Faculty Bibliography

BACKGROUND: Neutral endopeptidase (NEP) is a cell-surface peptidase that can regulate the activation of Akt kinase through catalytic-dependent and independent mechanisms. NEP expression is absent in approximately 50% of prostate cancers. The authors investigated whether NEP loss in vivo would result in Akt phosphorylation and potentially contribute to prostate cancer progression by examining the interaction of NEP, Akt, and phosphatase and tensin homolog (PTEN) in a prostate xenograft model and in clinical specimens from patients with prostate cancer. METHODS: Using a tetracycline-repressible expression system to express NEP in a tumor animal xenograft model, the effects of NEP were tested on tumor growth, Akt phosphorylation, and PTEN expression. The clinical relevance of NEP, phosphorylated Akt, and PTEN protein expression also was investigated in 204 patients who had undergone radical prostatectomy. RESULTS: The results indicated that the induction of NEP expression inhibited established xenograft tumor growth, diminished Akt phosphorylation, and increased PTEN protein levels. In humans, prostate cancers with complete loss of NEP expression were significantly more likely to express phosphorylated Akt (P = .02). Moreover, patients who had prostate cancers with concomitant loss of NEP and expression of phosphorylated Akt had an increased, independent risk of prostate-specific antigen (PSA) recurrence (P = .03). In the study cohort, loss of PTEN protein expression did not correlated significantly with phosphorylated Akt or with patients' clinical outcome. CONCLUSIONS: The findings from this investigation demonstrated that NEP loss leads to Akt activation and contributes to the clinical progression of prostate cancer

BACKGROUND: Function of the retinoblastoma tumor suppressor protein (pRB) may be compromised at a genetic level by gene loss or mutation or at a post-translational level by hyperphosphorylation. In this study, we examined adult soft tissue sarcomas (ASTS) to determine if alterations of pRB were associated with distinct patterns of pRB expression and clinical outcome. DESIGN: We investigated 86 ASTS patients using monoclonal antibodies that distinguish between hyperphosphorylated and underphosphorylated pRB products. We also used microsatellite analysis to investigate the genetic status of the RB locus. We correlated pRB alterations with proliferative activity, and with clinicopathological outcomes. RESULTS: Altered patterns of pRB expression are common in ASTS occurring in 84% of cases, and it is significantly associated with proliferative activity (p<0.001). Patients whose tumors either lack expression of pRB, or express hyperphosphorylated forms of pRB, have poor survivals compared to patients whose tumors exhibit a normal, underphosphorylated pattern of pRB expression (p=0.03). In addition, 63% of cases lacking expression of pRB showed loss-of-heterozygosity at the locus. CONCLUSIONS: Inactivation of pRB is common in adult STS, which may be due to either gene loss or post-translational modification, namely hyper-phosphorylation. Both mechanisms are associated with tumor cell proliferation and poor survival

Summary Background Large congenital melanocytic naevi (LCMN), which develop in utero and are present in approximately one in 20 000 newborns, are associated with markedly increased risks of cutaneous melanoma, leptomeningeal melanoma and neurocutaneous melanocytosis (NCM). Objectives This study examined clinical characteristics associated with melanoma and NCM among patients with LCMN, and estimated the risk of developing melanoma and NCM in these patients. Methods Two hundred and five LCMN patients enrolled in the New York University registry were studied. One hundred and seventy of these patients were followed prospectively. The remaining 35 patients had either melanoma at the time of entry into the registry (n = 6), or had insufficient follow-up information (n = 29). The outcome measures were the occurrence of melanoma and NCM. The associations between these outcomes and the clinical covariates (anatomical location of the LCMN, size of the LCMN, number of satellite lesions, family history of melanoma, patient sex and treatment) were assessed. Results Four of 170 (2.3%) prospectively followed patients developed melanomas, representing a standardized morbidity ratio of 324. Among the entire cohort (n = 205), there were associations between increasing numbers of satellite naevi and the occurrence of melanoma (P = 0.04), and the presence of NCM (P = 0.06). Compared with patients who did not develop these diseases, median LCMN diameters were larger among patients who developed melanoma (49 vs. 39 cm) and NCM (55 vs. 46 cm). Conclusions In LCMN patients, increasing numbers of satellite lesions and larger LCMN diameters are associated with melanoma and NCM

PURPOSE: Inactivation of the tumor suppressor gene, phosphatase and tensin homologue (PTEN), is a major alteration in preclinical melanoma models. We investigated the clinical relevance of PTEN expression in the primary melanoma patients with extended follow-up. EXPERIMENTAL DESIGN: We correlated PTEN expression with clinicopathologic variables and outcome in 127 primary melanomas (median follow-up, 12.8 years). We evaluated the associations between PTEN expression and proliferation and resistance to apoptosis (assessed by Ki-67 and Bcl-2, respectively). We also examined the effect of a favorable phenotype, defined as retained PTEN, low proliferative index, and low expression of Bcl-2 on disease-free survival and overall survival. RESULTS: Altered PTEN, Bcl-2, and Ki-67 expressions were observed in 55 of 127 (43.3%), 61 of 127 (48%), and 43 of 114 (37.7%) of cases, respectively. Decreased PTEN expression correlated significantly with the ulceration (P = 0.01). Rates of disease-free survival and overall survival in patients with favorable phenotype were 72% and 74% at 5 years versus 64% and 64% in patients with an unfavorable phenotype. At 10 years, the rates of disease-free survival and overall survival were 72% and 68% for patients with a favorable phenotype but declined to 60% and 55% in patients with an unfavorable phenotype. However, relationships between both PTEN and Bcl2 and patient survival were not significant as well as the associations between PTEN and Bcl-2 or Ki-67. CONCLUSIONS: Our data suggest that altered PTEN expression is common in primary melanomas and is associated with aggressive tumor behavior. However, PTEN alone provided limited prognostic value. Our findings show the need to examine molecular alterations identified in preclinical studies using an adequately large cohort of patients with extended follow-up to better assess the magnitude of their clinical relevance

PURPOSE: We determined the association between serum levels of shed Her-2/neu protein and disease progression in men with prostate cancer. MATERIALS AND METHODS: Serum from 279 patients enrolled in a prospective serum bank and database at New York University Medical Center was analyzed using the Food and Drug Administration approved Immuno-1 Her-2/neu assay. Patients were classified by the Prostate-Specific Antigen Working Group model into 5 groups, namely group 1-no evidence of cancer in 60, group 2-clinically localized disease in 67, group 3-prostate specific antigen increasing after therapy and no clinical metastases in 77, group 4-clinical metastases and castration sensitivity in 42, and group 5-clinical metastases and castration resistance in 33. A cutoff of 14 ng/ml for normal serum Her-2/neu was established based on the 95th order statistic in group 1. RESULTS: Of 279 patients 37 (13.3%) had increased serum Her-2/neu, that is 5%, 11.9%, 10.4%, 16.7% and 33.3% in groups 1 to 5, respectively. There was a significant difference between patients with (groups 4 and 5) and without (groups 2 and 3) clinical metastases (p = 0.006). In group 5 patients serum Her-2/neu was significantly higher than in group 2 patients (p <0.02). The risk of cause specific death increased significantly with each unit increase in serum Her-2/neu (p <0.001). CONCLUSIONS: Increased serum Her-2/neu correlates with the presence of metastatic disease and it may indicate an increased risk of death in patients with castrate, metastatic prostate cancer. The detection of serum Her-2/neu is a minimally invasive alternative to tumor sampling for identifying potential candidates for anti-Her-2/neu treatment strategies. Further studies are needed to optimize this assay for application in the clinical setting

Our purpose was to determine the clinical relevance of the detection of circulating tumor cells (CTCs) expressing urothelial and epithelial markers in bladder cancer patients. Sixty-two patients who presented to Memorial Sloan-Kettering Cancer Center between July 2000 and September 2001 were studied. Peripheral blood was tested by nested RT-PCR assay for uroplakins (UPs) Ia, Ib, II and III as well as for epidermal growth factor receptor (EGFR). We determined the sensitivity and specificity of each individual marker and the combinations of UPIa/UPII and UPIb/UPIII. The latter strategy was based on our data, which showed that UPIa and UPIb form heterodimers with UPII and UPIII, respectively. Forty patients had clinically advanced bladder cancer and 22 had no evidence of disease at the time of assay. Eight of the 22 patients recurred during the follow-up period. All 8 patients were positive at presentation for UPIa/UPII. The combination of UPIa/UPII provided the best sensitivity (75%) of detecting CTCs, with a specificity of 50%. The combination of UPIb/UPIII was the most specific (79%) but had modest sensitivity (31%). Detection of EGFR-positive cells alone and in combination with UPs was inferior to that for UPIa/UPII. Combinations of urothelial markers are superior to single urothelial or epithelial markers in detecting CTCs in bladder cancer patients. Further efforts are under way to confirm the potential predictive value of these markers in a prospectively designed study of a larger cohort of patients.