INHBA(+) cancer-associated fibroblasts generate an immunosuppressive tumor microenvironment in ovarian cancer.

Effective targeting of cancer-associated fibroblasts (CAFs) is hindered by the lack of specific biomarkers and a poor understanding of the mechanisms by which different populations of CAFs contribute to cancer progression. While the role of TGFß in CAFs is well-studied, less attention has been focused on a structurally and functionally similar protein, Activin A (encoded by INHBA). Here, we identified INHBA(+) CAFs as key players in tumor promotion and immunosuppression. Spatiotemporal analyses of patient-matched primary, metastatic, and recurrent ovarian carcinomas revealed that aggressive metastatic tumors enriched in INHBA(+) CAFs were also enriched in regulatory T cells (Tregs). In ovarian cancer mouse models, intraperitoneal injection of the Activin A neutralizing antibody attenuated tumor progression and infiltration with pro-tumorigenic subsets of myofibroblasts and macrophages. Downregulation of INHBA in human ovarian CAFs inhibited pro-tumorigenic CAF functions. Co-culture of human ovarian CAFs and T cells revealed the dependence of Treg differentiation on direct contact with INHBA(+) CAFs. Mechanistically, INHBA/recombinant Activin A in CAFs induced the autocrine expression of PD-L1 through SMAD2-dependent signaling, which promoted Treg differentiation. Collectively, our study identified an INHBA(+) subset of immunomodulatory pro-tumoral CAFs as a potential therapeutic target in advanced ovarian cancers which typically show a poor response to immunotherapy.

Stability Determination of Intact Humanin-G with Characterizations of Oxidation and Dimerization Patterns.

Humanin is the first identified mitochondrial-derived peptide. Humanin-G (HNG) is a variant of Humanin that has significantly higher cytoprotective properties. Here, we describe the stability features of HNG in different conditions and characterize HNG degradation, oxidation, and dimerization patterns over short-term and long-term periods. HNG solutions were prepared in high-performance liquid chromatography (HPLC) water or MO formulation and stored at either 4 °C or 37 °C. Stored HNG samples were analyzed using HPLC and high-resolution mass spectrometry (HRMS). Using HPLC, full-length HNG peptides in HPLC water decreased significantly with time and higher temperature, while HNG in MO formulation remained stable up to 95% at 4 °C on day 28. HNG peptides in HPLC water, phosphate-buffered saline (PBS) and MO formulation were incubated at 37 °C and analyzed at day 1, day 7 and day 14 using HRMS. Concentrations of full-length HNG peptide in HPLC water and PBS declined over time with a corresponding appearance of new peaks that increased over time. These new peaks were identified to be singly oxidized HNG, doubly oxidized HNG, homodimerized HNG, singly oxidized homodimerized HNG, and doubly oxidized homodimerized HNG. Our results may help researchers improve the experimental design to further understand the critical role of HNG in human diseases.

Comparison of laparoscopic enclosed electromechanical morcellation and vaginal enclosed scalpel morcellation at laparoscopic myomectomy: A prospective randomized trial.

AIM: This study aimed to compare the laparoscopic-enclosed electromechanical morcellation (LEM) with vaginal-enclosed scalpel morcellation (VSM) in laparoscopic myomectomy procedures. METHODS: One hundred eighteen patients who underwent laparoscopic myomectomy were enrolled the prospective randomized interventional clinical study in tertiary university hospital. After myomectomy, tissue removal was accomplished via either LEM using the in-glove morcellation technique or VSM. RESULTS: The median tissue removal time was longer in the LEM group (25 min [range: 14-55]) than the VSM group (20 min [range: 6-38] [p = 0.001]). Rescue analgesia requirement was significantly higher in the LEM group than the VSM group (mean rank: 56.92 vs. 40.92 doses, respectively; p < 0.001). There was no significant difference between preoperative and postoperative third month total scores of female sexual function index (FSFI) and subdomains in the LEM group. Conversely, all subdomains and total scores of FSFI (26.5 [16.7-34.8] vs. 22.7 [15.2-28.7]) except pain significantly worsened 3 months after operation in the VSM group. CONCLUSIONS: LEM was associated with a longer tissue removal time and increased postoperative analgesic requirement. On the other hand, VSM was associated with worsened postoperative sexual function from baseline.

Ovarian transplantation with robotic surgery and a neovascularizing human extracellular matrix scaffold: a case series in comparison to meta-analytic data.

OBJECTIVE: To report our experience with robot-assisted (RA) autologous cryopreserved ovarian tissue transplantation (ACOTT) with the use of a neovascularizing extracellular matrix scaffold. DESIGN: Case series with meta-analytic update. SETTING: Academic. PATIENT(S): Seven recipients of RA-ACOTT. INTERVENTION(S): Before or shortly after initiating chemotherapy, ovarian tissue was cryopreserved from 7 women, who then underwent RA-ACOTT 9.9 ± 1.8 years (range, 7-12 years) later. Perioperatively, they received transdermal estrogen and low-dose aspirin to enhance graft vascularization. Ovarian cortical pieces were thawed and sutured on an extracellular matrix scaffold, which was then robotically anastomosed to the bivalved remaining ovary in 6 cases and retroperitoneally (heterotopic) to the lower abdomen in 1 case. MAIN OUTCOME MEASURE(S): Ovarian function return, the number of oocytes/embryos, aneuploidy %, live births, and neonatal outcomes were recorded. Graft longevity was compared with the mean from the meta-analytic data. RESULT(S): Ovarian function returned 13.9 ± 2.7 weeks (11-16.2 weeks) after ACOTT, and oocytes were retrieved in all cases with 12.3 ± 6.9 embryos generated. In contrast to orthotopic, the heterotopic ACOTT demonstrated low embryo quality and an 80% aneuploidy rate. A recipient did not attempt to conceive and 2 needed a surrogate, whereas 4 of 4 delivered 6 healthy children, compared with 115 of 460 (25% pregnancy rate) from the meta-analytic data (n = 79). The mean graft longevity (43.2 ± 23.6/47.4 ± 22.8 months with/without sensitivity analysis) trended longer than the meta-analytic mean (29.4 ± 22.7), even after matching age at cryopreservation. CONCLUSION(S): In this series, RA-ACOTT resulted in extended graft longevity, with ovarian functions restored in all cases, even when the tissues were cryopreserved after chemotherapy exposure.

Comparison of open and a novel closed vitrification system with slow freezing for human ovarian tissue cryopreservation.

PURPOSE: To investigate the differences concerning post-thawing/warming follicle survival, DNA damage and apoptosis in human ovarian tissues cryopreserved by slow freezing, open, or closed vitrification methods. METHODS: A total of 50 pieces of 5 × 5 × 1 mm ovarian cortical pieces were harvested (5 donor ovaries; mean age 31 ± 6.62 years). From each donor, one cortical piece was used as baseline; the remaining were randomly assigned to slow freezing (SF), vitrification using open device (VF-open), or closed device (VF-closed) groups. After 8-10 weeks of cryostorage, tissues were evaluated 4 h after thawing/warming. Histological analysis was evaluated for follicle survival (primordial and primary follicle densities) by H&E staining. The percentages of primordial and primary follicles with DNA double-strand breaks (γH2AX) and apoptotic cell death pathway activation (AC3) were immunohistochemically assessed. Data were analysed using one-way ANOVA and LSD post hoc comparison. RESULTS: Compared to the baseline, primordial follicle (pdf) densities significantly declined in all cryopreserved groups (SF, VF-open, and VF-closed, P < 0.05). However, the total and non-apoptotic pdf densities were similar among SF, VF-open, and VF-closed. SF and VF with either open or closed devices did not increase the percentages of primordial or primary follicles with DNA double-strand breaks (DSBs) or apoptosis compared to the baseline or among the freezing methods in the present study. CONCLUSION: Based on the intact primordial follicle survival, DNA damage, and apoptosis rates after thawing/warming, SF vs VF with either open or newly developed closed devices appear to be comparable.

Impact of adjuvant chemotherapy or tamoxifen-alone on the ovarian reserve of young women with breast cancer.

PURPOSE: To determine the longitudinal impact of adjuvant chemotherapy and tamoxifen-only treatments on the reproductive potential of women with breast cancer by using a sensitive ovarian reserve marker anti-Mullerian hormone (AMH) as a surrogate. METHODS: One-hundred-and-forty-two women with a primary diagnosis of breast cancer were prospectively followed with serum AMH assessments before the initiation, and 12, 18 and 24 months after the completion of adjuvant chemotherapy or the start of tamoxifen-only treatment. The chemotherapy regimens were classified into Anthracycline-Cyclophosphamide-based (AC-based) and Cyclophosphamide-Methotrexate + 5-Fluorouracil (CMF). Longitudinal data were analyzed by mixed effects model for treatment effects over time, adjusting for baseline age and BMI. RESULTS: Both chemotherapy regimens resulted in significant decline in ovarian reserve compared to the tamoxifen-only treatment (p < 0.0001 either regimen vs. tamoxifen for overall trend). AMH levels sharply declined at 12 months but did not show a significant recovery from 12 to 18 and 18 to 24 months after the completion of AC-based or CMF regimens. The degree of decline did not differ between the two chemotherapy groups (p = 0.53). In contrast, tamoxifen-only treatment did not significantly alter the age-adjusted serum AMH levels over the 24-month follow up. Likewise, the use of adjuvant tamoxifen following AC-based regimens did not affect AMH recovery. CONCLUSIONS: Both AC-based regimens and CMF significantly compromise ovarian reserve, without a recovery beyond 12 months post-chemotherapy. In contrast, tamoxifen-only treatment does not seem to alter ovarian reserve. These data indicate that the commonly used chemotherapy regimens but not the hormonal therapy compromise future reproductive potential.

Are Epithelial Ovarian Cancers of the Mesenchymal Subtype Actually Intraperitoneal Metastases to the Ovary?

Primary ovarian high-grade serous carcinoma (HGSC) has been classified into 4 molecular subtypes: Immunoreactive, Proliferative, Differentiated, and Mesenchymal (Mes), of which the Mes subtype (Mes-HGSC) is associated with the worst clinical outcomes. We propose that Mes-HGSC comprise clusters of cancer and associated stromal cells that detached from tumors in the upper abdomen/omentum and disseminated in the peritoneal cavity, including to the ovary. Using comparative analyses of multiple transcriptomic data sets, we provide the following evidence that the phenotype of Mes-HGSC matches the phenotype of tumors in the upper abdomen/omentum: (1) irrespective of the primary ovarian HGSC molecular subtype, matched upper abdominal/omental metastases were typically of the Mes subtype, (2) the Mes subtype was present at the ovarian site only in patients with concurrent upper abdominal/omental metastases and not in those with HGSC confined to the ovary, and (3) ovarian Mes-HGSC had an expression profile characteristic of stromal cells in the upper abdominal/omental metastases. We suggest that ovarian Mes-HGSC signifies advanced intraperitoneal tumor dissemination to the ovary rather than a subtype of primary ovarian HGSC. This is consistent with the presence of upper abdominal/omental disease, suboptimal debulking, and worst survival previously reported in patients with ovarian Mes-HGSC compared to other molecular subtypes.

Dual targeting of GSK3B and HDACs reduces tumor growth and improves survival in an ovarian cancer mouse model.

OBJECTIVE: To investigate the anti-tumor effect of a newly-developed dual inhibitor (APCS-540) of glycogen synthase kinase 3 beta (GSK3B) and histone deacetylases (HDACs) in ovarian cancer cells. METHODS: The effects of APCS-540 on cancer cell proliferation, migration, invasion and cancer stemness were investigated in vitro in human (KURAMOCHI, OVCA420, OVSAHO) and mouse (BR-Luc, ID8, MOSE-HRas-Myc) ovarian cancer cells. Cisplatin-sensitive (A2780) and cisplatin-resistant (A2780cis) cell lines were used to evaluate APCS-540's effect on chemoresistance. The immunocompetent syngeneic mouse model BR-Luc was used to test the effect of APCS-540 on ovarian cancer progression and survival. RESULTS: APCS-540 showed significant anti-tumor effects in vitro in both human and mouse ovarian cancer cells. Importantly, APCS-540 demonstrated marked cytotoxicity against cisplatin-resistant cancer cells and reversed cisplatin-resistance when used in combination with platinum. APCS-540 significantly decreased cancer cell invasion. A significant 66% increase in survival was observed in mice treated with APCS-540 compared to control mice. CONCLUSION: Dual inhibition of GSK3B and HDACs via APCS-540 showed potent anti-tumor activity in vitro and in vivo, suggesting that APCS-540 may provide a novel treatment option for ovarian cancer, including the platinum-resistant disease.

Increased chemotherapy-induced ovarian reserve loss in women with germline BRCA mutations due to oocyte deoxyribonucleic acid double strand break repair deficiency.

OBJECTIVE: To assess whether woman who have BRCA mutations (WBM) experience more declines in ovarian reserve after chemotherapy treatment, as it induces oocyte death by deoxyribonucleic acid (DNA) damage, and BRCA mutations result in DNA damage repair deficiency. DESIGN: Longitudinal cohort study. SETTING: Academic centers. PATIENT(S): The 108 evaluable women with breast cancer were stratified into those never tested (negative family history; n = 35) and those negative (n = 59) or positive (n = 14) for a pathogenic BRCA mutation. INTERVENTION(S): Sera were longitudinally obtained before and 12-24 months after chemotherapy treatment, assayed for antimüllerian hormone (AMH), and adjusted for age at sample collection. MAIN OUTCOME MEASURE(S): Ovarian recovery, defined as the geometric mean of the after chemotherapy age-adjusted AMH levels compared with baseline levels. RESULT(S): Compared with the controls, the before chemotherapy treatment AMH levels were 24% and 34% lower in those negative or positive for BRCA mutations, consistent with accelerated ovarian aging in WBM. The WBM had a threefold difference in AMH recovery after chemotherapy treatment (1.6%), when compared with BRCA negative (3.7%) and untested/low risk controls (5.2%). Limiting the analysis to the most common regimen, doxorubicin and cyclophosphamide followed by paclitaxel, showed similar results. These findings were mechanistically confirmed in an in vitro mouse oocyte BRCA knockdown bioassay, which showed that BRCA deficiency results in increased oocyte susceptibility to doxorubicin. CONCLUSION(S): Women who have pathogenic BRCA mutations are more likely to lose ovarian reserve after chemotherapy treatment, suggesting an emphasis on fertility preservation. Furthermore, our findings generate the hypothesis that DNA repair deficiency is a shared mechanism between aging, infertility, and cancer. CLINICAL TRIAL REGISTRATION NUMBER: NCT00823654.

Can we rely on blind endometrial curettage for complete removal of focal intrauterine lesion? A prospective clinical study.

OBJECTIVE: To investigate the diagnostic and therapeutic efficiency of dilatation-curettage (D&C) combined with aspiration curettage for endometrial pathology compared to hysteroscopy alone in this study. MATERIAL AND METHODS: A total of 143 patients who have suspicion of endometrial mass like lesion, increased endometrial thickness (>5-mm at menopause and/or endometrial thickness upper than 5-mm in patients under tamoxifen treatment due to breast cancer during 2-D transvaginal ultrasonography examination) were enrolled. All patients underwent procedures in order of hysteroscopy, D&C plus aspiration and second look hysteroscopy. Data for age, menopausal status, tamoxifen treatment, endometrial histology, hysteroscopy and D&C findings were recorded and statistically analyzed. RESULTS: Initial hysteroscopy revealed focally growing endometrial lesion in 96 patients. Second look hysteroscopy showed persistent focal lesion in 77 patients (80 %) after D&C plus aspiration. Endometrial blind curettage failed to diagnose 42 % (25/60) of endometrial polyps, none of submucous myomas as well as 27 % (3/11) of premalignant and malignant endometrial lesions. The sensitivity, specificity, overall accuracy, positive predictive value and negative predictive value of hysteroscopy were found as 84.1 %, 83.3 %, 83.9 %, 93.8 %, and 63.8 %, respectively. CONCLUSIONS: Hysteroscopy showed significant superiority in the diagnosis and definitive treatment of endometrial pathologies specifically in focally growing endometrial lesions compared to D&C plus aspiration.

Fertility preservation in gynecologic cancers.

An increasing number of women in modern societies are delaying childbearing beyond the age of 35, and gynecologic cancers affect a significant proportion of reproductive age women who wish to preserve fertility for a future chance of childbearing. As a result, providing treatment options for fertility preservation in women with gynecologic cancer has become a crucial component of cancer survivorship care. In this review article, we discussed the current knowledge on fertility-sparing surgical approaches, as well as assisted reproductive technologies that can be utilized to preserve reproductive potential in women with cervical, endometrial, and ovarian cancer. A brief section on fertility preservation in pediatric gynecologic malignancies is also provided.

Robot-assisted orthotopic and heterotopic ovarian tissue transplantation techniques: surgical advances since our first success in 2000.

OBJECTIVE: To demonstrate the technical advances since the time we reported the first successful case in 2000 and our modern approach to autologous transplantation of frozen-thawed human ovarian tissue. DESIGN: A step-by-step video demonstration of three surgical approaches was created by editing the surgical footage obtained during ovarian transplantation procedures. SETTING: Academic. PATIENT(S): Three patients who previously underwent ovarian tissue harvesting and cryopreservation before gonadotoxic cancer treatments or radical cancer surgery are presented. INTERVENTION(S): The illustrated techniques include robot-assisted orthotopic (technique 1) and heterotopic (technique 2) approaches using the da Vinci Xi (Intuitive Surgical) robotic system and a decellularized human extracellular tissue matrix (Alloderm; LifeCell Corp.) as a tissue scaffold, as well as a percutaneous autotransplantation approach (technique 3). MAIN OUTCOME MEASURE(S): Successful completion of procedures without complications and ovarian graft function with demonstration of E2 production and follicle development. RESULT(S): All cases were completed without complications. Ovarian graft function was confirmed by E2 production, follicle growth by 10-14 weeks after transplantation, and later embryo development. CONCLUSION(S): Since our first report of successful restoration of ovarian function after orthotopic transplantation of frozen-banked ovarian tissue in 2000 (1), followed by our first reports of subcutaneous heterotopic transplantation techniques (2, 3), ovarian tissue cryopreservation followed by subsequent transplantation has become a promising fertility preservation option for young women with cancer who do not have sufficient time to undergo oocyte or embryo cryopreservation and for prepubertal girls (4, 5). The same approach also has the advantage of restoring ovarian endocrine function and fertility without a need for assisted reproduction (6, 7). In the very first successful procedure that we reported in 2000, we used conventional laparoscopy, and the tissues were reconstructed and mounted on a polycellulose scaffold (Surgicel) (1, 7). Since then, we have made significant modifications in our surgical approach with potential improvements in outcomes. Here we illustrate three main techniques of ovarian tissue transplantation resulting in the restoration of ovarian function in all cases. In the first two cases, we illustrated the robot-assisted orthotopic and heterotopic approaches using Alloderm. Robotic ovarian transplantation may increase precision, provide more delicate graft handling, and reduce the time from tissue thawing to transplantation (6, 8). Alloderm is regenerated de-epithelized human cadaver skin, which consists of several extracellular matrix components. It has been safely used in the surgery and dentistry fields for enhancing tissue regeneration and vascularization (9, 10). Furthermore, our earlier laboratory work indicated the critical role of extracellular matrix in primordial follicle growth initiation and preantral follicle growth (11, 12). Prior to our use of Alloderm as part of ovarian transplant procedures, we tested it in human ovarian xenograft models and found Alloderm to incorporate well with ovarian tissue (8). Only after that test did we adopt it for use in ovarian transplants. The utility of the extracellular tissue matrix may thus enhance our ovarian autotransplantation techniques by facilitating ovarian reconstruction and potentially improving neovascularization. In fact, we have seen improved follicle growth and response to ovarian stimulation with the use of Alloderm in our first cases (8). We use heterotopic ovarian transplantation when the pelvis is not suitable for autotransplantation due to past radiation or scarring or when there are other medical contraindications for transplantation in the pelvis. The third technique we illustrated was percutaneous heterotopic ovarian autotransplantation. This is a simple approach that can be used in surgically high-risk patients, as it is done with local anesthesia or IV sedation and without entering abdominal cavity. Additionally, same approach can be utilized when there is heightened concern that the ovarian tissue may harbor a disease that can recur, requiring close surveillance and easier removal of the ovarian graft. While ovarian endocrine function and follicle growth are restored with efficiency using the percutaneous ovarian transplants, our initial experience suggests that oocyte quality may be impaired in SC locations (2, 3, 13). Hence that technique may be more suitable when the only purpose is restoration of ovarian endocrine function. However, we have encountered recurrent live births from spontaneous conceptions following SC ovarian transplants, prompting the question of whether the grafted tissue can augment the function of in situ menopausal ovary (13, 14). While ovarian cryopreservation and transplantation may no longer be considered experimental, there are many exciting questions remaining to be answered on the full potential of this procedure.

Does lymphadenectomy effect postoperative surgical morbidity and survival in patients with adult granulosa cell tumor of ovary?

AIM: To evaluate the effect of lymphadenectomy on surgical morbidity and survival in adult granulosa cell tumor (AGCT) of the ovary. METHODS: Patients who underwent surgical treatment for AGCT between January 1993 and January 2016 were identified. Data were collected for patient age, menopausal status, surgical staging, lymphadenectomy, postoperative complications (anemia, wound infection, incisional hernia), length of hospital stay, follow-up duration, site and time for recurrence, management of recurrence and vital status. Histopathological records were also evaluated for number of cellular mitosis. RESULTS: Lymphadenectomy (pelvic-paraaortic) was performed in 53 (53%) of 98 patients. Decrease in postoperative hemoglobin level and increased wound infection and longer hospital stay were significantly higher in lymphadenectomy group (P = 0.003, 0.043 and <0.001, respectively). Tumor stage (HR 95% CI 14.9 [2.43-92.8]) and number of mitoses >5 (HR 95% CI 14.9 [2.43-92.8]) were significantly associated with recurrence (P = <0.001 and 0.02, respectively). Tumor stage was the only prognostic factor for predicting overall survival (HR 95% CI 8.47 [2.17-33.2]). Lymphadenectomy showed no effect on disease-free survival and overall survival both in multivariate Cox regression analyses (P = 0.46 and 0.69, respectively). Disease-free survival and overall survival were similar in lymphadenectomy and no lymphadenectomy groups (Log Rank P = 0.382, 0.741, respectively). CONCLUSION: Lymphadenectomy had no improved effect on survival and had negative effect on surgical morbidity in patients with AGCT.

The Effect of Adenomyosis in Myometrial Invasion and Overall Survival in Endometrial Cancer.

AIM: The aim of this study was to evaluate whether adenomyosis had an effect on myometrial tumor invasion, stage of the disease, and survival in endometrial cancer. METHODS: Endometrial cancer patients encountered between 2007 and 2016 were identified from pathology records. Patients who underwent suboptimal surgical or medical treatment or with insufficient clinical or surgical data were excluded. Patients diagnosed as having concurrent adenomyosis constituted the study group. Control group patients were randomly selected in a paired design according to the tumor grades in the study group, and for each tumor grade, 4 times as many as patients were included. Tumor stage, histologic type and grade, myometrial invasion, lymphovascular space invasion, presence and location of the adenomyosis in myometrial wall, distance from endometrial line, tumor in adenomyosis, adjuvant treatment, and relapse were primary outcomes.Age, body mass index, medical comorbidities, and type of operation were also recorded. Univariate and multivariate Cox proportional hazards regression models were performed for overall survival. RESULTS: Of those 1242 endometrial cancer patients, 80 with concurrent adenomyosis were identified and compared with 320 patients without adenomyosis following a paired selection based on tumor grade. Higher rates of myometrial invasion, lymphovascular space invasion, tumor diameter, and adjuvant treatments were found in the nonadenomyosis group compared with adenomyosis group (P ≤ 0.001). In patients with adenomyosis, rates of early-stage disease and overall survival were significantly higher compared with the control group (P = 0.001 and 0.01, respectively). CONCLUSIONS: Our results showed that adenomyosis is significantly associated with lower stage in endometrial cancer that may suggest a possible limiting effect on endometrial cancer spread. In addition, despite similar rates in disease-free survival and endometrial cancer-related death, overall survival rate was significantly higher in the presence of adenomyosis and might be considered as a good prognostic factor for endometrial cancer.

The Impact of Carbon Dioxide Pneumoperitoneum on Ovarian Ischemia-Reperfusion Injury during Laparoscopic Surgery: A Preliminary Study.

STUDY OBJECTIVE: To investigate whether carbon dioxide pneumoperitoneum causes ischemia-reperfusion injury to the ovaries during laparoscopic surgery. DESIGN: A prospective controlled clinical study (Canadian Task Force classification II-1). SETTING: A tertiary academic center. PATIENTS: Premenopausal women who underwent hysterectomy with bilateral salpingo-oophorectomy (HSO) via open abdominal and laparoscopic approaches between 2014 and 2015. INTERVENTIONS: In both surgical approaches, unilateral oophorectomy was performed immediately after abdominal entry, and the remaining contralateral ovary was excised at the end of the hysterectomy in order to compare the effect of these surgical procedures on ovarian tissue. Additionally, plasma samples were collected at the following time points: (1) before abdominal entry, (2) at the end of hysterectomy, and (3) before contralateral oophorectomy. Plasma samples were assessed for biochemical oxidative stress markers malondialdehyde (MDA) and 8-hydroxy-2'-deoxyguanosine (8-OHdG). Ovarian tissue samples were assessed for MDA and further evaluated for ischemia-reperfusion injury using a histologic scoring method. MEASUREMENTS AND MAIN RESULTS: Twenty premenopausal women undergoing HSO via open abdominal surgery (n = 10) and laparoscopy (n = 10) were included. Baseline characteristics (age, body mass index, parity, and gravida) and operative data (operative time, estimated blood loss, and intraoperative complication) were similar between groups. Perioperative plasma MDA levels, histologic scores, and tissue oxidative stress markers did not show a significant difference in either group or between groups. However, plasma 8-OHdG levels were significantly different when the second sample in the abdominal HSO group was compared with the first sample in the abdominal HSO group and the third sample in the laparoscopic HSO group (p = .012 and .001, respectively). CONCLUSION: Carbon dioxide pneumoperitoneum does not cause ischemia-reperfusion injury in the human ovaries at clinically safe levels of intra-abdominal pressure.

Application of Decellularized Tissue Scaffolds in Ovarian Tissue Transplantation.

In tissue engineering, decellularized scaffolds have been proved to have remarkable capacity to promote regeneration in various organs such as kidney, heart, lung, and liver. Marrying the field of cryobiology and reproductive medicine resulted in considerable progress and breakthroughs, which led to the emergence of ovarian tissue cryopreservation and transplantation as a promising option for fertility preservation. Here we describe an innovative application of decellularized tissue scaffolds as a regenerative platform for reconstruction of ovarian grafts for auto-transplantation.

Current state and controversies in fertility preservation in women with breast cancer.

On average, over 25000 women are diagnosed with breast cancer under the age of 45 annually in the United States. Because an increasing number of young women delay childbearing to later life for various reasons, a growing population of women experience breast cancer before completing childbearing. In this context, preservation of fertility potential of breast cancer survivors has become an essential concept in modern cancer care. In this review, we will outline the currently available fertility preservation options for women with breast cancer of reproductive age, discuss the controversy behind hormonal suppression for gonadal protection against chemotherapy and highlight the importance of timely referral by cancer care providers.

Robot-assisted Laparoscopic Transplantation of Frozen-thawed Ovarian Tissue.

STUDY OBJECTIVE: To show a new approach for orthotopic human ovarian tissue transplantation via robot-assisted laparoscopic surgery. DESIGN: A step-by-step video explanation of the surgical technique (Canadian Task Force classification III). SETTING: Academic medical center. INTERVENTIONS: The robot-assisted transplantation approach consisted of 3 steps: (1) reconstruction of the ovarian tissue graft, (2) preparation of the contralateral menopausal ovary as the recipient site, and 3) transplantation of the reconstructed graft to the bivalved contralateral ovary. Institutional review board approval was obtained. MEASUREMENTS AND MAIN RESULTS: Although still experimental, cryopreservation and subsequent transplantation of frozen-thawed ovarian tissue are currently the only available methods for prepubertal girls and young women with cancer who are not eligible for established fertility preservation options such as oocyte or embryo cryopreservation [1]. We performed the first reported autologous ovarian transplantation with a conventional laparoscopic technique [2]. To date, over 60 babies have been born after the orthotopic transplantation of cryopreserved ovarian tissue, and this number is growing [3,4]. Until recently, all of these children were born from ovarian transplants that were performed via laparotomy or conventional laparoscopy [5]. We have recently developed a robot-assisted ovarian transplantation procedure that uses an extracellular matrix scaffold to facilitate ovarian reconstruction, handling, and revascularization. Both of the procedures resulted in robust ovarian function and births [6]. The purpose of this video reports the surgical technique in detail, which uses the da Vinci Xi (Intuitive Surgical Inc, Sunnyvale, CA) robotic system for transplantation, and a decellularized human extracellular tissue matrix (Alloderm; LifeCell Corp, Branchburg, NJ) for graft reconstruction. CONCLUSION: Robotic ovarian transplantation may have several advantages, which include precision, more delicate graft handling, and reduced time from tissue thawing to transplantation. The collective usefulness of the extracellular tissue matrix may enhance this technique by enabling a niche for ovarian reconstruction and potentially enhanced revascularization. The feasibility and comparative advantages of this technique are currently being studied in ongoing trials.

Ovarian serous cystadenoma with ectopic adrenal tissue in a 65-year-old patient: A case report.

INTRODUCTION: Ectopic adrenal tissue is a very rare entity in adult females, especially in the ovary, and is generally diagnosed incidentally during surgery. Although it can present at various sites during childhood, it becomes atrophic by adulthood due to normally functioning adrenal glands. Patients are predominantly asymptomatic; however, in some cases endocrine symptoms such as hypertension and fasciotruncal obesity due to hormonal activity can be seen or neoplastic transformation can appear. PRESENTATION OF CASE: A 65-year-old patient with progressive pelvic pain and postmenopausal vaginal bleeding was evaluated by transvaginal ultrasound, which revealed bilateral adnexal masses measuring 5cm in size and a normal uterus with an increased endometrial thickness of 7mm. Initially the endometrial sampling result was reported as benign. The patient underwent abdominal hysterectomy and bilateral salpingo-oophorectomy and the pathological diagnosis was again benign, with serous ovarian cystadenoma being found in both ovaries. The pathologist also reported incidental ectopic adrenal tissue on the wall of the left ovarian cystadenoma. DISCUSSION: Ectopic adrenal tissue is infrequent in female genital organs especially at older ages. Only a few cases of ovarian ectopic adrenal tissue have been reported. To the best of our knowledge the present case is the fourth report in the English literature, and is of additional importance given the patient's age. CONCLUSION: Ectopic adrenal tissues are generally asymptomatic and revealed incidentally during surgery; however some cases have demonstrated the risk of neoplastic transformation. Therefore, surgeons must be aware of this rare entity that bears the risk of malignancy, and should surgically remove all suspicious lesions.

Contained Morcellation: Review of Current Methods and Future Directions.

Power morcellation of surgical specimen during laparoscopic surgery is a practical technology that provides the opportunity to perform several minimally invasive procedures. However, this technology brought forward additional risks and complications associated with dissemination of both benign and malignant tissues inside the abdominal cavity. Based on startling cases, Food and Drug Administration (FDA) announced a discouraging statement on the use of power morcellators that decreased the number of minimally invasive approaches in the following period. As a response to these concerns and negative impacts of the FDA statement, researchers developed several new approaches resulting in contained or in-bag morcellation methods. In this review, we aimed to discuss these current methods and provide an insight for future developments.