Enzalutamide versus flutamide for castration-resistant prostate cancer after combined androgen blockade therapy with bicalutamide: the OCUU-CRPC study.

BACKGROUND: Before the androgen target therapy era, flutamide was widely used for castration-resistant prostate cancer in Japan. Enzalutamide is currently the recommended treatment; however, the efficacy and safety of enzalutamide and flutamide after combined androgen blockade therapy with bicalutamide, has not been compared. METHODS: Patients with castration-resistant prostate cancer who received combined androgen blockade therapy with bicalutamide were randomly assigned to receive either enzalutamide or flutamide. The primary endpoint for efficacy was the 3-month prostate-specific antigen response rate. This trial is registered with ClinicalTrials.gov (NCT02346578) and the University hospital Medical Information Network (UMIN000016301). RESULTS: Overall, 103 patients were enrolled. The 3- (80.8% vs. 35.3%; p < 0.001) and 6-month (73.1% vs. 31.4%; p < 0.001) prostate-specific antigen response rates were higher in the enzalutamide than in the flutamide group. The 3-month disease progression rates (radiographic or prostate-specific antigen progression) were 6.4% and 38.8% in the enzalutamide and flutamide groups, respectively [hazard ratio (HR): 0.16; 95% confidence interval (CI): 0.05-0.47; p < 0.001]; the 6-month rates were 11.4% and 51.1%, respectively (HR 0.22; 95% CI 0.09-0.50; p < 0.001). Enzalutamide provided superior prostate-specific antigen progression-free survival compared with flutamide (HR 0.29; 95% CI 0.15-0.54; p < 0.001). Median time to prostate-specific antigen progression-free survival was not reached and was 6.6 months in the enzalutamide and flutamide groups, respectively. CONCLUSIONS: As an alternative anti-androgen therapy in patients with castration-resistant prostate cancer who fail bicalutamide-combined androgen blockade therapy, enzalutamide provides superior clinical outcomes compared with flutamide. Enzalutamide should be preferred over flutamide in these patients.

Childhood pheochromocytoma in a survivor of central primitive neuroectodermal tumor.

Pheochromocytoma and central nervous system primitive neuroectodermal tumor are both neural crest-derived tumors. The former is usually benign and develops mainly in adulthood and the latter brain tumor mainly occurs in childhood and has a poor prognosis. We report a case of a 15-year-old boy who developed pheochromocytoma after more than 10 years of complete remission of central primitive neuroectodermal tumor. Thus far, there have been no reports of childhood cancer survivors who developed pheochromocytoma. This quite rare occurrence of two tumors in a single patient may imply some unidentified linkage or common genetic background.

Basic in vitro experiment on the adhesive effects of sheet-type hemostatic agents used in combination with a liquid fibrin sealant.

BACKGROUND AND PURPOSE: Various hemostatic agents have been used quite effectively for hemostasis, as well as for providing effective adhesion during laparoscopic partial nephrectomies. In this study, we investigated the adhesiveness to the renal tissue of some sheet-type hemostatic agents used in combination with a liquid fibrin sealant. MATERIALS AND METHODS: In Experiment A, component solutions of the fibrin glue (liquid fibrin sealant) were dripped onto a kite string placed annularly on a porcine kidney slice. Then, one of the sheet-type hemostats--namely, the collagen, gelatin, or cellulose hemostat--was placed on the slices, and a string scale was used to measure the force needed to pull the string apart vertically from the kidney slice. Twelve slices were used for each group, and the weight data were analyzed statistically. The tissue adhering to each sheet-type hemostatic agent was fixed in formalin and sliced and then examined by light microscopy after hematoxylin and eosin staining. In Experiment B, the solutions were dripped onto the sheet-type hemostatic agent placed first on the slice, and the force needed for pulling apart the hemostat sheet from the slice was similarly examined. RESULTS: The combination of fibrin glue plus a collagen hemostat was clearly superior in Experiment A, but the hemostat and renal tissue could be pulled apart more easily in Experiment B. These results showed that fibrin glue could not exert its expected adhesive effect unless it is used in combination with another hemostatic agent or is directly applied to renal tissue. CONCLUSION: It is important to obtain further comparative data among agents and select the appropriate agents, taking into consideration the type of surgery.

Combination of a liquid fibrin sealant with sheet-type hemostatic agents: experimental evaluation in partial nephrectomy animal model.

Liquid fibrin sealants, together with sheet-type hemostatic agents, have been used during partial nephrectomies to secure effective hemostasis at the suture site. Using animal kidneys, we investigated which hemostatic agent might adhere most effectively to the renal tissue and serve best as a bolster. Liquid fibrin sealant alone, or in combination with a sheet-type hemostat, such as collagen, gelatin or oxidized-cellulose hemostat, was applied to the cut surface of the kidney of anesthetized rabbits, and the differences in the degree of adherence to the kidney and resultant hemostatic efficacy were evaluated. Histological analyses were also carried out to compare the degree of adherence of each of the aforementioned hemostats to the kidney tissue. Fibrin sealant plus the collagen or gelatin hemostat was found to have a stronger hemostatic effect than fibrin sealant applied alone or fibrin sealant plus oxidized-cellulose hemostat. The histological investigation showed that the fibrin sealant adhered well to kidney tissue when it was applied with the collagen or gelatin hemostat, showing the advantage of combining these two materials for achieving effective hemostasis. Fibrin sealant used in combination with the collagen or gelatin hemostat was the most suitable for obtaining a reinforced hemostatic effect at the suture site in a partial nephrectomy animal model.

A case of lymphomatoid granulomatosis-like lung lesions with abundant infiltrating IgG4-positive plasma cells whose serum IgG4 levels became high following the start of corticosteroid therapy.

A 59-year-old man with a history of prostate hyperplasia was admitted to our hospital for further examination of a lung mass and renal dysfunction. Lung biopsy specimens revealed that inflammatory cells had infiltrated into the blood vessel walls. We initially suspected lymphomatoid granulomatosis, but Epstein Barr virus-encoded small RNA was negative. However, 50% of the infiltrating plasma cells were positive for IgG4. Furthermore, the kidneys and prostate contained abundant IgG4-positive plasma cells. He was diagnosed with IgG4-related sclerosing disease even though serum IgG4 levels were not elevated (45.7 mg/dL). Prednisolone reduced the lung masses and ameliorated renal function, but the serum IgG4 level increased (377 mg/dL). Seronegative IgG4-related sclerosing disease should be considered when patients present with such symptoms and treatment responses, and the secretion of IgG4 might be blocked by its active synthesis.

Pharmacokinetic study of interleukin-2 following intravenous injection in hemodialysis patients with renal cell carcinoma.

The purpose of the present study is to determine the change in blood concentration of interleukin-2 (IL-2) after intravenous injection in hemodialysis patients and to assess its safety. Four hemodialysis patients who underwent nephrectomy due to renal cell carcinoma were treated with IL-2 at a dose of 350 000-700 000 JRU by intravenous injection. Pharmacokinetic parameters were analyzed from the serum IL-2 concentration, which reached its peak just after the end of infusion, followed by biphasic elimination, and was below the detection limit in all patients at 24 h postinfusion. In comparison with patients with normal renal function, the volume of distribution in the serum compartment was almost comparable (3820 +/- 2020 mL). Clearance (50.47 +/- 11.50 mL/min) decreased to 40%, and the half-life of the distribution phase (0.45 +/- 0.19 h) and that of the terminal phase (1.72 +/- 0.20 h) were distinctly longer. The area under the blood concentration-time curve was about two-fold higher than that of non-hemodialysis patients. In all patients, there were no serious adverse reactions. The results of the present study suggest that intravenous IL-2 therapy can be safely performed in hemodialysis patients.

Concentration gradient of oxalate from cortex to papilla in rat kidney.

BACKGROUND: The kidney eliminates the major fraction of plasma oxalate. It is well known that oxalate is freely filtered by glomeruli and secreted by the proximal tubules. However, the renal handling of oxalate in distal nephrons, which is considered as playing an important role in stone formation, remains obscure. METHODS: At 15-180 min after intravenous injection of 14C-oxalate to rats, the intrarenal localization of radioactivity was quantitatively measured by the radioluminographic method using a bioimaging analyzer. Tissue radioactivity was compared with plasma, and urinary radioactivities were measured by a liquid scintillation counter. The control study was conducted with 14C-inulin. RESULTS: The radioactivity of 14C-oxalate in the papilla was 10 times greater than in the cortex and eight times greater than in the medulla 180 min after injection when almost no radioactivity was present in the urine. In contrast, the radioactivity of 14C-inulin was nine times less in the papilla than in the cortex at the same time. CONCLUSION: Oxalate remains in the renal papilla for an extended period. This accumulation of oxalate may be attributed to calcium oxalate crystal fixation along the deep nephron which is considered to be the first step of stone formation.

The preventive effect of sodium pentosan polysulfate against renal stone formation in hyperoxaluric rats.

Sodium pentosan polysulfate (SPP), a semi-synthetic glycosaminoglycan, was administered to rats with hyperoxaluria, induced by a vitamin B6 deficient diet, as a model of calcium oxalate stone formation. We studied the preventive effects of SPP on stone formation as well as its inhibitory effects on stone growth by autoradiography and radioluminography after intravenous injection of (14)C-oxalate. The rats were divided into non-treated and SPP-treated groups. The non-treated rats were divided into three groups: one group was fed a regular diet, while the other two groups were fed a vitamin B6 deficient diet for 2 and 4 weeks, respectively. The SPP-treated rats were divided into two groups: one group was intravenously injected with SPP from the start of the vitamin B6 deficient diet for a total of 4 weeks and the other group was injected with the same amount of SPP after 2 weeks of the diet for 2 weeks. (14)C-oxalate renal macroautoradiograms were prepared, and calcium oxalate deposits in the renal tissues were compared between the non-treated and SPP-treated groups. The preventive effects on calcium oxalate stone formation were clearly observed in the group injected with SPP for 4 weeks. Even in the other SPP-treated group, in which the administration of SPP was started at 2 weeks after the start of the diet when calcium oxalate stone formation was already observed, the size of the calcium oxalate deposits observed after 4 weeks was smaller than that in the non-treated group fed a vitamin B6 deficient diet for 4 weeks. In conclusion, our results show that SPP has not only preventive effects on calcium oxalate stone formation but also growth inhibitory effects on stones in hyperoxaluric rats.

Differential effects of vecuronium on the thumb and the big toe muscles evaluated by acceleration measurement.

To clarify the differential effects of vecuronium on the thumb and on the big toe, train-of-four (TOF) stimuli were applied to the ulnar nerve at the wrist and the tibial nerve at the ankle in anesthetized patients using two acceleration transducers. Ten adult patients, aged 21-55 years, were studied. Anesthesia was induced by an intravenous injection of thiopental, and vecuronium 0.1 mg·kg-1 was used for paralysis. Anesthesia was maintained with nitrous oxide (66%)-oxygen-sevoflurane (1 MAC). The duration of time to the maximal twitch depression on the thumb and the big toe was 136.5±32.5 s and 183.0±40.1 s (P<0.05), respectively. The time to 25% recovery of the twitch height on the thumb and the big toe was 48.1±17.3 min and 39.1±11.6 min, respectively; the time to 50% recovery of twitch height on the thumb and the big toe was 54.1±16.1 min and 40.0±9.2 min (P<0.05), respectively. When paralysis was reversed at 25% of TOF ratio on the thumb, the value of the TOF ratio on the big toe was 58.5±18.2% (P<0.01).