FSH suppression and tumour control in patients with prostate cancer during androgen deprivation with a GnRH agonist or antagonist.

BACKGROUND: Gonadotropin releasing hormone (GnRH) antagonists suppress follicle-stimulating hormone (FSH) to lower levels than GnRH agonists. This may partially explain the differences between these agents on prostate cancer outcomes. In this post-hoc analysis, FSH and prostate specific antigen (PSA) responses and the impact of cross-over from leuprolide to degarelix were evaluated from a 1-year comparative study (CS21) and its extension study (CS21A). MATERIALS AND METHODS: Overall, 610 patients were enrolled in CS21, wherein PSA and FSH levels were evaluated monthly. CS21A evaluated 386 patients, including those previously treated with degarelix (n = 251) who continued to receive degarelix, and those previously treated with leuprolide (n = 135) who crossed-over to receive degarelix. PSA and FSH levels were evaluated in CS21A for 3 months after cross-over. The associations between measurements were assessed using Spearman's correlation coefficient. The impact of class variables on FSH suppression were evaluated using Analysis of Variance. RESULTS: Rapid PSA and FSH suppression was observed and maintained in the degarelix arm (CS21 and CS21A), while patients on leuprolide experienced rising PSA during CS21. Patients crossed-over from leuprolide to degarelix achieved a suppression of FSH and a significant PSA decrease. PSA and FSH levels were significantly (p < .05) correlated at months 1, 3, 6, 12 and 13 in the degarelix arm. CONCLUSIONS: Significant FSH suppression with GnRH antagonists may explain its advantage over GnRH agonists in terms of better prostate cancer control. The effect of profound FSH suppression is analogous to the need for profound testosterone suppression for tumor control.

Does mpMRI improve clinical criteria in selecting men with prostate cancer for active surveillance?

BACKGROUND: Active surveillance (AS) has excellent short to medium term outcomes in well-selected prostate cancer patients. Traditional biopsy-based selection criteria have been criticized for inaccurate determination of cancer grade and extent. We evaluated the incremental benefit of multiparametric magnetic resonance imaging (mpMRI) in patient selection using various AS criteria. METHODS: We retrospectively evaluated men who received mpMRI before radical prostatectomy between 2011 and 2014. Patients were classified as suitable for AS using four criteria: (1) Epstein, (2) National Comprehensive Cancer Network (NCCN) low-risk or (3) extended criteria (Gleason ⩽3+4, PSA ⩽15 ng/ml, clinical stage ⩽T2b) using clinical parameters. The incremental value of mpMRI was evaluated against the referent standard of surgical pathology in determining suitability for AS using sensitivity, specificity, likelihood ratios (LRs) and area under receiver operating curves (AUCs). RESULTS: We evaluated 208 men. Only one man fulfilled Epstein criteria (1) at pathology, who was neither identified using clinical criteria nor mpMRI. Using (2), clinical criteria had a sensitivity of 80%, specificity 75%, LR+ 3.3, LR- 0.3, AUC 0.78, while combined clinical-mpMRI criteria achieved a sensitivity of 80%, specificity 99.5% (P<0.01), LR+ 162, LR- 0.2 and AUC 0.90 (P<0.01 compared to clinical). Using (3), clinical criteria had a sensitivity of 74%, specificity 47%, LR+ 1.4, LR- 0.6, AUC 0.60, while combined clinical-mpMRI criteria achieved a sensitivity of 26% (P<0.01), specificity 97% (P<0.01), LR+ 8.3, LR- 0.8 and AUC 0.62 (P=0.85). CONCLUSIONS: Addition of mpMRI significantly improved selection of men for AS using NCCN low-risk criteria. For selecting men with limited prognostic grade group 2, mpMRI significantly improved specificity at the expense of sensitivity.

Prostatic carcinosarcoma 15 years after combined external beam radiation and brachytherapy for prostatic adenocarcinoma: a case report.

A 65-year-old man with a history of combined pelvic external beam radiation therapy (EBRT) and brachytherapy for prostatic adenocarcinoma 15 years prior underwent total pelvic exenteration for presumed rectal sarcoma with prostatic invasion. Pathology revealed carcinosarcoma of prostatic origin. This patient exhibited the longest reported interval between initial presentation with prostatic adenocarcinoma and development of carcinosarcoma. This case is also the first reported case of prostatic carcinosarcoma occurring after combined EBRT and brachytherapy. The increasing use of such combination high-dose radiation therapy may potentially lead to an increased incidence of secondary malignancies such as prostatic carcinosarcoma in the future.

Quantitative expression profile of PSGR in prostate cancer.

PSGR is a novel member of the G-protein-coupled olfactory receptor family. Our initial report showed predominant expression of the PSGR in human prostate gland and significant alterations of PSGR expression in primary prostate cancer (CaP) specimens. The aim of this study was to provide in-depth evaluations of the expression profile of PSGR in prostatic epithelial cells of CaP patients and to evaluate the association of PSGR expression characteristics with clinico-pathologic features. In total, 220 RNA specimens, from laser capture microdissected paired benign and malignant prostatic epithelial cells of 110 CaP patients, were analyzed for PSGR expression by quantitative real-time PCR. The differential expression of PSGR between the prostatic epithelial cells of malignant and benign glands was statistically significant (P<0.0001). Comparison of PSGR expression between paired benign and tumor cells revealed prostate tumor cell-specific overexpression in 67.2% of tumor specimens (74 of 110), decreased expression in 20.9% of tumor specimens (23 of 110) and no difference of PSGR expression between tumor and normal cells in 11.8% of specimens (13 of 110). In representative cases, PSGR expression patterns were independently confirmed by in situ RNA hybridization. The PSGR overexpression associated with higher percentage of pathologic stage, pT3, and a higher level of preoperative serum PSA. CaP cells of African-American CaP patients exhibited about two-fold increase of PSGR expression in comparison to the Caucasian American CaP patients. Strikingly high-percentage CaP cells overexpress PSGR warrants further studies of PSGR expression alterations to define subsets of CaPs.

Timing and patterns of recurrences and deaths from prostate cancer following adjuvant pelvic radiotherapy for pathologic stage T3/4 adenocarcinoma of the prostate.

To determine the timing and patterns of late recurrence after radical prostatectomy (RP) alone or RP plus adjuvant radiotherapy (RT). Between 1970 and 1983, 159 patients underwent RP for newly diagnosed adenocarcinoma of the prostate and were found to have positive surgical margins, extracapsular extension and/or seminal vesicle invasion. Of these, 46 received adjuvant RT and 113 did not. The RT group generally received 45-50 Gy to the whole pelvis, then a boost to the prostate bed (total dose of 55-65 Gy). In the RP group, 62% received neoadjuvant/adjuvant androgen deprivation vs 17% in the RT group. Patients were analyzed with respect to timing and patterns of failure. Only one patient was lost to follow-up. The median follow-up for surviving patients was nearly 20 years. The median time to failure in the surgery group was 7.5 vs 14.7 years in the RT group (P=0.1). Late recurrences were less common in the surgery group than the RT group (9 and 1% at 10 and 15 years, respectively vs 17 and 9%). In contrast to recurrences, nearly half of deaths from prostate cancer occurred more than 10 years after treatment. Deaths from prostate cancer represented 55% of all deaths in these patients. Recurrences beyond 10 years after RP in this group of patients were relatively uncommon. Despite its long natural history, death from prostate cancer was the most common cause of mortality in this population with locally advanced tumors, reflecting the need for more effective therapy.

Percentage of embryonal carcinoma and of vascular invasion predicts pathological stage in clinical stage I nonseminomatous testicular cancer.

We analyzed 92 clinical stage I nonseminomatous testicular germ cell tumors for primary tumor histological factors that would distinguish true pathological stage I disease (N = 54) from those patients who harbored occult disease and actually were later found to have pathological stage II disease (N = 38). Primary tumor pathological material was analyzed for vascular invasion, lymphatic invasion, tunical invasion, and quantitative determination of percentage of the primary tumor composed of embryonal carcinoma, yolk sac carcinoma, teratoma, and seminoma. Univariate logistic regression analyses revealed that vascular invasion (P = 0.0001), percentage of embryonal carcinoma (P = 0.0001), lymphatic invasion (P = 0.0001), and tunical invasion (P = 0.0013) were higher in pathological stage II and that percentage of teratoma (P = 0.0001) and of yolk sac carcinoma (P = 0.0174) were higher in stage I. Percentage of seminoma was not significant. Individually, these parameters were able to correctly predict occult disease 66.3 to 80.4% of the time. In multivariate logistic regression analysis, only vascular invasion and percentage of embryonal carcinoma remained significant, and a model using these two variables was able to correctly predict stage 85.9% of the time. Vascular invasion and determination of percentage of embryonal carcinoma should be assessed for all clinical stage I nonseminomatous germ cell tumor patients and the model presented herein can be used clinically to predict the likelihood of occult disease and dictate therapy.

Frequent detection of codon 877 mutation in the androgen receptor gene in advanced prostate cancers.

Prostatic tissue specimens derived from transurethral resections of patients with metastatic prostate cancer were analyzed for genetic alterations in the hormone-binding domain of the androgen receptor (AR) gene. Direct sequencing of the polymerase chain reaction-derived DNAs of 6 of 24 specimens revealed a codon 877 mutation (ACT-->GCT, Thr-->Ala) in the hormone-binding domain of the AR gene. This same AR mutation has been reported previously in a metastatic prostate cancer cell line, LNCaP, where this mutation confers upon the AR an altered ligand-binding specificity which is stimulated by estrogens, progestagens, and antiandrogens. It is possible that analogous to an activated/altered growth factor receptor oncogene, codon 877 mutant AR with altered ligand binding may provide a selective growth advantage in the genesis of a subset of advanced prostate cancer. Although estrogens are used infrequently, antiandrogens are used increasingly in hormonal therapy for patients with advanced prostate cancer. The stimulatory effect of these therapeutic agents on the codon 877 mutant AR further suggests that this frequently observed AR mutation may contribute to the treatment refractory disease.

PSGR, a novel prostate-specific gene with homology to a G protein-coupled receptor, is overexpressed in prostate cancer.

PSGR, a new prostate tissue-specific gene with homology to the G protein-coupled odorant receptor gene family, has been identified. Here we report the characteristics of the predicted protein sequence of PSGR and its prostate tissue specificity and expression profile in human prostate cancer and matched normal tissues. Using multiple tissue Northern blots from over 50 different tissues, PSGR expression was restricted to human prostate tissues. Paired normal and tumor specimens from 52 primary prostate cancers, obtained by laser capture microdissection or manual microdissection, were analyzed for PSGR expression by semiquantitative and real-time PCR assays. The differential expression of PSGR between normal and tumor tissues was highly significant (P < 0.001), and 32 of 52 (62%) matched prostate specimens exhibited tumor-associated overexpression of PSGR. Of note, there was very little or no expression of PSGR in many normal specimens in comparison with the generally high expression of PSGR seen in matched tumor specimens. In situ hybridization assays showed restricted PSGR expression in the epithelial cells of the normal and tumor tissue sections. Restricted expression of PSGR in prostatic epithelial cells, overexpression of the PSGR in a significant percentage of prostate cancers, and the predicted protein sequence of PSGR with seven transmembrane domains provide a foundation for future studies evaluating the potential of PSGR as a prostate cancer gene expression marker and the utility of PSGR protein as a novel target for developing immunotherapeutic strategies for prostate cancer.

A phase 2 multimodality trial of docetaxel/prednisone with sunitinib followed by salvage radiation therapy in men with PSA recurrent prostate cancer after radical prostatectomy.

BACKGROUND: In men with high Gleason PC and rapid PSA progression after surgery, failure rates remain unacceptably high despite salvage radiation. We explored a novel multimodality approach of docetaxel with anti-angiogenic therapy before salvage radiotherapy (RT). METHODS: This was a phase 2 single-arm prospective open-label trial with historic controls. Eligible men had a rising PSA of 0.1-3.0 ng ml(-1) within 4 years of radical prostatectomy, no metastases except resected nodal disease, no prior androgen-deprivation therapy (ADT) and Gleason 7-10. Men received four cycles of docetaxel 70 mg m(-2) every 3 weeks with low dose prednisone and sunitinib 37.5 mg daily for 14/21 days each cycle, with no ADT. Salvage prostate bed RT (66 Gy) started at day 100. The primary end point was progression-free survival (PFS) rate at 24 months. Safety data, quality of life (QOL) and dose-limiting toxicities (DLTs) were measured over time. RESULTS: Thirty-four men accrued in this multi-institutional clinical trial: 24% of men were node positive, 47% were Gleason 8-10, median PSA at entry was 0.54. The trial was terminated prematurely owing to excess DLTs (nine) including grade 3 hand-foot syndrome (n=4), neutropenic fever (n=2), AST increase (n=1), fatigue (n=1) and vomiting with diarrhea (n=1). PFS rate at 24 months was 51% (95% CI: 33, 67%) with a median PFS of 26.2 months (95% CI: 12.5, -). Six men (17.6%) had an undetectable PSA at 2 years. CONCLUSIONS: Sunitinib and docetaxel/prednisone followed by salvage RT resulted in excess pre-specified DLTs. Although nearly half of the men experienced durable disease control, efficacy was not greater than expected with radiation alone. The use of the intermediate end point of PFS in this salvage setting permitted an early decision on further development of this combination.

A novel human cancer culture model for the study of prostate cancer.

Research into molecular and genetic mechanisms underlying prostate carcinogenesis would be greatly advanced by in vitro models of prostate tumors representing primary tumors. We have successfully established an immortalized human prostate epithelial (HPE) cell culture derived from a primary tumor with telomerase. The actively proliferating early passaged RC-58T cells were transduced through infection with a retrovirus vector expressing the human telomerase catalytic subunit (hTERT). A high level of telomerase was detected in RC-58T/hTERT cells but not RC-58T cells. RC-58T/hTERT cells are currently growing well at passage 50, whereas RC-58T cells senesced at passage 7. RC-58T/hTERT cells exhibit transformed morphology. More importantly, these immortalized cells showed anchorage-independent growth as they formed colonies in soft agar and grew above the agar layer. Expression of androgen-regulated prostate specific gene NKX3.1 and epithelial specific cytokeratin 8 (CK8) but not prostate specific antigen (PSA) and androgen receptor was detected in RC-58T/hTERT cells. Prostate stem cell antigen (PSCA) and p16 were also expressed in this cell line. RC-58T/hTERT cells showed growth inhibition when exposed to retinoic acid and transforming growth factor (TGF)-beta1 known potent inhibitors of prostate epithelial cell growth. A number of chromosome alterations were observed including the loss of chromosomes Y, 3p, 10p, 17p, 18q and the gain of chromosomes 16 and 20. These results demonstrate that this primary tumor-derived HPE cell line retained its transformed phenotypes and should allow studies to elucidate molecular and genetic alterations involved in prostate cancer. This is the first documented case of an established human prostate cancer cell line from a primary tumor of a prostate cancer patient with telomerase.

p53 nuclear protein expression is an independent prognostic marker in clinically localized prostate cancer patients undergoing radical prostatectomy.

Immunohistochemical (IHC) staining for p53 protein nuclear expression was evaluated in archival paraffin-embedded radical prostatectomy specimens from 139 patients with clinically localized prostate cancer followed up from 1 to 8 (mean, 4) years. Elevated nuclear p53 protein expression was detected in 85 (61%) of 139 patients, being heterogeneous and focal in the majority of specimens. Only four specimens displayed homogeneous nuclear accumulation of p53 protein. Disease progression, most commonly prostate-specific antigen elevation, was noted in 46 (33%) patients, with 39 (85%) having positive p53 protein IHC stains. Conversely, 93 (67%) of 139 have not recurred, with 46 (49%) having positive p53. Of all 54 p53-negative patients, 47 (87%) have had no disease recurrence. An increased p53 protein IHC stain was associated with a higher pathological stage (T1 and T2, 51% versus >/=T3, 69%) and Gleason score 2-4, 17%; 5-7, 72%; and 8-10, 87.5%). Despite these associations, p53 IHC staining was an independent predictor of disease-free survival in a multivariate analysis of p53, age, race, stage, and grade. This study revealed that a majority of clinically localized prostate cancers heterogeneously express elevated nuclear levels of p53 protein in at least a subset of malignant cells, and that this expression is an independent predictor of disease progression in prostate cancer patients after radical prostatectomy.

Disparate results between proliferation rates of surgically excised prostate tumors and an in vitro bioassay using sera from a positive randomized controlled trial.

In vitro bioassay has been used extensively to test the effects of culturing cancer cells in sera from humans participating in dietary interventions, i.e, studies of modified intake of nutrients for the purpose of reducing cancer risk or progression. It has been hypothesized that cell proliferation rates determined by the in vitro bioassay indicate whether modification of dietary intake could decrease cancer cell growth in vivo. It has been suggested, however, that the in vitro bioassay may not correlate with tumor cell proliferation rates in prostate cancer. We investigated the concordance of cell proliferation rates from surgically excised prostate tumor tissue with the in vitro bioassay using sera from matched patients. We used samples from an earlier randomized clinical trial that showed that supplementation with flaxseed significantly inhibited prostate cancer cell proliferation rates in vivo as indicated by Ki67 staining in tumor specimens. Proliferation rates of LNCaP, DU145 and PC3 cell lines cultured in 10% human sera from participants in the flaxseed trial were determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Spearman's Rho correlation coefficients (ρ) indicated no association between Ki67 staining in prostate tumors and the in vitro bioassay for the three cell lines. These disparate findings suggest that the in vitro bioassay may not provide an accurate assessment of the environment in vivo.

Immunohistochemical and mutational analysis of the p53 tumour suppressor gene and the bcl-2 oncogene in primary testicular germ cell tumours.

The role of p53 in testicular germ cell tumours is still contradictory based on the finding of immunohistochemical overexpression at the protein level, but lack of mutations at the DNA level. In addition, p53 wild-type activity has been demonstrated in cell culture experiments. Overexpression of the proto-oncogene bcl-2 might block p53-induced apoptosis and might inhibit p53 functional activity. To clarify the apparent paradox with respect to p53 overexpression and lack of mutations, an immunohistochemical and mutational analysis of p53 and bcl-2 in TGCT was performed. Ten normal testes, 52 CIS and 151 clinical stage I nonseminomatous GCTs were included in our study. A commercially available anti-p53 polyclonal rabbit antibody and an anti-bcl-2-mouse monoclonal antibody were used to stain the 5pm sections. Staining was assessed by counting at least 500 cells from the area of the most intense staining in each tumour cell type, and this was scored semiquantitatively for intensity of staining on a 4 point scale. In addition, 30 primary GCTs were included in the mutational analysis: areas with p53 overexpression were identified and microdissected prior to DNA extraction. p53 exons 5-8 were amplified by polymerase chain reaction (PCR) followed by single strand conformation polymorphism analysis. Templates demonstrating band shifts on SSCP were subjected to direct DNA sequence analysis. None of the normal testes, 32/52 (62%) CIS, and 142/151 (94%) germ cell tumours exhibited p53 overexpression. p53 expression was significantly lower in mature teratomas (0.8 +/- 0.2) than in other germ cell tumour components (2.8 +/- 1.2, p > 0.001). PCR-SSCP did not reveal any missense mutations or deletions for the p53 gene. Bcl-2 protein expression was observed in none of the normal testes, in none of the CIS, and in 14/151 (9.3%) germ cell tumours. 13/14 germ cell tumours demonstrated bcl-2 expression only in the glandular and stromal elements of their teratomatous components whereas all other components were negative for bcl-2. Our results--p53 overexpression, lack of p53 mutations, undetectable bcl-2--are consistent with recent in vitro studies. High susceptibility of testicular cancer to drug-induced apoptosis appears to be the result of wild-type p53 and lack of bcl-2. Radiation and chemotherapeutic insensitivity of mature teratomas might be the result of bcl-2 overexpression and lack of p53 overexpression. Therefore, chemoresistance to DNA damaging agents might be reflected by the expression of p53 and bcl-2 and it might be useful to evaluate p53 and bcl-2 in primary tumours and metastatic lesions in order to identify patients early with primary or secondary chemoresistance.

Protein expression of p53, bcl-2, and KI-67 (MIB-1) as prognostic biomarkers in patients with surgically treated, clinically localized prostate cancer.

BACKGROUND: Protein expression in the primary tumor of the tumor suppressor gene p53 and the proto-oncogene bcl-2 have been shown to be prognostic biomarkers of cancer recurrence after radical prostatectomy in patients with clinically localized prostate cancer. Cancer cell proliferation as measured by immunohistochemical markers such as the MIB-1 antibody for Ki-67 has recently been suggested to be of prognostic value in prostate cancer. The goal of this study was to determine the clinical use of p53, Ki-67 (MIB-1), and bcl-2 immunohistochemical protein expression in the primary tumor as combined predictors of disease progression after radical prostatectomy (RP). METHODS: Protein expressions of p53, Ki-67, and bcl-2 were evaluated in archival paraffin-embedded RP specimens from 162 patients monitored from 1 to 10 years (mean, 4.5 years) and correlated to stage, grade, race, and serologic (prostate-specific antigen) recurrence after operation. RESULTS: Expression was detected in 112 (69.1%), 44 (27.2%), and 62 (38.3%) of 162 patients for p53 (1+ or greater), bcl-2 (1+ or greater), and Ki-67 (2+ or greater), respectively. Biomarker expressions were not correlated to age and race; however, all increased with increasing stage and grade. The degree of expression by percentage of malignant cells staining correlated to recurrence for p53 and Ki-67 but not for bcl-2. All three markers were correlated to raw and Kaplan-Meier recurrence by means of univariate analysis with recurrence estimates at 6 years of 60.7% versus 24.2%, 84.2% versus 38.6%, and 72.4% versus 30.6% comparing positive versus negative expression of p53, bcl-2, and Ki-67, respectively. p53 and bcl-2 remained as independent prognostic markers by Cox multivariate regression analysis. Although Ki-67 did not remain an independent marker, it added prognostic use in certain subsets of patients. CONCLUSIONS: p53, bcl-2, and Ki-67 (MIB-1) appear to be important biomarkers to predict recurrence in patients with clinically localized prostate cancer after RP, and all three biomarkers deserve further study.

Efficacy of radiographic chest imaging in patients with testicular cancer.

OBJECTIVE: To determine the efficacy of computed tomography of the chest (CTC) and plain radiograph (CXR) in the initial staging process of testicular germ cell tumors. METHODS: The medical records of 362 patients with testicular germ cell tumor treated at our center between January 1980 and August 1993 were reviewed with particular attention to initial chest screening studies. Two hundred one patients had both CXR and CTC, 24 CXR alone, and 20 CTC alone during initial staging. One hundred seventeen patients were excluded from analyses because of undergoing whole lung tomography (92), unknown staging (19), or inadequate follow-up (6). Analysis included findings based on abdominal staging results using computed tomography of the abdomen (CTA). RESULTS: Of the 201 patients who had both CTC and CXR, 117 (58.2%) had nonseminomas (NSGCT) and 84 (41.8%) had seminomas (SEM). Among the patients with NSGCT, 21 (17.9%) had chest metastasis, 16 (76.2%) of which were detected by CXR. The 5 that were missed on CXR had significant retroperitoneal disease documented by CTA and the knowledge of chest metastases potentially altered therapy in 2 patients. Only 2 of 84 (2.4%) patients with SEM had metastatic chest disease and both were identified by CXR. False-positive CTC following negative CXR resulted in costly and sometimes invasive additional procedures in 10 patients with NSGCT and 6 with SEM. None of the CXR-only patients had adverse consequences from the solitary study (at least 1 year follow-up). The CTC-only patients could have undergone CXR only and had similar outcome. CONCLUSIONS: CXR alone is preferable for initial chest staging in all patients with SEM and in patients with NSGCT with negative findings on CTA. CTC remains of slight benefit for patients with clinical Stage II and greater NSGCT and to evaluate further suspicious CXR findings in any patient, although it appears not to be necessary in patients who have clinical Stage I disease determined by CTA. These findings have important cost-saving implications.

Tortuous and aberrant external iliac artery precluding radical retropubic prostatectomy for prostate cancer.

A sixty-eight-year-old black man with clinical Stage A1 (T1a) adenocarcinoma of the prostate was found to have a tortuous and redundant left external iliac artery directly overlying the superior aspect of the prostate gland. The location of this blood vessel precluded radical retropubic prostatectomy. To our knowledge, this is the first reported example of this clinical situation. Computer-generated three-dimensional imaging from the computed tomography scan allowed accurate assessment of the vascular anomaly.

Adrenal cortical carcinoma with vena cava tumor thrombus requiring cardiopulmonary bypass for resection.

We believe this is the fifteenth case report of adrenal cortical carcinoma with tumor thrombus to the vena cava, and the fourth reported case of a left-side tumor propagating thrombus to the vena cava. The patient underwent successful resection which required cardiopulmonary bypass. The caval tumor thrombus was very friable and gelatinous, unlike many renal cell thrombi, and required special surgical considerations.

Transitional cell carcinomatous meningitis after M-VAC (methotrexate, vinblastine, doxorubicin, and cisplatin) chemotherapy.

The M-VAC (methotrexate, vinblastine, doxorubicin, and cisplatin) regimen has been utilized at our two institutions to treat 17 patients with advanced stage transitional cell carcinoma of the bladder. We report 2 cases of carcinomatous meningitis resulting from metastatic transitional cell carcinoma which occurred in patients treated with M-VAC. Review of the literature suggests that our experience with central nervous system metastases is not unique, and that treatment of advanced stage transitional cell carcinoma of the bladder with M-VAC may enhance the incidence of meningeal metastases. Carcinomatous meningitis, although rare, is a rapidly fatal manifestation of metastatic transitional cell carcinoma if left untreated. However, prompt diagnosis and early aggressive therapy may result in palliation and stabilization of neurologic status. We review the pathophysiology, diagnosis, and treatment of transitional cell carcinomatous meningitis.

Synchronous bilateral testis tumor: mixed germ cell and theca cell tumors.

Synchronous bilateral testis tumors of different histologic types are rare. All previous cases have demonstrated germ cell tumors on both sides. The simultaneous appearance of a germ cell tumor and a contralateral non-germ cell tumor has not been reported. We herein report a thirty-four-year-old man who presented with a mixed non-seminomatous germ cell tumor of the left testis and theca cell tumor of the right testis.

Prospective use of free prostate-specific antigen to avoid repeat prostate biopsies in men with elevated total prostate-specific antigen.

OBJECTIVES: We prospectively evaluated whether free PSA improves the specificity of PSA and can be useful as a clinical guide to avoid repeat prostate biopsies in patients with persistent PSA elevations, normal digital rectal examinations, and previous negative prostate biopsies. METHODS: Sixty-seven men with persistent PSA elevations (median 9.5, range 4.1-24.8 ng/mL), normal digital rectal examinations and two or more prior sextant biopsies (mean 2.8) had serum collected for measurement of total and free PSA. All patients were rebiopsied to determine the receiver operating characteristics of total PSA versus percent free PSA for prostate cancer detection. RESULTS: The study biopsy identified 11 prostate cancer cases. The median percent free PSA was significantly higher at 18.0% among men without prostate cancer compared to 6.7% in men with prostate cancer (P < 0.00005). When sensitivity was plotted against 1-specificity, the area under the receiver operating characteristic curve for percent free PSA was 0.93, compared to 0.69 for free PSA density, 0.66 for PSA density, and 0.51 for PSA. In patients with elevated total PSA levels, normal digital rectal examinations and two prior negative sets of sextant prostate biopsies, a cutoff of 10% free PSA would maintain sensitivity at 91% with a corresponding specificity of 86%. CONCLUSIONS: Selective measurement of percent free PSA can significantly improve the specificity of prostate cancer screening with PSA. A low percent free PSA (< 10%) appears to be a powerful predictor of prostate cancer even after two negative prostate biopsies.