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S P Lerner

Publications and source records attributed to S P Lerner.

At least 19 recordsLinked to original sources
PubMed2001

Preoperative plasma levels of transforming growth factor beta(1) strongly predict clinical outcome in patients with bladder carcinoma.

BACKGROUND: Elevated local and circulating levels of transforming growth factor (TGF)-beta(1) have been associated with cancer invasion, progression, and metastasis. The authors tested the hypothesis that preoperative plasma TGF-beta(1) levels would independently predict cancer stage and prognosis in patients with transitional cell carcinoma (TCC) of the urinary bladder. METHODS: The study group consisted of 51 patients who underwent radical cystectomy for muscle-invasive or intravesical immuno- and/or chemotherapy refractory Tis, Ta, or T1 TCC (median follow-up, 45.7 months). Preoperative plasma levels of TGF-beta(1) were measured and correlated with pathologic features and clinical outcome. Transforming growth factor-beta(1) levels also were measured in 44 healthy men without any cancer. RESULTS: The mean preoperative plasma TGF-beta(1) level in patients who eventually developed metastases to distant (11.9 +/- 0.9 ng/mL) or regional (9.6 +/- 2.4 ng/mL) lymph nodes was significantly higher than that in patients with nonmetastatic muscle-invasive TCC (5.4 +/- 1.1 ng/mL), which, in turn, was significantly higher than that in patients with nonmetastatic Tis, Ta, or T1 TCC (4.5 +/- 1.2 ng/mL) and healthy subjects (4.5 +/- 1.2 ng/mL; P < 0.001). Preoperative plasma TGF-beta(1) level was an independent predictor of lymphovascular invasion (P = 0.002), metastases to lymph nodes (P = 0.030), disease recurrence (P = 0.009), and disease specific survival (P = 0.015). In a subgroup of patients with muscle-invasive TCC, TGF-beta(1) level was associated with disease recurrence (P = 0.005) and death from bladder carcinoma (P = 0.001). CONCLUSIONS: The authors confirm that plasma TGF-beta(1) levels are elevated in patients with muscle-invasive TCC before cystectomy. Transforming growth factor-beta(1) levels are highest in patients with bladder carcinoma metastatic to lymph nodes and are a strong independent predictor of disease recurrence and disease specific mortality.

Adult↗
PubMed2001

Predictive value of expression of transforming growth factor-beta(1) and its receptors in transitional cell carcinoma of the urinary bladder.

BACKGROUND: The purpose of this study was to describe the expression patterns of transforming growth factor (TGF)-beta(1) and its receptors in transitional cell carcinoma (TCC) of the bladder, to investigate the relation between the TGF-beta(1) and its receptors, and to determine whether altered expression of TGF-beta or its receptors is associated with disease progression and survival in patients with TCC of the bladder. METHODS: Immunohistochemical staining for TGF-beta(1) and its receptors I and II was conducted on formalin fixed paraffin embedded archival cystectomy specimens of 80 patients with bladder TCC. Immunoreactivity was categorized as either positive or negative in a blinded fashion. RESULTS: Expression of TGF-beta(1), TGF-beta-RI, and TGF-beta-RII was altered in 51 (64%), 34 (43%), and 38 (48%) specimens, respectively. Sixty (75%) specimens had altered expression of at least 1 of the 3 TGF-betas, and 26 (33%) had altered expression of all 3. Expression of the three TGF-betas was highly concordant (P < 0.018). Loss of expression of TGF-beta-RI or TGF-beta-RII was associated with invasive tumor stage (P < 0.001), high grade (P < 0.006), and lymphovascular invasion (P < 0.030). Overexpression of TGF-beta(1) was associated with invasive tumor stage only (P = 0.024). With a median follow-up of 101 months, TGF-beta-RI was an independent predictor of both disease progression (P = 0.007) and disease specific survival (P = 0.006) whereas TGF-beta(1) was an independent predictor of disease progression only (P = 0.050). Transforming growth factor-beta-RII was not independently associated with either disease progression or survival. CONCLUSIONS: Altered expression of TGF-beta(1) and its receptors is common in TCC of the bladder. Overexpression of TGF-beta(1) is associated with the loss of expression of its receptors. Transforming growth factor-beta(1) and TGF-beta-RI are independently associated with clinical outcome in patients with bladder TCC treated by radical cystectomy.

Carcinoma, Transitional Cell↗
PubMed2001

Correlation of immunohistochemical molecular staging of bladder biopsies and radical cystectomy specimens.

PURPOSE: To determine the relationship of p53, retinoblastoma (RB), and p16 expression between precystectomy transurethral resection bladder (TURB) biopsy and matched cystectomy specimens; and to determine the value of p53 immunoreactivity for predicting progression and survival in patients undergoing radical cystectomy. METHODS AND MATERIALS: We performed p53 immunohistochemical staining on matched archival TURB and cystectomy specimens taken from 40 patients. Twenty-seven and 26 of these patients were also evaluated for RB and p16 expression, respectively. RESULTS: Twenty-eight (70%) of the TURB and 22 (55%) of the cystectomy specimens stained positive for p53. RB and p16 protein expression were altered in 19 (70%) and 19 (73%) of the TURB specimens, respectively, and 19 (70%) and 19 (73%) of the cystectomy specimens, respectively. There was a strong correlation between p53, RB, and p16 expression and TURB and cystectomy specimens (all p < 0.001). In preoperative and postoperative multivariate analyses, biopsy p53 and cystectomy p53 were independently associated with disease progression (p = 0.049 and p = 0.034, respectively) and bladder cancer-related death (p = 0.044 and p = 0.037, respectively). CONCLUSION: p53, RB, and p16 expression patterns on TURB specimens correlate with cystectomy specimens. p53 immunoreactivity is an independent predictor of disease progression and bladder cancer survival. These data support the potential of prognostic staging using immunohistochemical analysis on bladder biopsy specimens prior to neoadjuvant or definitive therapy.

Adult↗
PubMed2001

Methods to improve efficacy of intravesical mitomycin C: results of a randomized phase III trial.

BACKGROUND: Intravesical chemotherapy (i.e., placement of the drug directly in the bladder) with mitomycin C is beneficial for patients with superficial bladder cancer who are at high risk of recurrence, but standard therapy is empirically based and patient response rates have been variable, in part because of inadequate drug delivery. We carried out a prospective, two-arm, randomized, multi-institutional phase III trial to test whether enhancing the drug's concentration in urine would improve its efficacy. METHODS: Patients with histologically proven transitional cell carcinoma and at high risk for recurrence were eligible for the trial. Patients in the optimized-treatment arm (n = 119) received a 40-mg dose of mitomycin C, pharmacokinetic manipulations to increase drug concentration by decreasing urine volume, and urine alkalinization to stabilize the drug. Patients in the standard-treatment arm (n = 111) received a 20-mg dose without pharmacokinetic manipulations or urine alkalinization. Both treatments were given weekly for 6 weeks. Primary endpoints were recurrence and time to recurrence. Treatment outcome was examined by use of Kaplan-Meier analysis with log-rank tests. Statistical tests were two-sided. RESULTS: Patients in the two arms did not differ in demographics or history of intravesical therapy. Dysuria occurred more frequently in the optimized arm but did not lead to more frequent treatment termination. In an intent-to-treat analysis, patients in the optimized arm showed a longer median time to recurrence (29.1 months; 95% confidence interval [CI] = 14.0 to 44.2 months) and a greater recurrence-free fraction (41.0%; 95% CI = 30.9% to 51.1%) at 5 years than patients in the standard arm (11.8 months; 95% CI = 7.2 to 16.4 months) and 24.6% (95% CI = 14.9% to 34.3%) (P =.005, log-rank test for time to recurrence). Improvements were found in all risk groups defined by tumor stage, grade, focality, and recurrence. CONCLUSIONS: This study identified a pharmacologically optimized intravesical mitomycin C treatment with statistically significantly enhanced efficacy.

Administration, Intravesical↗
PubMed2001

Society of Urologic Oncology Biotechnology Forum: new approaches and targets for advanced prostate cancer.

PURPOSE: We provide an overview of advances in molecular based therapeutic strategies for prostate cancer and summarize the studies presented at the Society of Urologic Oncology Biotechnology Forum in 2000. MATERIALS AND METHODS: Three promising new treatment strategies are presented, and a critique of the advantages and limitations of each is offered by a leading expert in the field. RESULTS: Treatment results and the current state of dendritic cell based immunotherapy, monoclonal antibody therapy and anti-apoptotic treatment approaches are presented. CONCLUSIONS: Currently patients with advanced prostate carcinoma have expanded therapeutic options available in the form of molecular based phases II and III clinical trials.

Antibodies, Monoclonal↗
PubMed2001

E-cadherin expression predicts clinical outcome in carcinoma in situ of the urinary bladder.

OBJECTIVES: The clinical course of carcinoma in situ (CIS) of the bladder is highly variable. Our objective in this study was to describe E-cadherin expression patterns in CIS with and without papillary disease and to determine whether altered E-cadherin expression is associated with disease progression and survival in patients with CIS of the bladder. METHODS: Tumor specimens from 53 patients who had CIS in the absence of muscle-invasive carcinoma on bladder biopsy were identified. Formalin-fixed paraffin sections were processed using a hot citric acid antigen retrieval method, followed by immunostaining with anti-E-cadherin monoclonal antibody. Expression patterns were evaluated in a blinded fashion and scored as normal and abnormal, which included absent and various degrees of heterogeneous immunostaining. Outcomes analyzed were recurrence, progression, and survival. RESULTS: Loss of normal membrane E-cadherin immunoreactivity was found in 17 patients (32%). At a median follow-up of 131 months, abnormal E-cadherin expression was significantly associated with disease recurrence (P = 0.0087), disease progression (P = 0.0003), and bladder cancer-specific survival (P = 0.0285). In multivariate analyses, E-cadherin expression was independently associated with disease recurrence (P = 0.019, 95% confidence interval [CI] 1.342 to 5.940), disease progression (P = 0.002, 95% CI 2.049 to 17.989), and bladder cancer-specific survival (P = 0.025, 95% CI 1.179 to 10.432). CONCLUSIONS: Loss of E-cadherin expression in patients CIS with and without papillary disease of the bladder predicts disease recurrence, disease progression, and bladder cancer-specific death. CIS with and without papillary disease associated with abnormal E-cadherin expression may represent a biologically more aggressive cancer, requiring early definitive therapy. This hypothesis should be evaluated in larger studies and prospective clinical trials.

Adult↗
PubMed2001

Giant bilateral renal angiomyolipomas associated with tuberous sclerosis.

Renal angiomyolipomas in patients with tuberous sclerosis can be associated with significant morbidity, mostly related to complications from bleeding. We describe a patient with tuberous sclerosis and massive bilateral renal angiomyolipomas (total tumor burden 5500 g) who presented with acute right renal hemorrhage. She was treated with right renal artery embolization followed immediately by right nephrectomy and left partial nephrectomy. The patient had a creatinine nadir of 1.3 mg/dL postoperatively. We demonstrate that nephron-sparing surgery is feasible, even in the setting of very large angiomyolipomas, such as the one presented here, currently the largest such tumor by weight reported.

Adult↗
PubMed2001

Rebuilding the lower urinary tract after cystectomy: a roadmap for patient selection and counseling.

Numerous options exist for reconstructing the lower urinary tract after radical cystectomy. Deciding between continent and noncontinent urinary diversion can be challenging for both physician and patient. This process should be logical and should integrate factors including the patient's malignancy, comorbid disease, functional status, and personal preference. Thorough patient education and a delicate balance between risk and benefit are critical to the success of any strategy for urinary diversion. This review presents a basic algorithm for planning reconstructive options and counseling patients before cystectomy.

Counseling↗
PubMed2001

E-cadherin immunostaining of bladder transitional cell carcinoma, carcinoma in situ and lymph node metastases with long-term followup.

PURPOSE: We analyze the expression of E-cadherin in bladder transitional cell carcinoma, areas of carcinoma in situ and lymph node metastases, and determine the value of E-cadherin immunoreactivity for predicting disease progression and survival of patients with bladder transitional cell carcinoma. MATERIALS AND METHODS: The study group consisted of 77 patients who underwent radical cystectomy. Formalin fixed paraffin sections were processed with a hot, citric acid antigen retrieval method, followed by immunostaining with anti-E-cadherin monoclonal antibody and a standard avidin biotin complex technique. E-cadherin expression was also evaluated in carcinoma in situ sections (18) and in regional lymph node metastases (17). RESULTS: Loss of normal membrane E-cadherin immunoreactivity was found in 59 (77%) patients. Abnormal expression of E-cadherin was associated with muscle invasive disease (p = 0.010) and lymph node metastasis (p = 0.044). Of the 18 carcinoma in situ specimens 15 (83%) and of the 17 metastatic lymph nodes 13 (76%) had abnormal E-cadherin expression. Concordance rates of E-cadherin status in carcinoma in situ areas and metastatic lymph nodes with the primary tumors were 85% and 88%, respectively. At a median followup of 128 months, abnormal E-cadherin expression was significantly associated with disease progression (p = 0.0219) and bladder cancer specific survival (p = 0.037). E-cadherin expression and pathological stage but not grade were independent predictors of disease progression (p = 0.042, 0.047 and 0.158, respectively). CONCLUSIONS: In bladder cancer altered E-cadherin expression is associated with the degree of invasiveness, lymph node metastasis and increased risk of death from bladder cancer. Furthermore, E-cadherin status is an independent predictor of disease progression in patients treated with cystectomy for transitional cell carcinoma of the bladder.

Aged↗
PubMed2000

Prognostic value of P53 nuclear accumulation and histopathologic features in T1 transitional cell carcinoma of the urinary bladder.

OBJECTIVES: To determine whether molecular and histopathologic tumor features can predict disease progression in Stage T1 transitional cell carcinoma of the bladder. METHODS: Tumor specimens from 43 patients were analyzed with respect to grade, presence of carcinoma in situ, invasion deep or superficial to the lamina propria's muscularis mucosa, p53 expression using DO-7 and PAb1801 antibodies, age, and sex. Flow cytometry was performed on 30 patients from whom there was adequate paraffin-embedded tissue to assess DNA ploidy. Seven patients underwent immediate cystectomy as primary treatment and 36 patients retained their bladders and were at risk of recurrence and progression. RESULTS: The median follow-up was 79 months. Disease recurred in 17 patients (47.2%) and progressed in 6 (16.7%). Only 3 patients (7.0%) died of bladder cancer. None of the parameters investigated was statistically significant in predicting recurrence, progression, or survival. Only carcinoma in situ approached statistical significance (P = 0.0593) as a predictor of progression. Early cystectomy did not have a significant effect on cancer-specific survival (P = 0.3603). The concordance rate between the two p53 antibodies was 88% (P <0.0001). CONCLUSIONS: Deep invasion of the lamina propria, p53 positive immunohistochemistry, high grade, and aneuploidy were not significant adverse prognostic factors for either disease progression or survival. Carcinoma in situ associated with Stage T1 transitional cell carcinoma may represent a biologically more aggressive cancer requiring early definitive therapy, but this hypothesis should be evaluated in prospective clinical studies.

Adult↗
PubMed2000

In vivo adenovirus-mediated suicide gene therapy of orthotopic bladder cancer.

These studies were undertaken to determine the feasibility, safety, and efficacy of suicide gene therapy using adenoviral-mediated herpes simplex virus thymidine kinase (ADV/RSV-tk) and the prodrug ganciclovir (GCV) in an orthotopic murine bladder cancer model. We utilized a replication-defective adenoviral construct containing the beta-galactosidase gene as a control and the herpes simplex virus thymidine kinase gene as the therapeutic vector under the transcription control of the Rous sarcoma virus long terminal repeat promoter. Intravesically created, orthotopic bladder tumors were established in syngeneic C3H/He female mice. India ink injection and beta-galactosidase studies were performed to determine if transurethral administration, direct tumor injection, or the combination was the most efficient route of virus administration. Optimal dosing of ADV/RSV-tk was determined by direct tumor injection with increasing viral doses and treatment with GCV. Treatment efficacy, long-term survival, and toxicity were determined in separate but similar controlled experiments. Growth curve studies demonstrated reliable tumor formation by 14 days. Direct transvesical tumor injection resulted in the best distribution and intratumor gene expression as measured by X-gal staining. Dose-ranging experiments demonstrated an optimal viral dose of 5 x 10(8) plaque-forming units and a greater than twofold reduction in tumor growth for the animals treated with ADV/RSV-tk compared to controls. Efficacy studies demonstrated a greater than threefold reduction in tumor growth. No clinical or gross pathologic toxicity was detected. Long-term survival results suggested a survival benefit for the treatment animals compared to controls. We conclude that ADV/RSV-tk in combination with GCV provides effective therapy for orthotopic murine bladder cancer by significantly inhibiting tumor growth with limited toxicity to the host. These data provide further support for testing this suicide gene therapy strategy in human Phase I trials.

Adenoviridae↗
PubMed1999

Level of retinoblastoma protein expression correlates with p16 (MTS-1/INK4A/CDKN2) status in bladder cancer.

Recent studies have shown that patients whose bladder cancer exhibit overexpression of RB protein as measured by immunohistochemical analysis do equally poorly as those with loss of RB function. We hypothesized that loss of p16 protein function could be related to RB overexpression, since p16 can induce transcriptional downregulation of RB and its loss may lead to aberrant RB regulation. Conversely, loss of RB function has been associated with high p16 protein expression in several other tumor types. In the present study RB negative bladder tumors also exhibited strong nuclear p16 staining while each tumor with strong, homogeneous RB nuclear staining were p16 negative, supporting our hypothesis. To expand on these immunohistochemical studies additional cases were selected in which the status of the p16 encoding gene had been determined at the molecular level. Absent p16 and high RB protein expression was found in the tumors having loss of heterozygosity within 9p21 and a structural change (mutation or deletion) of the remaining p16 encoding gene allele, confirming the staining results. These results strongly support the hypothesis that the RB nuclear overexpression recently associated with poor prognosis in bladder cancer is also associated with loss of p16 function and implies that loss of p16 function could be equally deleterious as RB loss in bladder and likely other cancers.

Biopsy↗
PubMed1999

Renal cell carcinoma with an infrarenal vena caval tumor thrombus.

Extension of renal cell carcinoma (RCC) along venous drainage pathways is a well-recognized entity. All previously reported cases of inferior vena cava (IVC) involvement by RCC have been with tumor thrombus in the suprarenal IVC. We report a 45-year-old man who had RCC arising from the lower pole of the right kidney with a tumor thrombus totally occluding the infrarenal IVC. The patient underwent radical nephrectomy with successful ligation and resection of the infrarenal IVC.

Carcinoma, Renal Cell↗
PubMed1999

The loss of expression of transforming growth factor-beta receptors correlates with the histopathologic tumor grade in bladder transitional cell carcinoma patients.

Transforming growth factor-beta (TGF-beta), a pleiotropic growth factor, is a potent inhibitor of cellular proliferation in cells of epithelial origin. Recently, it has been suggested that a loss of sensitivity to TGF-beta through a loss of expression of TGF-beta receptors T beta R-I and T beta R-II--is associated with tumor initiation and progression. Therefore, to investigate the relationship between TGF-beta receptors expression and carcinogenesis of bladder TCC, this study examined the expression of T beta R-I and T beta R-II in 46 bladder TCC patients using immunohistochemistry. Since histopathological grade is a widely accepted marker of prognosis, the results were compared in relation to the three grades of bladder TCC. The results demonstrated that the loss of TGF-beta receptors expression is associated with increasing histopathological grades of bladder TCC. Specifically, both T beta R-I and T beta R-II were readily detected in all 10 normal bladder mucosa specimens. Likewise, all 6 specimens of grade I TCC samples expressed high levels of both TGF-beta receptors. However, among grade II TCC samples, T beta R-I and T beta R-II were detected in 78% and 89%, respectively: among grade III TCC samples, T beta R-I and T beta R-II were detected in 45% and 41%, respectively. These results suggested that loss of sensitivity to TGF-beta may play a role in the progression of TCC from low to high grade disease.

Adult↗
PubMed1999

Decreased expression of transforming growth factor beta receptor type I is associated with poor prognosis in bladder transitional cell carcinoma patients.

Transforming growth factor (TGF) beta, a potent growth inhibitor of proliferation in most cells, usually exerts its effects through an interaction with membrane receptors, type I (TbetaR-I) and type II (TbetaR-II). In the present study, the expression of TGF-beta receptors was correlated with tumor grade, pathological stage, and probability of progression and survival in patients with bladder transitional cell carcinoma (TCC). To this end, immunohistochemistry was carried out in specimens obtained from 59 patients who underwent either radical cystectomy or transurethral resection of bladder tumor. Among these patients, 18 (30.5 %) had loss of TbetaR-I expression, whereas 27 (44.0%) had loss of TbetaR-II expression. There was a correlation between the loss of expression of TbetaR-I and TbetaR-II and the tumor grade (P = 0.041 and P = 0.026, respectively). In addition, both pathological and lymph node status also were associated with the loss of TbetaR-I and TbetaR-II expression (P = 0.025 and P = 0.004, respectively). Interestingly though, only the loss of expression of TbetaR-I was associated with an increased probability of tumor progression and a decreased probability of survival (P = 0.0046 and P = 0.0022, respectively). These results suggest that the status of TbetaR-I expression may be a potential prognostic marker in patients with bladder TCC.

Activin Receptors, Type I↗
PubMed1999

Pathological features and prognostic significance of prostate cancer in the apical section determined by whole mount histology.

PURPOSE: We test the hypothesis that cancer in the apical section of the prostate is an important independent factor in predicting the progression of clinically localized prostate cancer. MATERIALS AND METHODS: We analyzed clinical data and whole mount histological step sections for 500 patients who had undergone radical retropubic prostatectomy for clinically localized prostate cancer. RESULTS: Cancer was in the apex of the prostate in 175 patients (35%). These patients had a larger cancer and higher incidence of positive surgical margins, and were more likely to have a poorly differentiated cancer than the 325 patients without cancer in the apex. However, the presence of apical cancer was not a significant predictor of clinical or prostate specific antigen progression in either univariate or multivariate Cox proportional hazards models when analyzed for the entire group or only in patients with tumor confined to the prostate. CONCLUSIONS: Apical cancer in a radical prostatectomy specimen is simply a sign of a larger volume cancer and is not independently associated with an increased risk of clinical or prostate specific antigen progression.

Adult↗
PubMed1998

Retinoids in the chemoprevention of bladder cancer.

Bladder cancer is strongly related to tobacco use and is estimated to cause 54,500 new cancer cases and 11,700 deaths in the United States in 1998. Approximately two thirds of new US cases will be superficial tumors, predominantly low-grade papillary. After standard therapeutic resection (with or without intravesical therapy), the superficial bladder tumor recurrence rate is 30% to 70% within 12 months of resection. Morbidity is substantial, with frequent cystoscopy, recurrence, resections, and possible cystectomy for progression to invasive cancers. Therefore, new approaches, including chemoprevention, are needed. Data suggest that bladder carcinogenesis is a multi-step, multifocal (field effect) process, possibly involving the spread of premalignant clones--all of which are prerequisites for effective chemopreventive approaches. To date, retinoids are the best-studied chemopreventive agents in this site, achieving mixed clinical results (with 13-cis-retinoic acid and etretinate) in superficial bladder tumors. This review includes the epidemiology and biology of bladder carcinogenesis in addition to preclinical and clinical retinoid data, and focuses on the most promising avenue of current retinoid chemoprevention in the bladder: the potent apoptosis-inducing retinoid fenretinide (4-HPR), which currently is in three phase III trials.

Anticarcinogenic Agents↗