Frequent and early loss of the EGR1 corepressor NAB2 in human prostate carcinoma.

The transcription factor EGR1 is frequently overexpressed in human prostate cancer and regulates the expression of several genes important for tumor progression. In addition, mice lacking the Egr1 gene show a defect in prostate tumorigenesis. NAB2 is a novel corepressor molecule that modulates EGR1 activity and is induced by the same stimuli that induce EGR1. The human NAB2 gene has been localized to 12q13.3-14.1, within a chromosomal region that is thought to harbor a prostate tumor suppressor. We have examined the expression of NAB2 in human prostate carcinoma specimens. We show here that NAB2 protein expression is lost in a majority of primary prostate carcinoma specimens, including many samples that have high EGR1 levels. This loss occurs early in the tumorigenic process and is sustained, as it is seen in precursor prostatic intraepithelial neoplasia lesions as well as in metastases. Furthermore, loss of NAB2 did not correlate with the tumor grade or stage. Our findings suggest that high levels of EGR1 coupled with low levels of NAB2 can result in high, unrestrained EGR1 transcriptional activity in human prostate cancers.

Pubovaginal sling using cadaveric fascia and bone anchors: disappointing early results.

PURPOSE: Pubovaginal sling procedures offer highly effective treatment for patients with female stress urinary incontinence. A recent modification of this technique is the use of cadaveric fascia lata as a sling material supported with titanium anchors placed bilaterally in the pubic bone. We reviewed our experience with this procedure and assessed our outcome. MATERIALS AND METHODS: A total of 154 consecutive patients underwent a bone anchored, cadaveric fascia pubovaginal sling procedure by a single surgeon from July 1998 to June 1999. All patients were evaluated preoperatively with a detailed history, pelvic examination and radiographic or multichannel video urodynamic studies to diagnose stress urinary incontinence. Our technique begins with the nonincision placement of titanium bone anchors transvaginally into the pubic bone bilaterally. A 2 cm. wide tunnel is created bluntly beneath the vaginal epithelium between the 2 puncture sites with a right angle clamp. A 2 x 7 cm. strip of cadaveric fascia is then passed through the tunnel, into the retropubic space and secured to 2-0 polypropylene sutures attached to the anchors. After securing the sling, the transvaginal puncture sites are closed with 2-0 polyglactin sutures. Patients were seen postoperatively at 6 weeks, and 3 and 6-month followup. Patient age averaged 60 years (range 38 to 85), with an overall average length of followup from surgery of 10.6 months (range 6 to 16). All patients were mailed a self-administered questionnaire and participated in a telephone interview with an office nurse to retrospectively assess outcome and evaluate for recurrent stress urinary incontinence. Recurrent stress urinary incontinence was graded as 0-none, 1-rare, 2-moderate and 3-severe. Repeat pubovaginal sling procedure that was performed in patients with grades 2 to 3 stress urinary incontinence was considered a failure for the purpose of our study. RESULTS: Of all 154 patients 58 (37.6%) had recurrent moderate to severe (grades 2 to 3) stress urinary incontinence at followup. A total of 26 patients underwent a second pubovaginal sling procedure for a reoperation rate of 16.9%. Intraoperative findings at reoperation revealed the titanium anchors to be in position, the polypropylene sutures to be intact, and retropubic fibrosis and scarring of the urethropelvic ligament suggesting appropriate retropubic placement of the sling in all cases. Uniformly all allogenic cadaveric fascia used for sling material appeared to be fragmented, attenuated or simply absent. Average time to reoperation was 9 months (range 3 to 15). CONCLUSIONS: Early results using a bone anchored cadaveric fascia pubovaginal sling procedure were discouraging. Based on findings at reoperation, we attribute this result to the failure of our sling material and have abandoned the use of cadaveric fascia allografts in all pubovaginal slings at our institution.

Impaired prostate tumorigenesis in Egr1-deficient mice.

The transcription factor early growth response protein 1 (EGR1) is overexpressed in a majority of human prostate cancers and is implicated in the regulation of several genes important for prostate tumor progression. Here we have assessed the effect of Egr1 deficiency on tumor development in two transgenic mouse models of prostate cancer (CR2-T-Ag and TRAMP). Using a combination of high-resolution magnetic resonance imaging and histopathological and survival analyses, we show that tumor progression was significantly impaired in Egr1-/- mice. Tumor initiation and tumor growth rate were not affected by the lack of Egr1; however, Egr1 deficiency significantly delayed the progression from prostatic intra-epithelial neoplasia to invasive carcinoma. These results indicate a unique role for Egr1 in regulating the transition from localized, carcinoma in situ to invasive carcinoma.

Unusual histologic types of high-grade prostatic intraepithelial neoplasia.

High-grade prostatic intraepithelial neoplasia (HGPIN) is the most likely precursor proliferation of peripheral zone, moderately to poorly differentiated prostatic adenocarcinomas. The usual cell type of the epithelial lining of HGPIN is a glandular epithelial cell with characteristic nuclear abnormalities. Here we report nine cases of unusual types of HGPIN, including three cases of signet-ring cell HGPIN, one case of small cell neuroendocrine HGPIN, and five cases of HGPIN with distinctive mucinous features. The three examples of signet-ring cell PIN were all associated with an invasive primary signet-ring cell carcinoma of the prostate. The HGPIN assumed a classical tufted and micropapillary architectural growth pattern, with the constituent cells exhibiting a morphologic appearance identical to that of the invasive signet-ring cells. The intraepithelial and invasive signet-ring cells were mucin negative and were immunoreactive for prostate-specific antigen (PSA). A fourth case displayed a mixed intraepithelial glandular-small cell neoplastic proliferation, where intraepithelial small cells were histologically identical to surrounding invasive small cell carcinoma cells. The small cell HGPIN and invasive small cell carcinoma cells were positive for the neuroendocrine markers chromogranin, synaptophysin, and neuron-specific enolase. In five cases, mucinous distension of HGPIN glands, producing a flat pattern of the epithelial lining layer, comprised the third unusual pattern of HGPIN. These blue mucinous secretions were readily detected by hematoxylin and eosin staining and were composed of both neutral (periodic acid-Schiff-positive) and acidic (alcian blue-positive) mucins. Herein we document the existence of an intraepithelial proliferation of neoplastic cell types-small cell neuroendocrine and signet-ring cell-that are usually considered as stromal-invasive cells in the prostate. The presence of these rare prostatic cell types in both HGPIN and invasive carcinoma provides further support for a close relationship between HGPIN and invasive carcinoma of the prostate. All three unusual types of HGPIN-signet-ring cell, small cell neuroendocrine, and mucinous-are important to diagnostically recognize because of the strength of association of HGPIN with invasive carcinoma.

Delayed infection of a pelvic lymphocele following pelvic lymphadenectomy.

Pelvic lymphocele is an infrequent complication of pelvic surgery, usually presenting shortly after surgery. We report a case of an infected pelvic lymphocele presenting more than 1 year after a staging pelvic lymphadenectomy for adenocarcinoma of the prostate. This case illustrates that late infection of pelvic lymphoceles can occur following a pelvic lymphadenectomy and radical prostatectomy.

Adrenal involvement from renal cell carcinoma: predictive value of computerized tomography.

Although adrenal involvement from renal cell carcinoma is rare, removal of the adrenal during radical nephrectomy continues to be standard practice. To assess the actual need for adrenalectomy, we elected to evaluate whether malignant involvement of the adrenal gland could be reliably diagnosed preoperatively by a computerized tomogram (CT) of the abdomen. A blinded retrospective review of preoperative abdominal CT in 157 patients with renal cancer revealed an abnormality of the ipsilateral adrenal gland in 38. Histopathology confirmed malignant involvement of the adrenal in 10 patients. Significantly, all 119 adrenal glands judged to be normal on the preoperative CT were confirmed to be uninvolved by the renal cancer on histopathological study. We conclude that abdominal CT is reliable in the preoperative evaluation of the ipsilateral adrenal gland and assessment of its noninvolvement with renal carcinoma. In such cases adrenal sparing nephrectomy may be considered (76% of our patients). None of these 119 patients had either macroscopic or microscopic adrenal involvement. When the adrenal is not identified, displaced or enlarged on CT (24% of our patients) adrenalectomy should be routinely performed as part of radical nephrectomy. Even in this select group adrenal involvement was present in only 26% of the cases.

Laparoscopic live-donor nephrectomy.

Laparoscopic nephrectomy with ablative intent has been performed clinically. The current study aimed to determine whether a physiologically and anatomically intact kidney suitable for transplantation could be harvested laparoscopically. Three weeks after an ablative laparoscopic right nephrectomy, 15 pigs were divided into two groups: the study group (n = 10) underwent a laparoscopic live-donor left nephrectomy of the solitary kidney and conventional autotransplantation; the control group (n = 5) underwent an open live-donor left nephrectomy of the solitary kidney and conventional autotransplantation. All study kidneys underwent laparoscopic in situ hypothermic perfusion. The mean length of the left renal artery and vein were similar in the study and control groups: 3.1 cm and 3.4 cm, respectively, in the study group compared with 2.5 cm and 3.8 cm, respectively, in the control group (P = 0.5). No intraoperative renal vascular injuries or postoperative ureteral complications were noted in either group. Renal histopathologic examination immediately after live-donor nephrectomy and at 1 month post-transplant showed similar findings in the two groups. The mean serum creatinine at 7 and 30 days postoperatively was not significantly different: 2.1 mg/dL and 1.6 mg/dL, respectively, in the study group and 1.7 mg/dL, and 1.4 mg/dL, respectively, in the control group (P = 0.4). We conclude that laparoscopic live-donor nephrectomy can be performed safely and reproducibly in the porcine model.