Prospective study on the relationship between clinical efficacy of secondary hormone therapy with flutamide and neuroendocrine differentiation in patients with relapsed prostate cancer after first line hormone therapy.

OBJECTIVE: The aim of this study was to prospectively verify the relationship between the clinical efficacies of secondary hormone therapy for castration-resistant prostate cancer (CRPC) following first line hormone therapy and neuroendocrine differentiation (NED). MATERIAL AND METHODS: Forty-six consecutive patients with CRPC following first line hormone therapy who were treated with flutamide as secondary hormone therapy were prospectively assessed with a median follow-up of 21 months. Serum chromogranin A (CgA), as a marker of NED, was measured using an immunoradiometric assay. RESULTS: Of the 46 patients, 22 (48%) responded to the secondary hormone therapy as a 50% or more reduction from baseline prostate-specific antigen (PSA) with a median response duration of 9.2 months. The PSA response group was correlated with significantly favorable cancer-specific survival (CSS) (92% vs 59% at 5 years, p = 0.0146) compared with the non-response group. Above-normal CgA levels at study entry were detected in 15 patients (33%), but no association with CSS was identified. Data on CgA kinetics were available in 35 patients. The CgA levels before and at 3 months during the treatment were similar. However, eight patients (23%) with an increase in CgA level of a quarter or more from baseline had a tendency for worse CSS (63% vs 84% at 5 years, p = 0.0507) compared with the remaining patients. CONCLUSION: Within limitations, in this study secondary hormone therapy with flutamide was effective for CRPC following first line hormone therapy. The above-normal CgA level in the first hormone resistance phase is mostly unrelated to prognosis. However, some patients with a remarkable increase in CgA in a short duration may have an unfavorable prognosis caused by NED as well.

Intravesical recurrence after surgical management of urothelial carcinoma of the upper urinary tract.

OBJECTIVES: To elucidate clinicopathological risk factors for intravesical recurrence (IVR) in patients undergoing nephroureterectomy for upper urinary tract urothelial carcinoma (UUT-UC). METHODS: We identified a study population of 151 consecutive patients without previous or concurrent bladder cancer who underwent nephroureterectomy for UUT-UC. IVR was assessed in relation to tumor location, size, and multifocality, operation modality and time, stage, grade, lymphovascular invasion, regional lymph node metastasis, preoperative urinary cytology, and perioperative chemotherapy. The median follow-up time was 24 months. RESULTS: Of 151 patients, 51 (34%) developed IVR after nephroureterectomy, and 50 (98%) of the patients presented with IVR within 2 years. Tumor multifocality and site (located in ureter) were determined as risk factors for IVR by univariate analysis. In a multivariate analysis, only tumor multifocality (relative risk: 4.024, p = 0.001) was an independent predictor of IVR. Ten-year cancer-specific survival rates for the patients with and without IVR were 68 and 52%, respectively (p = 0.06). CONCLUSIONS: Tumor multifocality is a significant risk factor in developing IVR after surgery for UUT-UC. These results indicate that despite most IVR occurring within 2 years of treatment, it is necessary to follow such patients more closely using cystoscopy. However, IVR is unlikely to indicate a poorer prognosis.

Metastasectomy for renal cell carcinoma as a strategy to obtain complete remission.

We report a case of 67-year-old Japanese woman with two types of metastasectomy for metachronous metastases of renal cell carcinoma (RCC). The initial nephrectomy for left RCC was performed in April 1977. The pathological diagnosis was clear cell carcinoma grade1-2, pT1b. In May 1996, computed tomography (CT) revealed a tumor in the upper pole of the remaining right kidney. The renal tumor was enucleated in June 1996. The histopathological diagnosis of the tumors was clear cell carcinoma. In December 1998, conventional B-mode ultrasound US detected solid tumors in the uncus, body, and tail of pancreas, and the patient underwent partial pancreatectomy, preserving the pancreatic head. Histologically, the tumor consisted of clear cell carcinoma. Eleven years following the second metastasectomy, patient was disease free without adjuvant therapy.

How do symptoms have an impact on the prognosis of renal cell carcinoma?

AIM: Symptomatic renal cell carcinoma (RCC) is well known to have a characteristic behavior. We therefore evaluated the impact of systemic symptoms on the prognosis of RCC. METHODS: Patard's criteria were used to classify symptoms before operation into three groups defined as: S1 (incidental tumor), S2 (localized symptoms) and S3 (systemic symptoms). Selected clinicopathological factors including gender, maximum tumor diameter, clinical stage, hemoglobin, C-reactive protein (CRP) and immunosuppressive acidic protein, nuclear grade and venous invasion were measured preoperatively in 252 patients. To determine impacts of them on the prognosis of RCC, we compared quantitative results using Cox multivariate analysis. RESULTS: The cancer-specific five-year survival rates were 93.1%, 71.0%, and 20.2% for S1 (144 patients), S2 (80 patients) and S3 (28 patients), respectively (P < 0.0001). By the univariate analysis, S2 and S3 were significant prognostic factors (risk ratio 4.5, P = 0.0003, risk ratio 19.15, P < 0.0001, respectively). By the multivariate analysis limited to preoperative clinical characteristics, S3 and CRP were independent factors (risk ratio 7.05, P = 0.0006, risk ratio 3.53, P = 0.0052, respectively). When pathological factors as well as preoperative clinical features were included on multivariate analysis, S3 and CRP remained to be independent predictive factors (risk ratio 6.01, P = 0.0031, risk ratio 2.64, P = 0.0040, respectively). Among pathological factors, only nuclear grade was a significant prognostic factor (risk ratio 2.92, P = 0.013). CONCLUSION: The presence of systemic symptoms is an independent prognostic factor along with nuclear grade and CRP.

Primary malignant melanoma of the female urethra.

A case of primary urethral malignant melanoma of a 69-year-old Japanese woman is presented. A hemorrhagic tumor measuring 1 cm in diameter was diagnosed by the stamp method. Clinically, the primary lesion was a T4 tumor infiltrating to the bladder neck, vagina, and vulva. Computed tomography did not detect any inguinal lymph node swelling or metastases to other sites. We selected radical extirpation, including cystectomy, ureterostomy, and bilateral inguinal and pelvic lymph node dissection. Although she subsequently underwent immunochemotherapy, consisting of dacarbazine, nimustine, vincristine, and beta-interferon, she died of the cancer 14 months postoperatively.

Significant relationship of matrix metalloproteinase 9 with nuclear grade and prognostic impact of tissue inhibitor of metalloproteinase 2 for incidental clear cell renal cell carcinoma.

OBJECTIVE: To examine the immunoreactivity of tumors for matrix metalloproteinases 2 and 9 (MMP-2, MMP-9), tissue inhibitors of metalloproteinases 1 and 2 (TIMP-1, TIMP-2), and membrane type MMP 1 (MT-MMP-1), to evaluate the optimum assessment of incidental renal cell carcinoma. METHODS: Tumor samples from 120 incidental clear cell renal cell carcinoma (ICRCC) patients without distant metastasis or invasion beyond Gerota's fascia were obtained by surgery. They were immunohistochemically stained for MMP-2, MMP-9, TIMP-1, TIMP-2, and MT-MMP-1. Immunoreactivity for these factors was analyzed by semiquantitative multivariate analysis for cancer-specific survival. RESULTS: The cancer-specific 5 and 10-year survival rates were 91.4% and 91.4%, respectively. Univariate analysis revealed that nuclear grade (P = 0.0064) and TIMP-2 (P = 0.034) were significant prognostic factors. Matrix metalloproteinase 9 has a significant relationship with high nuclear grade RCC (P = 0.017) and was found to be an independent prognosticator by Cox multiple regression analysis (P = 0.0028). CONCLUSIONS: Nuclear grade and TIMP-2 were significant prognostic factors of ICRCC. Multivariate analysis showed that a nuclear grade greater than 3 was associated with a 566% significant increase in the odds of cancer death. Strong expression of MMP-9 was associated with a 774% increase in the odds of high nuclear grade, with statistical significance. Although ICRCC is well known for having a favorable prognosis, patients with tumors having a high nuclear grade and strongly expressed MMP-9 and TIMP-2 should undergo strict postoperative follow-up.

Long-term outcome from a study on the prevention of postoperative recurrence in patients with renal cell carcinoma: could PBL be a predictor of postoperative recurrence in patients postoperatively treated with IFN-gamma?

This study examined the outcome of postoperative recurrence therapy on renal cell carcinoma (RCC) prevention involving treatment with single doses of interferon-gamma (IFN-gamma). From 1990-2000, 37 patients with no distant metastasis at the time they underwent a nephrectomy were enrolled in this investigation. Subcutaneous IFN-gamma was administered once a week. Total and differential white blood cells were counted before the pre-administration of IFN-gamma and then monthly thereafter for all patients. Blood lymphocyte subsets were analyzed phenotypically by direct immunofluorescence. Disease-free survival rates (DFSR) at 5 and 10 years were 81.7% and 75.9%, respectively. To clarify the effects of preoperative peripheral blood lymphocyte (PBL) and NK activity on DFSR, we categorized the patients into two groups according to the median number of PBL before the administration of IFN-gamma. Except for CD11b, PBL level had no effect on DFSR. Multiple logistic regression analysis showed that CD11b levels greater than 16.5% were associated with 25.35 odds ratio increase in the risk of postoperative recurrence. A multivariate analysis found that CD11b may be an independent factor for postoperative recurrence. In terms of preventing postoperative recurrence, our results showed that an elevated CD11b level may indicate patients who can benefit from further combination therapy.

Strong significant correlation between MMP-9 and systemic symptoms in patients with localized renal cell carcinoma.

OBJECTIVES: To identify a relationship between clinical symptoms and matrix metalloproteinase (MMP)-2 and MMP-9, tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2, and membrane type MMP-1. METHODS: Tumor samples from 232 patients with renal cell carcinoma with no distant metastasis were immunohistochemically stained for MMP-2 and MMP-9, TIMP-1 and TIMP-2, and membrane type MMP-1. The immunoreactivity of these factors was analyzed by semiquantitative multivariate analysis for correlation with clinical symptoms. RESULTS: Patard's criteria were used to classify symptoms at initial tumor clinical presentation, with three groups defined: S1, S2, and S3. The cancer-specific 5-year survival rate was 88.7%, 74.7%, and 67.6% for S1 (145 patients), S2 (69 patients), and S3 (18 patients), respectively (P = 0.0015). Multiple logistic regression analysis of preference was used to determine whether differences in the contribution of the symptoms were statistically significant. A maximal tumor diameter of 40 mm or greater and positive venous invasion were associated with a 262% and 281% increase in the odds of local symptoms, respectively. MMP-9 positive cases were associated with a 2979% increase in the odds of systemic symptoms with significance. CONCLUSIONS: This study found a strong significant correlation between the histopathologic expression of MMP-9 and the systemic symptoms of renal cell carcinoma. We propose the histopathologic measurement of MMP-9 as a useful tool for assessing the prognosis of patients with renal cell carcinoma with systemic symptoms.

Prostate-specific antigen failure within 2 years of radical prostatectomy predicts overall survival.

OBJECTIVE: This study attempts to determine whether prostate-specific antigen (PSA) failure following radical retropubic prostatectomy (RRP) affects patients' long-term overall survival. METHODS: This study examined 155 men diagnosed as clinical stages T1b-T3a who received RRP as primary therapy. To evaluate whether PSA failure following RRP affects overall survival, the patients were grouped into those who experienced PSA failure within 2 years and those who did not. Clinical failure-free survival, prostate cancer-specific survival and overall survival were used as endpoints. Comparisons of survival curves were performed using the log-rank test. Logistic regression analysis was performed to determine the variable most predictive of PSA failure within 2 years of surgery. RESULTS: At 10 years, the PSA failure-free survival rate, clinical failure-free survival rate, prostate cancer specific survival rate and overall survival rate of the 155 patients were 40.1%, 83.1%, 94.9% and 84.2%, respectively. The overall survival curve for patients with PSA failure within 2 years of surgery was significantly lower than for patients with no PSA failure within 2 years of surgery (P = 0.042). The multivariate logistic regression analysis demonstrated that PSA greater than 20 ng/mL and poor differentiation of the tumor were significant independent predictors of PSA failure within 2 years of surgery. CONCLUSION: These results imply that prospective studies should be conducted to detect patients at high risk for PSA recurrence in whom metastasis may occur early and to investigate postoperative treatments for these high-risk patients to improve overall survival.

Usefulness of contrast-enhanced ultrasound for the diagnosis of recurrent renal cell carcinoma in contralateral kidney.

We studied contrast-enhanced ultrasound (CEU) for recurrence of renal cell carcinoma (RCC) at the contralateral kidney during postoperative follow up of localized renal cell carcinoma. CEU successfully detected all recurring cases, despite the fact that 5/6 cases were observed using conventional ultrasound; the remaining one case was not detected using conventional ultrasound. CEU using Levovisto successfully revealed renal tumors as RCC. Lesions were diagnosed as cystic renal tumors by Bosniac classification, and pathological findings demonstrated RCC, in accordance with the prior tumor.

Immunosuppressive acidic protein detects high nuclear grade localized renal cell carcinoma.

OBJECTIVES: To identify a potentially useful preoperative predictor of high nuclear grade renal cell carcinoma (RCC). METHODS: Our investigation consisted of 181 patients with histologically confirmed clear cell RCC. The positive predictive value, sensitivity, and specificity for detecting nuclear grade RCC were calculated individually for the largest tumor diameter. Hemoglobin, alkaline phosphatase, C-reactive protein, ferritin, and immunosuppressive acidic protein (IAP) levels were also determined in all patients preoperatively. RESULTS: The distribution of patients by nuclear grade was 74 patients (41%) with grade 1, 75 (41%) with grade 2, and 32 (18%) with grades 3 and 4. With respect to sensitivity, tumor diameter detected 28 (87.5%) of 32 high nuclear grade RCC specimens, and hemoglobin, C-reactive protein, alkaline phosphatase, ferritin, and IAP detected 10 (31.2%), 25 (78.1%), 8 (25.0%), 16 (50%), and 27 (84.3%) of 32, respectively. Multiple logistic regression analysis showed that a higher than normal C-reactive protein and IAP was associated with a 252% and 405% increase in the odds of a high nuclear grade, respectively. In the Stage T1 cases, elevated IAP was also associated with a 989% increase in the odds of a high nuclear grade. CONCLUSIONS: IAP level may be a useful predictor for detecting high nuclear grade localized RCC preoperatively.

The impact of angiogenesis on the prognosis of advanced renal cell carcinomas.

We studied the relationship between angiogenic factors and clinical responses in advanced renal cell carcinomas (RCCs) and evaluated the angiogenic factors to clarify the potential impact of these factors on the cancer-specific survival. From January 1990 to December 2000, 148 patients underwent a nephrectomy for RCCs at our institution. Of the 32 patients who had distant metastasis, 17 met the histopathologic analysis requirements for an immuno-histochemical investigation. Fifteen of them were administered interferon-gamma and the remaining two patients were added to interferon-alpha and eight of seventeen patients also underwent radiation therapy. Both thymidine phosphorylase (TP) and Factor VIII immunostaining were performed. The overall survival rates at 1, 5 and 10 years were 82.4%, 30% and 30%, respectively. Three of these patients were diagnosed with lung metastasis and a complete response was seen in two, while a partial response was observed in one. In addition another patient who was diagnosed with bone metastasis also showed a partial response (group A). The remaining 13 patients showed progressive disease (group B). Group A had a higher TP-positive ratio (TP-PR) than that of group B. A multivariate analysis of the clinicopathologic data showed that a positive mean vascular area (PMVA) could be an independent factor regarding the potential impact of these factors on a long survival in advanced RCCS. PMVA was thus found to be an independent factor regarding the prognosis with advanced RCCs.

[Enucleation of renal cell carcinoma in von Hippel-Lindau disease using a microwave tissue coagulator].

The patient was a 37-year-old man who had undergone left nephrectomy under the diagnosis of left renal cell carcinoma associated with von Hippel-Lindau (VHL) disease 4 years ago. Computed tomography (CT) revealed 3 individual tumors 20 mm, 13 mm and 9 mm in maximum diameter in the right kidney. All three renal tumors were enucleated with a microwave tissue coagulator (MTC) without renal pedicle clamping. There were no major complications related to nephron-sparing surgery such as postoperative bleeding, persistent urine leakage and deterioration of renal function. Our findings suggest that renal tumors with VHL disease can be enucleated using a MTC safely and successfully without damaging renal function.