Superior in vitro and in vivo activity of trastuzumab-emtansine (T-DM1) in comparison to trastuzumab, pertuzumab and their combination in epithelial ovarian carcinoma with high HER2/neu expression.

BACKGROUND: Epithelial ovarian cancer (EOC) remains the most lethal gynecologic malignancy. The objective of this study was to compare the anti-tumor activity of HER2/neu-targeting monoclonal antibodies, trastuzumab (T), pertuzumab (P), combination of trastuzumab and pertuzumab (T+P) and trastuzumab-emtansine (T-DM1) in EOC with high HER2/neu expression. METHODS: Primary EOC cell lines were established and cell blocks were analyzed for HER2/neu expression. Cytostatic, apoptotic and antibody-dependent cell-mediated cytotoxicity (ADCC) activities of T, P, T+P and T-DM1 were evaluated in vitro. The in vivo antitumor activity was tested in xenograft models with 3+ HER2/neu expression. RESULTS: High (3+) HER2/neu expression was detected in 40% of the primary EOC cell lines. T, P, T+P, and T-DM1 were similarly effective in inducing strong ADCC against primary EOC cell lines expressing 3+ HER2/neu. The combination of T and P was more cytostatic when compared with that of T or P used alone (p<0.0001 and p<0.0001, respectively). T-DM1 induced significantly more apoptosis when compared with T+P (p<0.0001). Finally, T-DM1 was significantly more effective in tumor growth inhibition in vivo in EOC xenografts overexpressing HER2/neu when compared to T alone, P alone and T+P (p=0.04). CONCLUSION: In vitro and in vivo experiments with 3+ HER2/neu expressing EOC revealed limited anti-tumor activity of T or P. T-DM1 showed superior anti-tumor activity to T and P as single agents and as a combination. Our preclinical data support the design of clinical studies with T-DM1 for the treatment of chemotherapy-resistant EOC overexpressing HER2/neu.

When Things Go Wrong: Examining the Frequency and Aftermath of Critical Incidents Among OBGYN Residents.

OBJECTIVE: To examine the frequency with which obstetrics and gynecology (OBGYN) residents experience critical incidents (CIs) during residency and participate in postincident debriefing. METHODS: A survey was conducted to examine the frequency of CIs during training, abilities of residents to cope with CIs, and the impact of postincident debriefing. RESULTS: Among the 27 residents who responded (93.1%), 82.6% reported involvement in one ormore CIs during residency. There was a statistically significant difference in the cumulative number of CIs experienced when stratified by level of training. Following a CI, 39.2% of residents reported having an opportunity to debrief and only 30.4% "always" had enough support to cope. Among those who had debriefed, 100% felt that it had helped them to process the incident. CONCLUSION: OBGYN residents frequently experience CIs during their training years. Postincident debriefing is not the norm but is desired and may help residents process difficult clinical situations.

Robotic Versus Laparoscopic Hysterectomy for Benign Disease: A Systematic Review and Meta-Analysis of Randomized Trials.

We conducted a systematic review and meta-analysis to assess the safety and effectiveness of robotic vs laparoscopic hysterectomy in women with benign uterine disease, as determined by randomized studies. We searched MEDLINE, EMBASE, the Cochrane Library, ClinicalTrials.gov, and Controlled-Trials.com from study inception to October 9, 2014, using the intersection of the themes "robotic" and "hysterectomy." We included only randomized and quasi-randomized controlled trials of robotic vs laparoscopic hysterectomy in women for benign disease. Four trials met our inclusion criteria and were included in the analyses. We extracted data, and assessed the studies for methodological quality in duplicate. For meta-analysis, we used random effects to calculate pooled risk ratios (RRs) and weighted mean differences. For our primary outcome, we used a modified version of the Expanded Accordion Severity Grading System to classify perioperative complications. We identified 41 complications among 326 patients. Comparing robotic and laparoscopic hysterectomy, revealed no statistically significant differences in the rate of class 1 and 2 complications (RR, 0.66; 95% confidence interval [CI], 0.23-1.89) or in the rate of class 3 and 4 complications (RR, 0.99; 95% CI, 0.22-4.40). Analyses of secondary outcomes were limited owing to heterogeneity, but showed no significant benefit of the robotic technique over the laparoscopic technique in terms of length of hospital stay (weighted mean difference, -0.39 day; 95% CI, -0.92 to 0.14 day), total operating time (weighted mean difference, 9.0 minutes; 95% CI, -31.27 to 47.26 minutes), conversions to laparotomy, or blood loss. Outcomes of cost, pain, and quality of life were reported inconsistently and were not amenable to pooling. Current evidence demonstrates neither statistically significant nor clinically meaningful differences in surgical outcomes between robotic and laparoscopic hysterectomy for benign disease. The role of robotic surgery in benign gynecology remains unclear.

Clostridium perfringens enterotoxin C-terminal domain labeled to fluorescent dyes for in vivo visualization of micrometastatic chemotherapy-resistant ovarian cancer.

Identification of micrometastatic disease at the time of surgery remains extremely challenging in ovarian cancer patients. We used fluorescence microscopy, an in vivo imaging system and a fluorescence stereo microscope to evaluate fluorescence distribution in Claudin-3- and -4-overexpressing ovarian tumors, floating tumor clumps isolated from ascites and healthy organs. To do so, mice harboring chemotherapy-naïve and chemotherapy-resistant human ovarian cancer xenografts or patient-derived xenografts (PDXs) were treated with the carboxyl-terminal binding domain of the Clostridium perfringens enterotoxin (c-CPE) conjugated to FITC (FITC-c-CPE) or the near-infrared (NIR) fluorescent tag IRDye CW800 (CW800-c-CPE) either intraperitoneally (IP) or intravenously (IV). We found tumor fluorescence to plateau at 30 min after IP injection of both the FITC-c-CPE and the CW800-c-CPE peptides and to be significantly higher than in healthy organs (p < 0.01). After IV injection of CW800-c-CPE, tumor fluorescence plateaued at 6 hr while the most favorable tumor-to-background fluorescence ratio (TBR) was found at 48 hr in both mouse models. Importantly, fluorescent c-CPE was highly sensitive for the in vivo visualization of peritoneal micrometastatic tumor implants and the identification of ovarian tumor spheroids floating in malignant ascites that were otherwise not detectable by conventional visual observation. The use of the fluorescent c-CPE peptide may represent a novel and effective optical approach at the time of primary debulking surgery for the real-time detection of micrometastatic ovarian disease overexpressing the Claudin-3 and -4 receptors or the identification of residual disease at the time of interval debulking surgery after neoadjuvant chemotherapy treatment.

PIK3CA oncogenic mutations represent a major mechanism of resistance to trastuzumab in HER2/neu overexpressing uterine serous carcinomas.

OBJECTIVES: We evaluated the role of PIK3CA-mutations as mechanism of resistance to trastuzumab in primary HER2/neu-amplified uterine-serous-carcinoma (USC) cell lines. METHODS: Fifteen whole-exome-sequenced USC cell lines were tested for HER2/neu-amplification and PIK3CA-mutations. Four HER2/neu-amplified USC (2-harbouring wild-type-PIK3CA-genes and 2-harbouring oncogenic-PIK3CA-mutations) were evaluated in in vitro dose-titration-proliferation-assays, cell-viability and HER2 and S6-protein-phosphorylation after exposure to trastuzumab. USC harbouring wild-type-PIK3CA were transfected with plasmids encoding oncogenic PIK3CA-mutations (i.e., H1047R/R93Q) and exposed to trastuzumab. Finally, trastuzumab efficacy was tested by using two USC xenograft mouse models. RESULTS: Seven out of fifteen (46%) of the USC cell lines were HER2/neu-amplified by fluorescence in situ hybridisation. Within these tumours four out of seven (57%) were found to harbour oncogenic PIK3CA-mutations vs two out of eight (25%) of the HER2/neu not amplified cell lines (P=0.01). HER2/neu-amplified/PIK3CA-mutated USC were highly resistant to trastuzumab when compared with HER2/neu-amplified/wild-type-PIK3CA cell lines (P=0.02). HER2/neu-amplified/PIK3CA wild-type cell lines transfected with oncogenic PIK3CA-mutations increased their resistance to trastuzumab (P<0.0001). Trastuzumab was effective in reducing tumour growth (P=0.001) and improved survival (P=0.0001) in mouse xenografts harbouring HER2-amplified/PIK3CA wild-type USC but not in HER2-amplified/PIK3CA-mutated tumours. CONCLUSIONS: Oncogenic PIK3CA mutations are common in HER2/neu-amplified USC and may constitute a major mechanism of resistance to trastuzumab treatment.

A series of malignant ovarian cancers arising from within a mature cystic teratoma: a single institution experience.

BACKGROUND: Mature cystic teratoma (MCT) is the most common germ cell tumor. It accounts for 10% to 20% of all ovarian masses. The likelihood of malignancy arising from within an MCT is low, and prognosis is poor. METHODS: A single-institution retrospective chart review was completed of all cases of MCT from 2004 to 2012. Multiple variables were examined including procedure performed, residual disease after surgery, surgical stage, histologic type, site of primary disease, date of recurrence, whether or not adjuvant chemotherapy was given, and whether or not there was death secondary to disease. RESULTS: During the study period, 1.2% of MCTs exhibited malignant transformation. The average age at presentation was 53.7 years. Mean follow-up time was 23 months. The most common presenting symptoms were bloating and abdominal pain. The average tumor size was 18 cm. Of note, 33% of cases were at least surgical stage IIIC at the time of presentation, whereas the remainder were stage IC or lower. Four (44.4%) of the 9 cases were identified as mucinous adenocarcinoma in addition to 1 case each of malignant melanoma, squamous cell carcinoma, and poorly differentiated adenocarcinoma. Only 1 patient experienced recurrence. One patient had a known MCT that was being managed expectantly and exhibited malignant transformation to a mucinous adenocarcinoma. CONCLUSIONS: A large ovarian mass that is suspected to be a mature teratoma should be managed more aggressively in older patients. Our data suggest that although malignancy arising from mature teratomas is rare, it is more likely when patients are older than 40 years, the mass is greater than 18 cm, and there is any suspicion for a mucinous tumor. Like most ovarian tumors, these tumors most often present at later stages and, thus, can be difficult to treat. It is unclear what role chemotherapy or radiation plays in the management of these tumors.

Frequent femoral neck osteolysis with Birmingham mid-head resection resurfacing arthroplasty in young patients.

BACKGROUND: Mid-head resection total hip resurfacing arthroplasty was promoted as an alternative to traditional total hip resurfacing for patients with poor femoral head bone quality or abnormal femoral head morphology, because those patients are at high risk of failure with traditional total hip resurfacing. It is a large-headed metal-on-metal device that uses a short, bone-conserving stem. Good performance of the implant has been reported at short-term followup, but no information on the implant performance in the mid- or long-term is available. QUESTIONS/PURPOSES: In this study, we report (1) on the mid-term implant survivorship and hip scores in a single nondesigner surgeon series. Because of the occurrence of femoral neck osteolysis and pseudotumor in a subgroup of patients, we also investigated the following: (2) Were there any preoperative parameters that are associated with osteolysis? (3) Could we differentiate the osteolysis group from the others on the basis of implant component sizes, positions, and radiologic parameters? (4) Could we differentiate the osteolysis group from the others on the basis of metal ion levels? METHODS: Between 2006 and 2011, one surgeon performed a total of 49 Birmingham Mid-head Resection total hip resurfacing arthroplasties in 47 patients. The general indications for this procedure were young patients who were considered suitable for hip resurfacing arthroplasty but had avascular necrosis, large cysts, or severe deformity of the femoral head. Clinical followup including Oxford Hip Score (OHS) and UCLA hip scores were available preoperatively and at a mean of 6 years (range, 3-8 years) on all patients (100%), radiographic followup on 45 of 47 (96%), MRIs on 18 (38%), and metal ion levels on 37 (79%). Mean age at surgery was 50 years. Spearman's correlation was used to test the association between femoral neck osteolysis and preoperative parameters, implant component sizes and positions, and blood metal ion levels. RESULTS: We found 100% survival. Patients' median OHS was 46 of 48 (range, 35-48) and UCLA 8 of 10 (range, 4-10). However, 16% of the hips (seven of 45) demonstrated osteolysis in the femoral neck. Of the preoperative parameters, the osteolysis was associated with low weight (r = -0.337, p = 0.031) and to a lesser degree with female sex (r = 0.275, p = 0.067). Radiologically, the osteolysis was strongly associated with the presence of a pseudotumor on MRI (r = 0.663, p = 0.004). We could not differentiate the osteolysis group from the rest of the cohort on the basis of the implant sizes or radiographic implant component positions. The cohort's median whole blood cobalt was 1.77 ppb (range, 0.18-10.27 ppb) and chromium 1.88 ppb (range 0.36-10.09 ppb). There was no difference in the metal ion levels between the osteolysis group and the rest of the cohort. CONCLUSIONS: The high rate of silently developing femoral neck osteolysis associated with this implant is concerning and is expected to cause a high rate of failure at longer followup. We have instituted a program of annual clinical and radiologic followup for this group of patients. We have stopped implanting this device and recommend against its use. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Management of Borderline Ovarian Tumors Based on Patient and Tumor Characteristics.

BACKGROUND: Borderline ovarian tumors are staged similarly to invasive ovarian tumors. AIMS: We wanted to better understand which tumors were associated with disease recurrence. METHODS: We performed a retrospective cohort analysis at a single institution between 1984 and 2005. Cases were confirmed by pathology report. Multivariate analysis was done to evaluate factors associated with recurrence. RESULTS: 143 cases were identified. Mean follow-up was 73.5 months. The overall risk of recurrence was 12%. The hazard ratio for risk of recurrence was highest among seromucinous tumors at 4.04 and lowest among mucinous tumors at 0.53. Only 4% of mucinous tumors, 15.5% of serous tumors and 28.6% of seromucinous tumors recurred. 2% of mucinous tumors had an appendix positive for metastasis. No mucinous tumor had nodal disease. CONCLUSIONS: Based on our data, a low rate of appendiceal or lymph node involvement was observed in mucinous tumors, as was a low risk of recurrence. Less aggressive staging may be considered if a mucinous tumor is identified on frozen section with a normal-appearing appendix in the absence of pseudomyxoma peritonei. In patients with a serous or a seromucinous tumor, complete surgical staging is recommended. © 2015 S. Karger AG, Basel.

An unexpected mass of the urachus: a case report.

The urachus is a remnant of the urogenital sinus and allantois, which persists after antenatal involution. Despite its rudimentary postnatal presence, it can undergo metaplasia and tumor formation. Malignant transformation of the urachus is rare. However, these tumors can recur and develop pseudomyxoma peritonei. Thus, they should remain on the differential for any female patient with a pelvic mass. A 28-year old G9P2062 presented at 8 weeks' gestation requesting pregnancy termination. On ultrasound, a single live intrauterine pregnancy was visualized. Also identified was a left-sided 8- × 7- × 6-cm complex echogenic mass with thickened septations, heterogeneous appearance, and fluid-fluid levels suspicious for a mature cystic teratoma. Surgical termination of pregnancy and diagnostic laparoscopy was planned. Intraoperatively a multiloculated midline mass was identified and excised. Final pathology identified a mucinous urachal neoplasm of low malignant potential. The patient followed up with urology and underwent surgical staging. Midline location is a key feature that helps distinguish ovarian masses from urachal or bladder masses. Many urachal and bladder neoplasms are managed with complete surgical excision and staging, illustrating the importance of preoperative identification. If laterality of a mass is unclear, further imaging is recommended to characterize the mass preoperatively. This case also reveals the feasibility of a minimally invasive abdominal wall mass resection.

Associated characteristics and impact on recurrence and survival of free-floating tumor fragments in the lumen of fallopian tubes in Type I and Type II endometrial cancer.

OBJECTIVE: This study sought to evaluate characteristics of cases of free-floating tumor fragments within the lumen of fallopian tubes ('floaters') on final pathology for Type I and Type II endometrial adenocarcinoma, including relationships with disease recurrence and mortality. METHODS: A single institution experience of 1022 consecutive cases of uterine cancer presenting between 2005 and 2010 was retrospectively reviewed, with data extraction from electronic medical records. Associations of floaters with baseline characteristics were studied with logistic regression, and relationships with disease recurrence and survival were assessed with Cox proportional hazards models. RESULTS: Among 816 included cases of Type I or Type II endometrial adenocarcinoma, floaters were identified on final pathology for 20 patients (2.5%). Patient characteristics of cases with floaters mirrored the overall sample. With adjustment, presence of floaters trended towards association with laparoscopic/robotic approach (OR = 3.84; 95%CI 0.98-15.1), and was significantly associated with lymphovascular invasion (OR = 9.65; 95%CI 2.35-39.6) and higher stage disease. Although floaters were associated with increased risk of recurrence in unadjusted analysis (HR = 3.22; 95%CI 1.41-7.37), after adjustment for disease type, stage, and patient comorbidities, no evidence for impact on disease recurrence or overall survival was found. CONCLUSIONS: The presence of floaters is rare. Floaters were generally associated with more extensive disease, but no evidence was found to show any independent prognostic impact on risk of recurrence or death. In agreement with prior research, this study found a trend towards association of floaters with laparoscopic/robotic approach, indicating the possibility of floaters sometimes being the result of trauma from uterine manipulator insertion.

Efficacy of neratinib in the treatment of HER2/neu-amplified epithelial ovarian carcinoma in vitro and in vivo.

Epithelial ovarian carcinoma is the most lethal of gynecologic malignancies. There is a need to optimize the currently available treatment strategies and to urgently develop novel therapeutic agents against chemotherapy-resistant disease. The objective of our study was to evaluate neratinib's preclinical efficacy in treating HER2-amplified ovarian cancer. Neratinib's efficacy in treating HER2-amplified ovarian cancer was studied in vitro utilizing six primary tumor cell lines with differential HER2/neu expression. Flow cytometry was utilized to assess IC50, cell signaling changes, and cell cycle distribution. Neratinib's in vivo efficacy was evaluated in HER2-amplified epithelial ovarian carcinoma xenografts. Three of six (50%) ovarian cancer cell lines were HER2/neu-amplified. Neratinib showed significantly higher efficacy in treating HER2/neu-amplified cell lines when compared to the non-HER2/neu-amplified tumor cell lines (mean ± SEM IC50:0.010 µM ± 0.0003 vs. 0.076 µM ± 0.005 p < 0.0001). Neratinib treatment significantly decreased the phosphorylation of the transcription factor S6, leading to arrest of the cell cycle in G0/G1 phase. Neratinib prolonged survival in mice harboring HER2-amplified epithelial ovarian carcinoma xenografts (p = 0.003). Neratinib inhibits proliferation, signaling, cell cycle progression and tumor growth of HER2-amplified epithelial ovarian carcinoma in vitro. Neratinib inhibits xenograft growth and improves overall survival in HER2/neu-amplified ovarian cancer in vivo. Clinical trials are warranted.

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.

Correction of coagulopathy associated with non-bacterial thrombotic endocarditis (NBTE) by surgical debulking in a case of ovarian clear cell carcinoma.

•Ovarian cancer, particularly clear cell carcinoma, creates a hypercoagulable state.•This state can predispose to non-bacterial thrombotic endocarditis (NBTE).•NBTE can embolize and cause widespread arterial infarction.•NBTE is sometimes associated with a treatment refractory disseminated coagulopathy.•Surgical removal of the primary mass can sometimes reverse the coagulopathy.

An update on the current pharmacotherapy for endometrial cancer.

INTRODUCTION: Endometrial cancer (EC) is the most common gynecologic malignancy in the developed world and is increasing in incidence. While the mainstay of treatment for EC is surgery followed by chemotherapy and/or radiation therapy, the available pharmacotherapies are rapidly and constantly evolving. Understanding these new therapies is an important part of the research and clinical care of women with EC. A review of available literature from MEDLINE (1879-2015) was conducted for the historic treatments and current therapies available for endometrial tumors. AREAS COVERED: This article reviews the current conventional therapies and discusses novel therapeutic agents, some of which are available to clinicians while others are currently being investigated in the preclinical setting. EXPERT OPINION: Genomic and immunohistochemical characterization of endometrial cancer may soon be the best approach for the identification of aggressive forms of tumor. Targeted therapies will soon be standard in the management of endometrial cancer.

Immune checkpoint inhibitors in gynecologic cancers with lessons learned from non-gynecologic cancers.

INTRODUCTION: The immune system plays a critical role in controlling cancer through a dynamic relationship with cancer cells. Immunotherapy can establish a sustained immune response against recurring cancer cells leading to long-term remissions for cancer patients. The use of immune checkpoint inhibitors, which work by targeting molecules that regulate immune responses, might be a promising avenue of immunotherapeutic research in gynecologic cancers. AREAS COVERED: This review focuses on the use of immune checkpoint inhibitors targeting cytotoxic T lymphocyte antigen-4 (CTLA-4) and the programmed death receptors such as PD-1 and PD1-ligand in gynecologic cancers. Combinatorial approaches utilizing immunotherapeutic agents with conventional treatments as well as immune-related response criteria and the adverse effects arising due to checkpoint inhibitor immunotherapy have been also discussed in the review. EXPERT OPINION: After years of very little success, a better understanding of the pivotal role of the tumor microenvironment in suppressing anticancer immunity and the exploration of treatment regimens using immune checkpoint inhibitors alone or in combination have finally led to the development of effective cancer immunotherapies and to improve survival of patients with certain types of advanced cancers. While the clinical experience with immune checkpoint inhibitors in gynecologic cancer patients remains limited, early signal of clinical activity strongly suggest that immunotherapy will play a significant role in the year to come in at least a subset of gynecologic cancer patients.

Uterine didelphys and vaginal birth after cesarean delivery.

BACKGROUND: Müllerian anomalies are associated with adverse pregnancy outcomes. We discuss pregnancy in anomalous uteri, with a focus on uterine didelphys, in the setting of a prior cesarean delivery. CASE(S): A 30-year-old woman, gravida 2 para 1001, presented in latent labor at 40 1/7 weeks of gestation. Her first pregnancy was in the right horn of a didelphic uterus and resulted in a cesarean delivery in the setting of chorioamnionitis remote from delivery. The current pregnancy was in the left horn and resulted in a vacuum-assisted vaginal delivery after spontaneous labor. CONCLUSION: There is sparse literature on a trial of labor after cesarean delivery in a uterine didelphys.

Clostridium perfringens enterotoxin (CPE) and CPE-binding domain (c-CPE) for the detection and treatment of gynecologic cancers.

Clostridium perfringens enterotoxin (CPE) is a three-domain polypeptide, which binds to Claudin-3 and Claudin-4 with high affinity. Because these receptors are highly differentially expressed in many human tumors, claudin-3 and claudin-4 may provide an efficient molecular tool to specifically identify and target biologically aggressive human cancer cells for CPE-specific binding and cytolysis. In this review we will discuss these surface proteins as targets for the detection and treatment of chemotherapy-resistant gynecologic malignancies overexpressing claudin-3 and -4 using CPE-based theranostic agents. We will also discuss the use of fluorescent c-CPE peptide in the operative setting for real time detection of micro-metastatic tumors during surgery and review the potential role of CPE in other medical applications.

T-DM1, a novel antibody-drug conjugate, is highly effective against uterine and ovarian carcinosarcomas overexpressing HER2.

Ovarian and uterine carcinosarcoma (CS) are characterized by their aggressive clinical behavior and poor prognosis. We evaluated the efficacy of trastuzumab-emtansine (T-DM1), against primary HER2 positive and HER2 negative CS cell lines in vitro and in vivo. Eight primary CS cell lines were evaluated for HER2 amplification and protein expression by fluorescence in situ hybridization, immunohistochemistry, flow cytometry and qRT-PCR. Sensitivity to T-DM1-induced antibody-dependent-cell-mediated-cytotoxicity (ADCC) was evaluated in 4-h-chromium-release-assays. T-DM1 cytostatic and apoptotic activities were evaluated using flow cytometry based proliferation assays. In vivo activity of T-DM1 was also evaluated. HER2 protein overexpression and gene amplification were detected in 25 % (2/8) of the primary CS cell lines. T-DM1 and T were similarly effective in inducing strong ADCC against CS overexpressing HER2 at 3+ levels. In contrast, T-DM1 was dramatically more effective than T in inhibiting cell proliferation (P < 0.0001) and in inducing G2/M phase cell cycle arrest in the HER2 expressing cell lines (shift of G2/M: mean ± SEM from 14.87 ± 1.23 to 66.57 ± 4.56 %, P < 0.0001). Importantly, T-DM1 was highly active at reducing tumor formation in vivo in CS xenografts overexpressing HER2 (P = 0.0001 and P < 0.0001 compared to T and vehicle respectively) with a significantly longer survival when compared to T and vehicle mice (P = 0.008 and P = 0.0001 respectively). T-DM1 may represent a novel treatment option for the subset of HER2 positive CS patients with disease refractory to chemotherapy.

Surgical site infections in gynecology.

IMPORTANCE: Surgical site infections (SSIs) are preventable, yet nearly 2% of all surgical cases are complicated by an SSI. Each SSI increases the cost of a postoperative hospital stay by more than $10,000. Thus, SSI prevention has become the focus of health care systems and hospitals because it is a reducible health care cost. OBJECTIVE: The objective of this review was to better understand the guidelines and recommendations related to the prevention, diagnosis, and management of SSIs. EVIDENCE ACQUISITION: This study is a thorough review of the most up-to-date peer-reviewed articles and review articles as well as guidelines and recommendations of various professional organizations including the US Centers for Disease Control and Prevention and the American College of Obstetrics and Gynecology. RESULTS: A review of the literature has identified several evidence-based recommendations that physicians should adhere to in an effort to decrease the incidence of SSIs. CONCLUSIONS AND RELEVANCE: By adhering to clinical recommendations and evidence, we can correctly prevent, diagnose, and treat SSIs. In turn, this will improve health outcomes and decrease health care-related costs, thus increasing the value of health care that we provide to patients. Furthermore, we can gain improvements in the quality measures used by hospitals and insurers.