A case of synthetic oestrogen-induced autoimmune hepatitis with microvesicular steatosis.

WHAT IS KNOWN AND OBJECTIVE: Drug-induced liver injury (DILI) is a leading cause of acute liver failure in developed countries. Hepatotoxicity is a well-recognized adverse effect associated with synthetic oestrogens, which can cause cholestasis. The current report describes ethinyloestradiol (EE2)-associated highly unusual adverse effects of autoimmune hepatitis (AIH) and microvesicular steatosis (MS). DILI that fulfils the criteria for AIH is referred to as drug-induced autoimmune hepatitis (DIAIH). MS is a potentially severe liver lesion that results from mitochondrial dysfunction. We explore the pathophysiological mechanisms underlying DIAIH and MS. CASE SUMMARY: A 51-year-old woman presented with jaundice, increased liver enzymes and IgG, and positive ANA. She had been taking EE2 for 3 years. Liver biopsy showed prominent interface hepatitis with MS. A drug-lymphocyte stimulation test (DLST) using EE2 was positive. The liver biochemical parameters had normalized after the EE2 discontinuation; however, they exacerbated 5 months post-onset. Repeated liver biopsy showed interface hepatitis with no MS. Considering EE2-induced DIAIH, corticosteroids treatment was initiated. Then, all liver biochemical parameters had normalized, and the corticosteroids were successfully withdrawn. The patient continued to be in complete remission over the next 3 years. WHAT IS NEW AND CONCLUSION: Five remarkable points should be emphasized: (i) a long latency interval, despite the acute presentation; (ii) exacerbation of liver biochemical parameters, even after drug cessation; (iii) the paired liver biopsies indicating continuing inflammation and disappearance of toxic features; (iv) a positive DLST and the absence of fibrosis consistent with DIAIH and not AIH; and (v) a rare histological feature of MS. Intense immunoallergic reactions were likely triggers of MS in the current case. A possibility of DIAIH should be considered in cases of DILI which exhibit overt jaundice, autoantibodies, intense histological inflammation and a long latency period.

Cranial base chordoma--long term outcome and review of the literature.

BACKGROUND: The purpose of this study is to clarify the latest long-term therapeutic result for cranial base chordomas. We are seeking an improvement of long term therapeutic outcome through a review of cranial base chordomas treated in our institute and of the published literature in the era of multimodality therapy. MATERIALS AND METHODS: We retrospectively reviewed 13 consecutive patients with cranial base chordoma, including ten males and three females with mean age of 39.5 years (range 5-76 years). RESULTS: The method of initial treatment included surgery and post-operative conventional local irradiation (IR) in 9 patients, surgery and IR followed by post-operative stereotactic radiosurgery (SRS) in 2 patients, surgery as well as SRS in one patients, and surgery as well as SRS followed by IR in one patient. Subtotal removal (over 95%) was accomplished in eight patients. The mean follow-up period after completion of surgery and initial radiotherapy was 122 months (median 108 months). According to the Kaplan-Meier estimate method, the 5-year survival rate was 82.5%: 11 out of 13 patients survived longer than 5 years and five patients survived longer than 10 years. With a longer follow-up period than the previous reports, our series has provided a 5-year survival rate comparable to that of proton beam therapy. Although our series indicates a favourable outcome, surgical resection followed by IR or SRS failed to control tumour growth in five patients. CONCLUSIONS: IR and/or SRS provided results comparable with proton beam or heavy particle therapy in our series of cranial base chordomas probably because the radiation field must have covered the target of the tumour volume sufficiently, and reduction of gross tumour volume reduced the target size for radiotherapy. Pursuit of further effective combinations of IR and stereotactic radiotherapy (SRS, proton beam, heavy particle) after tangible resection, especially for residual and recurrent lesions, will be an acceptable framework to achieve a better therapeutic outcome for cranial base chordomas than at present.

Comparison of oral stereognosis in relation to age and the use of complete dentures.

The purpose of this study was to examine the age-related difference in oral sensory function by testing oral stereognostic ability (OSA) and to determine the effect of wearing complete dentures on OSA. Subjects were 20 dentate and 30 edentulous elderly patients free from oral symptoms and pathologies, and 30 younger dentate students as controls. The OSA tests were conducted with test pieces of 12 shaped forms. The duration time for recognition was noted and the answers were recorded using a three-point scale. anova and paired t-tests were used to examine significant differences. P-values <0.05 were considered to be statistically significant. The OSA score in older dentate participants and complete denture wearers was significantly higher than in younger dentate subjects. However, no significant difference was found in the OSA score between older dentate participants and complete denture wearers. When older edentulous subjects removed the maxillary and mandible complete dentures, the OSA score was significantly lower and the response time significantly longer than with dentures. Within the limitations of this study, an age-related difference in oral sensory function, as measured by OSA tests, was found. However, oral sensory function was not significantly different between fully dentate persons and complete denture wearers in the elderly.

Association of candidal activity with denture use and salivary flow in symptom-free adults over 60 years.

The purpose of this study was to examine the amount of palatal mucosa Candida species associated with denture use and stimulated salivary flow in symptom-free adults over 60 years. The subjects were 351 (189 men and 162 women) independently living elderly people with a mean age of 66.7 +/- 4.3 (SD) years. Candidal activity of palatal mucosa was evaluated by the pH change in the medium that was associated with the acid production of the yeast. Subjects whose stimulated salivary flow rate was less than 0.5 ml/min were placed in the hyposalivation group. A multiple logistic regression analysis was used to determine if an independent variable was statistically significant after controlling for other variables. Candidal activity of the palatal mucosa was significantly associated with the dental status of the maxillae (Kruskal-Wallis test, P < 0.001), but was not significantly associated with age or drug intake. In maxillary denture wearers, Candidal activity of palatal mucosa had a significantly positive correlation with candidal activity of tissue fitting surfaces of maxillary dentures (r = 0.806, P < 0.001). A multiple logistic regression analysis showed that high candidal activity of the palate was significantly associated with being male and wearing maxillary removable dentures. Stimulated salivary flow rate was likely to be negatively related to high candidal activity (P = 0.07). This study suggests that the activity of Candida species in the oral cavity is associated with the wearing of removable dentures and stimulated salivary flow, independent of age or gender even in the relatively healthy elderly.

The role of surgery in the treatment of brain metastasis: a retrospective review.

BACKGROUND: To study the role of surgery for brain metastasis, we reviewed the records of 646 patients with brain metastasis. METHODS: 340 patients underwent operative removal of the brain metastasis. During the same period, another 306 patients were treated without surgery. Criteria for surgery included the anatomical site, size over 3 cm, and cystic changes. Outcome was assessed by survival and cause of death. TREATMENT: 340 patients received surgical treatment, and 210 of these received radiation therapy. Another 306 patients were treated without surgery; 250 patients received conventional radiation and 56 patients were treated radiosurgically using a gamma knife. The surgical group was younger and had a better Karnofsky score than those of the non-surgical group. The median survival periods in the surgical and non-surgical groups were 21.0 months and 8.0 months, respectively. In patients whose brain lesions were first found before the systemic disease, the 5 year survival rates for the surgical and non-surgical groups were 35.2% and 18.2%, respectively. Although neurological causes accounted for 33.0% of deaths in the non-surgical group, and 13.2% of deaths in the surgical group; this difference was not significant. CONCLUSIONS: This retrospective review showed that patients with a brain metastasis treated surgically survived longer with better tumor control. To determine if this summary reflects the critical prognostic imbalance of population, further studies with randomized comparison are required.

Mesenchymal chondrosarcoma of the sellar region.

BACKGROUND: It is known that, although rare, mesenchymal chondrosarcoma can originate intracranially. However, no such malignant tumour has been described in the sellar region. CLINICAL PRESENTATION: We report a case of mesenchymal chondrosarcoma in a 21-year-old man who presented with double vision, right blepharoptosis and facial pain. Upon initial admission, no endocrinological abnormalities were found, and computed tomography and magnetic resonance imaging revealed a mass with calcification in the sella and right cavernous sinus. INTERVENTION: For this malignant tumour, three surgical resections, two sessions of gamma-knife radiosurgery, one session of fractional irradiation, and one cycle of chemotherapy were performed, resulting in only brief arrest of the tumour growth. Pathologically, the tumour consisted of undifferentiated small cells of high cellularity, and islands of hyaline cartilage. The undifferentiated small cells showed immunoreactivity for vimentin and ultrastructural features suggesting a mesenchymal origin. Lacunar cells in the islands were immunopositive for S-100 protein and vimentin. CONCLUSION: Although malignant tumours in the sellar region are rare, they should be considered in the differential diagnosis of various sellar tumours typified by non-functioning pituitary adenoma, and mesenchymal chondrosarcoma is one possible candidate.

Atrophy of the basal ganglia as the initial diagnostic sign of germinoma in the basal ganglia.

Germ-cell tumors of the central nervous system generally develop in the midline, but the tumors can also occur in the basal ganglia and/or thalamus. However, MR images have rarely been documented in the early stage of the tumor in these regions. We retrospectively reviewed MR images obtained on admission and approximately 3 years earlier in two patients with germinoma in the basal ganglia, and compared them with CT. In addition to hyperdensity on CT, both hyperintensity on T1-weighted images and a small hyperintense lesion on T2-weighted images were commonly seen in the basal ganglia. These findings may be early MRI signs of germinoma in this region, and the earliest and most characteristic diagnostic feature on MRI was atrophy of the basal ganglia, which was recognizable before development of hemiparesis.

Neurohypophyseal germinoma traced from its earliest stage via magnetic resonance imaging: case report.

BACKGROUND: We report a case in which magnetic resonance imaging (MRI) documented the formation of a neurohypophyseal germinoma from its earliest stage. CASE DESCRIPTION: A 9-year-old girl presented with polyuria, polydipsia, and growth retardation. Urinary and endocrinological examination indicated diabetes insipidus (DI) and growth hormone deficiency. No clear evidence of a mass in the hypothalamo-pituitary area was apparent on the first MRI scan. Follow-up MRIs and endocrinological examinations revealed that a tumor, arising from the stalk and posterior lobe of the pituitary gland, formed a mass and caused anterior pituitary function to deteriorate. Histologic diagnosis was germinoma based on open biopsy. CONCLUSION: Radiologic findings in this case indicated the primary site of this intrasellar germinoma to be the hypothalamo-neurohypophyseal region, designating this a "neurohypophyseal germinoma."

The generation of anti-tumoral cells using dentritic cells from the peripheral bloood of patients with malignant brain tumors.

Dendritic cells (DCs) can be the principal initiators of antigen-specific immune responses. We analyzed the in vitro-responses against brain tumor cells using DCs from the peripheral blood of patients with brain tumors. Peripheral blood mononuclear cells (PBMC) were obtained from 19 patients with malignant brain tumors: 12 metastatic brain tumors of lung adenocarcinoma, 7 high-grade astrocytomas. PBMC were cultured with 100 ng/ml of GM-CSF and 10 ng/ml of IL-4 for 5 7 days in order to produce mature DCs. The autologous tumor lysate (5 mg/ml, containing 1 x 10(6) cells) was then added to the cultured DCs. Using the DCs generated by these treatments, we assessed the changes that occurred in their immune responses against brain tumor via 51Cr-release and lymphocyte proliferation assays. We found that the matured DCs displayed the typical surface phenotype of CD3+, CD45+, CD80+ and CD86+. After the pulsation treatment with tumor lysate, DCs were found to have strong cytotoxic T lymphocyte activity, showing 42.5+12.7% killing of autologous tumor cells. We also found an enhancement of allogeneic T cell proliferation after pulsing the DC with tumor lysate. These data support the efficacy of DC-based immunotherapy for patients with malignant brain tumors.

Radiation-induced diffuse brain injury in the neonatal rat model--radiation-induced apoptosis of oligodendrocytes.

The mechanism of radiation-induced diffuse brain injury was investigated using a model of delayed myelination in the irradiated neonatal rat brain in which the number of oligodendrocytes decreases without associated necrosis of the cerebral white matter. Immunohistochemical analysis using antibody against the large myelin-associated glycoprotein, a specific marker of oligodendrocytes at an early stage of development, showed that the number of the oligodendrocytes associated with myelination decreased in the irradiated hemisphere 1 day after irradiation and remained low until 5 days after irradiation. In situ terminal deoxynucleotidyl transferase-mediated nick end-labeling assay revealed that apoptosis mainly occurred in the cerebral white matter of the irradiated hemisphere. Three hours after irradiation, apoptotic cells were found in the subcortical white matter and the periventricular white matter. Six hours after irradiation, apoptotic cells were found in the internal capsule, and the numbers of apoptotic cells in the periventricular white matter and subcortical white matter increased. One day after irradiation, the number of apoptotic cells in the periventricular white matter decreased. Three days after irradiation, apoptotic cells were not observed in the cerebral white matter. These results suggest that the oligodendrocytes associated with myelination may be damaged via radiation-induced apoptosis, and depletion of the oligodendrocytes may cause delay of myelination.

Serum concentrations of soluble interleukin-2 receptor in patients with malignant brain tumors.

BACKGROUND AND OBJECTIVES: Interleukin-2 receptor alpha (IL-2Ralpha) can combine with IL-2 firmly, and soluble IL-2Ralpha (sIL-2Ralpha) is elevated in sera from patients with various types of cancers. To investigate the role of this receptor, we studied the changes of serum sIL-2Ralpha in patients with malignant brain tumors. METHODS: SIL-2Ralpha was measured in 100 patients with malignant brain tumors (63 cancer metastasis, 16 malignant gliomas, 21 malignant lymphomas), and 51 patients with cancer who had no distant metastasis such as brain metastasis. RESULTS: In patients with 35 metastatic brain tumors from lung cancer, the levels of sIL-2Ralpha were not significantly different from levels in normal volunteers (311 +/- 62.4 U/ml). In patients with 25 metastatic brain tumors from lung adenocarcinoma, the mean level of serum sIL-2Ralpha was 352 +/- 94.0 U/ml. These same patients showed high levels of serum sIL-2Ralpha (492 +/- 101 U/ml) with regional lymph nodes metastasis. Serum sIL-2Ralpha concentration in 16 patients with malignant glioma varied greatly with the mean concentration of 328 +/- 192 U/ml. In 5 of 16 patients with malignant glioma, we could detect the significant increase of serum sIL-2Ralpha concentration from early stage of recurrence. CONCLUSIONS: Serum levels of sIL-2Ralpha could be a useful immunological marker in patients with malignant brain tumors.

Brain metastasis in patients with sarcoma: an analysis of histological subtypes, clinical characteristics, and outcomes.

BACKGROUND: The clinical characteristics of brain metastasis from sarcoma are not well known. We examined the incidence and the characteristics of brain metastasis in patients with sarcomas. METHODS: All sarcoma patients treated at our institution from 1975 to 1998 were reviewed for brain metastasis. Diagnosis of the primary tumor was confirmed histologically, and brain metastasis was confirmed using computed tomographic (CT) brain scan. RESULTS: Brain metastasis was found in 27 (5.6%) of 480 patients with systemic sarcoma (7.2% soft part sarcoma, 3.5% bone sarcoma, 15.1% distant metastasis). Of these 27 sarcoma patients with brain metastases, lung metastasis occurred in 16 patients (59.3%). Out of 10 patients surgically treated, 8 patients survived more than 16 months. Median survival period after craniotomy was 25.4 months. CONCLUSIONS: We recommend aggressive treatment for those patients with brain metastases whose performance scores are over 70.

Characteristic features of malignant lymphoma with central nervous system involvement.

BACKGROUND: Cerebral lymphoma is becoming increasingly common. METHODS: We reviewed the records of all our patients with non-Hodgkin's lymphoma (NHL) seen from April 1987 to August 1996 in our institute. Our analysis of these patients with lymphomatous central nervous system (CNS) involvement documents the clinical features, histology, and prognostic factors in CNS lymphoma. RESULTS: A total of 351 cases of NHL were treated in our institute. CNS lymphoma was found in 58 of 351 (16.5%) patients in our series. Forty-nine of 58 (84.5%) patients with CNS involvement also had systemic disease. Primary CNS lymphomas were detected in nine patients. Leptomeningeal infiltration was seen in 31 of 58 patients, whereas intracerebral infiltration was detected in 28 patients. Initial symptoms of CNS involvement included severe headache, muscle weakness, and other neurological signs. Malignant cells were detected in 32 of 132 studies in the cerebrospinal fluid examination. In the nine patients with primary CNS lymphoma, the median survival time was 16.5 months (range, 4-28 months). The overall median survival of the 58 CNS lymphoma patients was only 13.4 months (range, 1 to 32 months). CONCLUSIONS: Because prophylactic treatment was only successful in systemically well-controlled patients, control of systemic lymphoma seems to be of great importance.

[Severe hemolysis and SIADH-like symptoms induced by vincristine in an ALL patient with liver cirrhosis].

An 11-year-old boy was diagnosed as having acute lymphoblastic leukemia (ALL, L1) in 1987 and underwent treatment with an ALL high-risk protocol (prednisolone, vincristine (VCR), daunorubicin, 1-asparaginase), which resulted in complete remission. In 1990 he developed chronic hepatitis C and received interferon therapy. In December 1994, ALL recurred, and the patient was treated with VCR. He subsequently developed severe hemolysis (Hb 12.5 g/dl-->6.8 g/dl) with increases of indirect bilirubin, AST, and LDH. Furthermore, symptoms resembling a syndrome of inappropriate secretion of ADH (SIADH) and DIC developed. Upon incubation of the patient's red blood cells with VCR in vitro, extreme deformity of the cells was observed. These findings suggested that splenomegaly, due to liver cirrhosis which had developed rapidly from chronic hepatitis C while the patient was in an immunosuppressed state induced by anticancer drugs, had trapped the deformed red blood cells and resulted in severe hemolysis. The patient died on the 165th day after admission due to liver failure.

Establishment of two glioma cell lines from two surgical specimens obtained at different times from the same individual.

We established two glioma cell lines from two surgical specimens obtained at different times from the same patient. One (No. 9R), which was derived from the recurrent tumor (glioblastoma, grade IV), proliferated more rapidly in vitro than the other (No. 9) from the primary tumor (slightly anaplastic astrocytoma, grade II-III). No. 9R showed heterotransplantability in nude mice, whereas No. 9 did not. These findings indicate that No. 9R has a more aggressive or malignant nature than No. 9. Both cell lines showed homozygous deletion of the representative tumor suppressor p16 and p15 genes, but no p53 gene alteration. However, examination of the overall mRNA expression profile using a commercially available cDNA-spotted membrane revealed much higher expression levels of several mRNAs, at least, in No. 9R than in No. 9, although the relationship between these mRNAs and the growth potentials remained unknown. These two cell lines, derived from the same individual, with different proliferating potentials may be useful for studies on the molecular bases of glioma malignancy and progression.

Diverse oxygenations catalyzed by carbazole 1,9a-dioxygenase from Pseudomonas sp. Strain CA10.

Carbazole 1,9a-dioxygenase (CARDO) from Pseudomonas sp. strain CA10 is a multicomponent enzyme that catalyzes the angular dioxygenation of carbazole, dibenzofuran, and dibenzo-p-dioxin. It was revealed by gas chromatography-mass spectrometry and 1H and 13C nuclear magnetic resonance analyses that xanthene and phenoxathiin were converted to 2,2',3-trihydroxydiphenylmethane and 2,2',3-trihydroxydiphenyl sulfide, respectively. Thus, for xanthene and phenoxathiin, angular dioxygenation by CARDO occurred at the angular position adjacent to the oxygen atom to yield hetero ring-cleaved compounds. In addition to the angular dioxygenation, CARDO catalyzed the cis dihydroxylation of polycyclic aromatic hydrocarbons and biphenyl. Naphthalene and biphenyl were converted by CARDO to cis-1, 2-dihydroxy-1,2-dihydronaphthalene and cis-2,3-dihydroxy-2, 3-dihydrobiphenyl, respectively. On the other hand, CARDO also catalyzed the monooxygenation of sulfur heteroatoms in dibenzothiophene and of the benzylic methylenic group in fluorene to yield dibenzothiophene-5-oxide and 9-hydroxyfluorene, respectively. These results indicate that CARDO has a broad substrate range and can catalyze diverse oxygenation: angular dioxygenation, cis dihydroxylation, and monooxygenation. The diverse oxygenation catalyzed by CARDO for several aromatic compounds might reflect the differences in the binding of the substrates to the reaction center of CARDO.

[Troublesome factors in mitral valve repair for mitral valve regurgitation].

Limitations in the long-term results of medical treatment for mitral regurgitation are well recognized, but the advances in its surgical repair have produced good results. Therefore, early surgical intervention has been the focus of treatment in Europe and America. Increased surgical intervention depends on the development of technical skills in mitral reconstruction. This study investigated presurgical factors making surgical reconstruction difficult in 103 patients who underwent mitral operations performed from April 1994 to September 1997 in our hospital. Records were reviewed retrospectively for etiology, type of operation, and the immediate result of operation. The etiology of mitral regurgitation was prolapse in 65 patients (63%), restriction in 14, normal in 11, infectious endocarditis in 10, and others in 3. The type of prolapse involved the anterior leaflet in 22 patients (34%), posterior in 28 (43%), and both leaflets in 15 (23%). Valve repair was attempted in 74 patients, of which 16 were switched to valve replacement during operation. These included anterior leaflet prolapse in 9 patients, posterior leaflet in 1, both leaflets in 3, restriction in 2 and infectious endocarditis in 1. The success rate for reconstruction of anterior leaflet prolapse was not high. The cause of mitral regurgitation was mostly prolapse of the mitral valve, in our country as well as in Europe and America. Prolapsed posterior leaflet is much more common in Europe and America, and there is a high success rate reported for its valve reconstruction. In contrast, this study cannot recommend earlier surgical intervention because of difficult repair for anterior leaflet prolapse.