Soichi Mugiya

A Phase II Study of Sunitinib in Japanese Patients with Metastatic Renal Cell Carcinoma: Insights into the Treatment, Efficacy and Safety

OBJECTIVE This study aims to assess the efficacy and safety of sunitinib in Japanese patients with metastatic renal cell carcinoma (RCC). METHODS Fifty-one Japanese patients with prior nephrectomy, 25 treatment-naive patients (first-line group) and 26 cytokine-refractory patients (pretreated group) were enrolled in this phase II trial. Patients received sunitinib 50 mg orally, once daily, in repeated 6-week cycles (4 weeks on treatment, 2 weeks off). The primary endpoint was RECIST-defined objective response rate (ORR) with tumour assessments every 6 weeks via computed tomography or magnetic resonance imaging. Toxicity was assessed regularly. In the primary efficacy analysis of the intent-to-treat (ITT) population, ORR and 95% confidence interval were calculated based on independent review. Secondary time-to-event endpoints, such as progression-free survival (PFS), were estimated using the Kaplan-Meier method. RESULTS In the ITT population, ORR was 48.0% in the first-line group (after a median 4 cycles), 46.2% in the pretreated group (5 cycles) and 47.1% overall, with median times to tumour response of 7.1, 10.7 and 10.0 weeks, respectively. Median PFS was 46.0, 33.6 and 46.0 weeks, respectively. The most common treatment-related grade 3/4 adverse events and laboratory abnormalities were fatigue (20%), hand-foot syndrome (14%) and hypertension (12%), decreased platelet count (55%), decreased neutrophil count (51%), increased lipase (39%) and decreased lymphocyte count (33%). CONCLUSIONS In Japanese patients with RCC, sunitinib is consistently effective and tolerable with similar risk/benefit as that in Western patients, though there was a trend toward greater antitumour efficacy and higher incidence of haematological adverse events in Japanese patients.

Overall Survival and Updated Results from a Phase II Study of Sunitinib in Japanese Patients with Metastatic Renal Cell Carcinoma

BACKGROUND In a phase II, open-label, multicentre Japanese study, sunitinib demonstrated antitumour activity and acceptable tolerability in metastatic renal cell carcinoma patients. Final survival analyses and updated results are reported. METHODS Fifty-one Japanese patients with a clear-cell component of metastatic renal cell carcinoma (25 treatment-naïve; 26 cytokine-refractory) received sunitinib 50 mg orally, once daily (Schedule 4/2). Overall and progression-free survivals were estimated by the Kaplan-Meier method. Objective response rate (per Response Evaluation Criteria in Solid Tumours) and safety were assessed with an updated follow-up. RESULTS First-line and pretreated patients received a median 6.0 and 9.5 treatment cycles, respectively. Investigator-assessed, end-of-study objective response rate was 52.0, 53.8 and 52.9% in first-line, pretreated and overall intent-to-treat populations, respectively. The median progression-free survival was 12.2 and 10.6 months in first-line and pretreated patients, respectively. Fourteen patients per group died (56 and 54%), and the median overall survival was 33.1 and 32.5 months, respectively. The most common treatment-related Grade 3 or 4 adverse events and laboratory abnormalities were fatigue (24%), hand-foot syndrome (18%), decreased platelet count (55%), decreased neutrophil count (53%) and increased lipase (49%). No Grade 5 treatment-related adverse events occurred. Forty patients (78%) required dose reduction, and 13 (25%) discontinued, due to treatment-related adverse events. CONCLUSIONS With the median overall survival benefit exceeding 2.5 years, and acceptable tolerability, in first-line and pretreated Japanese metastatic renal cell carcinoma patients with Eastern Cooperative Oncology Group performance status 0/1, sunitinib showed a favourable risk/benefit profile, similar to Western studies. However, there was a trend towards greater efficacy and more haematological adverse events in Japanese patients.

Hazards of laparoscopic adrenalectomy in patients with adrenal malignancy.

We report the clinical outcomes of 2 patients undergoing laparoscopic adrenalectomy for adrenal malignancy. CASE REPORTS Case 1. A 50-year-old woman had Cushings syndrome due to left adrenal adenoma. Computerized tomography showed a 5 x 4.5 cm. tumor in the left adrenal gland that was slightly irregular (part A of figure). The tumor was removed en bloc without any damage by laparoscopic adrenalectomy. However, local recurrence and abdominal dissemination of the tumor occurred about 19 months after laparoscopic surgery. When the previously resected adrenal specimen was carefully reexamined, the diagnosis was changed to adrenocortical carcinoma. Although combination chemotherapy was administered, the patient died about 3 years aRer the first laparoscopic procedure. 1 Case 2. A 62-year-old man had left adrenal metastasis from poorly differentiated adenocarcinoma of the lung. Magnetic resonance imaging showed a 5.5 X 4.0 cm. tumor in the leR adrenal gland (part B of figure). We attempted to perform retroperitoneal adrenalectomy but the procedure had to be changed to open surgery (en bloc removal with an upper part of the kidney) because of severe adhesions between the kidney and adrenal tumor. The patient died of multiple metastases from lung cancer about 8 months after the surgery.

ENDOSCOPIC MANAGEMENT OF IMPACTED URETERAL STONES USING A SMALL CALIBER URETEROSCOPE AND A LASER LITHOTRIPTOR

PURPOSE We reviewed our experience with retrograde endoscopy using a small caliber ureteroscope and a laser lithotriptor in 104 consecutive patients with impacted ureteral stones and also analyzed the associated endoscopic findings. MATERIALS AND METHODS From July 1993 to October 1999 we performed retrograde endoscopic treatment in 104 patients with impacted ureteral stones. Average maximum stone diameter was 15.2 mm. (range 2 to 110), and 9 patients had stones larger than 3 cm. Mean duration of impaction was more than 14 months and the longest was 10 years. We used 6.9Fr rigid or 6.9 to 7.5Fr flexible ureteroscopes and a pulsed dye laser or holmium:YAG laser lithotriptor. RESULTS Of the 104 ureteral stones 100 (96.2%) were completely fragmented by a single endoscopic procedure. Although 1 uric acid stone could not be disintegrated by either the pulsed dye laser or electrohydraulic lithotripsy early in this series, it was discharged spontaneously 2 weeks after the procedure. Additional extracorporeal shock wave lithotripsy (ESWL*) was required in 3 patients who initially had stones larger than 3 cm. A month after treatment no patient had evidence of residual stones. Using adjuvant ESWL a 100% success rate was attained with minimal morbidity. Endoscopic observation revealed inflammatory polyps of the ureter in 22 patients (21.2%), and stricture adjacent to the stone in 16 (15. 4%). There were no significant complications. CONCLUSIONS Using a small caliber ureteroscope and a laser lithotriptor we could treat the target stone in all 104 patients with adjuvant ESWL in 3 cases. Endoscopic lithotripsy seems to be effective first line therapy for chronically impacted stones which are frequently associated with chronic inflammation, polyps and strictures, and avoids the futile repetition of ESWL and problems related to the prolonged passage of stone fragments.

Complications of Laparoscopic Adrenalectomy in 75 Patients Treated by the Same Surgeon

Objective: We analyzed the complications of endoscopic adrenalectomy. Methods: We retrospectively reviewed the operative and postoperative complications among 75 patients with adrenal tumors who underwent endoscopic adrenalectomy by the same surgeon. Results: Five patients (6.7%) were converted to open surgery. Of these, there were 2 with metastatic adrenal carcinoma, and 1 with adrenal tuberculosis. A total of 21 patients (28%) had 24 complications (32%). There was no mortality. As for access and pneumoperitoneum-related complications, 5 cases of subcutaneous emphysema and 3 of radiating shoulder pain occurred. Intraoperative complications included 2 cases of vascular injury, 2 of organ injury, and 4 of massive bleeding (>500 ml). Postoperative complications included 2 cases of mild paralytic ileus, 2 asthma, and 1 each of angina, wound infection, retroperitoneal hematoma, and contralateral atelectasis. Except for the patients with adrenal malignancy and adrenal tuberculosis, 71% of the complications occurred among the initial 25 patients with laparoscopic adrenalectomy and 80% occurred in the initial 10 retroperitoneoscopic patients. Conclusion: Although endoscopic adrenalectomy is a valuable alternative to open surgery, it should be done by a skilled laparoscopist in patients with adrenal inflammatory lesions or malignancy. Careful patient selection and correct choice of surgical approach according to the tumor size and the patient’s condition are the most important points for avoiding the complications of laparoscopic adrenalectomy.

Evaluation of S100A10, annexin II and B‐FABP expression as markers for renal cell carcinoma

This study aimed to analyze expression of S100A10, annexin II and B‐FABP genes in renal cell carcinoma (RCC) and their potential value as tumor markers. Furthermore, any correlation between the gene expression and prognostic indicators of RCC was analyzed. Expression of each gene was estimated by RT‐PCR in the non‐neoplastic (normal) and tumorous parts of resected kidney samples. Also, each antigen was immunostained in RCC and normal kidney tissues. Expression of the S100A10 gene averaged 2.5‐fold higher in the tumor than that in the normal tissues (n = 47), after standardization against that of β‐actin. However, expression of annexin II, a natural ligand of S100A10, was only 1.64‐fold higher. In the tissue sections of RCC, S100A10 and annexin II were immunostained in membranes. In the normal renal epithelia, however, both antigens were stained in the Bowmans capsule and the tubules from Henles loop through the collecting duct system, but not in the proximal tubules, from where most RCC are derived. In contrast, expression of the B‐FABP gene was 20‐fold higher in the tumor. No B‐FABP was immunohistochemically detected in normal kidney sections, but it was stained in the cytoplasm of RCC tissue sections. S100A10 and B‐FABP genes were overexpressed regardless of nuclear grade and stage of RCC. Immunopositivity in RCC tissues (n = 13) was 100% for S100A10 and annexin II, and 70% for B‐FABP; however, no clear relationship was observed in either antigen with nuclear grade and stage. It was found that all three performed well as RCC markers. B‐FABP was most specific to RCC, as it was expressed little in normal kidney tissues. (Cancer Sci 2007; 98: 77–82)

Significant Prognostic Factors for 5‐Year Survival after Curative Resection of Renal Cell Carcinoma

Background: Renal cell carcinoma (RCC) patients occasionally die of RCC even after curative resection. In this study, we investigated prognostic factors between survivors for more than 5 years and patients who died within 5 years after curative resection.

Endoscopic management of upper urinary tract disease using a 200-μm holmium laser fiber: initial experience in japan

OBJECTIVES To study the clinical effectiveness of the 200-microm holmium laser fiber for endoscopic management of upper urinary tract lesions. METHODS From January 1997 to March 1998, we performed retrograde endoscopic treatment in 25 patients with urinary tract lesions using a 200-microm holmium laser fiber. Nineteen patients had 20 stones (16 ureteral, 3 lower calyx, and 1 middle calyx), 4 had bleeding lesions in the lower calyx, 1 had transitional cell carcinoma involving the renal pelvis and upper calyx, and 1 had a ureteral stricture associated with an impacted ureteral stone. We used a 7.5F flexible ureterorenoscope for renal and upper ureteral lesions, and a 6.9F rigid ureteroscope for mid and lower ureteral lesions. For treatment, we used a holmium:yttriumaluminum-garnet laser generator and a 200-microm flexible quartz fiber. RESULTS All stones were successfully fragmented, including three lower caliceal stones. Lower caliceal bleeding spots were successfully cauterized for hemostasis in all 4 patients, and the pelvic tumor was successfully vaporized and ablated. In 1 patient, we had previously failed to treat a ureteral stricture with a 365-microm fiber because of inadequate visualization, but it was successfully incised using the 200-microm fiber. There were no significant complications such as ureteral obstruction or stenosis. CONCLUSIONS The improved flexibility of the new 200-microm holmium laser fiber facilitates treatment of stones, tumors, strictures, and lesions in the lower calyx, where access is difficult when using the previously available 365-microm fiber.

Retroperitoneoscopic treatment of a retrocaval ureter

Background : Retroperitoneoscopic surgery was performed on a 41‐year‐old man with a retrocaval ureter.

RETROPERITONEOSCOPY ASSISTED LIVE DONOR NEPHRECTOMY: THE INITIAL 2 CASES

PURPOSE We investigated retroperitoneoscopy assisted nephrectomy in living kidney donors. MATERIALS AND METHODS Gasless surgery was performed with a 10 cm. upper abdominal pararectus skin incision and 2 trocars. The abdominal wall was lifted using special retractors and the kidney was removed via the pararectus incision. RESULTS The operating time, blood loss, warm ischemic time and postoperative recovery period for the 2 donors were a mean of 210 minutes, 102 ml., 3.5 minutes and 4.5 days, respectively. There were no operative or postoperative complications. Postoperative recovery was significantly more rapid than after open donor nephrectomy. There were no differences with regard to graft biopsy findings or postoperative graft function between retroperitoneoscopy assisted and open donor nephrectomy. CONCLUSIONS Retroperitoneoscopy assisted nephrectomy could be advantageous for healthy kidney donors since it is minimally invasive.