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Biomedical subjects

S B Malkowicz

Publications and source records attributed to S B Malkowicz.

At least 19 recordsLinked to original sources
PubMed2001

Effects of Bowman-Birk inhibitor concentrate (BBIC) in patients with benign prostatic hyperplasia.

BACKGROUND: The Bowman-Birk inhibitor is a soybean-derived protease inhibitor that has anti-inflammatory and anticarcinogenic activities. METHODS: A Phase I trial of Bowman-Birk inhibitor concentrate (BBIC) in 19 male subjects with benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS) has been performed. RESULTS: The results of the trial indicated that there was no dose-limiting toxicity of BBIC. There was a statistically significant decrease in serum PSA levels in all BBIC-treated patients. Some BBIC-treated patients exhibited a relatively large reduction in serum PSA levels, ranging up to a 43% reduction. There was also a statistically significant decrease in serum triglyceride levels and a decrease in prostate volume in the treated patients. The scores recorded in response to a urinary symptom questionnaire indicated improved urinary activities in the BBIC-treated patients; however, the control subjects exhibited similar improvements in urinary activities during the course of the trial. CONCLUSIONS: The data obtained in this trial, particularly the data suggesting that BBIC treatment may lead to reduced serum PSA levels and reduced prostate volumes, suggest that a Phase II clinical trial of BBIC for the therapy of BPH is warranted.

Aged↗
PubMed2001

Isolation and characterization of the TERE1 gene, a gene down-regulated in transitional cell carcinoma of the bladder.

We have identified a novel cDNA product designated transitional epithelial response gene (TERE1), which was localized to chromosome 1p36. The TERE1 transcript (1.5 and 3.5 kb) is present in most normal human tissues including urothelium, but was reduced or absent in the majority of muscle invasive TCC tumors (22 out of 29 cases). The open reading frame encodes a protein of 338 amino acids (MW 36.8 KD). This protein is 57% homologous to a Drosophila protein called heix. We have shown by Western blotting and immuno-histochemistry with a polyclonal antibody to a specific TERE1 peptide, reduced or absent staining in muscle invasive tumors. Transfection of a sense TERE1 construct resulted in an 80-90% inhibition of cellular proliferation in two TCC cell lines and a lack of aneuploidy in the TERE1-transduced J82 cell line. These data suggest a potential role for this gene product in the progression of bladder cancer.

Adult↗
PubMed2001

Urologic complications of Crohn's disease.

Crohn's disease frequently can affect the genitourinary system, mainly in the form of urinary fistulae and urolithiasis. Diagnostic evaluation of fistulae associated with Crohn's disease has improved with the increasing use of computed tomography and MR imaging, along with other diagnostic modalities. Resective surgery is the main treatment in this group of patients. Kidney stones are common because of metabolic derangements and dehydration; however, these can be treated adequately with minimally invasive procedures, such as extracorporeal shock-wave lithotripsy, ureteroscopy, and percutaneous surgery. In addition, medical therapies can prevent recurrent stones.

Crohn Disease↗
PubMed2001

ROC optimization may improve risk stratification of prostate cancer patients.

OBJECTIVES: Rational treatment decision requires accurate projection of the clinical course of a patient. Current methods in clinical outcome analysis mostly focus on population data. We investigated the applicability and optimization of the widely used actuarial method to project individual clinical outcomes. METHODS: We designed and implemented a Clinical Outcome Prediction Expert (COPE) that performs, assesses, and optimizes actuarial prediction on individual cases. We analyzed a post-prostatectomy database, consisting of 1043 patients. Sixty percent of the database was used for training and 40% for validation. Stratified actuarial curves are used to project individual outcomes. The prostate-specific antigen (PSA) level, the Gleason score, and the clinical American Joint Commission on Cancer Staging T-stage before treatment were used as predictors. The area under the receiver operator characteristic (ROC) curve was used to measure predictive performance. RESULTS: We obtained simple optimized stratification of pretreatment PSA level of 10 ng/mL or less, or more than 10 ng/mL; Gleason score of 6 or lower, or higher than 6; and clinical AJCC T-stage of T2a or lower, or higher. The optimized univariate risk scores were used to generate a multivariate score. After optimization, we found the higher risk group consisted of patients with PSA more than 10 ng/mL, or with PSA of 10 ng/mL or less and Gleason score higher than 6 and clinical AJCC T-stage higher than T2a. The optimized multivariate risk score has the highest ROC area of 0.77 among all predictors. CONCLUSIONS: The best conditions to perform actuarial prediction on individual cases are not known a priori and require optimization. This study shows that ROC optimization simplifies risk stratification and may improve the accuracy of clinical outcome prediction.

Data Interpretation, Statistical↗
PubMed2001

Estimating the impact on prostate cancer mortality of incorporating prostate-specific antigen testing into screening.

OBJECTIVES: Whether early detection using prostate-specific antigen (PSA) and digital rectal examination (DRE) compared with DRE alone will reduce prostate cancer mortality awaits the results of ongoing prospective randomized trials. However, the impact that early detection could have on prostate cancer-specific survival can be estimated by assuming that PSA failure after radical prostatectomy (RP) will translate into death from prostate cancer. METHODS: The study population consisted of 1274 men with clinically localized prostate cancer who underwent RP in Boston, Massachusetts or Philadelphia, Pennsylvania between 1989 and 2000 and had a preoperative PSA level greater than 4 but not more than 10 ng/mL. The primary endpoint was actuarial freedom from PSA failure (defined as PSA outcome). RESULTS: The relative risk of PSA failure after RP for patients diagnosed with a PSA of greater than 4 to 5, 5 to 6, 6 to 7, or 7 to 8 ng/mL compared with greater than 8 up to 10 ng/mL was 0.3 (95% confidence interval [CI] 0.2 to 0.5), 0.5 (95% CI 0.4 to 0.8), 0.6 (95% CI 0.4 to 0.9), or 0.9 (95% CI 0.6 to 1.3), respectively. On the basis of the estimates of the 5-year PSA outcome, patients with a biopsy Gleason score of 5 or 6 (781 of 1274; 61%) consistently benefited from RP performed when the PSA at diagnosis was greater than 4 to 7 ng/mL compared with greater than 8 to 10 ng/mL (93% versus 78%, P <0.0001). A benefit to early detection was not found for the vast majority (266 of 312; 88%) of patients who had a biopsy Gleason score of 7 or higher. CONCLUSIONS: Early detection using both PSA and DRE-based screening may benefit men who present with biopsy Gleason score 5 or 6 prostate cancer and a PSA level greater than 4 to 7 ng/mL compared with greater than 8 up to 10 ng/mL. This finding awaits validation from ongoing prospective randomized trials.

Actuarial Analysis↗
PubMed2001

Using the receiver operating characteristic curve to select pretreatment and pathologic predictors for early and late postprostatectomy PSA failure.

OBJECTIVES: Pretreatment prostate-specific antigen (PSA), prostatectomy Gleason score, margin status, and pathologic T stage are known explanatory variables for the postprostatectomy PSA outcome. We used the receiver operating characteristic (ROC) curve to select those factors that were optimal for predicting early and late postoperative PSA failure. METHODS: We designed and implemented a clinical outcome prediction expert that performs, assesses, and optimizes the actuarial prediction on individual cases. A postprostatectomy database of 1022 patients was divided into 60% for training and 40% for validation. The ROC areas of the predictors were calculated over a range of cutoff time from 24 to 60 months. RESULTS: Multivariate pathologic T stage/prostatectomy Gleason score/margin status had the highest ROC area of 0.900. Patients with Stage T disease less than T3, negative surgical margins, and Gleason score of 6 or less had a 90% probability to be PSA failure free at 4 years versus 36% otherwise. The pathologic T stage/margin status accurately predicted PSA failure at 24 months or less after prostatectomy with an ROC area of 0.800. Lower risk patients (less than Stage T3, negative surgical margins) had a 94% probability to be PSA failure free at 2 years versus 46% otherwise. CONCLUSIONS: A combination of actuarial analysis and ROC optimization accurately identified the individual patients at high risk of early and late postprostatectomy PSA failure.

Actuarial Analysis↗
PubMed2001

The role of diethylstilbestrol in the treatment of prostate cancer.

OBJECTIVES: Diethylstilbestrol administration was a classic form of androgen deprivation therapy (ADT) that gradually fell out of favor because of its cardiovascular toxicity, economic disinterest on the part of manufacturers, and the emergence of novel therapeutic agents with a superior safety profile. The cost of contemporary agents and the efficacy of diethylstilbestrol (DES) have perpetuated the evaluation of this agent, especially in the circumstance of early hormone-refractory (clinical stage D2.5) disease. The objective of this study is to evaluate the status of DES-based therapies, and assess their efficacy and toxicity as a viable form of ADT. METHODS: Current research from single-institution and group studies, as well as basic scientific investigations related to DES, were assessed with regard to the population studied, dosage, criteria for response, response rate, duration of response, and toxicity. RESULTS: Contemporary basic research has demonstrated a direct apoptotic effect of DES on prostate cancer cells. There is also evidence to support the ability of DES to suppress testosterone production at extratesticular sites and inhibit dihydroepiandrosterone sulfate serum levels. Contemporary cooperative group trials for stage D2 disease incorporating a DES arm have demonstrated therapeutic efficacy and equivalence to orchiectomy, which is marred by significant cardiovascular toxicity. In smaller single-institution studies (n = 17 to 38) of patients with D2.5 disease, an average response rate of 55% is noted with a mean time to clinical progression of 6.4 months (2 to 18). Cardiovascular toxicity occurred in 10% to 30% of patients, with events including deep vein thrombosis, myocardial infarction, and transient ischemic attack. Edema and gynecomastia was also noted. Strategies to reduce thromboembolic events, such as dose reduction or the use of warfarin sodium were unsuccessful, whereas the use of low-dose aspirin (100 mg daily) resulted in only 1 of 38 vascular events. CONCLUSIONS: In contemporary studies of DES as an agent for ADT in D2.5 patients, a reasonable response rate (40% to 60%) of modest duration (5 to 8 months) is noted. Cardiovascular complications still persist, requiring the development of safe, effective antithrombolic therapy to take advantage of this phenomenon.

Androgen Antagonists↗
PubMed2001

The role of imaging studies and molecular markers for selecting candidates for radical prostatectomy.

For the typical patient who has newly diagnosed prostate cancer, clinically organ-confined disease of moderate grade, and a PSA less than 10 ng/mL, the current role of imaging studies and molecular biomarkers is limited. Bone scans are not necessary for newly diagnosed men with a PSA less than 10 ng/mL in the absence of bone pain. Similarly, abdominal and pelvic CT scanning rarely provides any useful diagnostic or staging information when the PSA is less the 20 ng/mL and is indicated rarely. Endorectal coil MR imaging adds staging information for patients with a PSA between 10 and 20 ng/mL, a Gleason score of 7 or less, and 50% or more positive biopsies on a sextant sampling. Indium 111 capromab pendetide scanning (ProstaScint) is FDA-approved to evaluate newly diagnosed patients at high risk for metastases. These patients have a Gleason score of 7 or greater and a PSA greater than 20 ng/mL, a Gleason score of 8 to 10 regardless of the PSA value, or clinical stage T3 disease and a Gleason score of 6 or greater. RT-PCR testing of blood or bone marrow for prostate-specific or prostate cancer-specific gene expression, or "molecular staging," is a promising technique whose current use is still investigational. Much useful information may be gained by careful study of prostate needle biopsy material. Aside from current Gleason grading and the number or percentage of cores involved with cancer, no molecular biomarker is approved for clinical use. p27, p53, bcl-2, Ki-67 (MIB-1), and the assessment of neovascularity hold promise, but prospective multicenter studies are needed. In the long-term, multiple gene expression profiling of biopsy material using gene chips may revolutionize the care of patients with prostate cancer and those who elect radical prostatectomy.

Antibodies, Monoclonal↗
PubMed2001

Phase II trial of toremifene in androgen-independent prostate cancer: a Penn cancer clinical trials group trial.

Toremifene has antiestrogenic and estrogenic properties in vitro and in vivo. In addition, it may have antiangiogenesis and antimicrotubule properties at higher doses. Studies have demonstrated the efficacy of this agent in the treatment of metastatic breast cancer. We performed a phase II trial of toremifene in patients with androgen-independent prostate cancer (AIPC). Patients with an increasing prostate-specific antigen level despite castrate testosterone levels and antiandrogen withdrawal were eligible. Patients could not have received prior salvage hormonal therapy or chemotherapy. Patients received toremifene at 300 mg/m2/d orally (maximum dose 640 mg/d). Fifteen patients were treated. Patients received treatment for a median of 13 weeks (range, 4-30 weeks). The median age was 72 years (range, 58-80 years). The median Eastern Cooperative Oncology Group performance status was 0. The treatment was well tolerated and toxicity was mild. Two patients had grade III hepatic toxicity; one had grade III hyperglycemia. There were no treatment-related deaths. No objective responses were demonstrated. In summary, toremifene is not effective therapy for AIPC at the dose and schedule evaluated in this trial.

Aged↗
PubMed2001

Recent developments in chemotherapy for bladder cancer.

Invasive bladder cancer is a chemotherapy-sensitive neoplasm. Historically, the development of cisplatin (Platinol)-based chemotherapy regimens has represented an important advance for patients with metastatic disease. More recently, investigations of new agents, such as gemcitabine (Gemzar) and paclitaxel (Taxol), have resulted in further options for these patients. Randomized trials comparing new regimens with cisplatin-based therapies have been initiated. The role of chemotherapy in the adjuvant and neoadjuvant settings is an area that is undergoing active investigation. The application of prognostic biological markers to risk-stratify patients has resulted in new avenues of investigation in these ongoing early disease trials.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2001

Predicting prostate specific antigen outcome preoperatively in the prostate specific antigen era.

PURPOSE: We evaluated the ability of previously defined risk groups to predict prostate specific antigen (PSA) outcome 10 years after radical prostatectomy in patients diagnosed with clinically localized prostate cancer during the PSA era. MATERIALS AND METHODS: Between 1989 and 2000, 2,127 men with clinically localized prostate cancer underwent radical prostatectomy, including 1,027 at Hospital of the University of Pennsylvania (study cohort) and 1,100 at Brigham and Women's Hospital (validation cohort). Cox regression analysis was done to calculate the relative risk of PSA failure with the 95% confidence interval (CI) in patients at intermediate and high versus low risk. The Kaplan-Meier actuarial method was used to estimate PSA outcome 10 years after radical prostatectomy. RESULTS: Compared with low risk patients (stages T1c to 2a disease, PSA 10 ng./ml. or less and Gleason score 6 or less) the relative risk of PSA failure in those at intermediate (stage T2b disease or PSA greater than 10 to 20 ng./ml. or less, or Gleason score 7) and high (stage T2c disease, or PSA greater than 20 ng./ml. or Gleason score 8 or greater) risk was 3.8 (95% CI 2.6 to 5.7) and 9.6 (95% CI 6.6 to 13.9) in the study cohort, and 3.3 (95% CI 2.3 to 4.8) and 6.3 (95% CI 4.3 to 9.4) in the validation cohort. The 10-year PSA failure-free survival rate in the 1,020 patients in the low, 693 in the intermediate and 414 in the high risk groups was 83%, 46% and 29%, respectively (p <0.0001). CONCLUSIONS: Based on 10-year actuarial estimates of PSA outcome after radical prostatectomy 3 groups of patients were identified using preoperative PSA, biopsy Gleason score and 1992 clinical T category.

Adult↗
PubMed2000

Utilizing predictions of early prostate-specific antigen failure to optimize patient selection for adjuvant systemic therapy trials.

PURPOSE: Prostate-specific antigen (PSA) failure within 2 years after radical prostatectomy (RP) has been shown to be a clinically significant predictor of distant failure. This study was performed to estimate 2-year PSA failure rates on the basis of readily available clinical and pathologic factors to identify patients for whom effective adjuvant systemic therapy is needed. PATIENTS AND METHODS: A Cox regression multivariable analysis was used to determine whether the percentage of positive prostate biopsies, PSA level, and the pathologic findings at RP in 1,728 men provided clinically relevant information about PSA outcome after RP. A bootstrapping technique with 2,000 replications was used to provide 95% confidence intervals for the predicted 2-year PSA failure rates, which were determined on the basis of the independent clinical and pathologic predictors of PSA outcome. RESULTS: The independent predictors of time to PSA failure included a percentage of positive prostate biopsies of greater than 34% (P: < or =.009), PSA level greater than 10 ng/mL (P: < or =.01), seminal vesicle invasion (P: =. 02), prostatectomy Gleason score of 8 to 10 (P: =.04), and positive surgical margins (P: =.0001). Predictions of 2-year PSA failure rates and bootstrap estimates of the 95% confidence intervals were arranged in a tabular format, stratified by independent clinical and pathologic predictors of PSA outcome. CONCLUSION: Patients who are most likely to benefit from effective adjuvant systemic therapy after RP can be identified using readily available clinical and pathologic data.

Biopsy↗
PubMed2000

Association of HPC2/ELAC2 genotypes and prostate cancer.

HPC2/ELAC2 has been identified as a prostate cancer (CaP) susceptibility gene. Two common missense variants in HPC2/ELAC2 have been identified: a Ser-->Leu change at amino acid 217, and an Ala-->Thr change at amino acid 541. Tavtigian et al. reported that these variants were associated with CaP in a sample of men drawn from families with hereditary CaP. To confirm this report in a sample unselected for family history, we studied 359 incident CaP case subjects and 266 male control subjects that were frequency matched for age and race and were identified from a large health-system population. Among control subjects, the Thr541 frequency was 2.9%, and the Leu217 frequency was 31.6%, with no significant differences in frequency across racial groups. Thr541 was only observed in men who also carried Leu217. The probability of having CaP was increased in men who carried the Leu217/Thr541 variants (odds ratio = 2.37; 95% CI 1.06-5.29). This risk did not differ significantly by family history or race. Genotypes at HPC2/ELAC2 were estimated to cause 5% of CaP in the general population of inference. These results suggest that common variants at HPC2/ELAC2 are associated with CaP risk in a sample unselected for family history or other factors associated with CaP risk.

Adult↗
PubMed2000

Prostate specific antigen outcome based on the extent of extracapsular extension and margin status in patients with seminal vesicle negative prostate carcinoma of Gleason score < or = 7.

BACKGROUND: Early (< or = 2 years) prostate specific antigen (PSA) failure after radical prostatectomy (RP) has been shown to predict for distant failure. After excluding patients with the pathologic predictors of early PSA failure, an analysis of PSA failure free (bNED) survival was performed to identify patients who may benefit from the use of postprostatectomy radiation therapy (RT). METHODS: Of 1,028 patients treated with RP for clinically localized prostate carcinoma between 1989 and 1999, 862 (84%) had either organ confined (OC), specimen confined (SC), or margin positive disease with negative seminal vesicles (SV) and a prostatectomy Gleason score < or = 7. A Cox regression multivariate analysis was performed in these patients evaluating the ability of the extent of extracapsular extension (ECE) (into but not through the capsule, SC focal ECE, SC established ECE, margin positive) and prostatectomy Gleason score (2-6 vs. 7) to predict time to postoperative PSA failure. RESULTS: SC focal ECE (P = 0.0017), SC established ECE (P < 0.0001), and margin positive disease (P < 0.0001) were significant predictors of time to postoperative PSA failure, whereas prostatectomy Gleason score and disease extending into but not through the capsule were not. Five-year bNED rates were 90%, 88%, 69%, 45%, and 33% for patients with OC, into but not through capsule, SC focal ECE, SC established ECE, and margin positive prostate carcinoma, respectively. CONCLUSIONS: Patients with SC ECE or margin positive prostate carcinoma and a prostatectomy Gleason score < or = 7 with no evidence of SV invasion may benefit from adjuvant postoperative RT.

Actuarial Analysis↗
PubMed2000

Loss of heterozygosity and tumor suppressor activity of Bin1 in prostate carcinoma.

The genetic events underlying the development of prostate cancer are poorly defined. c-Myc is often activated in tumors that have progressed to metastatic status, so events that promote this process may be important. Bin1 is a nucleocytoplasmic adaptor protein with features of a tumor suppressor that was identified through its ability to interact with and inhibit malignant transformation by c-Myc. We investigated a role for Bin1 loss or inactivation in prostate cancer because the human Bin1 gene is located at chromosome 2q14 within a region that is frequently deleted in metastatic prostate cancer but where no tumor suppressor candidate has been located. A novel polymorphic microsatellite marker located within intron 5 of the human Bin1 gene was used to demonstrate loss of heterozygosity and coding alteration in 40% of informative cases of prostate neoplasia examined. RNA and immunohistochemical analyses indicated that Bin1 was expressed in most primary tumors, even at slightly elevated levels relative to benign tissues, but that it was frequently missing or inactivated by aberrant splicing in metastatic tumors and androgen-independent tumor cell lines. Ectopic expression of Bin1 suppressed the growth of prostate cancer lines in vitro. Our findings support the candidacy of Bin1 as the chromosome 2q prostate tumor suppressor gene.

Adaptor Proteins, Signal Transducing↗