A GCIG international survey: clinical practice patterns of sentinel lymph node biopsies in cervical cancer.

PURPOSE: To evaluate the practice patterns among centers and physicians worldwide regarding sentinel lymph node biopsies (SLNB) in cervical cancer (CC) patients. METHOD: A validated 35-item questionnaire regarding SLNB in CC supported by the Gynecologic Cancer Intergroup (GCIG), and sponsored by the North-Eastern German Society of Gynaecologic-Oncology (NOGGO) was sent to all major gynecological cancer societies across the globe for further distribution from October 2015 and continued for a period of 7 months. RESULTS: One hundred and sixty-one institutions from around the world participated. One hundred and six (66%) of the participants were from university centers and 111 (69%) were gynecologic oncologists. One hundred and fifty-two (97%) performed lymphadenectomy (LNE) and 147 (94%) did so systematically; 97 (60%) used SLNB, due to lower morbidity (73%), reliability (55%) and time-saving (27%). In cases of positive SLNB (pN+), 39% of respondents stopped the operation and sent the patient for chemoradiation (CRT), 45% completed pelvic and paraaortic LNE, whereas 26% went on to perform a radical hysterectomy (RH) and systematic pelvic and paraaortic LNE. In case of negative SLNB (pN0), 39% of institutions still performed a systematic pelvic and paraaortic LNE. CONCLUSION: In this survey worldwide, SLNB adoption is an encouraging 60%, yet ample differences exist regarding strategy, and to a lower extent the techniques used. Lack of experience is the most common reason SLNB is not performed. Efforts to increase surgical education on SLNB technique and multicenter prospective trials providing evidence-based guidelines are warranted.

Prevention of metabolic disorders and reproductive performance deficits by the blockade of Angiotensin II AT1 receptor in female rats fed with cafeteria diet.

Besides the well-known detrimental effects of obesity on cardiovascular and metabolic function, studies have shown that obesity is also associated with impaired reproductive function in women. Alterations in Angiotensin II (Ang II) have been associated with obesity and with female reproduction. The aim of the present study was to evaluate the reproductive and metabolic effects of Ang II AT1 receptor blockade with losartan in an animal model of obesity, in which female rats were offered a palatable, high calorie diet from weaning to adulthood. Sexual behavior, ovulation rates and preovulatory levels of the hormones estradiol, progesterone, LH and prolactin were analyzed. Retroperitoneal and perigonadal fat pads, triglycerides and cholesterol (total, HDL and LDL), and insulin resistance were analyzed. Losartan prevented increases in fat pad storage, insulin resistance, as well as triglycerides and LDL levels induced by cafeteria diet intake. Losartan also prevented ovulatory deficits and loss of preovulatory surges of progesterone and LH in cafeteria-fed female rats probably through the prevention of the increase in body weight and body fat. No alterations in sexual behavior were observed. These results suggest, for the first time, that Ang II contributes to the development of the deleterious effects of obesity on preovulatory surges of LH and progesterone and on the reduction of ovulation in obese female rats.

Epigenetic inactivation of TCF2 in ovarian cancer and various cancer cell lines.

Transcription factor 2 gene (TCF2) encodes hepatocyte nuclear factor 1beta (HNF1beta), a transcription factor associated with development and metabolism. Mutation of TCF2 has been observed in renal cell cancer, and by screening aberrantly methylated genes, we have now identified TCF2 as a target for epigenetic inactivation in ovarian cancer. TCF2 was methylated in 53% of ovarian cancer cell lines and 26% of primary ovarian cancers, resulting in loss of the gene's expression. TCF2 expression was restored by treating cells with a methyltransferase inhibitor, 5-aza-2'deoxycitidine (5-aza-dC). In addition, chromatin immunoprecipitation showed deacetylation of histone H3 in methylated cells and, when combined with 5-aza-dC, the histone deacetylase inhibitor trichostatin A synergistically induced TCF2 expression. Epigenetic inactivation of TCF2 was also seen in colorectal, gastric and pancreatic cell lines, suggesting general involvement of epigenetic inactivation of TCF2 in tumorigenesis. Restoration of TCF2 expression induced expression of HNF4alpha, a transcriptional target of HNF1beta, indicating that epigenetic silencing of TCF2 leads to alteration of the hepatocyte nuclear factor network in tumours. These results suggest that TCF2 is involved in the development of ovarian cancers and may represent a useful target for their detection and treatment.

[Feasibility, activity, and change in the level of blood paclitaxel concentration after weekly paclitaxel therapy for a patient with recurrent ovarian cancer].

The patient was a 59-year-old woman with recurrent ovarian cancer. A CT scan of the abdomen showed enlargement of abdominal para-aortic lymph nodes (PAN) after the primary operation and 8 cycles of the combination chemotherapy with paclitaxel (TXL) and carboplatinum (CBDCA). As a second line chemotherapy for the patient, weekly administration of TXL (60 mg/m2/week x 3 weeks) was given. The toxicity was acceptable and less pronounced than with the standard TXL + CBDCA therapy. Peak blood TXL concentration, about 90 ng/ml, was achieved 4 hours after the administration of TXL. The blood TXL concentration was below the detectable limit 48 h after the administration of TXL. An almost 50% shrinkage in the size of the PAN was obtained after 2 cycles of treatment. Good QOL is being maintained without any repeated aggravation of the tumor.

Antenatal diagnosis of prune belly syndrome at 11 weeks of gestation.

We present a case of prune belly syndrome diagnosed by ultrasonography at 11 weeks of gestation. We believe this case to be the earliest detection of this syndrome.

[Recent progress in epidemiologic research of uterine cancer].

Although the mortality and incidence of cervical cancer have been decreasing, those of uterine-body, or endometrial, cancer have been increasing. The proportion of endometrial cancer was reported to have become 33.6% of primary uterine cancers in 1995. Infection with certain types of human papilloma virus (HPV) is considered to be etiologically important for the occurrence of cervical cancer. Because HPV is sexually transmitted, some risk factors for cervical cancer are associated with certain kinds of sexual behavior such as a young age at first intercourse, multiple partners, and infrequent use of barrier-type contraceptives such as condoms. Frequent conceptions and deliveries and histories of sexually transmitted diseases like infection with herpes simplex virus type 2 or chlamydia also have been suggested to be associated with the risk of cervical cancer. Smoking habits and infrequent intake of vegetables and fruits may be related to the increased risk of cervical cancer by supporting persistent infection of HPV through impaired immunological function. Although host factors such as a variant of a tumor suppressor gene like p53 have been assessed in terms of the risk of cervical cancer, these are not yet clearly elucidated. Estrogen stimulation of the endometrium unopposed by progesterone stimulation, namely, unopposed estrogen stimulation, is thought to be involved in the etiology of endometrial cancer. Frequent intake of animal fat, obesity or being overweight, infertility, and histories of diabetes mellitus, hypertension, and polycystic ovary syndrome have been reported to be risk factors for endometrial cancer, and they are thought to increase unopposed estrogen stimulation. Estrogen replacement therapy for postmenopausal symptoms, tamoxifen therapy for breast cancer, and taking sequential-type oral contraceptives have been shown to be exogenous risk factors for endometrial cancer in that they increase unopposed estrogen stimulation to endometrium.

[Ovarian cancer].

Age-adjusted ovarian cancer deaths and mortality rates have increased annually in Japan from 1968 to 1995, with the absolute number of deaths increasing 4-fold during these years. Internationally, the mortality rates are high in North America or northern Europe, but their incidences have gradually decreased. However, the incidences of ovarian cancer have increased in France, Spain, and Japan. Risk factors for epithelial ovarian cancer include older age, being northern European or North American, family history of ovarian cancer, nulliparity, infertility, and obesity, and preventive factors include oral contraceptive use, gravidity, lactation, tubal ligation, and hysterectomy.

Clinical factors and biomarkers which affect a new universal grading system for ovarian epithelial carcinoma.

OBJECTIVE: To detect clinical factors and biomarkers which affect a new grading system for ovarian epithelial cancer that was proposed by Shimizu et al. and to analyze the impact of those factors on malignant behaviors of the tumor. METHODS: Review and scoring of specimens of paraffin embedded tissues of epithelial ovarian cancer were carried out according to the new universal grading system in 110 women who underwent initial treatments including the primary operation in our university hospital between January 1990 and June 1999. As biomarkers, expression of Bcl-2, Bax, Bcl-X, and the accumulation of P53 protein were also studied immunohistochemically. RESULTS: This grading system functioned as a prognostic indicator. Five-year survivals of the patients was 77.6, 36.3, and 17.4%, for Grade 1, Grade 2, and Grade 3, respectively. The grade was also correlated with clinical stages, histologic subtypes, operative completeness, para-aortic lymph nodes metastasis, and the expression of Bax protein, with univariate analysis. Multivariate analysis revealed histological subtypes and para-aortic lymph nodes metastasis to be important factors which affected the grading system. CONCLUSION: These results demonstrate that the new universal grading system is useful, and that this grading system might reflect potential of metastasis or dissemination of the ovarian cancer.

The expression of a novel natural killer inhibitory molecule, Cho-1, on the chorionic cytotrophoblast cells of successful pregnancy, but not of spontaneous abortion.

The regulatory mechanism of the recognition and cytotoxicity by natural killer (NK) cells in placental tissue remains unclarified. Previous reports indicated that monoclonal antibody Cho-1-defined molecule (Cho-1 molecule) may act as the negative regulator in the cytotoxicity by human NK cells. The Cho-1 molecule is composed of non-covalently associated cell surface molecules of approximately 200 kDa and 40 kDa. In the present study we analyzed the expression of this novel molecule in extravillous cytotrophoblast cells, which are presumed to be exposed to the cytotoxic action by maternal NK cells, from clinical cases of successful pregnancy and spontaneous abortion. By using monoclonal antibody Cho-1, our immunohistochemical data indicated that the Cho-1 molecule is clearly expressed in the cytotrophoblast cells of the early phase of successful pregnancy, but only weakly expressed in those from spontaneous abortion. The cytotrophoblast cells in the late phase (9-10 months) of pregnancy also expressed this molecule. Fluorescence-activated cell sorter analysis also showed that it is expressed on the cytotrophoblast cell surface of successful pregnancy but not on that of spontaneous abortion, suggesting that Cho-1 antigen may act as a negative regulator of the cytotoxicity by NK cells in successful pregnancy of the fetus.

Surgery for germ cell tumors.

We performed a review of the current modalities of surgical treatment of malignant ovarian germ cell tumors by clinical stages and histological types. Stage IA dysgerminoma is performed with a unilateral salpingo-oophorectomy (USO) without chemotherapy. However, for Stage IB or IC patients with dysgerminoma, USO plus chemotherapy as a primary treatment may or may not be followed with a second-look operation (SLO). For non-dysgerminomas, USO is indicated only for Stage IA immature teratoma grade 1. The treatment for Stage IA immature teratoma grade 2 or 3 and other histological types is USO plus chemotherapy. Patients with Stage IB, IC or higher with non-dysgerminoma are treated with USO plus chemotherapy or USO with contralateral partial ovariectomy plus chemotherapy. For patients who require non-conservative surgery, a total abdominal hysterectomy (TAH) and a bilateral salpingo-oophorectomy (BSO) plus chemotherapy are performed. For patients with Stage II of all histological types, conservative surgery consists of USO and a cytoreductive operation plus chemotherapy, followed by SLO or a second cytoreductive operation. For non-conservative surgery, TAH+BSO with or without a cytoreductive operation plus chemotherapy is followed by SLO. Conservative surgery for patients with Stage III and IV is USO and a cytoreductive operation plus chemotherapy followed by a second cytoreductive operation. Non-conservative surgery is TAH+BSO with a cytoreductive operation plus chemotherapy, followed by SLO or a second cytoreductive operation. However, primary or secondary cytoreductive surgery with or without lymphadenectomy and SLO are still controversial in terms of improving patient survival.

A single nucleotide polymorphism in the matrix metalloproteinase-1 promoter in endometrial carcinomas.

Recent studies demonstrated that a single guanine insertion polymorphism in a matrix metalloprotease-1 promoter created an Ets binding site and affected the elevation of the transcriptional level of matrix metalloproteinase-1 (MMP-1). Furthermore, in tumor cell lines derived from melanoma and breast cancer, the incidence of the 2G / 2G genotype was significantly higher than that in the normal population. To evaluate the contribution of this polymorphism in endometrial carcinomas, we genotyped 100 endometrial carcinomas and then analyzed immunoexpression of MMP-1 in these carcinomas. We found that endometrial carcinoma patients showed a significantly higher rate of 1G / 2G or 2G / 2G genotype than control individuals, and that tumors containing the 2G allele(a) expressed MMP-1 protein more frequently than those with 1G / 1G genotype. Therefore, the single nucleotide polymorphism at the MMP-1 promoter affected the expression level of the MMP-1 protein, which may result in the association with more aggressive character in endometrial carcinoma. Our result suggests that the presence of 2G polymorphism at the MMP-1 promoter may be one of the risk factors for the development and / or progression of endometrial carcinoma.

[Effects of oral 5-HT3 antagonists on chemotherapy-induced emesis in patients with gynecologic cancers].

The efficacy of an intravenous 5-HT3 antagonist (granisetron) and four oral 5-HT3 antagonists (granisetron, ondansetron, tropisetron and ramosetron) on chemotherapy-induced emesis were investigated in 21 gynecologic cancer patients (63 courses). The severity of emesis after chemotherapy was classified in 4 grades (0: none, 1: slight loss of appetite, 2: severe loss of appetite, but tolerable, and 3: untolerable). The effect of 5-HT3 antagonists was judged by both the score for the severity of the emesis and the frequency of vomiting. The four oral 5-HT3 antagonists were almost the same in efficacy for 5 days after chemotherapy. Oral 5-HT3 antagonists were almost equipotent to intravenous granisetron for JT (paclitaxel + carboplatin) therapy or T (paclitaxel) therapy for 5 days after chemotherapy. However, they were ineffective for CAP (cisplatin + adriamycin + cyclophosphamide) therapy. From these results, oral 5-HT3 antagonists were proved to have a sufficient anti emetic effect after chemotherapy in cases of JT or T therapy. However, in cases of CAP therapy, intravenous 5-HT3 antagonists were thought to be preferable for the control of emesis due to chemotherapy.

Mutation of the SRC gene in endometrial carcinoma.

Recently, an activating mutation of the SRC gene has been implicated in about one-tenth of advanced colon cancers. The SRC 531 mutation results in truncation of SRC directly C-terminal to the regulatory Tyr 530 and appears to activate the Tyr 530. To investigate whether mutation of SRC plays an important role in the development and progression of gynecological tumors, we performed mutational analysis of the entire coding region of SRC in 70 ovarian carcinomas, 68 endometrial carcinomas and 3 endometrial stromal sarcomas by means of polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) followed by nucleotide sequencing and restriction fragment length polymorphism (RFLP) analysis. We found one truncated mutation at codon 531 (Gln to Stop) in an endometrial carcinoma. However, we found no mutation of this gene in ovarian carcinoma or endometrial stromal sarcoma. Our results suggest that mutation of SRC may be implicated in a small proportion of endometrial carcinomas.

A case of a sclerosing stromal ovarian tumor that expresses VEGF.

A case of a sclerosing stromal tumor (SST) of the ovary is presented. One of the tumor's characteristics was its high vascularity. On immunohistochemical staining, the vascular endothelial growth factor (VEGF) was positive for both cellular and edematous areas in the tumor. VEGF was thought to be a factor that affected the clinicopathological features of this tumor.

Emergency postpartum hysterectomy in obstetric practice.

OBJECTIVES: To review cases of emergency postpartum hysterectomies performed in the setting of life-threatening hemorrhaging. METHODS: A retrospective study of 17 patients who underwent postpartum hysterectomies during January 1, 1985-December 31, 1998 was undertaken. Maternal characteristics, method of delivery, antenatal complications for hysterectomy, obstetric history, placental location, blood loss before hysterectomy and during operation, intraoperative and postoperative complications, and operative procedures were investigated, as was whether prostaglandin F2alpha and/or oxytocin were administrated during labor. The operative procedures also were examined. RESULTS: The incidence was 1 in 6,978 deliveries (0.014%). All patients were transported from affiliated clinics. The leading cause for a hysterectomy was uterine rupture (35.3%), followed by disseminated intravascular coagulation (DIC) due to placental abruption (29.4%), and uterine atony (23.5%). Failure of internal iliac-artery ligation occurred in 7 patients. CONCLUSIONS: Internal iliac-artery ligation is not effective for patients with massive blood loss. In such cases, it is desirable for the private physician to make an early decision for maternal transport.

A report on more than 10,000 vaginal hysterectomies performed without ligation of the paracervical ligaments.

OBJECTIVE: To review 10,016 cases of total vaginal hysterectomy (TVH) performed in our department by a method without ligation of the paracervical ligaments. METHODS: From 1955 to 1997, a total of 10,016 TVHs without ligation of the paracervical ligaments were performed at the Department of Obstetrics and Gynecology, Sapporo Medical University Hospital. RESULTS: Of all 22,509 gynecological operations, 44.5% were TVHs, and 8.7% were total abdominal hysterectomies (TAHs). The operative time of our TVHs ranged from 31-60 minutes in 44.1% of the cases, and from 61-90 minutes in 35.3% of the cases. Blood loss was less than 300 ml in 85% of the cases. Abdominal conversion from the vaginal approach occurred in 110 cases (1%). Operative complications also occurred only in 0.7% (69) of the cases. CONCLUSION: TVH without ligation of the paracervical ligaments is a safe and convenient method that has very few complications and that can be utilized by many gynecologists.