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Five hundred and nineteen patients with primary bladder cancer were treated between January, 1969 and December, 1984, 12 of whom had developed upper urothelial tumors. These patients had received various transurethral treatment for the primary bladder lesions, except for one patient who had undergone total cystectomy and ileal conduit diversion. Overall incidence of patients with upper urinary tract tumors following bladder cancer was 2.3%. The incidence of patients with treated bladder tumors (13.2%) for dye workers was higher than that for the general population (1.1%). The interval between initial treatment of the bladder tumor and diagnosis of the upper tract tumor ranged from 7 to 170 months (mean 70 months). The incidence of upper tract tumors increased with the passage of time. We conclude that the occurrence of upper urinary tract tumors following primary bladder cancers is promoted by nonspecific chemical irritants against the urothelium already made unstable by certain urinary chemical carcinogens.

Using gas chromatography-mass spectrometry (GC/MS), urinary organic acid profile studies were carried out on a patient with dihydrolipoyl dehydrogenase (E3) deficiency. Elevated levels of 2-hydroxyglutaric acid, 2-hydroxyisocaproic acid and 2-oxoisocaproic acid were observed in addition to lactic acid, 2-oxoglutaric acid, 2-hydroxyisovaleric acid and 2-hydroxybutyric acid previously described in patients with E3 deficiency. The 2-oxoglutaric acid levels were significantly lowered after branched-chain amino acid restriction. In an acute period, the patient was slightly ketoacidotic and excreted larger amounts of 2-oxoglutaric acid and lactic acid than in a static period. It was shown that, prior to confirmatory enzyme studies, patients with E3 deficiency who were suspected to have atypical maple syrup urine disease or chronic lactic acidosis can be rapidly identified by GC/MS analysis of urinary acids.

We treated 519 patients with primary bladder cancer, of whom 12 had upper urothelial tumor during followup. Almost all patients had superficial bladder cancer at diagnosis. All but 1 of 12 patients who underwent total cystectomy with ileal conduit diversion also underwent various transurethral procedures for treatment of the primary bladder lesions. The over-all incidence of bladder cancer patients who subsequently had upper urinary tract tumors was 2.3 per cent. Among the patients with treated bladder tumors a higher incidence (13.2 per cent) was observed in dye workers than in the general population (1.1 per cent). The interval between initial treatment of the bladder cancer and diagnosis of the upper urinary tract tumor ranged from 7 to 170 months (mean 70 months). The frequency of upper urinary tract tumors increased with time. We conclude that the appearance of upper urinary tract tumor after diagnosis of primary bladder cancer may be promoted by nonspecific irritation of the urothelium, which previously was made unstable by urinary chemical carcinogens.

We report a 3-year-old Japanese girl who developed acute encephalopathy while receiving calcium hopantenate (Calcium D-(+)-4-(2, 4-dihydroxy-3,3-dimethylbutyramido) butyrate hemihydrate). She had hyperammonemia, elevated CPK, lactic acidemia and pyruvic acidemia, however, she did not show elevated SGOT or SGPT. Calcium hopantenate has been used in Japan for the treatment of mental retardation with behavior abnormalities. Recently there have been three reports on the occurrence of Reye-like syndrome in patients receiving this drug. Clinical signs and laboratory data of these patients are similar to those of Reye syndrome. Calcium hopantenate causes pantothenic acid deficiency in the young rat, which may reduce the content of coenzyme A. If this drug decreases coenzyme A biosynthesis, it may reduce beta-oxidation of fatty acids and levels of dicarboxylic acids would increase because of increasing omega-oxidation. We suspect that there is a possible relationship between the occurrence of acute encephalopathy and calcium hopantenate therapy.

Sixteen patients with locally advanced or metastatic bladder cancer were treated with cis-diamminedichloroplatinum (cis-DDP) alone or in combination with other drugs. Eight patients were given cis-DDP intravenously, 6 patients intraarterially and 2 by both methods. Seven patients (44%) showed a partial response, 2 showed a minor response and 4 remained unchanged. Of the 6 patients treated with arterial infusion, 3 achieved a partial response while only 2 of the 8 patients administered intravenously showed a partial response. Eight patients with deeply invasive bladder cancer were treated with cis-DDP alone or in combination with other drugs following radical cystectomy. Cis-DDP was administered every week for 3 courses and every month for 12 courses at a dose of 50 mg and cis-DDP, adriamycin and 5-FU (CAF) were administered at 3 weeks interval for 3 courses and every month for 12 courses. All patients in this group were alive with a median survival of 20 months. One patient had a recurrence 5 months postoperatively. Adjuvant chemotherapy with cis-DDP or their combination was effective. Toxicity was generally tolerable.

From June 1982 through December 1985, 25 patients who had undergone radical cystectomy with pelvic node dissection for pathologic stage-pT3 or -pT4 and/or N+ disease received adjuvant chemotherapy involving the injection of cis-platinum alone or in combination with adriamycin and 5-fluorouracil (CAF). Thirteen patients also received preoperative adjuvant chemotherapy involving the infusion of cis-platinum, adriamycin, and mitomycin C into the bilateral internal iliac arteries. Postoperative adjuvant chemotherapy was performed using the following two protocols. Protocol 1 (18 cases) consisted of cis-platinum alone being administered every week for 3 weeks and then every month for 1 year. In protocol 2 (7 cases), cisplatinum, adriamycin, and 5-fluorouracil were administered at 3-week intervals on three occasions and then every month for 1 year. Eighteen patients were still alive with no evidence of disease after an average of 26 months. One patient died as a result of factors unrelated to cancer. Local recurrence and distant metastasis occurred in 6 patients, of whom 3 were still alive for an average of 20.7 months. Three patients died of cancer progression after 9, 19, and 21 months. The survival rate for all 25 patients at 50 months was 77%. Nausea and vomiting occurred in most patients during the administration of cis-platinum. Mild myelosuppression developed in a few patients subjected to protocol 2. Our results indicate that adjuvant chemotherapy consisting of the administration of cis-platinum alone or in combination with other chemotherapeutic agents appears to be effective in patients with invasive bladder cancer.

Metabolic changes dependent upon clinical conditions were studied in an eight-month-old girl with propionyl CoA carboxylase deficiency. Only methylcitric acid and 2-methyl-3-oxovaleric acid were detected in the urine of the patient under clinically favorable conditions. During episodes of clinical decompensation, she excreted increased amounts of all the metabolites associated with this disorder. Four acetyl CoA precursors increased during clinical episodes: glutaric acid, a catabolic intermediate of lysine; 3-hydroxyisovaleric acid and 3-methylglutaconic acid, catabolic intermediates of leucine; and lactic acid. This suggests that under clinically favorable conditions the patient has an altered propionate metabolism which proceeds via normal acetyl CoA metabolism with sufficient capacity for acetyl CoA plus propionyl CoA metabolism. When the production of propionyl CoA exceeds the metabolic capacity, however, the catabolism of potent ketogenic amino acids is effectively suppressed in order to reduce acetyl CoA production.

A case of bilateral renal angiomyolipoma without tuberous sclerosis is reported. A 49-year-old woman was admitted to the general practitioner with a sudden onset of severe left flank pain. An excretory urogram and ultrasonogram revealed an enlargement of the left kidney. She was subsequently referred to our clinic for further investigation and treatment. Computed tomographic scan and magnetic resonance imaging using Tl-weighted image showed several tumors with a fatty, dense area in the bilateral kidney. An arteriogram demonstrated a hypervascular renal mass with aneurysms in her left kidney. Diagnosis of bilateral renal angiomyolipoma was confirmed by percutaneous needle biopsy. Superselective embolization of the tumor was successfully performed, preserving normal renal tissue. Gelatin sponges containing Carboquone (CQ sponge) were used as embolic material. Angiomyolipoma has become relatively easy to diagnose by CT, ultrasound, MRI and so on. However, there are some cases of angiomyolipoma which are indistinguishable from renal cell carcinoma using these modes of testing. Therefore, in selecting a conservative management, we indicated that percutaneous biopsy or open biopsy should be done to confirm the results of the above procedures. Moreover, therapeutic embolization for angiomyolipoma was concluded to be very useful.

The metabolic fates of the nigrostriatal toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its two-electron oxidation product, the 1-methyl-4-phenyl-2,3-dihydropyridinium species (MPDP+), have been examined in mouse brain and liver tissue fractions. Incubations of MPTP (50 microM and 1 mM) with mouse brain preparations result in the expected MAO B catalyzed formation of MPDP+. The four-electron oxidation product, the 1-methyl-4-phenyl-pyridinium species (MPP+), was the only other metabolite detected. The oxidation of 50 microM MPDP+ to MPP+ in the same preparations appears to be mediated by unidentified components present in membrane containing structures. The behavior of MPTP in mouse liver subcellular fractions is considerably more complex. NADPH-supplemented liver microsomes convert MPTP to the desmethyl and N-oxide metabolites. At high (1 mM) initial concentrations of MPTP there is evidence that NADPH-dependent, pargyline-insensitive liver microsomal enzymes also catalyze the oxidation of MPTP to MPDP+. Incubations of MPDP+ with mouse liver preparations containing the cytosolic fraction led to the rapid disappearance of the substrate and the quantitative formation of a metabolic product with mass spectral and diode array UV characteristics expected for a lactam structure. Menadione, an inhibitor of the cytosolic enzyme aldehyde oxidase, inhibits the formation of this product. Unambiguous characterization of this metabolite as 1-methyl-4-phenyl-5,6-dihydro-2-pyridone was achieved by comparison of its high-resolution 1H NMR and high-resolution EI mass spectra with the corresponding spectra of a synthetic standard.(ABSTRACT TRUNCATED AT 250 WORDS)

Two cases of adenomatous polyps with prostatic type epithelium are reported. The first case was of a 62-year-old male suffering from asymptomatic hematuria. Cystoscopic findings showed an urethral tumor in the prostatic urethra. He was treated by transurethral resection of the prostate. The second case was of a 47-year-old male with complaints of hematuria and doubtful findings in urinary cytology. Cystoscopic findings showed that he had an urethral tumor in the prostatic urethra as well as bladder tumor. Both were resected transurethrally. Histological examination revealed that both urethral tumors were papillary adenoma of the prostatic urethra, corresponding to the adenomatous polyps with prostatic type epithelium in the classification of AFIP. The peroxidase-antiperoxidase complex method was performed using the anti-prostatic acid phosphatase antibody and anti-prostatic-specific antigen antibody, and positive reactions were obtained which confirmed that the tumors originated in the prostatic tissue. Benign urethral tumor in males is not common and description of adenomatous polyps with prostatic type epithelium is very rare. We could find only 11 cases in the Japanese literature.

Urinary valproate metabolite and endogenous organic acid profiles in a 6-yr-old girl with Reye's syndrome were investigated by means of gas chromatography-mass spectrometry. 2-n-Propyl-3-oxovaleric acid, normally the major metabolite of valproate in man, was undetectable, while 2-n-propylglutaric acid, the end product via omega-oxidation was markedly increased. Polyunsaturated valproate was not found. Valproate-glucuronide was still found as the major metabolite. The clinical findings coupled with a greatly increased excretion of lactate and adipate was compatible with Reye's syndrome. Ketone bodies were not detectable. This case study shows that Reye's syndrome causes altered valproate metabolism, consistent with the defective mitochondrial beta-oxidation of medium chain fatty acids, and suggests that valproic acid should not be used in the treatment of seizures in patients with this syndrome.

An unusual instance of concordant chordee without hypospadias in identical twins with 47 XXY Klinefelter's syndrome is reported. The etiology of coincidental chordee without hypospadias and Klinefelter's syndrome is unknown.

The biotransformation of the tertiary amine 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was studied in isolated rat hepatocytes, in order to assess the relative contributions of the metabolic reactions previously described in studies with subcellular preparations. The oxidative pathway which produces the toxic metabolite 1-methyl-4-phenylpyridinium ion (MPP+) via the generation of the 2,3-dihydropyridinium derivative, MPDP+, accounted for approximately 90% of MPTP metabolism by hepatocytes. Mitochondrial monoamine oxidase type B (MAO B) was specifically responsible for the initial step of this conversion. In the endoplasmic reticulum, cytochrome P-450 catalyzed the demethylation of MPTP to form PTP, while the flavin-containing monooxygenase (FMO) was responsible for the generation of MPTP N-oxide. No other metabolite was detected in our hepatocyte incubations under any of the experimental conditions used. After pretreatment with the specific MAO B inhibitor, deprenyl, the rates of production of the two microsomal metabolites were enhanced, but the overall rate of MPTP conversion decreased by more than 60%. On the other hand, no significant difference in the rate of MPTP metabolism was found after the inhibition of cytochrome P-450 by SKF 525-A or with the use of methimazole, a competitive substrate for FMO. The SKF 525-A and methimazole treatments selectively inhibited the formation of PTP and MPTP N-oxide, respectively, but had no significant effect on the rate and extent of MPTP toxicity. MPP+ was the only metabolite which accumulated within the cell compartment under all the experimental conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Currently, one of the major clinical problems is diagnosis of inherited metabolic disorders in neonates which are caused by a defect of specific enzymes. In order to diagnose such diseases at an earlier stage, we have developed a new mass screening method, consisting of a gas chromatography mass spectrometry computer system with a newly developed 'Diagnosis Computer Program'. In this program, the chromatographic pattern of the urine of a patient with an inherited metabolic disorder is compared with that of a normal person. Internal standards are applied to simplify the comparison. The total ion current chromatogram is drawn with the relative retention times plotted on the horizontal axis and the relative intensities on the vertical axis. Diseases are diagnosed by characteristics and quantity of abnormal compounds in the urine. Reference to the stored mass spectra of abnormal compounds by a library search enables the diagnosis to be more precise. Using this program, twenty-six inherited metabolic disorders are routinely diagnosed. The diagnosis of tyrosinosis is used here as an example.

The parkinsonian-inducing compound 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is converted by isolated hepatocytes to its primary metabolite, the 1-methyl-4-phenyl-2,3-dihydropyridinium ion (MPDP+), and to its fully oxidized derivative, 1-methyl-4-phenylpyridinium ion (MPP+). Only the latter, however, accumulates in the cells. Incubation of hepatocytes in the presence of MPDP+ also results in the selective intracellular accumulation of MPP+. Conversion to MPP+ is more rapid and extensive after exposure to MPDP+, than with MPTP and the former is also more toxic. Addition of MPP+ itself is toxic to hepatocytes but only after a long lag period, which presumably reflects its limited access to the cell and its relatively slow intracellular accumulation. As previously shown with MPTP and MPP+, the cytotoxicity of MPDP+ is dose-dependent and is consistently preceeded by complete depletion of intracellular ATP. Similar to MPP+ but not MPTP, MPDP+ causes a comparable rate and extent of cytotoxicity and ATP loss in hepatocytes pretreated with the monoamine oxidase inhibitor pargyline. Pargyline blocks hepatocyte biotransformation of MPTP to MPP+, but it has no significant effect on MPP+ accumulation after exposure to either MPDP+ or MPP+. It is concluded that MPTP is toxic to hepatocytes via its monoamine oxidase-dependent metabolism and that MPP+ is likely to be the ultimate toxic metabolite which accumulates in the cell, causing ATP depletion and eventual cell death.

Eight ewes, divided into two groups based on age, with group 1 7-8 and group 2 1-3 years old, respectively, were administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intravenously (IV) at cumulative doses of 2.0 to 34.6 mg/kg body weight. Two group 1 sheep, given cumulative doses of 2 and 8.5 mg/kg, developed persistent severe neurologic signs of body stiffness and rigidity, paucity of movement, intention body tremors, and abnormal body posture and stance similar to those signs in MPTP-induced disease in people and primates. After their acute onset, these persistent signs were nonprogressive up to the observation period of 32 days post infusion. None of the younger ewes had persistent neurologic symptoms at equivalent cumulative doses (9.0 mg/kg). The only pathologic changes were microscopic lesions in the central nervous system, consisting of bilaterally symmetrical neuronal chromatolysis and necrosis limited to the substantia nigra and locus ceruleus. These lesions were found in two persistently affected and two younger sheep, suggesting age-based differences in dose response and the threshold of clinical expression of disease. Serum MPTP half-life was 11 days. Thus sheep exposed to MPTP could be an alternative model to the primate for the comparative study of clinical, pathologic, and biochemical mechanisms in MPTP neurotoxicity and Parkinson's disease in people.

Partial urethrectomy (at least to the bulbous portion) was performed simultaneously in 128 consecutive male patients undergoing radical cystectomy for bladder cancer. Transitional cell carcinoma developed subsequently in the distal urethral remnant in 5 patients (4.0%) followed for 2.6 to 5.7 years (mean 4.1 years) postoperatively. These 5 patients originally had nonpapillary, multifocal and histologically high grade (5) and low stage (4) bladder cancer, 4 with associated carcinoma in situ. Our results suggest that simultaneous total urethrectomy should be considered strongly for patients with high grade nonpapillary multifocal bladder cancer associated with carcinoma in situ. Furthermore, the pattern of distal urethral recurrence in our patients may provide information regarding the appropriate management of the male urethra in potential candidates for continent urinary diversion.

According to the records of Wakayama Labor Standard Office, at least 1,085 workers had been exposed to benzidine or beta-naphthylamine in the dyestuff factories in Wakayama City. By October 1988, 101 of them (9.3%) were confirmed to have urinary tract tumors. Including 2 other cases exposed in Osaka, a total of 103 cases of occupational uroepithelial cancer were studied here clinically. Site of tumors was bladder in 91 cases, renal pelvis in 2, ureter in 5 and papillomatosis type in 5. The age at the time of diagnosis ranged from 25 to 87 years with a mean of 53.8 years. The average latent period was 22.7 years, but the older the age of the worker at the start of exposure, the shorter was the latent period. In Wakayama, the proper system of healthy examination for chemical workers using urinary cytology was begun in 1970. Since then, more tumor cases have been discovered in comparison to the patients admitted with subjective symptoms of hematuria. The effectiveness of this group examination was significant in the incidence of total cystectomy in surgical treatment and in survival rate. In the comparative study between the groups of patients with occupational and spontaneous bladder cancer, the average age at diagnosis in the former was about ten years younger. Although the histological grade of tumor was not different between the two groups, the incidence of total cystectomy was lower and the survival rate was significantly higher in the occupational group.