Integrated mutational landscape analysis of poorly differentiated high-grade neuroendocrine carcinoma of the uterine cervix.

High-grade neuroendocrine cervical cancers (NETc) are exceedingly rare, highly aggressive tumors. We analyzed 64 NETc tumor samples by whole-exome sequencing (WES). Human papillomavirus DNA was detected in 65.6% (42/64) of the tumors. Recurrent mutations were identified in PIK3CA, KMT2D/MLL2, K-RAS, ARID1A, NOTCH2, and RPL10. The top mutated genes included RB1, ARID1A, PTEN, KMT2D/MLL2, and WDFY3, a gene not yet implicated in NETc. Somatic CNV analysis identified two copy number gains (3q27.1 and 19q13.12) and five copy number losses (1p36.21/5q31.3/6p22.2/9q21.11/11p15.5). Also, gene fusions affecting the ACLY-CRHR1 and PVT1-MYC genes were identified in one of the eight samples subjected to RNA sequencing. To resolve evolutionary history, multiregion WES in NETc admixed with adenocarcinoma cells was performed (i.e., mixed-NETc). Phylogenetic analysis of mixed-NETc demonstrated that adenocarcinoma and neuroendocrine elements derive from a common precursor with mutations typical of adenocarcinomas. Over one-third (22/64) of NETc demonstrated a mutator phenotype of C > T at CpG consistent with deficiencies in MBD4, a member of the base excision repair (BER) pathway. Mutations in the PI3K/AMPK pathways were identified in 49/64 samples. We used two patient-derived-xenografts (PDX) (i.e., NET19 and NET21) to evaluate the activity of pan-HER (afatinib), PIK3CA (copanlisib), and ATR (elimusertib) inhibitors, alone and in combination. PDXs harboring alterations in the ERBB2/PI3K/AKT/mTOR/ATR pathway were sensitive to afatinib, copanlisib, and elimusertib (P < 0.001 vs. controls). However, combinations of copanlisib/afatinib and copanlisib/elimusertib were significantly more effective in controlling NETc tumor growth. These findings define the genetic landscape of NETc and suggest that a large subset of these highly lethal malignancies might benefit from existing targeted therapies.

Robotic-assisted versus conventional laparoscopic surgery in the management of obese patients with early endometrial cancer in the sentinel lymph node era: a randomized controlled study (RObese).

BACKGROUND: Nearly 65% of patients with endometrial cancer who undergo primary hysterectomy have concurrent obesity. Retrospective data show advantages in using robotic surgery in these patients compared with conventional laparoscopy, namely lower conversion rate, increased rate of same-day discharge, and reduced blood loss. Nevertheless, to date no prospective randomized controlled trials have compared laparoscopic surgery versus robotic-assisted surgery in morbidly obese patients. PRIMARY OBJECTIVE: The robotic-assisted versus conventional laparoscopic surgery in the management of obese patients with early endometrial cancer in the sentinel lymph node era: a randomized controlled study (RObese) trial aims to find the most appropriate minimally invasive surgical approach in morbidly obese patients with endometrial carcinoma. STUDY HYPOTHESIS: Robotic surgery will reduce conversions to laparotomy in endometrial cancer patients with obesity compared with those who undergo surgery with conventional laparoscopy. TRIAL DESIGN: This phase III multi-institutional study will randomize consecutive obese women with apparent early-stage endometrial cancer to either laparoscopic or robot-assisted surgery. MAJOR INCLUSION/EXCLUSION RITERIA: The RObese trial will include obese (BMI≥30 kg/m2) patients aged over 18 years with apparent 2009 Federation of Gynecology and Obstetrics (FIGO) stage IA-IB endometriod endometrial cancer. PRIMARY ENDPOINT: Conversion rate to laparotomy between laparoscopic surgery versus robot-assisted surgery. SAMPLE SIZE: RObese is a superiority trial. The clinical superiority margin for this study is defined as a difference in conversion rate of -6%. Assuming a significance level of 0.05 and a power of 80%, the study plans to randomize 566 patients. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Patient recruitment will be completed by 2026, and follow-up will be completed by 2029 with presentation of data shortly thereafter. Two interim analyses are planned: one after the first 188 and the second after 376 randomized patients. TRIAL REGISTRATION: NCT05974995.

Concurrent endometrial cancer in atypical endometrial hyperplasia and the role of sentinel lymph nodes: clinical insights from a multicenter experience.

OBJECTIVE: This study aimed to evaluate the prevalence of concurrent endometrial cancer in patients pre-operatively diagnosed with atypical endometrial hyperplasia undergoing hysterectomy. Additionally, we assessed the occurrence of high to intermediate-risk and high-risk tumors according to the ESGO-ESTRO-ESP classification. The study also compared surgical outcomes and complications between patients undergoing simple hysterectomy and those undergoing hysterectomy with sentinel lymph node biopsy. METHODS: In this multicenter retrospective study, patients with a pre-operative diagnosis of atypical endometrial hyperplasia were identified and divided into two groups: Group 1, which included patients treated with total hysterectomy with or without bilateral salpingo-oophorectomy, and Group 2, where sentinel lymph node biopsy was incorporated into the standard surgical treatment. RESULTS: Among 460 patients with atypical endometrial hyperplasia, 192 received standard surgical management (Group 1) and 268 underwent sentinel lymph node biopsy (Group 2). A total of 47.2% (95% CI 42.6% to 51.7%) of patients were upgraded to endometrial cancer on final histopathological examination. High to intermediate-risk and high-risk tumors constituted 12.3% and 9.2% in Group 2 and 7.4% and 3.7% in Group 1. Lymph node metastases were identified in 7.6% of patients with concurrent endometrial cancer who underwent nodal assessment with at least unilateral mapping. Of the 12 sentinel lymph node metastases, 75.0% were micrometastases, 16.7% macrometastases, and 8.3% isolated tumor cells. No significant differences were found in estimated blood loss, operative time, and intra-operative and post-operative complications between the two groups. The rate of patients undergoing sentinel lymph node biopsy doubled every 2 years (OR 2.010, p<0.001), reaching 79.1% in the last 2 years. CONCLUSION: This study found a prevalence of concurrent endometrial cancer of 47.2%, and sentinel lymph node biopsy provided prognostic and therapeutic information in 60.8% of cases. It also allowed for the adjustment of adjuvant therapy in 12.3% of high to intermediate-risk patients without increasing operative time or complication rates.

Minimally invasive versus open pelvic exenteration in gynecological malignancies: a propensity-matched survival analysis.

OBJECTIVE: The primary endpoint of this study was to compare the disease-free survival of patients undergoing open versus minimally invasive pelvic exenteration. The secondary endpoints were cancer-specific survival and peri-operative morbidity. METHODS: A multi-center, retrospective, observational cohort study was undertaken. Patients undergoing curative and palliative anterior or total pelvic exenteration for gynecological cancer by a minimally invasive approach and an open approach between June 2010 and May 2021 were included. Patients with distant metastases were excluded. A 1:2 propensity match analysis between patients undergoing minimally invasive and open pelvic exenteration was performed to equalized baseline characteristics. RESULTS: After propensity match analysis a total of 117 patients were included, 78 (66.7%) and 39 (33.3%) in the open and minimally invasive group, respectively. No significant difference in intra-operative (23.4% vs 10.3%, p=0.13) and major post-operative complications (24.4% vs 17.9%, p=0.49) was evident between the open and minimally invasive approach. Patients undergoing open pelvic exenteration received higher rates of intra-operative transfusions (41.0% vs 17.9%, p=0.013). Median disease-free survival was 17.0 months for both the open and minimally invasive groups (p=0.63). Median cancer-specific survival was 30.0 months and 26.0 months in the open and minimally invasive groups, respectively (p=0.80). Positivity of surgical margins at final histology was the only significant factor influencing the risk of recurrence (hazard ratio (HR) 2.38, 95% CI 1.31 to 4.31) (p=0.004), while tumor diameter ≥50 mm at the time of pelvic exenteration was the only significant factor influencing the risk of death (HR 1.83, 95% CI 1.08 to 3.11) (p=0.025). CONCLUSION: In this retrospective study no survival difference was evident when minimally invasive pelvic exenteration was compared with open pelvic exenteration in patients with gynecological cancer. There was no difference in peri-operative complications, but a higher intra-operative transfusion rate was seen in the open group.

The immunohistochemical molecular risk classification in endometrial cancer: A pragmatic and high-reproducibility method.

INTRODUCTION: The aim of this study is to assess the clinical reproducibility and the potential oncological validity of the molecular information provided by the immunohistochemistry (IHC) to properly stratify the endometrial cancer patients. METHODS: Retrospective IHC analyses were conducted in a large series of 778 pre-operative uterine-confined ECs, studying the presence/absence of MLH1, MSH2, MSH6 and PMS2 to define the mismatch repair (MMR) stable or instable phenotype; the presence of p53 mutations and other molecular features. The molecular profile was correlated with histological, clinical and prognostic data. RESULTS: Based on IHC assessment, we defined 3 EC populations: stable MMR patients (MMRs), instable patients (MMRi) and p53 mutated patients (p53+). Our result demonstrated that the IHC stratification statistically correlated with the most relevant pathologic-clinical features: FIGO stage (p < 0.001), grading (p < 0.001), histotype (p < 0.001), presence of LVSI (p < 0.001), myometrial invasion and tumor dimension (p = 0.003 for both). These 3 IHC populations statistically reflected the EC risk class ESGO-ESMO-ESP classification 2021 (p < 0.001). These results were also confirmed in the Kaplan-Meier curves in terms of overall survival (OS) and disease-free survival (DFS) (p < 0.0001). The multivariate analyses demonstrated that absence of estrogen receptor (ER) impacted the OS (p = 0.011) and, the Age > 60 years and the ER-status the DFS (p = 0.041 and p = 0.004). CONCLUSION: In this large series, we demonstrated that the pragmatic and systematic use of IHC may have an important role to properly stratify, in terms of histological features and clinical outcomes, the EC patients.

Whole-exome sequencing of cervical carcinomas identifies activating ERBB2 and PIK3CA mutations as targets for combination therapy.

The prognosis of advanced/recurrent cervical cancer patients remains poor. We analyzed 54 fresh-frozen and 15 primary cervical cancer cell lines, along with matched-normal DNA, by whole-exome sequencing (WES), most of which harboring Human-Papillomavirus-type-16/18. We found recurrent somatic missense mutations in 22 genes (including PIK3CA, ERBB2, and GNAS) and a widespread APOBEC cytidine deaminase mutagenesis pattern (TCW motif) in both adenocarcinoma (ACC) and squamous cell carcinomas (SCCs). Somatic copy number variants (CNVs) identified 12 copy number gains and 40 losses, occurring more often than expected by chance, with the most frequent events in pathways similar to those found from analysis of single nucleotide variants (SNVs), including the ERBB2/PI3K/AKT/mTOR, apoptosis, chromatin remodeling, and cell cycle. To validate specific SNVs as targets, we took advantage of primary cervical tumor cell lines and xenografts to preclinically evaluate the activity of pan-HER (afatinib and neratinib) and PIK3CA (copanlisib) inhibitors, alone and in combination, against tumors harboring alterations in the ERBB2/PI3K/AKT/mTOR pathway (71%). Tumors harboring ERBB2 (5.8%) domain mutations were significantly more sensitive to single agents afatinib or neratinib when compared to wild-type tumors in preclinical in vitro and in vivo models (P = 0.001). In contrast, pan-HER and PIK3CA inhibitors demonstrated limited in vitro activity and were only transiently effective in controlling in vivo growth of PIK3CA-mutated cervical cancer xenografts. Importantly, combinations of copanlisib and neratinib were highly synergistic, inducing long-lasting regression of tumors harboring alterations in the ERBB2/PI3K/AKT/mTOR pathway. These findings define the genetic landscape of cervical cancer, suggesting that a large subset of cervical tumors might benefit from existing ERBB2/PIK3CA/AKT/mTOR-targeted drugs.

In vitro and in vivo activity of sacituzumab govitecan, an antibody-drug conjugate targeting trophoblast cell-surface antigen 2 (Trop-2) in uterine serous carcinoma.

OBJECTIVE: Uterine serous carcinoma (USC) is an aggressive variant of endometrial cancer with poor prognosis. Sacituzumab govitecan (SG) is a novel antibody-drug-conjugate (ADC) targeting trophoblast cell-surface antigen 2 (Trop-2), a transmembrane-calcium-signal-transducer, to deliver SN-38, the active metabolite of irinotecan. The objective of this study was to evaluate the expression of Trop-2 in USC and the preclinical activity of SG against primary USC cell-lines and xenografts. METHODS: We used immunohistochemistry (IHC) and flow-cytometry-based assays to evaluate Trop-2 expression and cell-viability in USC tissue and primary tumor-cell-lines after exposure to SG, non-targeting control ADC, and naked antibody hRS7-IgG. Antibody-dependent-cell-cytotoxicity (ADCC) against Trop-2+ and Trop-2- USC cell-lines was evaluated in vitro using 4-hr-Chromium-release-assays. In vivo activity of SG was tested against Trop-2+ USC xenografts by intravenous administration of SG, control ADC, and hRS7. RESULTS: Trop-2 expression by IHC was detected in 95.1% of USC samples (99/104). Primary tumor cell-lines overexpressing Trop-2 were significantly more sensitive to SG when compared to control ADC (p <0.05). Both SG and hRS7 mediated ADCC in Trop2+ USC cell-lines while no cytotoxicity was detected against Trop-2- cells. SG induced significant bystander killing of Trop-2- tumors when admixed with Trop-2+ tumors. SG caused growth-inhibition and increased survival in SG treated mice harboring Trop-2+ xenografts when compared to controls (p <0.05). CONCLUSIONS: SG is remarkably active against USC overexpressing Trop-2 in vitro and in vivo. Our results combined with SG clinical responses recently reported against multiple chemotherapy resistant human tumors further support clinical development of SG in USC patients with advanced/recurrent disease.

Sexual Function following Laparoscopic versus Transvaginal Closure of the Vaginal Vault after Laparoscopic Hysterectomy: Secondary Analysis of a Randomized Trial by the Italian Society of Gynecological Endoscopy Using a Validated Questionnaire.

STUDY OBJECTIVE: The effect of the different types of vaginal cuff closures on posthysterectomy sexual function has not been investigated in depth. We evaluated if there is a difference between transvaginal versus a laparoscopic closure after total laparoscopic hysterectomy (TLH) on female sexual function, using a validated questionnaire. DESIGN: Secondary analysis of a prospective randomized controlled trial. SETTING: Three academic research centers. PATIENTS: Women consenting to telephone interviews on their sexual life before and after undergoing TLH were included. INTERVENTIONS: Patients were randomly assigned to a laparoscopic or transvaginal approach for vaginal cuff closure at the end of TLH for benign indications. MEASUREMENTS AND MAIN RESULTS: A validated questionnaire (the Female Sexual Function Index [FSFI]) was used to explore sexuality before and after the operation. Of the 1408 patients enrolled in the primary study, 400 patients were asked to complete the questionnaire. Of them, 182 (41.4%) were eligible and accepted enrollment in the present analysis. No difference was found in terms of pre- and postoperative FSFI scores between groups. Patients with a low preoperative FSFI score (<26.55) had a significantly higher likelihood of having a postoperative sexual disorder (p <.001). Women who received bilateral adnexectomy before menopause and those with postoperative vaginal cuff hematoma had a significantly lower postoperative FSFI score (p = .001 and p = .04, respectively). After multivariable analysis, both variables maintained at least a tendency toward an association with a lower postoperative FSFI score (odds ratio, 2.696; 95% confidence interval, 1.010-7.194; p = 0.048 and p = 0.053; odds ratio, 13.2; 95% confidence interval, .966-180.5, respectively). CONCLUSION: Transvaginal and laparoscopic cuff closures after TLH have similar sexual postoperative outcomes. A patient with sexual problems before TLH is more likely to have a low FSFI score postoperatively. Premenopausal patients undergoing bilateral ovariectomy and those with postoperative vaginal cuff hematoma have a worse postoperative sexual life. (Clinicaltrials.gov, protocol number NCT02453165, registration date May 25, 2015.).

Percutaneous-Assisted versus Laparoscopic Hysterectomy: A Prospective Comparison.

OBJECTIVE: To evaluate the feasibility of percutaneous approach, we prospectively compared our experience in percutaneous-assisted hysterectomy (PSS-H) with that in a series of laparoscopic hysterectomies (LPS-Hs). METHODS: In this multicentric cohort study, from May 2015 to October 2017, 160 patients affected by benign and malignant gynecological conditions were considered eligible for minimally invasive surgery (MIS): 80 patients received PSS-H and 80 LPS-H. In each group, 30 cases of low-/intermediate-risk endometrial cancer were enrolled. For both groups, we documented preoperative outcomes, postoperative pain, and cosmetic outcomes. RESULTS: No statistically significant differences were noted in baseline characteristics or operative time. We observed significant differences in estimated blood loss: median of 50 cc (PSS-H) and 100 cc (LPS-H) (p = 0.0001). In LPS-H, we reported 4 (5.0%) intraoperative complications and 1 (1.3%) in PSS-H. Thirty-day complications were 4 (5%) in PSS-H and 11 (13.8%) in LPS-H (p = 0.058). No significative differences were found in visual analog scale score, despite a relevant disparity in cosmetic outcome (p = 0.0001). For oncological cases, the 2 techniques had comparable intra- and postoperative outcomes and oncological accuracy. CONCLUSIONS: In this study, we reported that PSS-H is comparable to LPS-H for intra- and perioperative outcomes and postoperative pain, while PSS-H seems to be superior in cosmetic outcomes and patient satisfaction. PSS-H may represent a valid alternative in ultra-MIS for benign gynecological conditions and low-/intermediate-risk endometrial cancer.

PARP-1 activity (PAR) determines the sensitivity of cervical cancer to olaparib.

OBJECTIVES: Cervical cancer (CC) remains a major health problem worldwide. Poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors (PARPi) have emerged as a promising class of chemotherapeutics in ovarian cancer. We explored the preclinical in vitro and in vivo activity of olaparib against multiple primary whole exome sequenced (WES) CC cells lines and xenografts. METHODS: Olaparib cell-cycle, apoptosis, homologous-recombination-deficiency (HRD), PARP trapping and cytotoxicity activity was evaluated against 9 primary CC cell lines in vitro. PARP and PAR expression were analyzed by Western blot assays. Finally, olaparib in vivo antitumor activity was tested against CC xenografts. RESULTS: While none of the cell lines demonstrated HRD, three out of 9 (33.3%) primary CC cell lines showed strong PARylation activity and demonstrated high sensitivity to olaparib in vitro treatment (cutoff IC50 values < 2 µM, p = 0.0012). Olaparib suppressed CC cell growth through cell cycle arrest in the G2/M phase and caused apoptosis (p < 0.0001). Olaparib activity in CC involved both PARP enzyme inhibition and trapping. In vivo, olaparib significantly impaired CC xenografts tumor growth (p = 0.0017) and increased overall animal survival (p = 0.008). CONCLUSIONS: A subset of CC primary cell lines is highly responsive to olaparib treatment in vitro and in vivo. High level of PARylation correlated with olaparib preclinical activity and may represent a useful biomarker for the identification of CC patients benefitting the most from PARPi.

PI3K oncogenic mutations mediate resistance to afatinib in HER2/neu overexpressing gynecological cancers.

OBJECTIVE: Aberrant expression of HER2/neu and PIK3CA gene products secondary to amplification/mutations are common in high-grade-serous-endometrial (USC) and ovarian-cancers (HGSOC). Because scant information is currently available in the literature on the potential negative effect of PIK3CA mutations on the activity of afatinib, in this study we evaluate for the first time the role of oncogenic PIK3CA mutations as a potential mechanism of resistance to afatinib in HGSOC and USC overexpressing HER2/neu. METHODS: We used six whole-exome-sequenced primary HGSOC/USC cell-lines and three xenografts overexpressing HER2/neu and harboring mutated or wild-type PIK3CA/PIK3R1 genes to evaluate the role of PI3K-mutations as potential mechanism of resistance to afatinib, an FDA-approved pan-c-erb-inhibitor in clinical trials in USC. Primary-USC harboring wild-type-PIK3CA gene was transfected with plasmids encoding oncogenic PIK3CA-mutations (H1047R/E545K). The effect of afatinib on HER2/PI3K/AKT/mTOR pathway was evaluated by immunoblotting. RESULTS: We found PI3K wild-type cell-lines to be significantly more sensitive (lower IC50) than PI3K-mutated cell-lines p = 0.004). In vivo, xenografts of primary cell-line USC-ARK2, transfected with the PIK3CA-H1047R or E545K hotspot-mutations, exhibited significantly more rapid tumor growth when treated with afatinib, compared to mice harboring ARK2-tumors transfected with wild-type-PIK3CA (p = 0.041 and 0.001, respectively). By western-blot, afatinib effectively reduced total and phospho-HER2 proteins in all cell-lines. However, H1047R/E545K-PIK3CA-transfected-ARK2-cells demonstrated a greater compensatory increase in phosphorylated-AKT proteins after afatinib exposure when compared to controls ARK2. CONCLUSIONS: Oncogenic PI3K mutations may represent a major mechanism of resistance to afatinib. Combinations of c-erb with PIK3CA, AKT or mTOR inhibitors may be necessary to more efficiently block the PIK3CA/AKT/mTOR pathway.

Inguino-abdominal combined approach for laterally extended pelvic resection: a step by step procedure.

This video article demonstrates an inguino-abdominal combined approach for laterally extended pelvic resection, a major surgical procedure for locally advanced primary or recurrent gynecological cancer infiltrating the pelvic sidewall, for which palliative therapy is the only alternative.1 After local institutional review board approval (protocol No CICOG 02/03/62), we made a step by step surgical video of an inguino-abdominal combined approach for laterally extended pelvic resection , defined as an en bloc resection of a pelvic tumor with pelvic sidewall structures, including the iliopsoas and/or obturator internus muscles.2 3 The patient, a 48-year-old woman, diagnosed with single pelvic platinum resistant recurrence after five lines of chemotherapy for serous ovarian cancer G3, International Federation of Gynecology and Obstetrics (FIGO) stage IIIC, BRCA wild type. The preoperative positron emission tomography/computed tomography scan detected uptake on the right side at the level of the external iliac region and obturator fossa: the tumor surrounded the right external iliac vessels by more than 50% of their circumferences, with possible involvement of the vascular wall and venous vascular compression (Tinelli's score=4).4 The tumor extended towards the obturator fossa, with possible involvement of the inguinal canal. Due to an uncertain pathological response, the size of the recurrence, and its close contiguity with the ureter and bowel, we decided to avoid radiation therapy as it could result in a ureteral or intestinal fistula. We performed a laterally extended pelvic resection, as shown step by step in the video.The procedure was conducted until complete removal of recurrence (R0). Estimated blood loss was 1000 mL and total operative time was 240 min. The patient was discharged after 15 days; we reported a urinary infection, a likely postoperative complication. The pathology report described a lymphnodal relapse of ovarian cancer (diameter=6 cm) with infiltration of surrounding tissue and in the sano margins. Six months after surgery, the patient is alive without evidence of relapse.The borders of pelvic surgical anatomy are continually extending, requiring surgeons to use a personalized approach and to continually update their anatomic knowledge. In this context, laterally extended pelvic resection could be a feasible surgical procedure, representing a salvage treatment in recurrent or persistent primary gynecological malignancies infiltrating the pelvic sidewall, when other approaches have failed. However, additional clinical trials are needed to confirm these results.3.

Robotic video endoscopic inguinal lymphadenectomy (R-VEIL) for vulvar cancer with sentinel node mapping using indocyanine green and near-infrared fluorescence imaging technology.

Objectives: Video endoscopy inguinal lymphadenectomy (VEIL) has emerged as the new frontier for the surgical staging of vulvar cancer (VC) [1, 2]. In this surgical film we show a step-by-step video presentation of a Robotic SLNmapping using ICG (Canadian Task Force classification III). Although the therapeutic benefit of SLN remains controversial in clinical N0 (cN0) with VC N 4 cm [3], it provides prognostic information that can guide further adjuvant treatment. Robotic sentinel lymphnode (SLN) mapping using indocyanine green (ICG) appears to be a suitable and attractive alternative to provide reliable staging with respect to other tracers [3, 4]. Methods: A 75-year-old severely obesewoman (BMI:47.8 kg/m2) with squamous VC grading 3, clinical stage II (cT = 5 cm, cN0, cM0) and with a pre-operative PET-CT scan negative for metastatic localizations, was admitted for surgery. Surgical staging was performed including radical vulvectomy with macroscopic resection margins larger than 2 cm., SLN mapping with ICG followed by systematic inguinal lymphadenectomy. Da Vinci Xi System® was used to perform it. Results: The operation was performed successfully with no intraoperative or postoperative complication. Operative time was 310 min overall. Twenty-five inguinal lymph nodes were removed (11 on the left, 14 on the right). The pathology report came back positive for SLN removed. The patient was discharged on day #4 and 20 days later started adjuvant radiochemotherapy. Conclusions: SLN with ICG is robotically feasible. However, we notice that further prospective trials are needed to compare ICG with other colorimetric and/or radioactive tracers in this subset of patients.

Laparoscopic vs transvaginal cuff closure after total laparoscopic hysterectomy: a randomized trial by the Italian Society of Gynecologic Endoscopy.

BACKGROUND: Vaginal cuff dehiscence following hysterectomy is considered an infrequent but potentially devastating complication. Different possible techniques for cuff closure have been proposed to reduce this threatening adverse event. OBJECTIVE: The aim of the present randomized study was to compare laparoscopic and transvaginal suture of the vaginal vault at the end of a total laparoscopic hysterectomy, in terms of incidence of vaginal dehiscence and vaginal cuff complications. Factors associated with vaginal dehiscence were also analyzed. This article presents the results of the interim analysis of the trial. STUDY DESIGN: Patients undergoing total laparoscopic hysterectomy for benign indications were randomized at the time of colpotomy to receive vaginal closure through transvaginal vs laparoscopic approach using a 1:1 ratio. Allocation concealment was obtained using a password-protected randomization database. Monopolar energy for colpotomy was set at 60W. Vaginal closure was performed with a single-layer running braided and coated 0-polyglactin suture. In all cases an attempt was performed to include the posterior peritoneum in the suture. Laparoscopic knots were tied intracorporeally. All patients were scheduled for a postoperative follow-up visit 3 months after surgery, to detect possible vaginal cuff complications. Univariate and multivariable analyses were performed to identify independent predictors of vaginal cuff dehiscence after total laparoscopic hysterectomy. RESULTS: After enrollment of 1408 patients, a prespecified interim analysis was conducted. Thirteen (0.9%) women did not undergo the postoperative assessment and were excluded. Baseline characteristics of the 1395 patients included (695 in the transvaginal group and 700 in the laparoscopic group) were similar between groups. Patients in the transvaginal group had a significantly higher incidence of vaginal dehiscence (2.7% vs 1%; odds ratio, 2.78; 95% confidence interval, 1.16-6.63; P = .01) and of any cuff complication (9.8% vs 4.7%; odds ratio, 2.19; 95% confidence interval, 1.43-3.37; P = .0003). Based on these findings, the data monitoring committee recommended that the trial be terminated early. After multivariable analysis, transvaginal closure of the vault was independently associated with a higher incidence of vaginal dehiscence and any vaginal complication; premenopausal status and smoking habit were independently associated with a higher risk of dehiscence. CONCLUSION: Laparoscopic closure of the vaginal cuff at the end of total laparoscopic hysterectomy is associated with a significant reduction of vaginal dehiscence, any cuff complication, vaginal bleeding, vaginal cuff hematoma, postoperative infection, need for vaginal resuture, and reintervention.

Laparoscopic Pelvic Exenteration With Radical Vaginectomy Using 3-Dimensional Vision and Multifunction Instrument.

STUDY OBJECTIVE: The video article describes a laparoscopic anterior pelvic exenteration with radical vaginectomy using the 3-dimensional (3D) vision and multifunction instruments. METHODS: This is a step-by-step video presentation of the laparoscopic anterior pelvic exenteration (Canadian Task Force classification III). Although the therapeutic benefit of the PE remains controversial, it is often performed in women with centrally recurrent pelvic tumors that previously received radiation therapy or in the locally advanced cases (ie, stage IIb-IVa) resistant to radiochemotherapy. The patient was a 61-year-old woman (body mass index 31.8 kg/m) with locally advanced squamous cervical cancer involving the bladder (International Federation of Gynecology and Obstetrics stage IVa) submitted to chemoradiotherapy with no response and was admitted for surgery. The preoperative positron emission tomography/computed tomography scan was negative for metastatic localizations.The surgery was performed including radical hysterectomy, cystectomy, and colpectomy with macroscopic resection margins larger than 2 cm; a subsequent Bricker's ileal conduit was completed. An Endoeye Flex 3D Videoscope (Olympsus System) and Thunderbeat device were used to perform it. RESULTS: The operation was performed successfully with no intraoperative or postoperative complications. Total duration of surgery was 330 minutes. The estimated blood loss was 100 mL. The patient was discharged on day 8. The pathology report was positive for relapse of cervical cancer (tumor diameter = 4 cm) with infiltration of the vagina and the posterior bladder's muscle. CONCLUSIONS: Laparoscopic anterior pelvic exenteration with radical colpectomy using 3D vision and multifunction instrument is a fast and safe procedure. However, we notice that further prospective trials are needed to compare this technique with other open surgery and minimally invasive approach (ie, robotically).

Single-Institution Propensity-Matched Study to Evaluate the Psychological Effect of Minimally Invasive Interval Debulking Surgery Versus Standard Laparotomic Treatment: From Body to Mind and Back.

STUDY OBJECTIVE: To further investigate the psycho-oncologic effect of minimally invasive surgery comparing patients submitted to minimally invasive interval debulking surgery (MI-IDS) with a balanced population treated by standard laparotomy (L-IDS). DESIGN: Single-institution propensity-matched study (Canadian Task Force classification II-2). SETTING: Division of Gynecologic Oncology, "Policlinico A. Gemelli" Foundation, Rome, Italy. PATIENTS: The investigational arm included 30 patients with advanced ovarian cancer treated with MI-IDS, whereas the control arm included a consecutive series of 30 patients with advanced ovarian cancer submitted to L-IDS. For every patient preoperative data were collected to assess the response to neoadjuvant chemotherapy. Perioperative data were also recorded. INTERVENTIONS: A General Well-Being Schedule (GWBS) and a clinical assessment of body uneasiness, the Body Uneasiness Test, were administered by a psycho-oncologist immediately before IDS and within 30 days after surgery to evaluate the psychological burden in both groups. MEASUREMENT AND MAIN RESULTS: Both groups were matched as closely as possible. No statistical differences were registered in terms of surgical procedures and residual tumor. A significantly longer median operative time in patients was counterbalanced by more favorable estimated blood loss and median length of stay and time to chemotherapy. No statistically significant differences were registered in terms of postoperative complications. Starting from a substantially homogenous psychological condition, psychometric evaluation underlined statistically significant differences in favor of MI-IDS. The mean GWBS score was 64.17 ± 11.77 in patients and 54.15 ± 14.76 in control subjects, with a statistically significant difference between the 2 groups (p = .004). CONCLUSION: MI-IDS seems to play an important role in the quality of life and oncologic outcomes. Even if presented data testified a further evolutionary step in oncologic patient care, more experience with larger groups of patients is desirable to deeply investigate and assess our results.

Preoperative Serum Human Epididymis Protein 4 Levels in Early Stage Endometrial Cancer: A Prospective Study.

OBJECTIVE: The aim of the study was to evaluate the prognostic value of human epididymis protein 4 (HE4) and cancer antigen 125 markers with pathological prognostic factor to complete the preoperative clinical panel and help the treatment planning. METHODS: This prospective multicenter study was conducted in 2 gynecologic oncology centers between 2012 and 2014 (Institute for Maternal and Child Health IRCCS Burlo Garofolo in Trieste and Catholic University of the Sacred Heart in Rome, Italy). We enrolled 153 patients diagnosed with clinical early (International Federation of Gynecology and Obstetrics stages I-II) type I endometrial cancer. RESULTS: Human epididymis protein 4 levels seemed to be strictly related to age (P < 0.001) and menopausal status (P < 0.002). Compared with myometrial invasion (MI), the HE4 values were significantly higher in case of invasion of greater than 50% of the thickness: MI of greater than 50%, median of 94.85 pmol/L (38.3-820.8 pmol/L), versus MI of less than 50%, median of 65.65 pmol/L (25.1-360.2 pmol/L), (P < 0.001). The HE4 levels increase significantly with increasing tumor size: diameter of larger than 2 cm, median of 86.9 pmol/L (35.8-820.8 pmol/L), versus diameter of smaller than 2 cm, median of 52.2 pmol/L (33.3-146.8 pmol/L), (P < 0.001). In our population, HE4 did not correlate with the histological grade, endometrial cancer type I versus type II (P = 0.86), the lymphovascular infiltration (P = 0.12), and the cervical invasion (P = 0.6). We established a new variable, considering 3 high-risk tumor features: MI of greater than 50% and/or histological G3 and/or type II. Human epididymis protein 4 levels significantly increase in high-risk tumors (high risk HE4, 93.6 pmol/L vs low-medium risk, 65.5 pmol/L; P < 0.001). CONCLUSIONS: A preoperative HE4 evaluation could help stratify patients with deep invasion and/or metastatic disease and is correlated with other relevant prognostic factors to be considered to tailor an adequate surgical strategy.

Needleoscopic Conservative Staging of Borderline Ovarian Tumor.

STUDY OBJECTIVE: To investigate the safety and technical feasibility of needleoscopic fertility-sparing staging of borderline ovarian tumors. DESIGN: Video article and review of the literature (Canadian Task Force classification Level III). SETTING: This 29-year-old woman had a right ovarian cyst suspicious for borderline ovarian tumor on preoperative magnetic resonance imaging and ultrasound showing the presence of a right unilocular ovarian cyst with a papillary projection. Informed consent for abdominal or laparoscopic approach was obtained from the patient in accordance with the local legislation. The patient also provided informed consent to use images and videos of the procedure. Institutional Review Board approval was not required for this kind of procedure. INTERVENTIONS: Treatment involved conservative staging with right ovarian cystectomy, peritoneal biopsies, infracolic omental biopsy, and peritoneal cytology. Instrumentation included two 2.4-mm needleoscopic instruments. The total operative time was 62 minutes, and estimated blood loss was <10 mL. No intraoperative complications were recorded. At the end of the surgical procedure, the outer diameter of the incision was increased by only up to 3 mm. The patient was discharged the day after the procedure. Histopathological analysis confirmed a serous borderline ovarian tumor. A 30 days postoperative follow-up, a satisfactory cosmetic result was reported by both the patient (score of 10 of out of a possible 10) and the surgeon (10 of 10). CONCLUSION: To the best of our knowledge, there are no previously published reports of needleoscopic treatment of borderline ovarian tumor, which represents a great challenge for ultra-minimally invasive approaches [1-3]. Based on our initial experience, the needleoscopic instruments could prove to be a beneficial tool in adnexal benign or borderline disease. At present, only a hybrid operative setting should be considered to overcome the lack of bipolar energy [4-6]. Further studies are needed to define the benefits, advantages, and costs of this novel approach.

Total Laparoscopic (S-LPS) versus TELELAP ALF-X Robotic-Assisted Hysterectomy: A Case-Control Study.

STUDY OBJECTIVE: To compare the feasibility and safety of the TELELAP ALF-X system and standard laparoscopy for total hysterectomy to treat patients with benign and early malignant gynecologic disease. DESIGN: Single-institution retrospective case-control study (Canadian Task Force classification II-2). SETTING: Catholic University of the Sacred Heart, Rome, Italy. PATIENTS: Between October 2013 and May 2015, 203 women underwent TELELAP-ALF X (group 1) or standard laparoscopic (group 2) total hysterectomy and were enrolled. INTERVENTIONS: Total standard laparoscopy vs TELELAP ALF-X robot-assisted hysterectomy for benign and early malignant gynecologic disease. MEASUREMENTS AND MAIN RESULTS: In group 1, the median age was 55 years (range, 40-79 years), median body mass index (BMI) was 25 kg/m(2) (range, 17-38 kg/m(2)), and 51 patients (58%) had undergone previous abdominal surgery. In the control group, the median age was 55 years (range, 34-90 years), median BMI was 25 kg/m(2) (range, 17-41 kg/m(2)), and 31 patients (27%) had previous abdominal surgery. The median operative time was 147 minutes (range, 58-320 minutes) in group 1 and 80 minutes (range, 22-300 minutes) in group 2 (p = .055). The median estimated blood loss was 57 mL (range, 0-600 mL) in group 1 and 99 mL (range, 0-400 mL) in group 2, with no significant differences between the 2 groups (p = .963). Procedures were successfully performed without conversion in 94.3% of cases in the group 1 and in all cases in group 2. Early postoperative pain was significantly lower in group 2. CONCLUSION: TELELAP ALF-X hysterectomy in patients with benign and early malignant gynecologic disease is feasible and safe, and can be considered a valid option for these patients.

Lynch Syndrome and Gynecologic Tumors: Incidence, Prophylaxis, and Management of Patients with Cancer.

This review provides a comprehensive update on recent evidence regarding gynecologic tumors associated with Lynch Syndrome (LS). Endometrial cancer (EC) and ovarian cancer (OC) are the first and second most common gynecologic malignancies in developed countries, respectively, and LS is estimated to be the hereditary cause in 3% of both EC and OC. Despite the increasing evidence on LS-related tumors, few studies have analyzed the outcomes of LS-related EC and OC stratified by mutational variant. This review aims to provide a comprehensive overview of the literature and comparison between updated international guidelines, to help outline a shared pathway for the diagnosis, prevention, and management of LS. Through the widespread adoption of the immunohistochemistry-based Universal Screening, LS diagnosis and identification of mutational variants could be standardized and recognized by international guidelines as a feasible, reproducible, and cost-effective method. Furthermore, the development of a better understanding of LS and its mutational variants will support our ability to better tailor EC and OC management in terms of prophylactic surgery and systemic treatment in the light of the promising results shown by immunotherapy.