Search

Although the incidence of the various gynecological cancers has been increasing in recent years, long-term survival is now possible for many patients thanks to advances in multimodality treatment. When treating gynecological cancer in adolescent and young adult (AYA) patients who desire future pregnancy, it is necessary to preserve the reproductive organs and their function to prevent loss of fertility. However, because treatment targets these organs, in the large majority of cases, patients must have these organs removed. In the subfield of oncofertility, treatment of the underlying disease takes priority, and the main principle is preventing delay in treatment. Close cooperation between obstetricians and gynecologists involved in reproductive medicine and oncologists involved in cancer treatment is necessary. In addition, it is important that clinicians work closely not only with other specialists but also with such medical professionals as nurses and counselors so that cancer patients of the AYA generation can be provided the support they need to fight their cancer with hope. Herein, we describe the current status of fertility-sparing therapy for AYA patients with gynecological cancer (cervical cancer, endometrial cancer, or ovarian cancer). In addition, we explain points to keep in mind during a patient's pregnancy after fertility preservation, the latest findings on assisted reproductive technology, and the challenges and prospects of fertility preservation therapy for patients with gynecologic cancer.

Introduction The Laparoscopic Approach to Cervical Cancer (LACC) trial, a prospective randomized phase III clinical trial reported in 2018, unexpectedly showed inferior oncologic outcomes in laparoscopic radical hysterectomy (LRH) for cervical cancer compared with those in open surgery. It was proposed that the spillage of tumor cells into the peritoneal cavity might cause the inferiority of LRH. It has been suggested, based on retrospective studies, that transvaginal closure of the vaginal cuff before the colpotomy part of the surgery may prevent this. Materials and surgical technique Before starting colpotomy, we closed the vaginal cuff transvaginally. After the assessment of the cutline of the vagina, the vaginal mucosa is pulled at the eight sites using the sutures. The four pairs of sutures on the diagonal line are ligated. A purse string suture is additionally placed on the vaginal mucosa to close the vaginal cuff completely. After that, we start the intracorporeal colpotomy using a vaginal pipe. Discussion Our technique is simple and quick. The blood loss during the transvaginal procedures is minimal. The use of the vaginal pipe helps keep the vaginal cuff closed during the colpotomy. Our technique may be an alternative to the conventional approach closing the vaginal cuff.

Fertility preservation (FP) for children is still challenging due to an information gap. In particular, there is little information about the surgical aspects of ovarian tissue cryopreservation (OTC) for children. In the present study, the appropriateness of preoperative management and the criteria of our cases were investigated with the aim of establishing a safe OTC procedure. A total of 25 girls who underwent OTC from November 2015 through May 2020 were retrospectively analyzed with IRB approval. The median age of the patients was 13 (1–17) years. The medical indications were varied (e.g., leukemia, lymphoma, brain tumor), and included rare diseases. Seventeen cases (68%) underwent OTC during chemotherapy or radiotherapy, and 21 (84%) had comorbidities. All cases underwent ovarian tissue retrieval (OTR) with laparoscopy, and the median operating time was 64 (36–97) min, with little bleeding. Although two had complications, all patients started treatment on schedule. The median WBC and CRP increases a day after OTR were 0 (− 4400 to + 5200)/µl and 0.21 (− 0.2 to 0.87) mg/dl, respectively, with no complications. As long as the preoperative criteria are met, OTC could be possible even for children with a severe blood condition. In such cases, the degrees of the WBC and CRP elevations are useful to assess surgical infection.

The aim of this retrospective analysis is to reveal clinicopathological findings and clinical outcome of patients with stage IB1/IB2 (FIGO 2018) uterine cervical cancer. Based on the database of the Japanese Gynecologic Oncology Group, 2194 patients with stage IB1/IB2 (FIGO 2018), who underwent radical hysterectomy between 1/1/2004–12/31/2008, were identified as eligible for this retrospective study. Patients with squamous cell carcinoma had significantly frequent lympho-vascular space invasion than those with non-squamous cell carcinoma in both stage IB1 and IB2 (stage IB1; 29.1% vs. 17.1%, p

This is the case report of primary malignant melanoma (MM) of uterine cervix treated by immune checkpoint inhibitor: the Pembrolizumab. Despite the merge of the novel drugs that has been strikingly improving prognosis of MM, we still struggle treatment of MM of uterine cervix that has aggressive characteristics with unknown etiology. We present our case to contribute its rarity of the disease case report, the primary MM of the uterine cervix that had poor response to pembrolizumab and had OS of 6 months. The treatment ineffectiveness is mainly considered for mucosal MM of low tumor mutation burden and its unusual type of pathology. Accumulation of retrospective studies exclusively on cervical melanoma needs to be proceeded to investigate on characteristics between poor and long survival to establish standardized treatment.

BRCA1/2 mutation carriers are at high risk for type II ovarian, fallopian tube or peritoneal cancer. Although risk-reducing salpingo-oophorectomy plays an important role in the prevention of these BRCA1/2-associated gynecological cancers, occult ovarian, fallopian tube, or peritoneal cancer is discovered upon risk-reducing salpingo-oophorectomy in 1–4% of BRCA1/2 mutation carriers. Notably, around 30% of BRCA1/2 mutation carriers who undergo risk-reducing salpingo-oophorectomy have undergone adjuvant chemotherapy for breast cancer. We describe the discovery and treatment of occult cancer at the edge of the left fimbria in a BRCA1 mutation carrier who had, just a short time previously, undergone neoadjuvant paclitaxel plus carboplatin (TC) chemotherapy for triple-negative breast cancer. During subsequent risk-reducing salpingo-oophorectomy, a 5.5-mm nodule was observed at the edge of the left fimbria. Microscopic examination of the tumour tissue revealed high-grade serous carcinoma with degenerate tumour cells and fibrosis. Peritoneal fluid was negative for cancer cells. Two months later, hysterectomy, omentectomy and retroperitoneal lymphadenectomy were performed. The final diagnosis was stage FIGO IA fallopian tube cancer. Adjuvant chemotherapy (TC administered every 3 weeks) was applied, and there has been no evidence of recurrence for 5 years. In applying gynecologic surgery and adjuvant chemotherapy, we followed the general recommendation for stage IA fallopian tube cancer. There is no standard strategy for the treatment of occult fallopian tube cancer detected after chemotherapy for BRCA1-associated triple-negative breast cancer. According to our experience in this case, we believe the clinical value of staging laparotomy in cases of a small occult BRCA1/2-associated gynecological cancer should be further investigated.

Introduction/Background The major fact-finding survey on oncofertility care has not been conducted to date in the field of gynecologic oncology. Therefore, we examined AYA (adolescent and adult) cancer patients with ovarian germ-cell tumors (OGT) on fertility preserving therapy and from oncofertility liaisons to elucidate the situation in Japan by AMED survey. Methodology AYA (age 15–39 years) cancer patients with OGT who received fertility-preserving therapy at the JSOG (Japan Society of Obstetrics and Gynecology) specialist training facilities nationwide from January 2009 to December 2013 (430 cases) were surveyed with respect to surgery applications, surgical styles, outcomes of pregnancy. Results No postoperative recurrence was observed in approximately 90% of 415 cases. The ovarian residual function rate was low at 12.8%. Approximately 80% of the cases were stage I cancer. Of the 415 patients, 82.9% underwent adnexectomy during surgery and 13.5% underwent cyst extraction. Abdominal operation and laparoscopy were performed in approximately half of the patients who underwent cyst extraction. Of the 415 patients who underwent surgery, 97 (23.4%) became pregnant. In the pregnancy cases, the rate of referal to the REI (reproductive endocrinology and infertility) specialists in the overall and chemotherapy groups remained at approximately 15%. Meanwhile, the reference rate to the REI specialists was low in the non-pregnant cases (0.8%). Conclusion AYA patients with OGT in Japan undergo therapies described in JSGO (Japan Society of Gynecologic Oncology) clinical guidelines. However, their pregnancy rate is low, and referral to the reproductive is not sufficiently used. Even though the AYA patients with OGT has normal menstruation, the ovarian reserve should be followed by the specialists. Therefore, referring to the REI specialists early on may improve survivorship for this kind of patients. Disclosure Nothing to disclose.

Introduction/Background The purpose of the study is to determine if superb microvascular imaging (SMI) and shear wave elastography (SWE) can be used for the early diagnosis of uterine cervical intraepithelial neoplasia and cancer. Methodology A case-control study was carried out in St. Marianna University School of Medicine Hospital between April 2017 and January 2018 on patients with uterine cervical dysplasia and uterine cervical cancer. Seventeen controls with eight subjects were investigated. An evaluation using SMI and SWE was conducted in addition to the conventional ultrasonic tomography and color doppler tests before or after the treatment. The colored races plastic intensity in the SMI was evaluated for three phases, strong, mediate, weak, and the blood flow rate was measured. The SWE was measured at several locations and the mean value was used as signal intensity. Results The target breakdown was one patient with uterine cervical cancer and seven patients with high-grade squamous intraepithelial lesions. For the subject and control cases, the intensity of the conventional colored races plastic was 6% vs. 0% (n.s.), and 94% vs. 100% for strong and weak phase, respectively. While for the control the measure, it was 39% vs. 0% and 61% vs. 100% for strong and weak phase, respectively. In addition, one patient with uterine cervical cancer exhibited a strong phase. The SWE evaluation of the uterine cervical hardness resulted in SWE level of 4.4±1.2, 2.2±0.3 for case and control, respectively (p Conclusion An evaluation using SMI and SWE utility suggested the identification of histologic changes such as minute vascular hyperplasia or malignant transformation of the uterine cervical lesion. Disclosure Nothing to disclose.

Introduction/Background In general, abnormal uterine cervical cytology is found in the first trimester, we evaluate the colposcopy, and perform a cervical biopsy if needed likewise in non-pregnancy. As a result, if the case is diagnosed to be cervical intraepithelial neoplasia (CIN), the risk of progression to invasive cancer during pregnancy is low and some cases of regression after delivery have been reported. In this study, we examined the transition of abnormal cervical biopsy from pregnancy to postpartum. Methodology We retrospectively examined the transition in histology during pregnancy and postpartum of 44 pregnant women who visited our oncology outpatient clinic from January 2014 to December 2018, including 27 cases of CIN1,6 cases of CIN2, 11 cases CIN3. Their mode of delivery includes 32 cases of vaginal delivery, 9 cases of cesarean section, 3 cases of unknown delivery style. Results The diagnosis of cervical biopsy abnormalities was 22 cases before pregnancy and early pregnancy respectively. At the transition change of cervical tissue diagnosis from early pregnancy to postpartum, 19 (73%) cases of CIN1 were improved and 7 cases (27%) were unchanged. There were no cases treated during pregnancy. 5 cases underwent cervical conjunctivectomy after delivery, and a radical hysterectomy was performed on 1 case who had progressed of the medical condition. Conclusion We found that the rate of regression of cervical tissue biopsy abnormalities in pregnant women decreased in the order of CIN1, CIN2 and CIN3, however, it is often relieved when giving birth. We assume that accurate diagnosis during early pregnancy is important because cervical cell collection and colposcopy get difficult as the gestational age goes further. In addition, cervical cytology was shown to be an important screen, because the diagnosis was often triggered by cervical cytology in early pregnan. Disclosure Nothing to disclose.

Aim Excision of ovarian endometrioma (OE) may induce the reduction of ovarian reserve. We evaluated pregnancy outcomes after laparoscopic cystectomy (LC), and the pre- and postoperative levels of anti-Mullerian hormone (AMH) to consider the ovarian reserve. Methods We enrolled 40 women with OE and 16 women with benign ovarian tumors who hoped to have a child and who underwent LC. To evaluate the ovarian reserve of 40 patients (OE group, n = 24; non-OE group, n = 16), we measured serum AMH levels before and after the surgery. Results In the 40 women who underwent LC for OE, the cumulative pregnancy rate was 50%. Prior to the cystectomy, serum AMH levels in the OE group, especially in patients over the age of 35, were significantly lower than those in the non-OE group. Rate of decline in serum AMH in the OE group was significant compared with that in the non-OE group 6 months after surgery. In patients over the age of 35 in the OE group, AMH levels 1 year after surgery decreased noticeably. Conclusion LC for OE could be a preferred surgical approach, but effective therapeutic strategies will have to be developed to prevent damage to the ovarian reserve, especially for older patients.

Objective: National health insurance coverage for the laparoscopic staging surgery for patients with stage IA endometrial cancer started from April 2014 in Japan. We conducted this retrospective study to evaluate the surgical outcomes of the laparoscopic surgery for patients with low-risk endometrial cancer compared with those of the laparotomy. Materials and methods: A total of 120 patients with presumed low-risk endometrial cancer, who were treated at Tottori University Hospital between 2005 and 2016, were eligible for this study. The laparoscopic staging surgery included only the pelvic lymphadenectomy and not the para-aortic lymphadenectomy. We evaluated the discrepancy between preoperative presumption and postoperative diagnosis of recurrent risk factors. Results: Forty patients underwent the laparoscopic surgery and 80 patients received the laparotomy. The laparoscopic surgery resulted in less intraoperative blood loss and shorter hospital stay. The operative time was significantly longer for the laparoscopic surgery compared with the laparotomy, but this difference was not seen in obese patients with a body mass index ≥30 kg/m2. The type of the surgical procedure did not affect the incidence of perioperative complications. Among 120 patients, 104 (86.6%) were diagnosed as FIGO stage IA, 118 (98.3%) with endometrioid adenocarcinoma grade 1 or 2, and 107 (89.1%) with myometrial invasion depth

Problem How is the tumor necrosis factor (TNF) α-induced inhibitor of apoptosis (IAP) protein expression in endometriotic stromal cells (ESCs) involved in cell viability and signaling pathways? Method of study Endometriotic stromal cells were isolated from ovarian chocolate cysts in 20 patients who underwent laparoscopic surgery. IAP protein expression and IκB phosphorylation were evaluated by Western blot analysis. Interleukin (IL)-8 protein expression and cell proliferation were assessed by ELISA. Results Cellular IAP (cIAP)-2 protein expression in endometriotic tissue was higher than that of endometrium. TNFα markedly enhanced cIAP-2 protein expression in ESCs. Pretreatment with a nuclear factor (NF)-κB inhibitor attenuated TNFα-induced cIAP-2 expression. An antagonist of IAPs abrogated TNFα-induced cIAP-2 protein expression and showed a decrease in TNFα-induced IL-8 protein expression and BrdU incorporation in ESCs. Conclusions TNFα and its downstream NFκB pathway have proven to be critical regulators of highly expressed cIAP-2 in ESCs. cIAP-2 may be a novel therapeutic target for endometriosis.

Excision of ovarian endometrioma (OE) may induce the reduction of ovarian reserve. We evaluated pregnancy outcomes after laparoscopic cystectomy (LC), and the pre- and postoperative levels of anti-Müllerian hormone (AMH) to consider the ovarian reserve.We enrolled 40 women with OE and 16 women with benign ovarian tumors who hoped to have a child and who underwent LC. To evaluate the ovarian reserve of 40 patients (OE group, n = 24; non-OE group, n = 16), we measured serum AMH levels before and after the surgery.In the 40 women who underwent LC for OE, the cumulative pregnancy rate was 50%. Prior to the cystectomy, serum AMH levels in the OE group, especially in patients over the age of 35, were significantly lower than those in the non-OE group. Rate of decline in serum AMH in the OE group was significant compared with that in the non-OE group 6 months after surgery. In patients over the age of 35 in the OE group, AMH levels 1 year after surgery decreased noticeably.LC for OE could be a preferred surgical approach, but effective therapeutic strategies will have to be developed to prevent damage to the ovarian reserve, especially for older patients.

Aims: We investigated the potential of gonadotropin-releasing hormone (GnRH) agonists and GnRH antagonists to inhibit cell proliferation in endometriotic and endometrial stromal cells. Methods: Twenty patients with ovarian endometriomas and 18 patients with uterine fibromas were recruited. Endometriotic and endometrial stromal cells were obtained from the ovarian chocolate cyst linings and the eutopic endometria of premenopausal women with uterine fibromas, respectively. Results: GnRH agonist or antagonist treatment attenuated tumor necrosis factor (TNF)-α-induced cell proliferation in the endometrial stromal cells, whereas endometriotic stromal cells did not respond to treatment. The endometriotic stromal cells exhibited a decreased expression of the type I GnRH receptor compared with the endometrial stromal cells. GnRH agonists or antagonists did not repress TNF-α-induced IL-8 production in endometriotic stromal cells. Conclusion: GnRH agonists and antagonists have similar effects in slowing the growth of endometrial stromal cells. Endometriotic stromal cells resist the antiproliferative effect of GnRH agonists and antagonists.

The purpose of this study was to clarify the usefulness of the gray-level histogram width for tissue characterization of the uterine myometrium.Thirty-five patients with uterine fibroids, 5 patients with adenomyosis, and 9 patients with extensive myometrial invasion by endometrial carcinoma were studied. The gray-level histogram width was determined by transvaginal ultrasonography. The Mann-Whitney U test was used for statistical analysis. Receiver operating characteristic curves were generated for use in tissue characterization.Significant differences in the gray-level histogram width were found between normal myometrium (54.2% ± 4.2%) and carcinoma (58.2% ± 3.9%), normal myometrium and fibroid (64.3% ± 5.2%), and carcinoma and fibroid. However, it was difficult to identify adenomyosis. The cutoff values to distinguish normal myometrium from carcinoma, normal myometrium from fibroid, and carcinoma from fibroid are 56, 58, and 64, respectively.The gray-level histogram width is useful for tissue characterization of the uterine myometrium.

Importance Ovarian endometrioma is the most common form of endometriosis. Laparoscopy is frequently chosen for its treatment because medical treatment alone is inadequate. However, the role of laparoscopic treatment of ovarian endometriomas has been challenged by evidence questioning the benefits of surgery, especially in cases of young or infertile women. Other therapeutic modalities include expectant management, medical therapy, and, in cases of infertility, ovulation induction and assisted reproductive technology. None of these treatments offer cure of endometriosis. Objective The objective of this study was to present data concerning the current management of endometrioma. Benefits and complications after treatment and the impact on in vitro fertilization outcome are also highlighted. Evidence acquisition An extensive literature search (PubMed) and Cochrane Library review up to December 2013 were performed using the following keywords: "endometrioma," "cystectomy," "infertility," "IVF," "malignant transformation," "management," and "recurrence." Results There is a lack of data from randomized trials to inform the optimal management of endometriomas with respect to pain relief, recurrence, and fertility. Conclusions and relevance Further studies are needed to determine the optimal management of endometrioma. Currently, there is no evidence that surgical management improves the fertility of women with endometrioma.

Problem The cytokine, interleukin-6 (IL-6), stimulates the production of human chorionic gonadotropine (hCG) in chorionic cells. The purpose of this study was to examine the role of nuclear factor-kappaB (NF-kappaB) during the induction of IL-6 by IL-1beta in human trophoblast cells. Method of study Reverse transcription-polymerase chain reaction was used to determine the gene expressions of IL-1, IL-1 receptor (IL-1R), IL-6R and gp130 in a human choriocarcinoma cell line, BeWo. The BeWo cells were cultured for 24 hr with IL-1beta (0-10 ng/mL), IL-1beta (10 ng/mL) together with IL-1 receptor antagonist (IL-1Ra) or NF-kappaB inhibitor, N-tocyl-l-phenylalanine chloromethyl ketone (TPCK). The concentrations of IL-6 in culture supernatants were measured by enzyme-linked immunosorbent assay. Results The gene expressions of IL-1R, IL-6R and gp130, but not IL-1beta, were observed. The concentration of IL-6 was enhanced by IL-1beta in a dose-dependent fashion. The addition of IL-1Ra neutralized the effects of IL-1beta on IL-6 secretion. IL-1beta induced expression of phosphorylated IkappaB and the activation of NF-kappaB. The addition of TPCK reduced the IL-1beta-induced IL-6 expression. Adding IL-1beta increased beta-hCG production in a dose-dependent manner, and the addition of TPCK neutralized the effect of IL-1beta. Conclusion IL-1beta may induce the IL-6 expression and hCG production in human BeWo cells via NF-kappaB.

Hepatocyte growth factor (HGF) is a mesenchymal-derived paracrine factor that acts through a c-met receptor. The activated c-met receptor recruits various signal proteins. We used a steroidogenic human granulosa-like tumor cell line (KGN cells) to analyze the biological function of HGF in human ovary cells. First, we designed a method to analyze local production and action of HGF in the human ovary. Although c-met mRNA is expressed in KGN cells, granulosa lutein, theca, and ovarian stroma cells, we observed HGF mRNA only in theca and stroma cells. Adding HGF to the medium enhanced mitogenic activity in KGN cells. We next examined the activation of intracellular signal transduction molecules induced by HGF in KGN cells. Here, we showed that HGF activated the distinct phosphorylation of Raf-1, MEK1/2, and ERK1/2, but did not induce phosphorylation of Akt. HGF enhanced the phosphorylation of Elk-1 and c-Jun as nuclear transcription factors. U0126, a MEK1/2 inhibitor, completely abrogated the phosphorylation of ERK1/2 and the cell proliferation in response to HGF. In contrast, H-89, a protein kinase A inhibitor, further enhanced the HGF-induced phosphorylation of ERK1/2 and cell proliferation. In addition, we revealed that HGF suppressed progesterone synthesis in KGN cells. Adding HGF suppressed the forskolin-induced steroidogenic acute regulatory protein (StAR) expression, which is a key regulator in progesterone synthesis. Crosstalk signals between PKA and the mitogen-activated protein kinase (MAPK) pathway were mutually inhibitory. These results demonstrated for the first time that theca cell-derived HGF may be capable of stimulating the proliferation of granulosa cells and suppressing progesterone synthesis via an activating MAPK pathway.

Lower limb lymphedema (LLL) is one of the most frequent postoperative complications of retroperitoneal lymphadenectomy for gynecologic cancer. LLL often impairs quality of life, activities of daily living, sleep, and sex in patients with gynecologic cancer. We conducted this study to evaluate the incidence and risk factors for LLL after gynecologic cancer surgery in patients who received assessment and periodic complex decongestive physiotherapy (CDP). We retrospectively reviewed 126 cases of gynecologic cancer that underwent surgery involving retroperitoneal lymphadenectomy at Tottori University Hospital between 2009 and 2012. All patients received physical examinations to detect LLL and underwent CDP by nurse specialists within several months after surgery. The International Society of Lymphology staging of lymphedema severity was used as the diagnostic criteria. Of 126 patients, 57 (45.2 %) had LLL, comprising 45 and 12 patients with stage 1 and stage 2 LLL, respectively. No patient had stage 3 LLL. LLL was present in 37 (29.4 %) patients at the initial physical examination. Multivariate analysis revealed that adjuvant concurrent chemoradiotherapy and age ≥55 years were independent risk factors for ≥stage 2 LLL. To minimize the incidence of ≥stage 2 LLL, gynecologic oncologists should be vigilant for this condition in patients who are ≥55 years and in those who undergo adjuvant chemoradiotherapy. Patients should be advised to have a physical assessment for LLL and to receive education about CDP immediately after surgery involving retroperitoneal lymphadenectomy for gynecologic cancer.

Endometriosis, a common disease affecting about 10 % of women of reproductive age, causes pelvic pain and infertility. Pelvic endometriosis is histologically categorized into peritoneal superficial endometriosis, ovarian endometrioma, and deep infiltrating endometriosis (DIE). Surgical treatment for endometriosis aims to relieve symptoms and preserve fertility, in most cases by restoring anatomy, by lysing adhesions, and by removing endometriotic lesions. Laparoscopic surgery, which is the standard surgical procedure for endometriosis, reduces pelvic pain and improves fertility by means of excision and ablation of endometriotic lesions. Managing endometriomas in women who wish to conceive is controversial because two main risks may occur after conservative surgery: recurrence of the disease and significant reduction in ovarian reserve. Surgical treatment for endometriosis should be tailored to the individual according to clinical presentation and personal wishes. In this chapter, we describe laparoscopic conservative surgery for pelvic endometriosis, particularly for ovarian endometrioma.

We performed a retrospective study to clarify the outcome of stage IB2–IIB patients with bulky cervical cancer who underwent neoadjuvant chemotherapy (NAC) followed by radical hysterectomy and adjuvant treatment. Sixty-five patients with bulky stage IB2–IIB cervical cancer, treated at Tottori University Hospital between 2001 and 2011, were examined retrospectively. The indication for adjuvant treatment was limited to the following pathological high-risk factors: pelvic lymph node (PLN) involvement, parametrial infiltration (PI), and a compromised surgical margin. Fifty-one patients had squamous cell carcinoma (SCC) and 14 non-SCC. Three patients were ineligible for radical hysterectomy after NAC, and underwent concurrent chemoradiotherapy. In 62 patients who underwent radical hysterectomy, 13 had only PLN involvement and 6 only PI, and 10 had both PLN involvement and PI. In 33 patients who had no adjuvant treatment, 6 recurred, and only one underwent salvage chemotherapy. In 29 patients who underwent adjuvant treatment, 15 recurred and 11 died. Multivariate Cox proportional analysis revealed that PLN involvement was an independent prognostic factor. Even if the indication for adjuvant treatment is limited to only high-risk patients, about 70 % of stage IB2–IIB patients with bulky cervical cancer could be cured by NAC followed by radical hysterectomy. Additionally, about 40 % of those patients could be cured without adjuvant treatment. In contrast, the strategy for patients with PLN involvement, who account for about 35 % of stage IB2–IIB bulky cervical cancer after NAC, should be carefully reconsidered based on quality of life and cost-effectiveness.

Apoptosis plays a critical role in maintaining tissue homeostasis and represents a normal function to eliminate excess or dysfunctional cells. Accumulated evidence suggest that apoptosis helps to maintain cellular homeostasis during the menstrual cycle by eliminating senescent cells from the functional layer of the uterine endometrium during the late secretory and menstrual phase of the cycle. BCL-2 family and Fas/FasL system have been extensively studied in human endometrium and endometriotic tissues. Eutopic endometrium from women with endometriosis reportedly has some fundamental differences compared with normal endometrium of women without endometriosis. The differences could contribute to the survival of regurgitating endometrial cells into the peritoneal cavity and the development of endometriosis. One mechanism that recently gained a lot of interest is the finding that apoptosis appeared in eutopic and ectopic endometrium of patients with endometriosis. This study is a current review of the literature focused on the physiological role of apoptosis in normal endometrium and the alterations in regulation of apoptosis in eutopic and ectopic endometrium from women with endometriosis. Finally, role of apoptosis in the treatment of endometriosis is reviewed to link the basic research findings into clinical applications.

Endometriosis causes pelvic pain and infertility in women of reproductive age. We explored TNFalpha-induced specific signaling pathways and gene expressions in endometriotic stromal cells (ESCs). Based on the data of the pathway specific cDNA array, we analyzed the role of TAK1, which is believed to work as a common mediator for NF-kappaB and MAPK pathways. Using the NF-kappaB pathway array, we found that TNFalpha upregulated ICAM-3, IL-6, IL-8, TAK1, JNK2, RelA, and TLR4 expressions. TNFalpha augmented the phosphorylation of TAK1. By transfection of TAK1 siRNA, TNFalpha-induced phosphorylation of IkappaBalpha, JNK1/2, and p38MAPK, as well as IL-6 or IL-8 expression, were repressed. TAK1 silencing in TNFalpha-pretreated ESCs caused a decrease in the proportion of cells in S-phase, and reduced TNFalpha-promoted BrdU incorporation. We provide the first evidence that TNFalpha and its downstream TAK1, which are key mediators for NF-kappaB and MAPK pathways, may be involved in the pathogenesis of endometriosis.

BACKGROUND: The survival of endometriotic cells in the ectopic site has been investigated from the aspect of susceptibility of endometriotic tissues to apoptosis. In order to investigate the nature of abnormal survival of endometriotic cells in ectopic locations, we compared drug-induced apoptosis in endometrial and endometriotic cells. METHODS: Endometrial stromal cells were obtained from normal endometrium in 11 patients who underwent hysterectomy for leiomyoma without endometriosis. Endometriotic cells were isolated from the chocolate cyst linings of the ovary in 13 patients who underwent laparoscopic surgery. Cells were cultured in the presence or absence of staurosporine. Apoptotic cell death was evaluated by staining nuclei with propidium iodide and phosphatidylserine (a marker of early apoptotic events) with Annexin V as well as by DNA fragmentation assay. The number of viable cells was estimated by modified MTT [3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide WST-8] assay. RESULTS: After 3 h of exposure to staurosporine, >50% of the endometrial stromal cells became Annexin V positive. In contrast, >30% of the endometriotic cells were Annexin V positive. DNA fragmentation was not clearly induced in the endometriotic cells. Less than 20% of the endometrial cells survived after staurosporine exposure, while >40% of the endometriotic cells survived. Cell death induced by staurosporine was partially blocked by incubation with the caspase inhibitor, N-benzyoxycarbonyl-Val-Ala-Asp(OMe)fluoromethyl-ketone (ZVAD-fmk), suggesting that a caspase cascade may play a role in the cell death process. CONCLUSIONS: Attenuated susceptibility to apoptosis in endometriotic stromal cells may be associated with abnormal survival in ectopic sites in an environment that is probably unfavourable. These results may be implicated in the pathophysiology of endometriosis.

Aim: We examined whether the detection of Ureaplasma urealyticum DNA in the cervix is associated with preterm labor and delivery. Methods: Eighty-two women (23 preterm labor cases and 59 controls) with no evidence of prophlogistic microorganisms on routine microbiologic examination were enrolled for this study. U. urealyticum colonization was examined using polymerase chain reaction of cervical swabs. Results: The positivity rate of U. urealyticum DNA in preterm labor cases was significantly higher than that in the controls (87.0%vs 45.8%, P = 0.0007). Women in the U. urealyticum-positive group more frequently delivered preterm compared with those in the negative group (36.2%vs 11.4%, P = 0.0111). In five cases that delivered preterm with histologically confirmed chorioamnionitis, U. urealyticum DNA was detected in the placenta. Conclusions: Cervical U. urealyticum colonization might be associated with preterm labor and delivery.

Purpose : To evaluate the effect on the coculture of murine embryos with a human ovarian granulosa tumor derived cell line (KGN cells). Methods : We observed microscopically the growth of murine preimplantation embryos in the coculture system with KGN cells or in the presence with exogenous stem cell factor (SCF). The reverse transcriptase–polymerase chain reaction (RT-PCR) method was used to analyze the gene expression of SCF in KGN cells cocultured with murine embryos. Results : The coculture system with KGN cells significantly increased the rate of embryo development to late blastocyst and to hatching stage. We also found that coculture with murine embryos enhanced the gene expression of SCF in KGN cells. Adding human recombinant SCF to the medium significantly enhanced embryo development to late blastocyst and hatching stage. Conclusions : KGN cells may facilitate preimplantion embryo development through SCF/c-kit paracrine system.

The cytokine, interleukin-6 (IL-6), stimulates the production of human chorionic gonadotropine (hCG) in chorionic cells. The purpose of this study was to examine the role of nuclear factor-kappaB (NF-kappaB) during the induction of IL-6 by IL-1beta in human trophoblast cells.Reverse transcription-polymerase chain reaction was used to determine the gene expressions of IL-1, IL-1 receptor (IL-1R), IL-6R and gp130 in a human choriocarcinoma cell line, BeWo. The BeWo cells were cultured for 24 hr with IL-1beta (0-10 ng/mL), IL-1beta (10 ng/mL) together with IL-1 receptor antagonist (IL-1Ra) or NF-kappaB inhibitor, N-tocyl-l-phenylalanine chloromethyl ketone (TPCK). The concentrations of IL-6 in culture supernatants were measured by enzyme-linked immunosorbent assay.The gene expressions of IL-1R, IL-6R and gp130, but not IL-1beta, were observed. The concentration of IL-6 was enhanced by IL-1beta in a dose-dependent fashion. The addition of IL-1Ra neutralized the effects of IL-1beta on IL-6 secretion. IL-1beta induced expression of phosphorylated IkappaB and the activation of NF-kappaB. The addition of TPCK reduced the IL-1beta-induced IL-6 expression. Adding IL-1beta increased beta-hCG production in a dose-dependent manner, and the addition of TPCK neutralized the effect of IL-1beta.IL-1beta may induce the IL-6 expression and hCG production in human BeWo cells via NF-kappaB.

Objective To examine the effect of interleukin-6 (IL-6) on estrogen production and aromatase activity using a human granulosa tumor cell line (KGN cells). The involvement of the mitogen-activated protein kinase (MAPK) cascade in the inhibitory effects of IL-6 on estrogen production was also evaluated. Design Molecular and biological studies of KGN cells. Setting Department of Obstetrics and Gynecology, Tottori University Hospital, Yonago, Japan. Main Outcome Measure(s) Gene expression of IL-6 and the IL-6 receptor was analyzed by reverse transcription–polymerase chain reaction and Southern blot analysis. KGN cells were cultured for 48 hours with IL-6 (0.1–10 ng/mL) or IL-6 (10 ng/mL) plus a mitogen activated protein kinase-extracellular signal regulated kinase kinase 1/2 (MEK1/2) inhibitor U0126 (10 μM). Estradiol concentration in the culture supernatants was measured by means of enzyme immunoassay, [1β- 3 H] androstenedione was added to the cell lysate supernatant, and aromatase activity was determined by measuring the amount of [ 3 H] H 2 O released upon the conversion of [1β- 3 H] androstenedione to estrone. To examine the activation of intracellular signal transduction molecules induced by IL-6, the phosphorylation of Stat3, p38 MAPK, and extracellular signal-regulated kinase 1/2 (ERK1/2) was examined by Western blotting. Result(s) Gene expression of IL-6 and its receptor was detected in KGN cells. Estradiol secretion was significantly inhibited by adding IL-6, which also suppressed aromatase activity to 50% of the control. In addition, pretreatment with U0126 restored the IL-6–induced suppression of aromatase activity. IL-6 markedly enhanced the phosphorylation of ERK1/2, but not Stat3 and p38 MAPK. U0126 markedly reduced the level of the IL-6–induced phosphorylation of ERK1/2. Conclusion(s) These findings demonstrate that IL-6 may reduce estrogen production via the MAPK signal pathway in human granulosa cells. The results may support the notion that IL-6 is related to impaired estrogen biosynthesis in patients with endometriosis.

Background We previously reported that the level of interleukin (IL)-6 is increased in the peritoneal fluid of women with endometriosis. This study was undertaken to assess the effects of IL-6 and soluble IL-6 receptor (sIL-6R) on in vitro sperm motility. Methods Sperm (n = 20) were cultured with IL-6 or sIL-6R, or with a combination of both. After 24 h cultures, sperm motility was evaluated using a computer-assisted semen analysis system. Gene and protein expressions of IL-6, IL-6 receptor (IL-6R), and glycoprotein 130 (gp130) were examined in sperm by RT-PCR analysis and western blot analysis. Results Addition of IL-6 or sIL-6R individually to the culture media had no affect on sperm motion. However, adding a combination of IL-6 and sIL-6R dose-dependently reduced the percentage of motile and rapidly moving sperm. Adding anti-IL-6R antibody abolished these adverse effects. Sperm expressed the gp130 gene and protein, but not IL-6 or IL-6R. Conclusions A combination of IL-6 and sIL-6R may be associated with gp130 expressed in the sperm and reduce sperm motility. IL-6 and sIL-6R may contribute to the pathogenesis of endometriosis-associated infertility.

Hepatocyte growth factor (HGF) is a mesenchymal-derived paracrine factor that acts through a c-met receptor. The activated c-met receptor recruits various signal proteins. We used a steroidogenic human granulosa-like tumor cell line (KGN cells) to analyze the biological function of HGF in human ovary cells. First, we designed a method to analyze local production and action of HGF in the human ovary. Although c-met mRNA is expressed in KGN cells, granulosa lutein, theca, and ovarian stroma cells, we observed HGF mRNA only in theca and stroma cells. Adding HGF to the medium enhanced mitogenic activity in KGN cells. We next examined the activation of intracellular signal transduction molecules induced by HGF in KGN cells. Here, we showed that HGF activated the distinct phosphorylation of Raf-1, MEK1/2, and ERK1/2, but did not induce phosphorylation of Akt. HGF enhanced the phosphorylation of Elk-1 and c-Jun as nuclear transcription factors. U0126, a MEK1/2 inhibitor, completely abrogated the phosphorylation of ERK1/2 and the cell proliferation in response to HGF. In contrast, H-89, a protein kinase A inhibitor, further enhanced the HGF-induced phosphorylation of ERK1/2 and cell proliferation. In addition, we revealed that HGF suppressed progesterone synthesis in KGN cells. Adding HGF suppressed the forskolin-induced steroidogenic acute regulatory protein (StAR) expression, which is a key regulator in progesterone synthesis. Crosstalk signals between PKA and the mitogen-activated protein kinase (MAPK) pathway were mutually inhibitory. These results demonstrated for the first time that theca cell-derived HGF may be capable of stimulating the proliferation of granulosa cells and suppressing progesterone synthesis via an activating MAPK pathway.

Objective To evaluate the effect of lipopolysaccharide (LPS) on the expression of tumor necrosis factor α (TNFα) and interleukin-8 (IL-8) protein in endometriotic stromal cells (ESC) and their effect on the proliferation of ESC. Design Prospective study. Setting Department of Obstetrics and Gynecology, Tottori University Hospital, Yonago, Japan. Patient(s) Seventeen patients who underwent laparoscopic surgery. Intervention(s) Endometriotic stromal cells were obtained from chocolate cyst linings of the ovary. Main outcome measure(s) We determined the effect of LPS on the production of TNFα and IL-8 and the effect of IL-8 antisense oligonucleotide and nuclear factor-κB (NF-κB) inhibitor on IL-8 production using ELISA. TNFα production was examined by immunocytochemical staining. We determined the effect of LPS and the effect of IL-8 antisense oligonucleotide and NF-κB inhibitor on LPS-promoted ESC proliferation. Result(s) LPS-stimulated ESC produced significant amounts of TNFα and IL-8 in a dose- and time-dependent fashion. Adding LPS promoted ESC proliferation. Anti-TNFα antibody and anti-IL-8 antibody inhibited the stimulatory effects of LPS. IL-8 antisense oligonucleotide and NF-κB inhibitor significantly decreased LPS-induced IL-8 protein production and LPS-induced ESC proliferation. Conclusion(s) Pelvic inflammation may promote the progression of endometriosis.

The nuclear factor kappaB (NF-kappaB) is a ubiquitously expressed transcription factor playing vital roles in innate immunity and other processes involving cellular survival, proliferation, and differentiation. This review highlights the importance of NF-kappaB in the pathophysiology of endometriosis. Constitutive activation of NF-kappaB has been shown in endometriotic lesions. Complex interactions of NF-kappaB with steroid receptors and apoptotic molecules in endometriosis resulting in opposing roles of NF-kappaB are discussed. NF-kappaB regulates the expression of cytokines mediating autocrine self-amplifying cycles of cytokine release and NF-kappaB activation, leading to maintenance of inflammatory reactions in endometriosis. NF-kappaB can contribute to the increased ability of endometriotic cells to invade and adhere to the peritoneal surface by regulating the expression of matrix metaloproteinases. We are presenting the role of NF-kappaB to regulate vascularization and oxidative stress in endometriotic cells. Effects of drugs used for the treatment of endometriosis on NF-kappaB pathway are presented and we show how drugs that inhibit the NF-kappaB can mediate the progression of endometriosis. Novel therapeutic strategies involving the NF-kappaB and applied in endometriosis are also discussed.