadelta to permit a gammadelta lineage choice and maturation in the gammadelta lineage. The findings could fit a model in which lineage commitment is determined before or independent of TCR gene rearrangement. However, these results could be compatible with a model in which distinct signals bias lineage choice and these signaling differences are not absolute or intrinsic to the specific TCR structure.

Multidisciplinary total eradication therapy (TET) in men with newly diagnosed oligometastatic prostate cancer.

To evaluate the outcomes of total eradication therapy (TET), designed to eradicate all sites of visible cancer and micrometastases, in men with newly diagnosed oligometastatic prostate cancer (OMPCa). Men with ≤ 5 sites of metastases were enrolled in a prospective registry study, underwent neoadjuvant chemohormonal therapy, followed by radical prostatectomy, adjuvant radiation (RT) to prostate bed/pelvis, stereotactic body radiation therapy (SBRT) to oligometastases, and adjuvant hormonal therapy (HT). When possible, the prostate-specific membrane antigen targeted 18F-DCFPyL PET/CT (18F-DCFPyL) scan was obtained, and abiraterone was added to neoadjuvant HT. Twelve men, median 55 years, ECOG 0, median PSA 14.7 ng/dL, clinical stages M0-1/12 (8%), M1a-3/12 (25%) and M1b-8/12 (67%), were treated. 18F-DCFPyL scan was utilized in 58% of cases. Therapies included prostatectomy 12/12 (100%), neoadjuvant [docetaxel 11/12 (92%), LHRH agonist 12/12 (100%), abiraterone + prednisone 6/12 (50%)], adjuvant radiation [RT 2/12 (17%), RT + SBRT 4/12 (33%), SBRT 6/12 (50%)], and LHRH agonist 12/12 (100%)]. 2/5 (40%) initial patients developed neutropenic fever (NF), while 0/6 (0%) subsequent patients given modified docetaxel dosing developed NF. Otherwise, TET resulted in no additive toxicities. Median follow-up was 48.8 months. Overall survival was 12/12 (100%). 1-, 2-, and 3-year undetectable PSA's were 12/12 (100%), 10/12 (83%) and 8/12 (67%), respectively. Median time to biochemical recurrence was not reached. The outcomes suggest TET in men with newly diagnosed OMPCa is safe, does not appear to cause additive toxicities, and may result in an extended interval of undetectable PSA.

Longitudinal assessment of urinary PCA3 for predicting prostate cancer grade reclassification in favorable-risk men during active surveillance.

BACKGROUND: To assess the utility of urinary prostate cancer antigen 3 (PCA3) as both a one-time and longitudinal measure in men on active surveillance (AS). METHODS: The Johns Hopkins AS program monitors men with favorable-risk prostate cancer with serial PSA, digital rectal examination (DRE), prostate magnetic resonance imaging and prostate biopsy. Since 2007, post-DRE urinary specimens have also been routinely obtained. Men with multiple PCA3 measures obtained over ⩾3 years of monitoring were included. Utility of first PCA3 score (fPCA3), subsequent PCA3 (sPCA3) and change in PCA3 were assessed for prediction of Gleason grade reclassification (GR, Gleason score >6) during follow-up. RESULTS: In total, 260 men met study criteria. Median time from enrollment to fPCA3 was 2 years (interquartile range (IQR) 1-3) and from fPCA3 to sPCA3 was 5 years (IQR 4-6). During median follow-up of 6 years (IQR 5-8), 28 men (11%) underwent GR. Men with GR had higher median fPCA3 (48.0 vs 24.5, P=0.007) and sPCA3 (63.5 vs 36.0, P=0.002) than those without GR, while longitudinal change in PCA3 did not differ by GR status (log-normalized rate 0.07 vs 0.06, P=0.53). In a multivariable model including age, risk classification and PSA density, fPCA3 remained significantly associated with GR (log(fPCA3) odds ratio=1.77, P=0.04). CONCLUSIONS: PCA3 scores obtained during AS were higher in men who underwent GR, but the rate of change in PCA3 over time did not differ by GR status. PCA3 was a significant predictor of GR in a multivariable model including conventional risk factors, suggesting that PCA3 provides incremental prognostic information in the AS setting.

Intravesical bacille Calmette-Guérin induces the antiangiogenic chemokine interferon-inducible protein 10.

OBJECTIVES: Intravesical bacille Calmette-Guérin (BCG) induces a variety of cytokines into the urine of patients with superficial transitional cell carcinoma (TCC) of the bladder. Recent data have shown that some cytokines have antiangiogenic activity. We sought to determine whether the potently antiangiogenic chemokine interferon-inducible protein 10 (IP-10) and its inducing antiangiogenic cytokines, interferon-gamma (IFN-gamma) and interleukin-12 (IL-12), are increased during intravesical BCG immunotherapy of bladder TCC. METHODS: Voided urine samples were collected sequentially from 8 patients before and after each weekly intravesical BCG treatment and from 4 patients receiving maintenance BCG treatments. The urinary output of IP-10, IFN-gamma, and IL-12 over 12 post-treatment hours was assessed by enzyme-linked immunosorbent assay. In vitro BCG and cytokine stimulations of human TCC and primary endothelial cell lines were also performed, and their supernatants were studied for IP-10. RESULTS: In all cases after intravesical BCG, patient urine was found to contain significant elevations of IP-10. Urinary IFN-gamma and IL-12 levels also increased in similar patterns after intravesical BCG. The peak weekly cytokine response per patient usually occurred between the fourth and sixth treatment for IFN-gamma and IP-10, but was less predictable for IL-12. Human TCC and endothelial cell lines were able to secrete IP-10 in response to BCG or interferon stimulation in vitro. CONCLUSIONS: Our small series demonstrates that IP-10 and its inducing cytokines are elevated in response to intravesical BCG. These data suggest that, in addition to a cellular immune response, BCG may induce a cytokine-mediated antiangiogenic environment that aids in inhibiting future tumor growth and progression.

Fertility options after vasectomy: a cost-effectiveness analysis.

OBJECTIVE: To evaluate cost per delivery using two different initial approaches to the treatment of postvasectomy infertility. DESIGN: Model of expected costs and results in the United States in 1994. SETTING: Men with postvasectomy infertility, evaluated and treated at centers with experience in vasectomy reversal or sperm retrieval and ICSI. PATIENT(S): Men with postvasectomy infertility, with a female partner < or = 39 years of age. INTERVENTION(S): Initial microsurgical vasectomy reversal was compared with retrieved epididymal or testicular sperm. Actual treatment charges, complication rates, and pregnancy and delivery rates obtained in the United States were used for cost per delivery analysis. MAIN OUTCOME MEASURE(S): Cost per delivery, delivery rates. RESULT(S): Cost per delivery with an initial approach of vasectomy reversal was only $25,475. (95% confidence interval $19,609 to $31,339), with a delivery rate of 47%. However, the cost per delivery after sperm retrieval and ICSI was $72,521. (95% confidence interval $63,357 to $81,685), with an average of $73,146 for percutaneous or testicular sperm retrieval and $71,896 for surgical epididymal sperm retrieval. The delivery rate after one cycle of sperm retrieval and ICSI was 33%. CONCLUSION(S): The most cost-effective approach to treatment of postvasectomy infertility is microsurgical vasectomy reversal. This treatment also has the highest chance of resulting in delivery of a child for a single intervention.

PIP: Calculations of cost per delivery for vasectomy reversal versus sperm retrieval-intracytoplasmic sperm injection (ICSI) under a wide variety of initial assumptions clearly indicate that vasectomy reversal is associated with lower costs per delivery and higher delivery rates. The data for the models on average postvasectomy infertility costs were derived from 6 specialized medical centers in the US in 1994; only men with female partners 39 years or younger were included. The overall vasectomy reversal pregnancy rate was 52%, with an estimated live delivery rate of 47%; for sperm retrieval and ICSI procedures, the mean weighted delivery rate per attempt was 33%. The average cost per delivery for vasectomy reversal (including pretreatment evaluation, surgeon's fee, anesthesia, ambulatory charges, complication costs, lost work costs, and delivery costs weighted for the number of procedures performed at each center) was US $25,475 (95% confidence interval, $19,609-31,339). In contrast, the cost per delivery after sperm retrieval and ICSI was US $72,521 (95% confidence interval, $63,357-81,685), with an average of $73,146 for percutaneous or testicular sperm retrieval and $71,896 for surgical epididymal sperm retrieval. Overall inpatient charges for delivery of a singleton gestation were $9845 ($37,947 for twin gestations and $109,765 for triplet gestations). Unless microsurgical epididymal sperm aspiration results improve dramatically or ICSI procedural costs and multiple gestation rates decrease, vasectomy reversal will remain the indicated treatment for men interested in fertility restoration after vasectomy.

Retroperitoneoscopic-guided radiofrequency ablation of renal tumors.

OBJECTIVE: Minimally invasive approaches to the management of renal tumors are being studied intensively in urology. Herein, we describe the use of multiple organ-sparing techniques for the management of tumors in a patient with von Hippel Lindau disease (VHL). MATERIALS AND METHODS: A 42 year-old woman with VHL underwent a right partial adrenalectomy and a left renal radiofrequency ablation (RFA) of two renal tumors. RESULTS: A 2.2 cm solitary right adrenal pheochromocytoma was resected using a transperitoneal approach. A retroperitoneal approach to the left kidney was performed and RFA of the two renal tumors completed using sonographic guidance. On the 5-month follow-up CT scan, there was no evidence of residual adrenal tumors and both renal lesions lacked contrast enhancement. No complications occurred during the post-operative recovery. CONCLUSIONS: Multiple organ-ablative laparoscopic procedures may be performed in a single sitting. Laparoscopic partial adrenalectomy is an effective technique in patients with bilateral tumors or a familial syndrome predisposing to multiple adrenal tumors. Further study of renal RFA is required to assess the long-term durability of the procedure.

Partial adrenalectomy in patients with multiple adrenal tumors.

Most adrenal tumors are found incidentally and appear as small solitary nodules on abdominal imaging. Occasionally, work-up demonstrates multifocal or bilateral adrenal tumors. Certain patients are predisposed to multiple lesions, such as those with hereditary forms of pheochromocytoma as seen in von Hippel-Lindau disease, multiple endocrine neoplasia type II, and von Recklinghausen's disease. Partial rather than total adrenalectomy should be considered for these patients in an attempt to preserve endogenous adrenocortical function. Partial adrenalectomy has also been used to resect other types of adrenal tumors, especially in patients with a solitary adrenal gland. A discussion of the indications for partial adrenalectomy and of the surgical technique follows.

Evidence of a treatable endocrinopathy in infertile men.

PURPOSE: We establish whether a subset of infertile men have decreased serum testosterone-to-estradiol ratios and whether this condition can be corrected with an oral aromatase inhibitor. MATERIALS AND METHODS: The serum testosterone-to-estradiol ratios of 63 men with severe male factor infertility or hypergonadotropic hypogonadism (mean follicle-stimulating hormone 21.2 +/- 1.8) were compared with those of an age matched, fertile, control reference group. Of the 63 men 43 were azoospermic with biopsy proved severe male infertility and 20 were oligospermic. The men with the lowest ratios (less than 20th percentile) were treated with 50 to 100 mg of the aromatase inhibitor testolactone orally twice daily. Testosterone-to-estradiol ratios and semen analyses were evaluated during testolactone therapy. RESULTS: Men with severe male infertility had significantly lower testosterone (328 versus 543 ng/dl, p <0.01) and higher estradiol (58.4 versus 43.5 ng/l, p = 0.01) than fertile control reference subjects, resulting in a decreased testosterone-to-estradiol ratio (x10(-1) = 6.9 +/- 0.6 versus 14.5 +/- 1.2, respectively, p <0.01). Of the 45 men treated with testolactone a correction of these abnormalities was seen and ratios (x10(-1)) increased into the normal range (5.0 +/- 0.3 to 12.7 +/- 1.2, p <0.01). Semen analyses were considered evaluable only in men with sperm in the ejaculate before aromatase inhibitor treatment. Semen analyses before and during testolactone treatment revealed significant increases in sperm concentration (16.1 to 28.9 million sperm per ml, p = 0.03) and motility (27.1% to 45.3%, p <0.01) in 12 oligospermic men. CONCLUSIONS: We identified an endocrinopathy in men with severe male factor infertility that is characterized by a decreased serum testosterone-to-estradiol ratio. This ratio can be corrected by aromatase inhibition, resulting in a significant improvement in semen parameters in oligospermic patients.

The genetic basis of renal epithelial tumors: advances in research and its impact on prognosis and therapy.

The genetics of renal cell carcinoma continues to elucidate the pathways of kidney tumorigenesis. The relationship between the VHL gene and clear cell carcinoma, MET and papillary carcinoma, and the families of genes that they regulate, continues to be unraveled. New hereditary kidney cancer syndromes, like familial oncocytoma and the Birt-Hogg-Dubé syndrome, have been identified and the search for the genes that cause them is under way. Researching the genetics of these disorders is essential for an understanding of sporadic kidney cancer genetics. This chapter will review the current knowledge of the hereditary kidney cancer syndromes, the genes that cause them, new advances in genetic research and techniques, and how this information impacts upon diagnostic, prognostic, and therapeutic methods of the future.

Intraoperative ultrasound during renal parenchymal sparing surgery for hereditary renal cancers: a 10-year experience.

PURPOSE: We review our 10-year experience with intraoperative ultrasound during renal parenchymal sparing surgery in patients with hereditary renal cancers. MATERIALS AND METHODS: Between 1991 and 2000, 68 nephron sparing procedures were performed on 26 women and 27 men, all but 1 of whom had a hereditary predisposition to renal cancer, for example von Hippel-Lindau, hereditary papillary renal cancer. Intraoperative ultrasound was performed after the surgeon removed all visible or palpable lesions. High frequency transducers (7 MHz.) and color Doppler were used in all cases. Lesions were characterized as simple cysts, complex cysts or solid masses, and were recorded on a map. RESULTS: A total of 935 lesions (mean 12.8 lesions per kidney) were removed in 68 nephron sparing operations performed on 53 patients. Of these lesions 870 were removed without while 65 required intraoperative ultrasound. In 17 of 68 (25%) procedures intraoperative ultrasound identified renal cancers that were not detectable by the surgeon. Mean tumor size of ultrasound detected lesions was 1.0 cm. (range 2 mm. to 4 cm.). Of the 32 cystic lesions identified by intraoperative ultrasound 5 contained renal carcinoma, and 29 of the 33 solid renal masses were renal cell carcinomas. During reoperations ultrasound enabled the surface of the kidney to be evaluated even when it was inaccessible due to scar tissue or adherent perinephric fat. CONCLUSIONS: Intraoperative ultrasound can be performed after all visible lesions have been removed and identifies additional tumors in 25% of patients with hereditary renal cancer, thus ensuring that as many tumors as possible have been removed during renal parenchymal sparing surgery.

Ureteroscopic biopsy of upper tract urothelial carcinoma: improved diagnostic accuracy and histopathological considerations using a multi-biopsy approach.

PURPOSE: We assessed the diagnostic accuracy of a ureteroscopic multi-biopsy approach to upper tract urothelial carcinoma compared with subsequently resected surgical specimens. MATERIALS AND METHODS: From 1990 to 1998, 45 upper tract lesions were ureteroscopically evaluated and biopsied with 3Fr cup forceps and/or an 11.5Fr resectoscope before nephroureterectomy or ureterectomy. A definitive diagnosis of urothelial carcinoma was made by biopsy in 40 lesions (89%). Each tumor was histopathologically graded but only staged if the lamina propria were uninvolved (Ta), and if the lamina propria were invaded by tumor (T1+). RESULTS: Of the 40 urothelial tumors 16 (40%) were in the renal pelvis, and 8 (20%) in the proximal and 16 (40%) in the distal ureter. Of the lesions 95% were papillary and 65% were grade 2. Ureteroscopic biopsy grade matched surgical pathological grade in 31 of the 40 cases (78%), and was less than surgical pathological grade in the remainder. Lamina propria was detected in 27 of the 40 biopsies, including 21 of the 34 cup (62%) and all 6 resection loop (100%) biopsies. Ureteroscopic biopsy staging in 27 cases revealed Ta and T1+ disease in 22 and 5, respectively. In the 5 cases in which ureteroscopic biopsy stage was T1+ surgical pathological stage was also pT1+ (range pT1 to pT3). Tumors were pathologically up staged to pT1+ (range pT1 to pT3) in 10 of the 22 cases (45%) in which ureteroscopic biopsy stage was Ta. Tumor location did not affect diagnostic accuracy. CONCLUSIONS: This multi-biopsy ureteroscopic approach provided the tissue diagnosis of urothelial carcinoma in 89% of cases and predicted exact histopathological grade in 78%. Although it is not accurate as a staging modality, multi-biopsy ureteroscopy may assess lamina propria invasion in two-thirds of cases.

Hand-assisted laparoscopic donor nephrectomy versus standard laparoscopic donor nephrectomy: a comparison study in the canine model.

The aim of this study was to compare live donor nephrectomy by hand-assisted laparoscopy to standard laparoscopy in a canine model. Fourteen dogs underwent a left laparoscopic nephrectomy; a standard laparoscopic nephrectomy technique was utilized in seven dogs. In a second group of seven dogs, a hand-assisted laparoscopic technique was used with a Dexterity Pneumo Sleeve hand port. All nephrectomies were performed as "donor" nephrectomies, dividing the vessels last. Total blood loss, operative warm ischemia, time and organ retrieval times were assessed for each group. The average operative time was significantly shorter for hand-assisted laparoscopic donor nephrectomy (32 +/- 8 minutes vs. 61 +/- 8 minutes; p = .02) than for the standard technique. The average warm ischemia (86 +/- 24 seconds vs. 224 +/- 52 seconds; p = .03) and average organ delivery times (4 +/- 3 seconds vs. 45 +/- 9 seconds; p < .01) also were shorter using the hand-assisted laparoscopic technique. No significant differences in average blood loss were found between the two groups (9 +/- 2 cc vs. 6 +/- 1 cc; p = 0.16, NS). Good parenchymal, ureteral, and vascular preservation was achieved by both techniques. Hand-assisted laparoscopy permits shorter operating times and warm ischemia times than standard laparoscopy in a canine model of donor nephrectomy. Hand assistance makes donor laparoscopic nephrectomy technically easier and significantly quicker to perform. If hand-assisted laparoscopy donor nephrectomy is confirmed to be a rapid and safe technique for removing an intact organ, laparoscopic nephrectomy will be a more widely accepted technique among urologists who participate in living related donor kidney transplantation.

Flexible transinguinal laparoscopy to assess the contralateral ring in pediatric inguinal hernias.

The incidence of contralateral patent processus vaginalis (CPPV) is >50% in infants with clinical unilateral inguinal hernia (CUIH) and decreases only slowly with advancing age. Laparoscopy through the hernia sac (transinguinal laparoscopy) to detect suspected CPPV is a safe and efficient way to minimize routine contralateral inguinal exploration, but can be technically difficult. We used flexible urologic instruments and/or angled cystoscopic lenses to make transinguinal laparoscopy easier. Over a 3-year period, 37 patients (34 boys and 3 girls) ranging in age from 4 months to 12 years (mean age 59 months) with CUIH underwent ipsilateral groin exploration and diagnostic transinguinal laparoscopy. Laparoscopy was performed with flexible 17F cystoscopes (26 cases), flexible 9F ureteroscopes (2 cases), and rigid 70 degrees cystoscope lenses (9 cases). We detected eight CPPV (22%) in our series of 20 right and 17 left inguinal hernias, in a mean transinguinal laparoscopy time of 4.5 minutes. At 26-month mean follow-up, no patient whose contralateral inguinal ring was deemed closed had developed a hernia. Flexible fiberoptic urologic scopes and/or angled cystoscope lenses make transinguinal laparoscopy easy and efficacious in the pediatric population. Our series represents the longest longitudinal study of transinguinal laparoscopy for the diagnosis of CPPV.

BCG-induced urinary cytokines inhibit microvascular endothelial cell proliferation.

PURPOSE: Angiogenesis is thought to depend on a net balance of molecules that inhibit or stimulate microvascular endothelial cells. A variety of molecules that affect angiogenesis are induced locally by the administration of intravesical bacille Calmette-Guerin (BCG) for superficial bladder cancer. We sought to determine whether BCG-induced urinary cytokines alter the effects of patient urine on assays of angiogenic activity. MATERIALS AND METHODS: Patients undergoing BCG treatment provided urine samples before and at peak cytokine production times after BCG instillation. Fifty-four urine samples from 8 patients were analyzed by ELISA for a panel of molecules known to affect angiogenesis, and tested for angiogenic activity in human dermal microvascular endothelial cell (HDMEC) proliferation and migration assays. To assess the role of specific BCG-induced cytokines, urinary HDMEC proliferation assays were repeated in the presence of neutralizing antibodies to tumor necrosis factor-alpha (TNF-alpha), interferon-inducible protein-10 (IP-10), and/or interferon-gamma (IFN-gamma). RESULTS: Urinary IFN-gamma, IP-10, TNF-alpha, and vascular endothelial growth factor (VEGF) were induced to nanogram/ml amounts by BCG treatment. While pre-BCG treatment urine samples minimally stimulated microvascular endothelial cell proliferation (+ 9%), post-BCG treatment urine became progressively inhibitory to endothelial cells (to -85%, p = 0.005) during weekly treatment courses. Neutralizing antibodies to TNF-alpha or to IP-10, either alone or in combination, greatly reduced this inhibitory effect. CONCLUSIONS: Intravesical BCG induces a cytokine-rich urinary microenvironment that is inhibitory to human endothelial cells. Urinary cytokine profiles and assays of angiogenic inhibition may provide prognostically important information regarding BCG treatment outcomes.

Birt-Hogg-Dubé syndrome, a genodermatosis associated with spontaneous pneumothorax and kidney neoplasia, maps to chromosome 17p11.2.

Birt-Hogg-Dubé syndrome (BHD), an inherited autosomal genodermatosis characterized by benign tumors of the hair follicle, has been associated with renal neoplasia, lung cysts, and spontaneous pneumothorax. To identify the BHD locus, we recruited families with cutaneous lesions and associated phenotypic features of the BHD syndrome. We performed a genomewide scan in one large kindred with BHD and, by linkage analysis, localized the gene locus to the pericentromeric region of chromosome 17p, with a LOD score of 4.98 at D17S740 (recombination fraction 0). Two-point linkage analysis of eight additional families with BHD produced a maximum LOD score of 16.06 at D17S2196. Haplotype analysis identified critical recombinants and defined the minimal region of nonrecombination as being within a <4-cM distance between D17S1857 and D17S805. One additional family, which had histologically proved fibrofolliculomas, did not show evidence of linkage to chromosome 17p, suggesting genetic heterogeneity for BHD. The BHD locus lies within chromosomal band 17p11.2, a genomic region that, because of the presence of low-copy-number repeat elements, is unstable and that is associated with a number of diseases. Identification of the gene for BHD may reveal a new genetic locus responsible for renal neoplasia and for lung and hair-follicle developmental defects.