碓井 宏和

OBJECTIVES: The prevention of chemotherapy-induced and radiotherapy-induced emesis is recommended by several guidelines; however, there are no evidence-based recommendations for the use of antiemetics in concurrent chemoradiotherapy (CCRT). The aim of the present study was to evaluate the efficacy and safety of antiemetic therapy comprising palonosetron and dexamethasone during CCRT. METHODS: This is a nonrandomized, prospective, single-center, open phase II study.Twenty-six consecutive patients with cervical carcinoma were treated with daily low-dose cisplatin (8 mg/m/d)-based CCRT (2 Gy/d, 25 fractions, 5 times a week). All patients received 0.75 mg of palonosetron on day 1 of each week and 4 mg of oral dexamethasone daily. The primary endpoint was the percentage of patients achieving a complete response, which was defined as no emetic episodes and no antiemetic rescue medication during treatment. RESULTS: Planned daily low-dose cisplatin-based CCRT was successful without delay or interruption in 46% (12/26) of the patients. The mean dose of total cisplatin was 184 (range, 136 to 200) mg/m.No patient vomited during the treatment period. The complete response rate during CCRT was 100%. A total of 81% patients were completely free from nausea. All patients tolerated the combination of palonosetron and dexamethasone and completed the scheduled regimen. Five patients exhibited grade 1 Cushingoid features that resolved after treatment. CONCLUSIONS: Antiemetic therapy comprising palonosetron and dexamethasone provided complete protection from nausea and vomiting in patients with cervical cancer receiving daily low-dose cisplatin-based CCRT.

Gestational trophoblastic neoplasia (GTN) is a rare tumor, and its genomic constitution is different from the maternal genome because of its gestational origin. Methotrexate (MTX) is a standard chemotherapeutic agent for low-risk GTN. An association between polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene and MTX treatment outcome has been reported in various diseases. Thus, we examined the association between clinical outcome and MTHFR polymorphisms in both tumor and blood DNA of low-risk GTN patients. MTHFR C677T (rs1801133) and A1298C (rs1801131) were genotyped using high-resolution melting assays in 62 Japanese low-risk GTN patients and in 52 antecedent molar tissues. We compared the genotypes of MTHFR polymorphisms with the clinical outcome of 5-day MTX treatment. Twenty-five patients entered remission and 37 patients developed drug resistance or adverse effects that necessitated a drug change. The MTHFR 677T allele in molar tissue was significantly related to the need for drug change (P=0.006; odds ratio [OR], 3.13; 95% confidence interval [CI], 1.31-7.49), in contrast to MTHFR 1298C (P=0.18; OR, 0.63; 95% CI, 0.32-1.25). The MTHFR 677T and 1298C alleles obtained from patients' blood DNA were not related to MTX treatment outcome (P=0.49; OR 1.31; 95% CI, 0.61-2.91 and P=0.10; OR 0.52; 95% CI, 0.22-1.15, respectively). These data demonstrate for the first time that the genotype of MTHFR 677TT in molar tissue is associated with ineffective MTX treatment in Japanese low-risk GTN patients.

PURPOSE: Antiemetic recommendations during concurrent chemoradiotherapy (cisplatin-based concurrent chemoradiotherapy (CCRT)) have not been established yet. The aim of this study was to investigate whether the combination of palonosetron plus aprepitant, without routine use of dexamethasone, could alleviate chemoradiotherapy-induced nausea and vomiting (CRINV). METHODS: This was a non-randomized, prospective, single-center, open phase II study. Patients with cervical cancer, who were treated with daily low-dose cisplatin (8 mg/m(2)/day) and concurrent radiation (2 Gy/day, 25 fractions, five times a week), were enrolled in this study. All patients received intravenous palonosetron (0.75 mg on day 1 of each week) and oral aprepitant (125 mg on day 1 and 80 mg on days 2 and 3 of each week). The primary endpoint was the percentage of patients with a complete response, defined as no emetic episodes and no use of antiemetic rescue medication during the treatment. RESULTS: Twenty-seven patients (median age, 50 years; range, 33-72 years) were enrolled in this study between June 2013 and April 2014. A total of 13 (48 %) patients showed a complete response to the antiemetic regimen, while 8 patients (30 %) had emetic episodes and 6 patients (22 %) used rescue medication without emetic episodes. No severe adverse effects caused by palonosetron plus aprepitant were observed. CONCLUSION: The combination of palonosetron plus aprepitant was permissive for the prevention of CRINV. This regimen should be considered for patients in whom dexamethasone is contraindicated or not well tolerated.

OBJECTIVE: To elucidate the diagnostic accuracy of macroscopic and histopathological diagnoses of molar pregnancy as compared with cytogenetic diagnosis as the gold standard. STUDY DESIGN: Patients were recruited for the molecular diagnostic study of suspected molar pregnancy at Chiba University Hospital between 2007 and 2011. Gynecologists performed macroscopic diagnoses immediately after the evacuation. Pathological diagnoses were then made by pathologists in routine bases without performing p57Kip2 immunostaining. Molecular cytogenetic diagnosis was performed via short tandem repeat (STR) polymorphism analysis. Androgenetic, biparental triploid, and biparental diploid odious tissues determined on STR polymorphism analysis were classified as complete hydatidiform mole (CHM), partial hydatidiform mole (PHM), and abortion, respectively. RESULTS: A total of 86 patients were enrolled. The number of CHMs, PHMs, and abortions on cytogenetic diagnoses were 64; 9, and 13, respectively. The concordance rate between macroscopic and cytogenetic diagnoses was 85% (CHM: 56, PHM: 4, and abortions: 13). The concordance rate between histopathological and cytogenetic diagnoses was 87% (CHM: 59, PHM: 5, and abortions: 10). The complete agreement rate among the 3 categories was 78% (CHM: 55, PHM: 3, and abortions: 10). CONCLUSION: Neither macroscopic nor histopathological diagnoses were perfect, but both were quite accurate in a single trophoblastic center.

Mature cystic teratomas (MCTs) in the ovaries have been thought to originate from germ cells from all developmental stages, i.e., from pre-meiotic oogonia through meiotic oocytes to mature post-meiotic ova. This view was based on research on MCTs by classical methods, including those involving centromeric heteromorphisms in karyotypes, enzyme polymorphisms, and DNA polymorphisms. However, insufficient genomic information was obtained in those studies. The current study aimed to confirm the cytogenetic origin of ovarian MCTs by using short tandem repeat (STR) polymorphism analysis to obtain sufficient genomic information, especially in connection with centromeric loci. Tissue samples of MCTs (57 ovaries from 51 patients, 91 MCTs, 156 specimens in total) obtained from cystectomies or oophorectomies were used. We categorized the specimens into two groups: i) solid components of MCTs and ii) cyst walls. The numbers of solid components of MCTs from pre-meiotic oogonia, primary oocytes, secondary oocytes, and ova were 0, 33, 16, and 15, respectively. There were no pre-meiotic oogonia in this series of solid-component specimens. We propose a hypothesis for the tumorigenesis of ovarian MCTs: the precursors of ovarian MCTs are not functional oocytes or ova, but are primary oocytes that have escaped from meiotic arrest. This hypothesis could satisfactorily explain the lack of pre-meiotic teratomas observed in this study and the nearly equal distribution of teratomas originating from primary oocytes, secondary oocytes, and ova in previous studies. Furthermore, this hypothesis could provide a starting point for determining the mechanism underlying tumorigenesis of ovarian MCTs. (c) 2016 Wiley Periodicals, Inc.

Ovarian non-gestational choriocarcinomas co-existing with adenocarcinoma are extremely rare and have been reported as epithelial ovarian carcinomas of a “non-germ cell origin” with “choriocarcinomatous differentiation”. Although the cellular origin of non-gestational choriocarcinoma may be post-meiotic ovarian germ cells or the dedifferentiation of epithelial ovarian carcinoma, detailed genetic evidence has not yet been obtained to support this. We herein present a case of ovarian non-gestational choriocarcinoma co-existing with adenocarcinoma in a 29-year-old woman. The tumor rapidly increased in size and lung metastases appeared soon after parturition. We genetically demonstrated that the cellular origin of ovarian non-gestational choriocarcinoma was a post-meiotic germ cell derivation using a short tandem repeat analysis. The co-existing adenocarcinoma component was also shown to be of the same germ cell origin. These tumors showed the same homozygous pattern. A molecular genetic approach may be important for understanding the clinicopathological features of such tumors.

Objective. To determine the primary remission rates and predictors of drug resistance in patients with post-molar low-risk gestational trophoblastic neoplasia (GTN) who were treated with a 5-day intramuscular methotrexate (5-day IM MTX) or a 5-day drip infusion etoposide (5-day DIV ETP) regimen. Methods. Between 1980 and 2014, 166 consecutive patients with low-risk post-molar GTN were initially treated with a 5-day IM MTX or a 5-day DIV ETP regimen. The primary remission rates, changes in chemotherapy due to drug resistance or toxicity, and relapse rates were compared. Furthermore, we analyzed the factors that influenced the development of resistance to MTX. Results. Primary remission rates were significantly higher among the ETP-treated patients than among the MTX-treated patients. Among the 42 patients who required a change in chemotherapy, 23 patients (22.6%) and 4 patients (6.3%) were diagnosed as being resistant to MTX and EPT, respectively. Maternal age and the presence of metastasis did not significantly influence the development of MTX resistance, although higher FIGO scores and pre-treatment human chorionic gonadotropin (hCG) levels of >5 x 10(4) mIU/mL were significantly more common among patients who developed MTX resistance. Moreover, a <30% decrease in hCG after the first cycles of MIX chemotherapy was significantly associated with the development of MIX resistance. Conclusions. All patients with low-risk GTN eventually achieved complete remission, although several patients developed drug resistance to the first-line chemotherapy. A <30% decrease in hCG during the first chemotherapy cycle may be an early indicator of drug resistance after commencing a 5-day MTX regimen. (C) 2015 Elsevier Inc. All rights reserved.

Pregnancy of unknown location is defined as empty endometrial cavity despite positive pregnancy test, and often develops as overt intrauterine or ectopic pregnancy. The pathophysiology of persistent pregnancy of unknown location, however, which involves continuous low serum human chorionic gonadotropin without any visible implantation site, is unknown. We report a case of left tubal pregnancy associated with additional conception in the contralateral tube. Left tubal pregnancy was suspected in a 40-year-old nulligravid woman after two embryo transfers following in vitro fertilization. Laparoscopic bilateral salpingectomy was performed for bilateral hydrosalpinx. Products from an additional conception were identified in the right tube. Short tandem repeat analysis using genomic DNA from resected specimens indicated two conceptions of different origin. The extra conception identified on microscopy may indicate one pathogenesis of persistent pregnancy of unknown location. Salpingectomy of the contralateral tube with hydrosalpinx is an option to prevent persistent occult pregnancy.

In developed countries, endometrial cancer (EC) is the most common malignancy among women. Unopposed estrogen therapy, obesity, nulliparity, diabetes mellitus and arterial hypertension have been linked to an increased risk of EC. However, the molecular mechanisms of EC oncogenesis and metastasis have not yet been fully elucidated. Our recent studies of microRNA (miRNA) expression signatures revealed that the microRNA-1/133a (miR‑1/133a) cluster is frequently downregulated in various types of human cancers. However, the functional role of the miR‑1/133a cluster in EC cells is still unknown. Thus, the aim of this study was to investigate the functional significance of the miR‑1/133a cluster and its regulated molecular targets, with an emphasis on the contributions of miR‑1/133a to EC oncogenesis and metastasis. We found that the expression levels of miR‑1 and miR‑133a were significantly reduced in EC tissues. Moreover, restoration of mature miR‑1 or miR‑133a miRNAs significantly inhibited cancer cell migration and invasion, suggesting that these clustered miRNAs act as tumor suppressors. Prediction of miRNA targets revealed that phosphodiesterase 7A (PDE7A) was a potential target gene regulated by both miR‑1 and miR‑133a. PDE7A was confirmed to be overexpressed in EC clinical specimens and silencing of PDE7A significantly inhibited cancer cell migration and invasion. Our data demonstrated that downregulation of the miR‑1/133a cluster promoted cancer cell migration and invasion via overexpression of PDE7A in EC cells. Elucidation of the molecular networks regulated by tumor-suppressive miRNAs will provide insights into the molecular mechanisms of EC oncogenesis and metastasis.

OBJECTIVES: It has been established that concurrent chemoradiotherapy (CCRT) is efficacious for cervical cancer, but adherence is unsatisfactory among elderly patients. To improve adherence, we have developed and initiated a daily low-dose cisplatin-based CCRT regimen. Here, we retrospectively evaluated the use of CCRT, especially for elderly patients. METHODS: The study included a total of 53 patients who were 70 years or older, had stage IB-IVA cervical cancer, and were initially treated with daily CCRT. The daily CCRT comprised pelvic external beam radiotherapy (2 Gy/d × 25) with daily low-dose cisplatin (8.0 mg/m(2) per day) and either low- or high-dose-rate intracavitary brachytherapy. RESULTS: The median age was 72 years (range, 70-85 years). The median follow-up duration was 32 months (range, 2-104 months). The 3-year overall survival rate was 79.0%. Daily cisplatin chemotherapy was successfully completed in 32 (60.4%) of the 53 patients. Grade 3 or 4 neutropenia was observed in 19 patients (36%). A late complication of grade 3 rectal hemorrhage occurred in 3 patients who received high-dose-rate brachytherapy. All primary tumors responded to daily CCRT; complete response was observed in 43 patients (91.5%) and partial response was observed in 4 patients (8.5%). CONCLUSIONS: Daily CCRT in patients 70 years and older had acceptable compliance and safety. Daily CCRT is suggested to be a good treatment option for elderly patients who have advanced cervical cancer and require concurrent cisplatin.

Objectives: This study aimed to identify the clinical and demographic characteristics and prognosis of patients with conditions diagnosed with postpartum choriocarcinoma based on the International Federation of Gynecology and Obstetrics 2000 prognosis scoring system or based on pathologically confirmed choriocarcinoma and to analyze the patients' clinical symptoms for early detection of this disease. Methods/Materials: Between January 1983 and August 2013, 24 consecutive women with postpartum choriocarcinoma were treated at 2 hospitals. Data on clinical and demographic characteristics, including initial presenting symptoms, type of antecedent pregnancy, fetal complications, and prognosis of these patients, were analyzed. According to the time interval between the previous delivery and the onset of disease, patients were divided into 2 groups: the short and long interval groups. Results: The most common symptom among the 24 patients with postpartum choriocarcinoma was irregular vaginal bleeding (14/24); in some cases, bleeding was caused by metastatic foci (7/24). Massive genital bleeding causing emergency hysterectomy and several obstetric complications, such as unknown severe fetal anemia and fetal growth retardation, was only observed in the short interval group. The overall primary remission rate was 91.7%. Conclusions: The most common symptom of patients with postpartum choriocarcinoma in the short and long interval groups was genital bleeding, and the overall prognosis may be improved by introduction of an appropriate chemotherapy regimen. Careful pathological examination of the placenta is needed in cases of fetomaternal hemorrhage, unknown fetal anemia, and abnormal obstetric events, including premature delivery, still birth, and infantile growth retardation, for the early detection of intraplacental choriocarcinoma.

Our recent studies of microRNA (miRNA) expression signatures indicated that microRNA-29a (miR-29a) was significantly downregulated in several types of human cancers, suggesting that miR-29a may be a putative tumor-suppressive miRNA in human cancers. The aim of this study was to investigate the functional significance of miR-29a in cervical squamous cell carcinoma (SCC) and to identify novel miR-29a-regulated cancer pathways and target genes involved in cervical SCC oncogenesis and metastasis. Restoration of miR-29a in cervical cancer cell lines (CaSKi, HeLa, ME180 and Yumoto) revealed that this miRNA significantly inhibited cancer cell migration and invasion. Gene expression data and in silico analysis demonstrated that heat-shock protein 47 (HSP47), a member of the serpin superfamily of serine proteinase inhibitors and a molecular chaperone involved in the maturation of collagen molecules, was a potential target of miR-29a regulation. Luciferase reporter assays showed that miR-29a directly regulated HSP47. Moreover, silencing of the HSP47 gene significantly inhibited cell migration and invasion in cancer cells and the expression of HSP47 was upregulated in cancer tissues and cervical intraepithelial neoplasia (CIN), as demonstrated by immunostaining. Downregulation of miR-29a was a frequent event in cervical SCC and miR-29a acted as a tumor suppressor by directly targeting HSP47. Recognition of tumor-suppressive miRNA-regulated molecular targets provides new insights into the potential mechanisms of cervical SCC oncogenesis and metastasis and suggests novel therapeutic strategies for treatment of this disease.

OBJECTIVE: We evaluated the usefulness of daily low-dose cisplatin-based concurrent chemoradiotherapy (daily CCRT) in patients with cervical cancer with an emphasis on elderly patients. METHODS: Between January 2003 and December 2008, a total of 65 patients with untreated stage IIA to IIIB cervical cancer were enrolled and 54 were selected for this nonrandomized prospective study. The daily CCRT comprised pelvic external beam radiotherapy (2 Gy/d × 25) with daily low-dose cisplatin (8.0 mg/m(2) per day) and either low- or high-dose rate intracavitary brachytherapy. RESULTS: The median age of the patients was 62 years (range, 29-85 years), and 21 patients (39%) were 70 years or older. The median follow-up period was 47 months (range, 4-107 months). Daily CCRT was successfully completed in 91% (49/54) of the patients. The mean total cisplatin dose was 191 mg/m (range, 128-224 mg/m(2)), and a neutropenia grade higher than 3 was observed in 24% of the patients. Of the 21 patients 70 years or older, 17 (81%) completed daily CCRT with acceptable toxicity. The 3-year overall survival (OS) rate for all the patients was 82.9%. No statistically significant differences in the OS rate and toxicity were observed between patients 70 years or older and those younger than 70 years. CONCLUSIONS: Daily CCRT showed acceptable toxicity and compliance, leading to the use of a high total dosage of cisplatin. The OS rate for daily CCRT was comparable to that for previously reported weekly CCRT. Daily CCRT could be an alternate choice for the CCRT treatment in elderly patients with cervical cancer.

OBJECTIVE: To examine whether preeclampsia is a predictive factor for fetal prognosis in complete hydatidiform mole coexistent with twin fetus (CHMCF). STUDY DESIGN: We performed a retrospective chart review for 17 cases of definitive CHMCF managed in our hospital between 1991 and 2011. RESULTS: Fifteen patients chose expectant management and the remaining 2 selected termination of the pregnancy. During expectant management 6 patients displayed hypertension with proteinuria, representing preeclampsia, by the 2nd trimester (11-24 weeks) and the other 9 did not (nonpreeclamptic). No babies from preeclamptic mothers survived, with 5 intrauterine fetal deaths at 16-29 weeks and 1 neonatal death at 22 weeks. By contrast, 5 babies from 9 nonpreeclamptic mothers (1 pre-term delivery at 29 weeks and 4 term deliveries) survived, while 4 pregnancies were lost by spontaneous abortion at 11-19 weeks. Low-risk gestational trophoblastic neoplasia (GTN) eventually occurred in both preeclamptic (4 of 6) and nonpreeclamptic (4 of 11) cases. Complicating preeclampsia correlated significantly with fetal demise and an increasing trend in serum hCG level but not with postmolar GTN. CONCLUSION: Complicating preeclampsia predicts poor survival of the fetus, but not subsequent GTN, in CHMCF. (J Reprod Med 2012;57:325-328)

Angiotensin II receptor-like 1 (APJ), a G protein-coupled receptor that was identified as a homologue of angiotensin II type 1 (AT1) receptor, exerts antagonistic effects on AT1-mediated vasoconstriction. Studies on pregnancy-induced hypertension (PIH) revealed aberrant activation of AT1 downstream signaling. In contrast, little is known about APJ in the pathophysiology of human pregnancy. In this study, we investigated APJ expression in normal human and PIH placentas. mRNAs were extracted from 50 placental villous tissues of 18 cases with severe PIH (8 late-onset, 4 early-onset, and 6 superimposed PIH) and 32 control pregnancies (including 6 preterm cases). Histopathologic studies were conducted using paraffin-embedded placental tissues from 12 control placentas (from 23 to 39 wk) and 23 PIH placentas (from 24 to 41 wk). Reverse transcriptase-polymerase chain reaction showed that APJ was cooperatively expressed with its ligand apelin and AT1 in controls and in late-onset PIH placentas but was significantly downregulated in early-onset PIH placentas with poor fetal growth. Quantitative reverse transcriptase-polymerase chain reaction analysis revealed upregulated APJ in late-onset PIH placentas but significantly downregulated APJ in early-onset PIH. In immunohistochemical staining, APJ was detected strongly in villous capillary endothelial cells and trophoblasts of late-onset PIH placentas. In contrast, APJ was poorly stained in endothelial cells of hypoplastic villi of early-onset PIH placentas. Collective data indicate that the apelin-APJ system is involved in fetoplacental circulation during human pregnancy. Impaired APJ expression in early-onset PIH placentas may reflect an aggravated placental condition with poor fetal growth.

OBJECTIVE: To review current follow-up measures of human chorionic gonadotropin (hCG) in uneventful postmolar patients, and to evaluate criteria for initiating chemotherapy. STUDY DESIGN: Between 1993 and 2011 hCG data from 395 patients with uneventful complete moles (CMs) (195 patients) and partial moles (PMs) (205 patients) were obtained at 4 hospitals in Japan. All patients had been followed regularly at various intervals based on the preceding hCG titers and normal hCG regression curve. RESULTS: All patients achieved hCG normalization spontaneously (range, 3.1-29.7 weeks). Approximately half of the patients with CM and PM had attained an undetectable hCG level at 9.3 and 8.3 weeks after evacuation of mole, respectively. The reconstructed normal hCG regression curve consisted of hCG levels of 1,000 mIU/mL at 5 weeks, 100 mIU/mL at 8 weeks and nondetectable hCG levels at 24 weeks. Plotting preceding hCG titers on this hCG regression curve, the intervals of visits to measure hCG were changing, and the real number of visits was significantly fewer than that of recommended weekly measurement of hCG (p < 0.0001). CONCLUSION: The use of the present hCG regression curve after evacuation of a molar pregnancy can aid in estimation of the risk of developing gestational trophoblastic neoplasia, especially in women who have suboptimal compliance and follow-up. (J Reprod Med 2012; 57:243-248)

BACKGROUND: It may be difficult to differentiate the consecutive occurrence of two independent molar pregnancies from gestational trophoblastic neoplasia after the initial molar pregnancy, especially when the interval between them is short. CASE: A 25-year-woman who had had a complete hydatidiform mole 6 months earlier presented with a 6-week history of secondary amenorrhea. Serum human chorionic gonadotropin had increased to 19,857 micro-international units/mL, with no gestational sac demonstrated. Dilation and curettage was performed. Pathologic examination identified a tiny amount of hydropic villi compatible with complete hydatidiform mole. Analysis of short tandem repeat polymorphisms revealed that the molar tissues of the From the Department of Reproductive Medicine, Graduate School of Medicine, first and second complete hydatidiform moles were of different genetic origin. The patient went into remission spontaneously without chemotherapy. CONCLUSION: Genetic profiling was useful to discriminate a recurrent mole from suspected gestational trophoblastic neoplasia. (Obstet Gynecol 2011; 117: 492-5) DOI: 10.1097/AOG.0b013e318205636b

Advanced ovarian cancer may extend into the spleen, and even the pancreatic tail, in which a splenectomy associated with distal pancreatectomy is crucial for optimal cytoreduction. A new linear stapler preloaded with tissue reinforcement is currently introduced. We herein report the first three cases of successful application of this device for distal pancreatectomy performed during cytoreductive surgery for ovarian cancer.

Aim: To determine the effectiveness of postoperative concurrent daily low-dose cisplatin-based chemoradiation (CCRT) in patients with high-risk cervical cancer. Patients and Methods: Patients with stage IB, IIA, or IIB cervical cancer who were initially treated with radical hysterectomy and pelvic lymphadenectomy, and were proven to have pelvic lymph node metastasis (pN1) or microscopic involvement of the parametrium (pT2b), participated in this study. Thirty-one patients received adjuvant CCRT with daily low-dose (6-8.5 mg/m(2)) cisplatin (daily CCRT group). A non-randomised control group of 44 patients received adjuvant radiotherapy alone (RT group). Results: Overall survival (OS) at 4 years was 61% in the RT group and 91% in the daily CCRT group (p=0.004). Hazard ratio for poorer recurrence-free survival (RFS) in the RT group vs. the CCRT group was 7.9 (p=0.006). In the daily CCRT group, daily cisplatin chemotherapy was successfully completed in 27 out of 31 patients, although toxicity of grade >= 3 was found in 29% for neutropenia and 17% for gastrointestinal tract toxicity. Conclusion: Postoperative adjuvant CCRT with daily low-dose cisplatin improved RFS and OS of pT2b or pN1 patients, with acceptable compliance.

ゴナドトロピン放出ホルモン(Gn-RH)受容体変異は、ゴナドトロピン単独欠損症(IHH)の原因である。ミスセンス変異遺伝子のホモ接合や複合ヘテロ接合例が大部分を占めている。ヘテロ接合例では臨床症状を呈さない。変異受容体の発現実験から、変異の種類により受容体機能低下の程度が異なることが明らかにされている。受容体機能低下が強い変異をもつ患者では、臨床症状もより強い傾向がみられる。変異受容体は、立体構造の変化から合成後に細胞膜に運ばれることなく分解される、すなわち、フォールディング異常により機能低下をきたす。非ペプチド性Gn-RH受容体アンタゴニストにより変異受容体のフォールディングが助けられ、細胞膜への発現、リガンド結合能、シグナル伝達は部分的に回復することがわかってきた。(著者抄録)

BACKGROUND: Complete hydatidiform mole (CHM) is a high-risk pregnancy for gestational trophoblastic neoplasia (GTN). Patients with CHM have a 10-30 chance of trophoblastic sequelae. CHM includes androgenic homozygous (monospermic) and androgenic heterozygous (dispermic) moles. It is controversial whether the risk of GTN is higher with heterozygous than with homozygous CHM. A prospective cohort study was conducted to assess risk of GTN in homozygous and heterozygous CHM using short tandem repeat (STR) polymorphisms, and a meta-analysis of previous reports.METHODSTwenty-eight consecutive molar pregnancies were evacuated and followed by regular hCG measurements to detect GTN. Persistent GTN was diagnosed according to the International Federation of Gynecology and Obstetrics 2000 system. Cytogenesis of the mole was determined by STR polymorphisms of molar tissue and parental blood. A meta-analysis of the GTN rate from previous reports was conducted using Mantel-Haenszel methods.RESULTSOf 28 molar pregnancies, 24 were homozygous and three were heterozygous CHM. The remaining mole was diandric triploidy (a partial hydatidiform mole). Of the 24 homozygous CHMs, six (25) cases developed GTN and received chemotherapy. Meanwhile, all three cases (100) of heterozygous mole developed GTN and needed chemotherapy. The GTN risk was higher in heterozygous (P = 0.029, Fisher's exact test) than homozygous moles. A systematic review revealed only five previous reports (with more than 15 cytogenetically diagnosed cases), and the pooled relative risk of persistent GTN for heterozygous mole was not significant (odds ratio, 2.0 95 confidence interval, 0.98-4.07).CONCLUSIONSHeterozygous CHM had a higher risk for GTN than homozygous CHM. © 2010 The Author.

OBJECTIVE: To compare serum human chorionic gonadotropin (hCG) titers using 2 commercially available hCG immunoassays in patients with gestational trophoblastic neoplasia (GTN). STUDY DESIGN: A total of 213 serum samples from 39 patients with uneventful moles and 697 serum samples from 17 patients with low-risk and high-risk GTN were obtained and subsequently measured with both the hCG C-terminal (hCG-CTP) and DPC Immulite 2000 tests. RESULTS: In patients with uneventful moles and GTN, serum hCG levels recorded using the hCG-CTP and DPC Immulite 2000 tests correlated well (r2 = 0.936 and r2 = 0.958). However, the serum hCG titers measured using the DPC Immulite 2000 assay were approximately 2.5- and 2.7-fold higher than those measured with the hCG-CTP test (p < 0.0001) when lower titers of hCG (< 40 mIU/mL) were tested. In addition, 3 and 1 patient, respectivelyl, with uneventful mole and GTN obtained positive results with the DPC Immulite 2000 test (3.0-4.2 mIU/mL) after demonstrating undetectable hCG levels with the hCG-CTP test (< 1.0 mIU/mL). CONCLUSION: At the lower levels of hCG, a few discrepancies between hCG titers measured using the 2 commercial immunoassays arose and may be attributed to the existence of hCG-related molecules. However, these hCG metabolites disappeared rapidly, the clinical importance of which remains unclear.

Context: Symptomatic uterine leiomyoma is associated with irregular uterine bleeding, anemia, and recurrent pregnancy loss. African-American women develop uterine leiomyomas at an earlier age and with higher frequency compared with Caucasian-American women or other races; however, the underlying mechanism for this discrepancy is unknown. Objective: Our objective was to determine whether gene targets of emerging leiomyoma therapeutics such as aromatase inhibitors and antiprogestins, which reduce tumor size and symptoms, are differentially expressed in tissues of African-American (n = 31), Caucasian-American (n = 34), and Japanese women (n = 36). Results: We found strikingly higher aromatase mRNA levels in leiomyoma compared with adjacent myometrium in African-American (83 fold), Caucasian-American (38 fold), and Japanese women (33 fold). Among the four major promoters that regulate aromatase expression in leiomyoma, the proximal promoter II accounted for higher aromatase mRNA levels in tissues from African-American women. Estrogen receptor subtype alpha mRNA levels were significantly, and 1.8- to 2.6-fold, higher in leiomyoma compared with adjacent myometrium in all groups, whereas leiomyoma estrogen receptor subtype beta mRNA levels were significantly elevated only in Japanese women. Leiomyoma progesterone receptor mRNA levels were significantly higher in Japanese women compared with African-American or Caucasian-American women. Conclusions: Leiomyoma tissues from African-American women contained the highest level of aromatase expression, which may result in elevated tissue concentrations of estrogen, and account for the higher prevalence and earlier incidence. Analysis of leiomyoma tissue for biomarkers may predict the response to hormonal treatments such as aromatase inhibitors. (J Clin Endocrinol Metab 94:1752-1756, 2009)

Background: The current study examined the clinical usefulness of YKL-40 in detection and prognosis of uterine cervical cancer. Patients and methods: Serum levels of YKL-40, cancer antigen 125 (CA 125), carbohydrate antigen 19-9 (CA19-9), and squamous cell carcinoma (SCC) antigen were determined by enzyme-linked immunosorbent assay in women with benign gynecologic disease (n = 24), cervical malignancy (SCC, n = 104 adenocarcinoma, n = 37), and age-matched healthy controls (n = 45). Immunohistochemical analysis for local YKL-40 expression was carried out on 28 adenocarcinomas. Results: Receiver operating characteristic curve analysis showed that YKL-40 [area under the curve (AUC)=0.882] was significantly better at discriminating adenocarcinoma from healthy control than SCC antigen, CA 125, and CA19-9. For SCC, YKL-40 (AUC=0.898) carried out similarly to SCC antigen and was better than CA 125 and CA19-9. Using a cut-off YKL-40 value of 92.2 ng/ml, sensitivity of YKL-40 in stage I adenocarcinoma (68%) was higher than that of the other three markers (11%-21%). Tumor-associated macrophages showed immunoreactivity for YKL-40 in 2 of 28 adenocarcinoma tissue samples, but adenocarcinoma cells themselves were nonimmunoreactive in all samples. Multivariate Cox regression analysis revealed that elevated pretreatment YKL-40 levels predicted unfavorable prognosis, independent of International Federation of Gynecology and Obstetrics stage and age at diagnosis. Conclusions: Pretreatment serum YKL-40 level is a possible prognosticator of cervical adenocarcinoma. © The Author 2008. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

The aim of this study was to assess acute toxicities of concurrent low-dose daily cisplatin and extended-field radiation therapy (EFRT) for carcinoma of the uterine cervix. Fifteen women with cervical cancer who were treated with concurrent daily low-dose cisplatin and EFRT were analyzed. Daily cisplatin dose was fixed to 8 mg/m(2), which was determined in the preceding phase I study using pelvic radiotherapy. Twelve patients underwent either combined external beam radiation therapy and intracavitary brachytherapy or external beam radiation therapy alone. Three other patients were treated with adjuvant chemoradiotherapy after surgery. A total dose of EFRT ranged from 40 to 45 Gy, with an additional boost to the gross tumor volume up to 50.4-55 Gy. A median total dose of cisplatin during entire radiation therapy course was 224 mg/m(2) (range, 200-240 mg/m(2)). In 14 of 15 patients (93%), daily cisplatin could be delivered continuously as planned without any modification. Administration of cisplatin had to be interrupted in only one patient for only 3 days. Fourteen patients developed grade 2 or worse leukopenia including five after treatment, grade 2 in four, grade 3 in eight, and grade 4 in two. Grade 3 thrombocytopenia was observed in three patients. Grade 2 or worse anemia was observed in 12. Three patients had grade 3 nonhematologic toxicities, diarrhea in two, and nausea/vomiting in one. Although moderate to severe hematologic toxicities are common, this study suggests that concurrent low-dose daily cisplatin and EFRT are feasible. A cumulative cisplatin dose of greater than 200 mg/m(2) during radiation therapy could be achieved by using daily cisplatin dose of 8 mg/m(2).

The aim of this study was to assess acute toxicities of concurrent low-dose daily cisplatin and extended-field radiation therapy (EFRT) for carcinoma of the uterine cervix. Fifteen women with cervical cancer who were treated with concurrent daily low-dose cisplatin and EFRT were analyzed. Daily cisplatin dose was fixed to 8 mg/m2, which was determined in the preceding phase I study using pelvic radiotherapy. Twelve patients underwent either combined external beam radiation therapy and intracavitary brachytherapy or external beam radiation therapy alone. Three other patients were treated with adjuvant chemoradiotherapy after surgery. A total dose of EFRT ranged from 40 to 45 Gy, with an additional boost to the gross tumor volume up to 50.4-55 Gy. A median total dose of cisplatin during entire radiation therapy course was 224 mg/m 2 (range, 200-240 mg/m2). In 14 of 15 patients (93%), daily cisplatin could be delivered continuously as planned without any modification. Administration of cisplatin had to be interrupted in only one patient for only 3 days. Fourteen patients developed grade 2 or worse leukopenia including five after treatment, grade 2 in four, grade 3 in eight, and grade 4 in two. Grade 3 thrombocytopenia was observed in three patients. Grade 2 or worse anemia was observed in 12. Three patients had grade 3 nonhematologic toxicities, diarrhea in two, and nausea/vomiting in one. Although moderate to severe hematologic toxicities are common, this study suggests that concurrent low-dose daily cisplatin and EFRT are feasible. A cumulative cisplatin dose of greater than 200 mg/m2 during radiation therapy could be achieved by using daily cisplatin dose of 8 mg/m2. © 2007, Copyright the Authors.

Molecular abnormalities in the epithelial cells of endometriosis and their relevance to carcinogenesis of the ovary have been well studied. On the other hand, the differences of proinflammatory microenvironments between endometriosis and ovarian carcinomas have not been well documented yet. In this study, the expression patterns of CXC chemokines (IL-8, ENA-78, GRO-alpha, 1-TAC, Mig, and SDF-1) and their receptors (CXCR2, CXCR3, and CXCR4) were compared among 12 ovarian carcinomas, 8 endometriosis, and 6 normal ovaries using quantitative reverse transcriptase polymerase chain reaction and immunohistochemistry. The CXCR3-mediated signaling in ovarian carcinoma cells in vitro was also investigated. In quantitative reverse transcriptase polymerase chain reaction, ENA-78 was up-regulated both in endometriosis and carcinomas, whereas I-TAC was detected exclusively in carcinomas. CXCR3 was up-regulated both in carcinomas and endometriosis. However, immunohistochemical studies revealed that the localization of CXCR3 in carcinomas was distinctively different from that in endometriosis. In carcinoma-endometriosis coexisting cases, CXCR3-positive lymphocytes in benign lesions decreased in proportion as CXCR3-positive tumor cells replaced the tissues. CXCR3 was also detected in ovarian carcinoma cell lines in vitro. Administration of interferon gamma (IFN-gamma)-inducible chemokines induced extracellular signal-regulated kinase phosphorylation in these carcinoma cells. The results indicated that CXC chemokines might contribute to the progression of ovarian carcinomas and endometriosis in different manners. Aberrant expression of IFN-gamma-inducible chemokines and CXCR3 in carcinoma cells in association with reduced CXCR3-positive immune cells raised the possibility that IFN-gamma-inducible chemokines might not exert effective antitumor immune responses but that they might work in favor of tumor progression. (c) 2007 Elsevier Inc. All rights reserved.

This study was designed to correlate tissue expression of CA125 with the corresponding serum value in endometrial cancer. The records of 52 endometrioid adenocarcinomas diagnosed were reviewed. Serum CA125 levels were examined before definitive surgery, and 20 U/ml was used as the cutoff value. Immunohistochemical staining for CA125 was assessed according to the ImmunoReactive Score. Statistical analyzes were performed to identify independent factor for high serum CA125 levels, including CA125 staining and the conventional pathologic features. Elevated serum CA125 levels were found in 15 of 52 patients (29 %) (range, 0.1-172.1; mean 22.6 U/ml). The frequency of positive CA125 tissue staining (35/52, 67 %) tended to be higher than that of elevated serum levels (p = 0.046). Fifteen patients with elevated serum CA125 levels statistically differed from the remaining 37 patients with normal serum CA125 level with respect to International Federation of Gynecology and Obstetrics (FIGO) stage (p = 0.027) and lymph node metastasis (p = 0.024), and tended to have positive washing cytology (p = 0.052). In multivariate analysis, elevated serum CA125 significantly correlated only with FIGO stage 111, but not with tumor size or CA125 tissue staining. Intrauterine tumor may not be the main source of serum CA125 in endometrial cancer, and elevated serum level is closely related to the presence of disseminated cancer cells in the peritoneal cavity.

RGS proteins (regulators of G protein signaling) serve as GTPase-activating proteins (GAPs) for G alpha subunits and negatively regulate G protein-coupled receptor signaling. In this study, we characterized biochemical properties of RGS5 and its N terminal (1-33)-deleted mutant (DeltaN-RGS5). RGS5 bound to G alpha (i1), Ga alpha (i3), G alpha (0), G alpha (0) and G alpha (q) but not to G alpha (s) and G alpha (13) in the presence of GDP/AlF4-, and accelerated the catalytic rate of GTP hydrolysis of G alpha (i3) subunit. When expressed in 293T cells stably expressing angiotensin (Ang) AT(1a) receptors (AT(1a)-293T cells), RGS5 suppressed Ang II- and endothelin (ET)-1-induced intracellular Ca2+ transients. The effect of RGSS was concentration-dependent, and the slope of the concentration-response relationship showed that a 10-fold increase in amounts of RGSS induced about 20-25 % reduction of the Ca2+ signaling. Furthermore, a comparison study of three sets of 293T cells with different expression levels of AT(1a) receptors showed that RGSS inhibited Ang II-induced responses more effectively in 293T cells with the lower density of AT(1a) receptors, suggesting that the degree of inhibition by RGS proteins reflects the ratio of amounts of RGS proteins to those of activated G alpha subunits after receptor stimulation by agonists. When expressed in AT(1a)-293T cells, DeltaN-RGS5 was localized almost exclusively in the cytosolic fraction, and exerted the inhibitory effects as potently as RGS5 which was present in both membrane and cytosolic fractions. Studies on relationship between subcellular localization and inhibitory effects of RGS5 and DeltaN-RGS5 revealed that the N terminal (1-33) of RGSS plays a role in targeting this protein to membranes, and that the N terminal region of RGSS is not essential for exerting activities. (C) 2001 Elsevier Science Inc. All rights reserved.

We have previously shown that not only G protein-coupled receptor kinase (GRK) 2, but also a catalytically inactive Lys220Trp GRK2 decreases endothelin (ET)-1-induced inositol 1,4,5-trisphosphate (IP3) formation, and demonstrated the presence of phosphorylation-independent desensitization mechanism. To clarify the role of GRK2 other than that as a kinase, we characterized an RGS (regulator of G protein signaling)-like domain in the amino-terminus of GRK2. Both GRK2(1-181) and GRK2(54-174) suppressed Ca2+ responses induced by angiotensin II (Ang II) and ET-1, and bound directly with G alpha q but not G alpha s nor G alpha i3 in the presence of GDP and AlF4-. These results demonstrate that GRK2 regulates Gq-mediated signaling negatively by direct interaction between its RGS domain and the transitional state of G alpha q, as well as through phosphorylation of activated receptors by its kinase domain.