William C. DeWolf

IS LOW SERUM FREE TESTOSTERONE A MARKER FOR HIGH GRADE PROSTATE CANCER

PURPOSE The association of free and total testosterone with prostate cancer is incompletely understood. We investigated the relationship of serum free and total testosterone to the clinical and pathological characteristics of prostate cancer. MATERIALS AND METHODS We retrospectively reviewed the clinical records of 117 consecutive patients treated by 1 physician and diagnosed with prostate cancer at our medical center between 1994 and 1997. Low free and total testosterone levels were defined as 1.5 or less and 300 ng./dl., respectively. RESULTS After evaluating all 117 patients we noted no correlation of free and total testosterone with prostate specific antigen, patient age, prostatic volume, percent of positive biopsies, biopsy Gleason score or clinical stage. However, in patients with low versus normal free testosterone there were an increased mean percent of biopsies that showed cancer (43% versus 22%, p = 0.013) and an increased incidence of a biopsy Gleason score of 8 or greater (7 of 64 versus 0 of 48, p = 0.025). Of the 117 patients 57 underwent radical retropubic prostatectomy. In those with low versus normal free testosterone an increased mean percent of biopsies demonstrated cancer (47% versus 28%, p = 0.018). Pathological evaluation revealed stage pT2ab, pT2c, pT3 and pT4 disease, respectively, in 31%, 64%, 8% and 0% of patients with low and in 40%, 40.6%, 12.5% and 6.2% in those with normal free testosterone (p>0.05). CONCLUSIONS In our study patients with prostate cancer and low free testosterone had more extensive disease. In addition, all men with a biopsy Gleason score of 8 or greater had low serum free testosterone. This finding suggests that low serum free testosterone may be a marker for more aggressive disease.

High dose bicalutamide for androgen independent prostate cancer: Effect of prior hormonal therapy

PURPOSE A pilot study of the antiandrogen bicalutamide at 150 mg. a day for androgen independent prostate cancer was performed. This study was based on the possibility that androgen independent cases might display responses to additional hormonal agents. MATERIALS AND METHODS The study included 31 androgen independent cases with an increasing prostate specific antigen (PSA) and progressive disease. PSA measurements were used as the primary method of assessing response. However, PSA decline was also correlated with clinical status. RESULTS Seven patients demonstrated PSA declines of greater than 50% for 2 months or more, for an overall response rate of 22.5%. Responses were observed almost exclusively in patients treated with long-term flutamide as part of a complete androgen blockade regimen (43% response rate) in contrast to patients treated with androgen deprivation without flutamide (6% response rate). Of the 7 PSA responding patients bicalutamide resulted in a significant improvement in performance status and a decrease in analgesic requirement in 4 and 3 remained asymptomatic. Bicalutamide at 150 mg. a day was well tolerated, with the most frequent side effect being mild exacerbation of hot flashes. CONCLUSIONS Bicalutamide at this dose is modestly effective for some patients with androgen independent prostate cancer, particularly for those previously treated with long-term flutamide. This study indicates that previous antiandrogen therapy alters the response to subsequent hormonal agents.

High Failure Rate of Indwelling Ureteral Stents in Patients with Extrinsic Obstruction: Experience at 2 Institutions

The indwelling ureteral stent commonly is used to bypass 2 types of obstruction: 1) intrinsic obstruction usually due to stones or ureteropelvic junction abnormalities or 2) extrinsic compression, for example by retroperitoneal tumor. To determine the success of this intervention at 2 institutions the medical records of all patients undergoing cystoscopic placement of a stent for ureteral obstruction were reviewed. Procedures were classified by several parameters, including the type and location of the ureteral obstruction, indications for stent placement and success of the procedure. Stent failure was defined arbitrarily as clinical occlusion of the stent within 30 days of placement. X-rays were reviewed as available to measure stricture length and location in patients with extrinsic obstruction. Of the procedures at Brigham and Womens Hospital in Boston, where silicone stents are used almost exclusively, 23 perforated indwelling stents placed for intrinsic obstruction were uniformly successful. In contrast, of 24 stents placed for extrinsic obstruction 11 failed (p less than 0.0005). At Beth Israel Hospital, where polyurethane stents are used most commonly, all 21 perforated indwelling stents placed for intrinsic obstruction were successful, while 9 of 22 stents placed for extrinsic obstruction failed (5 within the first 24 hours of placement, p less than 0.0005). The only parameter that seemed to be a predictor of stent failure was luminal size, and this only in silicone catheters. The reasons for this surprising failure rate of internal stents in the face of extrinsic obstruction are not known but may be related to previous studies that describe a relationship among ureteral peristalsis, venting side holes and flow rate.(ABSTRACT TRUNCATED AT 250 WORDS)

Extended Prostate Needle Biopsy Improves Concordance Of Gleason Grading Between Prostate Needle Biopsy And Radical Prostatectomy

PURPOSE We examined the concordance of Gleason scores in prostate needle biopsy specimens and the corresponding radical retropubic prostatectomy specimens in a cohort of patients grouped according to the number of cores obtained during diagnostic needle biopsy. MATERIALS AND METHODS We reviewed clinical and pathological data on a cohort of 466 men diagnosed with localized prostate cancer by needle biopsies who underwent radical retropubic prostatectomy between January 1, 1990 and July 31, 2001. Two study groups were identified, including 126 patients diagnosed with prostate cancer by extended needle biopsies (10 or more cores) and 340 diagnosed with cancer by nonextended needle biopsies (9 or fewer cores). Mean age was 60 years and median prostate specific antigen was 5.8 ng./ml. The median number of cores in the extended and nonextended biopsy groups was 12 and 6, respectively. The concordance of Gleason score in the needle biopsy and prostatectomy specimens was compared and correlated with the number of cores on needle biopsy. RESULTS In the whole cohort 311 patients (67%) had identical Gleason scores on the needle biopsy and prostatectomy specimens, while 53 (11%) were over graded and 102 (22%) were under graded on needle biopsy. In patients who underwent extended needle biopsies the accuracy rate for Gleason scoring was 76% with 10% over and 14% under graded. The highest accuracy rates were in patients with 13, 14 and 16 cores (89%, 87% and 100%, respectively). No patients in the extended needle biopsy group had a discrepancy of more than 2 Gleason units in grade in the biopsy and surgical specimens. In those who underwent nonextended needle biopsies the accuracy rate for Gleason scoring was 63% with 12% over and 25% under graded. There were significantly different rates of accuracy (p = 0.008) and under grading (p = 0.01) in the 2 needle biopsy groups. Patients with a needle biopsy Gleason score of less than 7 had significantly higher concordance with the prostatectomy Gleason score when extended biopsies were done compared with nonextended biopsies (p = 0.001). CONCLUSIONS Prostate cancer grading by extended needle biopsy is a better predictor of the final Gleason score than nonextended needle biopsy, as determined by radical prostatectomy histological evaluation. Therefore, extended prostate needle biopsy provides better guidance to determine the appropriate treatment in patients with prostate cancer.

MR Imaging of Renal Masses: Correlation with Findings at Surgery and Pathologic Analysis

Magnetic resonance (MR) imaging is useful in the characterization of renal masses. The MR imaging manifestations and pathologic diagnoses of 82 renal masses were reviewed and correlated. The MR imaging appearance of clear cell type renal cell carcinoma varies depending on the presence of cystic components, hemorrhage, and necrosis. Papillary renal cell carcinomas appear as well-encapsulated masses with homogeneous low signal intensity on T2-weighted images and homogeneous low-level enhancement after the intravenous administration of contrast material, or as cystic hemorrhagic masses with peripheral enhancing papillary projections. Transitional cell carcinoma may be seen as an irregular, enhancing filling defect in the pelvicaliceal system or ureter. Lymphomatous masses are usually hypointense relative to the renal cortex on T2-weighted images and enhance minimally on delayed gadolinium-enhanced images. Bulk fat is a distinguishing feature of angiomyolipoma. Oncocytoma has a variable and nonspecific appearance at MR imaging. MR imaging findings may allow the characterization of various renal masses and can provide valuable information for their clinical management.

Detection of circulating tumor cells in men with localized prostate cancer.

PURPOSE Using prostate-specific antigen (PSA) mRNA as a marker for prostatic epithelial cells, we have developed a sensitive technique that involves reverse transcription and polymerase chain reaction (RT-PCR) to detect circulating tumor cells in the peripheral blood of men with prostatic carcinoma (CaP). PATIENTS AND METHODS A sensitive RT-PCR assay was used to evaluate the peripheral blood of 135 men with a history of CaP. Fourteen men with benign prostate disease, many of whom had elevated serum PSA levels, were used as a control group. RESULTS All patients with benign prostate disease had a negative result in the RT-PCR assay. Of particular interest was a subgroup of 65 patients with clinically localized CaP evaluated before definitive local therapy. Five of these patients had detectable PSA mRNA by RT-PCR, suggesting circulating tumor cells. Within this group, systemic disease was detected by RT-PCR in some men with PSA levels less than 10 ng/mL and clinical stage B disease. Blood from men with hormone-refractory and progressive CaP demonstrated a higher frequency of PSA mRNA detectable by RT-PCR (10 of 20 patients). In contrast, none of seven patients with newly diagnosed metastatic prostate cancer and only one of seven patients with metastatic, hormone-responsive disease had blood that was positive for PSA mRNA by RT-PCR. CONCLUSION Circulating tumor cells can be detected in the blood of a subset of patients with clinically localized CaP and a larger subset of patients with progressive metastatic disease.

SALVAGE INTRAVESICAL THERAPY WITH INTERFERON-α2B PLUS LOW DOSE BACILLUS CALMETTE-GUERIN IS EFFECTIVE IN PATIENTS WITH SUPERFICIAL BLADDER CANCER IN WHOM BACILLUS CALMETTE-GUERIN ALONE PREVIOUSLY FAILED

PURPOSE We determined whether combining low dose bacillus Calmette-Guerin (BCG) interferon-alpha 2B would be effective for patients in whom previous BCG failed. MATERIALS AND METHODS A total of 40 patients in whom 1 (19) or more (21) previous induction courses of BCG failed received 6 to 8 weekly treatments of 1/3 dose (27 mg.) BCG plus 50 million units interferon-alpha 2B. Additional 3 week miniseries of further decreased BCG (1/10, 1/30 or 1/100) titrated to symptoms without changing the interferon-alpha 2B dose were given at 5, 11 and 17 months. In 12 patients a second induction course was given with 1/10 BCG plus 100 million units interferon-alpha 2B. There was multifocal disease in 39 patients, previous BCG had failed within 6 months in 34, disease was aggressive (stage T1, grade 3 or carcinoma in situ in 31, there had been 2 or more previous recurrences in 25 and disease history was greater than 4 years in 13. RESULTS At a median followup of 30 months 63% and 53% of patients were disease-free at 12 and 24 months, respectively. Patients in whom 2 or more previous BCG courses had failed fared as well as those with 1 failure. Of the 18 failures 14 occurred at the initial cystoscopy evaluation. Of 22 patients initially counseled to undergo cystectomy 12 (55%) are disease-free with a functioning bladder. Combination therapy was well tolerated. CONCLUSIONS While longer followup and larger multicenter studies are required to validate these encouraging findings, intravesical low dose BCG plus interferon-alpha 2B appears to be effective in many cases of high risk disease previously deemed BCG refractory. However, early failure while on this regimen should be aggressively pursued with more radical treatment options.

Persistent c-FLIP(L) Expression Is Necessary and Sufficient to Maintain Resistance to Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand–Mediated Apoptosis in Prostate Cancer

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been shown to induce apoptosis in a variety of tumorigenic and transformed cell lines but not in many normal cells. Hence, TRAIL has the potential to be an ideal cancer therapeutic agent with minimal cytotoxicity. FLICE inhibitory protein (c-FLIP) is an important regulator of TRAIL-induced apoptosis. Here, we show that persistent expression of c-FLIP(Long) [c-FLIP(L)] is inversely correlated with the ability of TRAIL to induce apoptosis in prostate cancer cells. In contrast to TRAIL-sensitive cells, TRAIL-resistant LNCaP and PC3-TR (a TRAIL-resistant subpopulation of PC3) cells showed increased c-FLIP(L) mRNA levels and maintained steady protein expression of c-FLIP(L) after treatment with TRAIL. Ectopic expression of c-FLIP(L) in TRAIL-sensitive PC3 cells changed their phenotype from TRAIL sensitive to TRAIL resistant. Conversely, silencing of c-FLIP(L) expression by small interfering RNA in PC3-TR cells reversed their phenotype from TRAIL resistant to TRAIL sensitive. Therefore, persistent expression of c-FLIP(L) is necessary and sufficient to regulate sensitivity to TRAIL-mediated apoptosis in prostate cancer cells.

MR classification of renal masses with pathologic correlation

To perform a feature analysis of malignant renal tumors evaluated with magnetic resonance (MR) imaging and to investigate the correlation between MR imaging features and histopathological findings. MR examinations in 79 malignant renal masses were retrospectively evaluated, and a feature analysis was performed. Each renal mass was assigned to one of eight categories from a proposed MRI classification system. The sensitivity and specificity of the MRI classification system to predict the histologic subtype and nuclear grade was calculated. Subvoxel fat on chemical shift imaging correlated to clear cell type (p < 0.05); sensitivity = 42%, specificity = 100%. Large size, intratumoral necrosis, retroperitoneal vascular collaterals, and renal vein thrombosis predicted high-grade clear cell type (p < 0.05). Small size, peripheral location, low intratumoral SI on T2-weighted images, and low-level enhancement were associated with low-grade papillary carcinomas (p < 0.05). The sensitivity and specificity of the MRI classification system for diagnosing low grade clear cell, high-grade clear cell, all clear cell, all papillary, and transitional carcinomas were 50% and 94%, 93% and 75%, 92% and 83%, 80% and 94%, and 100% and 99%, respectively. The MRI feature analysis and proposed classification system help predict the histological type and nuclear grade of renal masses.

The TRA-1-60 and TRA-1-81 human pluripotent stem cell markers are expressed on podocalyxin in embryonal carcinoma.

We have previously identified the cell adhesion protein podocalyxin expressed in a human pluripotent stem cell, embryonal carcinoma (EC), which is a malignant germ cell. Podocalyxin is a heavily glycosylated membrane protein with amino acid sequence homology to the hematopoietic stem cell marker CD34. Since the initial discovery of podocalyxin in a cancerous stem cell, numerous new studies have identified podocalyxin in many different human cancers and in embryonic stem cells lines (ES) derived from human embryos. Embryonal carcinoma, as do all human pluripotent stem cells, expresses TRA‐1‐60 and TRA‐1‐81 antigens, and although their molecular identities are unknown, they are commonly used as markers of undifferentiated pluripotent human stem cells. We report here that purified podocalyxin from embryonal carcinoma has binding activity with the TRA‐1‐60 and TRA‐1‐81 antibodies. Embryonal carcinoma cells treated with retinoic acid undergo differentiation and lose the TRA‐1‐60/TRA‐1‐81 markers from their plasma membrane surface. We show that podocalyxin is modified in the retinoic acid‐treated cells and has an apparent molecular mass of 170 kDa on protein blots as compared with the apparent 200‐kDa molecular weight form of podocalyxin expressed in untreated cells. Furthermore, the modified form of podocalyxin no longer reacts with the TRA‐1‐60/TRA‐1‐81 antibodies. Thus, embryonal carcinoma expresses two distinct forms of podocalyxin, and the larger version is a molecular carrier of the human stem cell‐defining antigens TRA‐1‐60 and TRA‐1‐81.