Twelve-month prostate volume reduction after MRI-guided transurethral ultrasound ablation of the prostate.

PURPOSE: To quantitatively assess 12-month prostate volume (PV) reduction based on T2-weighted MRI and immediate post-treatment contrast-enhanced MRI non-perfused volume (NPV), and to compare measurements with predictions of acute and delayed ablation volumes based on MR-thermometry (MR-t), in a central radiology review of the Phase I clinical trial of MRI-guided transurethral ultrasound ablation (TULSA) in patients with localized prostate cancer. MATERIALS AND METHODS: Treatment day MRI and 12-month follow-up MRI and biopsy were available for central radiology review in 29 of 30 patients from the published institutional review board-approved, prospective, multi-centre, single-arm Phase I clinical trial of TULSA. Viable PV at 12 months was measured as the remaining PV on T2-weighted MRI, less 12-month NPV, scaled by the fraction of fibrosis in 12-month biopsy cores. Reduction of viable PV was compared to predictions based on the fraction of the prostate covered by the MR-t derived acute thermal ablation volume (ATAV, 55°C isotherm), delayed thermal ablation volume (DTAV, 240 cumulative equivalent minutes at 43°C thermal dose isocontour) and treatment-day NPV. We also report linear and volumetric comparisons between metrics. RESULTS: After TULSA, the median 12-month reduction in viable PV was 88%. DTAV predicted a reduction of 90%. Treatment day NPV predicted only 53% volume reduction, and underestimated ATAV and DTAV by 36% and 51%. CONCLUSION: Quantitative volumetry of the TULSA phase I MR and biopsy data identifies DTAV (240 CEM43 thermal dose boundary) as a useful predictor of viable prostate tissue reduction at 12 months. Immediate post-treatment NPV underestimates tissue ablation. KEY POINTS: • MRI-guided transurethral ultrasound ablation (TULSA) achieved an 88% reduction of viable prostate tissue volume at 12 months, in excellent agreement with expectation from thermal dose calculations. • Non-perfused volume on immediate post-treatment contrast-enhanced MRI represents only 64% of the acute thermal ablation volume (ATAV), and reports only 60% (53% instead of 88% achieved) of the reduction in viable prostate tissue volume at 12 months. • MR-thermometry-based predictions of 12-month prostate volume reduction based on 240 cumulative equivalent minute thermal dose volume are in excellent agreement with reduction in viable prostate tissue volume measured on pre- and 12-month post-treatment T2w-MRI.

Extracellular vesicles such as prostate cancer cell fragments as a fluid biopsy for prostate cancer.

Extracellular vesicles (EVs) are cell-derived vesicles generated through a process of cell membrane shedding or storage vesicle release, as occurs during apoptosis, necrosis or exocytosis. Initially perceived as cellular by-products or 'dust' of insignificant biological importance, recent research has shed light on the role of EVs as mediators of intercellular communication, blood coagulation and disease progression. The prostate is a source of EVs and their abundance in complex biological fluids such as plasma, serum and urine make them compelling entities for a 'fluid biopsy'. As such, prostate cancer cell fragments (PCCF) are EVs generated by the tumor resident within the prostate and are also present in blood, expressing a portion of biomarkers representative of the primary tumor. High-throughput analytical techniques to determine biomarker expression on EVs is the last hurdle towards translating the full potential of prostate EVs for clinical use. We describe current state-of-the-art methods for the analysis of prostate-derived EVs in patient fluids such as plasma and the challenges that lie ahead in this emerging field of translational research.

3D prostate histology reconstruction: an evaluation of image-based and fiducial-based algorithms.

PURPOSE: Evaluation of in vivo prostate imaging modalities for determining the spatial distribution and aggressiveness of prostate cancer ideally requires accurate registration of images to an accepted reference standard, such as histopathological examination of radical prostatectomy specimens. Three-dimensional (3D) reconstruction of prostate histology facilitates these registration-based evaluations by reintroducing 3D spatial information lost during histology processing. Because the reconstruction accuracy may constrain the clinical questions that can be answered with these data, it is important to assess the tradeoffs between minimally disruptive methods based on intrinsic image information and potentially more robust methods based on extrinsic fiducial markers. METHODS: Ex vivo magnetic resonance (MR) images and digitized whole-mount histology images from 12 radical prostatectomy specimens were used to evaluate four 3D histology reconstruction algorithms. 3D reconstructions were computed by registering each histology image to the corresponding ex vivo MR image using one of two similarity metrics (mutual information or fiducial registration error) and one of two search domains (affine transformations or a constrained subset thereof). The algorithms were evaluated for accuracy using the mean target registration error (TRE) computed from homologous intrinsic point landmarks (3-16 per histology section; 232 total) identified on histology and MR images, and for the sensitivity of TRE to rotational, translational, and scaling initialization errors. RESULTS: The algorithms using fiducial registration error and mutual information had mean ± standard deviation TREs of 0.7 ± 0.4 and 1.2 ± 0.7 mm, respectively, and one algorithm using fiducial registration error and affine transforms had negligible sensitivities to initialization errors. The postoptimization values of the mutual information-based metric showed evidence of errors due to both the optimizer and the similarity metric, and variation of parameters of the mutual information-based metric did not improve its performance. CONCLUSIONS: The extrinsic fiducial-based algorithm had lower mean TRE and lower sensitivity to initialization than the intrinsic intensity-based algorithm using mutual information. A model relating statistical power to registration error for certain imaging validation study designs estimated that a reconstruction algorithm with a mean TRE of 0.7 mm would require 27% fewer subjects than the method used to initialize the algorithms (mean TRE 1.3 ± 0.7 mm), suggesting the choice of reconstruction technique can have a substantial impact on the design of imaging validation studies, and on their overall cost.

The clinical significance of in-depth pathological assessment of extraprostatic extension and margin status in radical prostatectomies for prostate cancer.

Despite recent Level 1 evidence on the benefits of adjuvant radiotherapy for locally advanced prostate cancer (PCa), the timing and decision to administer adjuvant radiotherapy post-radical prostatectomy (post-RP) remains debatable, particularly for patients with focal extraprostatic extension (EPE) and/or focal positive surgical margins (PSMs). In this study, we assess the utility of detailed pathological assessment of EPE and PSM, as this may influence the criteria for instituting adjuvant radiotherapy. A total of 148 RP cases (1993-2001) were identified retrospectively as having EPE and/or PSM. All slides were re-reviewed, incorporating recent proposals by the Collage of American Pathologists (CAP) for the reporting of EPE and PSM, and correlated with clinical data. Both EPE and PSM were found to be independent predictors of biochemical failure (BCF); however, only EPE was associated with metastasis and death. BCF was also more likely to be associated with cases that had non-focal EPE than focal EPE. Similarly, non-focal PSM cases had a significantly higher risk of BCF than focal cases. Our study confirms the value of detailed pathological assessment of EPE and PSM post-RP. The results support the concept of selective adjuvant radiotherapy in patients with EPE and PSM, based on focality and extent.

Randomized trial comparing cryoablation and external beam radiotherapy for T2C-T3B prostate cancer.

The objective was to evaluate the relative efficacy of cryoablation (CRYO) versus external beam radiation (EBRT) for clinically locally advanced prostate cancer in a randomized clinical trial. Patients with histologically proven, clinically staged as T2C, T3A or T3B disease were randomized with 6 months of perioperative hormone therapy to one of the two procedures. Owing largely to a shift in practice to longer term adjuvant hormonal therapy and higher doses of radiation for T3 disease, only 64 out of the planned 150 patients were accrued. Twenty-one of 33 (64%) in the CRYO group and 14 of 31 (45%) in the EBRT-treated group who had met the ASTRO definition of failure were also classified as treatment failure. The mean biochemical disease-free survival (bDFS) was 41 months for the EBRT group compared to 28 months for the CRYO group. The 4-year bDFS for EBRT and CRYO groups were 47 and 13%, respectively. Disease-specific survival (DSS) and overall survival (OS) for both groups were very similar. Serious complications were uncommon in either group. EBRT patients exhibited gastrointestinal (GI) adverse effects more frequently. Taking into account the relative deficiency in numbers and the original trial design, this prospective randomized trial indicated that the results of CRYO were less favorable compared to those of EBRT, and was suboptimal primary therapy in locally advanced prostate cancer.

Malignancy in horseshoe kidneys: review and discussion of surgical implications.

OBJECTIVE: Horseshoe kidney is one of the most common congenital anomalies of renal structure. Not infrequently, surgical management of both benign and malignant disorders is required in patients with horseshoe kidney due to the susceptibility to certain conditions. The literature suggests a greater proclivity to certain renal tumors with this anomaly. We present three cases of malignancy in horseshoe kidneys. The unique technical challenges presented by these cases and the surgical approaches are discussed. METHODS: Three patients with tumors involving horseshoe kidneys are reviewed and their management discussed. RESULTS: Two patients were found to have renal cell carcinoma (RCC) and one had transitional carcinoma (TCC). Computed tomography (CT) and angiography were used in the work-up and preoperative planning of these cases. One patient with RCC received pre-operative renal artery embolization. Partial nephrectomy was performed in each patient with an aim at early vascular control of the tumors, identification of the collecting systems and ureters, as well as ensuring a 1 cm surgical margin. No patient required dialysis post-operatively. One patient died in the early post-operative period of a myocardial infarction; one patient developed brain metastases 18 months post-operatively, received palliative radiation and is alive 42 months after surgery; the other patient was free of disease for approximately 36 months but recently developed osseous metastases to her pelvis. CONCLUSIONS: Techniques developed for partial nephrectomy may be used in the treatment of tumors in horseshoe kidneys. Survival is related to the grade and stage of disease.

Prostate targeting: PSP94 gene promoter/enhancer region directed prostate tissue-specific expression in a transgenic mouse prostate cancer model.

To date, only a few prostate-specific vector genes have been tested for prostate targeting in gene therapy of prostate cancer (CaP). Current clinical trials of gene therapy of CaP utilize the only two available vector genes with a combination of a rat probasin promoter and a human PSA promoter sequence in an adenovirus vector to target CaP. There is an urgent need to establish additional vector gene systems to sustain and propagate the current research. Since PSP94 (prostate secretory protein of 94 amino acids) is one of the three most abundant proteins secreted from the human prostate and is generally considered to be prostate tissue-specific in both human and rodents, we performed a transgenic experiment to assess the promoter/enhancer region of PSP94 gene-directed prostate targeting. Firstly, a series of progressive deletion mutants of a 3.84 kb PSP94 gene promoter/enhancer region (including parts of the intron 1 sequence) linked with a reporter LacZ gene was constructed and assessed in vitro in cell culture. Next, transgenic mice were generated with two transgene constructs using the SV40 early region (Tag oncogene) as a selection marker. PSP94 gene promoter/enhancer region-directed SV40 Tag expression specifically in the mouse was demonstrated in three breeding lines (A, B, C, n = 374) by immunohistochemistry staining of Tag expression. Specific targeting to the prostate in the PSP94 gene-directed transgenic CaP model was characterized histologically by correlation of SV40 Tag-induced tumorigenesis (tumor grading) with puberty and age (10-32 weeks). Prostatic hyperplasia was observed as early as 10 weeks of age, with subsequent emergence of prostatic intraepithelial neoplasia (PIN) and eventually high grade carcinoma in the prostate. The PSP94 transgenic mouse CaP model was further characterized by its tumor progression and metastatic tendency at 20 weeks of age and also by its responsiveness and refractoriness to androgen manipulation. This study indicates that the PSP94 gene promoter/enhancer has the potential for prostate specific targeting and may ultimately be of use in gene therapy of CaP.

Mycobacterial cell wall extract for treatment of carcinoma in situ of the bladder.

PURPOSE: Bacillus Calmette-Guerin (BCG) established immunotherapy as an effective modality for carcinoma in situ of the bladder and remains the most effective agent for treatment. However, as a live organism it has the potential for undesirable side effects and toxicity. This result has led to the search for other active and safer biological response modifiers. We investigated the efficacy of a mycobacterial cell wall extract (MCWE) from Mycobacterium phlei, which does not contain live bacteria, for management of carcinoma in situ of the bladder in humans. MATERIALS AND METHODS: The requirement for an emulsified preparation was investigated with photon correlation spectroscopy to determine the stability of the bacterial fragments. A total of 61 patients with histologically documented carcinoma in situ completed the study. Cell wall extract from M. phlei suspended in oil droplets to form an emulsion were instilled into the bladder at a dose of 4 mg. once weekly for 6 weeks and then monthly for 1 year. Response assessment was performed at 3-month intervals. Complete response to treatment indicated the absence of endoscopic and histological evidence of carcinoma in situ. Partial responders were those cases in which cystoscopy and biopsies were negative but cytology was suspicious for malignant cells. All other cases were considered failures. RESULTS: The need for an emulsified suspension of the cell wall extract was confirmed by the demonstration that the cell wall extract alone in urine aggregated, whereas the MCWE emulsion had remained stable. Kaplan-Meier estimates showed negative cystoscopy and biopsies in 62.5% at 12, 49.3% at 24 and 41.1% of patients at 60 weeks after therapy. After this point the number of responders had remained stable. Excellent tolerance with minimal toxicity was observed. CONCLUSIONS: Our study demonstrates clinical activity of low doses of MCWE against human bladder cancer. The results observed at the dosage used in our trial are less than those observed with live BCG. However, MCWE has a better toxicity profile and can be instilled in the presence of a disrupted urothelium. It also appears to exhibit activity in patients in whom BCG has failed.

Randomized comparative study of 3 versus 8-month neoadjuvant hormonal therapy before radical prostatectomy: biochemical and pathological effects.

PURPOSE: A prospective phase 3 trial was initiated to determine whether 8 compared with 3-month neoadjuvant hormonal therapy reduces prostate specific antigen (PSA) recurrence rates after radical prostatectomy. Our interim analysis includes secondary end points of differences in biochemistry, pathology and adverse events between the 2 groups. MATERIALS AND METHODS: Men with clinically confined prostate cancer were randomized to receive 7.5 mg. leuprolide intramuscularly monthly and 250 mg. flutamide orally 3 times daily for 3 or 8 months before radical prostatectomy. Our study was powered to detect a 35% decrease in PSA recurrence, assuming a 30% recurrence rate in the 3-month arm after 3 years. RESULTS: A total of 547 men were randomized between August 1995 and April 1998. Men in the 8 and 3-month groups were equally stratified for T stage (29% T1c, 70% T2), Gleason grade (68% less than 4, 32% 4 or greater) and pretreatment PSA (63% less than 10, 27% 10 to 20 and 10% greater than 20 microg./l.). Mean pretreatment PSA was slightly higher in the 8-month compared with the 3-month group (11.64 versus 9.95 microg./l., respectively, p = 0.0539). A total of 44 men withdrew from study before surgery and, therefore, were nonevaluable. Preoperative PSA nadir was less than 0.1 microg./l. in 43.3% versus 75.1% (p <0.0001), and 0.3 microg./l. or greater in 21% versus 9.2% after 3 versus 8 months, respectively (p <0.0006). Mean serum PSA decreased 98% to 0.12 microg./l. after 3 months, with a further 57% to 0.052 microg./l. from 3 to 8 months. Transrectal ultrasound determined that prostatic volume decreased 37% from a mean of 40.6 to 25.4 cc after 3-month neoadjuvant hormonal therapy (p = 0.0001) and a further 13% to 22.2 cc after 8 months (p = 0.03). Mean hemoglobin decreased 15% (148.2 to 125.4 gm./dl.) after 3-month neoadjuvant hormonal therapy but stabilized thereafter. Radical prostatectomy was completed in 500 men, while surgery was aborted intraoperatively in 3. Positive margin rates were significantly lower in the 8 than 3-month group (12% versus 23%, respectively, p = 0.0106). There were no fatal adverse events and no differences between the 2 groups in the severity or causality (p = 0.287, 0.0564) of adverse events, or incidence of increased liver enzymes or diarrhea (p = 0.691, 0.288, respectively). However, men in the 8-month group noticed a higher number of newly reported adverse events (4.5 versus 2.9, p <0.0001) and higher incidence of hot flushes than the 3-month group (87% versus 72%, respectively, p <0.0001). CONCLUSIONS: Ongoing biochemical and pathological regression of prostate tumors occurs between 3 and 8 months of neoadjuvant hormonal therapy, suggesting that the optimal duration of neoadjuvant hormonal therapy is longer than 3 months. Longer followup is needed to determine whether longer therapy alters PSA recurrence rates.

Molecular determination of perivesical and lymph node metastasis after radical cystectomy for urothelial carcinoma of the bladder.

PURPOSE: Current methods used to determine the pathological stage of the primary tumor and associated lymphatics after radical cystectomy are tedious, costly, and may lack the sensitivity afforded by molecular approaches such as reverse transcription-PCR (RT-PCR) for markers specific for urothelial tissue such as the uroplakin II (UPII) gene. Thus, we sought to evaluate an objective and sensitive molecular approach for the assessment of perivesical extension and lymph node status after radical cystectomy, based on the detection of UPII expression using RT-PCR and compare this assay to standard clinical and pathological examination. EXPERIMENTAL DESIGN: From November 1999 to September 2000, 27 patients with clinical T(a)-T(3)N(0)M(0) urothelial bladder cancer underwent radical cystectomy, 19 (70%) of which also had pelvic lymphadenectomy. At the completion of cystectomy, systematic biopsies of the external surface of the bladder specimen as well as from the largest palpable lymph node found at lymphadenectomy were obtained for molecular analysis. RT-PCR analysis for UPII mRNA was carried out on these biopsy specimens, and results were compared with data obtained from conventional pathological examination. RESULTS: Pathologically organ-confined tumors had a 42% (5 of 12) incidence of positive signals in the perivesical tissues and 17% (1 of 7) in the lymph nodes. Corresponding percentages for pT(3a)N(0) and pT(3b)-T(4)N(0) lesions were 67% (4 of 6)/25% (1 of 4) and 67% (4 of 6)/33% (2 of 6), respectively. Overall, pathologically node-negative cancers had a perivesical positivity rate of 54% (13 of 24) and a lymph node positivity rate of 25% (4 of 16). All patients with pathologically positive nodes had positive UPII signals in the lymph node sample. CONCLUSIONS: This molecular assay aimed at assessing perivesical extension and lymph node status after radical cystectomy appears to identify patients that may harbor residual disease not appreciated by conventional histology. Larger studies with 5-7-year follow-up will be required to determine the prognostic significance of such molecular information.

Results of salvage cryoablation of the prostate after radiation: identifying predictors of treatment failure and complications.

PURPOSE: We conduct a critical evaluation of cryoablation of prostate cancer after failure of full dose radiotherapy to identify predictors of treatment failure and complications. MATERIALS AND METHODS: A total of 125 cryoablation procedures were performed in 118 patients with proved local recurrence after full dose radiotherapy. Followup includes serial prostate specific antigen (PSA) and biopsy at 6,12 and 24 months. Kaplan-Meier plots were constructed for different PSA cutoffs. We separately analyzed different cohorts based on T stage, Gleason score, PSA before cryoablation and endocrine therapy status. RESULTS: Of the 118 patients 114 had serum PSA nadir less than 0.5 ng./ml. Median followup was 18.6 months (range 3 to 54). Of the biopsy cores 3.1% (23 of 745) from 7 patients contained persistent viable cancer. Kaplan-Meier plots showed patients free of histological failure leveling at 87% and free from biochemical failure at 68%, 55% and 34%, respectively, with PSA greater than 4, 2 and 0.5 ng./ml. PSA greater than 10 ng./ml. before cryoablation, Gleason score 8 or greater before radiation and stage T3/T4 disease appeared to predict an unfavorable biochemical outcome. Serious complications included 4 rectourethral fistulas (3.3%) and severe incontinence (6.7%). Strong predictors of complications included bulky disease for fistulas and prior transurethral surgery. CONCLUSIONS: Salvage cryoablation after radiation can achieve reasonable biochemical and histological results with acceptable morbidity. Cryoablation appears to be a reasonable treatment option for this patient population with few viable therapeutic options, provided vigorous patient selection criteria are adhered to.

Methods to improve efficacy of intravesical mitomycin C: results of a randomized phase III trial.

BACKGROUND: Intravesical chemotherapy (i.e., placement of the drug directly in the bladder) with mitomycin C is beneficial for patients with superficial bladder cancer who are at high risk of recurrence, but standard therapy is empirically based and patient response rates have been variable, in part because of inadequate drug delivery. We carried out a prospective, two-arm, randomized, multi-institutional phase III trial to test whether enhancing the drug's concentration in urine would improve its efficacy. METHODS: Patients with histologically proven transitional cell carcinoma and at high risk for recurrence were eligible for the trial. Patients in the optimized-treatment arm (n = 119) received a 40-mg dose of mitomycin C, pharmacokinetic manipulations to increase drug concentration by decreasing urine volume, and urine alkalinization to stabilize the drug. Patients in the standard-treatment arm (n = 111) received a 20-mg dose without pharmacokinetic manipulations or urine alkalinization. Both treatments were given weekly for 6 weeks. Primary endpoints were recurrence and time to recurrence. Treatment outcome was examined by use of Kaplan-Meier analysis with log-rank tests. Statistical tests were two-sided. RESULTS: Patients in the two arms did not differ in demographics or history of intravesical therapy. Dysuria occurred more frequently in the optimized arm but did not lead to more frequent treatment termination. In an intent-to-treat analysis, patients in the optimized arm showed a longer median time to recurrence (29.1 months; 95% confidence interval [CI] = 14.0 to 44.2 months) and a greater recurrence-free fraction (41.0%; 95% CI = 30.9% to 51.1%) at 5 years than patients in the standard arm (11.8 months; 95% CI = 7.2 to 16.4 months) and 24.6% (95% CI = 14.9% to 34.3%) (P =.005, log-rank test for time to recurrence). Improvements were found in all risk groups defined by tumor stage, grade, focality, and recurrence. CONCLUSIONS: This study identified a pharmacologically optimized intravesical mitomycin C treatment with statistically significantly enhanced efficacy.

Rodent PSP94 gene expression is more specific to the dorsolateral prostate and less sensitive to androgen ablation than probasin.

To date, the rodent ventral prostate (VP) has been the focus of many studies on androgen action, less attention has been directed to the lateral prostate (LP) and the dorsal prostate (DP). The rodent VP has no clear homologous counterpart in the human prostate. The rodent LP and DP is the only prostate lobe comparable to the peripheral zone of the human prostate, where hormone-induced prostate cancer mainly occurs. To explore its utility for prostate targeting, we have studied the gene expression of PSP94 with rat probasin (rPB), a gene commonly used for prostate targeting in prostate cancer research and a gene typically responsive to androgen regulation. Firstly, we demonstrated PSP94 gene transcription being more specific to the LP and DP lobes than rPB, where rPB RNA was detected in the LP and DP and other lobes at different levels. Secondly, we found that PSP94 gene transcription decreased relatively slowly in response to androgen deprivation but recovered rapidly in response to testosterone replacement after complete ablation of PSP94 transcription. In the VP, gene transcripts of rPB were specifically responsive to androgen deprivation; however, they responded relatively slowly in the LP and DP. RNase protection experiments indicated that the slow response was not due to abnormal persistence of PSP94 messenger RNA specifically in the DP and LP lobes in comparison with rPB. Thirdly, Western blot analysis revealed that both PSP94 and rPB expression is specific to the LP and DP at the protein level, exhibiting slow responses to testosterone replacement after castration. We conclude that PSP94 gene expression at the transcriptional level is more specific to the LP and DP than rPB and thus less sensitive to androgen ablation. This may have clinical implications for strategies to target the prostate in cancer therapy.

Use of the internet for self-education by patients with prostate cancer.

OBJECTIVES: To define use of the Internet for self-education by a cohort of patients with prostate cancer and to arrive at some relevant recommendations for the practicing urologist. Little has been published about patient use of the Internet in investigating their health conditions, specifically prostate cancer. METHODS: In April 1999, a self-administered, anonymous questionnaire was mailed to 490 men with the diagnosis of prostate cancer. Institutional ethics approval was obtained. Standard statistical analyses were performed. RESULTS: Of 490 questionnaires mailed, a total of 312 (63.7%) were available for analysis. Forty-eight percent of patients were 60 to 69 years old. Fifty-two percent of patients had never used a computer, and 25% described daily use. Only 35% of this cohort had used the Internet. Ninety-one patients had used the Internet to obtain information about prostate cancer, with 53 doing so after diagnosis but before deciding on treatment. Twenty-eight patients stated that Internet information influenced their decision about treatment. Not surprisingly, patients were more likely to use the Internet for health information if they were younger, had a higher education level, owned a personal computer, and had prior computing experience. Most patients could not recall the exact web sites they had visited but tended to recall the sites of some well-known institutions. CONCLUSIONS: In this Canadian cohort study, we found a substantial (and most likely, rapidly increasing) number of patients used the Internet to obtain health information. This information may influence patients' decisions regarding treatment and, as urologists, we should participate in the development of web sites directed toward shared decision-making. A list of practical recommendations has been formulated.

Recent developments in the management of testicular germ cell tumors.

Testicular germ cell tumors are now generally regarded as a highly curable cancer in the majority of cases, even when patients present with advance disease. However that does not imply that researchers and clinicians have become complacent in their efforts to improve our understanding and the treatment outcome of this disease. This is an overview of recent developments in the management of testis cancer.

PSP94 expression after androgen deprivation therapy: a comparative study with prostate specific antigen in benign prostate and prostate cancer.

PURPOSE: To examine the clinical use of PSP94 (prostate secretory protein of 94 amino acids) as an androgen independent marker, we conducted a comparative study of prostate samples including benign tissue and cancers which did and did not have androgen deprivation. MATERIALS AND METHODS: Among 163 radical prostatectomy cases 75 had androgen deprivation before operation, while surgery was performed in the remainder without prior hormone treatment. Considering the pathological up grading following hormone therapy, contiguous sections from radical prostatectomy samples were stained for PSP94 and prostate specific antigen (PSA) by immunohistochemistry, and equivalent tumor foci were evaluated by assessing the intensity and extent of the staining. RESULTS: In untreated benign prostate tissue PSP94 and PSA staining was positive and identical in all sections in the no pretreatment group. However, PSP94 expression in the androgen deprivation group was significantly higher than PSA in intensity (p = 0.0005) and extent (p = 0.034). In untreated cancer cases PSP94 intensity and extent demonstrated strong inverse association with Gleason grade (p <0.0001). In contrast, PSA expression was high in every grade, resulting in no statistical association with tumor grade. In the androgen deprivation group PSA staining was decreased in every grade compared to the no pretreatment group. On the other hand, PSP94 expression was decreased in grade 3 tumor foci but increased in grades 4 and 5 tumor foci compared with samples of the corresponding grade in the no pretreatment group (p = 0.0034). CONCLUSIONS: PSP94 expression in benign prostate persists under androgen deprivation compared to PSA. PSP94 synthesis in high grade tumor appears to be activated in the absence of androgen stimulation, indicating the possible alternative pathways in the regulation of PSP94.

Serum bound forms of PSP94 (prostate secretory protein of 94 amino acids) in prostate cancer patients.

PSP94 (prostate secretory protein of 94 amino acids) was regarded as a possible prostate cancer marker, however, it has been controversial. All prior studies were designed to test the free form in serum using antibodies to PSP94. Results presented here demonstrate that PSP94 exists in prostate cancer patients in two forms, free and bound, and that the majority is present as serum bound complexes. This result was demonstrated by using both native and SDS-PAGE analyses of serum proteins from prostate cancer patients. Chromatographic separation of serum total proteins by a molecular sieve column generated two peaks (peak I and II), which were reactive with rabbit antiserum to human PSP94 in Western blot experiments. Peak I was eluted before the IgG fraction at a molecular weight larger than 150 kDa, and peak II appeared after serum albumin ( approximately 67 kDa) was eluted. By using a biotinylated PSP94 as an indicator of the free form of PSP94, we demonstrate that peak I contains serum PSP94-bound complexes and peak II is likely the free form of serum PSP94. Since the molecular weight of serum PSP94-bound complexes is close to IgG during molecular sieve separation, serum PSP94 complexes were further purified through two rounds of protein A column separation, followed by DEAE-ion exchange column chromatography. In vitro dissociation tests of the purified PSP94-bound complexes showed that the binding of serum PSP94-complexes is probably via disulfide bonds and is chemically stable. The results presented here indicate that serum PSP94-bound complexes must be considered in evaluating the clinical utility of PSP94 as a prostate cancer marker.

In situ hybridization study of PSP94 (prostatic secretory protein of 94 amino acids) expression in human prostates.

BACKGROUND: The prostatic secretory protein of 94 amino acids (PSP94), also named beta-microseminoprotein, is one of the major proteins secreted by the human prostate. However, its value as a prognostic marker for prostate cancers is still under debate. The aim of the present study was to examine the expression pattern of this protein in fetal, pubertal, and aged human prostates. METHODS: Nonisotopic in situ hybridization using a digoxigenin-labeled riboprobe for PSP94 and immunohistochemistry were used to demonstrate the expression of PSP94 in different regions or zones of fetal, pubertal, and adult human prostates. Its localization pattern was also compared with those of two other major secretory proteins, prostate-specific antigen (PSA) and prostatic acid phosphatase (PAP), by immunohistochemistry. RESULTS: PSP94 mRNA and its protein were localized to the secretory epithelium of normal pubertal and adult human prostates. No hybridization signal and immunoreactivity of PSP94 were seen in fetal prostates at 6-7 months of gestation, whereas some glandular cells were positive to PSA and PAP immunostainings. In the adult prostates, PSP94 expression was intense in the acini in the peripheral zone, less intense in the transition zone, and variable in the central zone. Such a zonal expression pattern was more apparent in the pubertal prostates. However, no obvious differential expression pattern was observed in the immunohistochemistry of PAP and PSA, which showed a uniform staining of the secretory epithelia of the acini in all anatomic zones. The hybridization signals and immunoreactivity of PSP94 became reduced or lost in premalignant prostatic intraepithelial neoplastic lesions and different grades of prostatic carcinomas. CONCLUSIONS: Fetal prostates at 6-7 months of gestation already synthesize PSA and PAP but not PSP94. The delayed expression of PSP94 appears to correlate with the development of the prostate gland. A differential expression pattern of PSP94 is demonstrated in different anatomical zones, showing that this protein is more expressed and synthesized in the acini in the peripheral zone than in the central and transition zones. However, such a zonal pattern is not seen in the immunohistochemistry of PSA and PAP. The present study also shows that PSP94 is downregulated in different grades of prostate cancers.