You have accessJournal of Urology1 Apr 2009RANDOMIZED TRIAL OF COMBINATION VITAMIN E, SELENIUM AND SOY PROTEIN AMONG MEN WITH HIGH GRADE PROSTATIC INTRAEPITHELIAL NEOPLASIA (HGPIN) Neil E Fleshner, L Kapusta, K Hersey, A Farley, Nathan Lawrentschuk, B Donnelly, Joseph L Chin, Martin E Gleave, Laurence H Klotz, C Trypkov, D Tu, and W Parulekar Neil E FleshnerNeil E Fleshner More articles by this author , L KapustaL Kapusta More articles by this author , K HerseyK Hersey More articles by this author , A FarleyA Farley More articles by this author , Nathan LawrentschukNathan Lawrentschuk More articles by this author , B DonnellyB Donnelly More articles by this author , Joseph L ChinJoseph L Chin More articles by this author , Martin E GleaveMartin E Gleave More articles by this author , Laurence H KlotzLaurence H Klotz More articles by this author , C TrypkovC Trypkov More articles by this author , D TuD Tu More articles by this author , and W ParulekarW Parulekar More articles by this author View All Author Informationhttps://doi.org/10.1016/S0022-5347(09)60750-3AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail "RANDOMIZED TRIAL OF COMBINATION VITAMIN E, SELENIUM AND SOY PROTEIN AMONG MEN WITH HIGH GRADE PROSTATIC INTRAEPITHELIAL NEOPLASIA (HGPIN)." The Journal of Urology, 181(4S), p. 263 © 2009 by American Urological AssociationFiguresReferencesRelatedDetails Volume 181Issue 4SApril 2009Page: 263 Advertisement Copyright & Permissions© 2009 by American Urological AssociationMetricsAuthor Information Neil E Fleshner More articles by this author L Kapusta More articles by this author K Hersey More articles by this author A Farley More articles by this author Nathan Lawrentschuk More articles by this author B Donnelly More articles by this author Joseph L Chin More articles by this author Martin E Gleave More articles by this author Laurence H Klotz More articles by this author C Trypkov More articles by this author D Tu More articles by this author W Parulekar More articles by this author Expand All Advertisement PDF DownloadLoading ...

BACKGROUND Elevated levels of the cell cycle protein cyclin E, and low levels of its inhibitor, p27(Kip1), have been associated with a poor prognosis following breast cancer. Some studies have found that germline mutations in the breast cancer susceptibility gene, BRCA1, are also associated with an inferior survival rate. The relationship between cyclin E/p27(Kip1) levels, BRCA1 status and outcome has not been studied in detail. PATIENTS AND METHODS We analyzed a historical cohort of 288 Ashkenazi Jewish women who were diagnosed with breast cancer between 1980 and 1995 and were previously tested for BRCA1/2 mutations. Protein levels of cyclin E and p27(Kip1) were assessed by immunohistochemistry. Breast cancer-specific survival (BCSS) was the main outcome measured. RESULTS The median follow-up was 8 years. Thirty tumors carried germline BRCA1 mutations. These tumors were more likely to have high cyclin E protein levels [odds ratio (OR) 9.5; P <0.001] and low p27(Kip1) protein levels (OR 2.8; P=0.03) than tumors from patients without BRCA1/2 mutations. High cyclin E expression level was the strongest predictor of BRCA1 germline mutations (multivariate OR 4.7; P=0.004). On univariate analysis, high cyclin E protein levels [relative risk (RR) 2.6; P <0.001] and low p27(Kip1) protein levels (RR 2.3; P=0.006) were significant prognostic factors for a poorer BCSS. In Cox multivariate models, high cyclin E levels remained an independent indicator of poor outcome only in the subgroup of patients who did not receive chemotherapy (P=0.002). CONCLUSIONS In this ethnically restricted cohort, a high level of cyclin E is a characteristic of BRCA1-related breast cancer, and is a marker of poor prognosis following breast cancer, particularly in the absence of adjuvant chemotherapy.

Previous studies have shown that BRCA1-related breast cancers are often high-grade tumors that do not express estrogen receptors, HER2, p27(Kip1), or cyclin D1, but do express p53 and cyclin E. In addition, the expression of cytokeratin 5/6 (CK5/6), indicating a basal epithelial phenotype, is frequent in BRCA1-related breast cancer. Here, in a series of 247 breast cancers, we demonstrate that CK5/6 expression was associated with nearly all of the features of BRCA1-related breast cancer and was also associated with a poor prognosis. In a parsimonious multivariable proportional hazards model, protein levels of cyclin E, p27(Kip1), p53, and the presence of glomeruloid microvascular proliferation all independently predicted outcome after breast cancer. In this model, only cyclin E and p27(Kip1) levels were independent predictors in lymph node-negative cancers, whereas glomeruloid microvascular proliferation and tumor size independently predicted outcome in node-positive disease. The molecular determinants of the basal epithelial phenotype encapsulate many of the key features of breast cancers occurring in germ-line BRCA1 mutation carriers and have independent prognostic value. Basal breast cancer deserves recognition as an important subtype of breast cancer.

Purpose: To examine the change of histologic grade of untreated, favorable grade, prostate adenocarcinoma over time on repeat prostate biopsy. Materials and Methods: A prospective single-arm cohort study has been in progress since November 1995, to assess the feasibility of a watchful observation protocol with selective delayed intervention using clinical, histologic, and/or PSA progression as treatment indication in untreated, favorable grade, localized prostate adenocarcinoma. Patients are initially managed with watchful observation alone. When a patient meets the pre-defined criteria of disease progression, appropriate treatment is implemented according to his age, disease extent, co-morbidity, and preference. Eligible subjects must have clinical stage T1b-T2b N0M0, Gleason score (GS) ≤7, and PSA ≤15 ng/ml. Patients are followed every 3 months for the first 2 years and then every 6 months thereafter. At each visit, medical history, physical examination and blood tests including PSA are obtained. Transrectal ultrasound (TRUS) of the prostate and bone scan are performed every 6 and 12 months respectively. TRUS guided prostate biopsy is repeated at 12-18 months after enrolment to evaluate the change in the histologic grade of malignancy. Most initial and subsequent biopsies were centrally reviewed by one pathologist. Possible associations of the change in histologic grade with PSA doubling time (PSAdt), and the baseline clinical parameters of the patients are explored with correlation analysis. PSAdt is estimated from a linear regression of ln(PSA) on time, assuming a simple exponential growth model. Results: As of April 2001, 67(42%) of a total of 161 eligible patients underwent rebiopsy of prostate, and formed the basis of this analysis. None received any treatment prior to rebiopsy. 94 declined or were not subjected to the rebiopsy at the discretion of an attending physician. Median time to rebiopsy was 18 months (range: 9-58). Median age was 70 years (range: 58-81). The distribution of clinical stage, PSA at entry and initial GS was as follows: T1: T2 = 40:27, initial PSA < 5: 5-9.9:10-14.9 = 23:34:10, initial GS 4:5:6:7:GX = 2:13:37:14:1. Median follow-up was 29 months (range: 13-59). GS was unchanged in 21(31%), upgraded in 22(33%) and downgraded in 24(36%) on repeat biopsy (see Table). In 19(28%), there was no malignancy on rebiopsy. The higher initial GS did not predict a higher probability of GS upgrade. There was no statistically significant correlation between the change in histologic grade and PSAdt, or the baseline variables including age, initial PSA, and clinical stage. Conclusion: The histologic grade of malignancy can change over time as the biology of malignancy evolves. In our cohort, 19(28%) did not have malignancy on rebiopsy. This was most likely related to sampling error. Furthermore, there was no consistent upgrade of histologic grade on repeat biopsy at a median of 18 months. This may be due to a short interval between the two biopsies, and/or the favorable clinical and pathological parameters of our cohort which predict very slow biological evolution over time. Also, this observation is subject to the adequacy of biopsy sampling as well as intra- and inter-observer variability of GS. It remains to be seen whether or not upgrade of histologic grade is a useful predictor of disease progression requiring therapeutic intervention in patients managed with watchful observation. Tabled 1Initial GS →GX (n=1)GS 4 (n=2)GS 5 (n=13)GS 6 (n=37)GS 7 (n=14)Histological unchanged002136Histological upgraded116140Histological downgraded01 (no malignancy)5 (no malignancy)10 (no malignancy)8 (3: no malignancy) Open table in a new tab

PURPOSE:To study prostate-specific antigen (PSA) doubling time of untreated, favorable grade, prostate carcinoma. METHODS AND MATERIALS:A prospective single-arm cohort study has been in progress to assess the feasibility of a watchful observation protocol with selective delayed intervention using clinical, histologic, or PSA progression as treatment indication in untreated, localized, favorable grade prostate adenocarcinoma (T1b-T2bN0 M0, Gleason Score < or = 7, and PSA < or = 15 ng/mL). Patients are conservatively managed with watchful observation alone, as long as they do not meet the arbitrarily defined disease progression criteria. Patients are followed regularly and undergo blood tests including PSA at each visit. PSA doubling time (Td) is estimated from a linear regression of ln(PSA) on time, assuming a simple exponential growth model. RESULTS:As of March 2000, 134 patients have been on the study for a minimum of 12 months (median, 24; range, 12-52) and have a median frequency of PSA measurement of 7 times (range, 3-15). Median age is 70 years. Median PSA at enrollment is 6.3 (range, 0.5-14.6). The distribution of Td is as follows: <2 years, 19 patients; 2-5 years, 46; 5-10 years, 25; 10-20 years, 11; 20-50 years, 6; > 50 years, 27. The median Td is 5.1 years. In 44 patients (33%), Td is greater than 10 years. There was no correlation between Td and patient age, clinical T stage, Gleason score, or initial PSA level. CONCLUSION:Td of untreated prostate cancer varies widely. In our cohort, 33% have Td > 10 years. Td may be a useful tool to guide treatment intervention for patients managed conservatively with watchful observation alone.

Magnetic resonance image-guidance for interstitial thermal therapy has proven to be a valuable tool in its traditional role in device localization and, more recently, in monitoring heat deposition within tissue. However, a quantitative understanding of how temperature-time exposure relates to thermal damage is crucial if the predictive value of real-time MR thermal-monitoring is to be fully realized. Results are presented on interstitial laser coagulation of two canine prostate models which are shown to provide an opportunity to evaluate three models of thermal damage based on a threshold maximum temperature, an Arrhenius damage integral, and a temperature-time product. These models were compared to the resultant lesion margin as derived from post-treatment T(1)- and T(2)-weighted MR images, as well as from direct histological evaluation of the excised canine prostate. Histological evaluation shows that the thermal-injury boundary can be predicted from a threshold-maximum temperature of approximately 51 degrees C or an equivalent Arrhenius t(43) period of 200 minutes, but it is not reliably predicted using the temperature-time product. The methods described in this study are expected to have implications for the treatment of benign prostatic hyperplasia and prostate cancer with interstitial laser coagulation, which will be the focus of future human studies.

PURPOSE:Although the majority of patients with node positive transitional cell carcinoma of the bladder have disease progression, a definitive subset is cured by surgery only. Nuclear accumulation of p53 has been associated with disease progression in patients with superficial transitional cell carcinoma and decreased survival in those with muscle invasive disease. We determined whether p53 status would predict survival in a cohort with nodal metastasis.MATERIALS AND METHODS:We explored the comprehensive database of all 199 radical cystectomies performed at our institution between July 1988 and September 1999. The 59 patients in this database with node positive pathology comprise our study. We performed immunohistochemical analysis of specimens using the MAB1801 antibody with greater than 20% lymph node and primary tumor nucleus staining deemed positive. Additional covariates measured included patient age, sex, pathological disease stage, adjuvant chemotherapy and nodal stage. Disease-free survival curves were generated for the various covariates and compared using the log rank test. The Cox proportional hazards technique was used to determine covariate adjusted p53 survival.RESULTS:In the cohort overall median disease-free survival was only 21 months, although 18% of patients were disease-free at 5 years. There was evidence of p53 nuclear accumulation in 54% of cases and complete agreement of nodal with bladder p53 nuclear accumulation. No significant baseline differences were noted in the covariates with respect to p53 nuclear accumulation. For stratum specific disease-free survival univariate and multivariate analyses revealed that only pathological stages p0-p2b versus p3-p4 (hazards ratio 2.86, p = 0.03), and nodal stages N2 versus N1 and N3 versus N1 (hazards ratio 3.84, p = 0.01 and hazards ratio 13.3, p = 0.0002, respectively) were significantly associated with prolonged disease-free survival, while p53 nuclear accumulation was not.CONCLUSIONS:Despite credible evidence for p53 nuclear accumulation prognostication in patients with in situ and invasive transitional cell carcinoma, this marker is not predictive of disease-free survival in node positive disease.

Clear cell adenocarcinomas arising from female urethral diverticulae are rare. The optimal management of this clinical entity is uncertain. Two cases managed by a combination of surgery and XRT (radiotherapy) are presented. The common histopathological findings and treatment options are highlighted. Individualized patient management in a multi-disciplinary setting is recommended.

PURPOSE: Decreased levels of the cyclin-dependent kinase inhibitor p27Kip1 in breast cancer are associated with a poor outcome. The prognostic significance of BRCA1/2 mutations is less clear, and the relationship between BRCA1/2 mutation status, p27Kip1 protein levels, and outcome has not been studied. PATIENTS AND METHODS: Pathology blocks from 202 consecutive Ashkenazi Jewish women with primary invasive breast cancer were studied. Tumor DNA was tested for the three common BRCA1/2 founder mutations present in Ashkenazi Jews, and p27Kip1 expression was evaluated by immunohistochemistry. The median follow-up was 6.4 years. RESULTS: Thirty-two tumors (16%) were positive for a BRCA1/2 mutation. Low p27Kip1 expression was seen in 110 tumors (63%) and was significantly associated with BRCA1/2 mutations (odds ratio, 4.0; 95% confidence interval [CI], 1.4 to 11.1; P = .009). BRCA1/2 mutation carriers had a significantly worse 5-year distant disease-free survival (DDFS) compared with women without BRCA1/2 mutations (58% v 82%; P = .003). Similar results were seen for women whose tumors expressed low levels of p27Kip1, compared with those with high levels (5-year DDFS, 68% v 93%; P < .0001). In a multivariate analysis, both BRCA1/2 mutation and low p27Kip1 expression were associated with a shorter DDFS (relative risk [RR], 2.1; 95% CI, 1.0 to 4.3; P = .05; and RR, 3.9; 95% CI, 1.4 to 11.1; P = .01, respectively). CONCLUSION: In this study, we showed that BRCA1/2 mutations were associated with low levels of p27Kip1 in breast cancer. Both BRCA1/2 and p27Kip1 status were identified as independent prognostic factors.

BACKGROUND: Papillary carcinoma of the thyroid metastasizes to the brain in rare instances. In published series and case reports of metastatic papillary thyroid carcinoma, diagnosis of central nervous system (CNS) metastases has been determined by histologic methods. We present a case of papillary carcinoma metastatic to brain diagnosed by cytologic methods.CASE: A 43-year-old female, initially diagnosed at age 12 with papillary carcinoma of the thyroid metastatic to regional lymph nodes and lung, presented with head aches of increasing frequency and severity. A computed tomography scan confirmed a 1-cm nodule in the right inferior frontal lobe of the brain. For clinical reasons, the patient was followed with serial imaging for five years. At age 48 there was significant progression of the CNS disease, and the patient underwent stereotactic biopsy with drainage of cyst fluid. Cytologic examination of the cyst fluid and immunocytochemical studies confirmed the typical features of papillary thyroid carcinoma, including papillary clusters of cells with finely granular chromatin, micronucleoli, nuclear grooves and an associated psammoma body.CONCLUSION: Neurocytology is a useful technique in the examination of cystic lesions of the brain and may be the sole technique for determination of diagnosis.

Telomerase is a ribonucleoprotein that synthesizes telomeric DNA on chromosomal ends. Telomerase activation has been seen in many immortal cell lines and cancers. Telomerase activity was analyzed in prostate carcinoma; in coexistent prostatic intraepithelial neoplasia (PIN), benign prostatic hyperplasia (BPH), atrophy and normal tissue; and in benign prostate glands. Telomerase activity was detected in 80 of 87 (92%) prostate cancers. Forty-one matched samples (from a total of 32 cases) were available for comparative analysis. The presence of telomerase activity in adjacent PIN, BPH, and normal tissue was correlated with telomerase activity in the malignant epithelium. In these adjacent tissues, telomerase activity was found in 11 of 15 (73%) PINs, 13 of 26 (50%) BPHs, and 1 of 6 (16%) atrophy and 4 of 11 (36%) normal tissues. In contrast to the BPH tissue from cancer-bearing glands, all 16 BPH specimens from patients only diagnosed with BPH were telomerase activity negative. In cancer samples, there was no correlation between telomerase activity and Gleason grade or preoperation prostate-specific antigen level. Our data indicate that telomerase activity is present in most prostate cancers. The high rate of telomerase activity in the benign-appearing areas of these glands may be attributed either to the presence of occult cancer cells or to early molecular alterations of cancer that were histologically inapparent.

p27Kip1 is a cyclin-dependent kinase inhibitor that negatively regulates cell proliferation by mediating cell cycle arrest in G1. This study was undertaken to assess the prognostic value of p27Kip1 in localized human prostate cancer. Archival material from 113 radical prostatectomy specimens obtained between 1985 and 1993 was stained immunohistochemically for p27Kip1 protein using a commercially available antibody. Patient charts were reviewed for preoperative serum prostate-specific antigen, clinical and pathological staging, Gleason tumor grade, time to biochemical and clinical recurrence, and survival. Strong p27Kip1 staining was uniformly seen in benign prostatic epithelial components in all tumor sections. p27Kip1 staining was reduced in most prostate cancers and was variable in prostatic intraepithelial neoplasia. Decreased p27Kip1 staining (<25% of nuclei stained positive for p27Kip1) correlated with seminal vesicle involvement (P = 0.0032) and with higher Gleason grade (P = 0.0114). On univariate analysis, low p27Kip1 predicted an increased risk of treatment failure in the node-negative cohort (P = 0.0037) and in the subset who did not receive neoadjuvant hormonal therapy (P = 0.049). Low p27Kip1 expression was an independent predictor of treatment failure on multivariate analysis of lymph node negative prostate cancers following radical retropubic prostatectomy (n = 102; P = 0.047). Seminal vesicle involvement (P = 0.034) and positive surgical margins (P = 0.047) were also independent prognostic factors for disease recurrence. In patients who received preoperative neoadjuvant hormonal therapy, low p27Kip1 in the pathological specimen was an even stronger predictor of outcome than it was in the entire group (n = 23, P = 0.015).

Specimens from modified radical hysterectomies performed for invasive carcinoma of the cervix were analyzed with quantitative T2 magnetic resonance (MR) imaging and histologic study to determine to what degree there was a correlation between the findings of the two modalities. The mean T2 of cervical stroma was 48 msec, while the outer zone of the cervix had a mean T2 of 62 msec and the central canal region typically had T2 values of 115 msec +/- 20 (standard deviation). A total of nine cervical cancers were analyzed, and their mean T2 value was 79 msec. Separation between cervical stroma and tumor was good, with stromal T2 values ranging from 30 to 66 msec, while tumor T2s ranged from 60 to 97 msec. Statistical analysis indicated that these data were associated with a sensitivity of 89% and a specificity of 95%, with 95% confidence intervals of [50%,99.4%] and [74%,99.7%], respectively, for separating tumor from stroma on the basis of T2 value. Quantitative T2 imaging was found to provide an effective, nonsubjective means of classifying cervical anatomy and neoplastic disease.