Efficacy of dimethyl fumarate in Japanese multiple sclerosis patients: interim analysis of randomized, double-blind APEX study and its open-label extension.

BACKGROUND: Current data for the use of dimethyl fumarate (DMF) in Japanese patients with relapsing-remitting multiple sclerosis (RRMS) is limited. OBJECTIVES: To assess the efficacy of DMF in Japanese patients with RRMS. METHODS: The phase 3, multinational APEX study (ClinicalTrials.gov identifier: NCT01838668) consisted of two parts: a 24-week double-blind part where subjects were randomized to receive DMF 240 mg or placebo twice daily in East Asian and Eastern European countries, and an open-label extension part where all subjects received DMF. The primary endpoint was the total number of new gadolinium-enhancing lesions in Weeks 12-24. In this interim analysis, we report efficacy data in the Japanese subgroup (DMF n = 56; placebo n = 58) over 72 weeks, including an extension phase. RESULTS: DMF reduced the total number of new gadolinium-enhancing lesions in Weeks 12-24 by 85% versus placebo (p < 0.0001). At Week 24, the annualized relapse rate was also reduced by 48% with DMF, versus placebo. DMF reduced the probability of relapse from Week 8 and was sustained. The number of gadolinium-enhancing lesions was maintained through 72 weeks. CONCLUSIONS: DMF demonstrated sustained efficacy in this Japanese subgroup. The results were consistent with those observed in studies of DMF enrolling primarily Caucasian patients.

Microdosimetric evaluation of the neutron field for BNCT at Kyoto University reactor by using the PHITS code.

In this study, microdosimetric energy distributions of secondary charged particles from the (10)B(n,α)(7)Li reaction in boron-neutron capture therapy (BNCT) field were calculated using the Particle and Heavy Ion Transport code System (PHITS). The PHITS simulation was performed to reproduce the geometrical set-up of an experiment that measured the microdosimetric energy distributions at the Kyoto University Reactor where two types of tissue-equivalent proportional counters were used, one with A-150 wall alone and another with a 50-ppm-boron-loaded A-150 wall. It was found that the PHITS code is a useful tool for the simulation of the energy deposited in tissue in BNCT based on the comparisons with experimental results.

Computerized method for estimation of the location of a lung tumor on EPID cine images without implanted markers in stereotactic body radiotherapy.

The purpose of this study was to develop a computerized method for estimation of the location of a lung tumor in cine images on an electronic portal imaging device (EPID) without implanted markers during stereotactic body radiotherapy (SBRT). Each tumor region was segmented in the first EPID cine image, i.e., reference portal image, based on a multiple-gray level thresholding technique and a region growing technique, and then the image including the tumor region was cropped as a 'tumor template' image. The tumor location was determined as the position in which the tumor template image took the maximum cross-correlation value within each consecutive portal image, which was acquired in cine mode on the EPID in treatment. EPID images with 512 x 384 pixels (pixel size: 0.56 mm) were acquired at a sampling rate of 0.5 frame s(-1) by using energies of 4, 6 or 10 MV on linear accelerators. We applied our proposed method to EPID cine images (226 frames) of 12 clinical cases (ages: 51-83, mean: 72) with a non-small cell lung cancer. As a result, the average location error between tumor points obtained by our method and the manual method was 1.47 +/- 0.60 mm. This preliminary study suggests that our method based on the tumor template matching technique might be feasible for tracking the location of a lung tumor without implanted markers in SBRT.

Microdosimetry of neutron field for boron neutron capture therapy at Kyoto university reactor.

Microdosimetric single event spectrum in a human body simulated by an acrylic phantom has been measured for the clinical BNCT field at the Kyoto University Reactor (KUR). The recoil particles resulting from the initial reaction and subsequent interactions, namely protons, electrons, alpha particles and carbon nuclei are identified in the microdosimetric spectrum. The relative contributions to the neutron dose from proton, alpha particles and carbon are estimated to be about 0.9, 0.07 and 0.3, respectively, four depths between 5 and 41 mm. We estimate that the dose averaged lineal energy, yD decreased with depth from 64 to 46 keV microm(-1). Relative biological effectiveness (RBE) of this neutron field using a response function for the microdosimetric spectrum was estimated to decrease from 3.6 to 2.9 with increasing depth.

Microdosimetry of epithermal neutron field at the Kyoto University reactor.

Microdosimetric spectra were measured in order to gain the microdosimetric parameters of some epithermal neutron fields. Changes in dose mean lineal energy YD as a function of depth of heavy water showed a trend of softening with heavy water of the beam. The neutron absorbed dose was obtained by using the frequency mean lineal energy. Results show good agreement with measurements with the activation method using gold foil. This study demonstrated how microdosimetric parameters change in radiation quality as a function of heavy water depth.

Characterisation of an ultra-miniature counter for microdosimetric measurements in a therapeutic 400 MeV/A carbon beam.

Single event spectra of a clinical carbon beam have been measured by an ultra-miniature tissue-equivalent proportional counter (UMC). In order to cover the energy range of the Bragg peak, the incident energy of the carbon beam was degraded by aluminium plates. Single event spectra for carbon-events incident to the UMC were analysed and selected at several carbon energies using thin scintillation counters. It was found that the dose weighted lineal energy distributions have a doublet peak structure due to incident carbon beam and fragment contributions.

Clinical and endoscopic features of adult T-cell leukemia/lymphoma with duodenal involvement.

We describe three cases of adult T-cell leukemia/lymphoma (ATLL) with duodenal involvement and provide a review of the literature. The first case, a 74-year-old woman with acute subtype of ATLL, had multiple polypoid lesions from the bulbus extending into the descending portion of the duodenum. The second case, a 70-year-old man with lymphoma subtype of ATLL, had a polypoid tumor in the descending portion of the duodenum and multiple protruded lesions in the small and large intestines. The third case, a 67-year-old man with lymphoma subtype of ATLL, had a flat-elevated lesion in the descending portion of the duodenum, as well as a gastric ulcerated lesion. Biopsies from these lesions showed mucosal invasion of ATLL cells in each case. All patients received combination chemotherapy, which was successful in the first and third cases, accompanied by the disappearance of gastroduodenal lesions.

Sludge and stone formation in the gallbladder in bedridden elderly patients with cerebrovascular disease: influence of feeding method.

PURPOSE: The incidence of gallbladder sludge or gallstone formation in bedridden patients with cerebrovascular disease (CVD) remains obscure. The aim of this study was to determine the incidence, relationship to feeding method, and mechanisms of gallbladder sludge and gallstone formation in elderly patients with CVD. METHODS: Using ultrasonography, we determined the development of gallbladder sludge and gallstone over a 12-month period, the area of the gallbladder, the gallbladder contractile response to cerulein, and fasting levels of plasma cholecystokinin (CCK) in 40 bedridden elderly patients with CVD. The patients were divided into three groups based on the feeding method: oral ingestion (OI), nasogastric feeding (NF), and total parenteral nutrition (TPN). RESULTS: Gallbladder sludge and gallstone were not observed in any of the 14 OI patients, but occurred in 6 and 1 of the 11 NF patients, and in 14 and 3 of the 15 TPN patients, respectively. Fasting gallbladder areas were significantly larger in the TPN group than in the other two groups. The TPN group showed a marked decrease in cerulein-induced gallbladder contractility. Fasting plasma CCK levels were lower in the TPN group than in the OI group. CONCLUSIONS: Our results indicate that elderly patients with CVD confined to bed over long periods are not necessarily at risk of gallbladder sludge or gallstone formation, and the development of these features may be associated with the feeding method. The predisposition of CVD patients on TPN to gallbladder disease is probably caused by failure of gallbladder contraction, resulting from insufficient secretion of CCK and impaired sensitivity of the gallbladder to CCK.

Effect of intrarectal prostaglandin E2 analogue (enprostil) on trinitrobenzenesulphonic acid-induced colitis in rats.

Prostaglandins exert a protective effect on colonic mucosa in experimentally induced colitis. This study investigated the effect of enprostil, a prostaglandin E2 (PGE2) analogue, on trinitrobenzenesulphonic acid (TNBS)-induced colitis in rats. Each rat received a rectal enema containing TNBS (30 mg), followed 24 h later by intrarectal once-daily enprostil (200 microg). Enprostil-treated and control rats were killed on day 3 (enprostil group, n = 5; control, n = 6) or day 10 (enprostil group, n = 5; control, n = 5) after TNBS treatment. The area of damaged mucosa of the colon was measured relative to the total colonic area. We also determined the macroscopic score of mucosal damage, and measured PGE2, 6-keto-prostaglandin F1alpha (6-keto-PGF1alpha) and thromboxane B2 (TXB2) concentration in portal vein blood samples. Enprostil significantly reduced both the area of damaged mucosa (including the ulcer area) and the macroscopic score after 3 days' treatment compared with control. Similarly, enprostil significantly reduced plasma concentration of PGE2, 6-keto-PGF1alpha and TXB2 during the acute phase at day 3 of treatment compared with control, but not at day 10. These results suggest that PGE2 enema may have therapeutic potential for treating patients with proctitis or left-sided colitis.

[Three-dimensional imaging of hepatic and intrahepatic portal veins with helical CT: determination of optimal volume of contrast medium by intravenous injection using MIP technique].

In this study, the optimal volume of contrast medium in the liver for three-dimensional (3D) imaging of the hepatic and portal veins by helical CT were determined by intravenous injection using the MIP technique. In the 48 cases examined, CT images of the liver were obtained following the administration of contrast medium (90, 120, or 150 ml and 1.0 <, < or = 1.5 ml; 1.5 <, < or = 2.0 ml; 2.0 <, < or = 2.5 ml or 2.5 <, < or = 3.0 ml/kg) for determination of the optimal volume. The mean body weight of the patients was 59 kg. Contrast medium (Iopamidol 300 mgl/ml) was injected at a rate of 3 ml/sec, and scanning was initiated 70 sec after the beginning of injection. Images were obtained throughout the entire liver using 5-mm collimation. MIP images were graded from poor to excellent based on their visualization of the hepatic vessels. Images produced with 120 ml of contrast medium presented excellent images of hepatic vessels, superior to those produced with 90 ml (hepatic vein: p < .001, portal vein: p < .001). Images produced with 2.0 <, < or = 2.5 ml/kg of contrast medium presented excellent images of the portal vein, superior to those produced with 1.5 <, < or = 2.0 ml/kg ml (p < 0.05). It is evident from the present data that a contrast medium volume of more than 120 ml or 2.0 <, < or = 2.5 ml/kg is sufficient for three-dimensional imaging of hepatic vessels. These images may be a useful diagnostic tool in patients with hepatic disease.

Primary central nervous system lymphoma in Japan: a nationwide survey.

PURPOSE: To analyze clinical features, treatment results, and prognostic factors of primary central nervous system lymphoma (PCNSL) in Japan, we conducted a nationwide survey. METHODS AND MATERIALS: We analyzed 466 patients with histologically proven PCNSL treated between 1985 and 1994 at 62 institutions, including 56 medical schools. RESULTS: Patient and tumor characteristics of the 466 patients were not greatly different from those reported previously, except for the relatively high proportion of T-cell lymphoma (8.5%). The median survival time of the 466 patients was 18 months, and the 5- and 10-year survival rates were 15.2% and 8.2%, respectively. Complete response was observed in 63% of evaluable patients, but 64% of the complete responders developed recurrence (77% within the irradiated volume). Among patient- or tumor-related factors, higher age, worse performance status, presence of B symptom, multiple lesions, presence of meningeal dissemination, and elevated lactate dehydrogenase (LDH) level were associated with poorer survival, whereas no significant difference was observed in prognosis with respect to sex, T/B phenotype, or histological subclassification. In 410 patients receiving at least 40 Gy to the tumor, there was no difference in survival with respect to total radiation dose or field. Patients receiving 2 or more cycles of systemic chemotherapy had a slightly longer median survival time (22 months) and higher 5-year survival rate (20%) than those receiving radiotherapy alone (18 months and 17%, respectively), but the difference was not significant (p = 0.13). No chemotherapy protocol appeared to be better than any other. CONCLUSIONS: In addition to age and performance status, which are well-known prognostic factors, B symptom, tumor number, presence of meningeal dissemination, and serum LDH level also seemed to influence survival. Higher radiation dose was not associated with better prognosis. The role of chemotherapy could not be clarified because of the use of various protocols, but it seemed that the influence of various prognostic factors is greater than the effect of chemotherapy.

A mesenteric liposarcoma with production of granulocyte colony-stimulating factor.

A 77-year-old female was admitted to our hospital because of pyrexia and a right retroperitoneal mass. Leukocytosis and other inflammatory findings were noted. Bone-marrow aspiration revealed hypercellularity with no malignant cells. An additional mass was detected sonographically in the pelvis. The serum concentration of granulocyte colony-stimulating factor (G-CSF) was highly elevated (299 pg/ml). The tumors were removed at laparotomy, and the pelvic mass was found to arise from the ileocecal mesentery. Postoperatively, white blood cell count and serum G-CSF concentrations decreased to normal levels. The mesenteric tumor showed weakly positive immunostaining for human G-CSF, and Northern and polymerase chain reaction (PCR) analyses detected CSF and its mRNA in the mesenteric tumor.

[HR-CT evaluation of lung parenchymal alterations in patients following breast conservation therapy].

Twenty patients with early-stage breast cancer treated with breast conservation surgery and definite radiation, underwent computed tomography (added HR-CT) of the lungs before, immediately after, and at one, six, and twelve months after radiotherapy. During the follow-up period, 17 (85%) of the patients developed parenchymal alterations in the irradiated lung volume. We classified the parenchymal alterations into seven patterns: pattern 1 = septal line, 2 = nodular opacity, 3 = ground-glass opacity, 4 = consolidation, 5 = curvilinear opacity, 6 = aircyst accumulation, and 7 = irregularity of pleural surface. From one to six months after radiotherapy, 14 patients developed nodular opacities and ground glass opacities in the irradiated lung field. At 12 months after radiotherapy, fourteen patients were found to have aircyst accumulation and irregularity of the pleural surface. In this study, none of the patients presented any abnormal findings immediately after irradiation. There was no relationship between central lung distance or boost irradiation and the parenchymal alterations in the lung. On the other hand, there was a close relationship between oral anti-cancer agents and lung lesions. In conclusion, HR-CT was useful to evaluate morphologic changes in the irradiated lung.

Malignant lymphoma of the stomach after chemotherapy for hepatocellular carcinoma.

A rare case of malignant lymphoma of the stomach after treatment for hepatocellular carcinoma (HCC) is reported. A 72-year old man presented with a large mass on the right hypochondrium, which was diagnosed as HCC associated with chronic hepatitis C with cirrhosis. The inoperable tumor was treated conservatively with cisplatin, etoposide, carboplatin, and Lipiodol infused into the hepatic artery, together with transcatheter arterial embolization. The patient presented 38 months later with features suggestive of gastric ulceration. Endoscopy and histological examination of biopsy material confirmed the presence of malignant lymphoma of the stomach. He ultimately died as a result of hepatic failure. The clinical presentation suggests that gastric lymphoma was possibly related to the lymphotropic effect of hepatitis C virus (HCV) and exacerbated by intraarterial injection of the cytotoxic drugs.

Microdosimetric analysis of radiation from a clinical mammography machine using realistic breast phantoms and a miniature proportional counter.

We have measured the microdosimetric spectra of a Senographe 600T mammography machine employing an Mo target with 0.8 mm Be inherent filtration and 0.03 mm Mo added filtration, giving a half-value layer of 0.35 mm A1 at 28 kVp. In all of our measurements a large collimator producing a 24 cm x 30 cm field at 65 cm was used. Two different phantom compositions differing in the ratio of adipose to fibroglandular tissue were compared, using simulated breast material from Nuclear Associates. Spectra were taken at various depths and locations in simulated breasts of 3.4 and 5 cm thickness. The detector used was a miniature proportional counter having outer dimensions of 5 cm x 1.8 cm diameter, with a sensitive volume 0.5 mm x 0.5 mm. The small dimensions of the counter and the cavity allowed total embedding in the breast material with minimal disturbance of the photon and secondary electron spectrum. Our results show that there can be changes in the radiation quality amounting to as much as 17% (as measured by the dose mean lineal energy. yD) between breasts of different thickness, at the same relative position within the breast. There is little difference due to breast composition.

[A case of acute monocytic leukemia cutis treated with total skin electron beam irradiation].

A 35-year-old man with acute monocytic leukemia (AMoL) cutis was treated with total skin electron beam irradiation (TSEBI), because the widespread skin infiltration of AMoL appeared after induction chemotherapy. A skin nodule was authenticated as leukemic cell by biopsy. The patient was irradiated 4 times a week with 200 cGy per fraction to a total dose of 1200 cGy, using 6 MeV electrons from 8 directions. The therapy was accomplished separately on the upper and lower halves of the body. Focus-skin distance was 310 cm. An acrylic plate applicator 1 cm in thickness was used. The dimensions were 90 x 90 cm inside length and 90 cm in height. After completion of radiotherapy, the nodular lesions of the skin nearly disappeared. Although the patient survived only 3.5 months after beginning of radiotherapy due to systemic relapse, recurrence of the skin nodule was not seen. In this case TSEBI was therefore a useful treatment for skin infiltration of AMoL.

Development of a microwave-induced hyperthermia system with multiple applicators.

A hyperthermia system which has been developed for clinical use is described. Five helical coil applicators operating at the microwave frequency of 2450 MHz were used for inducing hyperthermia in superficial tumors to the depth of approximately 5 cm in regions of extreme curvature (i.e. extremities, breasts, head and neck) by superimposing several beams from the multiple applicators. The microwave generators were controlled by a microcomputer governed by temperature measurements from thermocouple probes inserted into the tissue. This system was evaluated with respect to the local specific absorption rate (SAR) of the electromagnetic energy for two agar gel phantoms. The relationship of temperature versus depth in four patients was measured with 2-4 applicators (total, 250-600 Watt). Up to May, 1989, 70 patients with superficial tumors, esophageal cancer and carcinoma colli had been treated with radiotherapy combined and local hyperthermia using this system.

[Successful treatment with tegafur and PSK in a patient with gallbladder cancer].

A 56-year-old man was admitted to Miyazaki Prefectural Hospital with a complaint of pain in the right upper quadrant. The liver was moderately enlarged on palpation with tenderness in the upper abdomen. Ultrasonography and abdominal CT showed gallbladder tumor with multiple space-occupying lesions in the liver. In addition, serum levels of CEA and CA19-9 were markedly elevated. These findings suggested gallbladder cancer with liver metastasis, and he was soon started on tegafur rectally (1,000 mg/day) and PSK orally (3.0 g/day). Two months later, the lesions in the liver almost disappeared, although little change in size of the gallbladder tumor was noted. This condition lasted for 6 months indicating partial response. Subsequently, he died of liver failure 14 months after the start of treatment. Since few antineoplastic agents have been reported to be effective against gallbladder cancer, tegafur and PSK might be a good combination for this disease.

[The applicability of pions to cancer radiotherapy. III. Measurement of x-ray and gamma-rays by NaI detector for the determination of the peak-region in pi- meson exposure].

A method of externally observing the stop-region of pi- meson for monitoring during exposure to a patient is discussed. Negative pi mesic X-rarys, gamma-rays and neutrons are emitted from the region where pi- mesons stop and produce stars. These radiations can be detected outside the exposed patient. Water phantom as normal tissue equivalent material was exposed by pi- mesons at various depths. The resulting gamma-ray yields were determined by counting the gamma-rays in coincidence with incident pi- mesons using a sodium iodide (NaI) detector. This type of gamma-ray measuring system is useful to make sure that the peak position of the depth-dose distribution in the patient is exactly situated at the desired one during exposure. It is suggested that the scintillation camera with a multiholecollimator is a powerful and convenient tool for the two dimensional peak positioning.