Aria F. Olumi

Extended Prostate Needle Biopsy Improves Concordance Of Gleason Grading Between Prostate Needle Biopsy And Radical Prostatectomy

PURPOSE We examined the concordance of Gleason scores in prostate needle biopsy specimens and the corresponding radical retropubic prostatectomy specimens in a cohort of patients grouped according to the number of cores obtained during diagnostic needle biopsy. MATERIALS AND METHODS We reviewed clinical and pathological data on a cohort of 466 men diagnosed with localized prostate cancer by needle biopsies who underwent radical retropubic prostatectomy between January 1, 1990 and July 31, 2001. Two study groups were identified, including 126 patients diagnosed with prostate cancer by extended needle biopsies (10 or more cores) and 340 diagnosed with cancer by nonextended needle biopsies (9 or fewer cores). Mean age was 60 years and median prostate specific antigen was 5.8 ng./ml. The median number of cores in the extended and nonextended biopsy groups was 12 and 6, respectively. The concordance of Gleason score in the needle biopsy and prostatectomy specimens was compared and correlated with the number of cores on needle biopsy. RESULTS In the whole cohort 311 patients (67%) had identical Gleason scores on the needle biopsy and prostatectomy specimens, while 53 (11%) were over graded and 102 (22%) were under graded on needle biopsy. In patients who underwent extended needle biopsies the accuracy rate for Gleason scoring was 76% with 10% over and 14% under graded. The highest accuracy rates were in patients with 13, 14 and 16 cores (89%, 87% and 100%, respectively). No patients in the extended needle biopsy group had a discrepancy of more than 2 Gleason units in grade in the biopsy and surgical specimens. In those who underwent nonextended needle biopsies the accuracy rate for Gleason scoring was 63% with 12% over and 25% under graded. There were significantly different rates of accuracy (p = 0.008) and under grading (p = 0.01) in the 2 needle biopsy groups. Patients with a needle biopsy Gleason score of less than 7 had significantly higher concordance with the prostatectomy Gleason score when extended biopsies were done compared with nonextended biopsies (p = 0.001). CONCLUSIONS Prostate cancer grading by extended needle biopsy is a better predictor of the final Gleason score than nonextended needle biopsy, as determined by radical prostatectomy histological evaluation. Therefore, extended prostate needle biopsy provides better guidance to determine the appropriate treatment in patients with prostate cancer.

MR Imaging of Renal Masses: Correlation with Findings at Surgery and Pathologic Analysis

Magnetic resonance (MR) imaging is useful in the characterization of renal masses. The MR imaging manifestations and pathologic diagnoses of 82 renal masses were reviewed and correlated. The MR imaging appearance of clear cell type renal cell carcinoma varies depending on the presence of cystic components, hemorrhage, and necrosis. Papillary renal cell carcinomas appear as well-encapsulated masses with homogeneous low signal intensity on T2-weighted images and homogeneous low-level enhancement after the intravenous administration of contrast material, or as cystic hemorrhagic masses with peripheral enhancing papillary projections. Transitional cell carcinoma may be seen as an irregular, enhancing filling defect in the pelvicaliceal system or ureter. Lymphomatous masses are usually hypointense relative to the renal cortex on T2-weighted images and enhance minimally on delayed gadolinium-enhanced images. Bulk fat is a distinguishing feature of angiomyolipoma. Oncocytoma has a variable and nonspecific appearance at MR imaging. MR imaging findings may allow the characterization of various renal masses and can provide valuable information for their clinical management.

Persistent c-FLIP(L) Expression Is Necessary and Sufficient to Maintain Resistance to Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand–Mediated Apoptosis in Prostate Cancer

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been shown to induce apoptosis in a variety of tumorigenic and transformed cell lines but not in many normal cells. Hence, TRAIL has the potential to be an ideal cancer therapeutic agent with minimal cytotoxicity. FLICE inhibitory protein (c-FLIP) is an important regulator of TRAIL-induced apoptosis. Here, we show that persistent expression of c-FLIP(Long) [c-FLIP(L)] is inversely correlated with the ability of TRAIL to induce apoptosis in prostate cancer cells. In contrast to TRAIL-sensitive cells, TRAIL-resistant LNCaP and PC3-TR (a TRAIL-resistant subpopulation of PC3) cells showed increased c-FLIP(L) mRNA levels and maintained steady protein expression of c-FLIP(L) after treatment with TRAIL. Ectopic expression of c-FLIP(L) in TRAIL-sensitive PC3 cells changed their phenotype from TRAIL sensitive to TRAIL resistant. Conversely, silencing of c-FLIP(L) expression by small interfering RNA in PC3-TR cells reversed their phenotype from TRAIL resistant to TRAIL sensitive. Therefore, persistent expression of c-FLIP(L) is necessary and sufficient to regulate sensitivity to TRAIL-mediated apoptosis in prostate cancer cells.

Multidisciplinary Care and Pursuit of Active Surveillance in Low-Risk Prostate Cancer

PURPOSE Multidisciplinary clinics offer a unique approach to the management of patients with cancer. Yet, limited data exist to show that such clinics affect management. The purpose of this study was to determine whether consultation at a multidisciplinary clinic is associated with selection of active surveillance in patients with low-risk prostate cancer. PATIENTS AND METHODS The study comprised 701 men with low-risk prostate cancer managed at three tertiary care centers in Boston, MA in 2009. Patients either obtained consultation at a multidisciplinary prostate cancer clinic, at which they were seen by a combination of urologic, radiation, and medical oncologists in a concurrent setting, or they were seen by individual practitioners in sequential settings. The primary outcome was selection of active surveillance. RESULTS Crude rates of selection of active surveillance in patients seen at a multidisciplinary clinic were double that of patients seen by individual practitioners (43% v 22%), whereas the proportion of men treated with prostatectomy or radiation decreased by approximately 30% (P < .001). On multivariate logistic regression, older age (odds ratio [OR], 1.09; 95% CI, 1.05 to 1.12; P < .001), unmarried status (OR, 1.66; 95% CI, 1.01 to 2.72; P = .04), increased Charlson comorbidity index (OR, 1.37; 95% CI, 1.06 to 1.77; P = .02), fewer positive cores (OR, 0.92; 95% CI, 0.90 to 0.94; P < .001), and consultation at a multidisciplinary clinic (OR, 2.15; 95% CI, 1.13 to 4.10; P = .02) were significantly associated with pursuit of active surveillance. CONCLUSION Multidisciplinary care is associated with increased selection of active surveillance in men with low-risk prostate cancer. This finding may have an important clinical, social, and economic impact.

Hypoxia-inducible factor linked to differential kidney cancer risk seen with type 2A and type 2B VHL mutations.

ABSTRACT Clear cell carcinoma of the kidney is a major cause of mortality in patients with von Hippel-Lindau (VHL) disease, which is caused by germ line mutations that inactivate the VHL tumor suppressor gene. Biallelic VHL inactivation, due to mutations or hypermethylation, is also common in sporadic clear cell renal carcinomas. The VHL gene product, pVHL, is part of a ubiquitin ligase complex that targets the alpha subunits of the heterodimeric transcription factor hypoxia-inducible factor (HIF) for destruction under well-oxygenated conditions. All VHL mutations linked to classical VHL disease compromise this pVHL function although some missense mutations result in a low risk of kidney cancer (type 2A VHL disease) while others result in a high risk (type 2B VHL disease). We found that type 2A mutants were less defective than type 2B mutants when reintroduced into VHL−/− renal carcinoma cells with respect to HIF regulation. A stabilized version of HIF2α promoted tumor growth by VHL−/− cells engineered to produce type 2A mutants, while knock-down of HIF2α in cells producing type 2B mutants had the opposite effect. Therefore, quantitative differences with respect to HIF deregulation are sufficient to account for the differential risks of kidney cancer linked to VHL mutations.

LOCALLY RECURRENT PROSTATE TUMORS FOLLOWING EITHER RADIATION THERAPY OR RADICAL PROSTATECTOMY HAVE CHANGES IN KI-67 LABELING INDEX, P53 AND BCL-2 IMMUNOREACTIVITY

PURPOSE We compare the biological phenotype of recurrent prostatic tumors after definitive local therapy (radiation or radical prostatectomy) with that of the same tumors before treatment. MATERIALS AND METHODS Cellular proliferation (Ki-67 labeling index), p53 nuclear reactivity and bcl-2 immunoreactivity were determined in pretreatment and posttreatment tumor specimens from 13 patients with local tumor recurrence following radiation, and in 18 patients with local tumor recurrence following radical prostatectomy. RESULTS Mean Ki-67 labeling index increased approximately 2-fold in locally recurrent tumors after radiation (10.5 versus 5.6%, p=0.0008) or surgery (6.0 versus 3.2%, p=0.0025) when compared with pretreatment tumors. We noted p53 nuclear reactivity in a significantly higher proportion of recurrences than in pretreatment tumors following radiation (54 versus 8%, p=0.032) and surgery (39 versus 5%, p=0.022). Although bcl-2 immunoreactivity was also seen in a higher proportion of recurrent tumors, this difference did not reach statistical significance for either radiation or surgery. CONCLUSIONS Recurrent tumors following either radiation or surgery differ significantly from the corresponding pretreatment tumors with respect to cellular proliferation and p53 nuclear reactivity.

MG-132 Sensitizes TRAIL-Resistant Prostate Cancer Cells by Activating c-Fos/c-Jun Heterodimers and Repressing c-FLIP(L)

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent because it induces apoptosis in cancer cells but not in normal cells. Unfortunately, some cancer cells develop resistance to TRAIL-induced apoptosis. Therefore, it is clinically relevant to determine the molecular mechanisms that differentiate between TRAIL-sensitive and TRAIL-resistant tumors. Previously, we have shown that the antiapoptotic molecule cellular-FLICE-inhibitory protein long isoform [c-FLIP(L)] is necessary and sufficient to maintain resistance to TRAIL-induced apoptosis. We have found that c-FLIP(L) is transcriptionally regulated by the activator protein-1 (AP-1) family member protein c-Fos. Here, we report that MG-132, a small-molecule inhibitor of the proteasome, sensitizes TRAIL-resistant prostate cancer cells by inducing c-Fos and repressing c-FLIP(L). c-Fos, which is activated by MG-132, negatively regulates c-FLIP(L) by direct binding to the putative promoter region of the c-FLIP(L) gene. In addition to activating c-Fos, MG-132 activates another AP-1 family member, c-Jun. We show that c-Fos heterodimerizes with c-Jun to repress transcription of c-FLIP(L). Therefore, MG-132 sensitizes TRAIL-resistant prostate cancer cells by activating the AP-1 family members c-Fos and c-Jun, which, in turn, repress the antiapoptotic molecule c-FLIP(L).

Impact on the clinical outcome of prostate cancer by the 2005 international society of urological pathology modified Gleason grading system.

The 2005 International Society of Urological Pathology (ISUP) Consensus Conference modified the Gleason grading system for prostate cancer. In the modified criteria, ill-defined glands with poorly formed lumina and large cribriform glands with smooth borders, classically described as Gleason pattern 3 adenocarcinoma, were redefined as Gleason pattern 4. To evaluate the clinical outcome of patients upgraded by the ISUP criteria, the histologic slides of 1240 consecutive radical prostatectomy specimens at a single institution were reviewed, and each case of adenocarcinoma was graded on the basis of the original and modified Gleason criteria. A total of 806 patients with prostate cancer of classical Gleason score 3+3=6 or 3+4=7 and modified Gleason score 6 to 8 were analyzed with a median overall follow-up of 12.6 years. In the study population, 34% of patients with classical Gleason score 3+3=6 prostate cancer were upgraded to modified Gleason score 7 or 8 by the ISUP criteria. Compared to patients with modified Gleason score 3+3=6 and patients with classical Gleason score 3+4=7, the upgraded patients were at intermediate risk for biochemical progression (paired log-rank P⩽0.003) and metastasis (paired log-rank P⩽0.04) after radical prostatectomy. The hazard ratio for upgrading was 1.60 (95% confidence interval, 1.09-2.35, P=0.02) for biochemical recurrence and 5.02 (95% confidence interval, 1.77-14.2, P=0.003) for metastasis. These results validate the prognostic value of the modified Gleason grading system and suggest that the recognition of an intermediate-risk histological pattern may be useful in the prognosis of patients with prostate cancer.

c-Fos as a proapoptotic agent in TRAIL-induced apoptosis in prostate cancer cells.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/Apo-2L promotes apoptosis in cancer cells while sparing normal cells. Although many cancers are sensitive to TRAIL-induced apoptosis, some evade the proapoptotic effects of TRAIL. Therefore, differentiating molecular mechanisms that distinguish between TRAIL-sensitive and TRAIL-resistant tumors are essential for effective cancer therapies. Here, we show that c-Fos functions as a proapoptotic agent by repressing the antiapoptotic molecule c-FLIP(L). c-Fos binds the c-FLIP(L) promoter, represses its transcriptional activity, and reduces c-FLIP(L) mRNA and protein levels. Therefore, c-Fos is a key regulator of c-FLIP(L), and activation of c-Fos determines whether a cancer cell will undergo cell death after TRAIL treatment. Strategies to activate c-Fos or inhibit c-FLIP(L) may potentiate TRAIL-based proapoptotic therapies.

Metformin Use and Prostate Cancer Risk

BACKGROUND Metformin may decrease prostate cancer (PCa) risk by reducing hyperinsulinemia-associated carcinogenesis or through direct effects on cancer cells. OBJECTIVE To evaluate the association between metformin use and PCa diagnosis. DESIGN, SETTING, AND PARTICIPANTS We used the Danish Cancer Registry and the Aarhus University Prescription Database to conduct a nested case-control study among men residing in northern Denmark from 1989 to 2011. We identified 12 226 cases of PCa and used risk-set sampling to select 10 population controls per case (n=122,260) from among men alive on the index date and born in the same year. A sensitivity analysis was conducted using subjects who had prostate-specific antigen (PSA) testing prior to 1 yr before the index date. INTERVENTION Metformin exposure was assessed using prescriptions redeemed before the index date. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using logistic regression. The association between metformin use and PCa diagnosis was determined, controlling for diabetes severity and other potential confounders. RESULTS AND LIMITATIONS Metformin users were at decreased risk of PCa diagnosis compared with never-users (adjusted OR [aOR]: 0.84; 95% CI, 0.74-0.96). Diabetics on no medication (aOR: 0.98; 95% CI, 0.89-1.09) or on other oral hypoglycemics (aOR: 0.98; 95% CI, 0.86-1.10) did not have a reduced risk of PCa, while users of insulin did have a reduced risk (aOR: 0.77; 95% CI, 0.64-0.93). In the PSA-tested group, metformin use was associated with decreased risk of PCa compared with nonuse (aOR: 0.66; 95% CI, 0.51-0.86). Diabetics on no medication (aOR: 1.03; 95% CI, 0.86-1.24), diabetics on other oral hypoglycemics (aOR: 0.92; 95% CI, 0.70-1.20), and insulin users (aOR: 0.83; 95% CI, 0.56-1.24) did not have a statistically significant reduced risk of cancer. CONCLUSIONS Metformin use was associated with decreased risk of PCa diagnosis, whereas diabetics using other oral hypoglycemics had no decreased risk. PATIENT SUMMARY We studied the relationship between metformin (a diabetic medication) and prostate cancer in Denmark. We found that metformin reduced the risk of prostate cancer diagnosis, whereas other oral antidiabetic medications did not.