The clinical trial of alternative relugolix administration for uterine leiomyoma prior to surgically treatment: a study protocol for Non-Adverse Relugolix Administration (NARA) trial.

BACKGROUND: Uterine leiomyomas are common for reproductive-aged women and affect women's quality of life due to heavy menstrual bleeding or dysmenorrhea. Leiomyomas grow according to estradiol exposure and decrease after post-menopause. In case serious symptoms are caused by leiomyomas, pharmacotherapy or surgical treatment is proposed. Prior to surgical treatment, pharmacotherapies aimed at the reduction of leiomyoma and uterine volume or improvement of anemia are introduced to conduct minimum invasive surgery (i.e., to reduce blood loss or surgical duration). Recently, relugolix (40 mg orally once daily) as a gonadotropin-releasing hormone (GnRH) receptor antagonist has proved its sufficient efficacy in suppressing estradiol levels without the transient estradiol flare-up compared with GnRH agonist. However, long-term administration should not be permitted liable to for climacteric disorder or osteoporosis, and evidence is lacking on the actual efficacy and extent of adverse effects of the every-other-day dosing regimen. This trial aimed to prove non-inferiority in volume reduction effect on leiomyoma and safety (i.e., reduction of adverse effects) by every-other-day administration after 2 months of everyday administration compared to daily administration throughout the duration. METHODS: A minimization adaptive randomized control trial (RCT) will be conducted. Patients (over 20 years old) harboring leiomyoma who will be undergoing surgical treatment will be invited to participate. Patients who are enrolled in the intervention group will receive every-other-day administration for 16 weeks after 8 weeks of daily administration. Patients who are enrolled in the control group will receive daily throughout the 24 weeks. The primary outcome is the leiomyoma volume reduction, and the secondary endpoints are the reduction of uterine volume, the occurrence of the climacteric disorder, genital bleeding days, change rate of serum hormone or bone turnover markers, and bone mineral density after 24 weeks compared to before administration. DISCUSSION: This study aims to prove both the non-inferiority in leiomyoma volume reduction and superiority in adverse effects occurrence reduction, which will provide a novel method to escape adverse effects while maintaining the effect of leiomyoma reduction. TRIAL REGISTRATION: Japan Registry of Clinical Trials jRCTs051230078. Registered on 26 July 2023.

Immunohistochemical Analysis of the Tissue Factor Pathway Inhibitor-2 in Endometrial Clear Cell Carcinoma: A Single-center Retrospective Study.

The tissue factor pathway inhibitor-2 (TFPI2) was recently identified as a diagnostic serum marker for ovarian clear cell carcinoma. Moreover, the immunohistochemical expression of TFPI2 in ovarian clear cell carcinoma was recently reported. This single-center retrospective study aimed to evaluate whether TFPI2 can be a specific biomarker for immunohistological diagnosis of endometrial clear cell carcinoma (ECCC). Immunohistochemical staining of TFPI2 in 55 endometrial carcinomas was evaluated at Nara Medical University Hospital. Thirteen ECCC samples were included as cases and 42 samples were included as a control (endometrioid carcinoma grade 1, 11 cases; grade 2, 11 cases; grade 3, 10 cases; serous carcinoma, 10 cases). The mean ± SD TFPI2 histoscore for diagnosing ECCC was 115.4 ± 87.9, which was significantly higher than that of non-ECCC (21.3 ± 45.9, P = 0.002). The best TFPI2 histoscore value obtained from the analyses of receiver operating characteristic curves for immunohistochemical diagnosis of ECCC was 15. With TFPI2 histoscores ≥15.0 as positive and <15.0 as negative, all 13 ECCC cases (100%) were positive for TFPI2, whereas 11 (26.2%) non-ECCC cases were positive for TFPI2. The sensitivity and specificity of TFPI2 for diagnosing ECCC were 100% and 73.8%, respectively. TFPI2 is expressed in ECCC and is useful for histopathological diagnosis.

Preoperative serum tissue factor pathway inhibitor­2 level as a prognostic marker for endometrial cancer.

Advanced endometrial cancer (EC) often recurs and has a poor prognosis. Various serum markers have been used for EC but their usefulness as biomarkers is still unclear; therefore, identifying new biomarkers is important. The present study aimed to investigate whether the tissue factor pathway inhibitor-2 (TFPI2) level was elevated in the preoperative serum of patients with EC and if it may be a prognostic factor. The present retrospective study included 207 patients who had a confirmed pathological diagnosis of EC and received surgical therapy as the initial treatment between January 2011 and December 2017. Survival analysis was performed using Kaplan-Meier analysis and the Cox proportional hazards regression model. The 5-year disease-free survival and overall survival (OS) rates were 73.3 and 83.7%, respectively. The cut-off value for predicting OS for TFPI2 level was 177 pg/ml as determined from the receiver operating characteristic curve. A TFPI2 value ≥177 pg/ml was significantly associated with age ≥65 years (P<0.001), diabetes (P=0.035), stage (P<0.001), myometrial invasion (P<0.001), lymphovascular invasion (P=0.004), lymph node metastasis (P=0.010), distant metastasis (P<0.001), cancer antigen (CA) 125 ≥36 U/ml (P<0.001) and CA 19-9 ≥38 U/ml (P<0.001). In multivariate analysis, high-grade carcinoma [hazard ratio (HR), 2.439; P=0.041], lymph node metastasis (HR, 2.116; P=0.038), distant metastasis (HR, 3.604; P=0.009) and TFPI2 level ≥177 pg/ml (HR, 2.42; P=0.043) were significant prognostic factors affecting OS in patients with EC. These results suggest that the preoperative serum TFPI2 level, along with its histological type, lymph node metastasis and distant metastasis, was a prognostic factor for OS in patients with endometrial cancer.

Successful vaginoscopic excision of the vaginal septum in a virgin girl of obstructed hemivagina and ipsilateral renal anomaly: Case report and review of literature.

Obstructed hemivagina and ipsilateral renal anomaly (OHVIRA) is a rare malformation that not only causes severe menstrual cramps shortly after menarche but can also lead to endometriosis and infection in the future. We report a case of OHVIRA successfully managed by vaginoscopic excision of the vaginal septum. A 12-year-old virgin girl presented to our hospital with dysmenorrhea and lower abdominal pain. OHVIRA was diagnosed using magnetic resonance imaging. Vaginoscopic surgery was performed for drainage of hematocolpos and excision of the vaginal septum. Vaginoscopic excision of the vaginal septum was performed using a resectoscope, without a vaginal speculum. The procedure was completed safely without injuring the hymen. This is the first case report of successful excision of the vaginal septum by vaginoscopic surgery for OHVIRA in Japan. Vaginoscopic excision may be one of the effective options for the treatment of vaginal obstruction.

Skeletal muscle metastasis as a first site of recurrence of cervical cancer: A case report and review of the literature.

RATIONALE: Cervical cancer primarily spreads through direct invasion or via local lymphatics, and hematogenous metastasis is infrequent. Previous reports have shown that lung, liver, and bone are the organs most frequently affected by hematogenous metastasis of cervical cancer, while skeletal muscle is very rarely involved. PATIENT CONCERNS: A 75-year-old Japanese woman presented with a painful muscular mass in her right lower abdomen. Five years ago, she was treated for her International Federation of Gynecology and Obstetrics stage IB2 cervical adenocarcinoma with radical surgery plus adjuvant chemotherapy. DIAGNOSES: The patient was diagnosed with isolated oblique muscle metastasis from cervical adenocarcinoma as a first site of recurrence. INTERVENTIONS: The patient was treated with salvage surgery consisting of partial resection of the oblique muscle and ilium. The tumor was completely excised with an adequate surgical margin by a partial resection of the oblique muscle and ilium OUTCOMES:: The patient is currently free of disease at 10 months after the development of recurrent disease. LESSONS: We describe a rare case of isolated oblique muscle metastasis as a first site of recurrence of the International Federation of Gynecology and Obstetrics stage IB2 cervical adenocarcinoma, which was successfully treated with surgery. Although skeletal muscle metastasis is rare, this condition should be considered during the follow-up period, especially when patients complain of muscular pain with insidious progression. The present case and our literature review highlighted the possibility that loco-regional treatment may be curative for selected recurrent cervical cancer developed in skeletal muscles.

Preoperative plasma D-dimer level is a useful prognostic marker in ovarian cancer.

A high pre-treatment plasma D-dimer level was recently identified as a poor prognostic factor in several malignancies. The aim of this study was to evaluate the prognostic significance of plasma D-dimer levels in epithelial ovarian cancer (EOC). Data of 199 patients were retrospectively analysed. The relationships between pre-treatment D-dimer levels and other clinical parameters and prognosis were evaluated. Univariate analysis identified age, pre-treatment plasma D-dimer level, massive ascites, residual tumours, pre-treatment CA125 level, histological type, and FIGO stage as predictors of overall survival. The multivariate analysis showed that a high pre-treatment plasma D-dimer level (p=.017), residual tumours (p < .001), and FIGO stage (p = .036) were independent risk factors of overall survival. Venous thromboembolism (VTE) did not influence overall survival (p=.091). High pre-treatment D-dimer levels are associated with a poor prognosis independent of VTE status in EOC patients, and might be a useful prognostic biomarker.Impact statementWhat is already known on this subject? In recent years, a high pre-treatment plasma D-dimer level has been identified as a prognostic factor in several malignancies, but only a handful of studies have assessed the role of pre-treatment plasma D-dimer levels in patients with EOC patients. Thus, the clinical significance and prognostic value of the plasma D-dimer level in EOC remain controversial, and there is also debate related to the association of the higher mortality rate among cancer patients with elevated D-dimer levels with VTE.What do the results of this study add? In our study, high pre-treatment D-dimer levels are associated with a poor prognosis independently of VTE in EOC patients.What are the implications of these findings for clinical practice and/or further research? The D-dimer level might emerge as a valuable prognostic biomarker, which will help doctors in the choice of initiating a more aggressive therapy, the combination of chemotherapy with anticoagulation therapy.

Subtype I (intrinsic) adenomyosis is an independent risk factor for dienogest-related serious unpredictable bleeding in patients with symptomatic adenomyosis.

We aimed to retrospectively analyze the risk factors of a continuous dienogest (DNG) therapy for serious unpredictable bleeding in patients with symptomatic adenomyosis. This is a retrospective study based on data extracted from medical records of 84 women treated with 2 mg of DNG orally each day between 2008 and 2017. 47 subjects were excluded from the original analyses due to an inadequate subcategorization into subtype I and subtype II and a lack of hemoglobin levels. The influence of various independent variables on serious unpredictable bleeding was assessed. Of the 37 eligible patients who received the continuous DNG therapy, 14 patients experienced serious unpredictable bleeding. Univariate analysis revealed that the serious bleeding group had subtype I adenomyosis (P = 0.027). There was no correlation between age, parity, minimum hemoglobin level before treatment, previous endometrial curettage, and duration of DNG administration, or uterine or adenomyosis size and the serious bleeding. A DNG-related serious unpredictable bleeding is associated with the structural type of adenomyosis (subtype I) in patients with symptomatic adenomyosis.

Search for conditions to avoid parametrectomy during radical hysterectomy for cervical cancer.

AIM: This study aimed to assess adequate conditions for omitting parametrectomy for stage IB1-IIA2 cervical cancer with the aim of reducing postoperative complications during Type III radical hysterectomy (RH). METHODS: We investigated factors associated with parametrial invasion (PMI) in patients who underwent Type III RH for stage IB1, IB2, IIA1, IIA2 and IIB cervical cancer at two tertiary institutions from November 2006 to February 2018. Both clinicopathological and preoperatively estimated factors were assessed. RESULTS: One hundred fifty-six patients were preoperatively diagnosed with stage IB1 to IIB disease. Thirty-four patients (21.8%) showed PMI on histological analyses. In the multivariate analysis, an age older than 50 years, tumor size larger than 40 mm, common iliac lymph node metastasis and lymphovascular space invasion were identified as significant risk factors for PMI (P-values = 0.008, 0.003, 0.004 and 0.004, respectively). The preoperatively estimated risk factors for PMI were an older age, larger tumor size, and common iliac lymph node metastasis (P-values = 0.007, 0.002 and 0.001, respectively). A combination of these three factors was sufficient to estimate PMI with a high specificity (100%) and positive predictive value (100%) in patients with stage IB1 to IIA2 disease. CONCLUSION: During RH, resecting the posterior layer of the vesicouterine ligament and the paracolpium without removing the cardinal ligament (avoiding parametrectomy) might be feasible for stage IB1-IIA2 cervical cancer in patients younger than 50 years presenting with smaller tumors (<40 mm) and no common iliac lymph node metastasis.

Magnetic resonance imaging findings for discriminating clear cell carcinoma and endometrioid carcinoma of the ovary.

BACKGROUND: Common cancerous histological types associated with endometriosis are clear cell carcinoma (CCC) and endometrioid carcinoma (EC). CCC is regarded as an aggressive, chemoresistant histological subtype. Magnetic resonance imaging (MRI) offers some potential advantages to diagnose ovarian tumors compared with ultrasonography or computed tomography. This study aimed to identify MRI features that can be used to differentiate between CCC and EC. METHODS: We searched medical records of patients with ovarian cancers who underwent surgical treatment at Nara Medical University Hospital between January 2008 and September 2018; we identified 98 patients with CCC or EC who had undergone preoperative MRI. Contrasted MRI scans were performed less than 2 months before surgery. Patients were excluded from the study if they had no pathology, other pathological subtype of epithelial ovarian cancer, and/or salvage treatment for recurrence and metastatic ovarian cancer at the time of study initiation. Clinically relevant variables that were statistically significant by univariate analysis were selected for subsequent multivariate regression analysis to identify independent factors to distinguish CCC from EC. RESULTS: MRI of CCC and EC showed a large cystic heterogeneous mixed mass with mural nodules protruding into the cystic space. Univariate logistic regression analysis revealed that the growth pattern (broad-based nodular structures [multifocal/concentric sign] or polypoid structures [focal/eccentric sign]), surface irregularity (a smooth/regular surface or a rough/irregular/lobulated surface), "Width" of mural nodule, "Height-to-Width" ratio (HWR), and presence of preoperative ascites were factors that significantly differed between CCC and EC. In the multivariate logistic regression analysis, the growth pattern of the mural nodule (odds ratio [OR] = 0.69, 95% confidence interval [CI]: 0.013-0.273, p = 0.0004) and the HWR (OR = 3.71, 95% CI: 1.128-13.438, p = 0.036) were independent predictors to distinguish CCC from EC. CONCLUSIONS: In conclusion, MRI data showed that the growth pattern of mural nodules and the HWR were independent factors that could allow differentiation between CCC and EC. This finding may be helpful to predict patient prognosis before operation.

Conceptual frameworks of synthetic lethality in clear cell carcinoma of the ovary.

Targeting non-oncogenes may result in the selective death of cancer cells. Clear cell carcinoma of the ovary (CCC) may exhibit resistance against conventional chemotherapy and is associated with poor prognosis. The aim of the present report was to review synthetic lethality-based therapies for CCC. Previous English-language studies were reviewed to accumulate preclinical and clinical data on targeting synthetic lethal partners. Synthetic lethal interactions have a variety of types, involving components of a backup or parallel pathway with overlapping functions, components encoded by paralogous pairs, subunit components that form heteromeric complexes and components that are arranged in a single linear pathway. A set of candidate gene targets potentially resulting in synthetic lethality have been previously identified. HNF class homeobox, AT-rich interaction domain 1A, ATR serine/threonine kinase, ATM serine/threonine kinase, checkpoint kinase 1 and phosphatase and tensin homolog may be the key partner genes. A variety of loss of function genes in CCC are driver or passenger events and may function as synthetic lethal pairs under replication stress conditions. Further clinical studies will be required to investigate the safety and therapeutic effect of synthetic lethality pairs in CCC tumor types with replication stress.

Potential signaling pathways as therapeutic targets for overcoming chemoresistance in mucinous ovarian cancer.

Cases of mucinous ovarian cancer are predominantly resistant to chemotherapies. The present review summarizes current knowledge of the therapeutic potential of targeting the Wingless (WNT) pathway, with particular emphasis on preclinical and clinical studies, for improving the chemoresistance and treatment of mucinous ovarian cancer. A review was conducted of English language literature published between January 2000 and October 2017 that concerned potential signaling pathways associated with the chemoresistance of mucinous ovarian cancer. The literature indicated that aberrant activation of growth factor and WNT signaling pathways is specifically observed in mucinous ovarian cancer. An evolutionarily conserved signaling cascade system including epidermal growth factor/RAS/RAF/mitogen-activated protein kinase kinase/extracellular signal-regulated protein kinase, phosphoinositide 3-kinase/Akt and WNT signaling regulates a variety of cellular functions; their crosstalk mutually enhances signaling activity and induces chemoresistance. Novel antagonists, modulators and inhibitors have been developed for targeting the components of the WNT signaling pathway, namely Frizzled, low-density lipoprotein receptor-related protein 5/6, Dishevelled, casein kinase 1, AXIN, glycogen synthase kinase 3ß and ß-catenin. Targeted inhibition of WNT signaling represents a rational and promising novel approach to overcome chemoresistance, and several WNT inhibitors are being evaluated in preclinical studies. In conclusion, the WNT receptors and their downstream components may serve as novel therapeutic targets for overcoming chemoresistance in mucinous ovarian cancer.

Sequential molecular changes and dynamic oxidative stress in high-grade serous ovarian carcinogenesis.

The mechanism of high-grade serous ovarian cancer (HGSC) development remains elusive. This review outlines recent advances in the understanding of sequential molecular changes associated with the development of HGSC, as well as describes oxidative stress-induced genomic instability and carcinogenesis. This article reviews the English language literature between 2005 and 2017. Clinicopathological features analysis provides a sequential progression of fallopian tubal epithelium to precursor lesions to type 2 HGSC. HGSC may develop over a long time after incessant ovulation and repeated retrograde menstruation via stepwise accumulation of genetic alterations, including PAX2, ALDH1A1, STMN1, EZH2 and CCNE1, which confer positive selection of cells with growth advantages through acquiring driver mutations such as BRCA1/2, p53 or PTEN/PIK3CA. Haemoglobin and iron-induced oxidative stress leads to the emergence of genetic alterations in fallopian tubal epithelium via increased DNA damage and impaired DNA repair. Serous tubal intraepithelial carcinoma (STIC), the likely precursor of HGSC, may be susceptible to DNA double-strand breaks, exhibit DNA replication stress and increase genomic instability. The induction of genomic instability is considered to be a driving mechanism of reactive oxygen species (ROS)-induced carcinogenesis. HGSC exemplifies the view of stepwise cancer development. We describe how genetic alterations emerge during HGSC carcinogenesis related to oxidative stress.

Comparison of the Different Definition Criteria for the Diagnosis of Amniotic Fluid Embolism.

INTRODUCTION: There are several sets of criteria for the diagnosis of Amniotic Fluid Embolism (AFE), but little is known about their degree of agreement. AIM: To evaluate the concordance of the Japan criteria for AFE in comparison with two definitions: the US AFE registration entry criteria (the US criteria) and UK Obstetric Surveillance System criteria for defining cases of amniotic fluid embolism (the UK criteria). MATERIALS AND METHODS: A retrospective observational study was conducted in which the AFE cases registered in the Obstetrical Gynaecological Society of Kinki District in Japan for the period of April 2005 to December 2012 have been analysed by the expert steering obstetric committee, organized by the members of the Obstetric Research group. Cohen's kappa coefficient was used to calculate the agreement among three clinical diagnoses. For inter-group comparison, the Pearson Chi-square test was used (for categorical) and Mann-Whitney test was used (for continuous variables). RESULTS: Among the 26 cases registered for this period, a total of 18 women were selected as having AFE according to the Japan criteria. Five women died (case fatality rate 27.8%). Agreement between the Japan criteria and the US and UK criteria was k = 0.453 and k = 0.538, respectively, reflecting moderate agreement. However, only 38.9% were given a diagnosis of AFE according to all three criteria. The factor that most often caused disagreement in diagnosis between the Japan criteria and the US criteria was "onset within 30 minutes postpartum". The UK criteria excluded "women with postpartum haemorrhage as the first presenting feature in whom there was no evidence of cardiorespiratory compromise". The case fatality rates in US and UK are higher than in Japan (50.0% and 38.5% vs 27.8%), but this did not result in a significant difference (p=0.497). CONCLUSION: The groups of subjects identified as having AFE by the Japan criteria had a medium agreement with the US (k=0.453) or UK criteria (k=0.538). These three definition criteria identified different subgroups of patients. Such disagreement has serious implications for research and treatment.

The conceptual advances of carcinogenic sequence model in high-grade serous ovarian cancer.

The present review focuses on the current status of molecular pathology in high-grade serous cancer (HGSC) and preneoplastic conditions. This article reviews the English-language literature on HGSC, precursor, fallopian tubal epithelium, secretory cells, ciliated cells, secretory cell expansion, secretory cell outgrowth (SCOUT), p53 signature, serous tubal intraepithelial carcinoma (STIC), DNA damage and immunohistochemistry in an effort to identify the precursor-carcinoma sequence in HGSC. The majority of HGSC originates from the fimbriated end of the fallopian tube secretory epithelial cells, while the small part of this disease may develop from ovarian cortical inclusion cyst (CIC). A series of morphological changes from normal fallopian epithelium to preneoplastic to neoplastic lesions were concomitant with the multistep accumulation of molecular and genetic alterations. Recent studies provide a stepwise progression of fallopian tubal epithelium to precursor lesions to carcinoma, with the aid of a 'secretory cell-SCE-SCOUT-p53 signature-STIC-HGSC sequence' model. Immunohistochemical markers, including p53, STMN1, EZH2, CCNE1, Ki67 and γ-H2AX, were gradually increased during the SCOUT-p53 signature-STIC-HGSC sequence. Conversely, PAX2 expression was decreased during the early phase of SCOUT development. Potential genes and proteins are involved in the evolutionary trajectory of the precursor-cancer lineage model. In the present review we examined detailed aspects of the molecular changes involved in malignant transformation from fallopian tube epithelium to HGSC. A precursor condition originating in 'field cancerization' may gain a growth advantage, leading to HGSC.

Current status of tertiary debulking surgery and prognosis after secondary debulking surgery for recurrent Müllerian epithelial cancer in Japan: a retrospective analysis of 164 patients (KCOG-G1402).

BACKGROUND: This study aimed to evaluate the current status of secondary debulking surgery (SDS) and tertiary debulking surgery (TDS; performed for recurrence after SDS) and to assess the overall survival after recurrence of Müllerian epithelial cancer in Japan. We also evaluated the data of patients who underwent a fourth debulking surgery (i.e., quaternary debulking surgery (QDS)). METHODS: We conducted a retrospective study of 164 patients with recurrent Müllerian epithelial cancers (i.e., ovarian, tubal, and peritoneal cancers). The SDS was performed between January 2000 and September 2014 in 20 Japanese hospitals. Clinicopathological data were collected and analyzed. RESULTS: Of the 164 patients, 66 patients did not have a recurrence or died after SDS. Ninety-eight patients had a recurrence after SDS. Forty-three of the 98 patients underwent TDS; 55 of the 98 patients did not undergo TDS and were classified into the non-TDS group. The overall survival (OS) after SDS was significantly better in the TDS group than in the non-TDS group. The median OS after SDS was 123 and 42 months in the TDS group and non-TDS group, respectively. Of the 43 patients who received TDS, 11 patients were further treated with QDS. The median OS after SDS was 123 months for patients who underwent QDS. CONCLUSIONS: This multicenter study on the prognosis of post-SDS is apparently the first report on QDS in Japan. Patients undergoing TDS have a good prognosis, compared to patients in the non-TDS group. Novel drugs are being evaluated; however, debulking surgery remains a necessary treatment for recurrence.

Skin-mucous membrane disorder and therapeutic effect of pegylated liposomal doxorubicin in recurrent ovarian cancer.

AIM: Hand-foot syndrome (HFS) induced by chemotherapy and molecule-targeting drugs is correlated with treatment efficacy. We conducted a retrospective analysis to evaluate the relationship between HFS and efficacy of pegylated liposomal doxorubicin (PLD) for recurrent ovarian cancer. METHODS: Patients were treated with PLD between July 2009 and May 2014. We evaluated patient characteristics, incidence of adverse events, clinical benefit (rate of complete response, partial response, and stable disease), progression-free survival, and overall survival. RESULTS: Twenty-seven patients were included in the study. Median age was 63 years (range, 41-77 years). The median number of cycles of PLD was 3 (range, 1-6). The clinical benefit rate was 33.3%, and progressive disease was noted in 18 patients (66.7%). Median overall survival was 6.7 months (range, 1.1-41 months). Compared with patients with grade 0/1 HFS and oral mucositis, patients with grade 2-4 toxicity (n = 9, 33.3%) had a significantly higher rate of clinical benefit (11.1% vs 77.7%; P < 0.001) and a longer median overall survival (3.7 months vs 20.8 months; P < 0.001). CONCLUSIONS: Severity of HFS and mucositis may be a predictive marker of PLD efficacy. The prevention and management of HFS and mucositis are important for continued treatment.

Genes Downregulated in Endometriosis Are Located Near the Known Imprinting Genes.

There is now accumulating evidence that endometriosis is a disease associated with an epigenetic disorder. Genomic imprinting is an epigenetic phenomenon known to regulate DNA methylation of either maternal or paternal alleles. We hypothesize that hypermethylated endometriosis-associated genes may be enriched at imprinted gene loci. We sought to determine whether downregulated genes associated with endometriosis susceptibility are associated with chromosomal location of the known paternally and maternally expressed imprinting genes. Gene information has been gathered from National Center for Biotechnology Information database geneimprint.com. Several researchers have identified specific loci with strong DNA methylation in eutopic endometrium and ectopic lesion with endometriosis. Of the 29 hypermethylated genes in endometriosis, 19 genes were located near 45 known imprinted foci. There may be an association of the genomic location between genes specifically downregulated in endometriosis and epigenetically imprinted genes.

Fetal programming theory: implication for the understanding of endometriosis.

Comparison of the transcriptomes and proteomes of the decidualization-specific genes that express high vs low levels of the eutopic and ectopic endometrium of women with endometriosis compared with controls, could be useful in understanding the pathogenesis of endometriosis. Genome-wide comparison between decidual tissue and non-decidual tissue identified many genes significantly modulated in the process of decidualization. Comparison of eutopic endometrium and endometriotic sites also revealed up- and down-regulated genes. A combined analysis of the experimental data showed specific genes up-regulated both at the endometriotic site and in the decidualization process, representing a broad diversity of molecular functions, including cell cycle regulation, angiogenesis and adhesion molecules. In contrast, down-regulated genes identified in endometriosis among genes overexpressed in decidualization encode Müllerian embryogenesis, which includes transcription factors, hormonal regulation and cytokine expression. The mechanism responsible for insufficient decidualization in endometriosis may be mediated through down-regulation of the Müllerian embryogenesis-related genes. In conclusion, a range of decidualization resistance has been associated with endometriosis. Future study will identify the putative mechanisms relating epigenetic changes of decidualization susceptibility genes in early life to the risk of developing endometriosis in adulthood.