Short-term outcomes of robot-assisted versus conventional laparoscopic surgery for early-stage endometrial cancer: A retrospective, single-center study.

AIM: We compared the short-term outcomes between conventional laparoscopic surgery (CLS) and robot-assisted surgery (RAS) to assess the technical feasibility of the latter for early-stage endometrial cancer. METHODS: We retrospectively compared the perioperative outcomes between two groups of 223 patients (CLS group, n = 102; RAS group, n = 121) with early-stage endometrial cancer. Surgical procedures included hysterectomy, bilateral salpingo-oophorectomy and retroperitoneal lymphadenectomy. We analyzed the data from intrapelvic surgery alone because para-aortic lymphadenectomy was performed via conventional endoscopic extraperitoneal approach without robot for both groups. RESULTS: No differences were identified in patients' age and body mass index. The mean operative time was 133 ± 28 versus 178 ± 41 min (P < 0.01), mean blood loss was 196 ± 153 versus 237 ± 146 mL (P = 0.047), mean length of postoperative hospital stay was 9 ± 4 versus 8 ± 3 days (P = 0.01) and mean rate of perioperative complications of Clavien-Dindo grade III or higher was 2.0 versus 3.4% (P = 0.53) for the CLS versus RAS groups, respectively. There was no significant difference in the number of resected lymph nodes. CONCLUSION: The operative time was significantly longer and blood loss was significantly greater in the RAS group than in the CLS group, without a significant difference in the number of resected lymph nodes. These differences are within an acceptable clinical range, showing that RAS is feasible and safe for early-stage endometrial cancer, providing short-term outcomes comparable to those of conventional surgery. Future studies are warranted to compare the long-term oncological outcomes by extending the observation period and including para-aortic lymphadenectomy data.

Short-term outcomes of robotic-assisted versus conventional laparoscopic radical hysterectomy for early-stage cervical cancer: A single-center study.

AIM: Our hospital adopted laparoscopic surgery for early-stage cervical cancer in August 1998, with robot-assisted surgery implemented in October 2013. This study aimed to compare short-term outcomes for conventional laparoscopic radical hysterectomy (LRH) and robot-assisted radical hysterectomy (RARH) and assess the technical feasibility of RARH for early-stage cervical cancer. METHODS: We retrospectively compared operative time, blood loss, number of resected lymph nodes, length of postoperative hospital stay, rate of positive vaginal margin and perioperative complications between two groups of 121 patients (LRH group, n = 57; RARH group, n = 64) with stage IA2 to IIB, among 164 patients who underwent endoscopic radical hysterectomy for early-stage cervical cancer performed between January 2010 and December 2017 by an expert surgeon, excluding cases of para-aortic lymphadenectomy. RESULTS: No differences in patient background, in terms of age and body mass index, were identified. For the LRH/RARH groups (mean ± standard deviation), results obtained were as follows: operative time, 211 ± 38/280 ± 59 min (P < 0.01); blood loss, 219 ± 114/370 ± 231 mL (P < 0.01); number of resected lymph nodes, 38.5 ± 15.9/50.2 ± 18.2 (P < 0.01); length of postoperative hospital stay, 11.6 ± 3.3/11.3 ± 4.8 days (P = 0.67); and perioperative complications with Clavien-Dindo classification of grade III or higher, 1.8/7.8% (P = 0.13). CONCLUSION: The operative time was significantly longer and blood loss greater in the RARH than LRH group. A greater number of lymph nodes were removed in the RARH group. However, these differences seem to be within a clinically acceptable range, showing that RARH is as feasible and safe as LRH in terms of short-term outcomes.

Long-term oncological outcomes of minimally invasive radical hysterectomy for early-stage cervical cancer: A retrospective, single-institutional study in the wake of the LACC trial.

AIM: The objective of this study was to investigate the long-term oncological outcomes of minimally invasive radical hysterectomy (MIRH) for the treatment of early-stage cervical cancer retrospectively in the wake of the laparoscopic approach to cervical cancer (LACC) trial. METHODS: A total of 109 patients with stage IA1 with lymphovascular space involvement, IA2, and IB1 cervical cancers were included in this study. The surgical and oncological outcomes were retrospectively evaluated. All patients underwent type C MIRH with a no-touch isolation technique for cervical tumor. RESULTS: The median number of resected pelvic lymph nodes was 36 (range, 14-94), and 10 patients (9.2%) had positive nodes. One patient (0.9%) had positive surgical margins. Forty-six patients (42%) underwent adjuvant therapy. The median follow-up time was 73 months (range, 30-146 months). Five patients (4.6%) developed recurrent disease, and 3 patients (2.8%) died of cervical cancer. The 5-year disease-free survival and overall survival rates were 96.3% and 97.2%, respectively. A comparison between patients with tumor diameter ≤ 2 cm (n = 59) and those with tumor diameter > 2 cm (n = 50) did not identify any significant differences, with 5-year disease-free survival 96.6% versus 94.0% and 5-year overall survival 98.3% versus 96.0%, respectively. CONCLUSION: In this retrospective study, MIRH with a no-touch isolation technique for stage IA to IB1 cervical cancer was a safe approach in terms of oncological outcomes. However, every surgeon who treats early-stage cervical cancer should inform each patient of the results of the LACC trial because it has an exceedingly high impact.

Resveratrol suppresses inflammatory responses in endometrial stromal cells derived from endometriosis: a possible role of the sirtuin 1 pathway.

AIM: Endometriosis is a chronic inflammatory disease. Sirtuin 1 (SIRT1) plays a role in regulation of inflammation. The role of SIRT1 in endometriosis remains unknown. We here addressed the anti-inflammatory effects of SIRT1 on endometriosis. METHODS: The expression of SIRT1 in human ovarian endometriomas and eutopic endometria were examined using immunohistochemistry and reverse transcription polymerase chain reaction (RT-PCR). Endometriotic stromal cells (ESC) obtained from endometriomas were exposed to either resveratrol or sirtinol, an activator or inhibitor of sirtuins, respectively, and tumor necrosis factor (TNF)-α-induced interleukin (IL)-8 release from the ESC was assessed at mRNA and protein levels. RESULTS: Both immunochemistry and RT-PCR demonstrated that SIRT1 was expressed in ESC and normal endometrial stromal cells. Resveratrol suppressed TNF-α-induced IL-8 release from the ESC in a dose-dependent manner while sirtinol increased IL-8 release. CONCLUSION: These opposing effects of SIRT1-related agents suggest that IL-8 release from the ESC is modulated through the SIRT1 pathway. Resveratrol may have the potential to ameliorate local inflammation in endometriomas.

Regulation of SIRT1 determines initial step of endometrial receptivity by controlling E-cadherin expression.

Sirtuin 1 (SIRT1), originally found as a class III histone deacetylase, is a principal modulator of pathways downstream of calorie restriction, and the activation of SIRT1 ameliorates glucose homeostasis and insulin sensitivity. We examined the role of SIRT1 in the regulation of uterine receptivity using Ishikawa and RL95-2 endometrial carcinoma cell lines. Exogenous expression of SIRT1 significantly enhanced E-cadherin expression, while small interfering RNA-mediated depletion of endogenous SIRT1 resulted in a significant reduction of E-cadherin expression. A SIRT1 activator resveratrol elevated E-cadherin expression in a dose dependent manner, while SIRT1 repressors nicotinamide and sirtinol exhibited a dose dependent reduction of E-cadherin expression. We also showed that both forced expression of SIRT1 and activation of SIRT1 promote E-cadherin-driven reporter gene constructs, and SIRT1 is localized at E-cadherin promoter containing E-box elements in Ishikawa cells. Using an in vitro model of embryo implantation, we demonstrate that exogenous expression of SIRT1 and stimulation of SIRT1 activity resulted in the Ishikawa cell line becoming receptive to JAR cell spheroid attachment. Furthermore, resveratrol enhanced E-cadherin and Glycodelin protein expression at sites of intercellular contact, suggesting an additive role of resveratrol in promoting implantation. The initial step of human reproduction depends on the capacity of an embryo to attach and implant into the endometrial wall, and these results revealed the novel mechanism that activation and increased expression of SIRT1 play an important role in uterine receptivity.

Resveratrol promotes expression of SIRT1 and StAR in rat ovarian granulosa cells: an implicative role of SIRT1 in the ovary.

BACKGROUND: Resveratrol is a natural polyphenolic compound known for its beneficial effects on energy homeostasis, and it also has multiple properties, including anti-oxidant, anti-inflammatory, and anti-tumor activities. Recently, silent information regulator genes (Sirtuins) have been identified as targets of resveratrol. Sirtuin 1 (SIRT1), originally found as an NAD+-dependent histone deacetylase, is a principal modulator of pathways downstream of calorie restriction, and the activation of SIRT1 ameliorates glucose homeostasis and insulin sensitivity. To date, the presence and physiological role of SIRT1 in the ovary are not known. Here we found that SIRT1 was localized in granulosa cells of the human ovary. METHODS: The physiological roles of resveratrol and SIRT1 in the ovary were analyzed. Immunohistochemistry was performed to localize the SIRT1 expression. SIRT1 protein expression of cultured cells and luteinized human granulosa cells was investigated by Western blot. Rat granulosa cells were obtained from diethylstilbestrol treated rats. The cells were treated with increasing doses of resveratrol, and subsequently harvested to determine mRNA levels and protein levels. Cell viability was tested by MTS assay. Cellular apoptosis was analyzed by caspase 3/7 activity test and Hoechst 33342 staining. RESULTS: SIRT1 protein was expressed in the human ovarian tissues and human luteinized granulosa cells. We demonstrated that resveratrol exhibited a potent concentration-dependent inhibition of rat granulosa cells viability. However, resveratrol-induced inhibition of rat granulosa cells viability is independent of apoptosis signal. Resveratrol increased mRNA levels of SIRT1, LH receptor, StAR, and P450 aromatase, while mRNA levels of FSH receptor remained unchanged. Western blot analysis was consistent with the results of quantitative real-time RT-PCR assay. In addition, progesterone secretion was induced by the treatment of resveratrol. CONCLUSIONS: These results suggest a novel mechanism that resveratrol could enhance progesterone secretion and expression of luteinization-related genes in the ovary, and thus provide important implications to understand the mechanism of luteal phase deficiency.

Alternative strategies to in vitro fertilization/intracytoplasmic sperm injection treatment for aged infertile women.

PURPOSE: This study aimed to maximize the chance of pregnancy and provide an optimal protocol for infertile female patients of advanced reproductive age as an alternative to in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) treatment. METHODS: We retrospectively analyzed medical records of 432 infertile women aged ≥38 at the beginning of the treatment. Stepwise non-IVF/ICSI treatments using timed intercourse or intrauterine insemination, with or without controlled ovarian stimulation, were adopted for all patients. In this population, we extracted 8 representative infertility factors and examined these effects on fertility rate by calculating clinical pregnancy rate. RESULTS: The prognosis for infertile women possessing at least one of the three factors, 'advanced female age (≥42 years)', 'endometriosis/adenomyosis', and 'tubal infertility' was apparently poor because only 5 out of 155 women were able to conceive (1.02% per cycle). In contrast, 95 patients without the four factors, 'advanced female age', 'endometriosis/adenomyosis', 'tubal infertility', and 'male infertility', were more likely to conceive (9.14% per cycle). CONCLUSIONS: Fertility centers can offer appropriate protocols for non-IVF/ICSI treatment and establish guidelines for aged infertile patients by examining infertility factors and considering their combinations.

Laparoscopic Myomectomy.

Laparoscopic myomectomy is minimally invasive treatment for patients suffering from fibroids, especially those wishing to maintain their fertility sparing potential. While this surgery requires intensive training in surgical skills such as intracorporeal suturing and specimen extraction, patients can also expect less adhesion and a quick return to normal activity. This surgery can be broken into three stages, each presenting its own specific and unique challenges-enucleation, reapproximation of the myoma bed, and specimen extraction. To prepare for the broad spectrum of cases where the size and number of fibroids can differ greatly, we have mastered several techniques for each stage of the procedure. To keep the surgery safe, we train for unexpected scenarios by practicing minimally invasive repair and reconstruction techniques. By following basic tenets and understanding the laparoscopic anatomy, we define the targets and boundaries of our dissection to ensure completeness. In this paper, techniques for the enucleation, reapproximation, and extraction will be presented in detail.

Effect of dienogest on pain and ovarian endometrioma occurrence after laparoscopic resection of uterosacral ligaments with deep infiltrating endometriosis.

OBJECTIVE: To evaluate the effect of dienogest (DNG) in preventing the occurrence of pain and endometriomas after laparoscopic resection of uterosacral ligaments (USLs) with deep infiltrating endometriosis (DIE). STUDY DESIGN: This retrospective analysis included 126 patients who underwent laparoscopic resection of USLs with DIE followed by postoperative administration of DNG or no medication. Every 6 months postoperatively, patients answered questions and underwent ultrasound examination to identify pain and/or endometrioma. RESULT: There were three (5.0%) cases of endometrioma in 59 patients from the DNG group and 21 (31.3%) cases in 67 patients from the no medication group (P=0.0002). Pain returned to preoperative levels in eight (11.9%) cases in the no medication group. No recurrence of pain occurred in the DNG group (P=0.0061). CONCLUSION: The administration of DNG after resection of USLs with DIE significantly reduces the occurrence rate of endometriosis-related pain and endometriomas.

HAND2-mediated proteolysis negatively regulates the function of estrogen receptor α.

A previous study demonstrated that the progesterone­inducible HAND2 gene product is a basic helix­loop­helix transcription factor and prevents mitogenic effects of estrogen receptor α (ERα) by inhibiting fibroblast growth factor signalling in mouse uteri. However, whether HAND2 directly affects the transcriptional activation function of ERα remains to be elucidated. In the present study, the physical interaction between HAND2 and ERα was investigating by performing an immunoprecipitation assay and an in vitro pull­down assay. The results demonstrated that HAND2 and ERα interacted in a ligand­independent manner. The in vitro pull­down assays revealed a direct interaction between HAND2 and the amino­terminus of ERα, termed the activation function­1 domain. To determine the physiological significance of this interaction, the role of HAND2 as a cofactor of ERα was investigated, which revealed that HAND2 inhibited the ligand­dependent transcriptional activation function of ERα. This result was further confirmed and the mRNA expression of vascular endothelial growth factor, an ERα­downstream factor, was decreased by the overexpression of HAND2. This inhibition of ligand­dependent transcriptional activation function of ERα was possibly attributed to the proteasomic degradation of ERα by HAND2. These results indicate a novel anti­tumorigenic function of HAND2 in regulating ERα­dependent gene expression. Considering that HAND2 is commonly hypermethylated and silenced in endometrial cancer, it is hypothesized that HAND2 may serve as a possible tumor suppressor, particularly in uterine tissue.

SIRT3 positively regulates the expression of folliculogenesis- and luteinization-related genes and progesterone secretion by manipulating oxidative stress in human luteinized granulosa cells.

SIRT3 is a member of the sirtuin family and has recently emerged as a vital molecule in controlling the generation of reactive oxygen species (ROS) in oocytes. Appropriate levels of ROS play pivotal roles in human reproductive medicine. The aim of the present study was to investigate SIRT3 expression and analyze the SIRT3-mediated oxidative response in human luteinized granulosa cells (GCs). Human ovarian tissues were subjected to immunohistochemical analysis to localize SIRT3 expression. Hydrogen peroxide and human chorionic gonadotropin were used to analyze the relationship between ROS and SIRT3 by quantitative RT-PCR and Western blotting. Intracellular levels of ROS were investigated by fluorescence after small interfering RNA-mediated knockdown of SIRT3 in human GCs. To uncover the role of SIRT3 in folliculogenesis and luteinization, mRNA levels of related genes and the progesterone concentration were analyzed by quantitative RT-PCR and immunoassays, respectively. We detected the expression of SIRT3 in the GCs of the human ovary. The mRNA levels of SIRT3, catalase, and superoxide dismutase 1 were up-regulated by hydrogen peroxide in both COV434 cells and human GCs and down-regulated by human chorionic gonadotropin. Knockdown of SIRT3 markedly elevated ROS generation in human GCs. In addition, SIRT3 depletion resulted in decreased mRNA expression of aromatase, 17ß-hydroxysteroid dehydrogenase 1, steroidogenic acute regulatory protein, cholesterol side-chain cleavage enzyme, and 3ß-hydroxysteroid dehydrogenase in GCs and thus resulted in decreased progesterone secretion. These results have the important clinical implication that SIRT3 might play a positive role in the folliculogenesis and luteinization processes in GCs, possibly by sensing and regulating the generation of ROS. Activation of SIRT3 function might help to sustain human reproduction by maintaining GCs as well as oocytes.