Akira Yajima

The incidence of, and factors leading to, parvovirus B19-related hydrops fetalis following maternal infection; report of 10 cases and meta-analysis

OBJECTIVES to clarify the approximation of the frequency of B19-related nonimmune hydrops fetalis (NIHF), and to know the critical period during which maternal infection led to NIHF. METHODS we investigated the characteristics of 10 cases of antenatal B19 infection diagnosed over the past 10 years in Miyagi prefecture, Japan, and performed a meta-analysis of these cases and those previously reported in the literature. RESULTS NIHF caused by intrauterine B19 infection was diagnosed between 11 and 23 weeks of gestation in 10 women over the past 10 years in Miyagi prefecture, Japan. The source of infection was the mothers older child in six out of 10 cases, and children at a kindergarten where the mothers worked in two cases. The interval between the onset of infection and the diagnosis of NIHF ranged from 2 to 6 weeks. B19 infection was responsible for 10 (15.2%) in 66 cases of aetiology unknown NIHF in this study, and for 57 (19.1%) of 299 cases of non-malformed or aetiology-unknown NIHF by meta-analysis of the literature. Meta-analysis of the 165 reported cases of antenatal B19 infection, including the 10 cases described above, showed that there was a 10.2% excess risk of fetal death in women infected with B19 during pregnancy and a 12.40% excess risk in women infected during the first 20 weeks of pregnancy. Transplacental transmission was confirmed in 69 (24.1%) of 286 cases. The mean gestational age at diagnosis of NIHF was 22.8 +/- 5.1 weeks. The mean interval between the onset of maternal infection and diagnosis of NIHF was 6.2 +/- 3.7 weeks. CONCLUSIONS these approximations will be useful for counselling and management for pregnant women. The critical period during which maternal infection led to NIHF correlated with the hepatic period of hematopoietic activity. These findings suggest that parvovirus B19 may have an affinity for erythroid lineage cells at the hepatic stage of hematopoiesis, which may strongly influence the clinical features of feto-maternal B19 infection.

Tumor angiogenesis, hepatocyte growth factor, and c-Met expression in endometrial carcinoma†

This study was designed to evaluate the significance of tumor angiogenesis and angiogenic factors such as hepatocyte growth factor (HGF) and c‐Met in determining the prognoses of 93 patients with endometrial carcinoma.

Clinical evaluation of schizophyllan combined with irradiation in patients with cervical cancer: A randomized controlled study

To evaluate the clinical effects of the anti‐tumor polysaccharide Schizophyllan (SPG), a randomized study was done on 220 patients with Stage II or Stage III cervical cancer who had been given irradiation, concomitantly. The tumor‐reducing effect of SPG was significant in patients in either stage. The time to recurrence was longer in SPG‐dosed patients with Stage II cancer, compared with findings in the control group. There was no significant difference in the time to recurrence in patients with Stage III cancer between the SPG and control groups. When comparing the 48‐month survival curve, the survival time of patients with Stage II cancer in the SPG group was significantly longer than in the control group. However, there was no significant difference in the survival rate of patients with Stage III cancer between the SPG‐ dosed and control groups.

Fetal arrhythmia during treatment of pregnancy-associated acute promyelocytic leukemia with all-trans retinoic acid and favorable outcome

Differentiation and subsequent development are intricately interwoven processes operating as an integrated whole to form the organism. As an approach to examine these interactions in early mammalian development, we used embryonic stem (ES) cell in vitro differentiation. ES cells can, depending upon the environment differentiated to neuroectoderm, mesoderm and hematopoietic cells. We developed a serum-free, chemically defined medium (CDM) in which ES cells survive and differentiate. In CDM, in the absence of exogenous factors, ES cells form neuroectoderm, upregulating the early neural marker Pax-6. This is consistent with the view that neuroectoderm development can represent a default state, where the absence or sequestration of mesoderm inducing factors permits neuroectoderm formation. In contrast, if CDM is supplemented with bone morphogenetic protein (BMP) 2 or 4 a process resembling primitive streak formation, least at the molecular level occurs, with the formation of mesoderm and subsequently endothelial and hematopoietic cells. If used with care, ES cell in vitro differentiation can act as a guide in understanding the environment which controls early differentiation events in mammals.

Expression of epidermal growth factor-related proteins and epidermal growth factor receptor in common epithelial ovarian tumors.

SummaryThe biologic significance of epidermal growth factor (EGF)-related proteins and EGF receptor (EGFR) in the development and progression of human ovarian carcinoma was studied in 17 ovarian cystadenomas, 6 mucinous tumors of low malignant potential (LMP), and 25 invasive adenocarcinomas by immunohistochemistry, Results were correlated with clinicopathologic features. We also examined immunoreactivity in five serous adenocarcinomas both before and after cisplatin chemotherapy. Amphiregulin (AR) expression was observed only in mucinous tumors (4 of 8 cystadenomas, 2 of 6 tumors of LMP, and 6 of 10 cystadenocarcinomas), but was not detected in the serous tumors or clear cell adenocarcinomas. EGF, cripto, and EGFR expression was significantly higher in mucinous cystadenocarcinomas than in mucinous cystadenomas or mucinous tumors of LMP. Three of five specimens obtained at a second operation after chemotherapy had more intense or diffuse immunostaining for transforming growth factor α (TGF-α) than the initial specimens did. Coexpression of more than two of the EGF-related proteins or EGFR significantly correlated with increased surgical stage in serous and clear cell carcinoma. AR expression seems to correlate with mucinous differentiation rather than with advanced stages of ovarian tumors. Our results indicate that expression of some EGF-related proteins is greater in certain subtypes of ovarian carcinomas than in their benign counterparts and that coexpression of these proteins is associated with advanced stage in serous and clear cell carcinoma. Increased TGF a expression may also be related to ovarian tumor resistance to cisplatin chemotherapy.

Phase II Study of Irinotecan and Cisplatin as First-Line Chemotherapy in Advanced or Recurrent Cervical Cancer

Irinotecan (CPT-11) and cisplatin are singly active against cervical cancer. We evaluated the efficacy and toxicity of CPT-11 plus cisplatin as first-line chemotherapy in patients with advanced or recurrent cervical cancer. Twenty-nine chemotherapy-naive patients with advanced or recurrent cervical cancer were treated with CPT-11 (60 mg/m2) on days 1, 8, and 15 by intravenous infusion over 90 min, followed by cisplatin (60 mg/m2 i.v.) on day 1 over 90 min. The patients’ median age was 57 years (range 35–75). Nineteen patients (66%) had advanced primary disease. Six patients with recurrent disease (21%) had been treated with prior radiotherapy. The remaining 4 patients (14%) had residual or recurrent disease after radical surgery. The histologic diagnoses were squamous cell carcinoma in 25 patients (87%), adenocarcinoma in 3, and adenosquamous cell carcinoma in 1. All eligible patients were included in the toxicity and response analysis based on the intent to treat. Two patients (7%) achieved a complete response and 15 (52%) a partial response (overall response rate: 59%, 95% confidence interval; 41–74%). Stable disease was recorded in 6 patients (21%) and progressive disease in 3 patients (10%). In 3 patients, image-guided evaluation of response was judged to be unfeasible at the time of independent extramural review (10%). The median time to response was 32 days (range 16–62 days). The median survival was 27.7+ months (range, 6.4–52.8+ months). Two dose-limiting side effects were observed: grade 3 (28%) or 4 (45%) neutropenia and grade 3 (7%) or 4 (7%) diarrhea. Other severe toxicities included anemia (45%), thrombocytopenia (3%), nausea/vomiting (31%), and alopecia (7%). The combination of CPT-11 with cisplatin is an active regimen for treatment of advanced or recurrent cervical cancer albeit with a significant degree of myelosuppression.

The Behavior of Endometrial Hyperplasia: A Prospective Study

Objective: To clarify the behavior of endometrial hyperplasia in a prospective study.

Menstrual cycle dependent expression of CD44 in normal human endometrium

CD44 is a cell surface glycoprotein known to be a hyaluronate receptor, which functions in lymphocyte homing and cancer metastasis. We have previously shown that CD44 molecules are expressed in normal endometrial tissue. In this study we immunohistochemically examined expression of CD44 glycoproteins in normal human endometrial tissue to gain insight into roles of CD44 molecules. No expression of the CD44 standard form was observed with 11 endometria in the proliferative phase. On the contrary, 13 of 19 secretory phase endometria were stained intensely by anti-CD44 standard form anti-body; all CD44-positive cases were in the mid and late secretory phases. Among the 13 CD44-positive endometria, four also were positive for the CD44 variant with exon v6. CD44 molecules were present at all but the luminal cell surfaces. These results indicate that expression of CD44 depends on menstrual cycle, suggesting that CD44 molecules might be involved in implantation of fertilized ovum in endometrium.

Intercellular Adhesion Molecule-1 and Hepatocyte Growth Factor in Human Endometriosis: Original Investigation and a Review of Literature

Defects in the cell-mediated immune system may play a role in the pathogenesis or progression of pelvic endometriosis. Possible mediators include macrophages, interleukins-1 and -6, and tumor necrosis factor-α. More recent work points to the involvement of adhesion molecules and growth factors. To clarify the pathogenesis of endometriosis, we compared the characteristics of soluble intercellular adhesion molecule-1 (soluble ICAM-1) and hepatocyte growth factor (HGF) in women with and without endometriosis. We found that, in patients with endometriosis, the concentrations of soluble ICAM-1 in peritoneal fluid increased and interfered with the activity of natural killer cells. We also found that HGF secretion was significantly increased in cultured endometrial stromal cells, and that HGF stimulated the proliferation and migration of, and morphogenic changes in, endometrial epithelial cells. HGF and ICAM-1 play important roles in the initiation and regulation of endometriotic lesions on the microenvironment level. The increased secretion of HGF by eutopic endometrial stromal cells may contribute to the pathogenesis of endometriosis, whereas the increased levels of soluble ICAM-1 may impair natural killer cell activity and accelerate the progression of the disease.

Correlations between p21 expression and clincopathological finding, p53 gene and protein alteration, and survival in patients with endometrial carcinoma

The p21 protein inhibits cyclin‐dependent kinases and mediates cell‐cycle arrest and cell differentiation. It is induced by wild‐type p53, but not by mutant p53. This study of 75 patients with endometrial carcinoma investigates the relationship between p21 expression and the functional status of p53, and the usefulness of p21 as a prognostic marker. Correlations were determined between p21 immunoreactivity, p53 overexpression as examined by immunohistochemistry, p53 DNA mutations as examined by polymerase chain reaction–single‐stranded conformation polymorphism (PCR–SSCP) analysis, and clinicopathological features, including the clinical outcome. Immunoreactivity for p21 and p53 and p53 mutations were detected in 47 (62·7 per cent), 37 (49 per cent), and 23 (31 per cent) patients, respectively. There were no significant correlations between the presence or absence of p21 immunoreactivity and p53 overexpression and DNA mutations. Survival curves revealed that patients with p53 overexpression tended to have a poorer prognosis than those without p53 overexpression (P=0·104), that patients with p53 mutations had a significantly worse prognosis than those without mutations (P=0·035), and that patients with p21 expression tended to have a better prognosis than those without p21 expression (P=0·074). Immunohistochemical analysis of p21 was not useful for evaluating the functional status of p53 in patients with endometrial carcinoma. Both p21 expression and p53 abnormalities were considered as prognostic indicators in patients with endometrioid endometrial carcinoma.