Role of denosumab in prostate cancer.

Prostate cancer is known to have a tissue tropism for bone. This tissue tropism coupled with the experience with androgen deprivation therapy (ADT) over the past decade has led to heightened awareness of bone complications. Osteopenia and subsequent skeletal-related events (SREs) are one of the more concerning repercussions of ADT along with cardiovascular sequelae. To combat this decrease in bone mineral density, several agents have been developed for bone protection. The largest experience is with bisphosphonates (BPs), but recently (2011) head to head trials have established the role of monoclonal antibodies, particularly in patients with prostate cancer bone metastasis. For patients initiating ADT, monthly denosumab increased bone mineral density, the time for occurrence of any bone metastasis and time for symptomatic bone metastasis. Denosumab is a fully human monoclonal antibody of the IgG(2) subtype that selectively binds and neutralizes receptor activator NF kappa B ligand (RANKL), inhibiting osteoclastogenesis and bone turnover. In vitro binding assays have shown high-affinity binding of denosumab and osteoprotegerin to both soluble and membrane-bound forms of human RANKL. As clinicians may be less familiar with this newer agent, we compiled this review to summarize denosumab's current clinical indications for bone stabilization and mechanism of reduction in tumor burden.

Construct validity in a high-fidelity prostate exam simulator.

BACKGROUND: All health care practitioners should be facile in the digital rectal exam (DRE) as it provides prostate, rectal and neurological information. The purpose of this study was first to justify our hypothesis that tissue elasticity is indicative of carcinomatous changes. Second, we employed urological surgeons to evaluate our prostate simulator in three ways: (1) authenticate that the elasticity of the simulated prostates accurately represents the range of normal prostate stiffness, (2) determine the range of nodule size reasonably palpable by DRE and (3) discern what degree of elasticity difference within the same prostate suggests malignancy. METHODS: Institutional Review Board-approved materials characterization, human-subjects experiments, histopathology and chart abstraction of clinical history were performed. Material characterization of 21 ex-vivo prostatectomy specimens was evaluated using a custom-built, portable spherical indentation device while a novel prostate simulator was employed to measure human-subject perception of prostatic state. RESULTS: From the materials characterization, the measurements of the 21 gross prostates and 40 cross-sections yielded 306 data points. Within the same prostate, cancer was always stiffer. Of the seven cases with an abnormal DRE, the DRE accurately identified adenocarcinoma in 85%. From the human-subjects experiments, the simulated prostates evaluated by urologists ranged in stiffness from 8.9 to 91 kPa, mimicking the range found on ex vivo analysis of 4.6-236.7 kPa. The urological surgeons determined the upper limit of stiffness palpated as realistic for a healthy prostate was 59.63 kPa while the lower limit of stiffness was 27.1 kPa. Nodule size less than 7.5 mm was felt to be too small to reasonably palpate. CONCLUSIONS: We found it is not the absolute elasticity of the nodule, but rather the relationship of the nodule with the background prostate elasticity that constitutes the critical tactile feedback. Prostate simulator training may lead to greater familiarity with pertinent diagnostic cues and diagnosis of prostate cancer.

Concordance in the perception of couples recovering from primary surgical treatment of prostate cancer.

Although prostate cancer affects men, research shows effects on both members of the couple. We analyzed concordance in couples recovering from primary surgical treatment of prostate cancer when surveyed on psychological domains including emotional status, relationship, self-image, partnership quality and support. Retrospective Sexual Surveys were utilized to survey physiological changes as well as psychological effects. In total, 28 heterosexual couples (56 people) were enrolled. Patients were treated between February 2002 and March 2007 with a median follow-up of 26 (range: 4-59) months. When polled on psychological aspects that may have been affected by treatment, overall concordance was 75.0%. Partnership had the highest concordance (92.2%) with treatment satisfaction questions following in second (90.7%). Subcategories focused on self-image (77.5%), relationship (67.3%), support (66.4%) and emotional status (55.6%), were less concordant. Although couples report relationships as strong and team-like, misconception between partners is widespread. Further research with regards to the effect of such disparities in couples might provide additional insight into improving recovery.

Sociodemographic factors associated with postprostatectomy radiotherapy.

PURPOSE: To determine if nonclinical factors affect the use of adjuvant radiation therapy after surgical resection of the prostate gland. METHODS: Using the National Cancer Institute's Surveillance Epidemiology and End Results (SEER) public use data files, we identified men with localized/regional prostate cancer who underwent postprostatectomy radiotherapy within 4 months of surgery. We used 2000 Census information to ascribe a median education and income level to these men based on the county of residence and ethnicity. RESULTS: Of 34,763 men who underwent surgical resection, 1549 received postprostatectomy radiotherapy. Those with higher tumor grade and from certain geographic regions (Seattle and Hawaii) had significantly higher rates of radiotherapy while being older and from other geographic regions (Detroit, Utah, and New Mexico) was protective. The use of additional radiation therapy was not affected by ethnicity, income level, or educational attainment. CONCLUSIONS: We found no socioeconomic or demographic disparities in the receipt of postprostatectomy radiotherapy. Geographic variation in postprostatectomy radiotherapy may be explained by limited evidence supporting its use in clinical practice.

The effect of sampling more cores on the predictive accuracy of pathological grade and tumour distribution in the prostate biopsy.

OBJECTIVE: To determine if increasing the number of cores at biopsy improves the predictive accuracy of the Gleason score or aids in anticipating the location and volume of prostate tumour. PATIENTS AND METHODS: The charts of 75 consecutive patients who underwent radical retropubic prostatectomy for clinical T1-2 adenocarcinoma of the prostate were reviewed retrospectively; 31 patients had a sextant biopsy (group 1) and 44 had > or = 8 cores taken (group 2). The concordance between biopsy data and final prostatectomy Gleason score, tumour location and volume was determined for each group. RESULTS: There were no differences in mean age, prostate-specific antigen level before biopsy or biopsy Gleason score for the two groups; 58% of group 1 had their final pathological grade changed after prostatectomy, vs 29% of group 2 (P < 0.05). In neither group was there a significant correlation between the percentage of cores positive for tumour and the percentage volume of prostate involved with cancer, or the ability of the biopsy to predict tumour location. CONCLUSION: Taking > or = 8 biopsy cores improved the pathological grading accuracy, which may be valuable in choosing a treatment for the patient with newly diagnosed prostate cancer.

The role of vascular endothelial growth factor in the tissue specific in vivo growth of prostate cancer cells.

Despite the fact that cancer cells can be found in many vascular beds, continued growth of the metastatic tumor focus exhibits a significant degree of 'organ tropism', with only certain organs exhibiting the ravages of metastatic disease. Since a limiting factor to the growth of metastases beyond 2 mm in diameter, may be a lack of angiogenesis, we sought to determine whether tumor overexpression of vascular endothelial growth factor (VEGF), a potent angiogenic factor related to prostate cancer metastasis, is causally related to organ specific tumor growth in a prostate cancer xenograft model. LnCaP-C4-2 is a subline of the human prostate cancer cell line LnCaP which unlike its parent, has a predilection for growth in bone, a common site for human prostate cancer metastasis. LnCaP-C4-2, is tumorigenic when injected intrafemorally in mice but requires co-injection of stromal components (Matrigel) to be tumorigenic in the subcutaneous site. Because of this site-specific tumorigenicity profile and relatively low VEGF mRNA and protein expression, this line was transfected with a full length cDNA encoding the 165 isoform of VEGF. Cells either overexpressing or not expressing the transfected gene were selected for study in vivo and in vitro. Overexpression of VEGF did not seem to affect in vitro cell growth. Such overexpression did affect tumorigenicity and in vivo tumor growth rates when cells were inoculated in the subcutaneus site. Interestingly, the dependency of subcutaneous tumorigenicity on Matrigel co-inoculation was still observed in cells overexpressing VEGF. In contrast to the impact that VEGF overexpression has on subcutaneous tumorigenicity, no such effect was observed when cells were inoculated in orthotopic/prostate (primary) or intrafemoral (metastatic) sites. In view of the importance of tumor-stromal interactions in growth of xenografts, we sought to determine if the host strain is important to the observed tumorigenicity effects of VEGF overexpression. No differences in subcutaneous tumorigenicity as a function of either Matrigel use or VEGF expression levels were observed when SCID/bg and RAG/pfp mouse strains were compared. In conclusion, our data indicate that the biological impact of prostate tumor VEGF overexpression is organ/site specific, leading to the speculation that it may play a part in the observed organ tropism of metastatic spread. In addition, these results highlight the importance of the tumor microenvironment in determining the biological impact of transfected and overexpressed genes in the study of tumor biology.

Radioactive implant migration in patients treated for localized prostate cancer with interstitial brachytherapy.

PURPOSE: In several of the initial patients undergoing brachytherapy at our institution radioactive implants were visible in the thorax on chest radiography. The clinical ramifications of this unanticipated finding were unclear. Thus, we investigated the incidence of brachytherapy seed migration to the chest and whether these seeds were associated with any clinical significance. MATERIALS AND METHODS: We retrospectively reviewed the records of all patients who underwent ultrasound or computerized tomography guided brachytherapy of 103palladium seeds from March 1997 to March 1999. This list of patients on brachytherapy was then matched against the radiology computer system to determine those who had undergone chest X-ray after brachytherapy. When the radiology report was unclear regarding brachytherapy seeds, chest x-rays were reviewed by one of us (R. O.) to determine the presence and position of the seeds. RESULTS: Post-brachytherapy chest x-rays were available in 110 of the 183 patients. In 78 cases no brachytherapy seeds were identified. Radioactive implants were identified on chest radiography in 32 patients (29%), including 1 to 5 seeds in 20, 8, 1, 2 and 1, respectively. No patients complained of any change in pulmonary symptoms after brachytherapy. CONCLUSIONS: Radioactive implants migrated after brachytherapy for localized prostate cancer in 29% of the patients who underwent post-procedure radiography. There did not appear to be a pattern to the seed distribution. However, while the incidence was not negligible, no patient appeared to have any acute pulmonary symptoms. Therefore, while the migration of radioactive implants to the chest is a real phenomenon, it appears to have no adverse clinical consequences in the early post-procedure period.

Orthotopic neobladder following cystectomy: indications, management, and outcomes.

Gross painless hematuria often prompts patients to seek medical attention. For some persons, especially those aged 55 to 80 years, this hematuria will prove to be the result of bladder cancer. Patients found to have muscle-invasive disease commonly undergo radical cystectomy and urinary diversion. The decision about which urinary diversion will be best suited to the individual patient is complex and depends on multiple factors relating to the patient and the tumor as well as a clear understanding about the risks and benefits of each diversion. This article will discuss issues such as cancer control, preoperative and postoperative care, management of the condition at home, and quality of life associated with the various urinary diversion options, with a special emphasis on orthotopic neobladder reconstruction. Awareness of the special issues associated with this procedure is needed to safely counsel and care for patients with these forms of bladder substitution.

A prospective pilot evaluation of urinary and immunohistochemical markers as predictors of clinical stage of urothelial carcinoma of the bladder.

OBJECTIVE: To determine, in patients newly diagnosed with bladder cancer, whether p53, epidermal growth factor receptor (EGFR), microvessel density (MVD), urinary bladder tumour antigen (BTA TRAKtrade mark, Bion Diagnostic Sciences, Redmond, WA) and cytology were predictive of clinical stage, evaluated as a function of the clinical stage obtained at transurethral resection of the bladder tumour with and without the addition of clinical grade, a known strong predictor of clinical stage. PATIENTS AND METHODS: Between December 1997 and September 1998, 22 men and seven women with a cystoscopic diagnosis of urothelial bladder carcinoma were prospectively enrolled in the study. Urine was collected for cytological and BTA TRAK evaluation before transurethral resection. Tumour grade and clinical stage were obtained from the transurethral resection specimen. MVD was evaluated by computerized calculations of 'optimal MVD' (OMVD) and 'area-weighted MVD' (AWMVD) while p53 and EGFR information was obtained by manual immunohistochemical techniques; 21 patients had sufficient tissue for all immunohistochemical assessments and comprised the study group. Univariate and multivariate comparisons were carried out to determine the contribution of each variable to the prediction of clinical stage. RESULTS: Although there was a trend, cytological analysis and p53 and MVD immunoreactivity did not significantly correlate with clinical stage, while tumour grade, BTA TRAK and EGFR immunoreactivity did. In a univariate analysis, tumour grade and BTA TRAK were related to clinical stage. In a multivariate analysis, grade was the single best predictor of clinical stage. This analysis also showed that the addition of BTA TRAK and MVD information to grade incrementally improved the predictive ability of grade. CONCLUSIONS: This pilot study suggests that BTA TRAK and MVD contribute incremental information to tumour grade in predicting the clinical stage of urothelial carcinomas of the bladder; grade remains the most important predictor. These results suggest that further work with BTA TRAK and MVD in more patients and on biopsy material obtained during clinic cystoscopy is warranted for the future development of less invasive methods of identifying patients with invasive bladder cancer.

Quality-of-life comparison of radical prostatectomy and interstitial brachytherapy in the treatment of clinically localized prostate cancer.

OBJECTIVES: Interstitial brachytherapy (BT) is increasingly utilized as a curative treatment for localized prostate cancer because it is perceived as less morbid than surgical alternatives. However, to date no studies have directly compared the quality of life and symptoms of patients with localized prostate cancer treated with curative intent by radical prostatectomy with those treated by either BT alone or BT combined with external beam radiation. METHODS: On June 1, 1998, 242 men with clinically localized Stage T1c to T3 adenocarcinoma of the prostate, treated at our institution with curative intent from January 1, 1997 to June 1, 1998, were mailed a questionnaire. Cross-sectional analysis of returned questionnaires was carried out. Patients were treated with either radical prostatectomy (RP), palladium-103 (Pd(103)) brachytherapy (115 Gy) monotherapy (BTM), or Pd(103) combined brachytherapy (90 Gy) and external beam radiation (40 to 45 Gy) (BTC). The primary outcome measures were the Functional Assessment of Cancer Therapy scale (FACT-G), American Urological Association (AUA)/international prostate symptom score (IPSS), "Urinary Function Questionnaire for Men after Radical Prostatectomy," and Brief Sexual Function Inventory. RESULTS: Data from 138 patients were included in the analysis; 27 had RP, 70 had BTM, and 41 had BTC. Total FACT-G and personal well-being scores were significantly lower in the BTC group. Brachytherapy monotherapy and RP had similar scores on the FACT-G, with surgical patients having the lowest IPSS scores. Correlations were noted between total FACT-G and urinary symptom score, degree of sexual function, frequency of diarrhea, and frequency of hot flashes. Bothersomeness of urinary function correlated with the degree of urinary control. The radical prostatectomy and BTM groups had improvement in quality of life, voiding, diarrhea, and sexual function with time, whereas the BTC group experienced a decline. CONCLUSIONS: Patients treated with BTC had an overall lower quality of life compared with those treated by RP and BTM, and RP patients reported fewer irritative or obstructive voiding complaints. Although the consistency and magnitude of these trends require further study, our data suggest that RP remains a well-tolerated and accepted option.

Microvessel density, p53, retinoblastoma, and chromogranin A immunohistochemistry as predictors of disease-specific survival following radical prostatectomy for carcinoma of the prostate.

OBJECTIVES: Angiogenesis has been shown to be related to p53 and retinoblastoma gene function as well as to neuroendocrine differentiation (as measured by chromogranin A staining) in prostate tumors. Studies have indicated that immunohistochemical assessment of p53, retinoblastoma, and chromogranin A in prostate cancers treated by radical prostatectomy can be useful in predicting disease-specific survival, whereas the degree of microvessel density (MVD), a measure of angiogenesis, correlates with disease recurrence. The ability of MVD, however, to predict disease-specific survival either alone or in conjunction with other prognostic factors has not yet been evaluated. The purpose of our study was to determine the relative importance of p53, retinoblastoma, and chromogranin A as well as MVD in the prediction of disease-specific survival following radical prostatectomy in conjunction with classical pathologic assessment. METHODS: From 1970 to 1984, radical prostatectomy was performed on 75 patients with clinical Stage A2 to B2 adenocarcinoma of the prostate. No neoadjuvant or adjuvant treatments were given, and patients were followed until death. Prostatectomy specimens were examined to evaluate conventional pathologic parameters. In addition, the tissue was immunohistochemically stained for p53, retinoblastoma, chromogranin A, and endothelial cells. A previously described computerized imaging system analyzed the microvessels and computed both "optimized" and "area-weighted" MVD scores. Proportional hazard models were used to investigate the simultaneous association of these variables with disease-specific survival. RESULTS: Of the 75 patients, 4 had follow-up of less than 3 months, and 29 patients had inadequate tissue for analysis of all immunohistochemical markers. The analyzed subset of 42 patients was found to be representative of the cohort of 71 patients. Multivariate analysis revealed that p53 and retinoblastoma have the greatest prognostic importance regarding disease-specific survival. Chromogranin A and optimized or area-weighted MVD scores were of no additional value when p53 and retinoblastoma were assessed. CONCLUSIONS: Microvessel density, as a determinant of angiogenesis and chromogranin A, does not seem to add significantly to the prognostic disease-specific survival information provided by conventional pathology combined with p53 and retinoblastoma assessment.