Effect of N-methyl-2-pyrrolidone on skin permeation of estradiol.

N-Methyl-2-pyrrolidone (NMP) increased the skin permeation of estradiol (E2) in Yucatan micropig epidermis using a modified Franz-type diffusion cell. The addition of NMP significantly increased the fluxes of E2 from water and soybean oil. The flux and skin concentration of E2 were higher from soybean oil than from water and increased with increasing NMP concentrations in soybean oil. Correlation was observed with E2 flux and skin concentration (R(2) = 0.804) NMP enhanced E2 skin permeation because NMP made E2 skin concentration higher. Thus, NMP (10%) was added to the oily gel made by isocetyl isostearate and hydrogenated phospholipid. E2 permeation from the gel without NMP was the same as that from soybean oil suspension. The flux of E2 from the gel with NMP was 0.6 microg/h per cm(2) and might be sufficient for estrogen replacement therapy.     

CXCL12/CXCR4 activation by cancer‐associated fibroblasts promotes integrin β1 clustering and invasiveness in gastric cancer

Cancer‐associated fibroblasts (CAFs) are reportedly involved in invasion and metastasis in several types of cancer, including gastric cancer (GC), through the stimulation of CXCL12/CXCR4 signaling. However, the mechanisms underlying these tumor‐promoting effects are not well understood, which limits the potential to develop therapeutic targets against CAF‐mediated CXCL12/CXCR4 signaling. CXCL12 expression was analyzed in resected GC tissues from 110 patients by immunohistochemistry (IHC). We established primary cultures of normal fibroblasts (NFs) and CAFs from the GC tissues and examined the functional differences between these primary fibroblasts using co‐culture assays with GC cell lines. We evaluated the efficacy of a CXCR4 antagonist (AMD3100) and a FAK inhibitor (PF‐573,228) on the invasive ability of GC cells. High CXCL12 expression levels were significantly associated with larger tumor size, increased tumor depth, lymphatic invasion and poor prognosis in GC. CXCL12/CXCR4 activation by CAFs mediated integrin β1 clustering at the cell surface and promoted the invasive ability of GC cells. Notably, AMD3100 was more efficient than PF‐573,228 at inhibiting GC cell invasion through the suppression of integrin β1/FAK signaling. These results suggest that CXCL12 derived from CAFs promotes GC cell invasion by enhancing the clustering of integrin β1 in GC cells, resulting in GC progression. Taken together, the inhibition of CXCL12/CXCR4 signaling in GC cells may be a promising therapeutic strategy against GC cell invasion.     

Induction of p53 protein by carbon-ion and proton beam irradiation in two close human lymphoblastoid cell lines with different p53 status

In this study, we compared the kinetics of the postirradiation p53 protein expression for carbon ion beam (290 MeV/n, LET 75 keV/mu m) and proton beam (65 MeV) with that of (13)7Cs-gamma ray. We used two human lymphoblastoid cell lines derived from the same donor with different p53 status. Wild-type p53 protein increased after irradiation and it was dose-dependent. Meanwhile, the mutated p53 protein level did not show any increase with irradiation. With the three forms of radiation, there was no significant difference as regards the p53 protein kinetics.     

A case of primary malignant lymphoma of the duodenum successfully treated with dose escalating chemotherapy

A 65-year-old woman with diabetes mellitus was hospitalized for heart failure and anemia in August 2001, and recovered with conservative treatment. An endoscopic examination revealed an ulcerative mass located in the duodenal bulb to the 2nd portion. Abdominal CT scan demonstrated tumor involvement in the pancreas head. The diagnosis of a diffuse large B-cell lymphoma, clinical stage IIE, was made by endoscopic biopsy. Although surgical resection of the localized intestinal tumor would have been a common choice for initial treatment, polychemotherapy was selected; the patient had diabetes mellitus and preferred polychemotherapy to surgical operation. Because of bulky intestinal mass, transmural disease and sensitive histological type, standard-dose chemotherapy was considered to include a high risk of intestinal perforation. We performed dose-escalating chemotherapy: A half dose of THP-COP (pirarubicin, cyclophosphamide, vincristine) was given at the start in October 2001, 60% THP-COP as the next cycle, 80% THP-COP as the 3rd cycle and thereafter. Without serious complications of the intestine, she received a total of 6 cycles of chemotherapy and subsequent involved field radiation. There has been no evidence of recurrence of disease 14 months from the start of chemotherapy. When conditions make surgical treatment difficult, dose-escalating chemotherapy in a treatment cycle may be considered as an alternative.     

Arrhythmogenic Right Ventricular Cardiomyopathy Accompanied by Chronic Myocarditis

Patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) classically present with ventricular arrhythmias and less commonly heart failure. ARVC is an inherited cardiomyopathy and generally based on a variant of desmosomal genes. Recently, the association between myocardial inflammation and ARVC has been a matter of great concern. We encountered a patient with ARVC who had a desmoglein-2 mutation with advanced right ventricular failure accompanying a preserved left ventricular function. Concomitant right ventricular myocarditis was detected four years after the diagnosis of ARVC. ARVC and myocarditis might have a deep pathophysiological association, at least in some cases.     

Clinical characteristics and treatment outcomes of patients with small cell carcinoma of the urinary bladder

BackgroundSmall cell carcinoma of the urinary bladder (SCUB) is rare. The optimal treatment for SCUB remains unclear. To address the problem of appropriate treatment for each case, we assessed single-modality and surgery-based multimodality treatments in patients with SCUB.Materials and methodsWe retrospectively reviewed the medical records of 12 patients with SCUB between 1990 and 2013. All patients underwent transurethral resection of the bladder tumor and were diagnosed with SCUB. Their clinicopathological characteristics were assessed, and the outcomes were compared according to the treatment modality.ResultsThe median (range) age at diagnosis was 66 years (range, 53–85 years). T1–4N0M0 was observed in 8 patients (66%), N1–3M0 in 2 (17%), and NanyM1 in 2 (17%). After transurethral resection of the bladder tumor, 6 patients (50%) underwent cystectomy alone, and 4 (33%) underwent cystectomy and presurgical or adjuvant chemotherapy with etoposide and cisplatin. During the median follow-up period of 20.7 months, 6 patients (50%) died of cancer, and 2 patients (17%) died of other causes. The median overall survival period was 1.9 years. The 5-year overall survival rate in patients who underwent cystectomy and chemotherapy was 75%, whereas that in those who underwent cystectomy alone and transurethral resection alone were 22% and 0%, respectively (p = 0.012). Recurrence-free survival was significantly correlated with cause-specific survival (r = 0.95; 95% confidence interval, 0.81–0.99; p < 0.001).ConclusionsRadical cystectomy with chemotherapy using the etoposide and cisplatin regimen improved the prognosis of patients with SCUB and TxNxM0. The time from initial progression to death due to cancer was very short, indicating that the initial treatment strategy is crucial.     

Technical report: a high-dose-rate interstitial brachytherapy boost for residual sinonasal undifferentiated carcinoma

Sinonasal undifferentiated carcinoma (SNUC) is a highly aggressive and uncommon neoplasm that arises from the mucosa of the nasal cavity or paranasal sinuses. The multidisciplinary approach that includes surgery, radiation therapy (RT), and chemotherapy has been proven to improve survival rates. However, there is no established evidence for the efficacy of further (boost) irradiation following definitive RT in SNUC patients with residual primary tumor. We describe a successful case of a patient with SNUC who had an uncontrolled primary tumor following induction chemotherapy and radical concurrent chemoradiotherapy (CCRT) and underwent a high-dose-rate interstitial brachytherapy (HDR-ISBT) boost. A 75-year-old Japanese woman with unresectable locally advanced SNUC (LA-SNUC) received induction chemotherapy followed by radical CCRT. However, because the residual primary tumor was evident after planned external beam RT, she underwent an HDR-ISBT boost, and the tumor decreased significantly. A complete response (the Response Evaluation Criteria in Solid Tumors, ver. 1.1) was achieved 2 months after brachytherapy, and the patient has been disease-free for 2 years following treatment initiation. In conclusion, an HDR-ISBT boost can be a safe and effective treatment option in patients with residual and inoperable LA-SNUC in the maxillary sinus after initial RT.     

Species differences in vacuolation of the choroid plexus induced by the piperidine-ring drug disobutamide in the rat, dog, and monkey

A subchronic oral toxicity study of disobutamide, a piperidine ring compound with antiarrhythmic activity, was conducted at doses of 30, 100, and 250 mg/kg in rats, 45 mg/kg in dogs, and 90 mg/kg in monkeys. Numerous vacuoles were observed in various organs such as the liver, kidneys, heart, lungs, spleen, thymus, stomach, and choroid plexus in these animals. The epithelium of the choroid plexus (CP), however, showed severe vacuolation in rats and monkeys but not in dogs. The vacuoles corresponded to enlarged and myelin-figured lysosomes observed by electron microscopy, revealing morphological characteristics which have been reported as drug-induced phospholipidosis. In a further study, the drug penetration to cerebrospinal fluid (CSF) and the drug concentration in CP were examined in these animals. Daily po doses of 250, 45, and 90 mg/kg were, respectively, administered to rats, dogs, and monkeys to maintain approximate equivalency in peak blood concentrations across species, over a course of 35 days. The concentration of the drug in the CP was higher in rats and monkeys than in dogs, and the CSF/serum ratio of the drug concentration was extremely high in rats. The uptake of the drug by the CP in vitro was high in rats, monkeys, and dogs, in this order. In dogs, both direct contact of the drug with the CP during incubation and intraventricular administration induced vacuolation in the epithelium. From these results it was concluded that differences of the drug's penetration into the CSF and its uptake by the choroid plexus epithelium are responsible for the species differences of CP vacuolation in the animals.     

Decreased portal vein flow during Kawasaki disease in a liver transplant patient

Abnormalities of liver function tests are frequently documented in patients with Kawasaki disease, but the mechanism responsible for this has not yet been established. Described herein is the case of a 1‐year‐10‐month‐old girl who underwent liver transplantation at 11 months of age. Eleven months after transplantation the patient was diagnosed with Kawasaki disease, which was associated with some portal flow reduction, and received i.v. immunoglobulin, after which fever abated with improvement of portal flow to its pre‐fever level. Abnormalities of liver function tests in Kawasaki disease patients may occur as a result of inflammation of both the biliary and portal systems. There are no reports on the potential relationship between Kawasaki disease and the portal vein, and accumulation of further data is necessary to better examine this relationship.