Gulden Menderes

Robotic Versus Abdominal Hysterectomy for Very Large Uteri

Robotic hysterectomy for very large uteri requires longer operative times but results in shorter hospital stays and decreased intraoperative blood loss.

Impact of body mass index on surgical outcomes and analysis of disease recurrence for patients with endometrial cancer undergoing robotic-assisted staging.

Objective This study aimed to evaluate the impact of body mass index (BMI) on the short- and long-term outcomes of patients with endometrial cancer who underwent robotic-assisted staging and to analyze disease recurrence and recurrence-free survival (RFS). Materials and Methods The charts of all consecutive patients with endometrial cancer who underwent robotic surgery from March 2007 to October 2012 were analyzed. Patients with follow-up less than 12 months after surgery were censored from the RFS analysis. Results Mean (SD) age for the 364 patients was 63.6 (10) years, and mean (SD) BMI was 34.8 (10.1) kg/m2. Conversions were in 3 (0.8%) of 364 cases. The mean (SD) operative time was 162.3 (54.6) minutes. Mean (SD) postoperative hospitalization was 1.6 (1.9) days. Histology included 80.5% endometrioid and 19.5% clear cell, serous, and carcinosarcomas. Mean (SD) pelvic and paraaortic lymph node counts were 15.9 (8.2) and 3.6 (4.3), respectively. Metastatic disease was diagnosed in 58 (16%) of 364 patients. The median follow-up was 29.3 months. The recurrence rates were 4.1% for the patients with endometrioid carcinoma and 14.1% for nonendometrioid histologies. Recurrences in patients with BMI less than 30 kg/m2 accounted for 68.2% of all recurrences (15/22 patients). The rest of recurrences (7/22 patients, 31.8%) were in obese patients. Moreover, when analyzed for each histologic subtype, recurrence rates were consistently higher for patients with BMI less than 30 kg/m2 when compared with patients with BMI greater than 30 kg/m2. The 3-year overall survival was 98.2%, and the 3-year RFS was 92%. Conclusions Obesity and morbid obesity did not affect adversely the operative outcomes for patients with endometrial cancer who were operated on using the robotic system. The recurrence rates were lower for patients with BMI greater than 30 kg/m2 compared with patients with BMI less than 30 kg/m2 for both endometrioid and nonendometrioid cancers.

Immunotherapy and targeted therapy for cervical cancer: an update.

The prognosis of patients with metastatic cervical cancer is poor with a median survival of 8–13 months. Despite the potency of chemotherapeutic drugs, this treatment is rarely curative and should be considered palliative only. In the last few years, a better understanding of Human papillomavirus tumor-host immune system interactions and the development of new therapeutics targeting immune check points have renewed interest in the use of immunotherapy in cervical cancer patients. Moreover, next generation sequencing has emerged as an attractive option for the identification of actionable driver mutations and other markers. In this review, we provide background information on the molecular biology of cervical cancer and summarize immunotherapy studies, targeted therapies, including those with angiogenesis inhibitors and tyrosine kinase inhibitors recently completed or currently on-going in cervical cancer patients.

Dual-Targeting Nanoparticles for In Vivo Delivery of Suicide Genes to Chemotherapy-Resistant Ovarian Cancer Cells

Ovarian cancer is the most lethal gynecologic cancer. Claudin-3 and -4, the receptors for Clostridium perfringens enterotoxin (CPE), are overexpressed in more than 70% of these tumors. Here, we synthesized and characterized poly(lactic-co-glycolic-acid) (PLGA) nanoparticles (NPs) modified with the carboxy-terminal–binding domain of CPE (c-CPE-NP) for the delivery of suicide gene therapy to chemotherapy-resistant ovarian cancer cells. As a therapeutic payload, we generated a plasmid encoding for the diphtheria toxin subunit-A (DT-A) under the transcriptional control of the p16 promoter, a gene highly differentially expressed in ovarian cancer cells. Flow cytometry and immunofluorescence demonstrated that c-CPE-NPs encapsulating the cytomegalovirus (CMV) GFP plasmid (CMV GFP c-CPE-NP) were significantly more efficient than control NPs modified with a scrambled peptide (CMV GFP scr-NP) in transfecting primary chemotherapy-resistant ovarian tumor cell lines in vitro (P = 0.03). Importantly, c-CPE-NPs encapsulating the p16 DT-A vector (p16 DT-A c-CPE-NP) were significantly more effective than control p16 DT-A scr-NP in inducing ovarian cancer cell death in vitro (% cytotoxicity: mean ± SD = 32.9 ± 0.15 and 7.45 ± 7.93, respectively, P = 0.03). In vivo biodistribution studies demonstrated efficient transfection of tumor cells within 12 hours after intraperitoneal injection of CMV GFP c-CPE-NP in mice harboring chemotherapy-resistant ovarian cancer xenografts. Finally, multiple intraperitoneal injections of p16 DT-A c-CPE-NP resulted in a significant inhibition of tumor growth compared with control NP in chemotherapy-resistant tumor-bearing mice (P = 0.041). p16 DT-A c-CPE-NP may represent a novel dual-targeting therapeutic approach for the selective delivery of gene therapy to chemotherapy-resistant ovarian cancer cells. Mol Cancer Ther; 16(2); 323–33. ©2016 AACR.

SYD985, a Novel Duocarmycin-Based HER2-Targeting Antibody-Drug Conjugate, Shows Antitumor Activity in Uterine Serous Carcinoma with HER2/Neu Expression

Uterine serous carcinoma (USC) is an aggressive form of endometrial cancer. Up to 35% of USC may overexpress the HER2/neu oncogene at strong (i.e., 3+) levels by IHC while an additional 40% to 50% express HER2/neu at moderate (2+) or low (1+) levels. We investigated the efficacy of SYD985, (Synthon Biopharmaceuticals), a novel HER2-targeting antibody–drug conjugate (ADC) composed of the mAb trastuzumab linked to a highly potent DNA-alkylating agent (i.e., duocarmycin) in USC. We also compared the antitumor activity of SYD985 in head-to-head experiments to trastuzumab emtansine (T-DM1), a FDA-approved ADC, against multiple primary USC cell lines expressing different levels of HER2/neu in in vitro and in vivo experiments. Using antibody-dependent cellular cytotoxicity (ADCC), proliferation, viability, and bystander killing assays as well as propidium iodide–based flow cytometry assays and multiple in vivo USC mouse xenograft models, we demonstrate for the first time that SYD985 is a novel ADC with activity against USC with strong (3+) as well as low to moderate (i.e., 1+/2+) HER2/neu expression. SYD985 is 10- to 70-fold more potent than T-DM1 in comparative experiments and, unlike T-DM1, it is active against USC demonstrating moderate/low or heterogeneous HER2/neu expression. Clinical studies with SYD985 in patients harboring chemotherapy-resistant USC with low, moderate, and high HER2 expression are warranted. Mol Cancer Ther; 15(8); 1900–9. ©2016 AACR.

Robotic-assisted Abdominal Cerclage Placement During Pregnancy and Its Challenges

STUDY OBJECTIVE To demonstrate a surgical video of 2 cases, in which the steps of robotic-assisted abdominal cerclage placement were delineated in one and a uterine vessel injury was repaired in the other. DESIGN Step-by-step explanation of the technique using a surgical video (Canadian Task Force classification III). SETTING The procedures were performed at a teaching hospital. The first patient was a 25-year-old gravida 4 para 0, with a history of cervical incompetence, who was 13 weeks pregnant at the time of surgery. She had failed McDonald cerclage and was referred for abdominal cerclage placement. The second patient was a 32-year-old gravida 6 para 0 who was 15 weeks pregnant. She had a history of 3 second-trimester miscarriages with painless cervical dilation and had failed McDonald cerclage during her previous pregnancy. Both patients were taken to the operating room for robotic-assisted abdominal cerclage placement early in the second trimester. INTERVENTIONS Robotic-assisted abdominal cerclage placement was performed with ultrasound guidance. The procedure was begun with formation of the bladder flap [1]. An avascular space between the ascending and descending branches of uterine artery, at the level of the cervicoisthmic junction, was subsequently developed. The Mersilene tape was passed through this space in a posterior-to-anterior direction and pulled taut until it was laid flat along the posterior uterine wall. Six knots were then placed with the Mersilene tape on the anterior aspect of the uterus. The free ends of the tape were trimmed and approximated with a nonabsorbable suture to prevent knot slippage. The vesicouterine reflection was then reapproximated, and correct cerclage placement was confirmed with transvaginal ultrasound. In the second case, an incidental uterine vessel injury occurred during development of the avascular space. Hemostasis was attained immediately by clamping the vessel with the fenestrated graspers. Permanent hemostasis required application of the vascular clips, proximally and distally on the lacerated arterial site. CONCLUSION A robotic approach was chosen for our patients requiring transabdominal cerclage placement during pregnancy, in an attempt to decrease the surgical morbidity associated with laparotomy [2,3]. Despite the challenges introduced by the enlarged gravid uterus, both procedures were successfully completed, and the patients delivered at term via cesarean section.

SYD985, a novel duocarmycin-based HER2-targeting antibody-drug conjugate, shows promising antitumor activity in epithelial ovarian carcinoma with HER2/Neu expression

BACKGROUND Epithelial ovarian cancer (EOC) is an aggressive and heterogeneous disease. <10% of EOC demonstrate HER2/neu 3+ receptor over-expression. However, moderate to low (i.e., 2+ and 1+) HER2/neu expression is reported in up to 50% of EOC. The objective of this study was to compare the anti-tumor activity of SYD985, a novel HER2-targeting antibody-drug conjugate (ADC), to trastuzumab emtansine (T-DM1) in EOC models with differential HER2/neu expression. METHODS The cytotoxicity of SYD985 and T-DM1 was evaluated using ten primary EOC cell lines with 0/1+, 2+, and 3+ HER2/neu expression in antibody-dependent cellular cytotoxicity (ADCC), proliferation, viability and bystander killing experiments. Finally, the in vivo activity of SYD985 and T-DM1 was also studied in ovarian cancer xenografts. RESULTS SYD985 and T-DM1 induced similar ADCC in the presence of peripheral blood lymphocytes (PBL) against EOC cell lines with differential HER2/neu expression. In contrast, SYD985 was 3 to 42 fold more cytotoxic in the absence of PBL when compared to T-DM1 (p<0.0001). Unlike T-DM1, SYD985 induced efficient bystander killing of HER2/neu 0/1+ tumor cells when admixed with HER2/neu 3+ EOC cells. In vivo studies confirmed that SYD985 is significantly more active than T-DM1 against HER2/neu 3+ EOC xenografts. CONCLUSIONS SYD985 is a novel ADC with remarkable activity against EOC with strong (3+) as well as moderate to low (i.e., 2+ and 1+) HER2/neu expression. SYD985 is more potent than T-DM1 in comparative experiments and unlike T-DM1, it is active against EOC demonstrating moderate/low or heterogeneous HER2/neu expression.

Robot-assisted abdominal cerclage during pregnancy

Background and Objectives: Cervical insufficiency is a difficult condition to diagnose and can lead to preterm birth, miscarriage, or perinatal infant morbidity and mortality. We conducted this retrospective case study and literature review to evaluate the safety and efficacy of robot-assisted abdominal cerclage during pregnancy. Methods: We conducted a case series and a systematic review that included patients who underwent robot-assisted abdominal cerclage during pregnancy from January 2010 through March 2016. Results: Six patients met the criteria for the case series. Median age was 34 years (range, 28–37) at the time of the procedure. In 5 cases, the indication for transabdominal cerclage was a failed vaginal cerclage in a previous pregnancy, whereas a scarred and shortened cervix caused by a previous dilatation and curettage–induced cervical laceration was the indication in the remaining case. Median operating time was 159.5 minutes (range, 124–204), and median estimated blood loss was 25 mL (range, 10–25). No surgeries were converted to laparotomies; all patients were discharged on postoperative day 1. The median gestational age at delivery was 37.5 weeks (range, 22–39). Five patients delivered between 36 and 39 weeks. No patients had chorioamnionitis or preterm premature rupture of membranes. One patient went into preterm labor at 22 weeks, and the cerclage was removed via minilaparotomy. Eight articles met the criteria for systematic review. Sixteen patients underwent robot-assisted abdominal cerclage during pregnancy. Median age was 31.5 years (range, 25–37). The major indication in most articles was previous failed transvaginal cerclage. The median gestational ages at time of procedure and delivery were 12 weeks (range, 10–15) and 37 weeks (range, 33–39), respectively. Conclusion: Robot-assisted abdominal cerclage is safe and effective during pregnancy.

A Simple Approach to Specimen Retrieval via Posterior Colpotomy Incision.

Introduction: Posterior colpotomy incision for specimen retrieval is infrequently used in gynecologic laparoscopic surgery unless a concomitant hysterectomy is performed. We aim to describe a simple and unique technique for creating the colpotomy incision and to describe intraoperative and postoperative outcomes. Methods: Fifty patients underwent adnexal specimen retrieval through a posterior colpotomy incision. After devascularization and detachment of the adnexal specimen, the posterior cul-de-sac was visualized. The colpotomy incision was created by introducing a 12- or 15-mm laparoscopic trocar through the vagina into the posterior vaginal fornix under direct visualization. Specimens were placed into laparoscopic bags and removed through the vagina. The colpotomy incision was closed vaginally. Charts were reviewed for intraoperative and postoperative outcomes. Results: Twenty-nine women underwent adnexal surgery for an adnexal mass, 14 women underwent surgery for pelvic pain, and 7 women underwent adnexal surgery for primary prevention of malignancy. The specimens removed ranged in size from 2 to 16 cm (mean 5.7). The mean time patients were under anesthesia was 103 minutes (SD 57.3). There were no operative complications related to the colpotomy incision and no cases of postoperative vaginal cellulitis or pelvic infection were reported. Only 1 woman with a prior vaginal delivery reported dyspareunia postoperatively. Conclusion: This simple technique for posterior colpotomy incision can easily be added to the gynecologic surgeons armamentarium and can be safely used for most women.

Comparison of lymphedema incidence between 2 lymphadenectomy techniques in patients with uterine cancer undergoing robotic staging.

Objective This study aimed to compare the incidence of lower extremity lymphedema in patients with uterine cancer after robotic staging using the following 2 methods: standard and selective pelvic lymphadenectomy. Materials and Methods Three hundred forty-four consecutive patients who presented with endometrial cancer from March 2007 to October 2012 underwent robotic staging. Surgeon A performed standard pelvic lymphadenectomy and surgeon B performed selective lymphadenectomy. Selective pelvic lymphadenectomy spared the lateral chain of the external iliac lymph nodes (LNs). The incidence of lymphedema and staging adequacy between the 2 groups were analyzed. Results Standard pelvic lymphadenectomy was performed in 238/344 (69.2%) patients and selective pelvic lymphadenectomy was performed in 106/344 (30.8%) patients. Conversion to laparotomy occurred in 2/344 cases (0.6%). Mean age for 344 patients was 63.6 (10) years and body mass index was 34.8 (10.1) kg/m2. The mean operative time was 162.3 (54.6) minutes. Postoperative hospitalization was 1.62 (1.93) days. Histology included 80.8% endometrioid adenocarcinomas and 19.2% clear cell, serous, and carcinosarcomas. Mean pelvic LN counts for the standard and selective pelvic lymphadenectomy groups were 16 (8.6) and 15.5 (7.1), respectively (P = 0.31). Mean numbers of para-aortic LNs retrieved for the standard and selective lymphadenectomy groups were 3.1 (4.1) and 4.9 (4.5), respectively (P < 0.01). Median follow-up was 29.3 months (interquartile range, 15.6–43.1 months). The difference in the incidence of lower extremity lymphedema was statistically significant: 4.6% (11/238 patients) in the standard lymphadenectomy group versus 0.9% (1/106 patients) in the selective lymphadenectomy group (P = 0.03). Conclusions When compared to the standard technique, selective pelvic lymphadenectomy with sparing of the lateral chain of the external iliac LNs is adequate and results in a lower incidence of lower extremity lymphedema.