Tomo Wakabayashi

Apoptosis in gastric carcinomas and its association with cell proliferation and differentiation.

The significance of apoptosis in human gastric carcinomas was investigated in comparison with proliferative activity and p53 accumulation, using an in situ DNA nick end labeling method and immunohistochemistry for both Ki‐67 antigen and p53 protein. Apoptotic labeling indices (LI) of 51 differentiated carcinomas (21 of early and 22 of advanced stage) were significantly lower than for 33 undifferentiated tumors (9 of early and 24 of advanced stage) (P<0.05). In both types, apoptotic LI of advanced stage lesions were significantly higher than for the early stage cases (P<0.005, P<0.03). The distribution of apoptotic cells was different from that of Ki‐67‐positive cells, generally exhibiting an inverse correlation for areas of predominance. In contrast, there was no significant correlation between p53 immunoreactivity and either apoptotic LI or Ki‐67 LI. It is concluded that in human gastric carcinomas the susceptibility to apoptosis is related to tumor cell differentiation and depth of invasion, and may play a role in selection of clonal subpopulations with high growth potential.

Active HIV-1 redistribution and replication in the brain with HIV encephalitis

SummaryThe central nervous system (CNS) is of particular importance in human immunodeficiency virus type 1 (HIV-1) infection. First, the CNS may be difficult to access for anti-retroviral treatment and may become a sanctuary for residual viruses. Second, HIV-1 infection may lead to AIDS dementia complex (ADC) culminating in HIV-1 encephalitis. In order to examine the pattern of drug resistance and the role of encephalitis in enhancing viral redistribution to the CNS, we compared pol gene quasispecies of the spleen and brain in two patients with and two patients without HIV-1 encephalitis, who had been treated with zidovudine (AZT). Although a variable degree of AZT resistance was noted in both the spleen and brain of all patients, phylogenetic analysis indicated that quasispecies developed rather independently in the systemic circulation (spleen) and CNS (brain) of patients without HIV-1 encephalitis, while similar pol gene sequences were obtained from the two compartments of patients with HIV-1 encephalitis. env gene V3 region of patients with HIV-1 encephalitis showed distinct quasispecies in the spleen and brain. Our results suggest that HIV-1 redistribution to CNS is more active in cases with encephalitis and that HIV-1 distributed late to CNS grow actively under certain selective pressure exerted on the V3 region of the env gene.

Cytomegalovirus (CMV) retinitis and CMV antigenemia as a clue to impaired adrenocortical function in patients with AIDS.

Objective:To elucidate the relationship between the activity of CMV disease and adrenocortical function in patients with AIDS. Design and patients:CMV retinitis and CMV antigenemia assay (CMV-Ag: numbers of polymorphonuclear leukocytes positive for CMV pp65 antigen per 1.5 × 105 cells) are the least invasive and easily accessible examinations to assess the CMV disease activity. All HIV-infected patients with CD4+ lymphocyte counts < 50 × 106/l who were admitted to the Research Hospital of the Institute of the Medical Science (University of Tokyo) between May 1995 to April 1996 were included in this study. Methods:Fundoscopic examination on CMV retinitis and CMV-Ag were chosen as methods to assess CMV activity because of their simplicity. Adrenocortical function was evaluated by basal plasma adrenocorticotropin, plasma cortisol, plasma aldosterone, plasma renin activity, and responses of plasma cortisol and plasma aldosterone to 250 µg intravenous cosyntropin [rapid adrenocorticotropin test (RAT)]. Results:Thirty patients were enrolled in this study with a maximum CD4+ lymphocyte count of 32 × 106/l. Eleven out of 30 patients showed impaired RAT response (37%). Fourteen out of 30 patients had CMV retinitis. A significant correlation was found between the presence of CMV retinitis and subnormal cortisol response (P < 0.005). Sixteen out of the 30 patients were CMV-Ag-positive. A significant correlation was found between CMV-Ag positivity and subnormal cortisol response to RAT (P < 0.005). CMV-Ag levels in the patients with subnormal cortisol response to RAT were significantly higher than those with normal response (P < 0.001). Importantly, five patients with subnormal cortisol response but not overt adrenal insufficiency at the time of RAT developed overt disease shortly afterwards. Autopsy was performed in six patients with subnormal cortisol response and showed multiple inclusion bodies indicative of CMV adrenitis. Conclusion:The adrenal gland is most frequently affected by CMV in AIDS patients. Our result suggests that CMV retinitis or CMV-Ag positivity independently serve as an indication of possible adrenal dysfunction.

Hepatocellular carcinoma with a solitary adrenal metastasis and poor hepatic functional reserve: Report of a case

A 54-year-old man with a 15-year history of liver disease, was found by his family physician to have multiple tumors in the right lobe of the liver and a large right retroperitoneal tumor. He was referred and admitted to our institute where a preoperative diagnosis of liver cirrhosis complicated by hepatocellular carcinoma and probable right adrenal metastasis was made. Because his hepatic functional reserve was so poor, only resection of the right adrenal tumor with a splenectomy for hypersplenism and a cholecystectomy for the prevention of cholecystitis secondary to the scheduled transcatheter arterial embolization was performed. The patient was discharged in good clinical condition 5 weeks after surgery.

Serological and histological characterization of the new mutant strain of lpr mice, CBA/KUms-lprcg/lprcg

CBA/KIJms‐lprcg/lprcg mice with a novel mutation producing systemic lymphoproliferation wereinvestigated for their serological and histological characteristics. The mutant mice showed elevatedlevels of serum immunoglobulin, C1q‐binding immune complexes and antibodies to nuclear antigenssuch as dsDNA and ssDNA and poly(ADP‐ribose). In contrast, histopathological lesions, e.g.glomerulonephritis, vasculitis or interstitial pneumonitis, were not revealed by histological andimmunofluorescent examinations, except for lymphocytic infiltration in various organs. These resultssuggest that this mutant mouse strain may provide a new animal model For autoimmunity. However, further investigations are required to clarify whether this strain is unique as compared with otherwell‐known lupus‐prone strains of mice with respect to serological and histological abnormalities andbecome to be a new model of systemic autoimmune disease.

Spontaneous rupture of hepatocellular carcinoma: An approach with delayed hepatectomy

Two cirrhotic patients with ruptured hepatocellular carcinoma (HCC), presenting with hemoperitoneum, were successfully treated by elective hepatectomy. Both of these patients, a 67-year-old female and a 76-year-old male, had first been taken to other primary hospitals by ambulance due to hypovolemic shock. They were then found to have a mass of approximately 5 cm in the cirrhotic liver. In the initial management, however, neither any direct hemostasis by surgery nor indirect measures such as transcatheter hepatic arterial embolization were performed in either case. Instead, conservative treatment consisting mainly of fresh blood and plasma transfusions were continued for more than a month until the liver function stabilized. In both hepatectomies, the use of a microwave tissue coagulator resulted in minimal intra-operative blood loss and an appreciably excellent post-operative course. These cases point to the effectiveness of a “wait and see” policy for selected patients with ruptured HCC.

Malignant Lymphomas in Japanese AIDS Patients

Seven non‐Hodgkins malignant lymphomas (MLs) were found in 25 Japanese AIDS (acquired immune deficiency syndrome) patients who died at two hospitals in Tokyo. All of these MLs originated from extranodal organs including the brain (three cases), skin (two cases) liver and adrenal gland. B cell markers were demonstrated in all of them. Epstein‐Barr virus (EBV) capsid antigen (EBVCA) was demonstrated in 5/7, nuclear antigen (EBNA) in 2/2, the W fragment of EBV DNA by in situ hybridization in 5/7 and the same fragment by PCR in 6/7, indicating high association of these MLs with EBV. The adult T cell leukemia/lymphoma (ATL), endemic in south‐west Japan and known to have a high association with HTLV‐I, was not found in this series. The incidence of ML among the present AIDS cases is higher than in any other autopsy reports from western countries, although statistical analysis did not show this to be significant in comparison to some of these reports at a level of p<0.05. In spite of apparent higher incidence, the histopathologic and immunophenotypic characteristics of AIDS‐associated MLs in Japan are in accordance with those in western countries. Acta Pathol Jpn 41: 744‐750, 1991.

Interdigitating reticulum cells in human renal grafts

Seventeen human renal graft biopsies taken 1 h to 50 days after transplantation and 3 human renal non-graft biopsies (2 minimal change and 1 non-tumour portion of angiomyolipoma) were investigated with immunoelectron microscopy in order to identify interdigitating reticulum cells (IDC) or dendritic cells (DC) in renal tissues. The antibodies used consisted of a rabbit polyclonal antibody of antihuman S100β protein, mouse monoclonal antibodies of antihuman HLA-DR, anti-CD3, and anti-CD1a. IDC or DC were identified in 11 renal grafts. They were found both in the glomerular and interstitial (peritubular) capillary lumens but not in the interstitium of 1 case; both were present in the interstitial capillary lumens and interstitium of another case, and in the interstitium only of 9 cases. In the remaining 6 grafts and 3 non-grafts they were not detected. These 6 grafts and 3 non-grafts did not show any pathological change except for foot process fusion of the glomerular epithelia in 2 cases of minimal change. These findings suggest that IDC or DC are not normally present in human renal tissues. The presence of the cell in the glomerular and peritubular capillary lumens of a biopsy taken after 1 h and their presence in the interstitial capillary lumens of another graft biopsy, suggest that the IDC or DC in human renal grafts are derived from recipients, not donors, and that they migrate from the circulating blood toward the interstitium.

Herpesvirus-like DNA Sequences in Japanese Patients with AIDS-related Kaposi's Sarcoma

The cause and origin of Kaposis sarcoma (KS) remain an enigma. Recently, Chang et al. reported a DNA fragment resembling human gamma herpesvirus that was specifically associated with KS tissue. In this paper, we report examination of three Japanese patients for presence of the KS-associated herpesvirus-like (KSHV) sequences. KSHV sequences were present in two of these patients, but could not be confirmed in the third because of DNA degradation. The KSHV sequences appeared to be present mainly in those tissues with KS invasion. Our results further demonstrate the presence of KSHV in KS lesions and support its role in the pathogenesis of KS.

Disseminated Pneumocystis Carinii Infection in a Hemophiliac Patient with Acquired Immunodeficiency Syndrome

A case of disseminated Pneumocystis carinii (PC) infection in a 28 year old Japanese male hemophiliac with acquired immunodeficiency syndrome (AIDS) is reported. The patient had displayed a high fever and diffuse faint interstitial infiltrates on chest X‐ray films without dyspnea three months before his death. At that time, no PC was detected after four consecutive induced sputum tests. Serum anti‐cytomegalovirus (CMV) IgM was positive by EIA. No treatment for PC and CMV was given at the patients request. Autopsy findings disclosed disseminated PC infection consisting of granulomas with caseation like necrosis and frothy exudate in the lungs and disseminated organized calcification in the blood vessels of extrapulmonary organs. PC cysts and/or trophozoites were detected in these lesions. Acta Pathol Jpn 42: 262‐266, 1992.