Evaluation of the SCA instrument for measuring patient satisfaction with cancer care administered via paper or via the Internet.

BACKGROUND: Patients' perspectives provide valuable information on quality of care. This study evaluates the feasibility and validity of Internet administration of Service Satisfaction Scale for Cancer Care (SCA) to assess patient satisfaction with outcome, practitioner manner/skill, information, and waiting/access. PATIENTS AND METHODS: Primary data collected from November 2007 to April 2008. Patients receiving cancer care within 1 year were recruited from oncology, surgery, and radiation clinics at a tertiary care hospital. An Internet-based version of the 16-item SCA was developed. Participants were randomised to Internet SCA followed by paper SCA 2 weeks later or vice versa. Seven-point Likert scale responses were converted to a 0-100 scale (minimum-maximum satisfaction). Response distribution, Cronbach's alpha, and test-retest correlations were calculated. RESULTS: Among 122 consenting participants, 78 responded to initial SCA. Mean satisfaction scores for paper/Internet were 91/90 (outcome), 95/94 (practitioner manner/skill), 89/90 (information), and 86/86 (waiting/access). Response rate and item missingness were similar for Internet and paper. Except for practitioner manner/skill, test-retest correlations were robust r = 0.77 (outcome), 0.74 (information), and 0.75 (waiting/access) (all P < 0.001). CONCLUSIONS: Internet SCA administration is a feasible and a valid measurement of cancer care satisfaction for a wide range of cancer diagnoses, treatment modalities, and clinic settings.

Assessment of early continence recovery after radical prostatectomy: patient reported symptoms and impairment.

PURPOSE: Patients considering radical prostatectomy often inquire as to when they can expect to regain urinary continence. However, there is a paucity of patient self-reported data regarding the recovery of continence during the initial 3 months after surgery. Our objectives were to assess urinary continence changes early in the postoperative period and determine which of 2 commonly used definitions of continence more closely relate to patient reported urinary impairment. MATERIALS AND METHODS: A prospective study of 90 men with clinically localized prostate cancer who selected radical prostatectomy as primary therapy was conducted. Repeated measures of urinary continence as defined by 1) total urinary control, 2) the use of 1 or 0 pads daily, and 3) small or no problem with urinary function were obtained with a brief survey preoperatively and postoperatively. RESULTS: At 56 days after removal of urethral catheters, the actuarial rates of urinary continence recovery based on definitions 1 to 3 were 43%, 84% and 82%, respectively. The use of definition 2 for continence resulted in a 1.9 times higher actuarial rate for continence recovery when compared to definition 1 at 56 days (p <0.001). However, strong agreement was observed between definitions 2 and 3 (kappa = 0.69). CONCLUSIONS: Urinary control is recovered in a significant proportion of men who undergo radical prostatectomy during the initial 3 months. Continence rates will vary significantly based on the use of alternative definitions. The clinical practice of asking patients how many pads daily they use may be valid, as it corresponds well to the impairment they have.

Functional p53 mutation as a molecular determinant of paclitaxel and gemcitabine susceptibility in human bladder cancer.

PURPOSE: Paclitaxel and gemcitabine are promising new agents for treatment of human bladder cancer. We determine how the presence or absence of p53 function impacts the cytotoxic effects of these chemotherapeutic agents in human bladder cancer. MATERIALS AND METHODS: The J82 human bladder cancer (TCC) cell line was transfected with a temperature sensitive p53 (tsp53) mutant that functions as mutated p53 at 37C but functions as wild-type (normal) p53 at 32C. Susceptibility of these inducible p53 TCC cells to paclitaxel and gemcitabine induced cytotoxicity was evaluated and kill significance determined between sub-lethal and lethal doses. RESULTS: Significant paclitaxel dose dependent cytotoxicity was observed in J82 TCC cells lacking normal p53 and tsp53 transfected cells at 37C, which was the mutant p53 temperature in transfectants between maximal and minimal kill concentrations for either (p <0.001). Likewise, significant cytotoxicity was observed in parental J82 TCC at 32C (p <0.001), while restoration of p53 function in tsp53 transfected cells on shift to 32C abrogated significant dose dependent cytotoxicity. Gemcitabine caused significant cell death in the cell lines incubated at either temperature and, thus, was equally effective regardless of cellular p53 function (p <0.001, respectively). CONCLUSIONS: Paclitaxel requires functionally mutated p53 to induce cell death in human bladder cells, indicating that it may be more effective against TCC with p53 mutations than against TCC, which lacks p53 abnormalities, while gemcitabine is effective regardless of p53 function. These findings provide a rationale for selecting chemotherapy based on the p53 status of individual bladder cancers.

Mxi1, a Myc antagonist, suppresses proliferation of DU145 human prostate cells.

BACKGROUND: Mxi1, an antagonist of c-Myc, maps to human chromosome 10q24-q25, a region altered in a substantial fraction of prostate tumors. Mice deficient for Mxi1 exhibit significant prostate hyperplasia. We studied the ability of Mxi1 to act as a growth suppressor in prostate tumor cells. METHODS: We infected DU145 prostate carcinoma cells with an Mxi1-expressing adenovirus (AdMxi1) in vitro, and measured Mxi1 expression, cell proliferation, soft agar colony formation, and cell cycle distribution. To explore mechanisms of Mxi1-induced growth arrest, we performed gene expression analysis. RESULTS: AdMxi1 infection resulted in reduced cell proliferation, reduced soft agar colony formation, and a higher proportion of cells in the G(2)/M phase of the cell cycle. This G(2)/M growth arrest was associated with elevated levels of cyclin B, and reduced levels of c-MYC and MDM2. CONCLUSIONS: The ability of AdMxi1 to suppress prostate tumor cell proliferation supports a role for Mxi1 loss in the pathogenesis of a subset of human prostate cancers. Prostate 47:194-204, 2001.

Prospects for an SV40 vaccine.

The identification of SV40 as a possible cause of human cancer leads to the question of whether the unique properties of the virus can be exploited to treat patients with SV40-positive mesotheliomas, which are otherwise refractory to successful intervention. A modified SV40 T antigen, from which the transforming domains have been removed, has been cloned into a vaccinia virus vector and tested in animal tumor model systems. It has been shown to be effective against both subsequent tumor challenge and pre-existing tumors. Thus, the potential exists for use of such a vaccine in mesothelioma patients.

Posttranslational truncation and inactivation of human E-cadherin distinguishes prostate cancer from matched normal prostate.

An essential event in the progression of adenocarcinoma is the loss of organized epithelial attachment (both to the basement membrane and to adjoining epithelial cells). The E-cadherin cell adhesion molecule has an established function in maintaining normal phenotype and tissue homeostasis, and loss of E-cadherin function has been implicated in tumorigenesis. Aberrations in E-cadherin are associated with prostate cancer progression; however, these aberrations are not simply a result of prodigious allelic loss. We have previously demonstrated a novel posttranslational truncation within the cytosolic domain of native Mr 120,000 E-cadherin to a membrane-bound Mr 97,000 species. We hypothesize that truncation of E-cadherin is an inactivating event that is significantly increased in localized prostate tumors and that it represents a novel molecular event that may distinguish prostate cancer from adjacent normal tissue. E-cadherin was characterized by Western blot analysis in matched normal and cancer tissue from 18 prostate cancer patients. Imaging and densitometry software were used to quantify the truncation of E-cadherin by measuring the ratio of Mr 97,000 E-cadherin to Mr 120,000 E-cadherin, which was significantly increased in the tumor aspect of the prostate gland. Herein, we report the first experiment comparing case-matched human normal and cancerous prostate tissue in the context of E-cadherin truncation.

Benign prostatic glands at surgical margins of radical prostatectomy specimens: frequency and associated risk factors.

OBJECTIVES: Elevation of serum prostate-specific antigen (PSA) after radical prostatectomy for prostate cancer is considered a surrogate marker of therapeutic failure. The most likely explanation for early PSA failure is considered to be due to local recurrent disease, provided the patient had a nondetectable PSA level after radical prostatectomy. Others have recently suggested that benign prostatic glands located on the surgical margins may often lead to detectable PSA levels. We examined the frequency of benign prostatic glands at the surgical margins of radical prostatectomy specimens and the factors associated with this finding. METHODS: One hundred nineteen consecutive radical prostatectomies were performed by two experienced oncologic surgeons. Whole-mount sectioning of the prostatectomy specimens was performed at 3-mm intervals. Bivariate and multivariate analyses were used to determine which clinical and pathologic factors were associated with benign glands on inked surgical margins. RESULTS: Of the 119 cases, 13 (11%) had benign glands on the inked surgical margins. Four of these 13 had tumor on the inked margins. The remaining 9 cases (8%) were organ confined (pT2), with negative surgical margins. Benign glands were most often seen to involve the apex focally (7 of 9 cases). On bivariate and multivariate analyses, a high Gleason score and prostate gland volume were significantly associated with finding benign glands on the surgical margins. Only 2 of 86 patients with follow-up had PSA recurrence at 59 and 67 days and neither had benign glands on the inked surgical margins. CONCLUSIONS: The presence of benign prostatic glands identified on inked surgical margins was an infrequent occurrence in this consecutive series of 119 whole-mount prostatectomy specimens. When benign glands were identified, they most often consisted of 1 to 3 glands at the apex margin. These findings suggest that benign glands on surgical margins are an unusual cause of postoperative detectable PSA.

Prospective assessment of patient reported urinary continence after radical prostatectomy.

PURPOSE: Reported urinary continence rates after radical prostatectomy vary. Although modifications of radical prostatectomy meant to improve outcome, such as nerve sparing or bladder neck preservation, are in widespread use, to our knowledge evidence to support these practices based on patient report is scant. We evaluated the potential effects of nerve sparing and bladder neck preservation on urinary continence after radical prostatectomy, and assessed the impact of various urinary continence definitions on the observed outcome. MATERIALS AND METHODS: We prospectively evaluated a cohort of men with prostate cancer who elected surgery with and without nerve sparing, and bladder neck preservation as primary therapy. A total of 482 men completed a brief urinary continence questionnaire preoperatively and postoperatively at a median followup of 18 months. Urinary continence was followed prospectively using the questionnaire and patient reported urinary continence recovery was based on 3 definitions of continence. RESULTS: Median time to continence recovery based on patient reporting was significantly shorter in the nerve sparing than in the nonnerve sparing group when continence was defined as no urinary leakage (5.3 versus 10.9 months, p <0.01). A multivariate model controlling for baseline factors revealed that significant predictors of continence outcome were preoperative continence, patient age, nerve sparing and the interaction of nerve sparing with age (p <0.05). The definition of urinary continence also affected outcome. CONCLUSIONS: The nerve sparing technique of radical prostatectomy was associated with improved recovery of urinary continence in an age dependent manner, whereas bladder neck preservation was not beneficial. Patient age and the sensitivity of the incontinence definitions, as reflected by the associated variable rates of preoperative baseline incontinence, are significant contexts for interpreting urinary function data after radical prostatectomy. These factors may partially explain the variation in continence rates in the literature.

Cancer cells engineered to secrete granulocyte-macrophage colony-stimulating factor using ex vivo gene transfer as vaccines for the treatment of genitourinary malignancies.

When irradiated and administered intradermally as vaccines, cancer cells engineered to secrete high levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) by gene transfer elicit potent anticancer immune responses in a variety of animal tumor models. Upon vaccination, antigens present in the cancer cells are phagocytosed and processed by skin dendritic cells. These dendritic cells then prime anticancer immune responses by presenting antigenic peptides to T cells. The immune responses generated are capable of eradicating small but lethal cancer cell inocula with minimal toxicity in preclinical animal tumor studies. To develop this vaccination strategy for the treatment of human genitourinary cancers, we have conducted phase I clinical trials using human genitourinary cancer cells as sources of cancer cell antigens. In the first human clinical trial of genetically engineered cancer cell vaccines, a phase I clinical trial of kidney cancer cell vaccines (n = 18), kidney cancer cells were removed at surgery, propagated briefly in vitro, and then genetically modified to secrete high levels of GM-CSF via ex vivo transduction with the retrovirus MFG-GM-CSF. After irradiation, the kidney cancer cells were administered as vaccines to 18 patients with advanced kidney cancers. Vaccine treatment, which caused few side effects, nonetheless appeared to trigger anticancer immune responses manifest as conversion of delayed-type hypersensitivity (DTH) skin responses against irradiated autologous cancer cells after vaccination. Biopsies of vaccine sites yielded findings reminiscent of biopsies from preclinical animal model studies, with evidence of vaccine cell recruitment of dendritic cells, T cells, and eosinophils. One patient with measurable kidney cancer metastases treated at the highest vaccine dose level experienced a partial treatment response. The bioactivity of GM-CSF-secreting autologous cancer cell vaccines was confirmed in a phase I clinical trial for prostate cancer (n = 8). Vaccine cells were prepared from surgically harvested prostate tumors by ex vivo transduction with MFG-GM-CSF in a manner similar to that used for the kidney cancer trial. Vaccine treatment was well tolerated and associated with induction of anticancer immunity as assessed using DTH skin testing. In addition, new antiprostate cancer cell antibodies were detected in serum samples from treated men as a consequence of vaccination. These first clinical trials of GM-CSF-secreting cancer cell vaccines for the treatment of genitourinary cancers have demonstrated both safety and bioactivity, in that very few side effects have been seen and anticancer immune responses have been detected. Future clinical studies will be required to assess vaccine treatment efficacy, refine vaccination dose and schedule, define the appropriate clinical context for the use of such vaccines, and ascertain optimal combinations involving vaccines and other local or systemic anticancer treatments.

Bladder neck-sparing modification of radical prostatectomy adversely affects surgical margins in pathologic T3a prostate cancer.

OBJECTIVES: To determine whether the bladder neck-sparing (BNS) modification of radical retropubic prostatectomy (RRP) alters the likelihood of positive surgical margins and postsurgical prostate cancer recurrence. METHODS: Surgical outcomes, as measured by pathologic margin status and progression-free survival, were evaluated in 751 consecutive RRP cases, among whom 222 underwent BNS technique. To reduce selection bias, comparison of positive margin rates between BNS and standard RRP was stratified by pathologic stage. Differences in surgical margin rates were assessed using the chi-square test, and effects of bladder neck preservation on prostate-specific antigen (PSA)-free survival were assessed, using multivariable Cox proportional hazards analysis. RESULTS: The clinical stage, Gleason score, and preoperative serum PSA profiles were similarly distributed between patients undergoing standard RRP and those undergoing the BNS modification. Surgical margins in the unstratified entire cohort were positive at rates similar to prior reports (28% BNS, 27% standard RRP). However, stratification by pathologic stage revealed that among pT3a cancers, BNS surgery was associated with significantly higher rates of positive surgical margins than was standard RRP (47% versus 20%; chi- square = 6.32, P = 0.01). Differences in positive margin rates were not seen between the two groups at other pathologic stages. The adverse effect of BNS technique on pT3a surgical margins was associated with a trend toward an adverse effect on PSA-free survival (Cox proportional hazards P = 0.016). CONCLUSIONS: The BNS modification of RRP can be associated with an increased rate of positive surgical margins specifically in cancers that have focally penetrated through the prostatic capsule (pT3a), with an associated trend toward decreased PSA-free survival in this group. BNS surgery may, therefore, compromise the ability to completely remove a subset of cancers focally penetrating the prostatic capsule.

Antitumor efficacy of tumor-antigen-encoding recombinant poxvirus immunization in Dunning rat prostate cancer: implications for clinical genetic vaccine development.

One potential use for prostate-cancer-associated genes discovered through ongoing genetics studies entails the construction of virus- or plasmid-based recombinant vector vaccines encoding these new tumor-associated antigens (TAA) to induce TAA-specific immune responses for the prevention or therapy of prostate cancer. Clinical trials evaluating prototypes of such recombinant vaccines are under way. TAA-encoding recombinant vector vaccines, however, have not previously been evaluated in a prostate-cancer animal model. For assessment of the potential susceptibility of prostate cancer to genetic immunization strategies using TAA-encoding recombinant vectors, the antitumor efficacy of a model recombinant viral vector encoding a TAA was evaluated in rat Dunning prostate cancer. Recombinant vaccinia was chosen as a prototype virus vector encoding a TAA for these studies, and beta-galactosidase was chosen as a model target TAA. Dunning AT-2 cells were transduced with a retroviral vector to express beta-galactosidase, and the susceptibility of tumorigenic AT-2-lacZ cells to immunization with vaccinia-lacZ was measured using protection studies in Copenhagen and nu/nu rats. Stably transduced AT-2-lacZ cells expressing beta-galactosidase as measured by enzymatic substrate-based assays were found to retain their tumorigenicity in vivo despite abundant expression of rat major histocompatibility complex (MHC) class I. Immunization with model TAA-encoding recombinant vaccinia-lacZ conferred significant protection against subsequent growth of AT-2-lacZ cells in vivo (P = 0.01); however, the efficacy of such immunization was markedly dependent on the volume of tumor challenge. The antitumor efficacy of TAA-encoding recombinant vaccinia immunization was abrogated in nu/nu rats, suggesting a T-cell-dependent mechanism of activity. These studies suggest that prostate cancer may be a suitable target for immunization strategies using TAA-encoding recombinant vectors. Such immunization strategies may be more effective in settings of minimal cancer burden.

Development and validation of the expanded prostate cancer index composite (EPIC) for comprehensive assessment of health-related quality of life in men with prostate cancer.

OBJECTIVES: Health-related quality of life (HRQOL) is an increasingly important endpoint in prostate cancer care. However, pivotal issues that are not fully assessed in existing HRQOL instruments include irritative urinary symptoms, hormonal symptoms, and multi-item scores quantifying bother between urinary, sexual, bowel, and hormonal domains. We sought to develop a novel instrument to facilitate more comprehensive assessment of prostate cancer-related HRQOL. METHODS: Instrument development was based on advice from an expert panel and prostate cancer patients, which led to expanding the 20-item University of California-Los Angeles Prostate Cancer Index (UCLA-PCI) to the 50-item Expanded Prostate Index Composite (EPIC). Summary and subscale scores were derived by content and factor analyses. Reliability and validity were assessed by test-retest correlation, Cronbach's alpha coefficient, interscale correlation, and EPIC correlation with other validated instruments. RESULTS: Test-retest reliability and internal consistency were high for EPIC urinary, bowel, sexual, and hormonal domain summary scores (each r >/=0.80 and Cronbach's alpha >/=0.82) and for most domain-specific subscales. Correlations between function and bother subscales within domains were high (r >0.60). Correlations between different primary domains were consistently lower, indicating that these domains assess distinct HRQOL components. EPIC domains had weak to modest correlations with the Medical Outcomes Study 12-item Short-Form Health Survey (SF-12), indicating rationale for their concurrent use. Moderate agreement was observed between EPIC domains relevant to the Functional Assessment of Cancer Therapy Prostate module (FACT-P) and the American Urological Association Symptom Index (AUA-SI), providing criterion validity without excessive overlap. CONCLUSIONS: EPIC is a robust prostate cancer HRQOL instrument that complements prior instruments by measuring a broad spectrum of urinary, bowel, sexual, and hormonal symptoms, thereby providing a unique tool for comprehensive assessment of HRQOL issues important in contemporary prostate cancer management.

Collagen injection for the treatment of incontinence after cystectomy and orthotopic neobladder reconstruction in women.

PURPOSE: We determine the clinical efficacy of endoscopically injected collagen for the treatment of new onset urinary incontinence in women following cystectomy and orthotopic neobladder. MATERIALS AND METHODS: Three women 58 to 74 years old underwent transurethral collagen injection for stress urinary incontinence following cystectomy and orthotopic neobladder. Before cystectomy 2 women denied having any stress urinary incontinence while 1 complained of mild incontinence. Onset of incontinence following cystectomy and neobladder formation ranged from 8 months to 3 years, and average pad use ranged from 3 to 5 per 24-hour period. All patients underwent video urodynamic evaluation before collagen injection. Neobladder capacity was 180 to 400 cc and Valsalva leak point pressures ranged from 30 to 60 cm. water. RESULTS: A total of 6 injections were given, including 3 injections in 1 patient, 2 in 1 and 1 in 1. All 3 women had significant improvement or became dry with initial injection but required repeat injections to maintain improved continence status. At 7 to 8 months after the last injection 1 woman was dry, 1 used 1 or no pad daily and 1 reported no durable change in stress urinary incontinence. CONCLUSIONS: Collagen injection appears to be a successful, minimally invasive treatment for new onset stress urinary incontinence following cystectomy and orthotopic neobladder in women.

Early castration reduces prostatic carcinogenesis in transgenic mice.

OBJECTIVES: To test the hypothesis that transgenic mouse models of prostate cancer could be useful for testing chemoprevention strategies by evaluating the effects of early castration on prostate carcinogenesis in TRAMP mice. Human prostate cancer, unlike other cancers, requires androgens for oncogenesis yet acquires partial androgen independence in the castrated milieu. This paradigm is the basis for an ongoing clinical trial using selective androgen deprivation for prostate cancer chemoprevention. However, preclinical correlates for hormonal prevention or other chemoprevention strategies of prostate cancer have not previously been demonstrated in autochthonous models of prostate carcinogenesis. METHODS: Magnetic resonance imaging was used to longitudinally measure prostate growth in castrated and noncastrated TRAMP mice, and mice were prospectively examined for the onset of advanced, palpable prostate cancer. Modulation of androgen-responsive oncogene expression, as well as oncogene expression in refractory cancers, was evaluated by Western blot. RESULTS: Early castration significantly reduced prostate tumor growth as measured by magnetic resonance imaging and improved cancer-free survival. Prevention of prostate cancer development in these mice was associated with durable suppression of androgen-responsive oncogene expression (T-antigen expression not detectable by Western blot); prostate cancers refractory to the hormonal prevention strategy demonstrated androgen-independent oncogene expression. CONCLUSIONS: These findings suggest that carcinogenesis related to androgen-responsive oncogene expression can be prevented in some cases by hormonal manipulation and that transgenic TRAMP mice are useful for the preclinical evaluation of hormonal and possibly other strategies of prostate cancer chemoprevention.

Induction of immunity to prostate cancer antigens: results of a clinical trial of vaccination with irradiated autologous prostate tumor cells engineered to secrete granulocyte-macrophage colony-stimulating factor using ex vivo gene transfer.

Vaccination with irradiated granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting gene-transduced cancer vaccines induces tumoricidal immune responses. In a Phase I human gene therapy trial, eight immunocompetent prostate cancer (PCA) patients were treated with autologous, GM-CSF-secreting, irradiated tumor vaccines prepared from ex vivo retroviral transduction of surgically harvested cells. Expansion of primary cultures of autologous vaccine cells was successful to meet trial specifications in 8 of 11 cases (73%); the yields of the primary culture cell limited the number of courses of vaccination. Side effects were pruritus, erythema, and swelling at vaccination sites. Vaccine site biopsies manifested infiltrates of dendritic cells and macrophages among prostate tumor vaccine cells. Vaccination activated new T-cell and B-cell immune responses against PCA antigens. T-cell responses, evaluated by assessing delayed-type hypersensitivity (DTH) reactions against untransduced autologous tumor cells, were evident in two of eight patients before vaccination and in seven of eight patients after treatment. Reactive DTH site biopsies manifested infiltrates of effector cells consisting of CD45RO+ T-cells, and degranulating eosinophils consistent with activation of both Th1 and Th2 T-cell responses. A distinctive eosinophilic vasculitis was evident near autologous tumor cells at vaccine sites, and at DTH sites. B-cell responses were also induced. Sera from three of eight vaccinated men contained new antibodies recognizing polypeptides of 26, 31, and 150 kDa in protein extracts from prostate cells. The 150-kDa polypeptide was expressed by LNCaP and PC-3 PCA cells, as well as by normal prostate epithelial cells, but not by prostate stromal cells. No antibodies against prostate-specific antigen were detected. These data suggest that both T-cell and B-cell immune responses to human PCA can be generated by treatment with irradiated, GM-CSF gene-transduced PCA vaccines.

Recombinant vaccinia-PSA (PROSTVAC) can induce a prostate-specific immune response in androgen-modulated human prostate cancer.

OBJECTIVES: Prostate cancer recurrence, evidenced by rising prostate-specific antigen (PSA) levels after radical prostatectomy, is an increasingly prevalent clinical problem in need of new treatment options. Preclinical studies have suggested that for tumors in general, settings of minimal cancer volume may be uniquely suitable for recombinant vaccine therapy targeting tumor-associated antigens. A clinical study was undertaken to evaluate the safety and biologic effects of vaccinia-PSA (PROSTVAC) administered to subjects with postprostatectomy recurrence of prostate cancer and to assess the feasibility of interrupted androgen deprivation as a tool for modulating expression of the vaccine target antigen, as well as detecting vaccine bioactivity in vivo. METHODS: A limited Phase I clinical trial was conducted to evaluate the safety and biologic effects of vaccinia-PSA administered in 6 patients with androgen-modulated recurrence of prostate cancer after radical prostatectomy. End points included toxicity, serum PSA rise related to serum testosterone restoration, and immunologic effects measured by Western blot analysis for anti-PSA antibody induction. RESULTS: Toxicity was minimal, and dose-limiting toxicity was not observed. Noteworthy variability in time required for testosterone restoration (after interruption of androgen deprivation therapy) was observed. One subject showed continued undetectable serum PSA (less than 0.2 ng/mL) for over 8 months after testosterone restoration, an interval longer than those reported in previous androgen deprivation interruption studies. Primary anti-PSA IgG antibody activity was induced after vaccinia-PSA immunization in 1 subject, although such antibodies were detectable in several subjects at baseline. CONCLUSIONS: Interrupted androgen deprivation may be a useful tool for modulating prostate cancer bioactivity in clinical trials developing novel biologic therapies. Immune responses against PSA may be present among some patients with prostate cancer at baseline and may be induced in others through vaccinia-PSA immunization.

Induction of tumor antigen-specific immunity in vivo by a novel vaccinia vector encoding safety-modified simian virus 40 T antigen.

BACKGROUND: Evidence that simian virus 40 (SV40) is associated with human mesotheliomas, osteosarcomas, and brain tumors suggests that a recombinant vaccine directed against lethal cancers expressing SV40 T antigen (Tag) could have clinical utility. To address this potential need, we designed a novel vaccinia virus construct that encodes an SV40 Tag in which oncogenic domains were excluded and immunogenic domains were preserved. We named this recombinant construct vaccinia-encoding safety-modified SV40 Tag (vac-mTag). METHODS: Purified vac-mTag was characterized by DNA sequencing, reverse transcription-coupled polymerase chain reaction, western blot analysis, and immunocytochemical techniques. Induction of Tag-specific immunity was examined by cytolytic T-cell assays, and the efficacy of vac-mTag in protecting animals against Tag-expressing tumors and in treating pre-established microscopic tumors was evaluated in vac-mTag-immunized BALB/c mice. RESULTS: The immune response elicited by vac-mTag in C57BL/6 and BALB/c mice included an SV40 Tag-specific cytolytic T-lymphocyte activity against syngeneic (identical genetic background) SV40 Tag-expressing tumor targets. Immunization of mice with a single dose of vac-mTag resulted in potent protection against subsequent challenge with a lethal mouse cancer expressing SV40 Tag. In addition, single-dose vac-mTag immunization coadministered with interleukin 2 produced a possible therapeutic effect against a preadministered microscopic (but lethal) burden of Tag-expressing tumor cells in vivo. CONCLUSION: vac-mTag induces an effective immune response in mice that is specific for a tumor-associated antigen. This response protects against a lethal tumor challenge and results in a possible therapeutic effect against Tag-expressing tumors in vivo. Thus, vac-mTag provides a new avenue for the development of therapies for human cancers thought to be associated with SV40.

Prospects and limitations of recombinant poxviruses for prostate cancer immunotherapy.

Prostate cancer is a disease that may be amenable to immunotherapy approaches, as evidenced by the ability to induce human cytotoxic immune responses against prostate cancer cells. Recent interest in recombinant poxvirus vaccines coupled with the need for new prostate cancer therapies has led to the development of several recombinant poxvirus agents designed for prostate cancer treatment. Whether these agents will be effective in treating prostate cancer is under investigation in several ongoing and upcoming clinical trials. In the meantime, data from preclinical tumor models have provided information that may aid in improving recombinant poxviruses for clinical use. While animal studies have shown the ability of recombinant poxvirus vaccination to induce an immune response that protects against lethal tumor, these antitumor effects are variable and depend on a number of factors. Co-expression of immunomodulating gene products, such as cytokines and costimulatory molecules, have been shown to influence antitumor immunity; in fact, cytokine delivery alone can be enough to protect against tumor-related death. Patterns and levels of recombinant antigen expression also affect the immune response to that antigen, as seen by studies of various poxvirus promoters and cell compartment-targeting sequences. In addition, vaccine strategies targeting self-antigens have shown that immunological tolerance can negatively impact the induction of antitumor and antigen-specific immunity. Although vaccinia virus has been most intensely studied thus far, other poxviruses, including fowlpox and canarypox, are also promising vaccine candidates. These alternative vectors may circumvent some of the disadvantages associated with vaccinia virus, such as pre-existing vaccinia immunity. A deeper understanding of these factors and others that impact the development of antitumor immunity will be necessary to guide the development of recombinant poxviruses for prostate cancer therapy.

Longitudinal cohort analysis of lethal prostate cancer progression in transgenic mice.

PURPOSE: Human prostate cancer is variably lethal, shows heterogeneous progression, and exhibits a spectrum of histopathology. Traditional rodent models of prostate cancer lack these characteristics. An alternative, autochthonous model of prostate cancer consists of transgenic mice which develop prostate cancer due to prostatic expression of SV40 T antigen. Lethal progression of such cancers in individual mice has not been previously characterized. Studies were undertaken to characterize the longitudinal progression of prostate cancers in these transgenic mice. METHODS: A prospective longitudinal cohort study was undertaken to characterize prostate cancer volume, progression, lethality, and histological heterogeneity in a transgenic mouse model of prostatic adenocarcinoma. Fifty-one transgenic mice were followed prospectively to determine the age at onset of palpable tumor and age at cancer-related death. Tumor volume was followed longitudinally by magnetic resonance imaging (MRI) in a subset of these mice and lethal cancers were evaluated by histopathology. RESULTS: Primary tumors became palpable at 10-38 weeks of age. Palpable tumors always preceded lethal progression. Cancer death followed 2-9 weeks later, and age at cancer death varied from 24 to 39 weeks of age. The histopathological changes were heterogeneous. Primary tumors were detectable by MRI before they became detectable by palpation. MRI showed that, analogous to human prostate cancers, volume of early stage primary tumors did not necessarily predict age at cancer death. CONCLUSION: Prostate cancer in transgenic mice mimics heterogeneic tumor progression in human prostate cancer, providing a uniquely relevant pre-clinical model. Tumor detection by MRI and palpation are valid surrogate measures of tumor progression in this model.

Clinical and biological characteristics of familial benign prostatic hyperplasia.

PURPOSE: We attempted to determine the clinical and biological characteristics of familial benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: Urinary flow rate, prostate size, symptom score, serum prostate specific antigen, testosterone and dihydrotestosterone were measured in subjects who participated in the nationwide Merck phase III finasteride clinical trial. Findings in the 69 men with familial BPH (3 or more family members with BPH, including the proband) were compared to those in the 345 with no family history of BPH. Logistic regression was used to detect relationships between familial BPH, and these variables before and after 5 alpha-reductase inhibition with finasteride. RESULTS: Familial BPH was characterized by large prostate size. Mean prostate volume in men with familial and sporadic BPH was 82.7 and 55.5 ml., respectively (p < 0.001). Other clinical findings, including serum androgen levels and response to finasteride, were similar in familial and sporadic BPH. The frequency of familial BPH in patients with prostate size in the largest and smallest deciles was 46 and 13%, respectively. CONCLUSIONS: Familial BPH in this group of patients was associated with large prostate size, normal serum androgen levels and normal response to 5 alpha-reductase inhibition. A genetic factor responsible for familial BPH may exert its influence through androgen independent control of prostatic growth.