Glucocorticoids manifest androgenic activity in a cell line derived from a metastatic prostate cancer.

The pathophysiological mechanism(s) by which androgen independence develops in prostate cancer remains to be determined. The identification in many prostate cancer specimens of a mutant androgen receptor, T877A, with altered ligand specificity has provided an explanation for some treatment failures. The T877A mutant androgen receptor recognizes a number of nonandrogenic compounds, including certain estrogens, progestins, and even antiandrogens as androgens. However, a comprehensive screen for hormonal agents which display agonist activity on this mutant has not been performed. In this study, we characterized this clinically important receptor mutant further and found that it can be activated by a wide range of compounds, including a number of endogenous glucocorticoids. Among the most clinically relevant compounds identified are DOC and corticosterone, both of which can effectively activate the mutant receptor at concentrations normally found in blood. Dexamethasone, a synthetic glucocorticoid frequently used in various contexts for prostate cancer therapy, is also recognized as an androgen by the mutant receptor. These unexpected findings suggest the need to: (a) reassess the role of adrenally derived glucocorticoids in prostate cancer disease progression; and (b) recognize the potential for iatrogenic stimulation of disease progression with certain glucocorticoid interventions.

Pilot study of dietary fat restriction and flaxseed supplementation in men with prostate cancer before surgery: exploring the effects on hormonal levels, prostate-specific antigen, and histopathologic features.

OBJECTIVES: Dietary fat and fiber affect hormonal levels and may influence cancer progression. Flaxseed is a rich source of lignan and omega-3 fatty acids and may thwart prostate cancer. The potential effects of flaxseed may be enhanced with concomitant fat restriction. We undertook a pilot study to explore whether a flaxseed-supplemented, fat-restricted diet could affect the biomarkers of prostatic neoplasia. METHODS: Twenty-five patients with prostate cancer who were awaiting prostatectomy were instructed on a low-fat (20% of kilocalories or less), flaxseed-supplemented (30 g/day) diet. The baseline and follow-up levels of prostate-specific antigen, testosterone, free androgen index, and total serum cholesterol were determined. The tumors of diet-treated patients were compared with those of historic cases (matched by age, race, prostate-specific antigen level at diagnosis, and biopsy Gleason sum) with respect to apoptosis (terminal deoxynucleotidyl transferase [TdT]-mediated dUTP-biotin nick end-labeling [TUNEL]) and proliferation (MIB-1). RESULTS: The average duration on the diet was 34 days (range 21 to 77), during which time significant decreases were observed in total serum cholesterol (201 +/- 39 mg/dL to 174 +/- 42 mg/dL), total testosterone (422 +/- 122 ng/dL to 360 +/- 128 ng/dL), and free androgen index (36.3% +/- 18.9% to 29.3% +/- 16.8%) (all P <0.05). The baseline and follow-up levels of prostate-specific antigen were 8.1 +/- 5.2 ng/mL and 8.5 +/- 7.7 ng/mL, respectively, for the entire sample (P = 0.58); however, among men with Gleason sums of 6 or less (n = 19), the PSA values were 7.1 +/- 3.9 ng/mL and 6.4 +/- 4.1 ng/mL (P = 0.10). The mean proliferation index was 7.4 +/- 7.8 for the historic controls versus 5.0 +/- 4.9 for the diet-treated patients (P = 0.05). The distribution of the apoptotic indexes differed significantly (P = 0.01) between groups, with most historic controls exhibiting TUNEL categorical scores of 0; diet-treated patients largely exhibited scores of 1. Both the proliferation rate and apoptosis were significantly associated with the number of days on the diet (P = 0.049 and P = 0.017, respectively). CONCLUSIONS: These pilot data suggest that a flaxseed-supplemented, fat-restricted diet may affect prostate cancer biology and associated biomarkers. Further study is needed to determine the benefit of this dietary regimen as either a complementary or preventive therapy.

Contemporary chemotherapeutic approaches for the treatment of hormone-refractory prostate carcinoma.

The medical management of hormone-refractory prostate cancer remains difficult and largely palliative. The development of effective antineoplastic agents has been frustrated by difficulty in the establishment of satisfactory objective response criteria for clinical trials. Nevertheless, recent trials indicate that mitoxantrone and spindle toxins such as docetaxel do show activity. Estramustine-based regimens have also been promising, and such combination regimens are now being explored rigorously. Benefiting from new molecular-biologic insights into the pathobiology of prostate cancer, novel strategies targeting new molecular pathways of cell regulation and cell-cell interaction (such as angiogenesis) are also being actively pursued.

Early onset baldness and prostate cancer risk.

Prostatic carcinoma is the leading cancer among American men, yet few risk factors have been established. Although increased androgen levels have long been associated with both prostatic carcinoma and baldness, to date no studies have shown an association between hair patterning and prostate cancer risk. A lack of standardized instruments to assess baldness or the assessment of hair patterning during uninformative periods of time may have precluded the ability of previous studies to detect an association. We hypothesized that baldness, specifically vertex baldness, should be assessed using standardized instruments and during early adulthood if an association with prostate cancer risk is to be found. To test this hypothesis, we included identical items related to hair patterning in surveys that were administered in two distinct prostate cancer case-control studies (Duke-based study, n = 149; 78 cases; 71 controls and community-based study, n = 130; 56 cases; 74 controls). In each, participants were provided with an illustration of the Hamilton Scale of Baldness and asked to select the diagrams that best represented their hair patterning at age 30 and again at age 40. From these data, the following five categories were created and compared: not bald (referent group); vertex bald early onset (by age 30); vertex bald later onset (by age 40); frontal bald early onset (by age 30); frontal bald later onset (by age 40); and frontal (at age 30) to vertex bald (at age 40). Separate analyses of the two studies are consistent and suggest an association between vertex baldness and prostate cancer [vertex bald early onset odds ratios, 2.44 [confidence interval (CI), 0.57-10.46)] and 2.11 (CI, 0.66-6.73), respectively; vertex bald later onset odds ratios, 2.10 (CI, 0.63-7.00) and 1.37 (CI, 0.47-4.06), respectively]. Although statistical significance was not achieved in either one of these studies, the concordance between the data suggests a need for future studies to determine whether early onset vertex baldness serves as a novel biomarker for prostate cancer and whether androgen production, metabolism, or receptor status differs among these men when compared to those who exhibit other types of hair patterning.

Interstitial brachytherapy for prostate cancer--just an expensive variant of 'watchful waiting'?

As a result of the recent resurgence of interest in interstitial brachytherapy, extended follow-up studies of early experience in this field are now being reported. However, such outcomes must be evaluated within the context of recent comprehensive assessments of the age-specific natural history of conservatively managed prostate cancer ('watchful waiting', i.e. no curative intervention). This raises issue with the contention that treating patients with low-grade cancer using brachytherapy alone results in a treatment-derived, extended, clinical-progression-free survival. The necessity for proposed randomized trials of brachytherapy (compared with conservative management in low-grade disease, and brachytherapy plus external beam radiotherapy) is discussed in this context. There is no consensus regarding the best modality for the treatment of localized prostate cancer, since no well-accepted, adequately powered randomized trial of competing modalities for this disease has ever been completed. Consequently, it has become common while counseling patients with the disease to place substantial emphasis on 'quality of life' considerations and the 'outcomes uncertainty management' issues associated with each option of therapy. There is even a question of whether every patient who is diagnosed with prostate cancer should be treated. However, while the importance of the variable biologic risk is generally widely accepted by experienced physicians caring for such patients, it is extremely difficult for the individual patient to weigh the evidence of the relative risks of progression dispassionately at the time of diagnosis. In this review, I wish to highlight several papers that have been published within the past year that are important in addressing this ongoing clinical problem. Any physician counseling patients about localized prostate cancer treatment should read and become familiar with the data herein: papers addressing the issues of interstitial brachytherapy outcomes, and the natural history of prostate cancer itself.

Treatment options, selection, and satisfaction among African American and white men with prostate carcinoma in North Carolina.

BACKGROUND: In the U.S., prostate carcinoma mortality is greatest among African Americans. In North Carolina, the state with the fourth largest population of African Americans, the prostate carcinoma mortality rate is 2.5 times greater among African Americans than among whites and is the highest reported rate for any state in the nation. To explore potential reasons for the racial differential in mortality, a study was undertaken to determine whether differences related to treatment existed between African American and white men who were diagnosed with prostate carcinoma during the period 1994-1995. METHODS: Cases were selected from 16 institutions within a region comprising 63 contiguous counties where the overall population was >20% African American. A stratified design was employed to accrue subjects into groups of even size according to race and disease stage (n = 231). A telephone survey was conducted, which assessed treatment options discussed by patients with their physicians, treatment(s) received, factors influencing treatment, satisfaction with treatments discussed and options given, and sociodemographic information. RESULTS: All measures related to treatment were consistently associated with stage at diagnosis (P < 0.001) rather than other variables measured (i.e., race, age, income, comorbidity, education, and residential status). Furthermore, most subjects reported that their physicians presented several treatment options (65%), that they were satisfied with the options presented (90%), and that the physician was the most important factor influencing their treatment decision (57%). CONCLUSIONS: These data suggest that African American and white men in North Carolina receive comparable treatment for prostate carcinoma. Therefore, efforts to reduce the racial disparity in mortality should be directed toward lessening the high incidence of later stage disease at diagnosis and exploring potential biologic differences that may increase the risk of more aggressive disease among African Americans.

The treatment of metastatic renal cell carcinoma patients with recombinant human gamma interferon.

PURPOSE: Activity has been reported in phase II single-center, open-label studies after administration of low-dose recombinant interferon gamma-1b (rIFN-gamma) to patients with metastatic renal cell carcinoma, with an overall objective response proportion of around 15%. To confirm these data and define the complete response rate, we conducted a multicenter open-label trial in which 204 patients with metastatic renal cell carcinoma were treated with rIFN-gamma. PATIENTS AND METHODS: Two hundred and seven patients (134 males, 73 females, mean age 59) were enrolled, and 202 were evaluable. rIFN-gamma, 60: microgram/m2, was administered subcutaneously once every 7 days until disease progression. RESULTS: There were three (1.5%) complete responses and three (1.5%) partial responses, for an overall response proportion of 3% (95% CI: 1.2%, 6.7%). The median response duration was 13.3 months (range: 2 to 23 months). The median survival was 13.4 months (5.5 months to 29.2 months). Three (1%) deaths were observed during the course of study; they were considered to be related to progressive metastatic renal cell carcinoma. Toxicity was minimal, with 14% of patients experiencing grade 3/4 toxicity. The most frequent adverse events were chills (59%), fever (58%), asthenia (53%), nausea (29%), and headache (18%). Multivariate analysis revealed that younger age, higher performance status, higher hemoglobin, and lower LDH were predictive of survival. DISCUSSION: Recombinant interferon gamma 1b has only minimal efficacy in the treatment of metastatic renal cell carcinoma. Pretreatment variables associated with increased survival were male sex, higher Karnofsky performance status, higher hemoglobin, and low LDH.

Alternative splicing of fibroblast growth factor receptor 2 (FGF-R2) in human prostate cancer.

Progression of prostate cancer from an androgen sensitive to androgen insensitive tumor has previously been shown to be accompanied by a change in alternative splicing of fibroblast growth factor receptor 2 (FGF-R2) in a rat model of prostate cancer. This change results in loss of the FGF-R2(IIIb) isoform and predominant expression of the FGF-R2(IIIc) isoform. We sought to determine whether this change in FGF-R2 splicing is also associated with androgen insensitivity in human prostate tumors. We analysed three well characterized human prostate cancer cell lines and three metastatic prostate tumors which have been maintained as xenografts in nude mice. One of the cell lines, LNCaP, and two of the xenografts, DUKAP-1 and DUKAP-2, have been characterized as androgen sensitive, whereas two of the cell lines, DU-145 and PC-3, and one of the xenografts, DU9479, display androgen independent growth. Using an RT-PCR based assay, we demonstrated that progressive loss of the FGF-R2(111b) isoform correlated with androgen insensitivity in these human prostate cancer models. These findings lend support to the hypothesis that that loss of FGF-R2(IIIb) may be one step in a series of events which lead to progression of human prostate cancer.

Enteric type adenocarcinoma of the upper tract urothelium associated with ectopic ureter and renal dysplasia: an oncological rationale for complete extirpation of this aberrant developmental anomaly.

PURPOSE: Intestinal metaplasia of the urothelium occurs in chronically irritated retained urinary segments and can progress to enteric adenocarcinoma. We present a unique clinical experience with a closed segment ureter from a dysplastic kidney draining ectopically into the seminal vesicle with malignant degeneration to enteric adenocarcinoma. The implications of this experience for management of this anomaly are discussed. MATERIALS AND METHODS: Clinical and pathological data were assimilated with the urological and pathological literature. RESULTS: Pathological examination revealed replacement of the urothelium of the renal pelvis and ureter with intestinal type metaplasia and multifocal transformation to mucinous (tubular villose) poorly differentiated adenocarcinoma. Preoperative computerized tomography failed to identify the extensive malignancy. CONCLUSIONS: Our experience demonstrates that this anomaly is another scenario in which closed spaced nonfunctional urothelium can undergo malignant degeneration. Since monitoring such units for tumor progression does not seem to be possible presently, conservative treatment appears hazardous. This new recognition of the risk of malignant metaplastic degeneration is an additional rationale to consider complete extirpation of these lesions as the most appropriate treatment in young men.

p53 immunohistochemical and genetic alterations are associated at high incidence with post-irradiated locally persistent prostate carcinoma.

PURPOSE: Several reports have shown that cells with p53 mutations display increased resistance to ionizing radiation, a treatment often used clinically for localized prostate carcinoma. MATERIALS AND METHODS: Totals of 18 post-irradiated locally recurrent prostatic carcinoma specimens and 25 (no radiation) stage D1 node-positive (TxN+MO) primary prostatic carcinoma specimens were tested for p53 immunoreactivity by immunohistochemistry. Of the 18 post-radiation locally recurrent prostatic carcinomas 10 were further analyzed by single strand conformational polymorphism to assess the validity of using this immunohistochemistry approach in irradiated tissue for detecting p53 alterations. Specimens showing p53 alterations by single strand conformational polymorphism were subjected to nucleotide sequence analysis or tested for loss of heterozygosity at a locus within the p53 gene. RESULTS: Of the 25 stage TxN+MO prostatic carcinomas without radiation 5 (20%) were immunoreactive (consistent with the reported incidence of positive immunoreactivity in clinical/surgical stage TxN+MO primary prostatic carcinomas). In contrast, 13 of 18 post-radiation locally recurrent prostatic carcinoma specimens (72%) were immunoreactive. Multivariate logistic regression analysis showed no dependence of p53 immunoreactivity to grade, stage or androgen status in the post-radiation locally recurrent prostatic carcinoma group, while 8 of 10 hormone naive prostatic carcinoma specimens (80%) were immunoreactive. The temporal relationship between p53 alterations and radiotherapy was assessed. Pre-irradiation prostatic carcinomas available from 5 patients with immunoreactive post-radiation locally recurrent disease were analyzed and all were immunoreactive. CONCLUSIONS: p53 Alteration in localized prostatic carcinoma is uncommon. Our study confirms others in that even aggressive locally advanced nonirradiated primaries (stage TxN+MO) contain only 20% incidence of p53 alterations. However, our study demonstrates that p53 alterations are found in the preponderant majority of post-radiation locally recurrent prostatic carcinoma specimens. Limited evaluation of pretreatment prostatic carcinoma biopsies uniformly documented the presence of p53 alterations before ionizing radiation, thereby demonstrating that p53 alteration was already present and was not radiation-induced or only correlated with late stage disease. This finding suggests a potential for p53 immunoreactivity to be used as a pretreatment marker that might predict local treatment failure with ionizing radiation. Large scale prospective trials would appear warranted to evaluate conclusively the potential prognostic applicability of p53 pre-screening before enrollment in definitive radiotherapy.

Phase III randomized trial of interleukin-2 with or without lymphokine-activated killer cells in the treatment of patients with advanced renal cell carcinoma.

BACKGROUND: Treatment with interleukin-2 (IL-2) and lymphokine-activated killer cells (LAK) resulted in responses in some patients with advanced renal cell carcinoma (RCC). However, the relative therapeutic benefit of the addition of LAK to IL-2 was unknown. METHODS: A randomized Phase III trial was conducted in patients with RCC comparing continuous intravenous infusion (CI) IL-2 alone with CI IL-2 plus LAK. Interleukin-2 was administered at 3 x 10(6) U/m2/day on days 1-5, 13-17, 21-24, and 28-31. Patients on the LAK treatment arm underwent leukapheresis on days 8-10 and LAK cell reinfusion on days 13-15. The results are reported with long-term follow-up. The published experience with IL-2 alone or with the addition of LAK was investigated in a quantitative literature survey. The response proportions were studied by schedule (high dose bolus, moderate dose, low dose) and by concomitant administration of LAK. RESULTS: Seventy-one patients were treated, 36 on the IL-2 arm and 35 on the IL-2 plus LAK arm. Four patients (6%) had major responses (two complete, two partial). The median survival of all patients was 13 months (95% confidence interval [CI], 9-18 months). There were no differences between treatment arms with regard to response (P = 0.61) and survival (P = 0.67). More patients on the LAK arm experienced pulmonary toxicity (P = 0.008). The overall weighted response proportion was 16% (95% CI, 8%-24%) for the 39 published series of 1291 patients treated with IL-2. The 95% confidence intervals for response proportion overlapped when compared by schedule and by administration of LAK. CONCLUSIONS: The dose and schedule of IL-2 used in this study resulted in a low level of antitumor activity and the addition of LAK did not improve the response rate against RCC. Given the infrequent, but reproducible, responses with IL-2 and interferon-based regimens, continued investigation of these agents is warranted as is the study of new cytokines. Alternative treatment strategies should be studied in RCC and new agents and treatment regimens that appear promising in Phase II studies must be studied in randomized trials.

Genetic alterations in prostate adenocarcinoma.

The genetic alterations associated with prostate carcinogenesis, its progression, and the emergence of androgen independence gradually are being defined. This article focuses on a number of genetic defects that have been identified in prostate cancer, specifically as they relate to disease progression, radiation resistance, and androgen independence.

The association of oncogenic human papillomaviruses with urologic malignancy. The controversies and clinical implications.

Sexually transmitted human papillomaviruses (HPV) are linked to both benign and malignant lesions of the genitourinary tract. Evidence links oncogenic HPV types with carcinomas of the penis and urethra. An association with other common sites of urologic malignancies (prostate, bladder) is controversial. Whereas the screening of sexually active females for HPV has received substantial attention, the presence of a potential male carrier state has received little scrutiny. Systemic immunotherapies based on expression of HPV-related proteins by infected or transformed human epithelia, however, may be possible in the near future.

Prostate cancer screening. Why the controversy?

The development of new technologies has stimulated a crusade of screening for earlier detection of prostate cancer. This effort has resulted in controversy regarding its clinical use in this format. Until randomized clinical screening trials define the value of prostate cancer screening, clinicians who use screening approaches must gain a strong understanding of the natural history of the disease, the strengths and weaknesses of available screening methodologies, and epidemiologic considerations of prostate cancer risk.

Oncogenic human papillomaviruses are rarely associated with squamous cell carcinoma of the bladder: evaluation by differential polymerase chain reaction.

While a strong association between oncogenic human papillomaviruses and squamous cell cancers of the genital tract (penis, urethra and cervix) is known to exist, there is substantial controversy regarding the association of human papillomaviruses and cancers of the bladder. Technical issues regarding assay technique and concern about potential contamination have marred interpretation of previous work. Moreover, because human papillomavirus has been associated predominantly with squamous cell cancers at other sites, any involvement of human papillomavirus and bladder epithelial carcinogenesis must address whether any association between human papillomavirus and squamous cell carcinoma of the bladder exists. Differential polymerase chain reaction and a rigorous protocol to avoid crossover contamination were used to analyze archival bladder carcinoma specimens (22 squamous cell carcinomas and 20 transitional cell carcinomas). Type specific primers for human papillomavirus types 16 and 18 were used as were general primers to detect types 6b, 11, 13, 16, 18, 31, 32, 33, 35, 45 and 51. Only 1 of 22 squamous cell carcinoma specimens (4.4%) was positive (human papillomavirus type 18)--a cadaveric renal transplant patient on chronic immunosuppression. Cervical specimens were human papillomavirus negative in this patient. No human papillomavirus deoxyribonucleic acid was detected in the 20 transitional cell carcinoma cohort. Our results confirm that these human papillomavirus types appear to have little association with invasive transitional cell cancers. Of greater significance, despite this (to our knowledge) first reported case of human papillomavirus type 18 detected in squamous cell carcinoma of the bladder (seen in an immunocompromised patient), we conclude that these oncogenic human papillomavirus types do not have a significant role in squamous cell carcinogenesis of the bladder.

Combination versus single agent therapy in effecting complete therapeutic response in human bladder cancer: analysis of cisplatin and/or 5-fluorouracil in an in vivo survival model.

An in vivo study of cisplatin (CDDP) and 5-fluorouracil (5FU) cytotoxicity was performed using a multidose matrix with a human bladder transitional cell carcinoma xenograft tumor line (DU4284) tested by subrenal capsule assay in 154 nude mice (NM-SRCA). Statistical analysis of initial growth inhibition at 20 days and host survival demonstrates therapeutic, cooperative interaction. Toxic doses of either CDDP or 5FU alone as well as low-dose combinations provided modest or no survival benefit. The single dose of CDDP (7 mg/kg) and of 5FU (100 mg/kg) was best (by analysis of efficacy and toxicity) of those tested and caused > 97% initial regression. While 94% of controls incurred tumor deaths by 225 days, 75% treated at this dose were tumor free and likely cured. Our conclusions were: (a) NM-SRCA human xenograft testing is excellent for rapid in vivo screening of promising treatment strategies to evaluate for efficacy at acceptable toxicity, but confirmation of true therapeutic impact should be sought by correlating initial growth inhibition with host survival; (b) enhanced survival seen only when CDDP/5FU are used together (versus either single agent) supports the value of pursuing histiotype-specific screening of potentially synergistic drug combinations; and (c) of clinical relevance, human transitional cell carcinoma is now identified as a histiotype in which a therapeutic, cooperative interaction between CDDP/5FU has been demonstrated in vivo.

A high association of oncogenic human papillomaviruses with carcinomas of the female urethra: polymerase chain reaction-based analysis of multiple histological types.

Using polymerase chain reaction with type-specific human papillomavirus type 16 and 18 primers, and general primers screening for 9 other genotypes, we analyzed archival surgical specimens of urethral carcinoma from 18 women (17 with invasive cancer and 1 with carcinoma in situ). Human papillomavirus was detected in invasive urethral carcinoma specimens from 10 of 17 women (59%) and in the patient with carcinoma in situ. Human papillomavirus type 16 was found in 8 patients with invasive carcinoma (47%) and 1 with carcinoma in situ, and general primer polymerase chain reaction demonstrated human papillomavirus that could not be typed in 2 patients (12%). Type 16 was detected in metastases from 4 patients; complete concordance for the presence of human papillomavirus in primary and metastatic disease was noted. Eight of 10 women with squamous cell carcinoma and both with transitional cell carcinoma harbored human papillomavirus; 5 women with undifferentiated carcinoma or adenocarcinoma were all negative for human papillomavirus. Concurrently excised cervical tissue was available from 5 patients; 1 had cervical carcinoma in situ positive for human papillomavirus of the same type as the urethral carcinoma. These findings strongly suggest that human papillomavirus, particularly type 16, is associated with a substantial number of carcinomas of the female urethra but a stratification of specific histotypes associated with human papillomavirus may exist.