Norm D. Smith

Nanoparticle-based bio-barcode assay redefines “undetectable” PSA and biochemical recurrence after radical prostatectomy

We report the development of a previously undescribed gold nanoparticle bio-barcode assay probe for the detection of prostate specific antigen (PSA) at 330 fg/mL, automation of the assay, and the results of a clinical pilot study designed to assess the ability of the assay to detect PSA in the serum of 18 men who have undergone radical prostatectomy for prostate cancer. Due to a lack of sensitivity, available PSA immunoassays are often not capable of detecting PSA in the serum of men after radical prostatectomy. This new bio-barcode PSA assay is ≈300 times more sensitive than commercial immunoassays. Significantly, with the barcode assay, every patient in this cohort had a measurable serum PSA level after radical prostatectomy. Patients were separated into categories based on PSA levels as a function of time. One group of patients showed low levels of PSA with no significant increase with time and did not recur. Others showed, at some point postprostatectomy, rising PSA levels. The majority recurred. Therefore, this new ultrasensitive assay points to significant possible outcomes: (i) The ability to tell patients, who have undetectable PSA levels with conventional assays, but detectable and nonrising levels with the barcode assay, that their cancer will not recur. (ii) The ability to assign recurrence earlier because of the ability to measure increasing levels of PSA before conventional tools can make such assignments. (iii) The ability to use PSA levels that are not detectable with conventional assays to follow the response of patients to adjuvant or salvage therapies.

Risk Factors and Management of Urine Leaks After Partial Nephrectomy

PURPOSE As nephron sparing surgery is used more frequently for select renal tumors, the incidence of urine leaks will likely increase. To our knowledge the risk factors of and management strategies for urine leaks have not been studied. We report our experience with the risk factors of and management for urine leaks after open and laparoscopic partial nephrectomy. MATERIALS AND METHODS We retrospectively reviewed the records of 127 consecutive patients who underwent partial nephrectomy between 2001 and 2007, including 70 with open and 57 with laparoscopic partial nephrectomy, as performed by 3 surgeons. Urine leak was defined as drain output consistent with urine greater than 48 hours after laparoscopic partial nephrectomy. RESULTS Of the patients 21 experienced a urine leak after partial nephrectomy, including 13.3% overall, and 10.5% after laparoscopic and 18.5% after open partial nephrectomy. Patients with a urine leak had significantly greater tumor size (3.2 vs 2.4 cm, p <0.044), endophytic locations (57% vs 19%, p <0.00027) and repair of collecting system defects during partial nephrectomy (95% vs 56%, p <0.00072). There was no association with the number of tumors removed, estimated blood loss, ischemia time, body mass index, age or other surgical complications. The median duration of urine leak was 20 days. While most urine leaks resolved with prolonged drainage, 38% of cases required further intervention. Patient age at surgery was the only factor that correlated with prolonged (greater than 30 days) urine leak. CONCLUSIONS Urine leak is a complication unique to partial nephrectomy that is more commonly noted when a larger endophytic mass involves the renal collecting system. Most leaks resolve with prolonged drainage or replacement of a ureteral stent.

The Incidence of Prostate Cancer Progression with Undetectable Serum Prostate Specific Antigen in a Series of 394 Radical Prostatectomies

PURPOSE Serum prostate specific antigen (PSA) has been reported to be a sensitive indicator of recurrent carcinoma after radical prostatectomy but it is not absolute. Disease progression with undetectable PSA levels has been described but the incidence of this phenomenon is unknown. MATERIALS AND METHODS We retrospectively analyzed the records of 394 consecutive men who underwent radical prostatectomy between 1980 and 1991 to characterize the incidence of recurrent carcinoma despite undetectable serum PSA levels. RESULTS Of the 394 men 133 had documented evidence of disease recurrence, 3 (2.3%) despite undetectable serum PSA levels (2 had local and systemic evidence of disease progression). Histological dedifferentiation characterized these recurrences. CONCLUSIONS Although a post-prostatectomy detectable serum PSA level precedes clinical evidence of disease progression by years, rare patients (2.3% in our series) in whom recurrent disease is characterized by marked histological dedifferentiation will remain negative for PSA.

LONG-TERM RESULTS OF RADICAL RETROPUBIC PROSTATECTOMY IN MEN WITH HIGH GRADE CARCINOMA OF THE PROSTATE

PURPOSE We sought to determine the efficacy of radical retropubic prostatectomy in men with high grade adenocarcinoma of the prostate in a population that had not been screened for prostate specific antigen (PSA). MATERIALS AND METHODS An inception cohort of 116 men surgically treated for prostate cancer between 1980 and 1991 was created in April 1992 and prospectively followed thereafter. Median followup was 7 years (range 2.2 to 14.6). RESULTS The major cause of death in this group of men was prostate cancer, not competing causes. Ten-year disease specific survival was 96% for organ confined (stage pT2c or less) and 78% for unconfined (stage pT3a or greater) disease. Five and 10-year PSA progression-free survival by pathological stage was 83 and 53% for organ confined disease, and 34 and 22% for unconfined disease with negative pelvic lymph node dissection (p = 0.001). Five and 10-year metastasis-free survival was 96% for organ confined disease, and 81 and 62% for unconfined disease (p = 0.011). Men with pelvic lymph node metastasis had 70 and 30% 5 and 10-year metastasis-free survival, and 75 and 55% disease specific survival, respectively. PSA progression-free survival was 33% at 5 years. A significantly decreased risk of PSA progression was observed in men with unconfined carcinoma who received adjuvant external beam radiotherapy. CONCLUSIONS In men with high grade prostate cancer the major cause of death was prostate cancer, not competing causes. Pathologically confined carcinoma had a significantly decreased rate of metastatic progression. These observations support the bias that early detection in these men at high risk for cause specific death may favorably impact survival.

Bladder cancer risk from occupational and environmental exposures

Approximately 50% of bladder cancer incidence in the United States has been attributed to known carcinogens, mainly from cigarette smoking. Following the identification of this important causative factor, many investigators have attempted to identify other major causes of bladder cancer in the environment. Genetic and epigenetic alterations related to carcinogenesis in the bladder have been linked to environmental and occupational factors unrelated to cigarette smoking and may account for a significant portion of bladder cancer cases in non-smokers. The interaction between genetics and exposures may modulate bladder cancer risk and influence the differing incidence, progression, and mortality of this disease in different genders and races. Comparative molecular studies are underway to measure the relative effects of environment and inheritance to account for observed differences in the epidemiology of bladder cancer. The use of geospatial tools and population-based data will offer further insight into the environmentally-linked causes of bladder cancer.

Transient potential receptor channel 4 controls thrombospondin-1 secretion and angiogenesis in renal cell carcinoma.

Angiogenic switch in renal cell carcinoma (RCC) is attributed to the inactivation of the von Hippel–Lindau tumor suppressor, stabilization of hypoxia inducible factor‐1 transcription factor and increased vascular endothelial growth factor. To evaluate the role of an angiogenesis inhibitor, thrombopsondin‐1 (TSP1), we compared TSP1 production in human RCC and normal tissue and secretion by the normal renal epithelium (human normal kidney, HNK) and RCC cells. Normal and RCC tissues stained positive for TSP1, and the levels of TSP1 mRNA and total protein were similar in RCC and HNK cells. However, HNK cells secreted high TSP1, which rendered them nonangiogenic, whereas RCC cells secreted little TSP1 and were angiogenic. Western blot and immunostaining revealed TSP1 in the cytoplasm of RCC cells on serum withdrawal, whereas, in HNK cells, it was rapidly exported. Seeking mechanisms of defective TSP1 secretion, we discovered impaired calcium uptake by RCC in response to vascular endothelial growth factor. In HNK cells, 1,2‐bis(o‐aminophenoxy)ethane‐N,N,N′,N′‐tetraacetic acid acetoxymethyl ester, a calcium chelator, simulated TSP1 retention, mimicking the RCC phenotype. Further analysis revealed a profound decrease in transient receptor potential canonical ion channel 4 (TRPC4) Ca2+ channel expression in RCC cells. TRPC4 silencing in HNK cells caused TSP1 retention and impaired secretion. Double labeling of the secretory system components revealed TSP1 colocalization with coatomer protein II (COPII) anterograde vesicles in HNK cells. In contrast, in RCC cells, TSP1 colocalized with COPI vesicles, pointing to the retrograde transport to the endoplasmic reticulum caused by misfolding. Our study indicates that TRPC4 loss in RCC leads to impaired Ca2+ intake, misfolding, retrograde transport and diminished secretion of antiangiogenic TSP1, thus enabling angiogenic switch during RCC progression.

Biomarkers For Prostate Cancer

The detection of prostate cancer using a blood test has by many standards changed the face of the disease. Despite this tremendous success, there are limitations attributed to the use of prostate specific antigen (PSA) as a means to screen and detect prostate cancer. PSA, as its name implies, is not specific for prostate cancer and as such is often found elevated in other prostatic diseases/symptoms associated with the aging male. Clearly, more specific marker(s) that could identify which individuals actually have prostate cancer and differentiate them from those without the disease would be of tremendous value. The search for more accurate and clinically useful biomarkers of prostate cancer has been extensive. This has focused on individual markers, as well as groups of markers. Included among these are PSA isoforms, pathological indicators and stains, nucleic acids and others. This article highlights the discovery of PSA as a first blood‐based biomarker for prostate cancer detection, as well as other molecular biomarkers and their potential application in detection of the disease. J. Cell. Biochem. 108: 3–9, 2009.

The RAZOR (randomized open vs robotic cystectomy) trial: Study design and trial update

The purpose of the RAZOR (randomized open vs robotic cystectomy) study is to compare open radical cystectomy (ORC) vs robot‐assisted RC (RARC), pelvic lymph node dissection (PLND) and urinary diversion for oncological outcomes, complications and health‐related quality of life (HRQL) measures with a primary endpoint of 2‐year progression‐free survival (PFS). RAZOR is a multi‐institutional, randomized, non‐inferior, phase III trial that will enrol at least 320 patients with T1–T4, N0–N1, M0 bladder cancer with ≈160 patients in both the RARC and ORC arms at 15 participating institutions. Data will be collected prospectively at each institution for cancer outcomes, complications of surgery and HRQL measures, and then submitted to trial data management services Cancer Research and Biostatistics (CRAB) for final analyses. To date, 306 patients have been randomized and accrual to the RAZOR trial is expected to conclude in 2014. In this study, we report the RAZOR trial experimental design, objectives, data safety, and monitoring, and accrual update. The RAZOR trial is a landmark study in urological oncology, randomizing T1–T4, N0–N1, M0 patients with bladder cancer to ORC vs RARC, PLND and urinary diversion. RAZOR is a multi‐institutional, non‐inferiority trial evaluating cancer outcomes, surgical complications and HRQL measures of ORC vs RARC with a primary endpoint of 2‐year PFS. Full data from the RAZOR trial are not expected until 2016–2017.

The etiology of urolithiasis in HIV infected patients.

PURPOSE It is commonly thought that urinary lithiasis in HIV infected patients on protease inhibitor therapy is composed primarily of the protease inhibitor itself. Since many HIV infected patients on protease inhibitors presenting to our institution had nonprotease inhibitor stones, we investigated potential underlying metabolic abnormalities that may account for the lithogenesis. MATERIALS AND METHODS We retrospectively reviewed all HIV infected patients on protease inhibitors with renal colic and evidence of nephrolithiasis who presented to our institution between June 1996 and January 2001. Patients were evaluated for stone composition and metabolic abnormalities of blood and urine when possible. RESULTS A total of 24 patients were identified, and all were or had been on protease inhibitors (indinavir 14, ritonavir 3, nelfnavir 2, unspecified 5). Of the 14 patients on indinavir only 4 (28.6%) had indinavir containing stones. The remaining stones in this group and in those not on indinavir contained various amounts of calcium oxalate monohydrate and dihydrate, ammonium acid urate and uric acid. Of 10 patients who underwent 24-hour urine collection for metabolic evaluation 8 (80%) had abnormalities, including hypocitraturia in 5, hyperoxaluria in 4, hypomagnesuria in 4, hypercalciuria in 3, increased supersaturation of calcium oxalate in 3 and hyperuricosuria in 2. Abnormalities in the levels of urinary phosphate and sodium were also observed. CONCLUSIONS HIV infected patients form many types of stones, which probably are attributable to underlying metabolic abnormalities rather than the use of protease inhibitors. A complete metabolic evaluation is warranted in these patients, as a means of guiding treatment to prevent future stone episodes, while avoiding the need to alter antiretroviral regimens.

Radiofrequency Ablation–Assisted Robotic Laparoscopic Partial Nephrectomy Without Renal Hilar Vessel Clamping Versus Laparoscopic Partial Nephrectomy: A Comparison of Perioperative Outcomes

OBJECTIVES Radiofrequency ablation (RFA)-assisted laparoscopic partial nephrectomy (LPN) may allow for improved hemostasis without need for renal hilar vessel clamping and elimination of warm ischemia to the kidney. We compare outcomes in patients undergoing radiofrequency ablation-assisted robotic clampless partial nephrectomy (RF-RCPN) and LPN. METHODS Thirty-six patients and 42 patients underwent LPN and RF-RCPN, respectively. In the RF-RCPN group, the Habib 4x RFA device was used to coagulate a margin of normal parenchyma around the renal mass to allow excision of the mass within a bloodless plane. Unlike in the LPN group, renal hilar vascular occlusion was not performed in the RF-RCPN group. RESULTS Tumors treated in the RF-RCPN group tended to be larger (2.8 vs. 2.0 cm) and more often endophytic (52.6% vs. 16.1%). Collecting system reconstruction occurred more often in the RF-RCPN group (78.6% vs. 30.6%). Operative duration was longer in the RF-RCPN group (373 vs. 250 minutes), but this included time for cystoscopy, ureteral stenting, and repositioning of the patient. Blood loss, transfusion rates, renal function, and complication rates did not differ between the two groups. No patients required renal hilar vessel clamping or nephrectomy to control bleeding in the RF-RCPN group. CONCLUSIONS The use of RFA-assistance during robotic partial nephrectomy allows excision of renal tumors without hilar vascular clamping, thus eliminating renal warm ischemia. Larger and more centrally located tumors were excised with RF-RCPN. No differences in blood loss, complication rate, postoperative bleeding, renal function, or recurrence rate were noted compared with LPN.