Tatsuya Takayama

Prognosis of Japanese Metastatic Renal Cell Carcinoma Patients in the Cytokine Era: A Cooperative Group Report of 1463 Patients

BACKGROUND Incidence rate of renal cell carcinoma (RCC) differs among countries. The rates of Asian countries are lower than those of countries in North America or Europe but are exceptionally high in Japanese males. Approximately 30% of patients with RCC have metastasis at initial diagnosis, and another 30% have metastasis after nephrectomy. Clinical studies of risk factors in patients with metastatic RCC (mRCC) are mainly based on data from non-Asian patients. OBJECTIVES We aimed to investigate the prognosis of Japanese patients and their prognostic factors. DESIGN, SETTING, AND PARTICIPANTS The subjects of this study were 1463 patients who were clinically diagnosed with RCC with metastasis in 40 Japanese hospitals between January 1988 and November 2002. MEASUREMENTS The primary end point was overall survival calculated from first diagnosis of mRCC to death or last follow-up. We also investigated the relationship between survival and clinical features. RESULTS AND LIMITATIONS The median overall survival time was 21.4 mo. The estimated survival rates at 1, 3, 5, and 10 yr were 64.2%, 35.2%, 22.5%, and 9.1%, respectively; they contrasted with data from the United States of 54%, 19%, 10%, and 6%, respectively for the same periods. A high percentage of patients had undergone nephrectomy (80.5%) and metastasectomy (20.8%), both of which were shown to prolong survival. CONCLUSIONS The median survival time in the present study was approximately twice as long as that of previous studies from North America or Europe. Early diagnosis of metastasis, nephrectomy, metastasectomy, and cytokine-based therapy seemed to improve the prognosis of RCC patients in the present study.

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.

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)

Control of Oxalate Formation from L-Hydroxyproline in Liver Mitochondria

Serine:pyruvate/alanine:glyoxylate aminotransferase (SPT/AGT) is largely located in mitochondria in carnivores, whereas it is entirely found within peroxisomes in herbivores and humans. In rat liver, SPT/AGT is found in both of these organelles, and only the mitochondrial enzyme is markedly induced by glucagon. Although SPT/AGT is a bifunctional enzyme involved in the metabolism of both L-serine and glyoxylate, its contribution to L-serine metabolism is independent of mitochondrial or peroxisomal localization (Xue HH et al., J Biol Chem 274: 16028-16033, 1999). Therefore, the species-specific and food habit-dependent organelle distribution might be required for proper metabolism of glyoxylate at the subcellular site of its formation. Glyoxylate formation from glycolate and that from L-hydroxyproline have been shown to occur in peroxisomes and mitochondria, respectively. The present study found that urinary excretion of oxalate was markedly increased when a large dose of L-hydroxyproline or glycolate was administered to rats. Oxalate formation from L-hydroxyproline but not that from glycolate was significantly reduced when mitochondrial SPT/AGT had been induced by glucagon. The hydroxyproline content of collagen is 10 to 13%, and collagen accounts for about 30% of total animal protein; therefore, these results suggest that an important role of mitochondrial SPT/AGT in carnivores is to convert L-hydroxyproline-derived glyoxylate into glycine in situ, preventing undesirable overflow into the production of oxalate.

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.

Prognostic factors of patients with metastatic renal cell carcinoma with removed metastases: a multicenter study of 556 patients.

OBJECTIVE To investigate the prognosis and prognostic factors of patients with metastatic renal cell carcinoma who underwent metastasectomy. METHODS We sent questionnaires to Japanese hospitals. The questionnaires included data of patients with metastatic renal cell carcinoma who had their metastatic lesions removed between January 1988 and December 2009. We collected them and retrospectively analyzed these data and calculated the overall survival from the first metastasectomy until death or last follow-up. We also analyzed the relationship between survival and clinico-pathologic features and determined adverse prognostic factors. Furthermore, we identified a poor prognostic group by counting the number of prognostic factors. RESULTS A sample size of 556 patients from 48 institutions was studied. The median overall survival was 80 months. Four adverse prognostic factors were detected: incomplete resection by metastasectomy (hazard ratio [HR], 2.15), brain metastasis (HR, 3.73), >1.0 mg/dL C-reactive protein (HR, 2.45), and the highest histologic grade in Japanese classification (nuclei of tumor cells are larger than nuclei of normal tubular cells; HR, 1.88). The median overall survivals of patients with 3 or 4 prognostic factors, 2 factors, and 0 and 1 factors were 10 months, 42 months, and 105 months, respectively. CONCLUSION Four adverse prognostic factors for predicting the survival of patients with removed metastases were identified. Patients with 3 or 4 of these adverse prognostic factors had a worse prognosis.

Reduction of transforming growth factor-β type II receptor is caused by the enhanced ubiquitin-dependent degradation in human renal cell carcinoma

Although dysregulation of transforming growth factor‐β (TGF‐β) signaling is implicated in renal carcinogenesis, its precise mechanism is unknown in renal cell carcinoma (RCC). In our study, we investigated Smad‐mediated TGF‐β signaling pathway and its regulatory mechanisms in surgical samples from patients with RCC. We found that immunoreactivity for nuclear phosphorylated Smad2 was significantly decreased in RCC compared to normal renal tissues, thereby TGF‐β signaling was suggested to be attenuated in RCC tissues. In accordance with the result, transcriptional downregulation of Smad4 and post‐transcriptional downregulation of TGF‐β type II receptor (TβR‐II) were frequently found in RCC tissues compared to normal renal tissues. Next, to clarify the reason why the protein level of TβR‐II was decreased in RCC, we investigated the activities of degradation and ubiquitination of TβR‐II. We found that both proteasome‐mediated degradation and ubiquitination of TβR‐II were markedly enhanced in RCC tissues. Moreover, we found that the level of Smad‐ubiquitination regulatory factor 2 (Smurf2), the E3 ligase for TβR‐II, was increased in RCC tissues of the patients with higher clinical stages compared to the normal tissues and was inversely correlated with the level of TβR‐II. Our results suggest that the low TβR‐II protein level is due to augmented ubiquitin‐dependent degradation via Smurf2 and might be involved in the attenuation of TGF‐β signaling pathway in RCC.

Primary prostatic endodermal sinus tumor (yolk sac tumor) combined with a small focal seminoma.

We report on a primary endodermal sinus tumor (EST) (yolk sac tumor) combined with a focal seminoma of the prostate occurring in a 24-year-old man. The prostate was widely infiltrated with neoplasms that penetrated the capsule and invaded into the bladder wall and urethra. Most areas of the tumor were composed of papillary and glandular epithelium in the fibrous or myxoid stroma. Schiller-Duval bodies and periodic acid-Schiff-positive hyaline bodies were focally present. In addition to yolk sac tumor, solid nests of seminoma were found in some areas. Immunohistochemistry using specific antibodies for alpha-fetoprotein and cytokeratin showed positive reaction on the EST portion, and placental alkaline phosphatase revealed positive staining in the seminoma portion and a part of EST. Tumor cells exhibited negative staining for prostate-specific antigen, prostatic acid phosphatase, carcinoembryonic antigen, vimentin, chromogranin A, and human chorionic gonadotropin. Despite radical surgery and ordinary cisplatin-based chemotherapy, the patient died 8 months after operation. At autopsy, only EST elements had metastasized to the lungs, liver, and brain, and no tumors were found in either testis. To our knowledge, this is the first reported case of a primary EST combined with a focal seminoma in the prostate.

Primary Hyperoxaluria Type 1 in Japan

Background/Aims: Current status of primary hyperoxaluria (PH) has not been surveyed in Japan. Methods: Japanese patients with PH were reviewed in the published literature. Results: Fifty-nine patients were diagnosed as PH from 1962 to 2003. The median ages both at diagnosis and at the onset of initial symptoms were 17 (range: 0.02–63) and 13 (range: 0–58) years, respectively. Twenty-nine (49%) patients were older than 20 years at diagnosis, among whom 26 (90%) already presented end-stage renal failure (ESRF) or soon evolved into ESRF. Among 30 (51%) diagnosed as PH under 20 years old, only 13 (43%) were already in a terminal stage of renal insufficiency. Ten patients were diagnosed as PH1 by liver biopsy. We identified two types of enzymatic phenotypes in 3 of those patients examined. In 1 case, immunoreactive SPT/AGT protein level was very low due to accelerated proteolysis, while in other 2 cases, the immunoreactivity was detected on mitochondria due to mistargeting. Of 9 cases having been subjected to kidney transplantation at a median age of 20 years (range 7.3–40.0), it was only 2 cases that were reported to be successful, while the median survival time of the kidney grafts being 1.4 years (range 0–7). Of 4 patients having undergone combined liver/kidney transplantations (at the ages of 1.3, 1.4, 9 and 41 years, respectively), the surgery was successful in 3 cases; in the remaining one case, however, rejection required removal of the transplanted kidney was observed. The overall survival ratio of all the 59 PH cases accounted for 77, 71 and 55% at 5, 10 and 20 years, respectively. Conclusion: Assuming that the majority of the 59 patients with PH reported was classified as PH1, it is postulated that morbidity of violent infantile PH1 in Japan might be less than those in the USA and Europe, and symptoms of elderly Japanese PH1 patients seem to be milder than those of Western patients. Establishment of an early detection system of PH1 and more popular application of combined liver/kidney transplantation deserve further study.