Importance of the neoadjuvant rectal (NAR) score to the outcome of neoadjuvant chemotherapy alone for locally advanced rectal cancer.

PURPOSE: The neoadjuvant rectal (NAR) score is a promising indicator of survival after preoperative chemoradiotherapy for rectal cancer. However, its effectiveness after neoadjuvant chemotherapy (NAC) alone has not been fully investigated. METHODS: We analyzed data retrospectively on 61 patients with rectal cancer, who received NAC followed by surgical resection between 2010 and 2015, and evaluated the impact of the NAR score on survival. RESULTS: The median NAR score was 14.9. Of the 61 patients, 13, 35, and 13 were classified as having NAR-low (< 8), NAR-intermediate (8-16), and NAR-high (> 16) scores, respectively. The median observation period was 49.0 months. According to the NAR score, the 3-year DFS in the NAR-low group was 100%, which was significantly better than that in the NAR-intermediate (64.8%, p = 0.041), and NAR-high (61.5%, p = 0.018) groups. When the NAR-intermediate and NAR-high groups were investigated as a single high-risk group, the 3-year DFS of the patients who received adjuvant chemotherapy was 88.7%, which was significantly better than that of the patients who did not receive adjuvant chemotherapy (53.3%, p = 0.042). CONCLUSIONS: The NAR score may predict the DFS and could serve as a favorable indicator of adjuvant chemotherapy after NAC alone.

ADAM17 is associated with EMMPRIN and predicts poor prognosis in patients with uterine cervical carcinoma.

Metalloproteinase activities of a disintegrin and metalloproteinase 17 (ADAM17), amphiregulin (AREG), extracellular matrix metalloproteinase inducer (EMMPRIN), and matrix metalloproteinases (MMPs) are involved in tumor biology. In patients with uterine cervical carcinoma, the expression and prognostic significance of ADAM17 remain to be fully elucidated. The expression of ADAM17, AREG, EMMPRIN, phospho-epidermal growth factor receptor (p-EGFR), phospho-extracellular signal-regulated kinase (p-ERK), MMP-2, and MMP-9 was assessed by immunohistochemistry and/or Western blotting from cervical carcinoma cell lines, SiHa and HeLa cells, and cervical carcinoma tissues. AREG activity was measured by ELISA assay. The correlation of ADAM17, AREG, EMMPRIN, and MMP-9 expression with patients' survival rates was assessed by Kaplan-Meier and Cox regression analyses. RNA interference (RNAi) experiment was performed using small interfering mRNA to ADAM17 and EMMPRIN. ADAM17, EMMPRIN, and MMP-9 protein content was overexpressed in cervical carcinoma tissues compared with normal cervical tissues (P < 0.05). Strong expression of ADAM17, AREG, EMMPRIN, and MMP-9 was significantly associated with stages, lymph node metastasis, differentiation, and parametrium invasion (P < 0.05). Overexpression of ADAM17, AREG, EMMPRIN, and MMP-9 was significantly correlated with short progression-free survival and overall survival (P < 0.05). Multivariate analysis suggested that lymph node metastasis, parametrium invasion, and ADAM17 expression were independent prognostic indicators for cervical cancer. ADAM17 RNAi decreased EMMPRIN, p-EGFR, p-ERK, MMP-2, and MMP-9 proteins in SiHa and HeLa cells. ELISA assay revealed that AREG activity was stimulated by ADAM17 and was reversed by ADAM17 RNAi in SiHa and HeLa cells. Our data suggest that the increased expression of ADAM17 in cervical cancer is significantly associated with aggressive progression and poor prognosis. ADAM17 may be a molecular marker for predicting the progression and prognosis in cervical cancer.

Suppression of progesterone production by stresscopin/urocortin 3 in cultured human granulosa-lutein cells.

BACKGROUND: Corticotropin-releasing hormone (CRH) and its receptors have been identified in female reproductive tissues. CRH regulates follicular maturation, ovulation, luteolysis and steroidgenesis. A CRH-related peptide stresscopin (SCP), or urocortin III (Ucn3), has recently been identified, but its functions in the ovary remain to be elucidated. In the present study, we investigated the effects of SCP/Ucn3 on progesterone production in cultured human granulosa-lutein cells. METHODS: The presence of SCP/Ucn3 and CRH type-2 receptor (CRHR2) in cultured granulosa-lutein cells from 21 infertile women (aged 22-36 years) was examined by RT-PCR and immunocytochemistry. The concentration of SCP/Ucn3 in follicular fluid, human serum and culture medium was examined by radioimmunoassay. Progesterone production by cultured granulosa-lutein cells treated with SCP/Ucn3 was examined by enzyme-linked immunosorbent assay. RESULTS: SCP/Ucn3 and CRHR2 mRNAs and proteins were expressed in granulosa-lutein cells. SCP/Ucn3 was detected in culture media of granulosa-lutein cells and follicular fluid. Treatment of cultured granulosa-lutein cells with 0.1, 1.0 or 10 nM SCP/Ucn3 decreased progesterone secretion when compared with untreated control (all P < 0.05). Concomitant treatment with the CRHR2 antagonist antisauvagine-30 counteracted the inhibitory effects of SCP/Ucn3 on progesterone secretion, suggesting a mediatory role of CRHR2. CONCLUSIONS: The present results suggest that the SCP/CRHR2 system is present in human ovaries and treatment with SCP/Ucn3 inhibits progesterone production by cultured granulosa-lutein cells through interaction with CRHR2.

Progesterone receptor modulator CDB-2914 induces extracellular matrix metalloproteinase inducer in cultured human uterine leiomyoma cells.

Effects of progesterone receptor modulator CDB-2914 on the expression of the extracellular matrix (ECM) components were examined in cultured human uterine leiomyoma and myometrial cells. ECM metalloproteinase inducer (EMMPRIN), matrix metalloproteinases (MMPs), tissue inhibitors of MMP (TIMPs) and collagen levels were assessed by Western blot analysis, MMP activity assay and real-time RT-PCR. RNA interference (RNAi) of EMMPRIN was performed using small interfering mRNA. In cultured leiomyoma cells, CDB-2914 treatment at concentrations greater than or equal to 10(-8) M significantly increased EMMPRIN, MMP-1 and MMP-8 protein contents and MMP-1, MMP-2, MMP-3 and MMP-9 mRNA levels, and activity of MMP-1, MMP-2, MMP-3 and MMP-9 in the medium. TIMP-1 and TIMP-2 were significantly decreased at mRNA and protein levels by CDB-2914 treatment at concentrations > or =10(-7) M in these cells. CDB-2914 treatment decreased types I and III collagen protein contents. However, CDB-2914 treatment did not affect the ECM component expression in cultured myometrial cells. RNAi of EMMPRIN abrogated CDB-2914-mediated both induction of MMPs and reduction of TIMPs and collagens in cultured leiomyoma cells. These results suggest that CDB-2914 modulates the expression of EMMPRIN, MMPs, TIMPs and collagens in cultured leiomyoma cells without comparable effects on myometrial cells.

Selective progesterone receptor modulator asoprisnil down-regulates collagen synthesis in cultured human uterine leiomyoma cells through up-regulating extracellular matrix metalloproteinase inducer.

BACKGROUND: A recent clinical trial demonstrated that selective progesterone receptor modulator asoprisnil is effective in reducing uterine leiomyoma volume. We investigated the effects of asoprisnil in vitro on the expression of the extracellular matrix (ECM)-remodeling enzymes and collagens in cultured leiomyoma and matching normal myometrial cells. METHODS: The expression of extracellular matrix metalloproteinase inducer (EMMPRIN), matrix metalloproteinases (MMPs), tissue inhibitors of MMP (TIMPs) and collagens were assessed by western blot analysis. RESULTS: Untreated cultured leiomyoma cells had significantly lower EMMPRIN (P < 0.05), MMP-1 (P < 0.05) and membrane type 1-MMP (MT1-MMP) (P < 0.01) protein contents, but significantly higher TIMP-1 (P < 0.05), TIMP-2 (P < 0.01), type I (P < 0.05) and type III (P < 0.01) collagen protein contents compared with untreated cultured myometrial cells. Treatment with asoprisnil at concentrations > or =10(-7) M for 48 h significantly (P < 0.05) increased EMMPRIN, MMP-1 and MT1-MMP protein contents, and decreased TIMP-1 (P < 0.05), TIMP-2 (P < 0.01), type I (P < 0.01) and type III (P < 0.05 at 10(-7) M; P < 0.01 at 10(-6) M) collagen protein contents in cultured leiomyoma cells compared with control cultures. However, asoprisnil treatment did not affect the protein contents of ECM-remodeling enzymes and collagens in cultured myometrial cells. CONCLUSIONS: These results suggest that asoprisnil may reduce collagen deposit in the ECM of cultured leiomyoma cells through decreasing collagen synthesis and enhancing the expression of EMMPRIN, MMPs and TIMPs without comparable effects on cultured myometrial cells.

Percutaneous pelvic perfusion with extracorporeal chemofiltration for advanced uterine cervical carcinoma.

This review was focused on a new intra-arterial infusion system with an extracorporeal chemofiltration circuit. After inferior vena cava isolation was percutaneously achieved by balloon catheter technique, cisplatin (140-240 mg/m(2)) was administered by intrauterine arterial infusion, with inferior and superior gluteal arterial embolization. The platinum-containing blood was pumped through an extracorporeal charcoal chemofiltration circuit. The percutaneous pelvic perfusion with extracorporeal chemofiltration (PPPEC) achieved a super high-dose cisplatin perfusion with the minimal adverse effects, allowing cisplatin dose escalation with further augmented tumor response. The results obtained in 23 patients who received neoadjuvant chemotherapy under PPPEC demonstrate that PPPEC has a better therapeutic advantage because of prompt tumor down-staging of locally advanced uterine cervical carcinoma with minimal adverse effects.

Endometrial Stromal Sarcoma Arising from Endometrial Polyp: A Case Report.

Endometrial stromal sarcoma (ESS) is a rare malignant tumor of the uterus. We report an uncommon case of ESS composed of both low-grade ESS and high-grade ESS arising from an endometrial polyp. On the findings of magnetic resonance imaging and contrast computed tomography, a patient was suspected of having uterine malignant tumor. She underwent a total abdominal hysterectomy with bilateral salpingo-oophorectomy. Macroscopically, the tumor was a polypoid lesion in the uterine cavity. The tumor was an endometrial polyp with ESS components. ESS was composed of low-grade ESS and high-grade ESS. By immunohistochemistry, both an endometrial polyp and low-grade ESS showed a positivity for CD10, estrogen receptor (ER), and progesterone receptor (PR). However, high-grade ESS showed only a focal and weak CD10 positivity with no immunostaining for ER and PR. A focal or diffuse positivity for α-smooth muscle actin and desmin was noted in both low-grade and high-grade ESS. The positive rates of Ki-67 and p53 in high-grade ESS were elevated up to over 95%. She was diagnosed as having ESS in a stage IA. After surgery, she received no further treatment. She has been without recurrence for 4 years since an initial surgery. In conclusion, immunohistochemical analyses are useful for make an accurate diagnosis of ESS showing a transition from low-grade ESS to high-grade ESS in addition to the conventional method.

A novel selective progesterone receptor modulator asoprisnil activates tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated signaling pathway in cultured human uterine leiomyoma cells in the absence of comparable effects on myometrial cells.

CONTEXT: We previously demonstrated that asoprisnil, a selective progesterone receptor modulator, induces apoptosis of cultured uterine leiomyoma cells. This study was conducted to evaluate whether asoprisnil activates TNF-related apoptosis-inducing ligand (TRAIL)-mediated apoptotic pathway in cultured uterine leiomyoma and matching myometrial cells. OBJECTIVE AND METHODS: After subculture in phenol red-free DMEM supplemented with 10% fetal bovine serum for 120 h, cultured cells were stepped down to serum-free conditions for 24 h in the absence or presence of graded concentrations of asoprisnil. The levels of TRAIL signaling molecules and cellular inhibitors of apoptosis protein were assessed by Western blot analysis. RESULTS: TRAIL contents in untreated cultured leiomyoma cells were significantly (P < 0.01) lower compared with those in untreated cultured myometrial cells. There was no difference in death receptor (DR)4 and DR5 contents between the two types of cells. Asoprisnil treatment significantly (P < 0.05) increased TRAIL, DR4, and DR5 contents in cultured leiomyoma cells in a dose-dependent manner with a cleavage of caspase-8, -7, and -3, and decreased X-linked chromosome-linked inhibitor of apoptosis protein contents. In cultured myometrial cells, however, asoprisnil treatment did not affect either TRAIL signaling molecule or cellular inhibitors of apoptosis protein contents. The concomitant treatment with 100 ng/ml P4 significantly (P < 0.05) reversed asoprisnil-induced increase in DR4 and cleaved poly(adenosine 5'-diphosphate-ribose) polymerase contents in cultured leiomyoma cells. CONCLUSIONS: These results suggest that asoprisnil induces apoptosis of cultured leiomyoma cells by activating TRAIL-mediated apoptotic pathway and down-regulating X-linked chromosome-linked inhibitor of apoptosis protein levels in the absence of comparable effects on myometrial cells.

Effects of levonorgestrel-releasing IUS and progesterone receptor modulator PRM CDB-2914 on uterine leiomyomas.

We have found that the use of levonorgestrel-releasing IUS results in a remarkable decrease in endometrial proliferation and a remarkable increase in apoptosis in the endometrium; therefore, it is effective for long-term management of menorrhagic women with uterine myomas because of the striking reduction in menorrhagia. This prompted us to characterize the effects of progesterone (P(4)) and progesterone receptor modulator (PRM) CDB2914 on uterine myoma growth. In vitro studies with cultured uterine leiomyoma cells and normal myometrial cells revealed that P(4) stimulated the proliferative activity in leiomyoma cells, but not in normal myometrial cells. P(4) increased EGF expression, whereas E(2) augmented EGF-R expression in leiomyoma cells, indicating that P(4) and E(2) act in combination to stimulate leiomyoma cell growth. P(4) also increased Bcl-2 expression and decreased TNF-alpha expression in those cells. Unlike the EGF expression, IGF-I expression in leiomyoma cells was inhibited by P(4). These results suggest that P(4) has dual actions on leiomyoma growth: one is to stimulate the growth through up-regulating EGF and Bcl-2 expression, and the other is to inhibit the growth through down-regulating IGF-I expression in the cells. By contrast, CDB2914 inhibited proliferation and stimulated apoptosis of leiomyoma cells without affecting normal myometrial cells. Furthermore, CDB2914 inhibited vascular endothelial growth factor and adrenomedullin expression in leiomyoma cells, but not in normal myometrial cells. The cell type-specific action of CDB2914 on leiomyoma cells, without affecting the surrounding normal myometrial cells, is meaningful for understanding the usefulness of CDB2914 in the medical treatment of uterine myomas.

Vascular endothelial growth factor +936 C/T polymorphism is associated with an increased risk of endometriosis in a Japanese population.

BACKGROUND: Vascular endothelial growth factor (VEGF) concentration in endometriosis patients is higher than controls, in serum and ascites, suggesting that VEGF may play an important role in the pathogenesis of endometriosis. In this study, we investigated whether polymorphisms in the VEGF gene are associated with endometriosis in a Japanese population. METHODS: Genotyping of VEGF -460 C/T, +405 G/C and +936 C/T polymorphisms were performed in 147 endometriosis cases diagnosed by laparotomy or laparoscopy at a university hospital, and 181 controls, by polymerase chain reaction-restriction fragment length polymorphism analysis. We compared the genotype distribution and allele frequency of these 3 polymorphisms between endometriosis patients and controls. RESULTS: No significant differences in the frequency and genotype distribution of VEGF -460 C/T, +405 G/C and +936 C/T polymorphisms were found between the endometriosis patients (all disease stages) and controls. However, a positive association was found between stage III-IV disease and the VEGF +936 T allele (p=0.018). CONCLUSIONS: The VEGF +936 T allele is associated with an increased risk of stage III-IV endometriosis in a Japanese population.

Association study between epidermal growth factor receptor and epidermal growth factor polymorphisms and endometriosis in a Japanese population.

OBJECTIVE: We investigated a possible association between endometriosis and polymorphisms in the genes encoding epidermal growth factor (EGF) receptor (EGFR) and EGF in a Japanese population. METHODS: We compared the distribution of the Egfr+2073 A/T and Egf+61 G/A polymorphisms by polymerase chain reaction-restriction fragment length polymorphism analysis in 146 affected women and 181 controls. RESULTS: No significant differences in the frequency and genotype distribution of the Egfr+2073 A/T and Egf+61 G/A polymorphisms were found between endometriosis patients with all disease stages and controls. Stratification by disease stage had no effect on the results. CONCLUSION: The Egfr+2073 A/T and Egf+61 G/A polymorphisms are not associated with an increased risk of endometriosis in a Japanese population.

A novel selective progesterone receptor modulator asoprisnil (J867) inhibits proliferation and induces apoptosis in cultured human uterine leiomyoma cells in the absence of comparable effects on myometrial cells.

CONTEXT: Asoprisnil, a selective progesterone (P4) receptor (PR) modulator (SPRM) with mixed P4 agonist/antagonist activities, reduces uterine leiomyoma volume in a dose-dependent manner in the presence of follicular phase estrogen concentrations. The evidence from clinical studies suggests that asoprisnil may directly target the uterine leiomyomata. OBJECTIVE AND METHODS: The present study evaluated the effects of asoprisnil on cell proliferation, the expression of apoptosis-related proteins, and apoptosis in cultured human uterine leiomyoma cells and matched normal myometrial cells. PR-A and PR-B expression in the two types of cells was comparatively evaluated. Cell proliferation, proliferating cell nuclear antigen (PCNA)-positive rate, and TUNEL-positive rate were assessed by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay, immunocytochemistry, and terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate nick end labeling (TUNEL) assay, respectively. The expression of apoptosis-related proteins and PR was assessed by Western blot analysis. RESULTS: Compared with untreated cultures, asoprisnil decreased the number of viable cultured cells, the PCNA-positive rate, and PCNA protein expression in cultured leiomyoma cells. Asoprisnil increased the TUNEL-positive rate, cleaved caspase-3, and cleaved poly(adenosine 5'-diphosphate-ribose) polymerase expression and decreased Bcl-2 protein expression in cultured leiomyoma cells. These effects were dose and time dependent. In cultured myometrial cells, however, asoprisnil did not affect cell proliferation and apoptosis. PR-B expression was elevated in cultured leiomyoma cells compared with cultured myometrial cells, whereas no differences in PR-A expression were noted between the two cell types. CONCLUSIONS: These results show that asoprisnil inhibits proliferation and induces apoptosis in cultured uterine leiomyoma cells in the absence of comparable effects on cultured normal myometrial cells, suggesting a cell type-specific effect.

Gonadotropin-releasing hormone antagonist cetrorelix down-regulates proliferating cell nuclear antigen and epidermal growth factor expression and up-regulates apoptosis in association with enhanced poly(adenosine 5'-diphosphate-ribose) polymerase expression in cultured human leiomyoma cells.

The objective of this study was to elucidate the effects of GnRH antagonist Cetrorelix on proliferation and apoptosis in human leiomyoma cells cultured in vitro. Isolated leiomyoma cells were subcultured in phenol red-free DMEM supplemented with 10% fetal bovine serum for 120 h and then stepped down to serum-free conditions in the presence or absence of graded concentrations of Cetrorelix (10(-5) to 10(-8) mol/liter) for 6 d. Cultured leiomyoma cells were used for semiquantitative RT-PCR, immunocytochemistry, Western blot analysis, and terminal deoxynucleotidyl transferase-mediated deoxyuridine 5-triphosphate nick-end labeling assay. RT-PCR analysis revealed the presence of mRNAs encoding for GnRH receptor and epidermal growth factor (EGF) in cultured leiomyoma cells. The number of viable cultured leiomyoma cells was significantly (P < 0.01) decreased by treatment with Cetrorelix compared with untreated control cultures. Immunocytochemical examination demonstrated that treatment with Cetrorelix attenuated the expression of proliferating cell nuclear antigen (PCNA) and EGF in cultured leiomyoma cells. Western blot analysis revealed that treatment with 10(-5) mol/liter Cetrorelix significantly (P < 0.01) decreased PCNA expression. In addition, treatment with 10(-5) mol/liter Cetrorelix remarkably increased the terminal deoxynucleotidyl transferase-mediated deoxyuridine 5-triphosphate nick-end labeling-positive rate and poly(ADP-ribose) polymerase expression at 24 h of treatment compared with untreated control cultures (P < 0.01). Furthermore, treatment with 10(-5) mol/liter Cetrorelix decreased immunoreactive EGF protein and EGF mRNA expression in cultured leiomyoma cells at 4 d of treatment. GnRH antagonist Cetrorelix may directly inhibit leiomyoma cell growth by down-regulating proliferation in association with a decrease in EGF mRNA expression and by up-regulating apoptosis in those cells.

Progesterone receptor modulator CDB-2914 down-regulates proliferative cell nuclear antigen and Bcl-2 protein expression and up-regulates caspase-3 and poly(adenosine 5'-diphosphate-ribose) polymerase expression in cultured human uterine leiomyoma cells.

The present study was conducted to evaluate the effects of the progesterone receptor modulator CDB-2914 on proliferative activity and apoptosis in cultured human uterine leiomyoma cells. Isolated leiomyoma cells were subcultured in phenol red-free DMEM supplemented with 10% fetal bovine serum for 120 h and then stepped down to serum-free conditions for 12, 24, 48, and 96 h in the absence or presence of graded concentrations of CDB-2914 (10(-9), 10(-8), 10(-7), and 10(-6) M). The number of viable cultured leiomyoma cells was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazodium bromide assay. Proliferating cell nuclear antigen (PCNA) expression was evaluated by immunocytochemistry and Western blot analysis. Apoptosis was examined by terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate nick end labeling (TUNEL) assay. Caspase-3, cleaved poly(ADP-ribose) polymerase (PARP), and Bcl-2 expression were assessed by Western blot analysis. Compared with untreated control cultures, treatment with CDB-2914 decreased the number of viable cultured leiomyoma cells and the PCNA-positive rate in those cells and increased the TUNEL-positive rate in cultured leiomyoma cells in a dose-dependent manner. Western blot analysis revealed that treatment with CDB-2914 significantly decreased the expression of PCNA and Bcl-2 protein and increased the expression of cleaved caspase-3 and cleaved PARP in a dose-dependent manner compared with untreated control cultures. These results suggest that CDB-2914 inhibits the proliferation of cultured leiomyoma cells by down-regulating PCNA expression and induces apoptosis by up-regulating cleaved caspase-3 and PARP expression and down-regulating Bcl-2 protein expression in those cells.

Transfection of antisense chorionic gonadotropin beta gene into choriocarcinoma cells suppresses the cell proliferation and induces apoptosis.

CONTEXT: Choriocarcinoma cells not only synthesize human chorionic gonadotropin (hCG), but also express LH/CG receptors on the cell membrane. This suggests that the hCG and LH/CG receptors may play a role in regulating the biological function of choriocarcinoma cells in an autocrine/paracrine manner. OBJECTIVE AND METHODS: The objective of this study was to ascertain whether the inhibition of CGbeta gene expression in choriocarcinoma cells affects their proliferation and apoptosis. Expression vector bearing antisense CGbeta gene was transfected into the choriocarcinoma cell line, JAr. CGbeta protein synthesis was monitored by Western immunoblot, and CGbeta mRNA expression was determined by RT-PCR. Cell proliferation was assessed by 3-[4,5-dimethlthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay and nuclear incorporation of 5-bromo-2'-deoxyuridine, and the apoptosis-positive rate was assessed by terminal deoxynucleotidyltransferase-mediated deoxy-UTP nick end labeling analysis and nuclear staining with Hoechst 32258. RESULTS: JAr cells transfected with antisense CGbeta gene (JAr-aCGbeta cells) showed a significant decrease in hCG production and cell proliferation compared with untransfected and mock-transfected cells. The apoptosis-positive rate of the JAr-aCGbeta cells significantly increased compared with that of the controls. LH/CG receptor expression in JAr-aCGbeta cells decreased compared with that in controls. By contrast, supplementation of exogenous hCG significantly increased the LH/CG receptor expression and viability of JAr-aCGbeta cells. CONCLUSIONS: These results suggest that hCG, through its binding to the LH/CG receptor, may augment proliferation and inhibit apoptosis in choriocarcinoma JAr cells, and that the introduction of an antisense gene may be a potential approach to the inhibition of choriocarcinoma cell growth.

Acute onset of polymyalgia rheumatica in pregnancy.

BACKGROUND: Polymyalgia rheumatica is uncommon in young women and remains a diagnostic challenge for pregnant women. CASE: A 28-year-old pregnant woman developed polymyalgia rheumatica in the third trimester. Laboratory investigations revealed elevated erythrocyte sedimentation rate and C-reactive protein levels with normal muscle enzyme levels and seronegativity for rheumatoid factor. Although her symptoms deteriorated as pregnancy progressed, she drastically improved by treatment with prednisone. She underwent cesarean delivery at 39 weeks. She was relapse-free of polymyalgia rheumatica after discontinuation of prednisone on the 50th postoperative day. CONCLUSION: The diagnosis of polymyalgia rheumatica is important to properly manage pregnancy.

Lack of association between endometriosis and N-acetyl transferase 1 (NAT1) and 2 (NAT2) polymorphisms in a Japanese population.

OBJECTIVE: We investigated the association between endometriosis and polymorphisms in the N-acetyltransferase 1 (NAT1) and N-acetyltransferase 2 (NAT2) genes in a Japanese population, having previously demonstrated a positive association with NAT2 polymorphisms in a UK population. METHODS: Genotyping for NAT1 alleles *3, *4, *10, and *11, and NAT2 alleles *4, *5A, *5B, *5C, *6A, and *7B was performed using polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP) and allele-specific PCR (AS-PCR) analysis in 145 ethnically Japanese, endometriosis patients and 182 controls. The NAT1 and NAT2 allele and genotype frequencies were compared in cases and controls using the Fisher exact test. RESULTS: No significant differences between cases and controls were observed in the frequencies of the NAT1 and NAT2 alleles (P = .13; P = .91) and genotypes (P = .24; P = .79), and the NAT2 acetylation phenotypes (P = .46). Dividing the cases into a subgroup, consisting of women with severe disease only (n = 80), had no effect on the results. CONCLUSION: The distribution of NAT1 and NAT2 allele and genotype frequencies were not significantly different between Japanese cases and controls. Our findings suggest that polymorphisms in NAT1 and NAT2 are unlikely to be associated with an increased risk of endometriosis in the Japanese population.

Aggressive Granulosa Cell Tumor of the Ovary with Rapid Recurrence: a Case Report and Review of the Literature.

Aggressive adult granulosa cell tumor (AGCT) of the ovary remains uncommon. We report a case of aggressive AGCT of the ovary who had rapid recurrence at two months after surgery. A patient was referred for further examination of a pelvic tumor. She underwent total abdominal hysterectomy, bilateral salpingo-oophorectomy, and pelvic lymphadenectomy. In the areas showing a sarcomatoid pattern, the mitotic count were 25/10 HPFs, and the mitoses were most prominent in foci composed of pleomorphic cells with enlarged and bizarre nuclei. In some areas, tumor cells with relatively uniform nuclei proliferated in a trabecular pattern. The mitotic count was 4/10 HPFs. Tumor cells were diffusely positive for α-inhibin. She was diagnosed as having aggressive AGCT. The Ki-67 labeling index in the sarcomatoid AGCT was higher (40%) than that in the areas of typical AGCT (3%). Immunostaining for p53 in the sarcomatoid AGCT was almost strongly positive, but that in typical AGCT was negative. Two months later after the initial surgery, a recurrent abdominal 12 cm-sized mass developed after performing adjuvant chemotherapy consisting of paclitaxel and carboplatin. She died of the disease at 3 months after initial surgery. A markedly higher mitotic count, a higher Ki-67 labeling index, and strong immunoreactivity of p53 in AGCT suggests highly malignant potential. In such a case, a careful follow-up is warranted due to the possibility of rapid recurrence.

The role of thyroid hormone in trophoblast function, early pregnancy maintenance, and fetal neurodevelopment.

OBJECTIVE: To review the literature on the roles of thyroid hormone in trophoblast function, early pregnancy maintenance, and fetal neurodevelopment. METHODS: MEDLINE was searched for English-language papers published from 1971 to 2003, using the key words "brain," "hypothyroidism," "placenta," "pregnancy," "threatened abortion," "thyroid hormone," "thyroid hormone receptor," "thyroid hormone replacement therapy," "thyroid hormone-responsive gene," and "trophoblast." RESULTS: Transplacental transfer of thyroid hormone occurs before the onset of fetal thyroid hormone secretion. Thyroid hormone receptors and iodothyronine deiodinases are present in the placenta and the fetal central nervous system early in pregnancy, and thyroid hormone plays a crucial role both in trophoblast function and fetal neurodevelopment. Maternal hypothyroxinemia is associated with a high rate of spontaneous abortion and long-term neuropsychological deficits in children born of hypothyroid mothers. Maternal iodine deficiency also causes a wide spectrum of neuropsychological disorders in children, ranging from subclinical deficits in cognitive motor and auditory functions to hypothyroid-induced cognitive impairment in infants. However, these conditions are preventable when iodine supplementation is initiated before the second trimester. Although thyroid hormone replacement therapy is effective for reducing the adverse effects complicated by maternal hypothyroidism, the appropriate dose of thyroid hormone is mandatory in protecting the early stage of pregnancy. CONCLUSIONS: Close monitoring of maternal thyroid hormone status and ensuring adequate maternal thyroid hormone levels in early pregnancy are of great importance to prevent miscarriage and neuropsychological deficits in infants.

Coexistence of endometrioid adenocarcinoma in atypical polypoid adenomyoma.

Atypical polypoid adenomyoma (APA) is a rare polypoid tumor of the uterus composed of atypical endometrial glands and smooth muscle cells. Concomitant development of endometrial adenocarcinoma in APA remains infrequent. We report a case of the coexistence of endometrioid adenocarcinoma in APA. A 41-year-old patient presented with abnormal genital bleeding. A polypoid mass was extruded from the external cervical os. She underwent transcervical resection of the polypoid mass arising from the lower uterine segment. Pathological examination revealed APA with the foci of well-differentiated endometrioid adenocarcinoma. Subsequently, she underwent total hysterectomy and bilateral salpingo-oophorectomy. No residual malignant lesions were found. Awareness of the close association of APA with the development of endometrial cancer is warranted. A meticulous pathological evaluation of specimen of APA is necessary for the detection of the coexistence of endometrial cancer.