Yasuki Kusanagi

Gastric morphology and immunophenotype predict poor outcome in mucinous adenocarcinoma of the uterine cervix

Endocervical-type mucinous adenocarcinoma (ECA) of the uterine cervix is defined as a tumor composed of cells resembling those of the endocervical glands, but recent studies have demonstrated that a minority of ECAs displays a gastric immunophenotype. The aim of this study was to assess the significance of the gastric phenotype. Fifty-three cases of mucinous adenocarcinoma of the uterine cervix (37 FIGO stage IB, 4 stage IIA, and 12 stage IIB) were reviewed and reevaluated using a newly established morphologic criteria for distinguishing gastric type adenocarcinoma, which was defined as a tumor showing clear and/or pale eosinophilic and voluminous cytoplasm, with distinct cell borders. The results were correlated with gastric immunophenotype, determined by HIK1083 and MUC6 immunostaining, and patient outcome. Following the current World Health Organization scheme (2003), 47 tumors (89%) were classified as ECA, 1 (2%) as intestinal type, 1 (2%) as mixed endocervical and intestinal type, and 4 (8%) as minimal deviation adenocarcinoma. Twelve of 47 (26%) ECAs and all 4 minimal deviation adenocarcinomas, reclassified as gastric type using the novel criteria, were frequently positive for HIK1083 with a rate of 75% (12/16), whereas only 11% (4/37) of nongastric tumors were positive. There was no significant difference in MUC6 reactivity between gastric and nongastric type tumors (31%, 5/16 vs. 16%, 6/37; P=0.4). Patients with gastric-type adenocarcinomas had a significantly decreased 5-year disease-specific survival rate (30 vs. 77%; P<0.0001), and the gastric type morphology was related to a significant risk for disease recurrence compared with the nongastric type (P=0.001; HR, 4.5; 95% confidence interval, 1.42-14.2). HIK1083-positivity was also related to decreased 5-year disease-specific survival rate (38% vs. 74%; P<0.005). Mucinous adenocarcinoma of the uterine cervix with gastric immunophenotype can be a distinct morphologic variant showing an aggressive clinical course.

Absence of High-Risk Human Papillomavirus (HPV) Detection in Endocervical Adenocarcinoma with Gastric Morphology and Phenotype

A subset of endocervical-type mucinous adenocarcinomas (ACs) of the uterine cervix exhibit a gastric phenotype and morphology, as reported in cases of minimal deviation AC in which the presence of human papillomavirus (HPV) has been rarely detected. To investigate the HPV-independent pathway of carcinogenesis in cases of gastric-type AC, we investigated the common high-risk HPV (hr-HPV) status in 52 nonsquamous cell carcinomas, using a PCR-based typing method and immunohistochemistry of p16INK4a (a cyclin-dependent kinase inhibitor that is overexpressed in both cancerous and precancerous cervical tissue, making it an ideal biomarker for cervical cancer cases). Using novel morphological criteria, seven of 52 (13.5%) carcinomas were designated as gastric-type ACs, all of which were negative for both hr-HPV DNA and p16INK4a. Nongastric-type ACs were frequently positive for both hr-HPV DNA (90%, 28/31) and p16INK4a (94%, 29/31) with adenosquamous and neuroendocrine carcinomas demonstrating the presence of hr-HPV DNA in 86% (6/7) and 83% (5/6) of cases, respectively. In these two types of carcinoma, 86% (6/7) and 100% (6/6) were positive for p16INK4a, respectively. Our data suggests that gastric-type AC appears to represent an oncogenic hr-HPV-independent neoplasm and therefore is a potential pitfall of HPV DNA testing and vaccination.

Significance of a diastolic notch in the uterine artery flow velocity waveform induced by uterine embolisation in the pregnant ewe

Objective To investigate the relation between placental embolisation and the diastolic notch in the uterine artery flow velocity waveform of pregnant ewes under general anaesthesia.

CONCENTRATIONS OF SERUM GRANULOCYTE- COLONY-STIMULATING FACTOR IN NORMAL PREGNANCY AND PREECLAMPSIA

OBJECTIVE In order to elucidate the potential role of granulocyte-colony-stimulating factor (G-CSF) during the course of normal pregnancy and preeclampsia, we measured the serum concentrations of G-CSF in both normal pregnant women and preeclamptic patients. METHODS Sera of 10 nonpregnant women, 34 normal pregnant women (n = 10, first trimester; n = 10, second trimester; n = 14, third trimester), 10 postpartum women, 10 mild preeclamptic patients, and 10 severe preeclamptic patients were collected. The serum concentrations of G-CSF were measured by enzyme immunoassay. RESULTS The serum level of G-CSF in normal pregnant women (third trimester: 38.3 +/- 15.3 pg/mL; mean +/- SD) was significantly increased when compared with the levels observed in nonpregnant women (20.3 +/- 10.1 pg/mL, p < 0.05), which was similar to the G-CSF concentrations in postpartum subjects (20.7 +/- 9.1 pg/mL). The mild and severe preeclamptic patients showed significantly higher levels of G-CSF (56.9 +/- 18.8 pg/mL, p < 0.05; 73.2 +/- 30.4 pg/mL, p < 0.0001, respectively) than those noted in the third trimester women. The preeclamptic patients who presented with edema had greater (p < 0.01) serum levels of G-CSF (75.5 +/- 25.0 pg/mL) compared with nonedematous patients (44.7 +/- 14.9 pg/mL). The serum levels of G-CSF significantly correlated with both weight gain (p < 0.05), diastolic blood pressure (p < 0.01), and systolic blood pressure (p < 0.01), but not with white blood cell counts. CONCLUSION Serum concentrations of G-CSF are increased in normal and, even more so, in preeclamptic pregnancies. Because there was no relationship between serum G-CSF concentration and the number of leukocytes, G-CSF might act not to promote the physiological leukocytosis of pregnancy, but to stimulate the function of leukocytes such as phagocytosis. Moreover, it might be that G-CSF plays important roles in the activation of granulocytes or vascular endothelial injury, which are considered to be important pathological conditions in the development of preeclampsia.

Identification of anti-α-enolase autoantibody as a novel serum marker for endometriosis

Diagnosis of endometriosis needs invasive maneuvers. New serum marker that possesses both high sensitivity and high specificity has long been desired. To establish novel serum marker for endometriosis, serum autoantibodies (autoAbs) were investigated using proteomic approach. AutoAbs in sera of endometriotic patients and healthy controls were analyzed using a mesothelial cell line, 2‐DE and Western blotting. Proteins in reacted spots were identified using MALDI TOF‐MS with MASCOT analysis. ELISAs were established using recombinant proteins and autoAb‐titers were estimated in sera of endometriotic patients, disease and healthy controls. Several autoAbs were identified. Anti‐α‐enolase (Eno1)‐autoAb levels in endometriotic patients were significantly elevated compared with both healthy and disease controls. Sensitivity and specificity of serum anti‐Eno1‐autoAb was nearly comparable to serum CA125. When anti‐Eno1‐autoAb and CA125 assays were combined, diagnostic sensitivity and accuracy improved. Serum anti‐Eno1‐autoAb can be a new serum endometriotic marker and it is useful as a supplement assay for CA125. This study validates further clinical evaluation of this novel marker.

Changes in serum concentrations of tumor necrosis factor α and adhesion molecules in normal pregnant women and those with pregnancy-induced hypertension

Aim:  To study whether serum tumor necrosis factor α gene (TNFα) and adhesion molecule levels are indicators of the onset of pregnancy‐induced hypertension (PIH), we compared levels of these molecules between normal pregnant women and PIH patients from the first to the third trimester.

Serum anti-PDIK1L autoantibody as a novel marker for endometriosis

OBJECTIVE To establish a novel serum marker for endometriosis, serum autoantibodies (autoAbs) were investigated using a proteomic approach. DESIGN Retrospective study. SETTING Departments of Molecular Pathology and Obstetrics and Gynecology in Ehime University and University Hospital. PATIENT(S) Sixty-nine patients with endometriosis, 38 disease control patients without endometriosis, and 44 healthy volunteers. INTERVENTION(S) Autoantibodies in sera of endometriotic patients and healthy controls were investigated using a human fibroblast cell line, two-dimensional gel electrophoresis, and Western blotting. Proteins in reacted spots were identified using MALDI time of flight mass spectrometry with MASCOT analysis. ELISAs were established using recombinant proteins, and autoAb-titers were estimated in sera of endometriotic patients and controls. MAIN OUTCOME MEASURE(S) Identification of serum autoAb useful for diagnosis of endometriosis. RESULT(S) Several autoAbs were identified. ELISAs were established and serum autoAb titers were estimated. Among those identified, anti-PDIK1L-autoAb levels were significantly elevated in endometriotic patients. Sensitivity (59.4%) and accuracy (72.8%) of serum anti-PDIK1L-autoAb assay were better than those of serum CA125 levels (36.2% and 62.9%, respectively) in diagnosis of endometriosis. Additionally, anti-PDIK1L-autoAb could detect endometriotic patients in early stages. CONCLUSION(S) Serum anti-PDIK1L-autoAb can be a new serum marker for the diagnosis of endometriosis. This study validates further clinical evaluation of this novel marker.

Cytokine Regulation of Intercellular Adhesion Molecule-1 Expression on Trophoblasts in Preeclampsia

In normal pregnancy, trophoblast (TR) invasion plays a crucial role in remodeling the spiral arteries to develop uteroplacental circulation. Disruption of this invasion is associated with deficient uteroplacental circulation, which can lead to the development of preeclampsia (PE) through abnormal expression of adhesion molecules in the placenta and high serum causative factors such as cytokines. We aimed to evaluate whether serum factors in PE influence intercellular adhesion molecule-1 (ICAM-1) expression of TRs. ICAM-1 expression of TRs was measured using flow cytometry and immunohistochemistry was performed to examine the localization of tumor necrosis factor-α (TNFα) and ICAM-1 in placentas derived from women with normal pregnancies and women with PE. Sera from PE patients significantly increased ICAM-1 expression on TRs compared to sera from normal pregnant women; this increase was blocked with an antibody to TNFα. TNFα also enhanced ICAM-1 expression on TRs through nuclear factor-ĸB activation. We conclude that ICAM-1 expressed on TRs is involved in PE pathogenesis and is regulated by cytokines.

Prenatal Sonographic Diagnosis of Treacher Collins Syndrome

A 31-year-old Japanese woman, gravida 3, para 1, was referred for sonography at 33 weeks’ gestation because of polyhydramnios. Sonography showed a singleton infant whose biometric measurements were consistent with gestational age. A careful examination showed no visceral abnormalities. Polyhydramnios was detected with an amniotic fluid index of 34 cm; a midsagittal scan showed marked micrognathia. Sonography of the face of the fetus showed antimongoloid slanting palpebral fissures, which are characteristic of Treacher Collins syndrome (Figure 1), and low-set ears. The patient delivered a female infant weighing 2434 g with typical features of Treacher Collins syndrome. The infant was unable to maintain an adequate airway due to extreme mandibular hypoplasia and required intubation in the delivery room. Intubation was exceptionally difficult due to the severe mandibular hypoplasia. Physical examination of the infant showed severe micrognathia, antimongoloid slanting palpebral fissures, a high arched palate, malar hypoplasia, low-set ears, and atresia of the auditory meatus, which are consistent with Treacher Collins syndrome. The early neonatal period was complicated by respiratory distress syndrome, which necessitated intubation and ventilation and subsequent tube feeding.

The Influence of the Maternal Heart Rate on the Uterine Artery Pulsatility Index in the Pregnant Ewe

We investigated the influence of the maternal heart rate on the uterine artery pulsatility index in pregnant ewes. We used an external pacemaker to alter the heart rate of 5 pregnant ewes at 16–17 weeks of pregnancy and examined the effect of changes in the maternal heart rate on the uterine artery flow velocity waveforms and the pulsatility index, as determined by Doppler velocimetry. The uterine artery pulsatility index showed a significant negative correlation with the maternal heart rate. There were no significant changes in other hemodynamic parameters. The maternal heart rate had a significant influence on the uterine artery pulsatility index.