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Biomedical subjects

Seth P Lerner

Publications and source records attributed to Seth P Lerner.

49 records · Page 3Linked to original sources
PubMed2003

Association of p53 and p21 expression with clinical outcome in patients with carcinoma in situ of the urinary bladder.

OBJECTIVES: To determine whether p53 and p21 expression in bladder carcinoma in situ (CIS) with or without papillary disease can predict disease recurrence, progression, and survival. METHODS: Immunohistochemical staining for p53 and p21 was carried out on paraffin-embedded tumor specimens from 47 and 39 patients, respectively, who had CIS with or without Ta or T1 disease, but without muscle-invasive cancer. Immunoreactivity was categorized as either positive (reactivity in 10% or more CIS cells) or negative. RESULTS: Expression of p53 and p21 was positive in 28 (60%) of 47 and 12 (31%) of 39 CIS tumors, respectively. p53 expression was not associated with clinical outcome. Positive p21 expression was associated with bladder cancer recurrence (P = 0.035) and progression (P = 0.033) when adjusted for the effects of clinical stage and grade. The combined p53/p21 expression status was independently associated with disease recurrence (P = 0.022), progression (P = 0.042), and cancer-specific survival (P = 0.031). Patients with p53+/p21+ expression were at significantly greater risk of disease recurrence, progression, and mortality than those having a p53+/p21- or p53-/p21- phenotype (not significantly different from each other statistically). CONCLUSIONS: In CIS without muscle-invasive disease, positive p21 expression was independently associated with bladder cancer recurrence and progression. Positive expression for both p53 and p21 puts patients with bladder CIS at the greatest risk of bladder cancer recurrence, progression, and, most importantly, mortality, suggesting a potential rationale for early definitive therapy in these patients. On the other hand, an intact pathway at the level of p21 seems to abrogate the detrimental effects of altered p53 immunoreactivity on the outcome of bladder CIS.

Adult↗
PubMed2003

Bladder cancer screening program for a petrochemical cohort with potential exposure to beta-napthylamine.

Approximately 1800 workers in pipe manufacturing plants in the United States may have been exposed to beta-napthlyamnine between 1970 and 1996. Once the chemical was detected, the contaminated additive in the resin was identified and discontinued. A bladder cancer-screening program was initiated in 1999. An annual two-stage screening program was developed to test for microscopic hematuria (stage one) and cytology (stage two), with a urology referral of positive or suspicious cytology. This paper presents the program methodology, cohort enumeration, recruitment, and enrollment strategies, and screening protocol. Enrollment data from the first 3 years are presented. Annual screening of a cohort of current and former employees is feasible. Original personnel records are often incomplete, making cohort identification important. Personal contact and follow-up are key elements of successful recruitment and retention.

2-Naphthylamine↗
PubMed2003

Plasma levels of insulin-like growth factor-1 and binding protein-3, and their association with bladder cancer risk.

PURPOSE: Because insulin-like growth factors (IGFs) and their binding proteins have been implicated in the development of prostate, breast, colon and lung cancer, we examined the role of IGF-1 and IGF binding protein-3 levels in bladder cancer risk. MATERIALS AND METHODS: We used an enzyme-linked immunosorbent assay to compare plasma levels of IGF-1 and IGF binding protein-3 in 154 patients with bladder cancer and 154 controls from an ongoing case-control study. RESULTS: Mean IGF-1 was significantly higher in cases than in controls (175.8 versus 153.2 ng./ml., p <0.01). Mean IGF binding protein-3 was significantly lower in cases than in controls (2,632.9 versus 3,056.6 ng./ml., p <0.01). The highest quartile plasma levels of IGF-1 were associated with an increased risk of bladder cancer (OR 3.10, 95% CI 1.43 to 6.70) and the highest quartile plasma levels of IGF binding protein-3 were associated with a reduced risk of bladder cancer (OR 0.38, 95% CI 0.19 to 0.78). The effects were more striking when IGF-1 and IGF binding protein-3 levels were analyzed together. In addition, a higher molar ratio of IGF-1-to-IGF binding protein-3 was associated with an increased risk of bladder cancer (OR 4.30, 95% CI 1.99 to 9.28). Dose-response relationships were evident when subjects were categorized into quartiles by the values of IGF-1, IGF binding protein-3 and the molar ratio in controls. CONCLUSIONS: To our knowledge this is the first study to suggest that patients with bladder cancer have higher plasma levels of IGF-1 and lower levels of IGF binding protein-3 than controls. Thus, measuring plasma IGF-1 and IGF binding protein-3 may be useful for assessing bladder cancer risk.

Case-Control Studies↗
PubMed2003

Cyclooxygenase-2 is highly expressed in carcinoma in situ and T1 transitional cell carcinoma of the bladder.

PURPOSE: We describe cyclooxygenase-2 (COX-2) expression patterns in patients with carcinoma in situ and/or stage T1 transitional cell carcinoma. We determined whether expression is associated with clinical outcome in these patients. MATERIALS AND METHODS: Immunostaining for COX-2 was performed on paraffin embedded bladder biopsy specimens from 2 independent groups of patients without muscle invasive carcinoma, including 39 with carcinoma in situ and 34 with stage T1 tumors. Immunoreactivity was scored as the percent of carcinoma in situ cells with cytoplasmic staining for COX-2 in the carcinoma in situ group and as the percent of stage T1 cells expressing COX-2 in the stage T1 transitional cell carcinoma group. We evaluated other molecular alterations, including E-cadherin, p21 and p53, because evidence suggests a biological association of COX-2 with alterations in these molecular markers. RESULTS: In the carcinoma in situ group 5 patients (13%) had no immunoreactivity, while 2 (5%), 5 (13%) and 27 (69%) had 10%, 20% and 30% or greater carcinoma in situ cells positive for COX-2, respectively. In the transitional cell carcinoma group 1 (3%), 4 (12%) and 29 (85%) patients had 10%, 20% and 30% or greater positive cells, respectively. COX-2 expression was not associated with any clinical or pathological parameters, or with molecular markers regardless of the cutoff used. It was also not associated with clinical outcomes in the stage T1 transitional cell carcinoma group. In the carcinoma in situ group COX-2 expression was significantly associated with disease recurrence using cutoffs of 0% and greater than 10% positive cells, and with disease progression using a greater than 20% cutoff. However, it was not associated with bladder cancer related survival. CONCLUSIONS: COX-2 is expressed in a high percent of patients with carcinoma in situ and stage T1 transitional cell carcinoma, supporting the rationale for chemoprevention studies with selective COX-2. We could not substantiate a role for COX-2 immunohistochemistry for the staging and prognosis of carcinoma in situ and/or stage T1 transitional cell carcinoma.

Adult↗
PubMed2003

Correlation of cyclooxygenase-2 expression with molecular markers, pathological features and clinical outcome of transitional cell carcinoma of the bladder.

PURPOSE: We investigated the relationship between cyclooxygenase-2 (COX-2) expression and molecular alterations commonly found in transitional cell carcinoma (TCC) of the bladder and determined whether COX-2 immunoreactivity is associated with cancer stage, progression and survival in patients undergoing radical cystectomy. MATERIALS AND METHODS: Immunohistochemical staining for COX-2 was done in archival tumor specimens from 80 patients who underwent radical cystectomy. Immunoreactivity was categorized as positive (reactivity in greater than 10% tumor cells) or negative. Microvessel density, E-cadherin, pRB, p16, p21, p53 and transforming growth factor (TGF)-beta1 and its receptors (types I and II) were also studied because evidence suggests a biological association between COX-2 and alteration of these molecules. RESULTS: COX-2 was over expressed in 62 patients (78%). COX-2 over expression was associated with muscle invasive pathological stage (p = 0.022), TGF-beta1 over expression (p = 0.004), decreased E-cadherin expression (p < 0.001), and altered expression of pRB (p = 0.003) and p16 (p = 0.006). At a median followup of 101 months COX-2 over expression was associated with disease progression (p = 0.038) and bladder cancer specific survival (p = 0.042). However, when adjusted for the effects of standard pathological features, only lymph node metastasis was associated with bladder cancer progression (p = 0.027) and mortality (p = 0.042). CONCLUSIONS: COX-2 is commonly expressed in patients with bladder TCC. Using the cutoff of 10% abnormal COX-2 expression is associated with the degree of invasiveness, alterations in TGF-beta1 and pRB/p16 pathways, and loss of cell adhesion. While COX-2 expression has limited prognostic value in patients with bladder TCC, it may serve as a target for therapy with selective COX-2 inhibitors.

Blotting, Western↗
PubMed2003

The addition of urinary urokinase-type plasminogen activator to urinary nuclear matrix protein 22 and cytology improves the detection of bladder cancer.

PURPOSE: We have previously reported that urinary urokinase-type plasminogen activator (uPA) and its receptor (uPAR) are elevated in patients with bladder cancer. In the current study we tested the hypothesis that urinary uPA and uPAR would add to the predictive ability of urinary nuclear matrix protein 22 (NMP22) and cytology for the diagnosis of bladder cancer. MATERIALS AND METHODS: Urinary uPA, uPAR and NMP22 were measured in voided specimens obtained before cystoscopy in 229 consecutive subjects at risk for transitional cell carcinoma (TCC), of whom 122 (53%) were found to have bladder TCC. Bladder washout samples for cytology were also collected in 191 subjects. Associations with TCC were tested by logistic regression. Nonparametric ROC curves were generated and AUCs were compared. RESULTS: Urinary uPA, uPAR and NMP22 were higher in patients with TCC than in controls (p <0.001, 0.016 and <0.001, respectively), while uPA (test for trend p = 0.018) was associated with the risk of TCC after adjusting for NMP22 (p = 0.028), urinary cytology (p <0.001), age (p = 0.107) and uPAR (test for trend p = 0.756). The overall AUC for determining TCC was not different between uPA and NMP22 (0.746 and 0.714, p = 0.092). However, in the high sensitivity region of the ROC curve the AUC of uPA was larger than that of NMP22. CONCLUSIONS: Adding uPA to NMP22 and cytology improves their ability to predict bladder TCC by a statistically and prognostically substantial margin. An approach using multiple biomarkers may improve the diagnostic accuracy of voided urinary diagnostic tests.

Adult↗
PubMed2003

Preoperative plasma soluble E-cadherin predicts metastases to lymph nodes and prognosis in patients undergoing radical cystectomy.

PURPOSE: We have previously reported that high urinary levels of soluble E-cadherin (sE-cadherin) are associated with an increased risk of bladder cancer. We determined whether plasma levels of sE-cadherin are associated with bladder cancer stage and prognosis. MATERIALS AND METHODS: The study group consisted of 50 patients who underwent radical cystectomy for muscle invasive cancer or intravesical therapy refractory Tis, Ta, or T1 bladder cancer; and 40 men without cancer. Preoperative plasma levels of sE-cadherin were measured using a commercially available enzyme-linked immunosorbent assay kit. RESULTS: Plasma sE-cadherin was higher in patients with bladder cancer than in healthy subjects (p <0.0001) and it was elevated in patients with metastases to regional and distant lymph nodes (p = 0.019 and 0.024, respectively). When adjusted for the effects of clinical stage and grade, preoperative sE-cadherin was independently associated with metastases to regional lymph nodes (p = 0.028) and disease progression (p = 0.006) but not with bladder cancer mortality. In postoperative models preoperative sE-cadherin and lymph node metastases were associated with disease progression (p = 0.017 and 0.042, respectively) after adjusting for the effects of pathological stage, grade and lymphovascular invasion but only lymph node metastases were associated with cancer specific mortality (p = 0.007). CONCLUSIONS: Higher plasma sE-cadherin is associated with bladder cancer. Higher preoperative plasma sE-cadherin has the potential to identify patients with metastases to regional and distant lymph nodes who are at increased risk for failure of local therapy with curative intent. These patients may benefit from more extensive lymph node dissection and/or combined modality treatment regimens.

Adult↗
PubMed2002

Urinary levels of urokinase-type plasminogen activator and its receptor in the detection of bladder carcinoma.

BACKGROUND: The authors found previously that plasma levels of urokinase-type plasminogen activator (uPA) and its receptor (uPAR) were elevated in patients with bladder carcinoma and were associated with features of biologically aggressive disease. In the current study, they tested the hypothesis that elevated urinary levels of uPA and uPAR would predict the presence of bladder malignancy by comparing the performance of uPA and uPAR with the performance of bladder wash-out cytology in the noninvasive diagnosis of bladder tumors. METHODS: An enzyme-linked immunosorbent assay was used to compare levels of uPA and uPAR in urine that was collected before cystoscopy from 122 patients with bladder carcinoma and from 107 participants in a control group. Seventy-two patients had clinical Tis or Ta transitional cell carcinoma, and 50 patients had invasive disease (>or= T1); 85 patients had clinical Grade 1-2 tumors, and 37 patients had Grade 3 tumors. For cytology, only high grade was considered positive. RESULTS: Urinary levels of uPA and uPAR were higher in patients with bladder carcinoma compared with levels in the control group (P < 0.001 and P = 0.016, respectively). However, only uPA levels were elevated in patients with abnormal urinary cytology (P = 0.006). After controlling for cytology (odds ratio [OR], 10.182; 95% confidence interval [95%CI], 4.451-23.291; P < 0.001), uPAR (P for trend = 0.168), and age (P = 0.091), those in the highest quartile for uPA had an increased risk of bladder carcinoma compared with those in the lowest quartile (OR, 3.022; 95%CI, 1.295-7.054; P for trend = 0.031). CONCLUSIONS: The current findings suggest that urinary levels of uPA, but not uPAR, are related to the risk of bladder carcinoma. The study confirmed the central role of urinary cytology in the noninvasive diagnosis of bladder carcinoma.

Adult↗
PubMed2002

Preoperative plasma levels of interleukin-6 and its soluble receptor predict disease recurrence and survival of patients with bladder cancer.

PURPOSE: Elevated levels of interleukin-6 (IL-6) are associated with metastasis and poor prognosis in various malignancies. Since the IL-6 soluble receptor (IL-6sR) potentiates the systemic effects of IL-6, each may independently impact the disease process. We tested the hypothesis that preoperative plasma IL-6 and IL-6sR levels would predict cancer stage and prognosis in patients with transitional cell carcinoma of the bladder. MATERIALS AND METHODS: The study group consisted of 51 patients who underwent radical cystectomy for transitional cell carcinoma and 44 men without cancer. Preoperative plasma levels of IL-6 and IL6sR were measured by enzyme-linked immunosorbent assay and correlated with pathological features and clinical outcome. RESULTS: IL-6 levels were higher in patients with bladder cancer than in healthy controls (p <0.001). In bladder cancer cases elevated levels of IL-6 and IL-6sR were associated with adverse pathological features, including muscle invasion, lymphovascular invasion and lymph node metastases (p <0.05). High levels of IL-6sR were also associated with pathological tumor grade (p = 0.036). In separate multivariate models that included clinical stage and grade IL-6 and IL-6sR levels were independent predictors of lymphovascular invasion, metastases to lymph nodes, disease recurrence and disease specific survival (p <0.05). In a preoperative Cox proportional hazards model IL-6 (p = 0.050) and IL-6sR (p = 0.035) predicted disease specific survival. CONCLUSIONS: We found that plasma IL-6 levels were higher in patients with bladder cancer than in healthy controls. Levels of IL-6 and IL-6sR were associated with cancer stage and metastases, and were strong independent predictors of disease recurrence and disease specific survival.

Adult↗
PubMed2002

Metastatic transitional cell carcinoma of the urinary bladder to the shoulder girdle.

Transitional cell carcinoma (TCC) of the bladder typically metastasizes to the pelvic lymph nodes and to visceral sites including the lungs, liver, and bones. Other sites include the brain, especially after systemic chemotherapy. To our knowledge, we report the first case of TCC metastatic to the soft tissue of the shoulder girdle and discuss common and unusual sites of metastasis in TCC.

Case Reports↗
PubMedDate not supplied

Bladder cancer clinical trials.

The urologic oncology community recognizes the importance of bladder cancer as a significant public health problem. As the fourth most common malignancy diagnosed in U.S. men and the ninth most common in women, bladder cancer is a highly prevalent cancer with an estimated 5-year prevalence of 490,000 patients in the U.S. (2001) and over 1,000,000 worldwide (2004). Bladder cancer is the most expensive cancer to diagnose and treat. Important clinical questions abound and there are a growing number of both NIH and industry funded clinical trials attempting to answer these questions. The EORTC has played a critical role in conducting phase II and large phase III randomized trials addressing critical questions in the management of non-muscle invasive and invasive bladder cancer. The present article reviews this important area of clinical trials research.

Antineoplastic Combined Chemotherapy Protocols↗
PubMedDate not supplied

Combination of adenovirus-mediated thymidine kinase gene therapy with cytotoxic chemotherapy in bladder cancer in vitro.

We evaluated efficacy, toxicity and potential synergism of adenoviral-mediated thymidine kinase (tk)- ganciclovir (GCV) gene therapy in combination with 4 cytotoxic chemotherapeutic agents (doxorubicin, cisplatin, mitomycin C, and methotrexate) in 3 human bladder cancer cell lines. Cell lines were exposed to (1) 10 different concentrations of adenovirus expressing tk plus GCV; (2) 8 different concentrations of either doxorubicin, methotrexate, mitomycin C or cisplatin; or (3) combination treatment consisting of either low-, medium- or high-dose tk-GCV gene therapy plus 8 different concentrations of a single chemotherapeutic agent. Cell survival was determined using a MTT-based cell proliferation-assay. For most combinations, adding chemotherapy to tk-GCV gene therapy did not result in any therapeutic benefit. In some scenarios, we observed modest improvement with combinations of high-dose tk-GCV gene therapy and high-dose standard chemotherapy over tk-GCV monotherapy. Low concentrations of methotrexate enhanced the antitumor effects of low- and medium-dose tk-GCV gene therapy. Low level negative interference between tk-GCV gene therapy and chemotherapy occurred in some combinations but was overall negligible. In general, adding chemotherapy to tk-GCV gene therapy did not demonstrate significant therapeutic benefit in vitro. High doses of chemotherapeutic agents should be used in combination with tk-GCV gene therapy in order to take advantage of the occasional instance where modest improvement occurred with combination therapy. Additional studies exploring the role of methotrexate in enhancing the tk-GCV system are required. Investigation of other, potentially more synergistic chemotherapeutic agents in combination with tk-GCV is warranted.

Adenoviruses, Human↗