Long term survival and predictors of disease reclassification in patients on an active surveillance protocol for prostate cancer.

INTRODUCTION: Up to 50% of patients will have disease reclassification while on active surveillance (AS) for their prostate cancer. Determining which patients will have reclassification that will impact their survival is difficult. We investigated clinicopathologic factors associated with disease reclassification and differences in both overall and metastasis free survival between those treated and those remaining on AS. MATERIALS AND METHODS: We performed a retrospective review of patients who were enrolled in an AS protocol between 1994 and 2000. Inclusion criteria for AS were: < cT2a disease, PSA < 10 ng/mL, < 50% of single core involvement, and Gleason score < 7, as well as sufficient follow up for evaluation (at least 1 subsequent transrectal ultrasound guided biopsy after initial diagnosis). RESULTS: There were 102 patients that met the inclusion criteria with median age of 70 years (IQR 68-73), follow up of 9.25 years (IQR 6.1-12.2) and time to disease reclassification of 4.7 years (IQR 2.8-7.9). Only prostate-specific antigen (PSA) density ≥ 0.15 was a significant predictor of disease reclassification with a hazard ratio of 5.5 (95% confidence interval 2.3-13.4, p < 0.01). There was no significant difference in metastasis free and overall survival between patients who received treatment and those that continued on AS despite reclassification of disease; this remained true even while stratifying patients by age ≥ 70 compared to those < 70 years old. CONCLUSIONS: PSA density is a significant predictor of disease reclassification and AS remains a safe option for patients with low risk prostate cancer with up to 10 years of follow up.

Perivascular epithelioid cell tumor (PEComa) of the urinary bladder associated with Xp11 translocation.

Perivascular epithelioid cell-containing tumors (PEComas) represent a rare family of neoplasms. Their dichotomous phenotypic features, including both myogenic and mylanocytic features, can make a definitive diagnosis difficult. Such tumors have been associated with the overexpression of transcription factor E3 (TFE3). An Xp11 translocation could account for the aberrant activity of TFE3 but has never before been described in affiliation with a PEComa of the urinary bladder. While PEComas of the bladder have exhibited benign clinical courses to date, here we present an intravesical PEComa shown to have an Xp11 translocation and resultant overexpression of TFE3, indicating an aggressive, metastatic nature. No consistent tumor characteristics have proven accurate at identifying aggressive tumors. However, mTOR inhibitors offer a mechanistic management strategy when systemic therapy is warranted.

Surgical outcomes in the management of isolated nodal recurrences: a multicenter, international retrospective cohort.

PURPOSE: We report a multicenter international cohort representing what is to our knowledge the largest surgical experience with managing isolated retroperitoneal nodal recurrence of renal cell carcinoma, a unique subset of locoregional disease, yet to be described in detail. MATERIALS AND METHODS: Patients with isolated nodal recurrence of pTanyN+M0 disease after nephrectomy were identified by retrospective chart review at 3 independent institutions. Progression-free survival was estimated by the Kaplan-Meier method and used to compare survival outcomes between primary T(1-2)N(any)M0 and T3N(any)M0 tumors as well as clear cell and nonclear cell histology renal cell carcinoma. RESULTS: A total of 22 patients met study inclusion criteria. Median time to local postoperative recurrence was 31.5 months (IQR 12.9-43.3). After resection of isolated nodal recurrence 10 patients (46%) had a secondary recurrence at a median of 11.2 months (IQR 8.1-18.4), of whom 2 (9%) died of the disease. Overall median progression-free survival was 12.7 months, including 24.8 months for T(1-2)N(any)M0 tumors, 9.9 months for T3N(any)M0 tumors, and 13.4 and 17.6 months for clear and nonclear cell renal cell carcinoma, respectively. CONCLUSIONS: Surgical resection represents the best curative option for patients who present with isolated retroperitoneal lymph node recurrence of renal cell carcinoma. Durable postoperative progression-free survival is attainable in many patients regardless of histology or clinical TNM stage. In addition, our cohort showed a lower renal cell carcinoma related mortality rate than in previous series of local metastasis. As such, all patients free of precluding comorbidities should be considered candidates for complete surgical resection performed by an experienced genitourinary surgeon.

Current management considerations for the incidentally detected small renal mass.

BACKGROUND: Nephron-sparing treatments remain underutilized for the management of small renal masses despite a rise in incidentally detected renal cell carcinoma and a downward stage migration. METHODS: Historical publications representative of currently accepted paradigms were reviewed, and the results of a contemporary scientific literature search conducted in PubMed focusing on studies involving humans, published in English, and inclusive of clinical trials, meta-analyses, randomized controlled trials, and practice guidelines are included. Results from contemporary retrospective trials augment the data when level I or II evidence is absent. RESULTS: Phase III clinical trial results substantiate the long-held tenet that partial nephrectomy is equivalent to radical nephrectomy with respect to safety and oncologic efficacy. Further, minimally invasive techniques using laparoscopy and robotic assistance to achieve partial nephrectomy appear equally effective to traditional open techniques. Although no prospective randomized studies are available, large retrospective studies support the notion that active surveillance and thermal ablative techniques are viable options for carefully selected patients. CONCLUSIONS: The management of small renal masses encompasses a host of therapeutic options, all of which must be considered and discussed with the individual patient.

Enrollment criteria controversies for active surveillance and triggers for conversion to treatment in prostate cancer.

In the era of widespread prostate-specific antigen screening, low-risk and very-low-risk prostate cancers are commonly identified, many of which will be of clinical insignificance. This has led to overtreatment and undue exposure to treatment-related morbidity in men harboring indolent tumors. Over the past 10 years, active surveillance (AS) has been evolving as a management strategy for these cancers. With continual reevaluation, the intent is to definitively treat tumors that are clearly progressive before the window of opportunity for cure has closed. To date, many of the surveillance parameters are without validation of utility, variably used, and without a standardized schedule. However, new instruments for characterizing prostate cancer offer the potential to better distinguish which men are best managed definitively at the outset from those who would be better served with observation. The findings of currently available AS cohorts suggest that initial expectant management of early prostate cancer is reasonable, showing that only approximately 30% of observed tumors are reclassified to ones of intermediate risk with short-term follow-up. Prostate cancer survival for men undergoing AS is close to 100% in all available studies, but long-term data remain scarce for those requiring delayed curative therapy.

Is the R.E.N.A.L. nephrometry scoring system predictive of the functional efficacy of nephron sparing surgery in the solitary kidney?

PURPOSE: We evaluated the ability of renal tumor complexity, as assessed by the R.E.N.A.L. (radius, exophytic, nearness to collecting system, anterior/posterior and location) nephrometry scoring system, to predict the functional efficacy of nephron sparing surgery. MATERIALS AND METHODS: We evaluated 42 patients who presented with an anatomically (32) or a functionally (10) solitary kidney and underwent partial nephrectomy. Each renal unit was assigned a R.E.N.A.L. nephrometry score using preoperative imaging. The CKD-EPI equation was applied to calculate the estimated glomerular filtration rate. The difference between the estimated glomerular filtration rate at baseline and at postoperative time points served as a measurement of the renal functional loss attributable to partial nephrectomy. RESULTS: In the 42 patients who underwent partial nephrectomy the mean preoperative estimated glomerular filtration rate was 61.5 ml/minute/1.73 m(2). The median total nephrometry score was 8 (range 4 to 10). In the immediate postoperative period the cohort mean estimated glomerular filtration rate of 48.6 ml/minute/1.73 m(2) was significantly less than the preoperative value (p <0.0001). At 6-month followup the mean estimated glomerular filtration rate had recovered at 54.1 ml/minute/1.73 m(2) but it remained significantly less than the preoperative value (p = 0.0002). We noted no relationship between the postoperative decrease in the estimated glomerular filtration rate and the assigned total nephrometry score or in any individual component of the R.E.N.A.L. scoring system related to the targeted lesion. CONCLUSIONS: Neither the individual components of the R.E.N.A.L. nephrometry scoring system nor the total nephrometry score predicted the realized functional loss, as assessed by the estimated glomerular filtration rate in patients with a solitary kidney treated with nephron sparing surgery. However, nephron sparing surgery was quite efficacious for preserving renal function since only a durable 11.6% decrease was noted in the estimated glomerular filtration rate.

Primary mixed neuroendocrine carcinoma of the bladder with large cell component: a case report and review of the literature.

Primary large cell neuroendocrine carcinomas (NECs) of the bladder are rarely encountered, and only a few reports have been documented. Frequently, they are found to be admixed with other histologies. In this report, we describe such a tumor found in a 65-year-old man who underwent radical cystectomy, after initial transurethral resection discovered a small cell NEC pathology. We also reviewed the limited number of neuroendocrine tumors reported containing a large cell component. Given the paucity of these tumors and the resultant difficulty in developing generalized treatment protocols, we promote the use of gene expression models to tailor chemotherapeutic regimens for individual tumors.

Advanced penile cancer.

Penile cancer is an uncommon disease in the industrialized world that most frequently presents at low stage and is cured with treatment of local and regional surgery. In cases of advanced cancer, the use of more aggressive surgical techniques and the addition of adjuvant therapy may be warranted. So far, few agents have been found that improve survival with metastatic disease and thus aggressive primary treatment is required. This review discusses diagnosis, staging, and therapy for high risk penile cancer.

Wilms' tumor metastatic to bilateral testes at presentation: case and review of the literature.

A 7-year-old male with bilateral palpable testicular masses was found to have metastatic stage IV Wilms' tumors associated with both left renal and lung lesions. The patient was treated successfully with testicular-sparing bilateral partial orchiectomies, radical nephrectomy, chemotherapy, and radiation, with 8 years free of recurrence. This is the only reported case of bilateral testicular tumors from metastatic Wilms' tumor that were present at the initial presentation. A review of the literature of all previous reported cases of metachronous or related testicular metastatic Wilms' tumors is reported.

Multiple endocrine neoplasia 2a presenting with pheochromocytoma and pituitary macroadenoma.

Multiple Endocrine Neoplasia type 2A (MEN-2a) is a rare disease associated with tumors of endocrine organs. Presentation most commonly is with medullary thyroid cancer and infrequently with other complaints. Pituitary adenoma has been seen coincidentally with this disease very rarely. Presented is a case of coincident MEN-2a with a symptomatic pituitary adenoma and an asymptomatic pheochromocytoma. A brief review is also provided.

Primary carcinoid tumor of the ileal efferent limb of an ileovesicostomy: a case report.

We report on the evaluation and management of a 47-year-old white male found to have primary carcinoid tumor of the ileal segment of his diverting ileovesicostomy thirty-five months after initial creation. Subsequent to presentation with intermittent gross hematuria, CT urogram highlights an 8 mm enhancing lesion near the enterovesical junction of urinary diversion. Office cystoscopy confirms presence of a lesion that was later endoscopically resected and found to be a well-differentiated carcinoid tumor. Evaluation with serum markers, direct visualization utilizing endoscopy, and imaging was without finding of alternate primary or metastatic lesions. The patient ultimately had the proximal ileal portion of his ileovesicostomy excised and the distal portion converted into an ileal conduit. After briefly discussing the carcinoid tumor and the carcinoid syndrome it may cause, we review the literature on the incidence of carcinoid tumors in a population requiring the use of intestine in the urinary tract.

Restoring barrier function to acid damaged bladder by intravesical chondroitin sulfate.

PURPOSE: Chondroitin sulfate (Stellar Pharmaceuticals, London, Ontario, Canada), which is less expensive and more inert than heparinoids, hyaluronan or pentosan polysulfate, has been introduced to restore the barrier function lost due to epithelial dysfunction in interstitial cystitis cases. To our knowledge chondroitin sulfate binding to damaged bladder as a function of the urinary pH range, its efficacy in restoring the bladder permeability barrier and the capacity of the damaged bladder to bind chondroitin sulfate have not been determined previously. MATERIALS AND METHODS: Chondroitin sulfate binding to bladder urothelium was investigated quantitatively using chondroitin sulfate highly labeled with Texas Red(R) and quantitative fluorescence microscopy in a mouse model of urothelial acid damage. The efficacy of restoring barrier function was determined using the passage of intravesically instilled (86)Rb, a potassium ion mimetic, through the urothelium into the bloodstream in a rat model of bladder damage. The binding capacity of acid damaged bladder was determined by fluorometry. RESULTS: Chondroitin sulfate bound tightly and exclusively to the mouse bladder surface damaged by acid but showed only minimal binding to undamaged bladder. There was no systematic variation in pH. The model showed some variability in the degree of damage induced. In rats chondroitin sulfate instillation restored permeability to (86)Rb to control levels. Binding was saturable at a mean +/- SEM 0.67 +/- 0.13 mg/cm(2) of the bladder surface. CONCLUSIONS: Chondroitin sulfate binds preferentially to damaged urothelium and restores the impermeability barrier. This suggests that the glycosaminoglycan layer is a major contributor to bladder urothelial impermeability. As determined by binding capacity, the dose applied in humans in Canada (400 mg per instillation) is sufficient to achieve maximum efficacy.

From microarray to biology: an integrated experimental, statistical and in silico analysis of how the extracellular matrix modulates the phenotype of cancer cells.

A statistically robust and biologically-based approach for analysis of microarray data is described that integrates independent biological knowledge and data with a global F-test for finding genes of interest that minimizes the need for replicates when used for hypothesis generation. First, each microarray is normalized to its noise level around zero. The microarray dataset is then globally adjusted by robust linear regression. Second, genes of interest that capture significant responses to experimental conditions are selected by finding those that express significantly higher variance than those expressing only technical variability. Clustering expression data and identifying expression-independent properties of genes of interest including upstream transcriptional regulatory elements (TREs), ontologies and networks or pathways organizes the data into a biologically meaningful system. We demonstrate that when the number of genes of interest is inconveniently large, identifying a subset of "beacon genes" representing the largest changes will identify pathways or networks altered by biological manipulation. The entire dataset is then used to complete the picture outlined by the "beacon genes." This allow construction of a structured model of a system that can generate biologically testable hypotheses. We illustrate this approach by comparing cells cultured on plastic or an extracellular matrix which organizes a dataset of over 2,000 genes of interest from a genome wide scan of transcription. The resulting model was confirmed by comparing the predicted pattern of TREs with experimental determination of active transcription factors.

Sulfhydryl based cationic surfactants and the impact of polyanions on disulfide bond formation: implications for gene transfer vectors.

Compacting plasmid DNA (pDNA) into a small size is a fundamental necessity for the efficient in vivo transfer of nucleic acids to somatic cells. An approach for accomplishing this is to condense pDNA using cationic detergents with sulfhydryl groups, near their critical micelle concentration. In this study, a model surfactant was used to study how the rate of disulfide bond formation relates to environmental factors. It was shown that the thiol detergent had the ability to form a disulfide bond when oxidized and the presence of polyanions was significantly increased. The addition of a reducing agent disrupted the disulfide bonds initially, but this was followed by disulfide bond reformation in a short time period.