Ovarian hepatoid carcinoma without staining for alpha-fetoprotein in the primary site

An ovarian hepatoid carcinoma associated with minimal alpha-fetoprotein (AFP) production is described. The tumor involved both ovaries, and had metastasized to the omentum, uterus and retroperitoneal lymph nodes. The neoplastic cells were arranged in sheets, had abundant eosinophilic cytoplasm, central nuclei and distinct cellular borders. Despite the morphologic similarity to the histology of a hepatocellular carcinoma, elevation of the serum AFP level was minimal, at 74.0 ng ml⁻¹ (normal range: under 20 ng ml⁻¹), and the value normalized after surgery and subsequent chemotherapy. An immunohistochemical technique revealed focal staining for albumin in the tumor tissue and AFP in the uterine metastasis. Since the primary tumor itself did not stain for AFP, it is suggested that there may be hepatoid ovarian carcinomas without AFP production, a situation found in some hepatocellular carcinomas.     

Prevention by Methionine of Enhancement of Hepatocarcinogenesis by Coadministration of a Choline-deficient L-Amino Acid-defined Diet and Ethionine in Rats

The effects of methionine on hepatocarcinogenesis induced by Coadministration of a choline-deflcient L-amino acid-defined (CDAA) diet and ethionine were examined. F344 male rats were divided into 4 experimental groups. Groups 1 and 2 received the CDAA diet and a choline-supplemented L-amino acid-defined (CSAA) diet, respectively. Group 3 received the CDAA diet containing 0.05% ethionine, and group 4 the CDAA diet containing 0.05% ethionine and 0.47% methionine. Animals were killed after 12 weeks of treatment. Histologically, the CDAA diet induced intracellular fat accumulation and foci. In contrast, ethionine caused not only foci, but also hyperplastic nodules, cholangiofibrosis and the proliferation of oval cells without such fat accumulation. Methionine abolished the development of all of the liver lesions induced by Coadministration of the CDAA diet and ethionine. To investigate the effects of methionine on induction of c- myc and c-Ha- ras expression, as well as generation of 8-hydroxyguanine (8-OHGua) and 2-thiobarbituric acid-reacting substances (TBARS), by Coadministration of the CDAA diet and ethionine, subgroups of 3 to 5 animals were killed at 2, 4, 8 or 11 days after the beginning of the experiment. Coadministration of the CDAA diet and ethionine markedly enhanced the level of expression of c- myc and c-Ha- ras , 8-OHGua formation and TBARS generation as compared with the CDAA or CSAA diet within 11 days, and methionine blocked these actions. These results indicate that addition of methionine prevents the induction of c- myc and c-Ha- ras expression, 8-OHGua formation and TBARS generation, as well as hepatocellular lesions, by Coadministration of the CDAA diet and ethionine in rats, and suggest a possible involvement of oxidative stress and gene expression in hepatocarcinogenesis by these agents.     

Randomized study with mitomycin C + 5-fluorouracil + cytosine arabinoside (MFC) + 5-fluorouracil,MFC + tegafur and uracil (UFT), and MF + UFT in advanced gastric cancer: Interinstitutional differences in a multicenter study in Japan

In a phase III randomized trial of adjuvant chemotherapy for gastric cancer, interinstitutional differences were analyzed. A trial of three regimens: mitomycin C, 5-fluorouracil(5-FU) and CA (MFC) + continuous oral 5-FU (Group C); MFC + continuous oral UFT(tegafur and uracil) (Group B); and MF + UFT (Group C) after operation was conducted in 466 patients with gastric cancer (stage II and III) at four hospitals in Japan (CIH, CAD, ACC and NCC). Patients were stratified by the institution, stage, and tumor size (8 cm ><). The 5-year survival rates were in the order of Group A (79.0%) > B (70.0%) > C (61.0%) (P = 0.1228) in total, A (95.0%) > B (80.0%) > C (58.0%) (P < 0.05) at CAD (82 patients), A > C> B at CIH (215), C> A > B at ACC (95), and B > A > C at NCC (78). The survival rate of patients with S2(serosal exposure), 8 cm < and NO-1 cancer was higher at CIH than at the other institutions. The interinstitutional differences in patient characteristics and surgical technique were more powerful than the differences among the three groups. © 1995 Wiley-Liss, Inc.     

Tinnitus and/or hearing loss elicited by facial mimetic movement

Temporary tinnitus and/or hearing loss elicited by contraction of facial mimetic muscles are often observed on the affected side in patients recovering from facial nerve paralysis and in those with facial spasm. In order to clarify the mechanism of this phenomenon, changes in auditory threshold and middle ear compliance during voluntary contraction of mimetic muscles were investigated. The results suggest that this type of tinnitus and/or hearing loss is due to nonacoustic contraction of the stapedial muscle synchronous with contraction of mimetic muscles.     

Superimposition of post-streptococcal acute glomerulonephritis on the course of IgA nephropathy: predominance of Th1 type immune response

A 23-year-old man was admitted with macrohematuria and systemic edema appearing after an acute upper respiratory tract infection. He had been diagnosed 6 years earlier with IgA nephropathy (IgA-N). On admission, hypertension, nephrotic syndrome and hypocomplementemia were evident together with a high titer of anti-streptokinase (ASK). Renal biopsy showed severe glomerular mesangial proliferation, segmental endocapillary proliferation and crescent formation. Immunofluorescence microscopy (IF) showed strong deposition of C3 and reduced deposition of IgA. Electron microscopy showed a so-called "hump" on the epithelial side of the glomerular basement membrane.These features were consistent with post-streptococcal acute glomerulonephritis (PSAGN) superimposed on IgA-N. Following 2 weeks of observation, blood pressure, C3 level and ASK titer returned to normal ranges, although nephrotic syndrome was still evident, which necessitated oral prednisolone (30 mg/day) therapy. Another biopsy taken 2 months later demonstrated regression of endocapillary proliferation and IF showed decreased deposition of C3. Immunohistochemical staining of the specimen taken on admission revealed the presence of numerous T cells and macrophages in the interstitium. Macrophages were also seen in the glomerular tuft. Many interstitial infiltrating cells were positive for interferon-gamma, but their number diminished after treatment. Our findings suggest that PSAGN complicating pre-existing IgA-N activates cellular immunity and augments renal tissue injury.     

Immunohistochemical expression of inducible nitric oxide synthase (iNOS) in human brain tumors: relationships of iNOS to superoxide dismutase (SOD) proteins (SOD1 and SOD2), Ki-67 antigen (MIB-1) and p53 protein

In this study, inducible nitric oxide synthase (iNOS) expression in a series of 158 human primary brain tumors was analyzed. To gain some insight into the biological significance of iNOS expression in tumor cells, comparative immunohistochemical analyses were employed to characterize the expression of iNOS, superoxide dismutase (SOD) proteins (SOD1 and SOD2), Ki-67 antigen (MIB-1) and p53 protein in these cells. Sixteen (39.0%) of the 41 glioblastoma multiforme (GBM) specimens showed iNOS immunoreactivity. Positive immunoreactions with iNOS were also detected in 2/8 anaplastic astrocytomas, 1/17 astrocytomas, 1/14 medulloblastomas and 1/11 primitive neuroectodermal tumors, but no positive reactions were observed in oligodendrogliomas (0/11), ependymomas (0/5), schwannomas (0/21), meningiomas (0/23) or pituitary adenomas (0/7). The MIB-1 labeling index of GBMs that expressed iNOS was significantly higher than that of GBMs that did not (0.025< P <0.05, Wilcoxon rank-sum test). Unlike iNOS-negative tumors, all iNOS-positive tumors coexpressed SOD1 or SOD2. In particular, there was a significant correlation between iNOS induction and SOD1 expression (P =1.65x10(-10), Fisher's exact test) in GBM specimens. There was no significant relationship between iNOS and p53 protein in any type of primary brain tumor (P >0.05, Fisher's exact test). No significant immunohistochemical reactions with iNOS, MIB-1 or p53 protein were observed in normal brain tissue sections. We conclude that primary brain tumors express iNOS, and that iNOS expression in brain tumor cells may depend, in part, on cellular proliferation potential. Based on the fact that SOD1 scavenges oxidative-stress species originating from large amounts of nitric oxide (NO) produced by iNOS, iNOS-expressing brain tumor cells may protect themselves against NO cytotoxicity by overinducing SOD1.     

Expression of hepatocyte growth factor and c-Met in the anterior horn cells of the spinal cord in the patients with amyotrophic lateral sclerosis (ALS): immunohistochemical studies on sporadic ALS and familial ALS with superoxide dismutase 1 gene mutation

To clarify the trophic mechanism of residual anterior horn cells affected by sporadic amyotrophic lateral sclerosis (SALS) and familial ALS (FALS) with superoxide dismutase 1 (SOD1) mutations, we investigated the immunohistochemical expression of hepatocyte growth factor (HGF), a novel neurotrophic factor, and its receptor, c-Met. In normal subjects, immunoreactivity to both anti-HGF and anti-c-Met antibodies was observed in almost all anterior horn cells, whereas no significant immunoreactivity was observed in astrocytes and oligodendrocytes. Histologically, the number of spinal anterior horn cells in ALS patients decreased along with disease progression. Immunohistochemically, the number of neurons negative for HGF and c-Met increased with ALS disease progression. However, throughout the course of the disease, certain residual anterior horn cells co-expressed both HGF and c-Met with the same, or even stronger intensity in comparison with those of normal subjects, irrespective of the reduction in the number of immunopositive cells. Western blot analysis revealed that c-Met was induced in the spinal cord of a patient with SALS after a clinical course of 2.5 years, whereas the level decreased in a SALS patient after a clinical course of 11 years 5 months. These results suggest that the autocrine and/or paracrine trophic support of the HGF-c-Met system contributes to the attenuation of the degeneration of residual anterior horn cells in ALS, while disruption of the neuronal HGF-c-Met system at an advanced disease stage accelerates cellular degeneration and/or the process of cell death. In SOD1-mutated FALS patients, Lewy body-like hyaline inclusions (LBHIs) in some residual anterior horn cells exhibited co-aggregation of both HGF and c-Met, although the cytoplasmic staining intensity for HGF and c-Met in the LBHI-bearing neurons was either weak or negative. Such sequestration of HGF and c-Met in LBHIs may suggest partial disruption of the HGF-c-Met system, thereby contributing to the acceleration of neuronal degeneration in FALS patients.     

Possible regulatory mechanism of DHA-induced anti-stress reaction in rats

To determine whether docosahexaenoic acid (DHA) affects stress responses in rats, we investigated its influence on several behavioral tests. Female rats were fed a diet deficient in (n-3) fatty acid from mating through pregnancy and lactation. Male pups fed the same diet as their dams were used for experiments. The effects of dietary (n-3) fatty acid deficiency and supplementation with DHA on psychological stress and conditioned-fear stress were investigated. The effect of DHA on psychological stress was examined by an elevated plus-maze test. The (n-3) deficient rats spent significantly (P<0.05) less time in the open arms; after 1 week of supplementation with DHA, they showed a significant (P<0.01) improvement. We then examined the paired effects of DHA and CRH on stress manifestations by an intracerebroventricular (i.c.v.) cannulation and behavior testing. An i.c.v. infusion of CRH (500 pmol) under resting conditions was shown to have stress-inducing effects on behavior such as decreases of rearing, smelling and feeding, and increases of face washing; the supplementation of DHA significantly improved these distress behaviors. Finally, conditioned fear was induced by 40 min forced exposure to a cage in which the rat had experienced footshocks (30 x 1 mA x 1 s) 1 day before. Freezing behavior was dramatically suppressed by the supplementation of DHA, even 48 h after the conditioning treatment. Furthermore, the effect of DHA on the conditioned fear stress response is maintained over a long-term period. The i.c.v. pre-treatment of rats with bicuculline, a GABA(A) receptor antagonist, enhanced the conditioned-fear-induced freezing time in a dose-dependent fashion in the (n-3) fatty acid deficient animals. Significantly, the DHA supplemented group was not affected by the pre-treatment with bicuculline. From these findings, it is concluded that the involvement of DHA in stress responses may act via a GABA(A) receptor-mediated mechanism.     

A case report of both CAF and docetaxel-resistant breast cancer responding to paclitaxel weekly therapy

A 58-year-old woman underwent CAF and docetaxel therapy for lung, liver and bone metastases from breast cancer operated on 14 years ago. Because of progressive disease due to secondary resistance to CAF and docetaxel, the patient was given three courses of paclitaxel therapy (60 mg/m2, day 1, 8, 15, repeated every 4 weeks). The paclitaxel weekly therapy brought about no adverse effects and remarkable effects against lung and liver metastases (PR). Although the duration of the response to the paclitaxel therapy was limited to about two months due to the progression of skull bone metastasis, paclitaxel weekly therapy may be effective against both CAF and docetaxel-resistant breast cancer.     

Monoclonal antibody to stage-specific fetal brain 68-kDa glycoprotein (FGP68) revealed increased FGP68 expression in human primary brain tumors

We have produced a novel rat IgG(2a) monoclonal antibody against a stage-specific fetal brain glycoprotein of 68 kDa (FGP68), and succeeded in applying it to staining paraffin sections. To gain some insight into the pathobiological significance of this FGP68, this monoclonal antibody was used in immunohistochemical studies to compare the expression of FGP68 and Ki-67 antigen (MIB-1) in 235 primary brain tumors. Approximately half of the glioblastomas multiforme (GBMs) (44/75) and anaplastic astrocytomas (9/17) as well as some astrocytomas (5/30), medulloblastomas (2/14) and primitive neuroectodermal tumors (2/10) had tumor cells that expressed FGP68; however, pilocytic astrocytomas (0/7), oligodendrogliomas (0/15), ependymomas (0/6), schwannomas (0/21), meningiomas (0/22) and pituitary adenomas (0/18) did not express FGP68. The values of the MIB-1 labeling index were statistically higher in GBMs (0.005< P<0.01, Wilcoxon rank-sum test) and anaplastic astrocytomas (0.025< P<0.05) that expressed FGP68 than in those that did not. Normal brain tissue from 20 individuals aged 3-75 years was negative for FGP68 and MIB-1. We conclude that primary brain tumors express FGP68, one of the oncofetal proteins derived from fetal brain, and that FGP68 expression in certain brain tumor cells may depend, in part, on proliferation potential. Based on the possibility that the stage-specific FGP68 plays an important role in brain embryogenesis, some of FGP68-expressing tumor cells might phylogenetically revert to more primitive cells.