Betamethasone use and risk factors for pulmonary edema during the perinatal period: a single-center retrospective cohort study in Japan.

BACKGROUND: A few studies have reported that maternal administration of antenatal corticosteroids increased the risk of pulmonary edema (PE). However, despite the increasing usage rate of betamethasone as antenatal corticosteroid, maternal administration of betamethasone as a risk factor for PE has not been well studied. This study aimed to evaluate how maternal backgrounds and complications, tocolytic agents, and betamethasone affect the incidence of PE during the perinatal period and determine the risk factor for PE. METHODS: This was a single-center retrospective cohort study in Kurashiki, Japan. The study subjects were patients who had been admitted to our hospital for perinatal management including pregnancy, delivery and puerperium between 2017 and 2020. The primary outcome measure was defined as the incidence of PE during hospitalization. First, in all study subjects, Cox proportional hazards model was used to determine the risk factor for PE during the perinatal period. Next, using propensity score matching, we divided the patients into the betamethasone and betamethasone-free groups and examined the association between betamethasone use and the incidence of PE with Cox proportional hazards model. RESULTS: During the study period, 4919 cases were hospitalized, and there were 16 PE cases (0.3%). In all analyzed subjects, the occurrence of PE was significantly associated with preeclampsia (hazard ratio 16.8, 95% confidence intervals (CI) 5.39-52.7, P < 0.001) and the combined use of the tocolytic agents such as ritodrine hydrochloride and magnesium sulfate, and betamethasone (hazard ratio 11.3, 95% CI 2.66-48.1, P = 0.001). In contrast, after propensity score matching, no statistically significant difference was found between the betamethasone and betamethasone-free groups in the incidence of PE (hazard ratio 3.19, 95% CI 0.67-15.3, P = 0.145). CONCLUSIONS: A combined use of tocolytic agents and antenatal corticosteroids such as betamethasone may be an independent risk factor for PE during the perinatal period. On the other hand, betamethasone use alone may not be associated with the incidence of PE. When tocolytic agents and betamethasone are administrated to pregnant women, it is important to pay attention to the appearance of maternal respiratory symptoms.

Classification using hierarchical clustering of tumor-infiltrating immune cells identifies poor prognostic ovarian cancers with high levels of COX expression.

Local immune status is influenced by the tumor microenvironment. This study aims to characterize the local immune/microenvironment status by examining tumor-infiltrating immune cells, as well as cyclooxygenase (COX) expression in tumor cells, and to analyze the relationship with the prognosis of ovarian cancers. Using immunohistochemical staining of 70 ovarian cancer specimens, the numbers of CD8+, CD57+, and CD1a+ cells infiltrating intraepithelial or stromal spaces were counted (six parameters). Hierarchical clustering was used to analyze the six parameters at one time. Expression of COX-1 and COX-2 in tumor cells was also analyzed by immunohistochemistry. Expression of both COX-1 and COX-2 was negatively correlated with intraepithelial CD8+ cells (P<0.05 for both). Hierarchical clustering using the six parameters classified ovarian cancers into three clusters. The overall and progression-free survival of cluster 1 with low CD8+ cell and high CD1a+ cell density was poorer than cluster 2 with high CD8+ cell density (P<0.05). The cluster classification did not correlate with clinical features, such as histology, stage, age, and amount of residual tumor. In a multivariate analysis, cluster 1 was an independent poor prognostic factor (P<0.05). Expression of both COX-1 and COX-2 was higher in cluster 1 than in cluster 2 (P<0.05, respectively). In conclusion, hierarchical clustering of tumor-infiltrating immune cells allows poor prognostic COX-high subgroup of ovarian cancer to be detected. COX may influence the pattern of tumor-infiltrating immune cells and prognosis in ovarian cancer.

Isolated levocardia: prenatal diagnosis and management.

Isolated levocardia (IL) is a rare condition of situs anomaly in which there is a normal left-sided heart (levocardia) with dextro position of the abdominal viscera. IL has been reported in children and adults with complex cardiac defects, whereas there are only few published reports regarding the prenatal diagnosis of IL. We report two prenatal cases of IL diagnosed by ultrasonography and magnetic resonance imaging (MRI). In both cases, fetal cardiac function remained within the normal range throughout pregnancy, and no treatment for the heart was required after birth. For the dextro position of abdominal viscera, one case was followed without any surgical procedure, but the other case required prophylactic operation due to malrotation of the small intestine. Although the prognosis of IL largely depends on the severity of associated cardiac anomaly, future bowel obstruction caused by intestinal malrotation may also be life-threatening. In this respect, prenatal diagnosis of IL is important, even when there is no associated cardiac structural anomaly. If IL is suspected in routine fetal ultrasonography, MRI may be recommended to obtain more detailed information on the anatomy of abdominal viscerae, and careful observation for bowel problems is required, especially after oral nutrition is started.

Immunostimulatory effect of Fms-like tyrosine kinase 3 ligand on peripheral monocyte-derived dendritic cells and natural killer cells: utilization for ovarian cancer treatment.

Systemic administration of Fms-like tyrosine kinase 3 ligand (FLT3L) has been considered to be a major route of delivery for tumor immunotherapy because expression of its receptor, FLT3, was detected predominantly in hematopoetic progenitor cells. However, several studies indicate that FLT3L locally overexpressed in tumor or dendritic cells (DCs) also shows an anti-tumor effect. In the current study, we found that FLT3 expression is not present in monocytes but is instead induced in DCs through the differentiation process resulting from stimulation by GM-CSF and IL-4. Addition of FLT3L further augmented FLT3 induction and also increased CD40 expression in DCs, leading to enhanced induction of lymphoblastoid cell line-targeted cytotoxic T-lymphocyte response and CD107a mobilization in CD8+ T cells. Furthermore, FLT3L also induced FLT3 expression in peripheral blood NK cells that showed an enhanced response detected by CD107a mobilization. In a murine ovarian cancer model, locally expressed FLT3L showed anti-tumor effects. Collectively, the current study indicates that FLT3L has an immunostimulatory effect on peripheral blood cells and FLT3L targeted to mature peripheral blood cells may serve as a useful tool for cancer immunotherapy.

Malignant transformation of mature cystic teratoma of the ovary including three cases occurring during follow-up period.

The aim of this study was to seek for factors which lead to the early diagnosis of malignant transformation from mature cystic teratoma. Fourteen patients with malignant transformation from mature cystic teratoma of the ovary were analyzed retrospectively for precise clinicopathology and prognosis. The results demonstrated that although all the patients with stage Ia disease were disease-free, only 2 out of 7 patients were stage Ic to IV and disease-free in the follow-up period. Pre-operative imaging correctly diagnosed tumors as malignant in all stage Ic to IV cases, but only in 2 out of 4 stage Ia cases with magnetic resource and none of the 2 cases with computed tomography, respectively. In malignant cases, elevation of the serum SCC and CEA was observed in 90.9 and 88.9%, respectively. On the other hand, in benign cases, a false positive elevation of the serum SCC and CEA was observed in 23.5 and 14.3%, which turned out to be normal in 40 and 52.9% cases in the repeated study, respectively. In conclusion neither imaging analysis nor tumor markers including SCC and CEA accurately diagnose malignant transformation of mature cystic teratoma in its early stage, suggesting that a combination of diagnostic means is important. In the follow-up cases, repeated measurement of serum markers proved useful in ruling out false positive cases.

Oncogenic property of acrogranin in human uterine leiomyosarcoma: direct evidence of genetic contribution in in vivo tumorigenesis.

To identify potential oncogenes that contribute to the development of uterine leiomyosarcoma, we conducted a cDNA microarray analysis between normal uterine smooth muscle and uterine leiomyosarcoma. We found that acrogranin (also named PCDGF or progranulin) is overexpressed in uterine leiomyosarcoma. With immunohistochemical staining of 12 leiomyosarcoma cases, we verified acrogranin expression in tumor cells. Furthermore, the intensity of acrogranin expression correlated with high histologic grade and poor prognosis. To directly analyze the oncogenic properties of acrogranin, we established an immortalized uterine smooth muscle cell line by transfection of human telomerase reverse transcriptase into primary culture. This cell line retained the original characteristics of uterine smooth muscle cells, including spindle-shaped extension as well as expression of vimentin, estrogen receptor alpha, progesterone receptor, and alpha smooth muscle actin. Transfection of acrogranin into the immortalized uterine smooth muscle cells resulted in colony formation in soft agar, but the diameter of the colonies did not exceed 100 mum. Transfection of both acrogranin and SV40 early region (SV40ER) into the immortalized uterine smooth muscle cells resulted in an increased number of colonies and increased colony size in soft agar versus transfection of SV40ER alone. We show that only immortalized uterine smooth muscle cells expressing both acrogranin and SV40ER are capable of tumor formation in nude mice. Thus, acrogranin is overexpressed in uterine leiomyosarcoma cells, particularly in high-grade cases, and forced expression of acrogranin in immortalized uterine smooth muscle cells contributes to malignant transformation, which suggest that acrogranin plays an important role in the pathogenesis of uterine leiomyosarcoma.

In vivo anti-tumor effect of dual release of cisplatin and adriamycin from biodegradable gelatin hydrogel.

The objective of this paper is to investigate the in vivo anti-tumor effect by dual release of cisplatin (CDDP) and adriamycin (ADM) from a biodegradable hydrogel. Hydrogels with different water contents were prepared through the chemical crosslinking of gelatin by various concentrations of glutaraldehyde. Aqueous solution of CDDP, ADM or their mixture (CDDP+ADM) was impregnated into the freeze-dried hydrogel, followed by air-drying to obtain the dried hydrogel incorporating the corresponding drug. Irrespective of the hydrogel water content, 8-20% of CDDP incorporated and 60-80% of ADM was released from the hydrogel in the phosphate-buffered saline solution (PBS) at 37 degrees C within the initial 6 h and thereafter little release was observed. When intratumorally applied into mice carrying a mass of Meth-AR-1 tumor cells, the hydrogel incorporating CDDP+ADM showed significant higher anti-tumor effect on the tumor growth suppression and on survival period than other drug applications. Combination effect assay revealed that the hydrogel incorporating CDDP+ADM showed a synergistic effect between the CDDP and ADM, while the solution form showed antagonistic. The concentration of CDDP and ADM in the tumor tissue maintained at higher levels over 14 days after application. The time course of in vivo CDDP retention was in a good accordance with that of hydrogel remaining, whereas ADM was released faster, followed by the sustained release for 14 days. No practically problematic change in the mouse body and blood biochemical parameters was observed by application of the hydrogel incorporating CDDP+ADM. We conclude that dual sustained release of CDDP and ADM attached to the tumor synergistically enhanced their in vivo anti-tumor effect through the trans-tissue delivery.

Tranilast inhibits the proliferation of uterine leiomyoma cells in vitro through G1 arrest associated with the induction of p21(waf1) and p53.

Uterine leiomyoma is a mesenchymal tumor composed of smooth muscle cells with fibrous tissues and many mast cells. Tranilast is known to suppress fibrosis or to work as a mast cell stabilizer and is reported to inhibit proliferation of vascular smooth muscle cells. In this study, we examined the effects of tranilast on cultured human leiomyoma cells in vitro to evaluate whether this agent has the potential to inhibit the growth of uterine leiomyomas. Tranilast inhibited the proliferation of cultured leiomyoma cells in a dose-dependent manner without any cytotoxic effect or induction of apoptosis. In association with the inhibitory effect, tranilast induced the cyclin-dependent kinase (CDK) inhibitor p21(waf1) and tumor suppressor gene p53 and decreased CDK2 activity. These results suggest that tranilast arrests the proliferation of uterine leiomyoma cells at the G0/G1 phase, through the suppression of CDK2 activity via an induction of p21(waf1) and p53. Tranilast was concluded to be a potent agent to inhibit proliferative activity of uterine leiomyoma cells.

Secreted frizzled related protein 1 is overexpressed in uterine leiomyomas, associated with a high estrogenic environment and unrelated to proliferative activity.

Secreted frizzled related protein 1 (sFRP1) is a modulator of Wnt signaling. Recently, aberrations of Wnt signaling were reported to be involved in the pathology of various human neoplasms. We investigated the expression and function of sFRP1 in uterine leiomyomas. Secreted FRP1 expression was increased in leiomyomas, compared with normal myometrium using Northern and Western blot analyses. Expression was strongest in the late follicular phase (high estrogenic milieu) of the menstrual cycle. Interestingly, expression was negligible in leiomyomas treated with GnRH agonist. Expression was also prominent in cells during E2 treatment, serum deprivation, and hypoxia. Moreover, induction of apoptosis by serum deprivation in a leiomyosarcoma cell line was enhanced by antisense inhibition of sFRP1. These results suggest that sFRP1 expression was associated with uterine leiomyomas, particularly under high estrogenic conditions. Secreted FRP1 expression was not associated with cell proliferation but rather occurred during cell protection against apoptosis in vitro. Strong sFRP1 expression under high estrogenic conditions seems to contribute to the development of uterine leiomyomas through the antiapoptotic effect of sFRP1, which appear to be independent of cell proliferation.

Intractable recurrent cervical cancer with pelvic bone involvement successfully treated with external hemipelvectomy.

The indication of external hemipelvectomy for lateral recurrent cervical cancer involving the pelvic bone is controversial. We report the second longest surviving patient of recurrent cervical cancer successfully treated by external hemipelvectomy. A 38-year-old woman who had undergone conization for stage Ia1 cervical cancer six years earlier had severe right inguinal pain. A large multicystic recurrent tumor was identified in the right obturator region. After chemotherapy and chemoradiation, the tumor regressed, but soon relapsed. The patient's symptoms flared and the tumor was enlarged involving the right iliac bone. We performed right external hemipelvectomy with amputation of the right lower extremity, right iliac wing and ischiopubic bone. There was no major complication after the operation and the patient was discharged on postoperative day 48. After 27 months of follow-up, she has no complaints and is without evidence of recurrence. In selected cases of intractable lateral recurrent cervical cancer with pelvic bone involvement, relief from tumor-related pain and a possibility of prolonged survival can be expected by external hemipelvectomy.

Neuropilin-1 promotes unlimited growth of ovarian cancer by evading contact inhibition.

OBJECTIVE: Neuropilin-1 (NRP-1) is a receptor for both semaphorin and vascular endothelial growth factor and is up-regulated in a variety of human cancers. While there are some reports of NRP-1 expression in ovarian neoplasm, those results differ in pattern of its expression and its role in ovarian cancer is still unclear. We sought to investigate the expression pattern and role of NRP-1 in ovarian cancer. METHODS: NRP-1 expression was analyzed with eighty-seven ovarian tissue samples by immunohistochemistry and four ovarian cell lines by quantitative RT-PCR and Western blotting. To detect its molecular role in ovarian cancer, WST-1 assay, invasion assay and soft agar assay were performed with or without NRP-1 suppression by the introduction of short hairpin RNAs. RESULTS: NRP-1 expression was found to be enhanced in ovarian cancer compared with ovarian surface epithelium (OSE), benign adenoma and tumors of low malignant potential. In vitro, NRP-1 expression was augmented threefold during malignant transformation of OSE cells with oncogene ras, suggesting an association between NRP-1 and oncogenesis. Suppression of NRP-1 reduced cell proliferation in a dense state, indicating that persistently high expression of NRP-1 in ovarian cancer enhances proliferation through evasion of contact inhibition. Suppression of NRP-1 also decreased cell growth in soft agar and invasion to the extracellular matrix in vitro. CONCLUSIONS: These results suggest that NRP-1 is not only associated with oncogenesis, but also with ovarian cancer malignancy, and this molecule is a targeting candidate for the treatment of ovarian malignancies.

Expression of cold-inducible RNA-binding protein in the normal endometrium, endometrial hyperplasia, and endometrial carcinoma.

Cold-inducible RNA-binding protein (CIRP), an 18-kD protein in the mouse and human, is induced by lowering the temperature of cultured cells. CIRP is possibly a cell cycle regulator because its overexpression results in prolongation of G1 phase in vitro. We investigated the immunohistochemical expression of CIRP in 39 endometrial carcinomas, 12 endometrial hyperplasias, and 27 normal endometria using polyclonal antibody against CIRP and confirmed by Western blot analysis. CIRP was localized in the nuclei of glandular, stromal, and endothelial cells. The intensity of CIRP expression in glandular cells during the menstrual cycle was inversely proportional to its proliferative (Ki-67) activity, whereas it remained unchanged in stromal and vascular endothelial cells. The intensity of CIRP expression in hyperplastic glands was variable, whereas CIRP expression was absent or markedly reduced in most of the endometrial carcinomas. These results suggest that CIRP may participate in the cell cycle regulation of normal endometrium and the loss of its expression may be involved in endometrial carcinogenesis.

Increased expression of calcium-binding protein S100 in human uterine smooth muscle tumours.

S100 proteins belong to the EF-hand Ca(2+ )-binding protein family and regulate a variety of cellular processes via interaction with different target proteins. Several diseases, including cancer and melanoma, are related to the abnormal expression of S100 proteins, which are expressed in cell- and tissue-specific manners. We investigated the expression of S100 family members in human uterine smooth muscle tumours. Expression of six members of the S100 protein family: S100A1, A4, A6, A7, A10 and A11, was found in human uterine leiomyoma and myometrium tissue, but expression of other members was not detected by RT-PCR. Real-time PCR showed that S100A11 expression was significantly increased in leiomyoma compared with myometrium. Suppression of S100A11 by small interfering RNA (siRNA) led to apoptosis, and the overexpression of S100A11 inhibited apoptosis in human uterine smooth muscle tumour cells. These findings suggest that S100A11 has an anti-apoptotic function and is related to the process of growth of human uterine leiomyoma.

PEP-19 overexpression in human uterine leiomyoma.

Although uterine leiomyomas represent one of the most common neoplasms in adult women, their pathogenesis remains poorly understood. A cDNA microarray analysis was performed to search for candidate genes expressed to a greater degree in leiomyoma compared with matched myometrium. A total of 15 candidate genes was obtained; neuron-specific protein PEP-19 (Purkinje cell protein 4; PCP 4) exhibited a striking difference in expression between leiomyoma and myometrium. Although PEP-19 expression has been reported exclusively in the central nervous system, the present study demonstrated that PEP-19 is also expressed in other human organs, including prostate, kidney and uterus. To clarify the role of PEP-19 in the pathogenesis of leiomyomas, PEP-19 expression was investigated for a series of human leiomyoma, as well as normal myometrium and leiomyosarcoma. PEP-19 mRNA and protein expression were much stronger in leiomyomas compared with normal myometrium, suggesting that PEP-19 might be involved in leiomyoma pathogenesis.