Search

We report the case of a patient who achieved complete remission (CR) of cisplatin-refractory metastatic pure seminoma after treatment with high-dose carboplatin and etoposide (CE) with peripheral blood stem cell transplantation as fourth-line chemotherapy. A 38-year-old man was diagnosed with advanced pure seminoma (pT3N3M1aS3). In the international germ cell consensus classification, his prognosis was classified as intermediate. He was treated with high-dose CE as fourth-line chemotherapy after treatment with BEP, VeIP, and TIN. After two cycles of high-dose CE, the concentrations of T-HCG and other tumor markers showed normal levels. A CT scan and PET–CT showed that the lymph node swelling had disappeared and there was no uptake. The CR has continued for 27 months after the treatment. High-dose CE might be less toxic and have a better prognostic outcome than other treatments as salvage chemotherapy for patients with cisplatin-refractory advanced testicular cancer.

Purpose We previously reported early efficacy results from a phase I/II study of definitive chemoradiotherapy using docetaxel, nedaplatin and 5-fluorouracil (DNF-R), and confirmed strong antitumor activity with an acceptable early toxicity profile for patients with esophageal cancer. Here, we present the long-term results of the study including late toxicity and survival. Methods Thirty-one patients were enrolled. Patients received 5-fluorouracil (400 mg/m2 civ, d1-5 and d8-12), nedaplatin (50 mg/m2 on d1 and 8), and docetaxel (20-30 mg/m2 on d1 and 8), repeated twice every 5 weeks with concurrent radiotherapy (59.4Gy/33fr). Study objectives in the phase II part included the CR rate, progression-free survival (PFS), overall survival (OS), and safety. Results Between December 2008 and February 2014, a total of 28 patients were registered. Grade 3/4 acute toxicities included neutropenia (43%), febrile neutropenia (7%), thrombocytopenia (18%), and esophagitis (21%). Grade 3/4 late toxicity included esophagostenosis (11%) and pleural effusion (7%), though these resolved with dilation and thoracic drainage, respectively. All patients achieved a response, with 23 (82.1%) CR cases (stege II/III 89%, T4/M1LYM 67%). With a median follow-up time of 69.8 months, the 3-/5-year PFS and OS were 68.4/68.4% and 71.5/66.8%, respectively. 5-year OS for stage II/III (nonT4) and T4/M1LYM were 68.4% and 28.6%, respectively. Conclusions The long-term results show that efficacy was maintained with high rate of PFS and OS compared with those of historical control, with durable responses and acceptable safety profile. DNF-R might be a promising regimen for definitive CRT for esophageal cancer.

This study was performed to assess the in vivo ocular toxicity of benzalkonium chloride (BAK) homologs compared with commercially available BAK (BAK mixture) and to assess the ocular toxicity of BAK homolog after repeated ocular application. Rabbit eyes were examined by ophthalmology and scanning electron microscopy (SEM) after 10 applications of BAK homologs with C12 (C12-BAK) and C14 (C14-BAK) alkyl chain lengths and a BAK mixture at concentrations of 0.001% (w/v), 0.003% (w/v), 0.005% (w/v), 0.01% (w/v) and 0.03% (w/v). The ocular toxicity of C12-BAK to rabbit eyes was examined by ophthalmology and histopathology after repeated ocular application for 39 weeks. In addition, the antimicrobial activities of C12-BAK and C14-BAK against A. niger, S. aureus and P. aeruginosa were assessed. Ocular toxicity of C12-BAK was less than those of the BAK mixture and C14-BAK. No ocular toxicity was noted after ocular application of 0.01% C12-BAK to rabbits for 39 weeks. C12-BAK showed antimicrobial activities at a concentration of 0.003%. These results suggest that the use of C12-BAK to replace BAK mixture as a preservative in ophthalmic solutions should be considered in order to reduce the incidence of the corneal epithelial cell injury induced clinically by BAK.

Collagenous fibroma, also known as desmoplastic fibroblastoma, is a benign fibrous soft tissue tumor showing gradual growth, commonly without aggressive local infiltration. Today, preoperative radiological diagnosis is important to avoid over-treatment and unnecessary extensive procedures, but is difficult because diagnostic imaging findings for collagenous fibroma have not been established. We report MR imaging findings of three collagenous fibromas in correlation with their histopathology. The characteristic rim enhancement on post-contrast T1-weighted images with fat suppression was present in all three cases, and we consider this to represent the difference in vascularity between the outer capsule-like fibrous tissue and the inside of the tumor.

Chondromyxoid fibroma (CMF) of the rib is exceedingly unusual and few detailed image findings have been reported. Plain radiograph, computed tomography (CT), and magnetic resonance (MR) imaging findings and pathological aspects of a case of CMF of the right 2nd rib in a 15-year-old woman are reported, which was difficult to diagnose preoperatively. Though it is challenging to diagnose CMF preoperatively, it is important to be aware that CMF can exhibit atypical prominent exophytic features in unexpected locations such as the ribs.

Halo-forming colony and its variant (non-halo forming) strains, designated NUM-Aa 5014 and NUM-Aa 5016, respectively, were isolated from periodontitis. They were identified as Aggregatibacter actinomycetemcomitans serotype f. The NUM-Aa 5014 strain showed an aggregated form in the broth culture and strong biofilm formation on hard surfaces, while NUM-Aa 5016 did not show this phenomenon. In a Congo red (CR)-binding assay, the halo-forming colony strain NUM-Aa 5014 was strongly bound by CR. ATCC 33384T and NUM-Aa 5016 showed low binding activity. The tight adherence (tad) locus of the NUM-Aa 5014 and 5016 strains contained 14 genes, flp-1-flp-2-tadV-rcpCAB-tadZABCDEFG, in 11,565 and 11,574 bp, respectively. Almost all genes were the same except the flp-1 and tadD genes between the NUM-Aa 5014 and 5016 strains. The homologies of flp-1 and tadD genes in the NUM-Aa 5014 and 5016 strains were 97.4% and 99.6% in amino acid sequences, respectively. These results suggest that the expression of genes in tad locus may play some roles in adherence and aggregation of A. actinomycetemcomitans.

A 52-year-old man with bilateral swelling in the scrotum was referred to the department of urology in our hospital in January 2013. Pathological examination of the scrotum revealed diffuse large B-cell lymphoma(DLBCL). Immunohistochemical staining revealed p53 overexpression, and polymerase chain reaction-single strand conformation polymorphism(PCRSSCP) revealed a point mutation in exon 7 of the p53 gene. Rituximab plus cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisolone(R-CHOP)therapy and intrathecal prophylaxis were initiated. After three courses of R-CHOP therapy, high-dose cytarabine was administered, followed by peripheral blood stem cell harvesting. Busulfan, etoposide, and Ara-C(BEA)therapy was then administered, followed by autologous peripheral blood stem cell transplantation(auto- PBSCT). Primary testicular lymphoma(PTL)is a rare, clinically aggressive form of extranodal lymphoma, and there is a high incidence rate of relapse in the central nervous system(CNS). The vast majority of cases are histologically DLBCL. The p53 mutation is an independent marker of poor prognosis in patients with DLBCL treated with R-CHOP therapy. Our patient has been disease free for 17 months after auto-PBSCT with high-dose chemotherapy, which results in a greater level of penetration into the CNS.

The objective of our study was to evaluate the exposure doses to patients and radiologists during transcatheter arterial embolization (TAE) for hepatocellular carcinoma (HCC) using a new angiographic unit with a digital flat-panel system.Doses were assessed for 24 procedures: 12 using a new unit with a digital flat-panel system and 12 using a conventional unit. Doses to patients' skin were evaluated with thermoluminescent dosimeters behind the left, middle, and right portions of the liver. The doses to the radiologists were measured by an electronic personal dosimeter placed on the chest outside a lead protector. The maximal skin doses to the patients and the dose equivalents, Hp(0.07), to the radiologists were compared between the two procedure groups with each angiographic unit.For procedures with the new unit, the mean maximal skin dose to the patients was 284 +/- 127 (SD) mGy (range, 130-467 mGy), and Hp(0.07) to the radiologists was 62.8 +/- 17.4 muSv. For procedures with the conventional unit, the maximal skin dose to the patients was 1,068 +/- 439 mGy (range, 510-1,882 mGy), and Hp(0.07) to the radiologists was 68.4 +/- 25.7 muSv. The maximal skin dose to the patients was significantly lower with the new unit than with the conventional unit (p0.0005). There was no significant difference in the Hp(0.07) to the radiologists between the two procedure groups.The new digital flat-panel system for angiographic imaging can reduce the radiation dose to patients' skin during TAE for HCC as compared with the conventional system.

We describe imaging and pathologic features of serous cystadenoma of the pancreas on multislice helical computed tomography CT (MS-CT) and surgical resection.Radiologic and pathologic features were analyzed in five patients. All patients underwent MS-CT and digital subtraction angiography (DSA), and four patients underwent magnetic resonance (MR) imaging. Preoperatively, three cases showed radiologic evidence of mainly solid appearance on MS-CT, and the suspected diagnoses were solid pancreatic tumors (patients 1-3). The other two cases showed radiologic evidence of macrocystic tumor of the pancreas, and the suspected diagnoses were mucinous cystic tumors (cases 4 and 5). All patients underwent surgery, and the diagnosis of serous cystadenoma was confirmed on pathologic examination.In three cases that showed a solid appearance on MS-CT, a microcystic appearance was identified on microscopic examination, and the tumors were found to be hypervascular lesions on multiphasic contrast-enhanced CT and DSA. In cases 1 and 2, the lesions showed high intensity with internal septation on T2-weighted MR images. In two cases, the tumors were classified as a macrocystic variant of serous cystadenoma, and no mural nodules, papillary projections, or calcifications were seen in the tumors.Imaging appearance of serous cystadenoma on MS-CT is various and sometimes indistinguishable from that of solid tumor or mucinous cystic tumors of the pancreas. Imaging findings of hypervascularity and a well-marginated high-intensity lesion with internal septation on T2-weighted MR imaging may be crucial to identify serous cystadenoma that contains no visible cystic compartments on MS-CT.

A 25-year-old man with suspected Gardner syndrome was introduced to our hospital by a dentist who, during examination of the patient, had found dental dysplasias and multiple osteomas of the jaw. Radiographs, endoscopy and biopsies revealed adenomatous polyposis of the colon. Genetic analysis of peripheral lymphocytes revealed a one-base deletion at codon 1556 in exon 15 of APC, which caused a frame shift and a premature stop at codon 1564. The pedigree analysis demonstrated five patients in his family who presented with dental abnormality and osteomas in addition to adenomatous polyposis of the colon. Although the relationship between the location of APC mutations and dental abnormalities remains controversial, this case supports the hypothesis that a mutation at around codon 1556 of APC is closely associated with dental abnormality and osteomas.

PURPOSE To evaluate the possibility of superparamagnetic iron oxide (SPIO)-enhanced magnetic resonance imaging (MRI) of the liver in predicting the histologic grade of hepatocellular carcinoma (HCC) and differentiating HCC from benign hyperplastic nodule (HPN). MATERIALS AND METHODS Thirty patients with 31 histologically proved HCC and HPN underwent MRI (1.5 Tesla). HCCs were graded into well-differentiated HCC (HCCw; n = 10) and moderately to poorly differentiated HCC (HCCmp; n = 15). HPN was categorized into dysplastic nodule (DN; n = 1) and focal nodular hyperplasia (FNH; n = 6). T2-weighted fast spin echo images were obtained before and after administration of SPIO. Signal-to-noise ratios (SNR) of the lesion and surrounding liver parenchyma and contrast-to-noise ratios (CNR) were calculated pre- and postcontrast study. Relative enhancement ratios (RER), also known as signal intensity reduction ratios of the lesions, were also calculated. RESULTS HCCw, HCCmp, DN, and FNH decreased in SNR after injection of SPIO. RER of HCCw was 19.5 +/- 13.3%, that of HCCmp was 6.8 +/- 5.8%, DN was 44.0%, and FNH was 42.9 +/- 4.8%. Significant statistical differences were seen between HCCw and HCCmp and HCC and HPN in RER. HCCw, HCCmp, and DN increased in CNR, and FNH decreased in CNR, but no lesion showed a statistically significant difference in CNR. CONCLUSION SPIO-enhanced MR images may help to predict the histologic grade of HCC and distinguish HCC from HPN.

The aim of this study was to investigate the effect of a transjugular intrahepatic portosystemic shunt (TIPS) on portal hypertensive gastropathy (PHG) and gastric hemodynamics.A total of 16 patients with cirrhosis and portal hypertensive gastropathy were prospectively studied. Of these, 12 patients underwent TIPS for esophageal varices and four for refractory ascites. Gastric mucosal blood flow (GMBF) was assessed by laser Doppler flowmeter, and total blood flow (TBF) in submucosa and mucosa by near-infrared endoscopy. Portal venous pressure was obtained by a transducer during the TIPS procedure. The severity of portal hypertensive gastropathy was classified as none, mild, or severe. The examinations were performed before and 2 wk after the procedure.TIPS significantly reduced portal venous pressure. PHG improved in all four patients with severe PHG and in five of 12 patients with mild PHG after treatment. Gastric mucosal blood flow increased from 49.0 to 55.6 ml/min/100 g after TIPS. In contrast, TBF decreased from 0.35/s to 0.27/s after treatment. Liver function tests showed no significant changes before and after the procedure.It is considered that TIPS may have a beneficial effect on PHG at least for a short time. The mechanism by which PHG improves may be closely related to the improvement of the injured gastric perfusion in cirrhotic patients with PHG.

Interrelationships among induction of cytochrome P-450 (CYP) 1A1/2, decrease in connexin 32 (Cx32), and liver tumor-promoting activity by β-naphthoflavone (BNF) in the promotion stage were examined in a 2-stage liver carcinogenesis model. A total of 20 male Fischer 344 rats were initiated with a single intraperitoneal injection of 150 mg/kg of diethylnitrosamine (DEN) or were given the saline vehicle alone. Starting 2 weeks later, they were fed a diet containing 2%, 1%, or 0% BNF for 6 weeks. All animals were subjected to a two-thirds partial hepatectomy at week 3 and were sacrificed at week 8. Absolute and relative liver weights were significantly increased in the DEN+BNF groups as compared to the DEN-alone group. Diffuse hepatocellular hypertrophy with cytoplasmic eosinophilia, sometimes accompanied by development of adenoma-like hepatic foci, was observed in the BNF-treated rats. Remarkable induction of cytochrome CYP 1A1/2 and significant increase in CYP 2E1 were noted in the DEN+BNF groups, and positive immunohistochemical staining for both was observed diffusely. The areas of Cx32-positive spots per hepatocyte in the centrilobular areas of livers of the BNF-treated rats were significantly decreased, but no changes were observed in periportal areas. The numbers and areas of foci positive for glutathione S-transferase placental form were increased in the BNF-treated groups. These results suggest that BNF is a liver tumor promoter that, unlike phenobarbital, does not induce CYP 2B1/2 isozymes, and there seems to be no direct relationship between CYP 1A1/2 induction and Cx32 reduction in BNF hepatocarcinogenesis.

The present study examined the prevalence of dementia in the Nagasaki Prefecture. The purposes of our investigation were (a) to study the relationship between aging and the prevalence of dementia and the ratio of Alzheimer's disease (AD) to vascular dementia (VD), (b) to understand the features of early-onset dementia as seen in patients from 60 to 65 years, and (c) to examine the recognition of dementia by family members. The subjects of the study, a total of 4,368, were all 60 years old and over and were residing in the three areas of Nagasaki Prefecture at the time of the investigation, August 1995. We adopted a two-stage design. The first-stage questionnaire that we developed was delivered to subjects, and we selected for the second stage those subjects who met the criteria outlined in the Methods section. The second-stage investigation was an interview by community nurses and psychiatrists. The prevalence of dementia in subjects 60 years and over was 6.2% (men: 5.9%; women:6.8%). The prevalence increased with age. The AD/VD ratio was 1.4, and was similar to the recent trend in Japan in that the ratio has reversed to resemble the western pattern. In regard to the family members' recognition of illness, the higher the severity of dementia, the higher the recognition ratio of family members became. Only half of these subjects were recognized as having dementia by their family members. In conclusion, the westernization of the AD/VD ratio in Japan was proved. There was little study about family recognition of dementia. In this study, it was remarkable that only half of the subjects were recognized as having dementia by their family members.

In a previous study, p-dichlorobenzene (pDCB), which is associated with tumorigenicity in male rat kidney and livers of mice of both genders, was found to produce acute increases in cell proliferation in those tissues. To determine whether sustained cell proliferation in the liver in susceptible species correlated with reported carcinogenic effects, we examined the effect of pDCB on cell proliferation in the livers and toxicity to the glutamine synthetase-expressing hepatocyte (GS+) subpopulation of male B6C3F1C3F1 mice and F344 rats. Mice were exposed for up to 4 weeks to 600, the maximally tolerated dose which increased liver tumors, 300 or 150 mg/kg. Rats were exposed to 300, 150 or 75 mg/kg for up to 4 weeks. In mice, the cumulative replicating fraction (CRF) in the livers of the high dose animals was significantly increased 16-fold at 1 week and 4-fold at 4 weeks. The CRF was also increased at 300 mg/kg at 1 week, but this subsided at 4 weeks. No increase was seen in the low dose group. In rats, the CRFs of the livers at 1 week were increased at 300 and 150 mg/kg, but returned to normal at 4 weeks. The size of the hepatic GS+ area was not affected in mice or in rats after 1 week of exposure, but comparable decreases were observed at all exposures at 4 weeks in mice. The data therefore suggest that sustained increases of cell division in the mouse liver may contribute to the increases in liver tumors. The transient increase in rat liver suggests that this is not sufficient to enhance tumor development. The absence of sustained increases of the CRFs at the low dose in mice, which was one-fourth of the hepatocarcinogenic dose, implies the existence of a threshold in pDCB hepatocarcinogenesis.

A 79-year-old female diagnosed with T cell/histiocyte-rich large B cell lymphoma in complete remission after six cycles of rituximab-combined chemotherapy developed severe anemia, reticulocytopenia, and bone marrow erythroid hypoplasia. She was diagnosed with pure red cell aplasia (PRCA) accompanied by Coombs-negative autoimmune hemolytic anemia evidenced by a lack of glycophorin-A-positive cells in the bone marrow, haptoglobin under the detection level, and a high titer of RBC-bound IgG. Anti-erythropoietin receptor (EPOR) antibody was detected in the serum, and oligoclonal α/β and γ/δ T cells were also detected in her peripheral blood by Southern blotting analysis. Parvovirus B19 DNA was not detected by PCR. Although the treatment with rituximab had limited efficacy (specifically, only for hemolysis), subsequent cyclosporine therapy led to prompt recovery of erythropoiesis with the disappearance of anti-EPOR antibody and oligoclonal T cells. This is the first case report of anti-EPOR antibody-associated PRCA in a patient with malignant lymphoma treated successfully with cyclosporine.

A chronic feeding study was carried out in Wistar rats using microencapsulated bromodichloromethane. The test substance was administered in the diet at doses of 0, 0.014, 0.055 and 0.22% for 24 months. Rats were sacrificed after 6, 12, 18 and 24 months of continuous dosing. The results showed a suppression of body weight gain in the 0.22% group for both males and females. Dose related changes were clearly observed in the liver with histopathological findings including fatty degeneration in the 0.014% or higher dose male groups, and fatty degeneration and granuloma in the 0.055 and 0.22% group females, as well as bile duct proliferation and cholangiofibrosis in the 0.22% group for both males and females. No significant differences in incidences or numbers of neoplastic changes were seen between control and any of the treatment groups. There were no dose-related non-neoplastic lesions in the kidneys of either sex. Lowest-observed-adverse-effect-level was determined to be 6.1 mg/kg/day under the present experimental conditions.

When considering surgery for branch duct-intraductal papillary mucinous neoplasms (BD-IPMNs) with suspected malignancy, it should be recognized that these lesions are frequently multifocal and are usually found in elderly patients with potential comorbidities that could affect the outcome of surgery. Clinical trials of chemoprevention have been conducted for a wide variety of malignancies. Twenty-two BD-IPMN patients participated in the trial at our institution from June 2004 to January 2007. Ten of the 22 patients who rejected surgical therapy although their lesions or clinical symptoms met the criteria for surgical resection of the International Association of Pancreatology guidelines were assigned to the treatment group. Sulindac (150 mg twice daily) and omeprazole (20 mg once daily) were administered to these patients for 18 months. The remaining 12 patients comprised the control group. Branch duct diameter and mural nodule heights were monitored by either magnetic resonance cholangiopancreatography (MRCP) or computed tomography (CT) and by endoscopic ultrasonography (EUS). Both branch duct diameter and mural nodule height of BD-IPMNs in the treatment group were significantly reduced, while those in the control group were unchanged. Immunohistochemical staining for cyclooxygenase-1 and -2 was negative in hyperplasia, adenoma and carcinoma portions of resected pancreatic specimens but was clearly positive for glutathione-S-transferase π (GST-π), suggesting that GST-π is a putative target molecule for sulindac. Although a larger scale randomized controlled study is needed in future, the present results suggest the promise of chemoprevention of carcinoma derived from BD-IPMNs by sulindac.

Four groups of 40 Wistar rats of each sex per dose level were fed diets containing 0, 80, 400 or 2000 ppm of the magnesium salt of bis(2,3-dibromopropyl)phosphate (Bis-BP) for 24 months. A high incidence of tumours was induced, in both sexes, in the digestive system. Tumours included papillomas and adenocarcinomas of the tongue, oesophagus and forestomach, adenocarcinomas of the intestine and hepatocellular adenomas (neoplastic nodules) and carcinomas. Pre-terminal mortalities were associated with an increased incidence of forestomach papillomas in both sexes, adenocarcinomas of the small intestine in male rats and increased incidence of hepatocellular carcinomas in females. The data suggest that Bis-BP is a more potent proximate carcinogen than tris-(2,3-dibromopropyl)phosphate (Tris-BP).

We conducted a comparative study of symptoms and social adjustment of schizophrenic patients on offshore islands and one urban region in Japan. In the evaluation of symptoms and social behavior by family members, no differences were observed between the two regions. Looking at social adjustment in the two regions, no differences were observed by family members either in the performance level or in the expectation level of socially expected activities. However, on the offshore islands, the expectation level of socially expected activities by family members was significantly higher than the level of self-accomplishment set by schizophrenic patients themselves. As for leisure activities, both family members and patients on the island evaluated the level of performance to be significantly higher than in the urban region, and the level of satisfaction of the patients themselves was also higher on the islands. Considering both these findings and Japanese traditional views of work and leisure, it is believed that on the islands patients are required to engage in more productive activities and less leisure activities than in the urban region. Further it seems that patients on the islands compared to patients in the urban region may have greater difficully in social adjustment.

Objective The purpose of this study is to evaluate predictive factors for discriminating benign from malignant intraductal mucin-producing neoplasm (IPMN) of the pancreas on multidetector row computed tomography (MDCT). Materials and methods Fifty-three patients with IPMN underwent MDCT, and the imaging and pathological findings were evaluated. In patients with branch duct-type tumors, sex and age of the patient, location, shape, size and multiplicity of the cystic lesion, presence of mural nodule, and maximum diameter of main pancreatic duct (MPD) dilatation were evaluated by logistic regression analysis. Results Tumors were classified as main duct-type (n = 7) and branch duct-type (n = 46). Among main duct-type tumors, all 7 lesions were diagnosed as malignant. Among 46 lesions of branch-type IPMN, 8 lesions were malignant, and 38 lesions were benign. On adjusted logistic regression analysis, combination factor of main duct dilatation and mural nodule or large cystic size had statistical significance for the risk of malignancy in branch duct-type IPMN. Conclusions Main duct-type IPMN is highly suggestive for malignancy. Combination factors of main ductal dilation and mural nodule, and main ductal dilation, and large cystic tumor size are thought to be predictive factors for malignant branch-type IPMN.

This study investigated the course of negative symptoms by examining the psychiatric symptoms of 59 new schizophrenic patients at the first consultation and again two years later using a structured interview--the Present State Examination. An examination of the total score of the nine negative symptoms, included in the "Chronic Schizophrenic Syndrome" by Wing, showed that 27 out of the 59 patients (45.8%) had lower symptom scores two years later than they did at the first consultation ("negative symptom improvement" group), while 20 patients (33.9%) had higher scores two years after the first consultation ("negative symptom deterioration" group). There were 12% more patients in the improvement group than in the deterioration group. No significant differences were observed between the "improvement group" and "deterioration group" in relation to the following factors--subclassification of schizophrenia, mode of onset, age at the first consultation, marital status at the time of onset, academic history, employment status prior to the onset, the history of hospitalization after the onset and maintenance therapy of neuroleptics. In relation to psychiatric symptoms at the first consultation, the patients in the "improvement group" had a variety of symptoms compared to the patients in the "deterioration group," and the presence of "incoherence of thought," "delusion of reference" and "special features of depression" was significantly higher in the improvement group than in the deterioration group.

The Nagasaki Center, designated as a World Health Organization (WHO) Collaborating Center in 1979, has taken the lead in generalizing ICD-10 (F) in Japan. The progress of ICD-10 (F)-related research, trials and publications has been as follows. The field trials of ICD-10 Clinical Descriptions and Diagnostic Guidelines (CDDG) 1986 draft were carried out with 129 patients by 61 clinicians in five institutions coordinated by Tokyo Medical and Dental University and Nagasaki University in 1988. The Japanese version of ICD-10 CDDG was published by Tooru et al. in February 1993. The field trials of ICD-10 Diagnostic Criteria for Research (DCR) 1990 version were conducted with 847 patients by 169 clinicians at 28 institutions and 2299 assessments were obtained. The Japanese version of ICD-10 DCR final version was published by Nakane et al. in May 1994. The Japanese version of the Glossaries and Conversion Tables between ICD-9 and ICD-10 was published by Nakane et al. in October 1994. The field trials of ICD-10 Multiaxial Presentation were conducted with 34 psychiatrists at six institutions in 1993 and the total of 676 assessments was obtained, and the adequacy and usefulness of the text were examined.

A 31-year-old man referred to our hospital for treatment of his chronic myeloid leukemia (CML) in the first chronic phase by bone marrow transplantation. We pretreated him with cyclophosphamide and total body irradiation and bone marrow transplantation (BMT) was carried out. On day 31, the engraftment was confirmed and on day 52, acute graft versus host disease (GVHD) was observed. On day 189, he lost consciousness due to cyclosporine A-induced leukoencephalopathy and 375 mg cyclosporine A was changed to 100 mg prednisolone. On day 199, liver dysfunction (AST 410 IU/L, ALT 557 IU/L, gammaGTP 385 IU/L, ALP 363 IU/L, D-Bil 0.3 mg/dl) developed and a liver biopsy was performed. PCR analysis of DNA from the liver biopsy specimen was positive for HHV-6 and immunostaining using anti-HHV-6 and anti-HHV-6b antibodies showed positive staining in the cytosol of hepatocytes. No other viruses were found to induce hepatitis. From these results, he was diagnosed as having HHV-6 hepatitis and it was successfully treated with gancyclovir (GCV) administration.

We have previously shown that the HDAC inhibitors (HDACI) activate the p53 molecule through acetylation of 320 and 373 lysine residues, upregulate PIG3 and NOXA and induce apoptosis in cancer cells expressing wild and pseudo-wild type p53 genes (Terui T, et al. Cancer Res 2003; 63:8948-54). It has also been reported that expression of the Coxsackie adenovirus receptor and subsequent transfection efficiency of the adenovirus in cancer cells were enhanced by HDACI treatment. In this study, we extended these observations to explore the combination effect of adenoviral vector carrying wild type p53 (Ad-p53) gene therapy with a HDACI, sodium butyrate (SB), on xenografted human gastric cancer cells (KATO-III) and hepatocellular carcinoma cells (HuH7) in nude mice. We first confirmed an increased expression of Coxsackie adenovirus receptors with an associated increment of transgene (X-gal) expression by SB treatment in KATO-III cells. We then injected Ad-p53 into subcutaneous tumors of KATO-III and HuH7 combined with intraperitoneal administration of SB and found a significantly higher growth suppressive effect than single treatments of each. Even a complete regression of tumors was observed in three of five mice treated with this combination while with single treatment no tumor regression was observed. Tumors treated with the combination showed higher numbers of TUNEL positive cells than those treated with a single modality. Moreover, necrotic changes were more evident in tumors treated with the combination than separately, a compatible finding to the observation that vascularity revealed by CD34 staining was poorer in tumors treated with the combination than those treated with p53 gene or SB alone. This was further supported by the finding that BAI-1 (brain specific angiogenesis inhibitor-1), an inhibitor of vascularization, was induced by SB treatment in KATO-III and HuH7 cells transfected with Ad-p53. Thus SB was shown to be an efficient potentiator of p53 gene therapy for cancer.

Takeshita K, Kutomi K, Takada K, Kohtake H, Furui S ultiphasic contrast enhancement CT with IV contrast administration has been used for the diagnosis of insulinomas [1–3]. Although recent reports of studies using MDCT have suggested improved performance in revealing these tumors, MDCT may fail to depict some lesions [1]. Because insulinomas are generally found as small nodules with a hypervascular nature, MDCT with intraarterial contrast infusion (MDCT-IA) may show the tumors more clearly by increasing the attenuation difference between the lesions and pancreatic parenchyma. Three-dimensional images obtained by this method may offer additional information for more accurate diagnosis or localization of the lesions. We describe the results of MDCT-IA in three patients with histologically proven insulinomas compared with those of MDCT with IV contrast material infusion (MDCT-IV) and digital subtraction angiography.

Arterial stimulation and venous sampling was effective in the localization of Beta-cell hyperplasia of the pancreas in the islets of Langerhans in an 84-year-old woman. The patient presented with repeated episodes of unconsciousness and hypoglycemia. She was first suspected of having insulinoma, but diagnostic imaging failed to reveal any tumors. Arterial stimulation and venous sampling (ASVS) and percutaneous transhepatic portal venous sampling (PTPS) were performed to localize the tumor. By ASVS, increases in immuno reactive insulin (IRI) were noted in renal vein blood samples (because a splenorenal shunt was present) after splenic arterial stimulation and venous sampling, and PTPS revealed a stepup in IRI from splenic venous blood samples. Preoperative diagnosis suggested Beta-cell hyperplasia in the pancreas tail. Intraoperative ultrasound failed to find a tumor. Intraoperative ASVS showed the site of increase IRI as the pancreas tail, so distal pancreatectomy and splenectomy were performed. However, hypoglycemia was observed constantly after this operation. Relaparotomy, causing additional resection, was conducted to confirm the precise location and to remove the residual Beta-cell hyperplasia of the pancreas. At the second resection, the existing part of Beta-cell hyperplasia was confirmed through intraoperative ASVS, and additional resection of the pancreas body and neck was performed. At this time, complete removal of the residual Beta-cell hyperplasia was confirmed through ASVS. The hypoglycemia and impaired consciousness disappeared after the operation, and the patient's blood sugar level was maintained at a normal level. Pathological findings revealed islets of Langerhans hyperplasia extending to 1 cm in the pancreas tail region. We conclude that pre- and intraoperative ASVS is a useful test for Beta-cell hyperplasia, which is difficult to diagnose through ordinary imaging techniques.

Two controversial issues regarding p53 are whether it is involved in apoptosis induction of tumor cells by a histone deacetylase (HDAC) inhibitor and, given that p53 is indeed involved, which genes of acetylated p53 targets are responsible for giving rise to apoptotic death. We, in the present study, first confirmed that some substantial extent of apoptotic cell death was seen when p53-deficient cells (KATO-III) were transfected with wild-type p53 and treated with sodium butyrate (SB) or trichostatin A. By Western blotting, using specific antibodies, we then demonstrated that residues 320, 373, and 382 lysines of p53 were acetylated in KATO-III cells transfected with wild-type p53 (KATO-III/p53) treated with a HDAC inhibitor. However, as revealed by terminal deoxynucleotidyl transferase-mediated nick end labeling staining, only those KATO-III cells transfected with K320R p53 or K373R p53 became insensitive to the HDAC inhibitor, suggesting that these two residues of p53 may be essential for HDAC inhibitor-induced apoptosis, whereas others such as K382R p53 may not. Furthermore, reverse transcription-PCR demonstrated that among various p53-related proapoptotic genes, expression of PIG3 and NOXA were clearly enhanced by SB treatment in KATO-III/p53 cells but not in KATO-III/K320R or KATO-III/K373R cells. Finally, we revealed that apoptosis could be evoked by SB even in cells where p53 mutations occur at residues other than 320 lysine or 373 lysine (TMK-1 and HSC-39 cells) and that this apoptosis was significantly, although not totally, suppressed by the anti-p53 antisense. It was, therefore, concluded that acetylation of the p53 molecule at residues 320 and 373, giving rise to up-regulation of PIG3 and NOXA, is one of the mechanisms for induction of apoptosis by HDAC inhibitors in cancer cells.

Multidetector row helical computed tomography (MD-CT) scanning is performed for the evaluation of pancreatic tumors. Three-phase contrast study is performed using 2.5-mm collimation, and the images are reconstructed at 1.25-mm intervals. CT angiography and pancreatic duct images using two- or three-dimensional techniques are reconstructed from the volumetric data. MD-CT can perform multiphasic scanning rapidly with an optimal temporal window. CT angiography obtained with MD-CT can delineate peripancreatic vasculature with high spatial resolution and sufficient vascular enhancement. Pancreatic duct images can provide important information in assessing pancreatic disease. MD-CT has the potential to improve detection and preoperative assessment of pancreatic tumors.

To investigate the effect of different iodine concentrations of contrast material on aortic and hepatic enhancement and the detectability of hypervascular hepatocellular carcinoma (HCC) with multi-detector row computed tomography (CT) and a uniphasic contrast material injection technique.Two hundred one patients with known or who were suspected of having HCC underwent multi-detector row CT; 58 patients with hypervascular HCC were identified. First-, second-, and third-phase scanning was started with the aortic arrival times plus 15 seconds, plus 30 seconds, and plus 105 seconds, respectively. All patients were assigned randomly into two groups. Patients in groups A and B received iopamidol with an iodine concentration of 300 mg/mL and 370 mg/mL, respectively, with the same total iodine load per patient per body weight. The liver and aorta enhancement and tumor-to-liver contrast (TLC) were measured. Depiction of hepatic arteries was evaluated visually by two radiologists.During the first phase, aortic enhancement was significantly (P.01) higher in group B, with no significant difference in hepatic enhancement between the two groups. During the second phase, aortic enhancement was significantly (P.01) higher in group A, with no significant difference in hepatic enhancement. The TLC was significantly (P.01) higher in group B during the first phase, but there was no significant difference between the two groups during the second phase. There was no significant difference in any parameters between the two groups during the third phase. Depiction of the hepatic arteries in group B was significantly (P.05) superior to that in group A.In the arterial phase, administration of a higher concentration of contrast material is effective for a significantly higher TLC.

Most cases of cholangiocarcinoma have reached an unresectable stage by the time they are discovered despite significant progress of diagnostic modalities. Many of these patients with obstructive jaundice are often treated by biliary drainage using stents to relieve the jaundice. However, the stent patency period is as short as 3 to 9 months because of tumor ingrowth or overgrowth, and mean survival is at most 12 months. Therefore, both continuous relief of obstructive jaundice and local control of the tumor are required in the treatment for advanced cholangiocarcinoma. In this investigation, we developed a new percutaneous transhepatic biliary drainage tube coated with carboplatin (carboplatin-coated tube; CCT). CCT continuously released a fixed amount of carboplatin for 4 weeks and showed an antitumor effect on human cholangiocarcinoma cell line HuCC-T1 in vitro. When CCT was embedded in subcutaneous tumor inoculated in nude mice, a significant reduction of tumor size with no apparent damage to normal adjacent tissue was observed. On the basis of these studies, 5 patients with inoperable cholangiocarcinoma were treated with CCT for 4 weeks. Overall efficacy rate of 5 patients with cholangiocarcinoma was 60% (partial response in 3 and no change in 2). No apparent side effect was observed in these patients. Thus, CCT may provide a new treatment modality for this disease. Randomized controlled trials comparing CCT therapy with palliative stenting are required to confirm these results.

A bout 90% of patients with primary hepatocellular carcinoma have unresectable disease at presentation [1 1;hepatic resection is the only curative treatment for the remaining 10% of patients. Chronic liver disease and liver cirrhosis, which preexist in up to 80% of patients with hepatocellular carcinoma, are associated with a significant increase in postoperative liver failure and mortality, thus reducing the disease resectability rates. Scoring systems have been develo_ [2, 3] to predict postoperative outcome in patients undergoing hepatectomy and thus improve the selection for surgery. The parenchymal hepatic resection rate-the percentage of the functioning liver volume to be resected to the entire functioning liver volume-is a major predictor of outcome [2, 3]. Preoperative transhepatic portal vein embolization has been used to induce atrophy of the corresponding liver lobe and a compensatory hypertrophy of the contralateral lobe [4] and hence increase resectability [5]. However, preoperative portal vein embolization may not always be sufficient to achieve the desired changes in hepatic volume and function and thus may fail to avert the onset of postoperative hepatic failure [6]. In such cases, additional measures that may augment hypertrophy within the remaining liver are desirable. This report describes the beneficial role of transcatheter arterial embolization performed after madequate response to a preoperative transhepatic portal vein embolization in a high-risk patient with hepatocellular carcinoma.

Groups of 30 Wistar rats of each sex were treated with 2,2'-methylenebis(4-ethyl-6-tert-butylphenol) (MBEBP) in the diet at levels of 0, 0.03, 0.1 and 0.3% for up to 18 months. In both sexes, survival rates of treated groups were similar to those of the controls. Body weight gain was depressed (0.3% group in males, 0.1 and 0.3% groups in females). Slight anaemia (0.3% groups in both sexes) and increase of blood urea nitrogen (0.3% groups in both sexes) were observed. Histopathologically, vacuolization of the parathyroid gland cells (0.3% group in males and all treated groups in females) and degenerative changes of the kidney (0.1 and 0.3% groups in males) were observed. No neoplastic responses following MBEBP administration were noted. From these results, the no-observed-adverse-effect level (NOAEL) for MBEBP toxicity was estimated as 12 mg kg-1 body wt. day-1 in male rats. In female rats, the lowest-observed-adverse-effect level (LOAEL) was estimated as 15 mg kg-1 body wt. day-1.

A confirmatory familiarization study of the Combined Repeat Dose and Reproductive/Developmental Toxicity Screening (ReproTox) test protocol proposed by the Organization for Economic Cooperation and Development (OECD) was performed using nitrobenzene, a testicular toxicant. The agent was given daily by gavage to groups of 10 male and 10 female Sprague-Dawley rats at doses of 100, 60, 20 and 0 mg/kg body weight. Some of the high dose animals exhibited neurological signs, and two males and 9 females died. Hemolytic anemia due to methemoglobin formation was evident in treated males. Histopathologically, treated males showed atrophy of seminiferous tubules of the testis, reactive changes secondary to hemolytic anemia in the hematopoietic organs, and hepatocellular swelling. Cerebral gliosis was observed in middle and high dose males. Male fertility was not affected. The body weights of pups from treated dams were lowered, and their postnatal loss was increased. Most of the known toxicological properties of this chemical was demonstrated in the present study, with the exception of reduced fertility. Therefore, the ReproTox protocol was concluded as being useful as a screening test of existing high production volume chemicals. It should be noted that while the reproductive toxicity test alone is insensitive for detection of male fertility disturbances associated with testicular toxicity, the latter easily be distinguished on morphological grounds.

General toxicity studies on 2, 2'-methylenebis(4-methyl-6-tert-butylphenol) (MBMBP) were conducted using male and female Wistar rats. LD&lt50&gt values were greater than 5 g/kg BW by oral administration for both sexes. Diarrhea was observed until 5 days. In the subchronic test, rats were fed diet containing MBMBP at 0, 0.12, 0.6 or 3.0% for 12 weeks. Severe suppression of body weight gain was observed in both sexes of 0.6 and 3.0% groups. Death accompanied by hemorrhage from nasal cavity was observed in 0.6 and 3.0% males and 3.0% females. Dose-dependent toxicity to the liver in both sexes was observed in blood chemical analysis. Histopathologically, testicular atrophy and decrease of spermatogenesis were dose- and time-dependently observed in all treated males. Atrophy of ovaries was evident in 0.6 and 3.0% females. Thymus atrophy and bone marrow hypoplasia were observed in both sexes of 0.6 and 3.0% groups. In the chronic test, rats were fed diet containing MBMBP at 0, 0.01, 0.03 and 0.1% for 18 months. Body weight gain was only suppressed in both sexes receiving 0.1%. Histopathologically, testicular atrophy and decrease of spermatogenesis were apparent in 0.1% males. No neoplastic response by MBMBP administration was noted. NOAEL was concluded to be 0.03% in the diet (12.7 mg/kg BW/day for male rats and 15.1 mg/kg BW/day for female rats).

The acute and subchronic toxicity studies on 2,2'-methylenebis (4-ethyl-6-tert-butylphenol) (MBEBP) were conducted using male and female Wistar rats. In acute toxicity test, the LD50 values were estimated to be greater than 10 g/kg BW by oral and intraperitoneal administration in each sex. In subchronic toxicity test, groups of 10 rats of each sex were fed a diet containing 0.2, 1.0 or 5.0% of MBEBP and examined at 4 and 12 weeks. Body weight gain was significantly depressed at doses of 1.0 and 5.0% in both sexes, but the depression in the 1.0% group was severer than that in the 5.0% group in males. Hematological analysis showed slight but significant decrease of hemoglobin in the 1.0 and 5.0% groups of both sexes. Urine analysis showed no remarkable changes in all treated rats of both sexes. In biochemical analysis of serum, decrease of triglyceride level and cholinesterase activity, and increase of amylase activity were observed in treated rats. Histopathologically, testicular atrophy and decrease of spermatogenesis were observed in male rats fed 1.0 or 5.0% MBEBP for 4 and 12 weeks and vacuolization of parathyroid gland cells was observed in female rats fed 1.0 and 5.0% MBEBP for 12 weeks. In subchronic test, the lowest observable adverse effect levels for MBEBP toxicity were estimated to be 171 mg/kg BW/day in male rats and 180 mg/kg BW/day in female rats.

The gelatin-starch syrup microencapsulation method was applied to subacute toxicity studies of tribromomethane (TBM), dibromochloromethane (DBCM) and bromodichloromethane (BDCM). Groups of Wistar rats (7 males and 7 females) both sexes were given diet containing microcapsules of each of these trihalomethanes (THMs) at the following concentrations: TBM, 0.068, 0.204 and 0.612% in males, and 0.072, 0.217 and 0.651% in females; DBCM, 0.020, 0.062 and 0.185% in males, and 0.038, 0.113 and 0.338% in females; BDCM, 0.024, 0.072 and 0.215% in males, and 0.024, 0.076 and 0.227% in females. Suppression of body weight gain was seen in each high-dose males fed TBM or BDCM and females fed DBCM or BDCM. Histopathologically, hepatic lesions such as vacuolization and swelling of liver cells were significantly noted in both sexes of all groups fed TBM, in both sexes of the middle- and high-dose groups fed DBCM, and in males of the high-dose group and in females of the middle- and high-dose groups fed BDCM. In addition, single cell necroses were observed in males and females fed DBCM and in males fed BDCM. Hepatic cord abnormalities were also noted in males of the high-dose group fed BDCM. Although no increases in serum transaminase activities (ASAT, ALAT) were evident in either sex fed any of the THMs, decreases in triglyceride content, cholinesterase and lactate dehydrogenase activity were observed. Renal lesions reported to occur in gavage studies were not found in the present feeding study. Lowest-observed-adverse-effect-level (LOAEL) of TBM and no-observed-adverse-effect-level (NOAEL) of DBCM and BDCM were determined to be 56.4 mg/kg, 18.3 mg/kg and 20.6 mg/kg, respectively, under the present experimental conditions.

Dysfunction of TGFβ signal transduction has been shown to result in leukemogenesis. It has been generally accepted that Smads mediate the TGFβ signaling to inhibit cell proliferation, while several Smad4-impaired cell lines retain certain levels of responsiveness to TGFβ, suggesting an additional TGFβ signaling pathway for cell cycle arrest. Here we demonstrate evidence for a novel signal pathway for G1 arrest linking TGFβ and p53/Protein phosphatase 2A (PP2A) in CD4+ T lymphocyte and megakaryocytes. TGFβ induced growth suppression, associated with increment of PP2A activity was clearly observed in cells with impaired Smad signal. In these cells, upon TGFβ stimulation, PP2A was transiently recruited by heteromeric complex of TGFβ receptors (TβRs), released into cytosol, and activated. Subsequently, PP2A dephosphorylated p53 to import it into nucleus by interacting with importin-α/β followed by p21Waf1 induction. The recruitment of PP2A by TβRs and TGFβ-induced growth suppression as well as nuclear import of p53 were inhibited by introduction of siRNA for PP2A-Bα. Based on these preliminary observation, we next used human peripheral CD4+ T lymphocytes, which are reportedly impaired in Smad signaling, but sensitive to TGFβ when stimulated with PHA and IL-2. Growth suppression induced by TGFβ was almost completely abolished by siRNA for p53 (siRNA-p53), but not by siRNA for Smad4 (siRNA-Smad4). Further, nuclear translocation of p53 was inhibited by siRNA for PP2A-Bα(siRNA-Bα). These results suggest that growth suppressive activity of TGFβ in certain immunological responses could be ascribed to PP2A/p53 signal transduction. Thus these results define a novel pathway of TGFβ-induced growth suppression linking p53-PP2A, and suggest that loss of function of p53 which is frequently observed in hematological malignancies may result in the escape from growth inhibitory signal of TGFβ.

Recent studies have suggested that chromosomal deletions might represent a mechanism of inactivation of DNA repair system in various hematological malignancies, including myeloid leukemias. However, the precise mechanisms remain unclear. Damaged DNA binding protein-2 (DDB2), a DNA repair factor induced by tumor suppressor p53, plays an important role in the nucleotide excision repair of UV-damaged DNA. Despite frequent mutations of p53 in human leukemic cells, the role of DDB2 on the leukemogenesis is unkown. In this study, we examined expression of DDB2 mRNA in four human myeloid leukemia cell lines (K562, KG1, HL60, and MEG01) and in fresh leukemic cells obtained from 4 patients with myeloid leukemias. In all leukemia cells, expression of DDB2 mRNA was remarkably decreased as compared to that of CD34 cells We then assayed DDB2-dependent DNA repairing activity in the leukemic cells using specific antibodies against photoproducts, and found that DNA repairing activity was reduced. When a plasmid encoding DDB2 gene (pCV-DDB2) was transduced into K562 cells, the DNA repairing activity was significantly restored. Finally we tested the expression of DDB2 mRNA in five myeloid leukemias obtained from patients, and found loss of DDB2 expression in four patients. These results suggested that in human myeloid leukemias, suppression of DDB2 expression may contribute to accumulation of gene mutation through the dysfunction of DNA repair.

TGFβ has been reported to play an important role in regulating the proliferation of hematopoietic cells. Dysfunction of signal transduction pathway of TGFβ may result in leukemogenesis. It has been generally accepted that Smads mediate the TGFβ signaling to inhibit cell proliferation, while several Smad4-defective cell lines have been shown to retain certain levels of responsiveness to TGFβ, suggesting an additional TGFβ signaling pathway for cell cycle arrest. We previously demonstrated the evidence for a novel signal pathway for G1 arrest linking TGFβ and p53/Protein phosphatase 2A (PP2A) in CD4+ T lymphocyte and megakaryocytes (ASH, San Diego, 2003). We also showed that, upon TGFβ stimulation, PP2A was transiently recruited by heteromeric complex of TGFβ receptors (TβRs), released into cytosol, and activated. Subsequently, PP2A dephosphorylated p53 to import it into nucleus by interacting with importin-α/β, followed by p21Waf1 induction. In this study, we extended our observation to explore TGFβ-induced growth suppression is required for increment of PP2A activity by using SiRNA against PP2A. When PP2A of CD4+ lymphocytes was knocked-down by specific SiRNA for PP2A, the recruitment of PP2A by TβRs and TGFβ-induced growth suppression as well as nuclear import of p53 were inhibited. As a result, TGFβ stimulation induces PP2A activation and subsequently dephosphorylated-p53 was translocated into nucleus. Thus these results further define a novel pathway of TGFβ-induced growth suppression linking p53-PP2A, and suggest that dysfunction of p53 may result in the escape from growth inhibitory signal of TGFβ in hematological malignancies.