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Current Status of Partial Nephrectomy in the Management of Kidney Cancer.

BACKGROUND: The technique of partial nephrectomy for managing renal cancers is well recognized, but guidelines regarding indications for its use are not generally accepted. METHODS: The authors review the indications for partial nephrectomy in various clinical situations, and they include their own experience to clarify the utility of the technique. RESULTS: Intraoperative renal ultrasound and helical computed tomography can assist the surgeon in technical decisions. Partial nephrectomy is considered when nephrectomy would render the patient anephric and dependent on dialysis. CONCLUSIONS: The technical and operative advances in partial nephrectomy make the approach increasingly attractive for patients with kidney cancer in a variety of clinical circumstances.

Journal Article↗

The TRC8 hereditary kidney cancer gene suppresses growth and functions with VHL in a common pathway.

VHL is part of an SCF related E3-ubiquitin ligase complex with 'gatekeeper' function in renal carcinoma. However, no mutations have been identified in VHL interacting proteins in wild type VHL tumors. We previously reported that the TRC8 gene was interrupted by a t(3;8) translocation in a family with hereditary renal and non-medullary thyroid cancer. TRC8 encodes a multi-membrane spanning protein containing a RING-H2 finger with in vitro ubiquitin ligase activity. We isolated the Drosophila homologue, DTrc8, and studied its function by genetic manipulations and a yeast 2-hybrid screen. Human and Drosophila TRC8 proteins localize to the endoplasmic reticulum. Loss of either DTrc8 or DVhl resulted in an identical ventral midline defect. Direct interaction between DTrc8 and DVhl was confirmed by GST-pulldown and co-immunoprecipitation experiments. CSN-5/JAB1 is a component of the COP9 signalosome, recently shown to regulate SCF function. We found that DTrc8 physically interacts with CSN-5 and that human JAB1 localization is dependent on VHL mutant status. Lastly, overexpression of DTrc8 inhibited growth consistent with its presumed role as a tumor suppressor gene. Thus, VHL, TRC8, and JAB1 appear to be linked both physically and functionally and all three may participate in the development of kidney cancer.

3T3 Cells↗

Pathway analysis of kidney cancer using proteomics and metabolic profiling.

BACKGROUND: Renal cell carcinoma (RCC) is the sixth leading cause of cancer death and is responsible for 11,000 deaths per year in the US. Approximately one-third of patients present with disease which is already metastatic and for which there is currently no adequate treatment, and no biofluid screening tests exist for RCC. In this study, we have undertaken a comprehensive proteomic analysis and subsequently a pathway and network approach to identify biological processes involved in clear cell RCC (ccRCC). We have used these data to investigate urinary markers of RCC which could be applied to high-risk patients, or to those being followed for recurrence, for early diagnosis and treatment, thereby substantially reducing mortality of this disease. RESULTS: Using 2-dimensional electrophoresis and mass spectrometric analysis, we identified 31 proteins which were differentially expressed with a high degree of significance in ccRCC as compared to adjacent non-malignant tissue, and we confirmed some of these by immunoblotting, immunohistochemistry, and comparison to published transcriptomic data. When evaluated by several pathway and biological process analysis programs, these proteins are demonstrated to be involved with a high degree of confidence (p values < 2.0 E-05) in glycolysis, propanoate metabolism, pyruvate metabolism, urea cycle and arginine/proline metabolism, as well as in the non-metabolic p53 and FAS pathways. In a pilot study using random urine samples from both ccRCC and control patients, we performed metabolic profiling and found that only sorbitol, a component of an alternative glycolysis pathway, is significantly elevated at 5.4-fold in RCC patients as compared to controls. CONCLUSION: Extensive pathway and network analysis allowed for the discovery of highly significant pathways from a set of clear cell RCC samples. Knowledge of activation of these processes will lead to novel assays identifying their proteomic and/or metabolomic signatures in biofluids of patient at high risk for this disease; we provide pilot data for such a urinary bioassay. Furthermore, we demonstrate how the knowledge of networks, processes, and pathways altered in kidney cancer may be used to influence the choice of optimal therapy.

Adult↗

Treatment of kidney cancer with autologous tumor cell vaccines of short-term cell lines derived from renal cell carcinoma.

BACKGROUND: We established short-term cultures of autologous tumors from patients with renal carcinoma for use as active specific immunotherapy (i.e., autologous vaccine). METHODS: Between 9/91 and 9/99 the cell biology laboratory of the Hoag Cancer Center received 69 kidney tumor samples that had been surgically excised, including 43 primary tumors and 26 metastatic lesions. Efforts were made to establish short-term tumor cell cultures to use as autologous tumor cell vaccines. Prior to treatment, patients underwent a baseline skin test for delayed tumor hypersensitivity (DTH) and then received s.c. injections of 10 million irradiated tumor cells that were given with various adjuvants weekly x3 and then monthly x5. RESULTS: Cell lines were established for 55/69 patients (80%) including 36/43 (84%) from primary tumors and 19/26 (73%) from distant metastases. Vaccines were prepared for 41 patients; 27 were treated. At the time of this analysis, follow up data was available for 26 patients with a median follow up > 5 years. Treatment was well-tolerated. Of 10 patients who had no evident disease at the time of treatment, nine were alive 1-8 years later; 5/8 had conversion of their DTH test from negative to positive. For 16 patients with measurable metastatic disease at the time of treatment, there were no objective tumor responses; their median survival was 5.0 months. Among these 16 patients, only 1/8 DTH tests converted, but three had a positive baseline DTH test; one was previously treated with interleukin-2 and tumor infiltrating lymphocytes and two others were previously treated with autolymphocyte therapy. CONCLUSIONS: Vaccine therapy with short-term cultures of autologous tumor cells is feasible, well-tolerated and associated with conversion of DTH and long-term survival in patients who are free of disease at the time treatment is initiated. However, significant anti-tumor responses were not seen in patients with measurable disease at the time vaccine treatment was initiated.

Adult↗

[The results of the organ-preserving surgical treatment of patients with kidney cancer].

42 patients underwent conservative surgery for renal cancer. Conservative surgery was applied in 6 patients with only kidney, in 17--with unilateral cancer and contralateral kidney damaged by urological disease, in 17--with simultaneous tumorous process and in 8 patients with unilateral renal cancer and sound contralateral organ. Terms of postoperative follow-up ranged from 9 to 121 months, 14 patients have died for this period, exacerbation of cancer or metastasis being the cause of death in 9 of them. 5-year survival rate made up 64.4% although with regard to deaths related to cancer it equaled 81%. In 5 patients operated kidneys demonstrated complete functional failure due to nephrosclerosis. 5-year survival rate correlated inversely with advance of the process and was higher in unilateral lesions as compared to that of patients with bilateral tumors.

Adenocarcinoma↗

[Scope of lymphadenectomy in organ-sparing operations in kidney cancer patients].

Organ-saving operations (extended lymphadenectomy) were performed in 125 patients with renal carcinoma (RC) in the urological clinic of I. M. Sechenov Moscow Medical Academy between 1992 and 2002. In view of specific segment-by-segment lymph flow off the right and left kidneys, it is thought valid to remove paracaval and aortocaval lymph nodes in saving operations on the right kidney but in cancer of the left kidney it is recommended to remove paraaortic lymph nodes. Basing on the anatomical features, lympho-dissection should be made from the crus of the diaphragm to bifurcation of the aorta. Metastases to the regional lymph nodes were diagnosed in 12 (9.6%) patients. In 8 of 12 patients with pN+ lymph node metastases were microscopic. Frequency of lymphogenic metastases directly correlated with the size and stage of the tumor, cancer cells differentiation degree. Metastatic involvement of the regional lymph nodes in renal cancer is an unfavourable prognostic factor as 5-year survival for the overall group of patients was 71.7% while for patients with pN+ it was 41.7%.

Humans↗

Pseudouridine and uridine in normal kidney and kidney cancer tissues.

The tissue concentrations of a modified nucleoside, pseudouridine, and a normal nucleoside, uridine, were measured with high-performance liquid chromatography. Human kidneys were obtained from five patients with renal cell carcinoma and divided into a noncancerous part and a cancerous part. The pseudouridine concentration in the cancerous part of the kidneys ranged between less than 2-2.8 nmoles/g and in the noncancerous part 4.3-19.4 nmoles/g (mean 10,9 nmoles/g). The uridine concentration in the cancerous and noncancerous parts of the kidney ranged between 19.6-179.1 nmoles/g (mean 110.7 nmoles/g) and 117.5-235.6 nmoles/g (mean 191.5 nmoles/g), respectively. The pseudouridine concentration appeared to be approximately seven times higher in the noncancerous part as compared to the cancerous part of the kidney. In the case of uridine, the difference was less pronounced.

Carcinoma, Renal Cell↗

Renotropic growth factor found in cancer patient sera after removal of cancer-bearing kidney.

We have used two sets of primary human kidney culture systems for assaying human renotropic growth factor in day 5 postnephrectomized human sera. The first set of primary kidney cell cultures was prepared from one hydronephrotic kidney and used for assaying the renotropic growth stimulating activity of six kidney cancer patients sera simultaneously. The level of renotropic growth-stimulating activity varies from patient to patient. The postnephrectomized sera of three patients showed rather small (27 to 68%) increase over their prenephrectomized sera. The postnephrectomized sera of the remaining three patients showed a much greater (2.69- to 3.19-fold) increase over their prenephrectomized sera. Variation in the growth-stimulating activities produced in these uninephrectomized kidney cancer patients is most probably due to different levels of renal function loss by removal of the cancer-bearing kidney. Each cancer-bearing kidney has a different proportion of healthy kidney region to diseased (nonfunctional) region. The second set of primary kidney cell cultures was prepared from a healthy noncancerous region of a cancer-bearing kidney and used to assay for renotropic growth-stimulating activities in two different unilaterally nephrectomized kidney transplantation donor sera. Increased levels of growth-stimulating activity are quite similar and high (4.19- to 4.79-fold increase above their prenephrectomized sera). These high and similar assay values of the renotropic growth factor produced in two healthy humans suggest the sensitivity and reliability of the assay method with the use of the noncancerous cells from the cancer-bearing kidney.

Cells, Cultured↗

Kidney cancer.

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Humans↗