Ke-Hung Tsui

PROGNOSTIC INDICATORS FOR RENAL CELL CARCINOMA: A MULTIVARIATE ANALYSIS OF 643 PATIENTS USING THE REVISED 1997 TNM STAGING CRITERIA

PURPOSE We determine independent prognostic indicators for renal cell carcinoma using the revised 1997 TNM staging criteria. MATERIALS AND METHODS The records of 643 consecutive patients undergoing partial or radical nephrectomy at our institution between 1987 and 1998 were reviewed. Preoperative evaluation of functional status using the Eastern Cooperative Oncology Group (ECOG) criteria was performed in all cases. Renal cell carcinoma grade and stage were evaluated using the 1997 American Joint Committee on Cancer grading and TNM staging criteria, respectively. Patients were followed for a mean plus or minus standard deviation of 47+/-40 months (median 87). Kaplan-Meier survival curves were used to determine 5-year cancer specific survival for all patient groups. Univariate analysis using log rank sum tests was performed to evaluate the prognostic significance of overall TNM stage, tumor stage, disease grade and ECOG status. Multivariate analysis was performed to determine which factors had an independent impact on survival of patients with renal cell carcinoma. RESULTS The 5-year cancer specific survival rate was 91%, 74%, 67% and 32% for TNM stages I, II, III and IV lesions, respectively (p<0.001). Analysis demonstrated a survival rate of 83% for stage T1, 57% for stage T2, 42% for stage T3 and 28% for stage T4 disease (p<0.001), and 89% for grade 1, 65% for grade 2, and 46% for grades 3 and 4 (p<0.001). Multivariate analysis revealed that overall TNM stage and grade of disease were the most important prognostic indicators for renal cell carcinoma (p<0.001). ECOG classification was a less significant predictor (p = 0.031) and tumor stage was not shown to have any independent impact on patient survival (p = 0.138). CONCLUSIONS Better survival rates of patients with localized and advanced renal cell carcinoma can be demonstrated with recent advances in diagnosis and treatment. The revised 1997 TNM criteria manifest an appropriate adjustment in staging renal cell carcinoma based on these improvements, with overall stage correlating with cancer specific survival. In contrast, while effectively predicting survival, tumor stage did not demonstrate an independent impact on renal cell carcinoma prognosis under multivariate analysis. Instead, other factors, such as ECOG status and more importantly grade of disease, appeared to affect survival significantly as independent elements. Based on our recent experience with patients treated for renal cell carcinoma in the era of enhanced technology and improved survival, tumor grade and molecular markers may serve as useful adjuncts to TNM staging in guiding treatment and predicting survival outcomes.

Efficacy of Nephron-Sparing Surgery for Renal Cell Carcinoma: Analysis Based on the New 1997 Tumor-Node-Metastasis Staging System

PURPOSE To analyze the experience with nephron-sparing surgery as a treatment modality for renal cell carcinoma (RCC). PATIENTS AND METHODS Between 1980 and 1997, 146 patients underwent partial nephrectomy at the University of California-Los Angeles Medical Center. A matched group of 125 patients who underwent radical nephrectomy at the same institution between 1986 and 1997 were selected for comparison. Patients were monitored for an average period of 57 months. Patients were staged according to both the 1997 and 1987 tumor-node-metastasis (TNM) staging criteria. Survival data were calculated in terms of both staging criteria. RESULTS When comparing cancer-specific survival rates for patients with T1 lesions under both the 1987 and 1997 TNM staging criteria, no statistically significant difference in survival was noted (P =.53), although most of the tumors in our series measured < or = 4 cm. Patients with T2 lesions (1997 TNM) demonstrated a significant decrease in survival (66%) when compared with patients with T1 lesions (100%; P <.001). No statistically significant difference in survival for patients with T1 RCC treated with either radical or partial nephrectomy was noted (P =.219). Survival rates of partial and radical nephrectomies for patients with unilateral T1 RCC and a normal contralateral kidney also were not significantly different (P =.53). In contrast, for patients with lesions greater than T1, survival rates were significantly higher with radical versus partial nephrectomy (P =.001). CONCLUSION Partial nephrectomy has become an effective method of treating T1 RCC lesions as categorized by both the 1987 and the revised 1997 TNM staging criteria. Selected patients with localized unilateral RCC lesions less than 7 cm (ideally, < 4 cm) and a normal contralateral kidney will benefit from partial nephrectomy.

RENAL CELL CARCINOMA: PROGNOSTIC SIGNIFICANCE OF INCIDENTALLY DETECTED TUMORS

PURPOSE We determined the prognostic significance of incidentally discovered renal cell carcinoma in the era of increased incidental detection. MATERIALS AND METHODS We reviewed the records of 633 consecutive patients who underwent radical or partial nephrectomy for renal cell carcinoma at our institution between 1987 and 1998. Patients were divided into those who were asymptomatic and tumor was diagnosed incidentally and those diagnosed after presenting with any of the classic symptoms of renal cell carcinoma or subsequent metastasis. All renal cell carcinoma lesions were assigned a stage and grade according to 1997 TNM criteria. All patients were followed postoperatively to assess survival rates, and monitor recurrence and metastasis. RESULTS Of the 633 patients 95 (15%) were treated for incidentally discovered renal cell carcinoma and 538 (85%) presented with symptoms secondary to renal cell carcinoma at diagnosis. Patient age and sex distribution were similar in the 2 groups. Stage I lesions were observed in 62.1% of patients with incidental renal cell carcinoma and in 23% with symptomatic renal cell carcinoma. In contrast, stage IV lesions were present in 27.4% of patients with incidental versus 54% with symptomatic renal cell carcinoma. Thus, incidental lesions were of significantly lower stage than those causing symptoms (p <0.001). Similarly 15.8% of incidental but 42.4% of symptomatic lesions were grade 3 or 4 (p = 0.006). Patients were followed postoperatively for a mean of 47 months plus or minus 40 months. The 5-year cancer specific survival rate was significantly higher for incidental than for symptomatic tumors (85.3% versus 62.5%). Likewise, the local and distal recurrence rates were higher for symptomatic lesions. When adjusted for stage, no difference in survival was noted in the 2 groups for stages I to III disease and a minimally significant difference was noted for stage IV cancer. Multivariate analysis of stage and grade attributed the survival difference in stage IV disease to the significantly higher grade of symptomatic lesions. CONCLUSIONS At presentation incidental tumors are of significantly lower stage and grade than tumors producing symptoms. Subsequently these clinically and histologically less aggressive lesions lead to better patient survival and decreased recurrence. Thus, the detection of renal cell carcinoma before symptom onset enables treatment of less aggressive tumors and provides a better prognosis for patients. Given these data efforts should be directed toward the development of a screening protocol to detect these lesions early, so that they may be prevented from progressing to the point when symptoms are apparent and prognosis becomes worse. In addition, the significant correlation of tumor grade with survival in our study further demonstrates the prognostic value of tumor grade and molecular markers for the future evaluation and treatment of renal cell carcinoma.

Is adrenalectomy a necessary component of radical nephrectomy? UCLA experience with 511 radical nephrectomies.

PURPOSE We determine the incidence and characteristics of adrenal involvement in localized and advanced renal cell carcinoma, and evaluate the role of adrenalectomy as part of radical nephrectomy. MATERIALS AND METHODS The records of 511 patients undergoing radical nephrectomy with ipsilateral adrenalectomy for renal cell carcinoma at our medical center between 1986 and 1998 were reviewed. Mean patient age was 63.2 years (range 38 to 85), and 78% of the subjects were males and 22% were females. Patients were divided into subgroups of 164 with localized (stage T1-2 tumor, group 1) and 347 with advanced (stage T3-4N01M01, group 2) renal cell carcinoma. Staging of tumors was performed according to the 1997 TNM guidelines. A retrospective review of preoperative computerized tomography (CT) of the abdomen was performed. Radiographic findings were subsequently compared to postoperative histopathological findings to assess the predictive value of tumor characteristics and imaging in determining adrenal metastasis. RESULTS Of the 511 patients 29 (5.7%) had adrenal involvement. Average size of the adrenal tumor was 3.86 cm. (standard deviation 1.89). Tumor stage correlated with probability of adrenal spread, with T4, T3 and T1-2 tumors accounting for 40%, 7.8% and 0.6% of cases, respectively. Upper pole intrarenal renal cell carcinoma most likely to spread was local extension to the adrenal glands, representing 58.6% of adrenal involvement. In contrast, multifocal, lower pole and mid region renal cell carcinoma tumors metastasized hematogenously, representing 32%, 7% and 4% of adrenal metastasis, respectively. The relationship between intrarenal tumor size (mean 8.9 cm., range 3 to 17) and adrenal involvement (independent of stage) was not statistically significant. Renal vein thrombus involvement was demonstrated in 8 of 12 cases (67%) with left and 2 of 9 (22%) with right adrenal involvement. Preoperative CT demonstrated 99.6% specificity, 99.4% negative predictive value, 89.6% sensitivity and 92.8% positive predictive value for adrenal involvement by renal cell carcinoma. CONCLUSIONS With a low incidence of 0.6%, adrenal involvement is not likely in patients with localized, early stage renal cell carcinoma and adrenalectomy is unnecessary, particularly when CT is negative. In contrast, the 8.1% incidence of adrenal involvement with advanced renal cell carcinoma supports the need for adrenalectomy. Careful review of preoperative imaging is required to determine the need for adrenalectomy in patients at increased risk with high stage lesions, renal vein thrombus and upper pole or multifocal intrarenal tumors. With a negative predictive value of 99.4%, negative CT should decrease the need for adrenalectomy. In contrast, positive findings are less reliable given the relatively lower positive predictive value of this imaging modality. Although such positive findings may raise suspicion of adrenal involvement, they may not necessarily indicate adrenalectomy given the low incidence, unless renal cell carcinoma with risk factors, such as high stage, upper pole location, multifocality and renal vein thrombus, is present.

Discovery of novel bladder cancer biomarkers by comparative urine proteomics using iTRAQ technology.

A urine sample preparation workflow for the iTRAQ (isobaric tag for relative and absolute quantitation) technique was established. The reproducibility of this platform was evaluated and applied to discover proteins with differential levels between pooled urine samples from nontumor controls and three bladder cancer patient subgroups with different grades/stages (a total of 14 controls and 23 cancer cases in two multiplex iTRAQ runs). Combining the results of two independent clinical sample sets, a total of 638 urine proteins were identified. Among them, 55 proteins consistently showed >2-fold differences in both sample sets. Western blot analyses of individual urine samples confirmed that the levels of apolipoprotein A-I (APOA1), apolipoprotein A-II, heparin cofactor 2 precursor and peroxiredoxin-2 were significantly elevated in bladder cancer urine specimens (n = 25-74). Finally, we quantified APOA1 in a number of urine samples using a commercial ELISA and confirmed again its potential value for diagnosis (n = 126, 94.6% sensitivity and 92.0% specificity at a cutoff value of 11.16 ng/mL) and early detection (n = 71, 83.8% sensitivity and 94.0% specificity). Collectively, our results provide the first iTRAQ-based quantitative profile of bladder cancer urine proteins and represent a valuable resource for the discovery of bladder cancer markers.

CL1-GFP: an androgen independent metastatic tumor model for prostate cancer.

PURPOSE The mechanisms responsible for tumor progression to androgen independence in prostate cancer (CaP) remain unknown. To characterize these changes and provide a basis for rational therapeutic strategies for advanced CaP, an in vivo model from a highly aggressive androgen independent CaP cell line with distinct cellular and molecular properties was developed. MATERIALS AND METHODS An aggressive androgen-independent cell line designated CL1 was derived from a slow-growing, and androgen-dependent, parental LNCaP cell line through in-vitro androgen-deprivation and selection. CL1 was stably transfected with a green fluorescence protein gene (CL1-GFP) and orthotopically injected into SCID mice. The pathologic behavior, histology, and molecular determinants of CL1 tumor and metastases were determined and characterized by standard light and fluorescent microscopy, and quantitative RT-PCR analysis. RESULTS CL1 is an anaplastic prostate cancer cell line which demonstrates extensive local invasion and metastases to various organs that can be visualized via GFP expression. When compared with parental LNCaP cells, RT-PCR analysis of the tumor revealed an over-expression of EGFR, b-FGF, VEGF, TGF-beta, IL-8, IL-6, and bcl-2 and a down regulated expression of the p53, E-cadherin and PTEN. In contrast to LNCaP cells, CL1 tumors express lower levels of androgen receptor and barely detectable PSA mRNA. CONCLUSIONS CL1-GFP represents an aggressive androgen-independent CaP tumor model derived through androgen deprivation whose pathologic development and molecular properties in animals resembles the clinical characteristics of hormone refractory prostate cancer (HRPC). Metastatic sites of CL1-GFP can be visualized with fluorescence microscopy offering a unique therapeutic model for the evaluation of drug sensitivity and other therapeutic modalities.

Triiodothyronine Modulates Cell Proliferation of Human Prostatic Carcinoma Cells by Downregulation of the B-Cell Translocation Gene 2

Studies suggest that triiodothyronine (T3) and cognate nuclear receptors (hTR) are involved in regulation of prostatic cell growth and differentiation. To probe mechanisms for T3 effects, we studied prostate carcinoma cells, investigating the effect of T3 on expression of the B‐cell translocation gene 2 (BTG2), which regulates the G1/S transition of the cell cycle.

Curcumin Blocks the Activation of Androgen and Interlukin-6 on Prostate-Specific Antigen Expression in Human Prostatic Carcinoma Cells

Curcumin, a naturally occurring compound, exhibits anticancer chemopreventive effects. We evaluated the effects and mechanisms of curcumin on the gene expression of prostate-specific antigen (PSA) in human androgen-sensitive prostatic carcinoma cells. LNCaP cells were used to determine the effect of curcumin on PSA expression. Quantitative PSA expression was assessed by reverse transcription polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), and immunoblot assay. The modulation of androgen, interlukin-6 (IL-6), and prostate-derived Ets factor (PDEF) on the PSA gene was identified by transient gene expression assay with the use of a PSA reporter vector. The effect of curcumin on the activity of androgen receptors was evaluated by electrophoretic mobility shift assay (EMSA). Immunoblot assays, RT-PCR, and ELISA indicated that curcumin treatments blocked the stimulation of methyltrienolone (R1881) and IL-6 on PSA gene expression in LNCaP cells. The effects of curcumin appear to be mediated via the androgen response element of PSA gene. Results from immunoblot assay and EMSA revealed the modulation of curcumin on the expression of androgen receptor and androgen receptor binding activity on androgen response element of PSA gene. Although overexpression of PDEF dramatically enhanced PSA gene expression, the results of immunoblot assays and transient reporter assays indicated that curcumin treatments did not affect the gene expression of PDEF. Curcumin inhibits R1881- and IL-6-mediated PSA gene expression in LNCaP cells through down-regulation of the expression and activity of androgen receptors.

l-Mimosine blocks cell proliferation via upregulation of B-cell translocation gene 2 and N-myc downstream regulated gene 1 in prostate carcinoma cells

L-Mimosine, an iron chelator and a prolyl 4-hydroxylase inhibitor, blocks many cancer cells at the late G1 phase. B-cell translocation gene 2 (Btg2) regulates the G1/S transition phases of the cell cycle. N-myc downstream regulated gene 1 (Ndrg1) is a differentiation-inducing gene upregulated by hypoxia. We evaluated the molecular mechanisms of L-mimosine on cell cycle modulation in PC-3 and LNCaP prostate carcinoma cells. The effect of L-mimosine on cell proliferation of prostate carcinoma cells was determined by the [3H]thymidine incorporation and flow cytometry assays. L-Mimosine arrested the cell cycle at the G1 phase in PC-3 cells and at the S phase in LNCaP cells, thus attenuating cell proliferation. Immunoblot assays indicated that hypoxia and L-mimosine stabilized hypoxia-inducible factor-1α (HIF-1α) and induced Btg2 and Ndrg1 protein expression, but downregulated protein levels of cyclin A in both PC-3 and LNCaP cells. L-Mimosine treatment decreased cyclin D1 protein in PC-3 cells, but not in LNCaP cells. Dimethyloxalylglycine, a pan-prolyl hydroxylase inhibitor, also induced Btg2 and Ndrg1 protein expression in LNCaP cells. The transient gene expression assay revealed that L-mimosine treatment or cotransfection with HIF-1α expression vector enhanced the promoter activities of Btg2 and Ndrg1 genes. Knockdown of HIF-1α attenuated the increasing protein levels of both Btg2 and Ndrg1 by hypoxia or L-mimosine in LNCaP cells. Our results indicated that hypoxia and L-mimosine modulated Btg2 and Ndrg1 at the transcriptional level, which is dependent on HIF-1α. L-Mimosine enhanced expression of Btg2 and Ndrg1, which attenuated cell proliferation of the PC-3 and LNCaP prostate carcinoma cells.

Blood loss and the need for transfusion in patients who undergo partial or radical nephrectomy for renal cell carcinoma.

PURPOSE We assessed blood loss and subsequent transfusion associated with nephrectomy performed for suspected renal cell carcinoma to establish guidelines for preoperative autologous blood donation and identify a subgroup of patients that may benefit from erythropoietin administration. MATERIALS AND METHODS We retrospectively reviewed the charts of 211 patients who underwent partial (73%) or radical (23%) nephrectomy for presumed renal cell carcinoma at our institution between 1990 and 1999. Patients were divided into groups 1-44.5% treated with radical nephrectomy for localized disease, 2-21.3% radical nephrectomy for metastatic lesions invading the renal vasculature or inferior vena cava, 3-8% radical nephrectomy for metastatic disease with locally extensive lesions and 4-26.5% partial nephrectomy for localized lesions. Patient charts were evaluated for preoperative and postoperative hematocrit, estimated blood loss, transfusions received, surgical complications and underlying disease. RESULTS Median estimated blood loss was 200, 400, 250 and 555 cc in groups 1 to 4, respectively. However, patients in groups 2 and 3 had a substantially greater range of blood loss than those in groups 1 and 4, respectively. The incidence of those with a blood loss of greater than 1 l. was 7%, 36%, 24% and 11% in groups 1, to 4, respectively. The incidence of those requiring transfusion was significantly lower in group 1 than in groups 2 to 4 (18% versus 44%, 24% and 30%, respectively, p <0.009). Mean transfusion requirement plus or minus standard deviation was significantly greater in groups 2 and 3 than in 1 and 4 (2.3 +/- 1.08, 5.5 +/- 4.4, 11.3 +/- 9.6 and 2.3 +/- 1.7 units, respectively, p <0.05). No significant difference was noted in the change in hematocrit as a result of surgery in the 4 groups (p >0.05). Similarly underlying disease and operative complications did not have a significant effect on blood loss or transfusion (p >0. 05). CONCLUSIONS Radical or partial nephrectomy for localized renal cell carcinoma leads to consistent and well tolerated operative blood loss that rarely results in the need for substantial transfusion. In contrast, nephrectomy for advanced disease may cause a risk of greater blood loss and subsequent need for the transfusion of multiple units of blood. While preoperative autologous blood donation may have limited value in this regard due to the high cost and number of units needed, preoperative erythropoietin administration may be a viable option. Prospective randomized studies are currently planned.