T CELLS ACTIVATED IN VITRO AS IMMUNOTHERAPY FOR RENAL CELL CARCINOMA: CHARACTERIZATION OF 2 EFFECTOR T-CELL POPULATIONS

PURPOSE: Effector T cell populations generated using 2 methods of in vitro activation are currently being tested in separate clinical trials as immunotherapy for patients with advanced cancer, including renal cell carcinoma. To determine the most appropriate method of activation for cancer immunotherapy in vitro antitumor activity of the 2 effector T-cell populations were compared. METHODS AND METHODS: The effector T-cell populations were generated concurrently by activation of peripheral blood mononuclear cells from patients with advanced renal cell carcinoma or other cancer using soluble anti-CD3 monoclonal antibody (3T cells) or anti-CD3 and anti-CD28 monoclonal antibodies immobilized on beads (3/28T cells). After 14-day culture the phenotype and functional activity of the cells were tested. RESULTS: Fold expansion of CD4(+) cells for 3T cultures was lower than for 3/28T cultures but expansion of CD8(+) cells was similar for both cultures. Expression of CD69 was higher on 3T cells. 3T and 3/28T cells exhibited similar ability to kill various human tumor cell lines. Although both effector T-cell populations produced Th1-type cytokines upon re-stimulation, 3T cells secreted a higher level of interferon-gamma and tumor necrosis factor-alpha compared with 3/28T cells. Intracellular cytokine analysis demonstrated that the percent of cells producing interferon-gamma was higher in CD4(+), CD8(+), CD25(+), CD69(+) and CD45RO(+) 3T cells compared with 3/28T cells. CONCLUSIONS: These data suggest that 3T cells may have increased efficacy as immunotherapy for patients with cancer due to higher levels of tumoricidal cytokine production than 3/28T cells.     

A POSTOPERATIVE PROGNOSTIC NOMOGRAM FOR RENAL CELL CARCINOMA

PURPOSE: Few published studies have combined prognostic factors to predict the likelihood of recurrence after surgery for renal cell carcinoma. We developed a nomogram for this purpose. MATERIALS AND METHODS: With Cox proportional hazards regression analysis, we modeled pathological data and disease followup for 601 patients with renal cell carcinoma who were treated with nephrectomy. Predictor variables were patient symptoms, including incidental, local or systemic, histology, including chromophobe, papillary or conventional, tumor size, and pathological stage. Treatment failure was recorded when there was either clinical evidence of disease recurrence or death from disease. Validation was performed with a statistical (bootstrapping) technique. RESULTS: Disease recurrence was noted in 66 of the 601 patients, and those in whom treatment was successful had a median and maximum followup of 40 and 123 months, respectively. The 5-year probability of freedom from failure for the patient cohort was 86% (95% confidence interval 82 to 89). With statistical validation, predictions by the nomogram appeared accurate and discriminating with an area under the receiver operating characteristic curve, that is a comparison of the predicted probability with the actual outcome of 0.74. CONCLUSIONS: A nomogram has been developed that can be used to predict the 5-year probability of treatment failure among patients with newly diagnosed renal cell carcinoma. The nomogram may be useful for patient counseling, clinical trial design and patient followup planning.     

RENAL CELL CARCINOMA IN CHILDREN: EXPERIENCE AT A SINGLE INSTITUTION IN JAPAN

PURPOSE: We analyzed the presentation, treatment and survival of 4 children with renal cell carcinoma. MATERIALS AND METHODS: We retrospectively reviewed the pathological and hospital records of 4 Japanese children diagnosed with renal cell carcinoma at our hospital from 1970 to 1998. RESULTS: In the 1 boy and 3 girls with an average age of 8 years 7 months at diagnosis the most common presenting complaints were gross hematuria in 75% and a palpable abdominal mass in 50%. Computerized tomography revealed characteristic calcification within the tumor in 3 of the 4 patients (75%). In the remaining case the lesion had high density areas with microcalcification, as confirmed by histopathological study. In 2 patients with regional lymph node metastasis calcification was also observed in the metastatic lesions. Disease was stages I to III in 1, 1 and 2 patients, respectively. All patients underwent transabdominal nephrectomy with regional lymphadenectomy. One patient with stage I disease had multiple metastases 15 months later and died of disease 55 months postoperatively. However, the remaining 3 patients received adjuvant interferon therapy and they are without evidence of recurrence a mean of 51.3 months postoperatively. CONCLUSIONS: Calcification within the tumor and/or metastatic lesions or high density areas in the tumor on screening computerized tomography are characteristic findings suggestive of pediatric renal cell carcinoma. Adjuvant therapy with interferon may provide some benefit in select pediatric patients. Further studies of a larger number of pediatric renal cell carcinoma cases may be necessary to establish the optimal diagnostic and therapeutic regimen.     

IMMUNOTHERAPY,INCLUDING GENE THERAPY,FOR METASTATIC MELANOMA

Current standard therapy for distant metastatic melanoma is ineffective and often compromises the quality of a patient's life. Immunotherapy is briefly reviewed in relation to its many forms: from local non-specific to the more recent specific vaccines, including those using specific melanoma peptides (e.g. from the proteins encoded by melanoma-associated gene (MAGE)) and those involving genetically transduced autologous melanoma cells using retroviral vectors in vitro. The mode of action of genetically transduced melanoma cells incorporating the granulocyte macrophage colony stimulating factor (GM-CSF) gene (GVAX) is presented as a paradigm for cytokine-mediated strategies. Trials of GVAX and other cytokine gene strategies are under way in Brisbane, Boston and Amsterdam, and some interim perspectives on the clinical outcomes and immunological mechanisms involved are sketched. Some of the compounding problems in immunotherapeutic strategies for cancer are identified, and possible adjunct manoeuvres for overcoming them are discussed.     

LAPAROSCOPIC RADICAL NEPHRECTOMY: CANCER CONTROL FOR RENAL CELL CARCINOMA

PURPOSE: We evaluated the clinical efficacy of laparoscopic versus open radical nephrectomy in patients with clinically localized renal cell carcinoma. MATERIALS AND METHODS: Between 1991 and 1999, 67 laparoscopic radical nephrectomies were performed for clinically localized, stages cT1/2 NXMX, pathologically confirmed renal cell carcinoma. During this period 54 patients who underwent open radical nephrectomy with pathologically confirmed stages pT1/2 NXMX disease were also identified. Medical and operative records were retrospectively reviewed and telephone followup was done to assess patient status. RESULTS: In the laparoscopic and open groups average tumor size was 5.1 (range 1 to 13) and 5.4 cm. (range 0.2 to 18), respectively, which was not statistically significant. No patient had laparoscopic port site, wound or renal fossa tumor recurrence in either group. All patients were followed at least 12 months. In the laparoscopic group 2 cancer specific deaths occurred at a mean followup of 35.6 months. In the open group there were 2 cancer specific deaths and 3 cases of disease progression at a mean followup of 44 months. Kaplan-Meier disease-free survival and actuarial survival analysis revealed no significant differences in the laparoscopic and open radical nephrectomy groups. Also, no differences were noted in the complication rate. CONCLUSIONS: Laparoscopic radical nephrectomy is an effective alternative for localized renal cell carcinoma when the principles of surgical oncology are maintained. Initial data show shorter patient hospitalization and effective cancer control with no significant difference in survival compared with open radical nephrectomy.     

RENAL CELL CARCINOMA IN BOTH MOIETIES OF CROSSED FUSED ECTOPIA

Crossed fused renal ectopia is an uncommon condition and cases of malignant tumours in such anomalies are exceedingly rare. The first case where simultaneous involvement of both moieties and perirenal fat by tumour occurred is reported here. A comparison of the appearances of radiological investigations with the anatomical specimen is presented, as is a literature review of this topic.     

PULMONARY NODULES IN PATIENTS WITH A HISTORY OF RADICAL NEPHRECTOMY FOR RENAL CELL CARCINOMA

Background:
Nine patients with a history of radical nephrectomy for renal cell carcinoma underwent surgical removal of newly detected pulmonary nodules at the Hiroshima University Hospital. Six patients had metastatic lung tumors two patients had bronchogenic primary carcinomas and one had a granulomatous infection.
Methods:
To determine if any characteristics can distinguish a new primary carcinoma from metastatic renal cell carcinoma, we reviewed the nine patients described above. The patients with pulmonary metastases and those with new primary lung cancers did not differ in age, sex, history of smoking, clinical stage and pathological findings of the renal primary site, on the location and size of the pulmonary nodules.
Results:
Only the interval between the nephrectomy and the appearance of the new pulmonary lesion may be a predictive factor. This interval was 48 and 51 months for the patients with new primary lung cancers but varied from 0 to 39 months for the patients with metastatic renal cell carcinoma. A solitary nodule had an equal chance of being metastatic or primary. Conclusions: These results indicate that a solitary nodule that is detected at a longer inferval after radical nephrectomy may be a new primary lung cancer. Once new pulmonary nodules are identified in a patient with a history of radical nephrectomy for renal cell carcinoma, surgical excision is required for a final diagnosis before initiating therapy for metastases.     

PROGNOSTIC SIGNIFICANCE OF THE 1997 TNM CLASSIFICATION OF RENAL CELL CARCINOMA

PURPOSE: The TNM classification of renal cell carcinoma was recently revised in 1997. The most significant change from the previous edition (1987) is an increase in the size cutoff between T1 and T2 tumors from 2.5 to 7.0 cm. We compared the 1997 and 1987 TNM staging classifications in predicting patient outcome. MATERIALS AND METHODS: A total of 381 patients who underwent nephrectomy for renal cell carcinoma at our hospital between 1968 and 1994 were identified. Mean patient age was 61 years (range 15 to 89) and mean followup was 64.5 months. All pathological slides were re-reviewed in uniform manner and staged using the 1987 and 1997 TNM classifications. The impact of numerous pathological factors and each staging classification on disease specific survival and freedom from progression were statistically analyzed, and Kaplan-Meier survival curves were generated and compared. RESULTS: The 1997 TNM classification resulted in a redistribution of 170 cases previously classified as stage II (T2N0M0) to stage I (T1N0M0) under the new system. Both classifications were strong predictors of survival on univariate and multivariate analyses, and essentially equivalent in the ability to predict patient outcome. However, comparison of survival curves on Kaplan-Meier life tables revealed better separation of survival for stage I (T1N0M0) and stage II (T2N0M0) cases under the 1997 TNM classification, with survival for TNM stage I essentially remaining unchanged. CONCLUSIONS: The 1997 TNM classification of renal cell carcinoma appears to be equivalent to the previous classification in predicting outcome but permits better stratification of cases according to survival and, therefore, may have improved clinical usefulness.     

THE MANAGEMENT OF RENAL CELL CARCINOMA WITH INFERIOR VENA-CAVAL INVOLVEMENT

Seven patients with renal cell carcinoma involving the inferior vena cava underwent surgical resection between 1975 and 1991. Pre-operative staging defined five patients with stage T3bNoMo disease, one patient with stage T3bN₁Mo, and one patient with stage T3bNoM 1 disease.¹ At operation one patient had tumour thrombus filling the right atrium. Two patients had tumour thrombus within the intrahepatic vena cava and four infrahepatic tumour thrombus. The mean follow-up is 34.4 months (median 40 months). Four patients have been followed for over 4 years. Three of these patients are survivors, two have remained disease-free since their initial surgery. The other patient had a liver resection at 49 months for a solitary metastases; he is currently disease free. One patient died at 38 months from a gastrointesinal haemorrhage. Three patients are 12 months or less postoperation. Operative mortality was zero. The mean postoperative hospital stay was 14.7 days. Data suggests that 3–10% of renal cell carcinomas will involve the inferior vena cava.² The small number of patients in this series suggests that many patients with renal cell carcinoma involving the inferior vena cava are not referred for surgical assessment. These patients are potential surgical candidates. Their survival after surgical resection, excluding the group with extension of tumour thrombus into the hepatic cava or above, is not reduced when compared with other patients with renal carcinoma.^3,4     

OBSERVATIONS ON THE GROWTH RATE OF RENAL CELL CARCINOMA

We retrospectively reviewed the records of 18 patients to investigate the growth rate of renal cell carcinoma (RCC). Growth rates were calculated from two or more gross measurements of neoplastic foci in the kidney (6 cases) and lung (12 cases). RCCs in primary sites grew slowly and the tumor volume doubling time (DT) raged from 372 to 579 days (468 ± 84.6). Pulmonary metastases present in 12 cases grew rapidly, with a DT ranging from 20 to 154 days (89.4 ± 43.0). Tumors in both the kidney and lung were composed of cancer cells with equal proliferative activity, as determined by immunohisto chemical analysis of argyrophilic nucleolar organizer regions and proliferating cell nuclear antigen activity. Thus, our results suggest that, in addition to the proliferative activity of cancer cells, the microenvironment of the specific region is an important determinant of the growth rate of cancer cells.     

SPONTANEOUS REGRESSION OF OSSEOUS METASTASIS IN RENAL CELL CARCINOMA

A case of spontaneous regression of an osseous metastasis in renal cell carcinoma is presented. The extreme rarity of this phenomenon, especially in this location, is pointed out, as only three other cases have been published so far.     

SURGICAL TREATMENT OF RENAL CELL CARCINOMA EXTENDING INTO THE VENA CAVA

Background:
Renal cell carcinoma has a tendency to invade the vasculature and the prognostic implications of intravena caval tumor thrombectomy remains controversial. We reviewed our clinical experience with RCC patients who underwent tumor thrombectomy and radical nephrectomy.
Methods:
Surgery was carried out in 13 renal cell carcinoma patients with inferior vena cava extension over the past seven years. Diagnosis of intracaval tumor extension and thrombus formation was made by imaging techniques including ultrasonography and computed tomography. Cavography and magnetic resonance imaging were also performed in some cases.
Results:
The level of the tumor thrombus was infrahepatic (V2a) in nine cases and retrohepatic (V2b) in four. Ultrasound and magnetic resonance imaging were extremely useful in defining the extent of the thrombus in addition to detecting its presence. The caval thrombi were reached simply by ligation and division of the short hepatic veins in the V2a cases, but liver mobilization was required in the V2b cases. There were no operative deaths. Two patients who had metastases on surgery died of the disease eight and 13 months after surgery. Four of the 11 patients in whom no evidence of metastasis was found on surgery also died of the disease between nine and 16 months postoperatively. The remaining seven patients are still alive at periods of 6–74 months after surgery, with or without residual tumors. The nature of the intracaval tumor thrombi seems to affect the overall prognosis for survival. Elevated levels of acute phase reactants and immunosuppressive acidic protein were associated with short survival times.
Conclusions:
Our experience suggests that aggressive surgery should be considered in selected patients with non-metastatic renal cell carcinoma extending into the vena cava.     

PROGNOSTIC SIGNIFICANCE OF MICROVESSEL COUNT IN LOW STAGE RENAL CELL CARCINOMA

Background:
It has been postulated that tumors beyond a certain size are dependent on angiogenesis, which might also be related to distant metastasis. We therefore assessed the prognostic significance of tumor microvasculature in renal cell carcinoma.
Methods:
Tumor specimens from 84 patients with primary renal cell carcinoma were examined by immunohistochemical staining for factor VIII. Individual microvessels were counted in a 200 × field overlying the area of highest neovacularization.
Results:
The mean number of microvessels in patients with metastases was significantly higher than that in patients who were disease-free for more than three years ( P = 0.004). The survival of patients with less than 30 microvessels per 200 × field was significantly higher than that of patients with more than 30 microvessels per 200 × field ( P = 0.007). Multivariate analyses revealed that these microvessel counts were the only significant predictor of prognosis in 45 patients with T1-2 and MO tumors ( P = 0.028).
Conclusions:
Assessment of tumor microvasculature is therefore probably one of the most important prognostic predictors in renal cell carcinoma.     

ANALYSIS OF nm23 GENE EXPRESSIONS IN HUMAN BLADDER AND RENAL CANCERS

We measured nm23-H1 and nm23-H2 mRNA levels in tissues from 22 human bladder cancers and 16 renal cell carcinomas, and in 7 bladder cancer and 6 renal cancer cell lines by Northern blot and slot blot hybridization analyses. Differences in mRNA levels were evaluated in primary tumor tissues and in paired normal tissues and cell lines. Moreover, nrh23 gene expression in primary tumor tissues was compared with clinicopathological features. High nm23-H1 and nm23-H2 expression was observed in cancerous areas of human bladder tissue ( nm23-H1 : p = 0.001, nm23-H2 : p = 0.001) and bladder cancer cell lines ( nm23-H1: p = 0.001, nm23-H2: p< 0.001) compared with that in normal bladder mucosa. However, mRNA levels of both nm23 genes were not associated with histological grade, pathological stage, tumor metastasis or prognosis. On the other hand, in human renal cell carcinomas, levels of both nm23 mRNAs in tumor tissues were similar to those in paired normal kidneys, but elevated in cultured cell lines ( nm23-H1: p= 0.002, nm23-H2: p = 0.014). Moreover, there was a tendency towards high nm23 gene expression in grade 2 tumors compared with grade 1 (grade 1 vs grade 2, nm23-H1: p = 0.107, nm23-H2: p = 0.008; no grade 3 tumors in this study) and in high stage renal cancers (stage II vs stage III, nm23-H1: p = 0.023, nm23-H2: p = 0.005). From these results, we suggest that reduced nm23 mRNA levels are not associated with metastasis of either bladder or renal cancers and there may be some tissue-specific differences in the expression patterns of nm23-H1 and nm23-H2 in human cancers.     

LACK OF RETROPERITONEAL LYMPHADENOPATHY PREDICTS SURVIVAL OF PATIENTS WITH METASTATIC RENAL CELL CARCINOMA

PURPOSE: Patients with metastatic renal cell carcinoma have a reported 5-year survival of 0% to 20%. The ability to predict which patients would benefit from nephrectomy and interleukin-2 (IL-2) therapy before any treatment is initiated would be useful for maximizing the advantage of therapy and improving the quality of life. MATERIALS AND METHODS: A retrospective analysis of the x-rays and charts of patients treated at the National Institutes of Health Surgery Branch between 1985 and 1996, who presented with metastatic renal cancer beyond the locoregional area and the primary tumor in place, was performed. Preoperative computerized tomography or magnetic resonance imaging, or radiological reports if no scans were available, were used to obtain an estimate of the volume of retroperitoneal lymphadenopathy. Operative notes were used to evaluate whether all lymphadenopathy was resected or disease left in situ, or if any extrarenal resection, including venacavotomy, was performed. Mean survival rate was calculated from the time of nephrectomy to the time of death or last clinical followup. If patients received IL-2 therapy, the response to treatment was recorded. Mean survival and response rate for IL-2 were compared among patients in 3 separate analyses. Patients without preoperatively detected lymphadenopathy were compared with those with at least 1 cm.3 retroperitoneal lymphadenopathy. Also, the patients who had detectable lymphadenopathy were divided into subgroups consisting of all resected, incompletely resected, unresectable and unknown if all disease was resected. Each subgroup was compared with patients without detectable preoperative lymphadenopathy. Patients with less than were compared to those with greater than 50 cm.3 retroperitoneal lymphadenopathy. Patients undergoing extrarenal resection at nephrectomy (complex surgery) due to direct invasion of the tumor into another intra-abdominal organ were compared with those undergoing radical nephrectomy alone, regardless of lymph node status. Statistical analysis was done with the Mantel-Cox test for comparison of survival on Kaplan-Meier curves and with Fisher's exact test for response rates for IL-2. RESULTS: A total of 154 patients with metastatic renal cell carcinoma underwent cytoreductive nephrectomy as preparation for IL-2 based regimens. There were 82 patients with metastatic renal cell carcinoma and no preoperative retroperitoneal lymphadenopathy who survived longer (median 14.7 months) than the 72 with lymphadenopathy (median 8.5, p = 0.0004). Patients with incompletely resected, unresectable or an unknown volume resected had decreased survival compared to those with no retroperitoneal lymphadenopathy. A multivariate analysis of survival was performed evaluating the known prognostic indicators, performance status and tumor burden, as represented by the number of organs involved with metastases, and the new prognostic factor, lymphadenopathy. Lymphadenopathy was more closely associated with survival than performance status, and appeared to be a new prognostic variable. Patients with and without retroperitoneal lymphadenopathy at initial presentation had similar rates for treatment with IL-2 (54% for both groups). Of the 82 patients with no lymphadenopathy 11 (13%) had long-term survival greater than 5 years. Of the 6 complete responses to IL-2, 5 occurred in this group. Only 1 other patient with incompletely resected retroperitoneal lymphadenopathy survived longer than 5 years. No significant difference in survival was seen between patients who did or did not undergo complex surgery. CONCLUSIONS: Patients who presented with metastatic renal cancer and retroperitoneal lymphadenopathy had a shorter survival than those with no detectable retroperitoneal lymphadenopathy. It is warranted to continue to perform complex extrarenal resection during nephrectomy since no significant difference in the response rate for IL-2 or mean survival compared with those of patients undergoing nephrectomy alone is currently detectable.     

THE DIAGNOSTIC VALUE OF BONE SCAN IN PATIENTS WITH RENAL CELL CARCINOMA

PURPOSE: Bone scan is performed as part of the evaluation of bone metastasis. We assessed the diagnostic value of bone scan in patients with renal cell carcinoma. MATERIALS AND METHODS: Bone scan was performed at presentation in 205 patients with confirmed renal cell carcinoma. Abnormal hot areas were further evaluated by x-ray, computerized tomography or surgery. RESULTS: Of the 56 patients (27%) with an abnormal bone scan 32 (57%) had osseous metastatic lesions. Overall bone metastasis was present in 34 of the 205 patients (17%). Bone scan had 94% sensitivity and 86% specificity. Of the 124 patients with clinically localized, stages T1-2N0M0 disease exclusive of bone metastasis 6 (5%) had bone metastasis only, whereas 28 of 81 (35%) with locally advanced or metastatic disease had bone metastasis, including 12 (35%) who complained of bone pain and 19 (56%) who presented with other symptoms due to local tumor growth or metastasis at other sites. Three patients (9%) were asymptomatic. There was osseous metastasis without other metastasis, enlarged regional lymph nodes or bone pain in 7 patients, including 1 with stage T1b (2% of all with that stage), 2 with stage T2 (5%), 1 with stage T3a (4%), 1 with stage T3b (6%), 1 with stage T3c (14%) and 1 with stage T4 (6%) disease. CONCLUSIONS: Bone scan may be omitted in patients with stages T1-3aN0M0 tumors and no bone pain because of the low proportion of missed cases with bone metastasis.