Current state of fertility preservation for adolescent and young adult patients with gynecological cancer.

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.

Value of adjuvant chemotherapy and informed microscopic examination for occult gynecologic cancer detected upon risk-reducing salpingo-oophorectomy after chemotherapy for BRCA1/2-associated breast cancer: a case report.

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.

Clinico-pathological characteristics of patients with stage IB1-IB2 (FIGO 2018) uterine cervical cancer: a nationwide study in Japan.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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 < 0.0001, stage IB2; 50.5% vs. 39.7%, p = 0.0009). Among 1262 patients with stage IB1, 61.2% (772/1262) were low-risk group, 29.4% (371/1262) were intermediate-risk group (single risk: 23.3%, double risks: 6.1%). Of 932 patients with stage IB2, 32.1% (299/932) were low-risk group, 59.1% (551/932) were intermediate-risk group (single intermediate-risk: 31.0%, double intermediate-risk: 28.1%). Disease-free survival rate and overall survival rate of stage IB1 patients were significantly better than those with stage IB2 (5-year DFS; 94.7% vs. 88.6%, p < 0.001, 5-yrs OS; 98.5% vs. 95.1%, p < 0.001). Stage IB1 Patients with double intermediate-risk showed significantly worse survival than those with single intermediate-risk (5-yrs DFS: 96.1% vs. 84.6%, p < 0.001, 5-yrs OS: 98.9% vs. 93.0%, p = 0.029). Multivariate analysis revealed that double intermediate-risk was the independent prognostic factor in stage IB1, but non-squamous cell carcinoma and intermediate-risk in stage IB2. CONCLUSION: Non-squamous cell carcinoma and intermediate-risk decreased survival in patients with stage IB2, whereas double intermediate-risk was a negative impact on survival in stage IB1.

Surgical management of unilateral oophorectomy for ovarian tissue cryopreservation in high-risk children and adolescents with varied backgrounds.

PURPOSE: 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. METHODS: A total of 25 girls who underwent OTC from November 2015 through May 2020 were retrospectively analyzed with IRB approval. RESULTS: 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. CONCLUSION: 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.

Deep vein thrombosis and serum D-dimer after pelvic lymphadenectomy in gynecological cancer.

INTRODUCTION: Venous thromboembolism prevention during the perioperative period requires comprehensive risk-level assessment. The aim of this study was to evaluate the incidence of deep vein thrombosis and to assess the cut-off levels of serum D-dimer as a screening strategy for deep vein thrombosis during the perioperative period. METHODS: A total of 205 patients (ovarian cancer: 68, endometrial cancer: 76, cervical cancer: 61) who underwent gynecological surgery, including retroperitoneal lymph node dissection, were enrolled. We retrospectively analyzed the data on the cut-off value of D-dimer assessed using area under the receiver operating characteristic curve preoperatively, and 2 or 3 months, postoperatively. All patients underwent leg vein ultrasonography regardless of the serum D-dimer level. Furthermore, CT scans were performed to evaluate both disease status and venous thromboembolism, including pulmonary thromboembolism. Statistical analyzes were performed using the Mann-Whitney U-test (D-dimer values of each cancer), Chi-square test, Fisher's exact test (incidence of deep vein thrombosis), and one-way analysis of variance (patient characteristics). RESULTS: A total of 205 patients (ovarian cancer: 68, endometrial cancer: 76, cervical cancer: 61) who underwent gynecological surgery, including retroperitoneal lymph node dissection, were included in the analysis. Deep vein thrombosis rates were significantly higher in patients with ovarian cancer (P<0.001). The postoperative D-dimer value was significantly higher than the preoperative value. Postoperative D-dimer values were also significantly higher in patients who received adjuvant chemotherapy (P=0.001). The cut-off value of D-dimer was 1.55 µg/mL preoperatively (sensitivity, 48.0%; specificity, 94.1%), and this value was higher postoperatively, at 1.95 µg/mL (sensitivity, 37.0%; specificity, 90.9%). CONCLUSION: Postoperative D-dimer values are higher not only after surgery but also in patients who received adjuvant chemotherapy. The cut-off value of D-dimer at 2 or 3 months postoperatively was higher than preoperative value.

Analysis of pregnancy outcome and decline of anti-Müllerian hormone after laparoscopic cystectomy for ovarian endometriomas.

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-Müllerian 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.

Incidence and risk factors for lower limb lymphedema after gynecologic cancer surgery with initiation of periodic complex decongestive physiotherapy.

BACKGROUND: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Outcome of stage IB2-IIB patients with bulky uterine cervical cancer who underwent neoadjuvant chemotherapy followed by radical hysterectomy.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Gonadotropin-releasing hormone analogues reduce the proliferation of endometrial stromal cells but not endometriotic cells.

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.

A simple technique of vaginal cuff closure to prevent tumor cell spillage in laparoscopic radical hysterectomy for uterine cervical 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.

Primary malignant melanoma of uterine cervix treated with pembrolizumab as adjuvant immunotherapy.

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.

Comparison of laparoscopic surgery and conventional laparotomy for surgical staging of patients with presumed low-risk endometrial cancer: The current state of Japan.

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 <50%. CONCLUSION: The laparoscopic staging surgery is a feasible and safe alternative to the laparotomy for patients with presumed low-risk endometrial cancer, especially for obese patients. To perform the laparoscopic surgery for patients with stage IA endometrial cancer under the current national health insurance system, it is important to limit the candidates to low-risk disease based on a precise diagnosis before the surgery.

Tissue characterization of uterine myometrium using the ultrasound gray-level histogram width.

PURPOSE: The purpose of this study was to clarify the usefulness of the gray-level histogram width for tissue characterization of the uterine myometrium. METHODS: 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. RESULTS: 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. CONCLUSION: The gray-level histogram width is useful for tissue characterization of the uterine myometrium.

Reduction of estrogen production by interleukin-6 in a human granulosa tumor cell line may have implications for endometriosis-associated infertility.

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 microM). Estradiol concentration in the culture supernatants was measured by means of enzyme immunoassay, [1beta-(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 [1beta-(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.

Current treatment of endometrioma.

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.

Lipopolysaccharide-promoted proliferation of endometriotic stromal cells via induction of tumor necrosis factor alpha and interleukin-8 expression.

OBJECTIVE: To evaluate the effect of lipopolysaccharide (LPS) on the expression of tumor necrosis factor alpha (TNFalpha) 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 TNFalpha and IL-8 and the effect of IL-8 antisense oligonucleotide and nuclear factor-kappaB (NF-kappaB) inhibitor on IL-8 production using ELISA. TNFalpha production was examined by immunocytochemical staining. We determined the effect of LPS and the effect of IL-8 antisense oligonucleotide and NF-kappaB inhibitor on LPS-promoted ESC proliferation. RESULT(S): LPS-stimulated ESC produced significant amounts of TNFalpha and IL-8 in a dose- and time-dependent fashion. Adding LPS promoted ESC proliferation. Anti-TNFalpha antibody and anti-IL-8 antibody inhibited the stimulatory effects of LPS. IL-8 antisense oligonucleotide and NF-kappaB 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 cellular inhibitor of apoptosis protein-2 is a possible target of novel treatment for endometriosis.

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.

The role of NF-kappaB in 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.

Apoptosis and endometriosis.

Apoptosis is a distinctive form of programmed cell death resulting in the efficient elimination of cells without eliciting an inflammatory response. Endometriosis is characterized by the presence of endometrial cells with capacity to avoid apoptosis outside the uterus. Apoptosis plays a fundamental role for the pathogenesis of endometriosis. Eutopic endometrium from women with endometriosis has increased expression of anti-apoptotic factor and decreased expression of pro-apoptotic factors compared with endometrium from healthy women. These differences could contribute to the survival of regurgitating endometrial cells into the peritoneal cavity and development of endometriosis. Increased apoptosis of Fas-bearing immune cells in the peritoneal cavity may leads to their decreased scavenger activity that eventually results in prolonged survival of ectopic endometrial cells in women with endometriosis. This study is a current review of the literatures focused on the physiological role of apoptosis in normal endometrium and alterations in regulation of apoptosis in eutopic and ectopic endometrium from women with endometriosis. The role of apoptosis in the treatment of endometriosis is also reviewed.