Outcome of maintenance systemic chemotherapy with drug-free interval for metastatic urothelial carcinoma.

OBJECTIVE: Aiming to achieve long-term disease control, maintenance systemic chemotherapy (MSC) with a 1-3-month drug-free interval is continued in selected patients. We report our experience of MSC for metastatic urothelial carcinoma (UC). METHODS: Of 228 metastatic UC patients treated with systemic chemotherapy, 40 (17.5%, 40/228) had continuously undergone MSC. Data on the regimen, cycle number, and reason for the discontinuation of MSC were also collected. We analyzed OS from the initiation of MSC until death or the last follow-up, using the log-rank test to assess the significance of differences. RESULTS: The median number of cycles of chemotherapy was 6, and the responses were CR in 6, PR in 20, SD in 13, and PD in 1 before MSC. Gemcitabine plus CDDP or carboplatin was mainly performed as MSC (70%, 28/40). MSC was repeated quarterly in 30 (75%, 30/40), every two months in 8 (20%, 8/40), and with other intervals in 2 (5%, 2/40). Overall, a median of 3.5 cycles (range: 1-29) of MSC was performed. The reason for the discontinuation of MSC was PD in 24 (60%, 24/40), favorable disease control in 9 (22.5%, 9/40), and myelosuppression in 3 (7.5%, 3/40), and for other reasons in 2 (5%, 2/40). MSC was ongoing in 2 (5%, 2/40). The median OS was 27 months from the initiation of MSC. PS0 (P = 0.0169), the absence of lung metastasis (P = 0.0387), and resection of the primary site (P = 0.0495) were associated with long-term survival after MSC. CONCLUSIONS: In selected patients, long-term systemic chemotherapy could be performed with a drug-free interval. Our maintenance strategy with cytotoxic drugs may become one of the treatment options for long-term disease control.

Role of lymph node dissection in the treatment of urothelial carcinoma of the upper urinary tract: multi-institutional relapse analysis and immunohistochemical re-evaluation of negative lymph nodes.

AIM: To determine the role of lymph node dissection (LND) in the treatment of urothelial carcinoma (UC) of the upper urinary tract (UUT). PATIENTS AND METHODS: [Study-1] A retrospective multi-institutional study evaluated 293 patients undergoing predominantly nephroureterectomy for UC of the UUT. Of 293 patients, 267 patients had pure UC and 26 demonstrated other histological components. Regarding the pathological node status, 130 patients had pN0 disease, 141 patients had pNx disease and 22 patients had pN+ disease. The sites of initial recurrence and time to first recurrence were reviewed. The sites of recurrence were classified as locoregional or distant recurrence. The relationship between node status and future recurrence was analyzed. [Study-2] Fifty-one patients treated by nephroureterectomy at Hokkaido University Hospital were included. All had LND and all LNs were negative on hematoxylin and eosin staining. We re-evaluated the presence of micrometastasis in LND specimens by anti-cytokeratin immunohistochemistory. RESULTS: [Study-1] Of 293 patients, 76 developed disease relapse. Regional lymph node recurrence was the most common site (34 patients). On multivariate analyses that adjusted for the effect of tumor stage and tumor grade, pNx (skipping LND) was an adverse factor not only for locoregional recurrence, but also for distant relapse. [Study-2] Immunohistochemistry identified micrometastases in 7 (14%) of 51 patients. Regarding survival, 5 of these 7 patients with micrometastases were alive at last follow-up. CONCLUSIONS: On relapse analysis, skipping LND was an adverse factor not only for locoregional recurrence, but also for distant relapse. Immunohistochemistry detected micrometastases in about 14% of patients previously diagnosed as pN0. These findings further support a potential therapeutic benefit of LND by eliminating micrometastases.

Docetaxel plus prednisolone for the treatment of metastatic hormone-refractory prostate cancer: a multicenter Phase II trial in Japan.

BACKGROUND: Docetaxel-based chemotherapy has been shown to be effective and well tolerated by Western patients with metastatic hormone-refractory prostate cancer (HRPC). This study was undertaken to assess the feasibility of docetaxel in combination with prednisolone in Japanese patients with HRPC. METHODS: Patients aged 50-74 years with measurable metastatic HRPC were included in this non-comparative Phase II study. Treatment consisted of docetaxel 70 mg/m(2) once every 3 weeks plus prednisolone 5 mg twice daily, for a maximum of 10 cycles. The primary endpoint was overall tumor response rate, assessed by Response Evaluation Criteria in Solid Tumors; secondary endpoints included prostate-specific antigen (PSA) response and toxicity. RESULTS: A total of 43 patients were evaluable for efficacy and toxicity. The response rate was 44.2% (90% CI, 31.2-57.8%), with partial responses in 19/43 patients. The median duration of response was 19.3 weeks. PSA responses were recorded in 44.4% of patients (95% CI, 27.9-61.9%). The most common non-hematological adverse events (of any grade) possibly related to treatment were alopecia (88.4%), anorexia (65.1%) and fatigue (53.5%). Grade 3/4 leukopenia and neutropenia occurred in 81.4 and 93.0% of patients, respectively; however, the grade 3/4 rates of febrile neutropenia (16.3%) and infection without fever (14.0%) were lower. CONCLUSION: The combination of docetaxel and prednisolone was feasible and active in Japanese patients with HRPC, with a manageable adverse-event profile similar to that observed in Western patients.

Clinical and endocrinological features of adrenocorticotropic hormone- independent bilateral macronodular adrenocortical hyperplasia.

PURPOSE: We report clinical findings in 5 patients with adrenocorticotropic hormone independent bilateral macronodular adrenocortical hyperplasia. MATERIALS AND METHODS: In 4 males and 1 female 32 to 61 years old (median age 50) we evaluated clinical symptoms, endocrinological and radiological characteristics, treatment modality and postoperative clinical course. RESULTS: All cases presented with some features of Cushing's syndrome. Endocrinological examination revealed autonomous adrenal cortisol production with suppressed adrenocorticotropic hormone and a loss in the diurnal circadian rhythm of plasma cortisol. Abdominal computerized tomography showed bilateral enlargement of the adrenal glands with multiple nodules. 131Iodine labeled adosterol scintigraphy demonstrated remarkable bilateral uptake by the adrenal glands. The pituitary gland appeared normal on magnetic resonance imaging. Open unilateral complete adrenalectomy and contralateral partial adrenalectomy were performed in patient 1, open bilateral complete adrenalectomy was done in patients 2 and 3, and 2 and 1-stage laparoscopic bilateral complete adrenalectomy was performed in patients 4 and 5. Single removed adrenal glands weighed 32 to 108 gm. (median 60). The histological diagnosis was macronodular adrenocortical hyperplasia in all cases. Postoperative followup was 3 to 90 months. Clinical symptoms of Cushing's syndrome disappeared or improved after surgery in all cases. CONCLUSIONS: Although adrenocorticotropic hormone independent bilateral macronodular adrenocortical hyperplasia is a rare form of Cushing's syndrome, physicians are advised to consider it when diagnosing and treating cases of Cushing's syndrome with enlarged bilateral adrenal glands. Bilateral complete adrenalectomy is currently recommended as the treatment of choice.

Laparsocopic ureteroureterostomy for retrocaval ureter.

Two cases of retrocaval ureter are reported that were successfully treated by a laparoscopic approach. Case 1 was a 20-year-old woman who presented with symptoms of a right ureter stone. Case 2 was a 23-year-old woman who had suffered from recurrent right flank pain with gross hematuria. A transperitoneal approach was used for case 1, and a retroperitoneal approach was used in case 2. Both were successfully treated with laparoscopic ureteroureterostomy using an intracorporeal suture technique. Laparoscopic surgery should be the first choice for retrocaval ureter not only because of the minimal invasiveness but also because of the cosmetic advantage compared to conventional open surgery. Further technical and instrumental advances are essential for intracorporeal suturing.

Impact of nephron-sparing surgery on quality of life in patients with localized renal cell carcinoma.

OBJECTIVES: The aim of the study is to evaluate the impact of nephron-sparing surgery on postoperative quality of life (QOL) in patients with localized renal cell carcinoma, compared with radical nephrectomy. METHODS: From 1986 to 1996, a total of 66 patients with localized small renal cell carcinoma <4 cm in diameter and a functioning contralateral renal unit underwent radical nephrectomy (n = 51) or nephron-sparing surgery (n = 15). Of these, 50 patients evaluated various dimensions of QOL using standardized self-rating questionnaires, EORTC QLQ-C30. RESULTS: There is no significant difference in 5-year overall survival between the nephron-sparing surgery group and the radical nephrectomy group. With regard to postoperative QOL, patients who underwent nephron-sparing surgery showed a significantly higher score on physical function than patients treated with radical nephrectomy (p<0.05). Nephron-sparing surgery was additionally superior to radical nephrectomy in terms of fatigue, sleep disturbance, pain and constipation. CONCLUSION: Selected patients with localized, small, unilateral renal cell carcinoma and a normal contralateral kidney will benefit from nephron-sparing surgery.

Use of an implanted marker and real-time tracking of the marker for the positioning of prostate and bladder cancers.

PURPOSE: A real-time tracking radiotherapy was investigated to assess its usefulness in precise localization and verification of prostate and bladder cancers. METHODS AND MATERIALS: The real-time tracking radiation therapy (RTRT) system consists of implantation of a 2.0-mm gold marker into a clinical target volume (CTV), three-dimensional radiation treatment planning (3DRTP) system, and the use of two sets of diagnostic x-ray television systems in the linear accelerator room, image processing units, and an image display unit. The position of the patient can be corrected by adjusting the actual marker position to the planned marker position, which has been transferred from the 3DRTP and superimposed on the fluoroscopic image on the display unit of the RTRT system. The position of the markers can be visualized during irradiation and after treatment delivery to verify the accuracy of the localization. Ten patients with prostate cancer and 5 patients with bladder cancer were examined using this system for the treatment setup on 91 occasions. RESULTS: After manual setup using skin markers, the median of absolute value of discrepancies between the actual position of the marker and the planned position of the marker for prostate cancer was 3.4 (0.1-8.9) mm, 4.1 (0.2-18.1) mm, and 2.3 (0.0-10.6) mm for the lateral, anteroposterior, and craniocaudal directions, respectively. The 3D median distance between the actual and planned positions of the marker was 6.9 (1.1-18.2) mm for prostate cancer and 6.9 (1.7-18.6) mm for bladder cancer. After relocation using RTRT, the 3D distance between the actual and planned position of the marker was 0.9 +/- 0.9 mm. Median 3D distances between actual positions after treatment delivery and planned positions were 1.6 (0.0-6.3) mm and 2.0 (0.5-8.0) mm during daily radiotherapy for the marker in patients with prostate cancer and bladder cancer, respectively. CONCLUSION: We believe the new positioning system can reduce uncertainty due to setup error and internal organ motion, although further improvement is needed for the system to account for the rotational and elastic changes of the affected tissues.

The relationship between technical parameters of external beam radiation therapy and complications for localized prostate cancer.

BACKGROUND: This study was performed to review retrospectively the clinical course of chronic rectal bleeding as a complication of external beam radiation therapy for localized prostate cancer and to analyze the relationship between technical parameters of radiation therapy and the complications. METHODS: Seventy-one patients with stages A2, B and C were treated with local-field radiotherapy (total dose 52.5-66 Gy, daily dose 2.0-3.28 Gy, field area 30-81 cm2, number of fields 3-15 ports, planning simulations X-ray or CT-based) between 1989 and 1998 at three institutions. The protocols were consistent during this same period at these institutions. RESULTS: Multivariate analysis revealed pretreatment PSA and Gleason sum to be statistically significant predictors of 5 year prostatic specific antigen (PSA) relapse-free rates in a median follow-up period of 42 months (range 12-119 months). The significant risk factors for higher grading of acute morbidity were a biological equivalent dose, alpha/beta = 10(BED10) > or =65 Gy, dose per fraction > or =3.0 Gy, field area > or =42 cm2, fewer ports and X-ray planning simulation. However, no parameter was associated with higher grading of late morbidity. Eleven patients (15.4%) experienced a late GI complication: grade 1 (4.2%), grade 2 (9.8%), grade 3 (1.4%). The median time to occurrence of rectal bleeding was 12 months after radiotherapy and the mean duration of morbidity was 11 months. CONCLUSIONS: Higher total dose and dose per fraction, larger field area, fewer ports and X-ray simulation increased the grades of acute morbidity. A majority of chronic rectal bleedings were transient and responded to conservative treatment.

An improved intravesical model using human bladder cancer cell lines to optimize gene and other therapies.

Orthotopic implantation of human bladder cancer cells into immunodeficient mice is an important tool for studying the biology and effects of therapy. Nevertheless, the incidence of tumor implantation and growth by transurethral instillation of the human bladder cancer cells into murine bladders has been low or not reproducible. However, using a modified intravesical technique and the human bladder cancer cell lines, KU-7 and UM-UC-2, we have been able to obtain a high and reproducible incidence of superficial bladder tumors. Furthermore, intravesical administration of the LacZ adenovirus vector resulted in significant beta-galactosidase expression in these bladder tumors as well as the normal urothelium, which was associated with the removal of the glycosoaminoglycan layer. Because this modified technique produces a high incidence of superficial human tumor growth and allows the efficacy of gene transfer to be evaluated, it should be a useful model for the study of intravesical gene therapy for human bladder cancer.

Reduction of integrin beta4 and enhanced migration on laminin in association with intraepithelial spreading of urinary bladder carcinomas.

PURPOSE: The aim of the present study was to investigate the biological and molecular basis of intraepithelial spreading (IES) of carcinomas in situ (CIS) of the urinary bladder, which were considered to be precursors of nodular invasive carcinomas. MATERIALS AND METHODS: The propensity for IES of human transitional carcinoma cells was examined by inoculation into murine renal pelvis and urinary bladder, and the biological character of the cells with a high propensity for IES was explored in vitro. RESULTS: Three of 6 cell lines exhibited a high propensity for IES. When cultured on laminin, these IES cells scattered, whereas 3 non-IES cells and 2 immortalized transitional epithelial cells did not. IES cells showed strong adhesiveness, haptotaxis and enhanced migration on laminin compared with both non-IES and immortalized transitional epithelial cells. In IES cells, expression of the integrin beta4 subunit was markedly reduced and the integrin alpha6beta1 complex was predominant compared with the integrin alpha6beta4 complex. Transfection of IES cells with integrin beta4 subunit cDNA inhibited their ability to migrate on laminin and their propensity for IES. In addition, expression of the integrin beta4 subunit was reduced in surgically resected specimens of CIS of the urinary bladder. CONCLUSION: The results indicate that a reduction in integrin beta4 plays a role in IES of CIS of the urinary bladder through enhanced migration on laminin.

Treatment of metastatic nonseminomatous germ cell tumors of the testis: significance of the international consensus prognostic classification as a prognostic factor-based staging system.

BACKGROUND: We reviewed treatment results in patients with metastatic nonseminomatous germ cell tumors of the testis and examined the significance of the International Consensus Prognostic Classification to make appropriate risk-based decisions concerning induction chemotherapy. METHODS: We divided 37 patients treated with platinum-based combination chemotherapy into good, intermediate, and poor prognostic groups utilizing the International Consensus Prognostic Classification. The data was analyzed for both overall survival and progression-free survival among the 3 prognostic groups. RESULTS: Among the 37 patients, 10 died (8 of progressive disease, 1 of pneumonia during induction chemotherapy and 1 of cyclophosphamide-induced hemorrhagic cardiomyolitis during salvage chemotherapy). The survivors were followed for 6 to 1 84 months from the beginning of induction chemotherapy (median, 80 months). Five of the 37 patients (14%) were classified as having a good prognosis, 1 8 (48%) as intermediate, and 14 (38%) as having a poor prognosis. The patients in the poor prognostic group had a 5-year overall survival of only 40%, while those in the good and intermediate groups had 5-year overall survivals of 100% and 94%, respectively. When we applied the International Consensus Prognostic Classification to patients with advanced disease classified by the Indiana University Staging System, these patients could be clearly divided into good-risk and poor-risk groups. CONCLUSIONS: The International Consensus Prognostic Classification is easily applicable and accurate for risk assessment in patients with metastatic nonseminomatous germ cell tumors of the testis. This classification will now be widely used in general oncology practices and for clinical trials in these patients.

The significance of Ras guanine nucleotide exchange factor, son of sevenless protein, in renal cell carcinoma cell lines.

PURPOSE: The aim of the present study is to clarify the significance of the Ras guanine-nucleotide exchange reaction in the proliferation of human renal cell carcinoma cell lines. MATERIALS AND METHODS: We examined the expression of human son of sevenless-1 (hSos-1) protein and the epidermal growth factor (EGF) receptor in human renal cell carcinoma cell lines by Western blot analysis. Additionally, a dominant negative H-ras mutant, N116Y, which is known to inhibit the Ras guanine-nucleotide exchange reaction, was transfected into these cell lines by lipofection. RESULTS: Human renal cell carcinoma cell lines expressed much higher amounts of the EGF receptor and hSos-1 protein than normal kidney tissue. Moreover, the N116Y ras mutant could strongly suppress cellular proliferation in these cell lines. CONCLUSIONS: Augmentation of the Ras guanine-nucleotide exchange reaction might be essential to the proliferation of human renal cell carcinoma cells.

[Tumor size and DNA ploidy changes in renal cell carcinomas--flow cytometric analysis of DNA content in renal cell carcinomas associated with von Hippel-Lindau disease].

BACKGROUND: Renal cell carcinomas (RCCs) develop in 8-63% of von Hippel-Lindau disease (VHL) patients, and loss of 3p segments, chromosome aberrations found in 90% of sporadic RCCs, has also been observed in RCCs associated with VHL. In fact, comparative analysis showed that the chromosome aberrations in RCCs associated with VHL are similar to those found in sporadic RCCs. VHL patients have the whole spectrum of tumors from small early lesions to large ones in the same kidney, providing a unique opportunity to analyze tumors in different stages of development. Subsequently deoxyribonucleic acid (DNA) content in RCCs of VHL patients was examined and correlated to their tumor size to gain some insight in the progression of sporadic RCCs. METHODS: From 1988 to 1991, we have experienced 6 cases of RCCs associated with VHL who underwent partial or radical nephrectomy. A total number of 52 paraffin-embedded samples from 33 RCCs from 6 patients with VHL was analyzed by flow cytometry. RESULTS: The sizes of tumors ranged from 0.2 to 8.2 cm. DNA aneuploid patterns demonstrated in none of 9 tumors less than 1.6 cm, 4 of 14 tumors (29%) as large as 1.6 to 2.5 cm, and 5 of 10 tumors (50%) larger than 2.5 cm (p < 0.05). Twelve tumors less than 1.8 cm showed DNA diploid, so the smallest size of aneuploid tumors was 1.8 cm. CONCLUSION: These data suggest that DNA ploidy change (diploid to aneuploid) in RCCs probably takes place as tumors grow approximately 1.8 cm in size.

[Treatment of advanced testis cancer with a high dose chemotherapy regimen (PVeBV)].

BACKGROUND: The prognosis of patients with testis cancer classified as being in the advanced extent according to the Indiana University staging system is still poor even when treated with cisplatin based chemotherapy. METHODS: Attempting to increase the efficacy of chemotherapy in this high risk group, we have adopted PVeBV chemotherapy (high dose CDDP+VBL+VP-16+BLM) for recent 8 patients with such advanced conditions. In this study, we analized the treatment outcome of those patients retrospectively. RESULTS: Two patients died during the first course of PVeBV chemotherapy due to cancer progression, while 6 patients treated with 3 to 4 cycles of PVeBv were eligible and assessable for response, survival, and toxicity. Five of those 6 achieved pathological CR (pCR) following surgical resection of residual masses after 3 cycles of PVeBV. The other case was saved by salvage chemotherapy with autologous BMT. All 6 patients were long-term disease free survivors in median follow up of 46 months. With the rG-CSF application and vigorous hydration, acute phase toxic effects (myelosuppression, pulmonary fibrosis and nephrotoxicity) were manageable in this intensive regimen. Long term toxic effects such as peripheral neuropathy and ototoxicity were also tolerable and quality of life in such advanced cancer patients was preserved well. CONCLUSION: To improve a cure rate of high risk testis cancer, the dose escalation of induction chemotherapy should be considered.

Nephron sparing surgery for renal cell carcinoma in von Hippel-Lindau disease.

PURPOSE: We evaluated the technical feasibility and followup outcomes of a nephron sparing operation for localized renal cell carcinoma and von Hippel-Lindau disease. MATERIALS AND METHODS: Our 5 patients underwent initial nephron sparing surgery followed by serial computerized tomography. RESULTS: All but 1 renal lesion was resected in 9 initial nephron sparing operations. Postoperative computerized tomography revealed 35 lesions of which 8 had enlarged. Four patients underwent secondary renal surgery and adequate renal function was preserved. CONCLUSIONS: Even with the high risk of local recurrence nephron sparing surgery is an appropriate approach for these patients.

[5-Fluorouracil and alpha-2a interferon in patients with hormone-refractory prostate cancer].

BACKGROUND: Hormone-refractory metastatic prostate cancer remains a disease for were limited therapeutic options are available. Therefore, the establishment of newly, more effective chemotherapy is expected. Experimental data suggest that PC-3, a human hormone refractory prostate cancer cell line, showed a 2-fold increase in 5-Fluorouracil (5FU) sensitivity in the presence of alpha-2a Interferon (IFN alpha 2a) at 100 IU/ml, compared to that without IFN alpha 2a. Based on this data, we treated 11 patients with 5FU and IFN alpha 2a in order to determine the clinical response and toxicity of this combination chemotherapy. METHODS: One course of this combination chemotherapy consisted of a continuous intravenous infusion of 5FU at 600 mg/m2/day for 5 days (D1-D5) with IFN alpha 2a 3 million units (MU) intramuscularly 3 times weekly (D1, D3, D5) followed by a bolus injection of 5FU at 600 mg/m2 and IFN alpha 2a at 3 MU/day on D15 and D22. RESULTS: Based on the Response Criteria for Prostate cancer Treatment, one of 9 patients with bony metastasis had partial response, 2 patients with nodal disease on the CT scan obtained partial response. Six of 11 patients had more than 50% decrease in post-therapy prostatic antigen levels, 3 of whom obtained complete response. Significant myelosuppression did not occur. There were no chemotherapy-related deaths. CONCLUSION: These results suggest that the combination of 5FU and IFN alpha 2a, although preliminary, is an active regimen against hormone-refractory metastatic prostate cancer.

Gelsolin: a candidate for suppressor of human bladder cancer.

Human transitional cell carcinomas of the bladder frequently reveal chromosomal abnormalities that span a range between chromosome 9p12 and 9qter, even at early stages of bladder carcinogenesis. Because the gene that encodes an actin-regulatory protein, gelsolin, is localized in chromosome 9q33, we examined the expression of gelsolin in a number of human bladder cancer cell lines and tissues. In all 6 cell lines and in 14 of the 18 tumor tissues (77.8%), gelsolin expression was undetectable or extremely low in comparison with its expression in normal bladder epithelial cells. Furthermore, upon the introduction of the exogenous human or mouse authentic gelsolin cDNA into a human bladder cancer cell line, UMUC-2, gelsolin transfectants of UMUC-2 greatly reduced the colony-forming ability and the tumorigenicity in vivo. These results suggest that gelsolin plays a key role as a tumor suppressor in human urinary bladder carcinogenesis.