Vena cava thrombectomy and primary repair after radical nephrectomy for renal cell carcinoma: single-center experience.

BACKGROUND: Inferior vena cava (IVC) reconstruction for locally advanced renal cell carcinoma (RCC) includes resection with and without interposition grafting, patch graft, or primary repair. The proposed benefits of lateral venorrhaphy and primary repair are avoidance of foreign material, a more expeditious repair, and preservation of lower extremity venous outflow. METHODS: A single-center retrospective review of 22 patients with RCC and IVC tumor thrombus treated with radical nephrectomy, lateral venorrhaphy, thrombectomy, and primary vena cava repair between July 2002 and June 2009 was carried out. Demographic data, diagnostic information, radiographic cross-sectional imaging, and procedural outcomes were examined. RESULTS: Among the 13 men and nine women, the mean age was 62.1 years (42-83); mean tumor size was 9.8 cm (3-17 cm), and 90% (n = 18) of the cases with RCC were identified pathologically as clear cell adenocarcinoma; on the basis of the classification system adopted by Neves, level I was for 50% (n = 11), level II for 32% (n = 7), level III for 9% (n = 2), and level IV for 9% (n = 2) of the patients. All patients underwent en bloc radical nephrectomy with tumor thrombus removal and primary IVC repair. Mean total operative time was 547.9 ± 138.5 minutes, whereas mean IVC cross-clamp time was 10.8 minutes (6-29 minutes). There were no intraoperative deaths or pulmonary embolism and all IVC margins were found to be pathologically negative. Postoperative complications included one pulmonary embolism, one exacerbation of chronic lymphedema, and two cases of new onset erectile dysfunction. Mean follow-up was 36.4 ± 23.2 months (6-92 months). There were no radiographic or clinically significant changes in mean IVC diameter during follow-up. Five late deaths (23%) occurred as a result of metastatic RCC over a mean period of 24 months (range, 12-48), but without any local recurrences. CONCLUSION: For advanced RCC with tumor thrombus extension into the IVC, lateral venorrhaphy and primary IVC repair avoids complicated caval reconstructions and results in high patency rates with a low local tumor recurrence rate.

Suppression of prostate tumor growth by U19, a novel testosterone-regulated apoptosis inducer.

Androgens control prostate homeostasis and regulate androgen response genes. Here, we report the identification and characterization of U19, a novel testosterone-regulated apoptosis inducer with tumor suppressive activity. U19 is an evolutionarily conserved protein expressed in many human tissues, with the most abundant expression in the prostate, bone marrow, kidney, and lymph nodes. Overexpression of U19 in 12 surveyed cell lines induced apoptosis, and new protein synthesis is required for apoptosis induction. Expression of U19 in xenograft prostate tumors markedly induced apoptosis and inhibited tumor growth in vivo. Consistent with its tumor-suppressive role, U19 down-regulation was observed in all of the surveyed prostate cancer cell lines and in 19 of 23 clinical human prostate tumor specimens. Loss of heterozygosity analysis revealed U19 allelic loss in 19 of the 23 specimens. Furthermore, two of the specimens had homozygous U19 deletions, and one specimen had hypermethylated U19 promoter, indicating that U19 can be inactivated genetically or epigenetically. These observations suggest that U19 is growth inhibitory and tumor suppressive and that the disruption of androgen-dependent growth inhibition via U19 down-regulation is commonly associated with prostate cancer progression.

Fifteen-year experience with renal cell carcinoma with associated venous tumor thrombus.

BACKGROUND: For patients with renal cell carcinoma with venous tumor thrombus (VTT), the importance of the extent of the VTT on survival has inconsistent published results. The aim of the study was to evaluate the prognostic value of the VTT on morbidity and mortality of our patients with renal cell carcinoma. METHODS: This was a single institution review of all patients who underwent resection of renal cell carcinoma with VTT over a 15-year period. RESULTS: Thirty-seven patients (26 men, 11 women) with a mean age of 61 years were analyzed. The majority of the cohort were of Neves level II (n = 19), while 8 were of Neves 0 (only renal vein) or I, and 10 were of Neves III (extending into retrohepatic cava) or IV (extending supradiaphragmatically). When compared with Neves 0-II patients, there were more Neves III-IV patients with operative time >3 hours (70% vs 30%), blood loss >2,000 mL (70% vs 33%), and intensive care unit stay longer than one day (60% vs 30%) (P ≤ .05 each). Mean follow-up was 58 months. The overall 5-year survival was 71%, and all 10 patients with Neves III-IV had survived since the operation. CONCLUSION: We found advanced tumor thrombus involvement did not impact long-term survival; however, cases with suprahepatic VTT had increased operative time, blood loss, and duration of hospital stay.

Implications of therapy choice on overall survival in metastatic renal cell carcinoma: a single institution experience.

PURPOSE: To compare the effect of high-dose interleukin-2 (HD IL-2) vs other cytokine therapies on 1-, 2, and 5-yr overall survival in patients with metastatic renal cell cancer (RCC). PATIENTS AND METHODS: We conducted a retrospective chart review of patients with untreated metastatic RCC treated by a single investigator. The different treatment groups included HD IL-2, low-dose IL-2 alone or in combination, interferon alpha alone and other therapies. The primary end point was survival from time of treatment. RESULTS: A total of 85 patients were studies with a median follow up of 13 mo (0.6-112.9). Median age at treatment was 59 yr with predominantly male patients and histology of clear cell type. Thirty-four percent received HD IL-2 and treatment was initiated less than 6 mo from the time of diagnosis in 66%. For all patients, median survival was 16 mo with a 5-yr survival of 12%. Two factors were good predictors of overall survival: Karnofsky performance status (KPS) of 100 (p < 0.0001) and soft tissue metastasis (p = 0.01). When comparing HD IL-2 to all other groups, median survival was 18 vs 14 mo and 1-yr survival was 74% vs 51%, respectively. CONCLUSION: HD IL-2 is associated with clinically meaningful improvement in median and 1-yr survival.

Dual regulation of proliferation and growth arrest in prostatic stromal cells by transforming growth factor-beta1.

In a preliminary study, we observed that TGF-beta1 induced both proliferation and growth arrest in prostatic stromal cells, depending on the concentration of TGF-beta1 used in the culture medium. In this study, we explored possible mechanisms of this dual effect of TGF-beta. Primary cultures of prostatic stromal cells, established from clinical surgical specimens and treated with low doses of TGF-beta1 (0.001-0.01 ng/ml), resulted in an increase in cell proliferation. The addition of neutralizing antibody against platelet-derived growth factor (PDGF)-BB, but not anti-PDGF-AA, abrogated this stimulatory effect of TGF-beta1. TGF-beta1 treatment resulted in a dose-related increase in PDGF-BB production as measured by ELISA. Cells underwent growth arrest at high concentrations of TGF-beta1 (1.0 and 10 ng/ml). An inhibitor of cyclin-dependent kinase (cdk), p15INK4b, was up-regulated at both transcript and protein levels in these cultures by TGF-beta1 in a dose-related manner as determined by RT-PCR and Western blot analysis. The transcript, but not the protein, for another cdk inhibitor, p21Cip1, was up-regulated with treatment of TGF-beta1 to these cells. Levels of other cdk inhibitors, such as p16INK4a and p27Kip1, were constitutively expressed in prostatic stromal cells and were not significantly affected by TGF-beta1 treatment. Finally, the growth arrest effect of TGF-beta1 was abrogated when antisense oligonucleotides to p15INH4b, but not p21Cip1, were added to the culture medium. These data indicate that the dual effect of TGF-beta1 is mediated, at least, by up-regulation of PDGF-BB and p15INK4b, respectively.

Overexpression of adrenomedullin gene markedly inhibits proliferation of PC3 prostate cancer cells in vitro and in vivo.

The expression of the gene encoding adrenomedullin (AM), a multifunctional peptide hormone, in the prostate is localized to the epithelial cells. Prostate cancer cells are derived from prostatic epithelial cells. To elucidate the potential role of the AM gene in prostate cancer progression, we have stably-transfected the PC3 human prostate cancer cell line with an AM gene expression vector. The AM-transfected PC3 sublines were studied along with parental and empty vector transfected PC3 cells as controls. The average level of AM in the conditioned media of AM-transfected cells was 0.959+/-0.113 nM, a physiologically relevant concentration. The ectopic expression of AM gene inhibited the proliferation of PC3 cells in culture dishes. In addition, anchorage-independent growth of the transfected sublines was virtually abolished in soft agar assays. Flow cytometry studies showed that overexpression of AM gene caused a very significant G(1)/G(0) cell cycle arrest. In vivo experiments demonstrated that AM gene expression markedly inhibited the growth of xenograft tumors in nude mice. Our in vivo and in vitro studies suggest that AM could strongly suppress the malignancy of prostate cancer cells, via autocrine and/or paracrine mechanisms.

Vitamin D deficiency predicts prostate biopsy outcomes.

PURPOSE: The association between vitamin D and prostate biopsy outcomes has not been evaluated. We examine serum vitamin D levels with prostate biopsy results in men with an abnormal prostate-specific antigen and/or digital rectal examination. EXPERIMENTAL DESIGN: Serum 25-hydroxyvitamin D (25-OH D) was obtained from 667 men, ages 40 to 79 years, prospectively enrolled from Chicago urology clinics undergoing first prostate biopsy. Logistic regression was used to evaluate the associations between 25-OH D status and incident prostate cancer, Gleason score, and tumor stage. RESULTS: Among European American (EA) men, there was an association of 25-OH D <12 ng/mL with higher Gleason score ≥ 4+4 [OR, 3.66; 95% confidence interval (CI), 1.41-9.50; P = 0.008] and tumor stage [stage ≥ cT2b vs. ≤ cT2a, OR, 2.42 (1.14-5.10); P = 0.008]. In African American (AA) men, we find increased odds of prostate cancer diagnosis on biopsy with 25-OH D < 20 ng/mL [OR, 2.43 (1.20-4.94); P = 0.01]. AA men demonstrated an association between 25-OH D < 12 ng/mL and Gleason ≥ 4+4 [OR, 4.89 (1.59-15.07); P = 0.006]. There was an association with tumor stage ≥ cT2b vs. ≤ cT2a [OR, 4.22 (1.52-11.74); P = 0.003]. CONCLUSIONS: In AA men, vitamin D deficiency was associated with increased odds of prostate cancer diagnosis on biopsy. In both EA and AA men, severe deficiency was positively associated with higher Gleason grade and tumor stage.

Overexpression of transforming growth factor ß1 in malignant prostate cells is partly caused by a runaway of TGF-ß1 auto-induction mediated through a defective recruitment of protein phosphatase 2A by TGF-ß type I receptor.

OBJECTIVES: To elucidate the mechanism of transforming growth factor (TGF)-ß1 overexpression in prostate cancer cells. METHODS: Malignant (PC3, DU145) and benign (RWPE1, BPH1) prostate epithelial cells were used. Phosphatase activity was measured using a commercial kit. Recruitment of the regulatory subunit, Bα, of protein phosphatase 2A (PP2A-Bα) by TGF-ß type I receptor (TßRI) was monitored by coimmunoprecipitation. Blockade of TGF-ß1 signaling in cells was accomplished either by using TGF-ß-neutralizing monoclonal antibody or by transduction of a dominant negative TGF-ß type II receptor retroviral vector. RESULTS: Basal levels of TGF-ß1 in malignant cells were significantly higher than those in benign cells. Blockade of TGF-ß signaling resulted in a significant decrease in TGF-ß1 expression in malignant cells, but not in benign cells. Upon TGF-ß1 treatment (10 ng/mL), TGF-ß1 expression was increased in malignant cells, but not in benign cells. This differential TGF-ß1 auto-induction between benign and malignant cells correlated with differential activation of extracellular signal-regulated kinase (ERK). Following TGF-ß1 treatment, the activity of serine/threonine phosphatase and recruitment of PP2A-Bα by TßRI increased in benign cells, but not in malignant cells. Inhibition of PP2A in benign cells resulted in an increase in ERK activation and in TGF-ß1 auto-induction after TGF-ß1 (10 ng/mL) treatment. CONCLUSIONS: These results suggest that TGF-ß1 overexpression in malignant cells is caused, at least in part, by a runaway of TGF-ß1 auto-induction through ERK activation because of a defective recruitment of PP2A-Bα by TßRI.

17Beta-estradiol at low concentrations acts through distinct pathways in normal versus benign prostatic hyperplasia-derived prostate stromal cells.

The aim of this study was to identify differential responses to low concentrations of 17beta-estradiol (E2) in primary stromal cell cultures derived from either normal organ donors or benign prostatic hyperplasia or hypertrophy (BPH) specimens. Furthermore, we sought to identify the potential mechanism of E2 action in these cell types, through either a genomic or nongenomic mechanism. We initially treated stromal cells derived from five normal prostates or five BPH specimens with low concentrations of E2 (0.001-1.0 nM) and analyzed their growth response. To determine whether genomic or nongenomic pathways were involved, we performed studies using specific estrogen receptor antagonists to confirm transcriptional activity or MAPK inhibitors to confirm the involvement of rapid signaling. Results of these studies revealed a fundamental difference in the mechanism of the response to E2. In normal cells, we found that a nongenomic, rapid E2 signaling pathway is predominantly involved, mediated by G protein-coupled receptor-30 and the subsequent activation of ERK1/2. In BPH-derived prostate stromal cells, a genomic pathway is predominantly involved because the addition of ICI 182780 was sufficient to abrogate any estrogenic effects. In conclusion, prostate stromal cells respond to far lower concentrations of E2 than previously recognized or examined, and this response is mediated through two distinct mechanisms, depending on its origin. This may provide the basis for new insights into the causes of, and possible treatments for, BPH.

Intra-operative pubic arch interference during prostate seed brachytherapy in patients with CT-based pubic arch interference of < or =1cm.

PURPOSE: There are only a few reports on the frequency of intra-operative pubic arch interference (I-PAI) during prostate seed brachytherapy (PB). MATERIALS AND METHODS: Two hundred and forty-three patients with a CT-based pubic arch interference (PAI) of < or =1 cm and a prostate volume of < or =50-60 cc underwent PB. Those patients requiring needle repositioning by > or =0.5 cm on the template were scored as having I-PAI. The incidence of I-PAI and its impact on biochemical control were analyzed. RESULTS: Intra-operative PAI was encountered in 47 (19.3%) patients. Forty two patients (17.3%) had I-PAI in 1-2 needles, two (0.8%) had I-PAI in four needles and three patients (1.2%) had I-PAI in six needles. Overall, 1.4% of needles required repositioning due to I-PAI. BMI>27 kg/m(2) and wider (>75 mm) pubic bone separation at mid ramus (PS-ML) were associated with a lower incidence of I-PAI. At a median follow-up of 50.1 months, the 3- and 5-year bPFS was 97.3% and 95.2%, respectively. The 5-year bPFS rates for patients with and without I-PAI were 95.6% and 95%, respectively (p=0.28). CONCLUSIONS: The use of CT-based PAI of < or =1cm as a selection criterion for PB is a simple and reliable method for minimizing the incidence of I-PAI and maintaining excellent biochemical control rates.

Topoisomerase II alpha expression in testicular germ cell tumors.

OBJECTIVES: Inhibitors of topoisomerase II alpha (TopoIIalpha), an enzyme with a crucial role in DNA maintenance, are included in the chemotherapy protocols for testicular germ cell tumors (GCTs). Despite the success of current chemotherapy regimens, a significant number of patients experience relapse. We analyzed TopoIIalpha expression in primary and metastatic testicular GCTs because this enzyme is a target for some antineoplastic agents. METHODS: Primary GCT specimens from 109 patients, including 57 seminomas and 52 mixed GCTs (41 embryonal carcinomas, 23 yolk sac tumors, 19 seminomas, 8 choriocarcinomas, 17 teratomas with immature elements, and 16 teratomas with mature elements), were obtained from our archives. The metastatic lesions from 11 of the patients with mixed GCTs included seven teratomas with mature components, five embryonal carcinomas, one yolk sac tumor, one choriocarcinoma, and one teratoma with immature components. Representative sections were subjected to immunohistochemistry with monoclonal antibody against TopoIIalpha, and the nuclear staining findings were evaluated. RESULTS: Most embryonal carcinoma (100%), yolk sac tumor (95%), seminoma (88%), and choriocarcinoma (62%) components of the GCTs were TopoIIalpha immunoreactive. None of the teratoma specimens with mature elements expressed TopoIIalpha. CONCLUSIONS: The results of our study have shown that TopoIIalpha is expressed in most seminomas, embryonal carcinomas, yolk sac tumors, and choriocarcinomas, suggesting a possible mechanism of sensitivity of these components to TopoIIalpha inhibitors. Teratomas with mature and immature elements expressed low levels of TopoIIalpha, which might contribute to their chemoresistance. These findings imply that the variable chemoresponsiveness of testicular GCTs could have an underlying molecular basis.

The p53 tumor suppressor gene and nuclear protein: basic science review and relevance in the management of bladder cancer.

PURPOSE: An extensive body of literature regarding p53 has accumulated during the last 2 decades. The cellular mechanisms of p53 are complex yet well-defined, whereas its clinical usefulness in the management of bladder cancer remains controversial. We outline the basic constitutive functions of p53 and summarize its current role in the management of transitional cell carcinoma of the bladder. MATERIALS AND METHODS: We conducted a MEDLINE based literature review concerning the fundamental mechanisms of p53 and its role in the management of bladder cancer. RESULTS: The p53 gene is a tumor suppressor gene that acts as "guardian of the genome." Many diverse cellular events, including DNA damage and hypoxia, activate the p53 gene. The p53 protein functions as a transcription factor, regulating downstream genes involved in cell cycle arrest, DNA repair and programmed cell death. Loss of p53 function confers genomic instability, impaired apoptosis and diminished cell cycle restraint. Therefore, p53 mutations select for certain critical features of malignancy. Alteration of P53 is the most common mutation in human cancer. Roughly half of all human malignancies, including many urological cancers, exhibit p53 mutations. In bladder cancer p53 mutations have been associated with higher tumor grade and advanced stage, as well as progression of superficial disease to muscle invasion. Moreover, p53 nuclear over expression appears to be an independent predictor of disease progression and decreased survival after cystectomy. CONCLUSIONS: The importance of p53 mutation in tumor cell biology is irrefutable. Wild-type p53 mediates imperative functions such as regulation of the cell cycle and programmed cell death. Deficiency of p53 function by mutation or inactivation abrogates normal cell cycle checkpoints and apoptosis, generating a favorable milieu for genomic instability and carcinogenesis. However, despite the manifest importance of p53 in human malignancy, its current role in the management of bladder cancer appears somewhat limited. A multitude of retrospective studies have associated p53 mutations with adverse outcomes in superficial and muscle invasive disease. Nonetheless, randomized prospective studies are needed to determine the potential clinical implications of p53 in bladder cancer.

Pigment epithelium-derived factor, a human testis epididymis secretory product, promotes human prostate stromal cell growth in culture.

PURPOSE: We identified and characterized unrecognized testicular secretory proteins that impact human prostate growth. MATERIALS AND METHODS: Human spermatocele fluid served as a source of testicular epididymal secretions and prostatectomy specimen benign prostatic hyperplasia stromal cells as the in vitro prostate growth promoting effects indicator. RMPI plus medium supplemented with 10% fetal bovine serum MALDI-TOF, MS FBS and ITS+ (Collaborative Research-Becton Dickinson, Bedford, Massachusetts) served as positive and negative controls, respectively. Whole and fractionated spermatocele fluid or specific proteins without and with select polyclonal or monoclonal antibodies were added to routine 6-day cultures. The observation of significantly increased 6-day cell counts compared with appropriate controls (p <0.05) was judged to reflect cell growth. Amino acid microsequencing and MALDI-TOF MS sequence analysis were done on persistent protein bands from active spermatocele fluid fractions. RESULTS: Whole and fractionated human spermatocele fluid increased stromal cell culture numbers significantly. Sequence analysis of 47 and 17 kDa 1-dimensional gel bands in the final active fraction identified a major peptide with sequence homology to human pigment epithelium-derived factor (PEDF). The presence of PEDF was confirmed by Western blot analysis. Addition of recombinant PEDF to incomplete medium significantly increased stromal cell culture number. PEDF antibodies neutralized or markedly decreased the stromal stimulating effect of spermatocele fluid and PEDF. CONCLUSIONS: The observations presented provide evidence for human testis/epididymis secretion of PEDF and for a PEDF in vitro growth promoting effect on benign prostatic hyperplasia stroma. The concept that testicular epididymal secretory proteins may influence normal and abnormal prostate growth warrants continued consideration.