Riedel's thyroiditis association with IgG4-related disease.

CONTEXT: IgG4-positive (+) plasma cells have been reported in both Riedel's thyroiditis (RT) and Hashimoto's thyroiditis (HT). These cells are the hallmark of IgG4-related disease (IgG4-RD). OBJECTIVE: We sought to determine whether RT is part of IgG4-RD spectrum. DESIGN, SETTING AND PATIENTS: This was a case-control study performed at a tertiary medical centre. We included RT cases from the period 1958 to 2008 that had sufficient paraffin-embedded tissue for IgG4 immunostaining. Controls were patients with HT, age and gender matched, with similar pathology criteria. MAIN OUTCOME MEASURE: The main outcome measures were the intensity of the IgG4 staining and the clinical and histological correlates with IgG4-RD. RESULTS: Six pairs of RT and HT were analysed. The mean age was 44·7 years. In both groups, 5/6 cases had positive IgG4 staining. The mean number of IgG4 + cells/ HPF, normalized to the degree of inflammation, was 3·2 ± 3·0 SD (RT) vs 0·9 ± 0·7 (HT), P = 0·15, for fibrotic areas and 2·1 ± 2·3 SD vs 1·0 ± 0·8 (P = 0·39) for areas with lymphoid aggregates. We found the number of IgG4 +  cells in RT to be inversely correlated with the duration of disease (P = 0·046). Three RT cases had associated comorbidities from the IgG4-RD spectrum while none of the HT cases had such conditions. CONCLUSIONS: Riedel's thyroiditis is a component of IgG4-RD with the density of the IgG4 +  lymphocytic infiltrate being time dependent. In this small study, we did not identify differences in IgG4 infiltration between RT and HT, minimizing the utility of this marker in RT diagnosis.

Prevalence of parathyroid carcinoma in 348 patients with multiple endocrine neoplasia type 1 - case report and review of the literature.

OBJECTIVE: To report the prevalence of parathyroid carcinoma (PC) in patients with multiple endocrine neoplasia type 1 (MEN1) and review of the literature. BACKGROUND: Primary hyperparathyroidism (PHP) is the most common manifestation of MEN1. The occurrence of PC in patients with MEN1 is rare and the literature regarding the clinical manifestations - including the prevalence of the disease - is scarce. CONTEXT: Single tertiary care centre experience from 1977 to 2013. DESIGN: Electronic search of the medical records to identify a cohort of patients with MEN1. Literature review based on current case reports. PATIENTS: Single case of PC in a cohort of 348 patients with MEN1. Ten cases of PC in patients with MEN1 reported in the literature. MEASUREMENT: Clinical features of PC in patients with MEN1. RESULTS: The prevalence of PC in 348 patients with MEN1 was found to be 0·28% (95% CI, 0-1·4%). Based on the current published cases of PC in patients with MEN1, 54·5% were women, mean age at diagnosis was 48·3 years, and the serum PTH concentrations at least four times the upper limit of the reference range in 73% of the cases. CONCLUSION: PC in patients with MEN 1 is rare with a prevalence of 0·28%, and the clinical features are similar to PC in patients without MEN1.

Review of our experience with neuroblastoma and ganglioneuroblastoma in adults.

BACKGROUND: Neuroblastomas and ganglioneuroblastomas (NB/GNB) are malignant tumors that rarely occur in adults. Their disease progression and appropriate treatment are unclear. METHODS: All adults (age ≥18 years) were evaluated for histologically confirmed NB/GNB within our institution. Data were collected via chart review and direct patient contact. RESULTS: From 1980 to 2009, a total of 15 adult patients with NB/GNB were evaluated: six men (mean age 23 years, range 19-33 years) and nine women (mean 34 years, range 20-66 years). Their overall average age at diagnosis was 30 years. Tumor-related symptoms occurred in ten patients: Pain (abdominal 3, back 2, pelvic 1, groin 1) was more common than a mass (abdominal 2) or dysmenorrhea (1). Five patients had tumors found incidentally by computed tomography (4) or chest radiography (1). Primary tumor origins were in the pelvis (4), mediastinum (3), abdomen (2), adrenal gland (2), retroperitoneum (2), and mixed locations (2). Altogether, 12 patients underwent surgical resection (biopsy in 3; resections of R0 in 5, R1 in 3, R2 in 4). Ten underwent chemotherapy. Histology showed four GNBs and 11 NBs. Five patients with stage I disease survived a mean of 21 years (range 10-40 years). Two are alive today. Three stage III patients died at 2, 6, and 9 years after diagnosis (mean 5.7 years). Six of seven patients (one was lost to follow-up) with initial stage IV neuroblastoma died within 5 years (mean 2.7 years). NB and GNB patients had similar survivals. CONCLUSIONS: Adult-onset NB/GNB is rare. Symptoms appear to occur later when incurable stage IV disease is detected. Complete surgical resection can lead to long-term, disease-free survival in stage I patients.

Comparison of methods to detect neoplasia in patients undergoing endoscopic ultrasound-guided fine-needle aspiration.

BACKGROUND & AIMS: Digital image analysis (DIA) and fluorescence in situ hybridization (FISH) can be used to evaluate biliary strictures with greater accuracy than conventional cytology (CC). We performed a prospective evaluation of the accuracy of CC, compared with that of DIA and FISH, in detection of malignancy in patients undergoing endoscopic ultrasonography (EUS) fine-needle aspiration (FNA). METHODS: We collected a minimum of 6 FNA samples from each of 250 patients during EUS. CC or DIA and FISH analyses were performed on every other specimen (from every other FNA pass); patients were randomly assigned to the first test performed. CC slides were reviewed by gastrointestinal cytopathologists who were blinded to all data. Findings from cytohistologic analysis, after a minimum 24-month follow-up period, were used as the standard (n = 202; median age, 65 years). RESULTS: Aspirates were collected from lymph nodes (n = 111), pancreas (n = 61), gastrointestinal lumen wall (n = 9), periluminal mass (n = 4), liver (n = 8), and miscellaneous sites (n = 9). Matched samples provided a mean of 3.2 passes for CC and 1.6 passes for DIA and FISH. The data indicate a potential lack of utility for DIA. The combination of CC and FISH detected malignancy with 11% greater sensitivity than CC alone (P = .0002), but specificity was reduced from 100% to 96%. CONCLUSIONS: FISH analysis identifies neoplastic lesions with significantly greater sensitivity than CC in patients with diverse pathologies who underwent EUS with FNA, despite limited tissue sampling for FISH analysis.

Shared gene expression alterations in prostate cancer and histologically benign prostate from patients with prostate cancer.

Prostate cancer (PCa) field effect alterations provide important clues regarding the initiation of these tumors and suggest targets for prevention or biomarkers for early detection. However, biomarkers of PCa field effects that have passed independent validation are lacking, largely because these alterations are subtle and difficult to distinguish from unrelated small changes in gene expression. We hypothesized that shared expression alterations in PCa and benign prostates containing PCa (BPCs) would have a higher potential for independent validation than alterations identified in BPCs alone. Expression analyses were performed on 37 PCas and 36 unmatched BPCs and were contrasted with 28 benign prostates (BPs) from patients free of PCa. Most of the protein-coding genes and nonexonic RNAs selected according to the hypothesis were validated by quantitative RT-PCR in an independent set of 51 BPCs and BPs. A statistical model based on two markers distinguished BPCs from BPs in the RT-PCR set and in an external microarray (area under the curve = 0.84 and 0.90, respectively). In addition, genes with predominant expression in stroma were identified by expression profiling of pure stroma and epithelial cells. Pathway analysis identified dysregulated platelet-derived growth factor receptor signaling in BPC stroma. These results validate our approach for finding PCa field effect alterations and demonstrate a PCa transcriptome fingerprint in nonneoplastic cells in prostates containing cancer.

Candidate serum biomarkers for prostate adenocarcinoma identified by mRNA differences in prostate tissue and verified with protein measurements in tissue and blood.

BACKGROUND: Improved tests are needed for detection and management of prostate cancer. We hypothesized that differential gene expression in prostate tissue could help identify candidate blood biomarkers for prostate cancer and that blood from men with advanced prostate disease could be used to verify the biomarkers presence in circulation. METHODS: We identified candidate markers using mRNA expression patterns from laser-capture microdissected prostate tissue and confirmed tissue expression using immunohistochemistry (IHC) for the subset of candidates having commercial antisera. We analyzed tissue extracts with tandem mass spectrometry (MS/MS) and measured blood concentrations using immunoassays and MS/MS of trypsin-digested, immunoextracted peptides. RESULTS: We selected 35 novel candidate prostate adenocarcinoma biomarkers. For all 13 markers having commercial antisera for IHC, tissue expression was confirmed; 6 showed statistical discrimination between nondiseased and malignant tissue, and only 5 were detected in tissue extracts by MS/MS. Sixteen of the 35 candidate markers were successfully assayed in blood. Four of 8 biomarkers measured by ELISA and 3 of 10 measured by targeted MS showed statistically significant increases in blood concentrations of advanced prostate cancer cases, compared with controls. CONCLUSIONS: Seven novel biomarkers identified by gene expression profiles in prostate tissue were shown to have statistically significant increased concentrations in blood from men with advanced prostate adenocarcinoma compared with controls: apolipoprotein C1, asporin, cartilage oligomeric matrix protein, chemokine (C-X-C motif) ligand 11 (CXCL11), CXCL9, coagulation factor V, and proprotein convertase subtilisin/kexin 6.

What are the keys to successful thyroid FNA interpretation?

There is much concern expressed in the literature regarding the lack of predictive power of the thyroid fine needle aspiration/biopsy (TFNAB) approach to defining the nature of clinically detected thyroid nodules. This has been exacerbated in the past decade or more by the routine use of ultrasonography (US) in examining the thyroid as well as the introduction of molecular testing in the realm of thyroid pathology. Some have even gone so far as to suggest replacing the TFNAB with molecular signature testing to reduce the degree of uncertainty for a specific cytological diagnosis. This review addresses those concerns with a re-emphasis on understanding the basic keys to successfully evaluating a patient with a thyroid nodule by routine TFNAB examination. These keys include bringing to bear an experienced group of physicians in an integrated team approach, a sharpened focus on the TFNAB cytological categories and a grounded understanding of the predictive ability of molecular testing in a given patient when the cytological interpretation creates too much uncertainty in the minds of the patients and clinicians in attempting to reach a decision on how to manage a thyroid nodule. With this practical approach in mind, the false-negative and false-positive rates of "negative (benign)" and "positive (malignant)" thyroid aspirates should be no more than 1%; and the prevalence of an "indeterminate" aspirate - the area in TFNAB attracting the most attention for improvement with novel biomarkers - should be 10% or less. Thus, physicians should be capable of managing at least 90% of patients undergoing TFNAB in a confident manner without further testing beyond the routine, future re-examination of the patient's nodule to re-assess for any change in its nature or its impact on the patient's quality of life. The other 10% can then be considered for molecular testing in a manner tailored to those individuals truly in need of a more sophisticated - and expensive - approach to the characterization of their thyroid nodules. As the era of US has matured - just as with the era of serum PSA testing for prostate cancer in men - we have experienced a paradigm shift: Given the incidence of thyroid nodules in the U.S. adult population in comparison with the risk of dying of thyroid malignancy, the main role of TFNAB is to reduce the need for surgical intervention.

Renal oncocytoma growth rates before intervention.

OBJECTIVE: To describe the growth rates of oncocytomas before treatment with surgical resection or percutaneous ablation. PATIENTS AND METHODS: This single-institution retrospective study included 33 consecutive, pathologically proven renal oncocytomas with serial contrast-enhanced computed tomography scans spanning at least 1 year before intervention, from 2000 to 2009. Tumours were measured by two radiologists, and growth rates and interobserver variability were calculated. The mean (range) pre-procedural imaging surveillance period was 36 (12-124) months (median 33 months). RESULTS: The mean (SD) oncocytoma size was 17 (11) mm (range 4-47 mm, median 15 mm) in maximum transverse diameter on initial imaging and grew to a mean (SD) of 26 (5) mm (range 10-83 mm, median 23 mm) by the time of treatment. Overall, the mean (SD) and median growth rates were 2.9 (2.6) mm/year and 2.7 mm/year, respectively (range -1.2-10.9 mm/year). After weighting by the se of each tumour's growth rate, the mean (SD) change was 2.1 (1.2) mm/year. The mean (range) interobserver variability for each tumour measurement was 1 (0-7) mm with an intraclass correlation coefficient of 0.99. CONCLUSIONS: Renal oncocytomas grow at a rate similar to reported growth rates of renal cell carcinoma. As the observation of growth does not distinguish between benign and malignant renal tumours, growth of small renal masses under active surveillance should be carefully considered before a switch is made to intervention.

Laparoscopic ultrasound-assisted liposuction for lymph node dissection: a pilot study.

BACKGROUND: Lymphadenectomy is a surgical technique for staging and treating cancer. Laparoscopic lymphadenectomy for obese patients is challenging. Laparoscopic ultrasound-assisted liposuction (UAL) has been successful in porcine models. The current study aimed to evaluate whether UAL facilitates pelvic laparoscopic lymphadenectomy in obese subjects. METHODS: The UAL technique was evaluated in two human cadavers and in six obese Ossabaw pigs. Both a standard and a prototype ultrasonic probe with a wider contact surface were tested. Pelvic lymphadenectomy comparing UAL with standard monopolar cautery was performed using obese Ossabaw pigs. The animals were survived for 2 weeks. Descriptive data regarding intra- and postoperative outcomes were recorded, including histologic analysis of dissected tissue after 2 weeks. Cytologic analysis of aspirated fluid coming from UAL also was recorded. RESULTS: The UAL procedure was safely performed for all the cadavers and animals. Lymph node exposure and clean exposure of surrounding structures were dramatic compared with monopolar assisted dissection. One animal was excluded from further analysis due to ultrasonic device malfunction (a broken footswitch cord). In general, UAL notably debulks adipose tissue with dramatic field exposure. Postoperative adhesions were present in all animals undergoing either monopolar or UAL dissection. Histology showed areas of foreign body reaction from mild to severe, with no predominance of either extreme seen with monopolar or UAL dissection. Cytologic analysis of collected pooled oil emulsion did not contain lymph node tissue. CONCLUSION: The UAL approach permits pelvic lymphadenectomy in the obese animal and cadaver model, with excellent exposure of lymph nodes and surrounding pelvic anatomy. The use of a new ultrasonic prototype probe with a wider contact surface allowed dissection with less mechanical and thermal penetration of tissue. Further studies are needed to assess oncologic safety (cancer cell dissemination), postoperative healing, and adhesion formation.

A multivariable model using advanced cytologic methods for the evaluation of indeterminate pancreatobiliary strictures.

BACKGROUND & AIMS: Ancillary cytologic tests including digital image analysis (DIA) and fluorescence in situ hybridization (FISH) have been developed to improve the sensitivity of routine cytology (RC) for the diagnosis of malignancy in pancreatobiliary strictures. The goal of this study was to retrospectively compare the performance of RC, DIA, and FISH on clinical brushing specimens. METHODS: Endoscopic retrograde cholangiopancreatography brushings were obtained from 498 consecutive patients with pancreatobiliary strictures and analyzed by RC, DIA, and FISH as per standard practice. RC diagnostic categories included negative, atypical, suspicious, or positive. Aneuploid/tetraploid histograms were considered positive for DIA. FISH was performed using UroVysion (Abbott Molecular, Inc, Des Plaines, IL) and classified as negative, trisomy, tetrasomy, or polysomy. RESULTS: The sensitivity of polysomy FISH (42.9%) was significantly higher than RC (20.1%) when equivocal RC results were considered negative (P < .001) with identical specificity (99.6%). There was a significant difference in time for diagnosis of carcinoma between FISH diagnostic categories (P < .001) and between RC diagnostic categories (P < .001). Logistic regression analysis revealed that polysomy FISH, trisomy FISH, suspicious cytology, primary sclerosing cholangitis status, and age were associated with carcinoma (P < .05). CONCLUSIONS: Polysomy FISH had high sensitivity without compromise to specificity. DIA was not a significant independent predictor of malignancy. Multivariable modeling using RC, FISH, age, and primary sclerosing cholangitis status can be used to estimate the probability of carcinoma for an individual patient. We recommend including FISH as a routine test where available, along with RC, in the evaluation of indeterminate pancreatobiliary strictures.

Expression of immunosuppresive B7-H3 ligand by hormone-treated prostate cancer tumors and metastases.

PURPOSE: Prostate cancer cells uniformly express the immune cell inhibitory B7-H3 ligand. Enhanced B7-H3 expression correlates with increased disease progression and cancer-specific death after radical prostatectomy (RP). EXPERIMENTAL DESIGN: To further assess whether B7-H3 expression is hormone regulated and persists as a viable target during (or after) androgen-ablative therapy, we examined B7-H3 ligand expression within primary and metastatic cancer lesions in response to neoadjuvant hormone therapy (NHT) or palliative hormone deprivation. Tumor B7-H3 in RP specimens from men treated with >/=3 months of NHT was compared with B7-H3 in tumors from matched patients who received no therapy before RP. Hormone-treated and untreated metastatic lesions involving bone were also compared for levels of B7-H3 expression. RESULTS: Of 165 consecutive RP specimens in each cohort studied, sufficient tissues were available for 148 patients (89.7%) treated with NHT versus 127 patients (77.0%) treated with surgery alone. B7-H3 was expressed in 142 (95.9%) tumors from NHT patients compared with 122 (96.0%) tumors from patients treated with surgery alone (P = 0.91). B7-H3 expression intensity in RP specimens was not affected by NHT (P = 0.12). Bone metastases from 11 (32.4%) untreated and 23 (67.6%) androgen-ablated patients revealed that B7-H3 expression increased in response to hormone therapy (P = 0.04) relative to untreated lesions. CONCLUSIONS: Taken together, B7-H3 expression seems to remain stable (or may even increase) in response to hormone therapy. As such, B7-H3 may represent an attractive target to improve treatment of men with high-risk hormone-treated or refractory prostate cancer.

Cystic change in thyroid carcinoma: Prevalence and estimated volume in 360 carcinomas.

PURPOSE: The aim of this study was to determine the prevalence and amount of cystic change in thyroid cancer. This study also examined associated sonographic characteristics of cystic malignant thyroid nodules to help recognize these clinically important nodules. METHODS: This study was a retrospective review of 360 malignant thyroid nodules surgically removed at our institution between January 1, 2002 and December 31, 2004. All patients had signed research authorization. All patients had preoperative sonograms and surgical pathologic proof of their thyroid malignancy. The 360 malignant nodules were found in 307 patients. All scans were performed using 7- to 15-MHz transducers, and most studies included a digital video clip of the cancer. The preoperative ultrasound examinations were retrospectively reviewed by three radiologists and a sonographer. An estimate of cystic component percentage was derived by consensus. The presence of a mural nodule, thick irregular wall, microcalcifications, and prominent vascularity was also recorded. RESULTS: Of the 360 carcinomas, 318 (88.3%) were solid to minimally (less than 5%) cystic, 33 (9.2%) were 6-50% cystic, 9 (2.5%) were 51-100% cystic. Of the nine (2.5%) malignancies that were greater than 50% cystic, all had other suspicious findings including mural nodules, microcalcifications, increased vascularity, and/or a thick irregular wall about the cystic portion. CONCLUSION: The vast majority (88%) of thyroid cancer is uniformly solid or has minimal (1-5%) cystic change by sonography. Marked cystic change (>50% of the nodule) occurred in only 2.5% of cancers, which had other sonographic findings worrisome for malignancy.

Expression and significance of androgen receptor coactivators in urothelial carcinoma of the bladder.

Urothelial carcinoma (UC) of the bladder is approximately three times more common in men than women. While the etiology for this gender difference in incidence remains unknown, a role for androgen receptor (AR) signaling has been suggested. The mechanisms by which AR activity is regulated in UC cells, however, are largely elusive. Here, we explore the significance of coregulators that are critical for the formation of a functional AR transcriptional complex, in UC cells. Using two AR-positive UC cell lines, TCC-SUP and UMUC3, we demonstrate the expression of the coactivators NCOA1, NCOA2, NCOA3, CREBBP, and EP300 in UC cells. small interfering RNA-mediated knockdown of the AR or any of these coactivators markedly impacted cell viability and abrogated androgen-dependent cell proliferation. Noteworthy, contrary to AR-positive prostate cancer cells, expression of these AR-associated coactivators was not androgen regulated in UC cells. To assess the clinical relevance of coactivator expression, we performed immunohistochemistry on paraffin-embedded sections from 55 patients with UC of the bladder. We found that while 24 out of 55 (44%) of tumors expressed the AR, each of the coactivators was expressed by 85-100% of the bladder cancers. Moreover, we noted a significant downregulation of NCOA1 expression in tumors versus adjacent, non-tumor bladder urothelium, with a mean of 68% (range 0-100) of tumor cells demonstrating NCOA1 staining versus a mean of 81% (range 0-90) of non-tumor cells (P=0.03). Taken together, our data suggest an important role for AR-associated coactivators in UC and point toward differences in the regulation of AR activity between bladder and prostate cancer cells.

Quantitative fluorescence in situ hybridization and its ability to predict bladder cancer recurrence and progression to muscle-invasive bladder cancer.

Fluorescence in situ hybridization (FISH) testing is used to detect bladder cancer in urine specimens. The purpose of this study was to determine whether there are associations between the percentage of chromosomally abnormal cells by FISH and time to bladder cancer recurrence and progression to metastasis. Clinical records were searched to identify patients with urine FISH results, history of non-invasive bladder cancer, and at least one follow-up pathological diagnosis. Covariates analyzed included age, gender, smoking status, treatment after FISH, cystoscopy result, and prior stage of bladder cancer. The percentage of abnormal cells (hazard ratio [HR] 1.03, 95% CI 1.02-1.03; P < 0.001), age (HR 1.02, 95% CI 1.00-1.03; P = 0.033), male gender (HR 0.60, 95% CI 0.41-0.87; P < 0.001), treatment (HR 0.37, 95% CI 0.25-0.55; P < 0.001), and history of TIS/T1-stage tumors (HR 1.66, 95% CI 1.23-2.24; P = 0.001) were significantly associated with time to cancer recurrence. Time to invasive cancer was significantly associated with the percentage of abnormal cells (HR 1.02, 95% CI 1.01, 1.03; P < 0.001), history of TIS/T1 tumor (HR 3.73, 95% CI 1.88, 7.38; P = 0.001), and treatment (HR 0.33, 95% CI 0.13, 0.83; P = 0.019), suggesting that the percentage of abnormal cells independently predicts cancer recurrence and progression to invasive disease in patients with a history of non-invasive bladder cancer.

The impact of discordance between biopsy and pathological Gleason scores on survival after radical prostatectomy.

PURPOSE: Although discordance in the Gleason score between biopsy and radical prostatectomy specimens has been well recognized, the prognostic importance of this discrepancy has not been definitively established. We investigated the association of Gleason score discordance with postoperative systemic progression and death from prostate cancer. MATERIALS AND METHODS: We evaluated the records of 8,054 consecutive patients who underwent radical prostatectomy between 1987 and 2003. Gleason score at biopsy and prostatectomy was categorized as 6 or less, 3 + 4, 4 + 3 and 8 to 10. Cox proportional hazard regression models were used to analyze the impact of biopsy Gleason score on postoperative survival in patients in each pathological Gleason score stratum. RESULTS: Discordance in Gleason score was associated with adverse pathological features, including advanced tumor stage, lymph node metastasis and positive surgical margins (each p <0.001). On multivariate analysis increasing biopsy Gleason score was significantly associated with systemic progression in patients with pathological 3 + 4 and 8 to 10 cancer (HR 1.44, 95% CI 1.17-1.76, p <0.001 and HR 1.24, 95% CI 1.03-1.48, p = 0.023, respectively). It was also an independent predictor of death from prostate cancer in patients with pathological Gleason 3 + 4 tumors (HR 1.62, 95% CI 1.23-2.15, p <0.001). However, adding biopsy Gleason score to our institutional Gleason score, prostate specific antigen, and seminal vesicle and margin status scoring algorithm minimally increased the concordance statistic for the association of that algorithm with cancer specific mortality from 0.827 to 0.842. CONCLUSIONS: Biopsy Gleason score predicts systemic progression and cancer death in patients with pathological Gleason 3 + 4 tumors. Nevertheless, adding biopsy Gleason score to Gleason score, prostate specific antigen, and seminal vesicle and margin status did little to increase the predictive value of the model, which emphasizes the relative importance of pathological criteria for risk stratification.

Locally recurrent prostate cancer after initial radiation therapy: a comparison of salvage radical prostatectomy versus cryotherapy.

PURPOSE: We compared the treatment outcomes of salvage radical prostatectomy and salvage cryotherapy for patients with locally recurrent prostate cancer after initial radiation therapy. MATERIALS AND METHODS: We retrospectively reviewed the medical records of patients who underwent salvage radical prostatectomy at the Mayo Clinic between 1990 and 1999, and those who underwent salvage cryotherapy at M. D. Anderson Cancer Center between 1992 and 1995. Eligibility criteria were prostate specific antigen less than 10 ng/ml, post-radiation therapy biopsy showing Gleason score 8 or less and prior radiation therapy alone without pre-salvage or post-salvage hormonal therapy. We assessed the rates of biochemical disease-free survival, disease specific survival and overall survival in each group. Biochemical failure was assessed using the 2 definitions of 1) prostate specific antigen greater than 0.4 ng/ml and 2) 2 increases above the nadir prostate specific antigen. RESULTS: Mean followup was 7.8 years for the salvage radical prostatectomy group and 5.5 years for the salvage cryotherapy group. Compared to salvage cryotherapy, salvage radical prostatectomy resulted in superior biochemical disease-free survival by both definitions of biochemical failure (prostate specific antigen greater than 0.4 ng/ml, salvage cryotherapy 21% vs salvage radical prostatectomy 61% at 5 years, p <0.001; 2 increases above nadir with salvage cryotherapy 42% vs salvage radical prostatectomy 66% at 5 years, p = 0.002) and in superior overall survival (at 5 years salvage cryotherapy 85% vs salvage radical prostatectomy 95%, p = 0.001). There was no significant difference in disease specific survival (at 5 years salvage cryotherapy 96% vs salvage radical prostatectomy 98%, p = 0.283). After adjusting for post-radiation therapy biopsy Gleason sum and pre-salvage treatment serum prostate specific antigen on multivariate analysis salvage radical prostatectomy remained superior to salvage cryotherapy for the end points of any increase in prostate specific antigen greater than 0.4 ng/ml (HR 0.24, p <0.0001), 2 increases in prostate specific antigen (HR 0.47, p = 0.02) and overall survival (HR 0.21, p = 0.01). CONCLUSIONS: Young, healthy patients with recurrent prostate cancer after radiation therapy should consider salvage radical prostatectomy as it offers superior biochemical disease-free survival and may potentially offer the best chance of cure.

Renal ischemia time in laparoscopic surgery: an experimental study in a porcine model.

OBJECTIVES: Laparoscopic nephron sparing surgery is becoming more common, only limited by experience of the surgeon and the renal ischemia time. It is currently unknown if laparoscopic surgery alters the accepted 30 min threshold for renal ischemia. The purpose of this study was to define the normothermic ischemic threshold in the laparoscopic setting. METHODS: Twenty-four domestic female pigs underwent a laparoscopic transperitoneal procedure after randomization to one of five treatment groups: 30, 60, 75, 90, and 120 min of unilateral renal ischemia. One animal was used as a control specimen and was not exposed to any surgery or pneumoperitoneum. The contralateral kidney in each animal was used as an individual control for the corresponding time of pneumoperitoneum. The animals were euthanized after 3 weeks, when both renal units were harvested and data were analyzed. RESULTS: Three animals died secondary to complications from their procedure and were replaced. There was no association between urine volume and ischemic time, but urine creatinine and creatinine clearance decreased significantly as ischemic time increased. The control animal and 30 min ischemic group had similar results. Functional renal parameters decreased in those animals exposed to greater than 75 min of ischemia. The histologic analysis did not show any significant differences among the experimental groups. CONCLUSION: Renal function begins to deteriorate between 75 and 90 min of renal vascular occlusion in this two-renal unit laparoscopic porcine model.

Human calmodulin-like protein (CLP) expression in oral squamous mucosa and in malignant transformation.

PURPOSE: The purpose of this study was to test whether calmodulin-like protein (CLP) is expressed in normal human oral mucosal cells and if downregulation of CLP occurs in malignant transformation. MATERIALS AND METHODS: Oral mucosal tissue was taken from three individuals in a double-blind manner. The samples were cut, measured, and homogenized. Total RNA was extracted and reverse transcribed. Each cDNA sample was subjected to polymerase chain reaction (PCR). PCR fragments were purified, cloned, and sequenced to verify the presence of CLP. Three oral mucosal tissue samples with biopsy-confirmed squamous cell carcinoma were obtained. These samples demonstrated regions of normal epithelial cells as well as invasive squamous cell carcinoma. One normal breast epithelial sample was also obtained for positive control. Sections were stained with an affinity-purified CLP antibody and counterstained with a diluted hematoxylin. Two observers evaluated the specimens for expression of CLP. Staining patterns and intensity were noted in normal oral mucosa, comparing them to the normal breast epithelium sample. Staining patterns and intensity were then observed in squamous tumor cells, comparing them to the patterns of benign squamous mucosa. RESULTS: CLP coding sequences were positively identified from the normal oral mucosal tissue samples by reverse transcription and polymerase chain reaction (RT-PCR) with 100% identity to the published CLP sequence (accession #M58026). In the three oral mucosa tissue samples with known squamous cell carcinoma, expression of CLP was readily detected in areas of normal oral mucosa, while a notable downregulation of CLP expression occurred in areas of malignant transformation. The staining intensity was equivalent to the staining seen in the benign breast epithelium used as a control. In the areas of squamous cell carcinoma, a decrease in CLP immunoreactivity occurred. There was a sharp contrast in staining quality and clarity between benign and malignant tissue. In the majority of the carcinoma regions, a complete lack of immunoreactivity was noted. CONCLUSIONS: The RNA for human CLP is found in normal oral mucosa. CLP expression is seen in normal oral mucosa with a downregulation of CLP expression in malignant transformation.

Androgen deprivation increases p300 expression in prostate cancer cells.

Standard therapy for nonorgan confined prostate cancer aims to block the production or action of androgens. Although initially successful, antiandrogen therapy eventually fails and androgen depletion independent (ADI) disease emerges. Remarkably, ADI prostate cancers still rely on a functional androgen receptor (AR). Aberrant expression of coregulatory proteins required for the formation of productive AR transcriptional complexes is critical for ADI AR activation. Previously, we have shown that the transcriptional coactivator p300 is required for ADI activation of the AR and is up-regulated in prostate cancer, in which its expression is associated with cell proliferation and predicts aggressive tumor features. The mechanism responsible for the deregulated expression of p300, however, remains elusive. Here, we show that p300 expression in prostate cancer cells is subject to androgen regulation. In several prostate cancer model systems, addition of synthetic and natural androgens led to decreased expression of p300 in a time-dependent and dose-dependent manner. Experiments using AR antagonists or small interfering RNA targeting the AR revealed that down-regulation of p300 depends entirely on the presence of a functional AR. It is noteworthy that androgens down-regulated p300 protein expression while leaving messenger levels unaltered. Conversely, both short-term and long-term androgen deprivation resulted in marked up-regulation of p300 expression. The androgen deprivation-induced increase in p300 expression was not affected by the addition of cytokines or growth factors or by cotreatment with antiandrogens. Moreover, increased p300 expression upon androgen starvation is crucial for prostate cancer cell proliferation, as loss of p300 expression severely reduces expression of cyclins governing G(1)-S and G(2)-M cell cycle transition and decreases 5-bromo-2'-deoxyuridine incorporation.

B7-H3 ligand expression by prostate cancer: a novel marker of prognosis and potential target for therapy.

B7 coregulatory ligands can be aberrantly expressed in human disease. In the context of cancer, these ligands may act as antigen-specific inhibitors of T-cell-mediated antitumoral immunity. We recently reported that B7-H1 expression by carcinomas of the kidney and bladder portends aggressive disease and diminished survival. The expression of these proteins in prostate cancer, however, has not been investigated. We evaluated B7-H3 and B7-H1 protein expression in the pathologic specimens of 338 men treated for clinically localized prostate cancer between 1995 and 1998 with radical retropubic prostatectomy. Expression levels of B7-H3 in prostate cancer were correlated with pathologic indicators of aggressive cancer as well as clinical outcome. We report that B7-H3 is uniformly and aberrantly expressed by adenocarcinomas of the prostate, high-grade prostatic intraepithelial neoplasia, and four prostate cancer cell lines, whereas B7-H1 is rarely expressed. B7-H3 is expressed by benign prostatic epithelia, although at a more reduced level relative to neoplastic tissue. Increasing levels of B7-H3 intensity correlate with worsening clinicopathologic features of prostate cancer. Marked B7-H3 intensity, present in 67 (19.8%) specimens, confers a >4-fold increased risk of cancer progression after surgery (risk ratio, 4.42; P < 0.001). A survey of normal tissues revealed that B7-H3 is expressed within the liver, urothelium, and fetal kidney. In summary, B7-H3 is aberrantly expressed in all prostate cancers and represents an independent predictor of cancer progression following surgery. Moreover, B7-H3 encompasses a novel diagnostic and potential therapeutic target for the clinical management of prostate cancer and, perhaps, other malignancies as well.