Development and validation of a 32-gene prognostic index for prostate cancer progression.

The accurate determination of the risk of cancer recurrence is an important unmet need in the management of prostate cancer. Patients and physicians must weigh the benefits of currently available therapies against the potential morbidity of these treatments. Herein we describe the development of a gene expression-based continuous risk index and a validation of this test in an independent, blinded cohort of post-radical prostatectomy (RP) patients. A gene expression signature, prognostic for prostate-specific antigen (PSA) recurrence, was identified through a bioinformatic analysis of the expression of 1,536 genes in malignant prostate tissue from a training cohort of consecutive patients treated with RP. The assay was transferred to a real-time RT-PCR platform, and a continuous risk index model was constructed based on the expression of 32 genes. This 32-gene risk index model was validated in an independent, blinded cohort of 270 RP patients. In multivariate analyses, the risk index was prognostic for risk of PSA recurrence and had added value over standard prognostic markers such as Gleason score, pathologic tumor stage, surgical margin status, and presurgery PSA (hazard ratio, 4.05; 95% confidence interval, 1.50-10.94; P = 0.0057). Furthermore, RP patients could be stratified based on the risk of PSA recurrence and the development of metastatic disease. The 32-gene signature identified here is a robust prognostic marker for disease recurrence. This assay may aid in postoperative treatment selection and has the potential to impact decision making at the biopsy stage.

Long-term outcomes of organ preservation in patients with small cell carcinoma of the bladder.

BACKGROUND: Small cell carcinoma of the bladder is an uncommon but clinically aggressive disease. There is no standard surgical or medical management for the disease. METHODS: Between 1995 and 2009, 28 patients underwent transurethral resection (TUR) and/or cystectomy, chemotherapy, and/or radiation for small cell carcinoma of the bladder at our institution. RESULTS: The median follow-up for survivors was 34 months. Patients presented most often with muscle-invasive disease (T2-4 - 89%), and 21% had lymph node/distant metastases. Tobacco use and chemical exposure were noted in 64 and 4% of patients, respectively. Patients with T1-2N0M0 had a median survival of 22 months compared to 8 months for those with more advanced disease (p = 0.03). Patients with T3-4 or nodal/metastatic disease who were given chemotherapy had an improved survival compared to those with T3-4 or nodal/metastatic disease who did not undergo chemotherapy (13 vs. 4 months, p = 0.005). The median time to recurrence of the entire cohort was 8 months, overall and cancer-specific survival was 14 months, and 5-year survival was 11%. CONCLUSIONS: Small cell carcinoma of the bladder is an aggressive disease with poor outcomes. Patients with T1-2N0M0 disease survived longer than those with advanced disease. Patients with T3-4 or nodal/metastatic disease had improved survival with chemotherapy.

Penile cancer: organ-sparing techniques.

To compare the oncological safety of treating patients with penile cancer with conservative techniques developed to preserve function, cosmesis and psychological well-being with more radical ablative strategies. We conducted an extensive review of the literature of penile-preserving and ablative techniques and report on the oncological as well as functional outcomes. There were no randomised studies comparing penile-preserving and ablative techniques. Most studies consisted of retrospective cohorts. The quality of evidence was level 3 at best. Cancer-specific survival is similar in penile-preserving and ablative approaches for low-stage disease. Penile preservation is better for functional and cosmetic outcomes and should be offered as a primary treatment method in men with low-stage penile cancer.

Long-term outcomes of surgical management for nonmalignant perineal disease.

PURPOSE: A number of nonmalignant perineal diseases (focal and systemic) require surgery. The long-term outcome of various types of wound coverage for these diseases is not well described. We report the outcomes of perineal reconstruction for these diseases. MATERIALS AND METHODS: We identified 32 patients who underwent surgery from July 1995 to December 2012 for a nonmalignant conditions, including local disease (perineal gangrene and focal granulomatous/idiopathic lymphangitis) and regional/systemic disease (post-radiation lymphedema, lymphedema praecox and hidradenitis suppurativa), who had greater than 1-year followup. Wound closure was achieved by split-thickness skin graft, primary closure, musculocutaneous flap or healing by secondary intention. Long-term cosmetic/functional outcomes were measured semiquantitatively. RESULTS: Median patient age was 57 years (range 41 to 86) and median followup was 60 months (range 12 to 99). Of the patients 23 (72%) received a split-thickness skin graft, 2 (6%) underwent primary closure, 2 (6%) received a pedicled flap and 5 (16%) healed by secondary intention. Patients with perineal gangrene (21), focal granulomatous lymphangitis (4) and focal idiopathic lymphangitis (1) had favorable cosmetic/functional results regardless of closure type. All 4 patients with perineal gangrene who received a penile split-thickness skin graft and had erectile function before illness regained function after closure. Grafting for systemic lymphatic disease, such as post-radiation lymphedema in 3 cases, lymphedema praecox in 2 and hidradenitis suppurativa in 1, had mostly unfavorable cosmetic/functional long-term results. CONCLUSIONS: Wound closure, including grafts/flaps, for local cutaneous and lymphatic diseases affecting the perineum have excellent cosmetic and functional results. In contrast, grafts for regional/systemic diseases have suboptimal results and may assume the characteristics of the original disease.

Complications and long-term results of salvage cystectomy after failed bladder sparing therapy for muscle invasive bladder cancer.

PURPOSE: Radical cystectomy has been the standard treatment for muscle invasive bladder cancer. Combined modality therapy involving transurethral bladder tumor resection, external beam radiation and chemotherapy is an effective alternative to cystectomy in selected patients. Salvage cystectomy is reserved for those in whom combined modality therapy fails. We characterized complications associated with salvage cystectomy. MATERIALS AND METHODS: From 1986 to 2007 of 348 patients undergoing bladder sparing therapy 102 (29%) underwent salvage cystectomy, 91 of whom were treated at Massachusetts General Hospital after receiving combined modality therapy for T2-T4aNxM0 bladder cancer. Patients underwent transurethral bladder tumor resection followed by chemoradiation (40 Gy). Early assessment was performed by cystoscopy/re-biopsy. Patients with complete response continued with consolidation chemoradiation (total dose 64 Gy). Immediate salvage cystectomy (50 of 91) was performed for persistent disease, while delayed salvage cystectomy (41 of 91) was performed for an invasive recurrence. Complications were classified using the Clavien system. RESULTS: Median patient age was 69.4 years (range 27.5 to 88.9) and median living patient followup was 12 years (range 0 to 23). Of the patients 99% (90 of 91) underwent ileal diversion. Complications of any grade within 90 days occurred in 69% (63 of 91) of patients and 16% (15 of 91) experienced major complications within 90 days. Of the patients 21% (19 of 91) required hospital readmission within 90 days. The 90-day mortality rate was 2.2% (2 of 91). Significant cardiovascular/hematological complications (pulmonary embolism, myocardial infarction, deep vein thrombosis, transfusion) within 90 days were more common in the immediate than in the delayed cystectomy group (37% vs 15%, p = 0.02). Tissue healing complications (fascial dehiscence, wound infection, ureteral stricture, anastomotic stricture, stoma/loop revisions) were more common in the delayed than in the immediate cystectomy group (35% vs 12%, p = 0.05). CONCLUSIONS: Salvage cystectomy is associated with acceptable morbidity, although complication rates are slightly higher than for other cystectomy series. Immediate cystectomies have more cardiovascular/hematological complications while delayed cystectomies have more tissue healing complications.

A close surgical margin after radical prostatectomy is an independent predictor of recurrence.

PURPOSE: The term close surgical margin refers to a tumor extending to the inked margin of the specimen without reaching it. Current guidelines state that a close surgical margin should simply be reported as negative. However, this recommendation remains controversial and relies on limited evidence. We evaluated the impact of close surgical margins on the long-term risk of biochemical recurrence after radical prostatectomy. MATERIALS AND METHODS: We identified 1,195 consecutive patients who underwent radical prostatectomy and lymphadenectomy for localized prostate cancer at our institution from 1993 to 1999. In 894 of these patients associations between margin status and location, Gleason score, pathological stage, preoperative prostate specific antigen, prostate weight and age with the risk of biochemical recurrence were examined. RESULTS: Of these 894 patients 644 (72%) had negative margins and of these patients 100 (15.5%) had close surgical margins. In the group with prostate specific antigen failure, median time to recurrence was 3.5 years. In the group without recurrence median followup was 9.9 years. Cumulative recurrence-free survival differed significantly among positive, negative and close surgical margins (p <0.001). On multivariate analysis a close surgical margin constituted a significant, independent predictor of recurrence (HR 2.1, 95% CI 1.04-4.33). Gleason score and positive margins were the strongest prognostic factors. CONCLUSIONS: In this cohort close surgical margins were independently associated with a twofold risk of postoperative biochemical recurrence. Further evaluation of the clinical significance of close surgical margins is indicated as they might be an indicator of local recurrence and of relevance when considering salvage therapy.

Animal models in urinary diversion.

We set out to critically assess the value of animal experimentation in urinary diversion through intestinal segments, as some authors question the effectiveness of animal research, criticising the methodological quality, lack of standardization, inadequate reporting and the few systematic reviews in this field. Based on a comprehensive MEDLINE literature search (MeSH database; search terms: urinary diversion, urinary reservoirs, continent, rat, dog, animal models) we retrieved and evaluated all full-length papers published in English, German, French, and Spanish languages from 1966 to 2011 reporting the use of animal models in the setting of urinary diversion. Studies were stratified according to the addressed research question. Within each category species, gender, number of animals, age at procedure, type of diversion, mortality, length of follow-up, experimental procedure and outcome were recorded and tabulated. In all, 159 articles were judged to be relevant and while there are numerous animal models only a few have been used in more than one study. Animals were used for the systematic study of new surgical techniques (93 articles) or metabolic and functional consequences of urinary reconstruction (66 articles). For the latter purpose, the most often used animal is the rat, whereas the dog model is preferred for technical experimentation. In many studies, the validity of the model is at least questionable. Animal experiments have repeatedly been conducted addressing the same question, often with striking discrepancies in outcome. Animal studies were even performed after a surgical technique had been pioneered in humans. The use of animal models in urinary diversion is far from standardized rendering the results less than ideal for comparison across studies. Due to differences in anatomy and physiology, the applicability of findings in animal experiments to clinical urology is limited. Continued effort is needed to optimise the use of animal models in experimental urology.

Long-term outcome of excisional organ sparing surgery for carcinoma of the penis.

PURPOSE: We present our experience with penile sparing surgery for localized carcinoma in situ and T1 penile squamous cell carcinoma. We report outcomes and recommendations for a penile sparing approach. MATERIALS AND METHODS: A total of 60 patients underwent penile sparing surgery for penile squamous cell carcinoma since 1995. Four patients without recurrence had less than 6 months of followup and were excluded from study. Data included disease stage, cellular differentiation, tumor site, penile sparing surgery type and recurrence information. RESULTS: Followup was adequate in 28 patients with carcinoma in situ and in 28 with T1 disease. The overall recurrence rate was 21.4% with equal recurrences of carcinoma in situ and T1 tumors (each 21.4%). Mean ± SD time to recurrence was 4.28 ± 2.81 years (range 0.5 to 11). More than 25% of recurrences developed after 5 years. Mean followup in censored patients was 5.47 ± 3.88 years (maximum 16). There was no difference in time to recurrence after carcinoma in situ and T1 tumors (p = 0.738). T1 tumors on the glans carried a slightly higher risk of recurrence (p = 0.049). At 5 years 13.8% of patients at risk had late recurrence with a mean time to recurrence of 7.25 ± 2.62 years. No patients with carcinoma in situ showed invasion or metastasis. Two patients with T1 disease presented with metastasis and 3 had late metastasis. CONCLUSIONS: Penile sparing surgery is a safe option for local control for appropriate carcinoma in situ and T1 squamous cell carcinoma of the penis. Carcinoma in situ recurrence may be re-treated with penile sparing surgery. T1 tumors that recur require more aggressive resection. Our data show significant late recurrences in patients and the need for long-term followup.

Retrospective analysis of prostate cancer recurrence potential with tissue metabolomic profiles.

BACKGROUND: In clinical care of prostate cancer patients, an improved method to assess the risk of recurrence after surgical treatment is urgently needed. We aim to retrospectively evaluate the ability of ex vivo tissue magnetic-resonance-spectroscopy-based metabolomic profiles to estimate the risk of recurrence. METHODS: PCa recurrence is defined biochemically as the detection of serum PSA after radical prostatectomy. Sixteen consecutive PCa-recurrent cases, those with an initial PSA increase of 0.69 +/- 0.26 ng/ml monitored 47.7 +/- 2.6 months after prostatectomy were paired by age and Gleason score with cases without recurrence of the same pathological and clinical stages (n = 16/each). We analyzed ex vivo intact-tissue spectroscopy results from these 48 individuals at the time of prostatectomy at 14T. From these spectra, we identified the 27 most common and intense spectral metabolic regions for statistical analyses. RESULTS: Principal component analysis (PCA) on these spectral regions from cases of clinical-stage-matched groups with and without recurrence identified four pathology-related principal components. Canonical analysis of these four and the first nine principal components for cases in the two groups defined metabolomic profiles as the canonical score that can differentiate the two groups with statistical significance. By applying the coefficients from PCA and canonical analysis to the pathological-stage-matched groups, recurrence was predicted with an accuracy of 78%. CONCLUSIONS: Results indicate the potential of tissue metabolomic profiles measured with ex vivo spectroscopy to identify PCa aggressiveness in terms of cancer recurrence. With further study, this may greatly contribute to the future design of clinical strategy for personalized treatment of PCa patients.

Cystatin B as a tissue and urinary biomarker of bladder cancer recurrence and disease progression.

PURPOSE: Using proteomic techniques, we sought to identify novel protein biomarkers in tissue and urine from patients with transitional cell carcinoma (TCC). EXPERIMENTAL DESIGN: Urinary and tissue proteomes were analyzed and differentially expressed proteins were identified by mass spectrometry. One of the proteins, cystatin B, was further analyzed in TCC tissue by immunohistochemistry and in urine by semiquantitative Western blot analysis. RESULTS: Cystatin B tissue staining intensity significantly increased concordantly with TCC grade (P = 0.0008). Elevated urinary cystatin B levels correlated with increasing tumor grade (P = 0.062) and stage (P = 0.0047). Patients with elevated levels of cystatin B had a shorter mean +/- SE time to disease recurrence (12 +/- 1.82 months) compared with patients who had low levels (28.8 +/- 2.26 months; P = 0.0047). Similarly, patients with elevated cystatin B levels had a shorter time to grade/stage progression compared with patients with low urinary cystatin B (P = 0.0007). By multivariate Cox regression analysis, an elevated cystatin B level was the most significant variable predicting disease recurrence (hazard ratio, 3.8; 95% confidence interval, 1.5-9.5; P = 0.0049) and grade/stage progression (hazard ratio, 10.4; 95% confidence interval, 1.6-201.5; P = 0.0104). CONCLUSIONS: Cystatin B is elevated in tissue and urine of bladder cancer patients. Cystatin B urine levels are positively correlated with tumor grade, stage, and shorter time to disease recurrence and progression. Consequently, cystatin B may be useful as a novel predictive biomarker in TCC of the bladder.

Multidisciplinary team streamlines hospital schedules, patient care.

Massachusetts General Hospital staff members use data to reassess patient flow, optimize facilities and enhance patient experience.

A prospective study of symptom distress and return to baseline function after open versus laparoscopic radical prostatectomy.

PURPOSE: We assessed and compared outcomes following open and laparoscopic radical prostatectomy. MATERIALS AND METHODS: Patients who were scheduled to undergo open or laparoscopic radical prostatectomy were enrolled in the study and followed prospectively. Before surgery the patients were administered a multi-item validated questionnaire, and were followed by telephone and with mail questionnaires periodically for 12 months. Complications were recorded from chart review and compared. Symptom distress and return to baseline for various parameters were compared between the 2 groups. RESULTS: Of the patients 102 who underwent open prostatectomy and 104 treated with laparoscopic prostatectomy were enrolled in the study. At 1 year 90% in the open and 91% in the laparoscopic group returned the questionnaire. Symptom distress between the 2 groups did not differ at any time during followup. There was no significant difference in return to baseline at 1 year for continence, erectile function or physical function. Of the patients 95% had a return to baseline physical function, approximately 90% do not wear a pad and approximately 50% returned to baseline erectile function with or without phosphodiesterase type 5 inhibitors at 1 year. Although complications were few there was a significant difference in the number for laparoscopic vs open prostatectomy with a slightly higher rate of hematuria and lymphocele formation in the laparoscopic group. Cancer control at 1 year was excellent in both groups. CONCLUSIONS: Radical prostatectomy is an effective form of therapy for patients with clinically localized cancer of the prostate. The open and laparoscopic techniques have similar functional outcomes, and these data provide patients a realistic view of what to expect following these 2 methods of radical prostatectomy.

TIP30 is associated with progression and metastasis of prostate cancer.

Tat-interacting protein 30 (TIP30), a transcriptional repressor for ERalpha-mediated transcription, possesses several characteristics of a tumor suppressor in certain human and mouse cells. It is reported that deletion of TIP30 gene preferentially increases tumorigenesis in the female knockout mice. Here, we analyzed TIP30 gene expression in the databases of several DNA microarray studies of human prostate cancer and show that TIP30 is specifically overexpressed in metastatic prostate cancers. We demonstrate that TIP30 nuclear expression is associated with prostate cancer progression and metastasis by immunohistochemical analysis in primary and metastatic prostate cancers. Consistent with these data, we also show that knockdown of TIP30 expression, through use of a short hairpin RNA-expressing plasmid, suppresses the cellular growth of PC3 and LNCaP prostate cancer cells. Ectopic overexpression of TIP30 stimulates metastatic potential of prostate cancer cells in an in vitro invasion assay, whereas knockdown of TIP30 inhibits the prostate cancer cells invasion. Finally, we demonstrate that ectopic overexpression of TIP30 enhances androgen receptor mediated transcription, whereas knockdown of TIP30 results in a decreased transcription activity. These data provide evidence that TIP30 plays a role in prostate cancer progression and that TIP30 overexpression may promote prostate cancer cell growth and metastasis.

The potential of nanoparticle-enhanced imaging.

Accurate lymph node staging in genitourinary malignancy is an important component in the diagnostic algorithm and therapeutic planning. A promising new method for lymph node staging is lymphotrophic nanoparticle enhanced magnetic resonance imaging. This novel technique uses ultrasmall superparamagnetic iron oxide particles, which localize in lymph nodes and provide detailed characterization of these nodes independent of typically accepted size criteria. This review provides a brief overview of the presently accepted methods for noninvasive lymph node staging and thoroughly discusses lymphotrophic nanoparticle enhanced MR imaging: a technique that can be used for accurate detection of lymph node metastases and will likely play a major role in noninvasive lymph node staging in genitourinary cancer in the near future.

Metabolomic Prediction of Human Prostate Cancer Aggressiveness: Magnetic Resonance Spectroscopy of Histologically Benign Tissue.

Prostate cancer alters cellular metabolism through events potentially preceding cancer morphological formation. Magnetic resonance spectroscopy (MRS)-based metabolomics of histologically-benign tissues from cancerous prostates can predict disease aggressiveness, offering clinically-translatable prognostic information. This retrospective study of 185 patients (2002-2009) included prostate tissues from prostatectomies (n = 365), benign prostatic hyperplasia (BPH) (n = 15), and biopsy cores from cancer-negative patients (n = 14). Tissues were measured with high resolution magic angle spinning (HRMAS) MRS, followed by quantitative histology using the Prognostic Grade Group (PGG) system. Metabolic profiles, measured solely from 338 of 365 histologically-benign tissues from cancerous prostates and divided into training-testing cohorts, could identify tumor grade and stage, and predict recurrence. Specifically, metabolic profiles: (1) show elevated myo-inositol, an endogenous tumor suppressor and potential mechanistic therapy target, in patients with highly-aggressive cancer, (2) identify a patient sub-group with less aggressive prostate cancer to avoid overtreatment if analysed at biopsy; and (3) subdivide the clinicopathologically indivisible PGG2 group into two distinct Kaplan-Meier recurrence groups, thereby identifying patients more at-risk for recurrence. Such findings, achievable by biopsy or prostatectomy tissue measurement, could inform treatment strategies. Metabolomics information can help transform a morphology-based diagnostic system by invoking cancer biology to improve evaluation of histologically-benign tissues in cancer environments.

Preventing migration of stones during fragmentation with thermosensitive polymer.

PURPOSE: To define a method of stabilizing stones during extracorporeal (SWL) and intracorporeal lithotripsy with a thermosensitive polymer. MATERIALS AND METHODS: Using a thermosensitive polymer that is either a liquid or a gel, depending on the temperature, both calcium oxalate and plaster of Paris phantom stones were placed in the polymer gel or saline, and SWL was performed. Comparisons were made between the effectiveness of the fragmentation in the two media. Also, in-vivo studies using the polymer to prevent migration of ureteral stones were performed in swine. Electrohydraulic lithotripsy was used on a small stone implanted in the distal ureter with the polymer instilled proximally. Once in the ureter, the polymer converted to a gel. After completion of the procedure, the polymer was restored to a liquid form by infusion of cold saline and expelled from the ureter. Three of the pigs underwent treatment of the stone, convalesced for 7 days, and then had urine collections from both ureters to compare the glomerular filtration rates, fractional sodium excretion, urine/plasma creatinine ratio, and urine/plasma urea ratio on the treated and the contralateral (control) sides. RESULTS: The polymer did not enhance fragmentation when used with SWL but prevented stone migration in the in-vivo studies. The physiologic parameters were not significantly different on the treated and the control sides. The polymer was easily removed from the ureter by infusing cold water. CONCLUSION: The use of this thermosensitive polymer proximal to ureteral stones prevents migration and is not traumatic to the ureter.

Metabolic characterization of human prostate cancer with tissue magnetic resonance spectroscopy.

Diagnostic advancements for prostate cancer have so greatly increased early detections that hope abounds for improved patient outcomes. However, histopathology, which guides treatment, often subcategorizes aggressiveness insufficiently among moderately differentiated Gleason score (6 and 7) tumors (>70% of new cases). Here, we test the diagnostic capability of prostate metabolite profiles measured with intact tissue magnetic resonance spectroscopy and the sensitivity of local prostate metabolites in predicting prostate cancer status. Prostate tissue samples (n = 199) obtained from 82 prostate cancer patients after prostatectomy were analyzed with high-resolution magic angle spinning proton magnetic resonance spectroscopy, and afterwards with quantitative pathology. Metabolite profiles obtained from principal component analysis of magnetic resonance spectroscopy were correlated with pathologic quantitative findings by using linear regression analysis and evaluated against patient pathologic statuses by using ANOVA. Paired t tests show that tissue metabolite profiles can differentiate malignant from benign samples obtained from the same patient (P < 0.005) and correlate with patient serum prostate-specific antigen levels (P < 0.006). Furthermore, metabolite profiles obtained from histologically benign tissue samples of Gleason score 6 and 7 prostates can delineate a subset of less aggressive tumors (P < 0.008) and predict tumor perineural invasion within the subset (P < 0.03). These results indicate that magnetic resonance spectroscopy metabolite profiles of biopsy tissues may help direct treatment plans by assessing prostate cancer pathologic stage and aggressiveness, which at present can be histopathologically determined only after prostatectomy.