K.C. Balaji

Increasing incidence of all stages of kidney cancer in the last 2 decades in the United States: an analysis of surveillance, epidemiology and end results program data.

PURPOSE Since the 1980s with the increased use of abdominal imaging, such as computerized abdominal tomography, renal cancer has commonly been diagnosed as an incidental mass. We analyzed the renal cancer incidence from 1973 to 1998 in the Surveillance, Epidemiology and End Results program by historic staging of localized, regional or distant disease to evaluate possible stage migration due to increased abdominal imaging. MATERIALS AND METHODS We used renal cancer data from the Surveillance, Epidemiology and End Results 9 registries, public use, August 2000 submission (National Cancer Institute, Bethesda, Maryland), which represents approximately 14% of the United States population. We analyzed the age adjusted renal cancer incidence from 1973 to 1998 using the 1990 American standard million population. We compared the incidence of the 3 stages of renal cancer from 1973 to 1985 and 1986 to 1998 by the chi-square test and used joinpoint regression analysis to determine whether there was a significant change in the intragroup or intergroup incidence rate with time. RESULTS During 1973 to 1985 the rate of localized, regional and distant renal cancer was 45%, 23% and 32% compared with 54%, 21% and 25%, respectively, from 1986 to 1998 (p = 0.45). However, the plot of incidence rate versus diagnosis year by stage showed an increasing trend in the 3 stage groups. The annual percent change in the localized, regional and distant groups was 3.7 (95% confidence interval [CI] 3.2 to 4.2), 1.9 (95% CI 1.2 to 2.6) and 0.68 (95% CI 0.1 to 1.3) per 100,000 population, respectively (p <0.05). The 3 groups also had significantly different growth rates (p <0.01). CONCLUSIONS There was no significant difference in stage at presentation of renal cancer diagnosed in 1973 to 1985 compared with that diagnosed in 1986 to 1998. While the lack of a decrease in distant disease despite the increased detection of regional and localized renal cancer implies that a proportion of innocuous renal cancer cases may be detected by increased abdominal imaging, the increased incidence of renal cancer in all 3 categories indicates that other factors may also be contributing to the increasing incidence of renal cancer.

Effect of vitamin C on prostate cancer cells in vitro : Effect on cell number, viability, and DNA synthesis

Many studies describe the protective role of vitamin C (ascorbic acid) against cancer development and in treatment of established cancer. The present study investigated whether ascorbic acid demonstrates a therapeutic benefit for prostate cancer.

MECHANISM OF STONE FORMATION

This article reviews the physical principles involved in urolithiasis. For urinary stones to form, crystals must form first and they then should be retained in the urinary tract. These phenomena require the interaction between the forces of saturation, crystal inhibition, crystal nucleation, growth aggregation, and retention, which all occur in a complex solution. In the latter part of the article the authors review the relevance of these physical principles in the lithogenesis of the most common urinary stones.

Protein Kinase D1 Suppresses Epithelial-to-Mesenchymal Transition through Phosphorylation of Snail

Cancer cells undergo epithelial-mesenchymal transition (EMT) as a program of increased invasion and metastasis during cancer progression. Here, we report that a novel regulator of EMT in cancer cells is protein kinase D1 (PKD1), which is downregulated in advanced prostate, breast, and gastric cancers. Ectopic reexpression of PKD1 in metastatic prostate cancer cells reversibly suppressed expression of mesenchyme-specific genes and increased epithelial markers such as E-cadherin, whereas small interfering RNA-mediated knockdown of PKD1 increased expression of mesenchyme markers. Further, PKD1 inhibited tumor growth and metastasis in a tumor xenograft model. PKD1 phosphorylates Ser(11) (S11) on transcription factor Snail, a master EMT regulator and repressor of E-cadherin expression, triggering nuclear export of Snail via 14-3-3σ binding. Snail S11 mutation causes acquisition of mesenchymal traits and expression of stem cell markers. Together, our results suggest that PKD1 functions as a tumor and metastasis suppressor, at least partly by regulating Snail-mediated EMT, and that loss of PKD1 may contribute to acquisition of an aggressive malignant phenotype.

Upper tract recurrences following radical cystectomy: an analysis of prognostic factors, recurrence pattern and stage at presentation.

PURPOSE We study the incidence and pattern of upper tract recurrences following radical cystectomy for bladder cancer, and analyze the prognostic factors. MATERIALS AND METHODS A retrospective study was performed on 529 patients who underwent radical cystectomy and urinary diversion at Memorial Sloan-Kettering Cancer Center between July 1989 and June 1997. Data related to upper tract recurrence were analyzed. RESULTS Of the 529 patients 16 (3%) had upper tract recurrence. Median followup was 16.9 months for the entire group and 49.1 months for patients with upper tract recurrence, with a median time to recurrence of 37.2 months. Of 12 upper tract recurrences 7 (58%) were locally advanced at surgery (p3a or greater with or without lymph node metastasis) and 5 of 16 patients with recurrence (31.3%) had bilateral tumors (2 synchronous and 3 metachronous). Overall survival from the time of diagnosis of upper tract recurrence after radical cystectomy was poor, with a median of 10 months (confidence interval 1 to 19). CONCLUSIONS The incidence of upper tract recurrence following radical cystectomy is low (3%). However, the incidence of bilateral tumors (31.3%) and locally advanced stage at the time of operation (58%) is higher than expected for upper tract tumors in the general population. Survival of patients with upper tract recurrence is poor, with a median of 10 months.

Protein kinase C μ is down-regulated in androgen-independent prostate cancer

Abstract Progression to androgen independence (AI) is the main cause of death in prostate cancer. Our prior differential gene expression studies by microarray analysis in progressive prostate cancer cell line model identified dysregulation of protein kinase C μ (PKCμ) expression in prostate cancer. In this study, quantitative ribonuclease protection assay and immunoblot analysis demonstrate down regulation of PKCμ at transcription and translational level, respectively, in AI C4-2 cells compared to its parental androgen dependent (AD) LNCaP prostate cancer cells. Significantly lower PKCμ kinase activity was confirmed in C4-2 cells by in vitro kinase assay. Immunohistochemical studies of prostate cancer tissue from patient progressing to AI prostate cancer demonstrated that PKCμ expression is decreased in 100% of AI human prostate cancers. The consistent down regulation of PKCμ in cell line models and human prostate cancer tissues suggests a possible functionally significant role for PKCμ in progression to AI in prostate cancer.

Protein Kinase D1–Mediated Phosphorylation and Subcellular Localization of β-Catenin

beta-Catenin is essential for E-cadherin-mediated cell adhesion in epithelial cells and also acts as a key cofactor for transcription activity. We previously showed that protein kinase D1 (PKD1), founding member of the PKD family of signal transduction proteins, is down-regulated in advanced prostate cancer and interacts with E-cadherin. This study provides evidence that PKD1 interacts with and phosphorylates beta-catenin at Thr(112) and Thr(120) residues in vitro and in vivo; mutation of Thr(112) and Thr(120) results in increased nuclear localization of beta-catenin and is associated with altered beta-catenin-mediated transcription activity. It is known that mutation of Thr(120) residue abolishes binding of beta-catenin to alpha-catenin, which links to cytoskeleton, suggesting that PKD1 phosphorylation of Thr(120) could be critical for cell-cell adhesion. Overexpression of PKD1 represses beta-catenin-mediated transcriptional activity and cell proliferation. Epistatic studies suggest that PKD1 and E-cadherin are within the same signaling pathway. Understanding the molecular basis of PKD1-beta-catenin interaction provides a novel strategy to target beta-catenin function in cells including prostate cancer.

Antiproliferative effects of c-myc antisense oligonucleotide in prostate cancer cells: A novel therapy in prostate cancer

OBJECTIVES To explore the possibility of using antisense oligonucleotide therapy for prostate cancer, we investigated the effect of c-myc-antisense-oligonucleotide (c-myc-As-ODN) in human prostate cancer cell lines such as LNCaP, PC3, and DU145. METHODS LNCaP, PC3, and DU145 cells were incubated in the presence of c-myc-As-ODN. Dose (0 to 10 microM) and time dependent (1 to 6 days) effects on proliferation and viability were examined by [3H]thymidine incorporation and MTT assay, respectively. Flow cytometry analysis was carried out to analyze cell cycle status by determining the DNA content in LNCaP cells. Control cultures received either c-myc-sense-ODN or scrambled (nonsense) nucleotides. RESULTS Time- and dose-dependent decreases in DNA synthesis and cell viability were noted for all three prostate cancer cell lines after c-myc-As-ODN treatment. Further studies using LNCaP cells indicated that these changes were accompanied by an increase in the percentage of cells with less than 2N DNA content after c-myc-As-ODN treatment. The results suggest that c-myc-As-ODN induces cell death. Comparison of a c-myc-As-ODN-treated group with a group subjected to isoleucine deprivation revealed that thymidine incorporation was almost the same in c-myc-As-ODN-treated LNCaP cells and in LNCaP cells at early S phase. CONCLUSIONS These results suggest that c-myc-As-ODN inhibits prostate cancer cell growth and proliferation mainly by decreasing cell viability.

Radical nephrectomy performed by open, laparoscopy with or without hand-assistance or robotic methods by the same surgeon produces comparable perioperative results

PURPOSE Radical nephrectomy can be performed using open or laparoscopic (with or without hand assistance) methods, and most recently using the da Vinci Surgical Robotic System. We evaluated the perioperative outcomes using a contemporary cohort of patients undergoing radical nephrectomy by one of the above 4 methods performed by the same surgeon. MATERIALS AND METHODS The relevant clinical information on 57 consecutive patients undergoing radical nephrectomy from September 2000 until July 2004 by a single surgeon was entered in a Microsoft Access Database and queried. Following appropriate statistical analysis, p values < 0.05 were considered significant. RESULTS Of 57 patients, the open, robotic, laparoscopy with or without hand assistance radical nephrectomy were performed in 18, 6, 21, and 12 patients, respectively. The age, sex, body mass index (BMI), incidence of malignancy, specimen and tumor size, tumor stage, Fuhrman grade, hospital stay, change in postoperative creatinine, drop in hemoglobin, and perioperative complications were not significantly different between the methods. While the estimated median blood loss, postoperative narcotic use for pain control, and hospital stay were significantly higher in the open surgery method (p < 0.05), the median operative time was significantly shorter compared to the robotic method (p = 0.02). Operating room costs were significantly higher in the robotic and laparoscopic groups; however, there was no significant difference in total hospital costs between the 4 groups. CONCLUSIONS The study demonstrates that radical nephrectomy can be safely performed either by open, robotic, or laparoscopic with or without hand assistance methods without significant difference in perioperative complication rates. A larger cohort and longer follow up are needed to validate our findings and establish oncological outcomes.

EFFECT OF NEOADJUVANT HORMONAL THERAPY ON PROSTATIC INTRAEPITHELIAL NEOPLASIA AND ITS PROGNOSTIC SIGNIFICANCE

PURPOSE We studied the effect of neoadjuvant hormonal therapy on prostatic intraepithelial neoplasia in patients undergoing radical prostatectomy and assessed the effect of prostatic intraepithelial neoplasia on disease recurrence as measured by serum prostate specific antigen (PSA). MATERIALS AND METHODS A total of 278 patients with clinically localized prostate cancer were included in phase II and III studies evaluating radical prostatectomy alone versus radical prostatectomy following neoadjuvant hormonal therapy at Memorial Sloan-Kettering Cancer Center between October 1991 and August 1996. Patient data related to prostatic intraepithelial neoplasia were analyzed. RESULTS Of 275 evaluable patients 145 (52.7%) had prostatic intraepithelial neoplasia. Of 50 patients treated with neoadjuvant hormonal therapy (hormone group) 22 (44%) had a lower incidence of prostatic intraepithelial neoplasia compared to 69 of 80 controls (86.3%) (chi-square test p<0.0001). Of 262 patients (95.3%) with followup PSA 44 (16.8%) had PSA recurrence at a median followup of 32 months, with a median time to recurrence of 30 months. PSA recurrence was noted in 23 of 145 patients with compared to 21 of 130 without prostatic intraepithelial neoplasia (chi-square test p = 0.95), and did not significantly differ between the hormone group (25 of 142, 17.6%) and controls (19 of 130, 14.6%) (chi-square test p = 0.45). CONCLUSIONS While patients treated with neoadjuvant hormonal therapy had significantly lower incidence of prostatic intraepithelial neoplasia, neither prostatic intraepithelial neoplasia nor neoadjuvant hormonal therapy significantly affected PSA recurrence at a median followup of 32 months.