A plain language summary of results from the GARNET study of dostarlimab in patients with endometrial cancer.

WHAT IS THIS SUMMARY ABOUT?: Dostarlimab, also known by the brand name JEMPERLI, is a medicine that can be used to treat certain types of endometrial cancer. GARNET is an ongoing phase 1 clinical study that is testing the safety and side effects of dostarlimab and the best way to administer it to patients. The results presented in this summary are from a time point in the middle of the study. WHAT WERE THE RESULTS?: The results from the GARNET study published in 2022 showed how well dostarlimab worked for people participating in the study. Dostarlimab was found to reduce the size of tumors in patients with certain types of endometrial cancer. The patients treated with dostarlimab had side effects that could be managed and few severe side effects. WHAT DO THE RESULTS MEAN?: The results of the GARNET study led to dostarlimab being approved to treat patients with certain types of endometrial cancer. For patients with advanced-stage endometrial cancer, or endometrial cancer that has come back after chemotherapy (recurrent), there are few treatment options. The results suggest that dostarlimab may provide long-term benefits for these patients.

A prospective investigation of fluorescence imaging to detect sentinel lymph nodes at robotic-assisted endometrial cancer staging.

BACKGROUND: The accuracy of sentinel lymph node mapping has been shown in endometrial cancer, but studies to date have primarily focused on cohorts at low risk for nodal involvement. In our practice, we acknowledge the lack of benefit of lymphadenectomy in the low-risk subgroup and omit lymph node removal in these patients. Thus, our aim was to evaluate the feasibility and accuracy of sentinel node mapping in women at sufficient risk for nodal metastasis warranting lymphadenectomy and in whom the potential benefit of avoiding nodal procurement could be realized. OBJECTIVE: To evaluate the detection rate and accuracy of fluorescence-guided sentinel lymph node mapping in endometrial cancer patients undergoing robotic-assisted staging. STUDY DESIGN: One hundred twenty-three endometrial cancer patients undergoing sentinel lymph node sentinel node mapping using indocyanine green were prospectively evaluated. Two mL (1.0 mg/mL) of dye were injected into the cervical stroma divided between the 2-3 and 9-10 o'clock positions at the time of uterine manipulator placement. Before hysterectomy, the retroperitoneal spaces were developed and fluorescence imaging was used for sentinel node detection. Identified sentinel nodes were removed and submitted for touch prep intraoperatively, followed by permanent assessment with routine hematoxylin and eosin levels. Patients then underwent hysterectomy, bilateral salpingo-oophorectomy, and completion bilateral pelvic and periaortic lymphadenectomy based on intrauterine risk factors determined intraoperatively (tumor size >2 cm, >50% myometrial invasion, and grade 3 histology). RESULTS: Of 123 patients enrolled, at least 1 sentinel node was detected in 119 (96.7%). Ninety-nine patients (80%) had bilateral pelvic or periaortic sentinel nodes detected. A total of 85 patients met criteria warranting completion lymphadenectomy. In 14 patients (16%) periaortic lymphadenectomy was not feasible, and the mean number of pelvic nodes procured was 13 (6-22). Of the 71 patients undergoing pelvic and periaortic lymphadenectomy, the mean nodal count was 23.2 (8-51). Of patients undergoing lymphadenectomy, 10.6% had lymph node metastasis on final hematoxylin and eosin evaluation. Notably, the sentinel node was the only positive node in 44% of cases. There were no cases in which final pathology of the sentinel node was negative and metastatic disease was detected upon completion lymphadenectomy in the non-sentinel nodes (no false negatives), yielding a sensitivity of 100%. Of the 14 sentinel nodes ultimately found to harbor metastases, 3 were negative on touch prep, yielding a sensitivity of 78.6% for intraoperative detection of sentinel node involvement. In all 3 of the false-negative touch preps, final pathology detected a single micrometastasis (0.24 mm, 1.4 mm, 1.5 mm). As expected, there were no false-positive results, yielding a specificity of 100%. No complications related to sentinel node mapping or allergic reactions to the dye were encountered. CONCLUSION: Intraoperative sentinel node mapping using fluorescence imaging with indocyanine green in endometrial cancer patients is feasible and yields high detection rates. In our pilot study, sentinel node mapping identified all women with Stage IIIC disease. Low false-negative rates are encouraging, and if confirmed in multi-institutional trials, this approach would be anticipated to reduce the morbidity, operative times, and costs associated with complete pelvic and periaortic lymphadenectomy.

Outcome of robotic surgery for endometrial cancer as a function of patient age.

OBJECTIVE: This study aimed to evaluate and compare robot-assisted surgical staging on clinical outcomes, including quality of life and survival, as a function of patient age. METHODS: Evaluation and comparison of perioperative morbidity, survival, and postoperative quality of life after prospective accumulation of clinical information including outcome measures for patients with endometrial cancer during the first 5 years of a robotic program, based on the following 3 age categories: women older than 80 years, women between 70 and 80 years, and women younger than 70 years. RESULTS: All consecutive patients with endometrial cancer undergoing robotic surgery (n = 303) were included, with 197 women younger than 70 years, 75 women between 70 and 80 years, and 31 women older than 80 years. There were significantly more patients with advanced stage (stage II to IV in 17%, 34%, and 35%, P = 0.02) and grade 3 disease (26%, 43%, and 58%, P = 0.002) with increasing age. The perioperative data showed similar grade I or II complications (Clavien-Dindo classification) between the groups, but significantly more grade III and IV complications for women older than 80 years compared with women 80 years or younger (10% vs 1%, P = 0.004). The time needed to resume chore activities was significantly shorter for patients 70 years or older than patients younger than 70 years [8.9 (8.7) vs 18.8 (25.5) days, P = 0.048]. Overall, all patients irrespective of age were highly satisfied with the procedure. There was no difference between young and elderly patients for disease-free survival (P = 0.99). CONCLUSIONS: Patient's age did not influence minor postoperative morbidity or overall satisfaction after robotic assisted surgery for endometrial cancer. Elderly patients had more major postoperative morbidity but resumed activities quicker than younger patients.

Impact of robotics on the outcome of elderly patients with endometrial cancer.

OBJECTIVE: To evaluate the impact of introducing a robotics program on clinical outcome of elderly patients with endometrial cancer. METHODS: Evaluation and comparison of peri-operative morbidity and disease-free interval in 163 consecutive elderly patients (≥70years) with endometrial cancer undergoing staging procedure with traditional open surgery compared to robotic surgery. RESULTS: All consecutive patients ≥70years of age with endometrial cancer who underwent robotic surgery (n=113) were compared with all consecutive patients ≥70years of age (n=50) before the introduction of a robotic program in December 2007. Baseline patient characteristics were similar in both eras. Patients undergoing robotic surgery had longer mean operating times (244 compared with 217minutes, p=0.009) but fewer minor adverse events (17% compared with 60%, p<0.001). The robotics cohort had less estimated mean blood loss (75 vs 334mL, p<0.0001) and shorter mean hospital stay (3 vs 6days, p<0.0001). There was no difference in disease-free survival (p=0.61) during the mean follow-up time of 2years. CONCLUSION: Transitioning from open surgery to a robotics program for the treatment of endometrial cancer in the elderly has significant benefits, including lower minor complication rate, less operative blood loss and shorter hospitalization without compromising 2-year disease-free survival.

Prospective quality of life outcomes following robotic surgery in gynecologic oncology.

PURPOSE: To characterize the health-related quality of life (HRQL) of patients undergoing robotic surgery for the treatment of gynecologic cancers. METHODS: 211 patients completed a quality of life questionnaire before surgery. Postoperative questionnaires, consisting of the same assessment with the addition of postoperative questions, were given at 1 week, 3 weeks, 3, 6, and 12 months after surgery. The Functional Assessment of Cancer Therapy-General (FACT-G) and its subscales were used to evaluate HRQL. Patient-rated body image was evaluated using the Body Image Scale. Statistical significance was measured by the Wilcoxon signed-rank test. Minimally important difference (MID) values were analyzed to evaluate clinical significance. RESULTS: Overall HRQL and body image decreased at 1 week after surgery and returned to baseline by 3 weeks. Physical and functional well-being decreased at 1 week after surgery and returned to baseline by 3 months after surgery. However, using MID criteria, physical well-being returned to baseline by 3 weeks. Social well-being did not change significantly. Emotional well-being increased immediately by 1 week after surgery. CONCLUSION: Patient reported HRQL outcomes following robotic surgery for the treatment of gynecologic cancers suggests a rapid return to pre-surgery values.

Vaginal vault dehiscence after robotic hysterectomy for gynecologic cancers: search for risk factors and literature review.

INTRODUCTION: Vaginal vault dehiscence following robotic-assisted hysterectomy for gynecologic cancer may be attributed to surgical techniques and postoperative therapeutic interventions. We searched for risk factors in patients with gynecologic cancers and complemented this with a literature review. METHODS: Evaluation of prospectively gathered information on all consecutive robotic surgeries for gynecologic cancers was performed in a tertiary academic cancer center between December 2007 and March 2012. The literature was reviewed for articles relevant to "gynecologic oncology" and "robotics" with "vaginal cuff dehiscence" in the English and French languages. Respective authors were contacted to complete relevant information. RESULTS: Seven dehiscences were identified of 441 cases with established gynecologic cancers. The closures in these 7 were performed using interrupted 1-Vicryl (Ethicon Inc) (3/167; 1.8%), combination of interrupted 1-Vicryl and 1-Biosyn (Covidien Inc) (3/156, 1.9%), and V-Loc (Covidien Inc) (1/118, 0.8%) sutures. Associated risk factors included adjuvant chemotherapy and/or brachytherapy, early resumption of sexual activity, and low body mass index (mean, 23 ± 3.23 kg/m²). Dehiscences occurred regardless of suturing by staff or trainees. Review of operative videos did not reveal a detectable etiologic factor, such as excessive cautery damage to the vaginal cuff or shallow tissue sutured. All 7 colporrhexis repairs were performed through a vaginal approach without the need of laparoscopy or laparotomy. CONCLUSIONS: Postoperative chemotherapy, brachytherapy, and early resumption of sexual activities are risk factors for vaginal vault dehiscence. Surgical technique, particularly the use of delayed absorbable sutures, deserves further evaluation.

Brain metastases in women with epithelial ovarian cancer: multimodal treatment including surgery or gamma-knife radiation is associated with prolonged survival.

OBJECTIVE: To explore the impact of treatment modality on survival in patients with brain metastases from epithelial ovarian cancer. METHODS: We conducted a retrospective review of cases of ovarian cancer with brain metastases treated at institutions in three countries (Canada, China, and India) and conducted a search for studies regarding brain metastases in ovarian cancer reporting survival related to treatment modality. Survival was analyzed according to treatment regimens involving (1) some form of surgical excision or gamma-knife radiation with or without other modalities, (2) other modalities without surgery or gamma-knife radiation, or (3) palliation only. RESULTS: Twelve patients (mean age 56 years) with detailed treatment/outcome data were included; five were from China, four from Canada, and three from India. Median time from diagnosis of ovarian cancer to brain metastasis was 19 months (range 10 to 37 months), and overall median survival time from diagnosis of ovarian cancer was 38 months (13 to 82 months). Median survival time from diagnosis of brain metastasis was 17 months (1 to 45 months). Among patients who had multimodal treatment including gamma-knife radiotherapy or surgical excision, the median survival time after the identification of brain metastasis was 25.6 months, compared with 6.0 months in patients whose treatment did not include this type of focused localized modality (P = 0.006). Analysis of 20 studies also indicated that use of gamma-knife radiotherapy and excisional surgery in multi-modal treatment resulted in improved median survival interval (25 months vs. 6.0 months, P < 0.001). CONCLUSION: In the subset of patients with brain metastases from ovarian cancer, prolonged survival may result from use of multidisciplinary therapy, particularly if metastases are amenable to localized treatments such as gamma-knife radiotherapy and surgical excision.

Objectif : Explorer les effets de la modalité de traitement sur la survie chez les patientes qui présentent des métastases cérébrales attribuables au cancer épithélial de l'ovaire. Méthodes : Nous avons mené une analyse rétrospective des cas de cancer de l'ovaire donnant lieu à des métastases cérébrales qui ont été traités dans des établissements se situant dans trois pays (Canada, Chine et Inde); de plus, nous avons mené une recherche qui visait les études ayant traité des métastases cérébrales associées au cancer de l'ovaire qui faisaient mention des taux de survie liés aux modalités de traitement. La survie a été analysée en fonction de schémas de traitement mettant en jeu (1) une forme quelconque d'excision chirurgicale ou de radiochirurgie par scalpel gamma avec ou sans autres modalités, (2) d'autres modalités sans chirurgie ni radiochirurgie par scalpel gamma ou (3) des modalités palliatives seulement. Résultats : Douze patientes (âge moyen : 56 ans) comptant des données détaillées en ce qui concerne le traitement / les issues ont été admises à l'étude; cinq d'entre elles étaient de la Chine, quatre du Canada et trois de l'Inde. Le délai médian entre le diagnostic de cancer de l'ovaire et l'apparition de métastases cérébrales était de 19 mois (plage de 10 à 37 mois), et la durée de survie médiane globale à la suite du diagnostic de cancer de l'ovaire était de 38 mois (de 13 à 82 mois). La durée de survie médiane à la suite du diagnostic de métastases cérébrales était de 17 mois (de 1 à 45 mois). Chez les patientes ayant subi un traitement multimodal qui faisait appel à la radiochirurgie par scalpel gamma ou à l'excision chirurgicale, la durée de survie médiane à la suite de l'identification des métastases cérébrales était de 25,6 mois, par comparaison avec 6,0 mois chez les patientes dont le traitement ne faisait pas appel à ce type de modalité localisée ciblée (P = 0,006). L'analyse de 20 études a également indiqué que le recours à la radiochirurgie par scalpel gamma et à l'excision chirurgicale dans le cadre d'un traitement multimodal a donné lieu à une amélioration de l'intervalle de survie médian (25 mois vs 6,0 mois, P < 0,001). Conclusion : Dans le sous-ensemble des patientes qui présentent des métastases cérébrales attribuables au cancer de l'ovaire, le recours à un traitement multidisciplinaire pourrait mener à une prolongation de la survie, particulièrement lorsque les métastases se prêtent à des traitements localisés tels que la radiochirurgie par scalpel gamma et l'excision chirurgicale.

E2F3b over-expression in ovarian carcinomas and in BRCA1 haploinsufficient fallopian tube epithelium.

We have previously shown that the E2F3 oncogene is up-regulated as part of a "preneoplastic expression profile" in fallopian tube epithelium (FTE) of women with BRCA1 mutations. We studied E2F3 expression in FTE and carcinomas of women with BRCA1 or BRCA2 mutations or wildtype for both genes. Significantly more foci of TP53 positive cells in histologically normal FTE from women with BRCA1 mutations but not in wildtype or BRCA2 mutated individuals had E2F3 protein overexpression relative to adjacent normal FTE, which occurred in the context of focally increased proliferation, potentially explaining the increased neoplastic potential of tubal TP53 foci in women with BRCA1 mutations. To assess mechanisms of E2F3 deregulation in ovarian or tubal carcinogenesis, we studied E2F3 and its two isoforms E2F3a and E2F3b in wild-type ovarian carcinomas and ovarian carcinomas associated with germline BRCA1 and BRCA2 mutations. The expression of E2F3b, but not E2F3a, was correlated with the expression of BRCA1 in all three genetic groups. In primary cultures of FTE from women with BRCA1 mutation or wildtype for BRCA1 and BRCA2, siRNA-induced BRCA1 deficiency led to increased E2F3b but not E2F3a expression. Our results suggest that E2F3b and BRCA1 are functionally connected, and BRCA1 haploinsufficiency in normal FTE may lead to up-regulation of E2F3b and increased proliferation before the development of intraepithelial neoplasia. These data support that E2F3b up-regulation is an important preneoplastic event in FTE from BRCA1 mutation carriers.

Accuracy of sentinel lymph node detection following intra-operative cervical injection for endometrial cancer: a prospective study.

OBJECTIVE: The objective of this study is to evaluate the detection rate and diagnostic accuracy of sentinel lymph node (SLN) mapping using intra-operative cervical injection of filtered 99mTc-sulfur colloid (99mTc-SC) and patent blue in patients with endometrial cancer. METHODS: Prospective evaluation of the first 100 endometrial cancer patients undergoing SLN mapping using cervical injection of patent blue combined with filtered 99mTc-SC in the operating room was done. Patients underwent robotic-assisted lymphatic mapping with frozen section, hysterectomy, BSO, and completion bilateral lymphadenectomy (including para-aortic nodes in grade 2 and 3 tumors). RESULTS: At least one SLN was detected in 92% of patients; in 66 of these (72%) bilateral SLN were detected, and in 15 cases the SLN was in the para-aortic area. Eleven percent of all patients had lymph node metastases, and 4 of which had pre-operative grade 1 tumor. The SLN was the only positive node in 44% of the cases with positive nodes. Sensitivity was 89% with 1 false negative result, yielding a negative predictive value of 99% (95% CI 93-100). Specificity was 100% (95% CI 94-100), and positive predictive value was 100% (95% CI 60-100). No complications or anaphylactic reactions were noted. CONCLUSIONS: Intra-operative SLN biopsy, using cervical injection of patent blue and filtered 99mTc-SC in endometrial cancer patients is feasible and yields adequate detection rates.

Microparticles from ovarian carcinomas are shed into ascites and promote cell migration.

OBJECTIVE: Microparticles are cellular-derived vesicles (0.5-1.0 µm) composed of cell membrane components, which are actively shed from the surface of various cells, including epithelial cells. We compared microparticles in ascites between women with ovarian carcinoma and women with benign ovarian pathology, and isolated tumor-derived (epithelial cell adhesion molecule [EpCAM]-positive) microparticles for functional analysis and proteomics. MATERIALS AND METHODS: Cases included 8 patients with benign ovarian neoplasms and 41 with ovarian carcinoma. Ascites from a high-grade stage III serous carcinoma was used for functional and proteomic analysis. Cancer cells were isolated using EpCAM-coated beads, microparticles were isolated by ultracentrifugation/flow cytometry, and sorting was achieved using markers (eg, EpCAM). Binding and migrations assays were performed with 3 ovarian cancer cell lines. Proteomic analysis of EpCAM-positive microparticles and ascites cancer cells was performed by mass spectrometry. RESULTS: Microparticles in benign pelvic fluid were similar to early and advanced-stage ascites (2.4 vs 2.8 vs 2.0 × 106 microparticles/mL). Advanced stage had a greater proportion of EpCAM-positive microparticles than early or benign disease (13.3% vs 2.5% vs 2.1%; P = 0.001), and serous histology had more than endometrioid (13.2% vs 1.8%; P = 0.01). Microparticles bound to the surface of 3 cultured cell lines, and were internalized into the EpCAM-positive microparticles, resulting in more cell migration than buffer alone or EpCAM-negative microparticles (P = 0.007). A dose-dependent increase was seen with increasing numbers of EpCAM-positive microparticles. Proteomics revealed that most proteins in EPCAM-positive microparticles were shared with cancer cells, and many are associated with cell motility and invasion, such as fibronectin, filamin A, vimentin, myosin-9, and fibrinogen. CONCLUSIONS: Ascites from advanced-stage and serous ovarian carcinomas contain large numbers of tumor-derived microparticles. In vitro, these microparticles bind to cancer cells and stimulate migration. Tumor-derived microparticles in ascites could mediate the predilection for peritoneal spread in serous ovarian carcinomas.

Safety and antitumor activity of dostarlimab in patients with advanced or recurrent DNA mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H) or proficient/stable (MMRp/MSS) endometrial cancer: interim results from GARNET-a phase I, single-arm study.

BACKGROUND: Dostarlimab is a humanized monoclonal antibody that binds with high affinity to PD-1, resulting in inhibition of binding to PD-L1 and PD-L2. We report interim data from patients with endometrial cancer (EC) participating in a phase I trial of single-agent dostarlimab. METHODS: GARNET, an ongoing, single-arm, open-label, phase I trial of intravenous dostarlimab in advanced solid tumors, is being undertaken at 123 sites. Two cohorts of patients with EC were recruited: those with dMMR/MSI-H disease (cohort A1) and those with proficient/stable (MMRp/MSS) disease (cohort A2). Patients received dostarlimab 500 mg every 3 weeks for 4 cycles, then dostarlimab 1000 mg every 6 weeks until disease progression. The primary endpoints were objective response rate (ORR) and duration of response (DOR) per RECIST V.1.1, as assessed by blinded independent central review. RESULTS: Screening began on April 10, 2017, and 129 and 161 patients with advanced EC were enrolled in cohorts A1 and A2, respectively. The median follow-up duration was 16.3 months (IQR 9.5-22.1) for cohort A1 and 11.5 months (IQR 11.0-25.1) for cohort A2. In cohort A1, ORR was 43.5% (95% CI 34.0% to 53.4%) with 11 complete responses and 36 partial responses. In cohort A2, ORR was 14.1% (95% CI 9.1% to 20.6%) with three complete responses and 19 partial responses. Median DOR was not reached in either cohort. In the combined cohorts, the majority of treatment-related adverse events (TRAEs) were grade 1-2 (75.5%), most commonly fatigue (17.6%), diarrhea (13.8%), and nausea (13.8%). Grade≥3 TRAEs occurred in 16.6% of patients, and 5.5% discontinued dostarlimab because of TRAEs. No deaths were attributable to dostarlimab. CONCLUSION: Dostarlimab demonstrated durable antitumor activity in both dMMR/MSI-H (ORR 43.5%) and MMRp/MSS EC (ORR 14.1%) with a manageable safety profile. TRIAL REGISTRATION NUMBER: NCT02715284.

FOXP3+ regulatory T-cells are abundant in vulvar Paget's disease and are associated with recurrence.

OBJECTIVE: To characterize clinical features of vulvar Paget's disease, and examine the quantity of immunosuppressive regulatory T-cells in vulvar Paget's tissue. METHODS: Vulvar Paget's cases from 1992 to 2007 from two institutions were identified by pathology database search. Regulatory T-cells were identified with FOXP3 immunohistochemistry and quantified at the dermal-epidermal junction using image analysis software. Thirteen non-neoplastic inflammatory cases were stained for comparison. RESULTS: Cases included 33 women treated for primary vulvar Paget's, and 7 referred at recurrence. Of the 24 primary cases with greater than 5 months follow-up, recurrence was documented in 12/24(50%). Eight women (20%) recurred multiple times, but no recurrences were invasive. Significantly more patients with positive margins developed recurrent disease (82% vs 23%, p=0.01). Secondary neoplasms occurred in 10/40(25%). FOXP3+ cells at the dermal-epidermal junction were quantified in 29 primary and 13 recurrent tissue samples. FOXP3+ cells were absent in surrounding normal vulvar skin. FOXP3+ cells averaged 66/HPF in primary vulvar Paget's and 66/HPF in recurrent Paget's, compared to 22/HPF in non-neoplastic inflammatory cases (p=0.0003, p=0.001). Primary cases with positive surgical margins had more FOXP3+ cells than those with negative margins (85 vs 49, p=0.01). Recurrent cases with positive margins had more FOXP3+ cells than negative cases (84 vs 33, p=0.06). FOXP3 levels in primary specimens were higher in cases which recurred (78 vs 35, p=0.02). CONCLUSIONS: Increased regulatory T-cells may be associated with more extensive cases of vulvar Paget's disease that result in positive surgical margins and are associated with recurrence of disease, suggesting immunosuppression as a key factor.

Familial small cell carcinoma of the ovary.

Ovarian tumors have a low incidence in childhood, accounting for 1% of malignancies within the ages of 0-17 years. Small cell carcinoma of the ovary is a rare histology and historically has a poor prognosis. We report a case of an 11-year-old female diagnosed with small cell carcinoma of the ovary and hypercalcemia (SCCOHT). There was a strong family history of the disease, a reduction in the age of onset in the proband, and the absence of BRCA mutations. This case suggests the phenomenon of genetic anticipation in an ovarian cancer.

Ovarian carcinomas with genetic and epigenetic BRCA1 loss have distinct molecular abnormalities.

BACKGROUND: Subclassification of ovarian carcinomas can be used to guide treatment and determine prognosis. Germline and somatic mutations, loss of heterozygosity (LOH), and epigenetic events such as promoter hypermethylation can lead to decreased expression of BRCA1/2 in ovarian cancers. The mechanism of BRCA1/2 loss is a potential method of subclassifying high grade serous carcinomas. METHODS: A consecutive series of 49 ovarian cancers was assessed for mutations status of BRCA1 and BRCA2, LOH at the BRCA1 and BRCA2 loci, methylation of the BRCA1 promoter, BRCA1, BRCA2, PTEN, and PIK3CA transcript levels, PIK3CA gene copy number, and BRCA1, p21, p53, and WT-1 immunohistochemistry. RESULTS: Eighteen (37%) of the ovarian carcinomas had germline or somatic BRCA1 mutations, or epigenetic loss of BRCA1. All of these tumours were high-grade serous or undifferentiated type. None of the endometrioid (n = 5), clear cell (n = 4), or low grade serous (n = 2) carcinomas showed loss of BRCA1, whereas 47% of the 38 high-grade serous or undifferentiated carcinomas had loss of BRCA1. It was possible to distinguish high grade serous carcinomas with BRCA1 mutations from those with epigenetic BRCA1 loss: tumours with BRCA1 mutations typically had decreased PTEN mRNA levels while those with epigenetic loss of BRCA1 had copy number gain of PIK3CA. Overexpression of p53 with loss of p21 expression occurred significantly more frequently in high grade serous carcinomas with epigenetic loss of BRCA1, compared to high grade serous tumors without loss of BRCA1. CONCLUSION: High grade serous carcinomas can be subclassified into three groups: BRCA1 loss (genetic), BRCA1 loss (epigenetic), and no BRCA1 loss. Tumors in these groups show distinct molecular alterations involving the PI3K/AKT and p53 pathways.

Xenografts of primary human gynecological tumors grown under the renal capsule of NOD/SCID mice show genetic stability during serial transplantation and respond to cytotoxic chemotherapy.

OBJECTIVES: Human cancer tissue xenograft models may provide a more accurate reflection of tumor biology than cell lines. This study evaluates the genetic and phenotypic stability of primary human gynecological tumors grown as serially transplanted xenografts. The response to conventional chemotherapy and novel molecular targeted chemotherapy is assessed in one of the transplantable xenograft lines. METHODS: Fresh tumor was transplanted beneath the renal capsule of NOD/SCID mice. Transplantable tumor lines were derived from 5 tumors (4 ovarian carcinomas and 1 uterine sarcoma), and serially transplanted for 2-6 generations. Comparisons were made between primary tumor and corresponding transplantable xenografts by CGH array, immunohistochemistry, and BRCA mutation analysis. Transplantable xenografts created from known BRCA1 germline mutation carriers were analyzed for histopathologic response (tumor volume, apoptotic and mitotic indices) to combination carboplatin/paclitaxel and to PARP inhibitor (PJ34). RESULTS: Unsupervised hierarchical cluster analysis applied to a 287 feature CGH array demonstrated a low degree of intratumoral genetic variation in 4/5 cases, with greater degree of variation in the fifth case (clear cell ovarian carcinoma derived from an omental sample). Assessment of proliferation using MIB-1 staining was concordant between primary tumor and transplantable xenograft in all ovarian cancer cases. BRCA mutation analysis identified germline BRCA1 mutation for further testing and this xenograft showed a significant response to carboplatin/paclitaxel chemotherapy, including a decrease in tumor volume and proliferation but did not demonstrate a response to the poly (ADP-ribose) polymerase-1 inhibitor PJ34. CONCLUSIONS: Xenografts derived from gynecologic tumors can be serially transplanted and grown under renal capsule of NOD/SCID mice with minimal genetic change. This model may be used to study progression of tumors, identify therapeutic targets, and test treatment modalities in tumors with well-characterized abnormalities in genes of fundamental importance in ovarian carcinogenesis, such as loss of BRCA1.

Advancing surgical simulation in gynecologic oncology: robotic dissection of a novel pelvic lymphadenectomy model.

INTRODUCTION: Pelvic lymphadenectomy is a key component of the surgical treatment of several gynecologic cancers and involves mastery of complex anatomic relationships. Our aim was to demonstrate that the anatomy relevant to robotic pelvic lymphadenectomy can be modeled using low-cost techniques, thereby enabling simulation focused on surgical dissection, a task that integrates technical skills and anatomic knowledge. METHODS: A model of pelvic lymphadenectomy was constructed through experimentation with several different materials and a number of prototypes. In the final version, blood vessels were simulated by rubber tubing stented with wire and lymph nodes by cotton balls. Adipose and areolar tissue were simulated by a gelatin solution poured into the model and then allowed to cool and semisolidify. Three gynecologic oncologists and 2 gynecologic oncology fellows dissected the model using the surgical robot (da Vinci Surgical System) and completed a structured questionnaire. Five additional gynecologic oncologists assessed the model at a national conference. RESULTS: The model received high ratings for face and content validity. Median ratings were almost all 4 of 5 or higher (range, 3-5). Participants who dissected the model (n = 5) unanimously rated it as "useful for training throughout residency and fellowship." CONCLUSIONS: A novel low-cost inanimate model of pelvic lymphadenectomy has been developed and rated highly for face and content validity. This model may permit more regular simulation sessions compared with alternatives such as cadaveric dissection and animal laboratories, thereby complementing them and facilitating distributed practice.

Virtual reality robotic surgery simulation curriculum to teach robotic suturing: a randomized controlled trial.

The objective of this randomized, controlled trial was to assess whether voluntary participation in a proctored, proficiency-based, virtual reality robotic suturing curriculum using the da Vinci(®) Skills Simulator™ improves robotic suturing performance. Residents and attending surgeons were randomized to participation or non-participation during a 5 week training curriculum. Robotic suturing skills were evaluated before and after training using an inanimate vaginal cuff model, which participants sutured for 10 min using the da Vinci(®) Surgical System. Performances were videotaped, anonymized, and subsequently graded independently by three robotic surgeons. 27 participants were randomized. 23 of the 27 completed both the pre- and post-test, 13 in the training group and 10 in the control group. Mean training time in the intervention group was 238 ± 136 min (SD) over the 5 weeks. The primary outcome (improvement in GOALS+ score) and the secondary outcomes (improvement in GEARS, total knots, satisfactory knots, and the virtual reality suture sponge 1 task) were significantly greater in the training group than the control group in unadjusted analysis. After adjusting for lower baseline scores in the training group, improvement in the suture sponge 1 task remained significantly greater in the training group and a trend was demonstrated to greater improvement in the training group for the GOALS+ score, GEARS score, total knots, and satisfactory knots.

Virtual reality surgical simulators- a prerequisite for robotic surgery.

The field of computer assisted minimally invasive surgery is rapidly expanding worldwide, including in India. With more hospitals in India contemplating the acquisition of a robotic platform, training of robotic surgeons is becoming essential. Virtual reality simulators can be used for surgeons to become acquainted with the robotic console prior to live surgery. Our aim was to evaluate the amount of simulator training required before a surgeon first operates on the da Vinci® Surgical System. Simulations were conducted on the Intuitive Surgical's da Vinci® Robot Skill Simulator using the software obtained from Mimic Technologies. Participants included attending staff surgeons experienced in robotic surgery and novices. A set of seven activities were chosen for each participant. Based on the mean exercise score from the first attempt, staff surgeons outperformed the novices in all exercises. However, the difference in score between the staff and the novices decreased after the participants repeated the exercises and by the sixth attempt most of the novices obtained similar scores to the staff, suggesting that this might be at present the minimum set of repetitions indicated (or required) prior to performing life robotic surgery.

Controversies in the treatment of early stage endometrial carcinoma.

Despite the publication of numerous studies, including some multicentered randomized controlled trials, there continues to be vigorous debate regarding the optimal management of early stage endometrial cancer, including the extent of surgery and the role of adjuvant chemotherapy and radiation. Resolving these questions has become increasingly important in view of the increase of endometrial cancer, related to the aging population and the alarming incidence of obesity. Furthermore, there are more surgical challenges encountered when operating on elderly patients or on patients with increased BMI and the associated comorbidities, such as diabetes, hypertension, heart disease, and pulmonary dysfunction. This paper will focus on the advantages of minimally invasive surgery, the value of lymphadenectomy including sentinel lymph node mapping, and some of the current controversies surrounding adjuvant chemotherapy and radiation.

Identification of a preneoplastic gene expression profile in tubal epithelium of BRCA1 mutation carriers.

Microinvasive carcinomas and high-grade intraepithelial neoplasms are commonly discovered within the fallopian tube of BRCA1 mutation carriers at the time of risk-reducing salpingo-oophorectomy, suggesting that many BRCA1-mutated ovarian carcinomas originate in tubal epithelium. We hypothesized that changes in gene expression profiles within the histologically normal fallopian tube epithelium of BRCA1 mutation carriers would overlap with the expression profiles in BRCA1-mutated ovarian carcinomas and represent a BRCA1 preneoplastic signature. Laser capture microdissection of frozen sections was used to isolate neoplastic cells or histologically normal fallopian tube epithelium, and expression profiles were generated on Affymetrix U133 Plus 2.0 gene expression arrays. Normal-risk controls were 11 women wild type for BRCA1 and BRCA2 (WT-FT). WT-FT were compared with histologically normal fallopian tube epithelium from seven women with deleterious BRCA1 mutations who had foci of at least intraepithelial neoplasm within their fallopian tube (B1-FTocc). WT-FT samples were also compared with 12 BRCA1 ovarian carcinomas (B1-CA). The comparison of WT-FT versus B1-FTocc resulted in 152 differentially expressed probe sets, and the comparison of WT-FT versus B1-CA resulted in 4079 differentially expressed probe sets. The BRCA1 preneoplastic signature was composed of the overlap between these two lists, which included 41 concordant probe sets. Genes in the BRCA1 preneoplastic signature included several known tumor suppressor genes such as CDKN1C and EFEMP1 and several thought to be important in invasion and metastasis such as E2F3. The expression of a subset of genes was validated with quantitative reverse transcription-polymerase chain reaction and immunohistochemistry.