Matthew P. Schlumbrecht

Rate of vaginal cuff separation following laparoscopic or robotic hysterectomy

OBJECTIVE Vaginal cuff separation is a rare but serious complication following hysterectomy. The goal of our study was to determine the rate of vaginal cuff separation and associated risk factors in patients undergoing laparoscopic or robotic hysterectomy. METHODS We retrospectively identified patients who underwent a minimally invasive simple or radical hysterectomy at one institution between January 2000 and 2009. Fishers exact test, Wilcoxon rank sum test and multiple logistic regression were used to determine associations between variables and increased risk of separation. RESULTS A total of 417 patients underwent laparoscopic (n=285) or robotic (n=132) hysterectomy during the study period. Three hundred and sixty-two underwent simple hysterectomy (249 laparoscopic, 113 robotic) and 57 underwent radical hysterectomy (36 laparoscopic, 19 robotic). Seven (1.7%) patients developed a cuff complication and all had a diagnosis of malignancy. Three (1.1%) patients in the laparoscopy group suffered a vaginal cuff evisceration (n=2) or separation (n=1). Four patients in the robotic group (3.0%) had a vaginal evisceration (n=1) or separation (n=3). There was no difference based on surgical approach (p=0.22). Vaginal cuff complications were 9.46-fold higher among patients who had a radical hysterectomy (p<0.01). Median time to presentation of vaginal cuff complication was 128 days (range, 58-175) in the laparoscopy group and 37 days (range, 32-44) in the robotic group. CONCLUSIONS The overall risk of vaginal cuff complication was 1.7%. There appears to be no difference in cuff complication rates based on surgical approach. Radical hysterectomy, however, was associated with a 9-fold increase in vaginal cuff complications.

A Phase I Trial of Liposomal Doxorubicin, Bevacizumab and Temsirolimus in Patients with Advanced Gynecologic and Breast Malignancies

Purpose: Liposomal doxorubicin (D) and bevacizumab (A) are active single agents in gynecologic and breast malignancies which share a resistance mechanism: upregulation of hypoxia inducible factor (HIF-1α). We, therefore, added temsirolimus (T), which inhibits HIF-1α, to D and A (DAT). Trial objectives were assessment of safety, preliminary efficacy, and identification of biological response correlates. Patients and Methods: Cycle length was 21 days, with IV D, A, and T on day 1; T on days 8 and 15 (3+3 dose-escalation design with expansion cohorts). Mutational assays for PIK3CA, BRAF, KRAS, and immunhistochemistry for PTEN loss were conducted. Results: This article details 74 patients with gynecologic and breast malignancies who received at least one dose of drug on study. Median patient age: 52 (27–79); prior regimens: 4 (1–11). Responses: 1 (1.4%) complete response (CR), 14 (18.9%) partial responses (PR), and 13 (17.6%) with stable disease (SD) ≥ 6 months (total = 37.9%). The most common grade 1 toxicities were fatigue (27%) and anemia (20.2%). Notable grade 3/4 toxicities: thrombocytopenia (9.5%), mucositis (6.7%), and bowel perforation (2.7%). PIK3CA mutations or PTEN loss were identified in 25 of 59 (42.3%) of tested patients. Among these, nine (36%) achieved CR/PR and four (16%) had SD ≥ 6 months (CR+PR+SD ≥ 6 months = 52%). Conclusions: DAT is well tolerated with manageable side effects. Responses observed warrant further evaluation. Mutational analyses were notable for a high percentage of responders with phosphoinositide-3-kinase pathway aberrations. Clin Cancer Res; 17(21); 6840–6. ©2011 AACR.

S100A4 mediates endometrial cancer invasion and is a target of TGF-β1 signaling

The molecular mechanisms of endometrial cancer invasion are poorly understood. S100A4, also known as FSP1 (fibroblast-specific protein 1), has long been known to be a molecular marker of fibrosis in a variety of different fibrotic diseases of the lungs, liver, kidney, and heart. We demonstrate here that increased expression of S100A4 is associated with advanced stage endometrial cancer and decreased recurrence free survival. To verify the essential role of S100A4 in invasiveness of endometrial cancer, S100A4 expression was downregulated by RNAi in HEC-1A cells, which resulted in undetectable S100A4 protein and significantly decreased migration and invasion. Owing to the established connection between TGF-β1 and S100A4 induction in experimental models of kidney and liver fibrosis, we next examined whether TGF-β1 could also regulate S100A4 in endometrial cancer cells. TGF-β1 stimulated endometrial cancer cell migration and invasion with a concomitant increase in S100A4 protein. Induction of S100A4 was associated with the activation of Smads. TGF-β1-mediated endometrial cancer cell motility was inhibited by S100A4 siRNA. In aggregate, these results suggest that S100A4 is a critical mediator of invasion in endometrial cancer and is upregulated by the TGF-β1 signaling pathway. These results also suggest that endometrial cancer cell invasion and fibrosis share common molecular mechanisms.

Clinicodemographic factors influencing outcomes in patients with low-grade serous ovarian carcinoma

Low‐grade serous carcinoma (LGSC) of the ovary is a rare tumor that is distinct from its high‐grade counterpart. The objective of this study was to determine whether patient demographic factors and clinical treatment histories affected survival in a population of women with LGSC.

Molecular clustering based on ERα and EIG121 predicts survival in high-grade serous carcinoma of the ovary/peritoneum

Assessment of estrogen receptor (ER) expression by immunohistochemistry has yielded inconsistent results as a prognostic indicator in ovarian carcinoma. In breast and endometrial carcinomas, panels of estrogen-induced genes have shown improved prognostic capability over the use of ER immunohistochemistry alone. For both breast and endometrial cancers, overexpression of estrogen-induced genes is associated with better prognosis. We hypothesized that analysis of a panel of estrogen-induced genes can predict the outcome in ovarian carcinoma and potentially differentiate between tumors of varying hormonal responsiveness. From a cohort of 219 women undergoing ovarian cancer surgery from 2004 to 2007, 83 patients were selected for inclusion. All patients had advanced stage ovarian/primary peritoneal high-grade serous carcinoma and underwent primary surgical debulking, followed by adjuvant treatment with platinum and taxane agents. The expression of ERα and six genes known to be induced by estrogen in the female reproductive tract (namely EIG121, sFRP1, sFRP4, RALDH2, PR, and IGF-1) was measured using quantitative RT-PCR. Unsupervised cluster analyses were used to categorize patients as high or low gene expressors. Gene expression results were then compared with those for ER immunohistochemistry. Clusters were compared using χ2 analyses, and Cox proportional hazards models were used to evaluate survival outcomes. The median follow-up time was 38.7 months (range: 1–68). A cluster defined by EIG121 and ERα segregated tumors into distinct groups of high and low gene expressors. Shorter overall survival (OS) was associated with high gene expression (HR 2.84 (1.11–7.30), P=0.03), even after adjustment for other covariates. No difference in ER immunohistochemistry expression was noted between gene clusters. In contrast to other hormonally driven cancers, high expression of ERα and the estrogen-induced gene EIG121 predicts shorter OS in patients with high-grade serous ovarian carcinoma. Such a biomarker panel may potentially be used to guide management with estrogen antagonists in this patient population.

Lifestyle modification in cervical cancer survivors: An ongoing need

Objective With the introduction of multimodality therapy for cervical cancer, many women will be long-term survivors in need of comprehensive surveillance care. Our goals were to evaluate patterns of obesity and smoking in a cohort of cervical cancer survivors and to assess the potential influence of these comorbidities on subsequent follow-up. Methods We reviewed the records of patients treated for invasive cervical cancer at our institution from 2000 to 2003 who had no evidence of disease for 3 or more years. Demographic and clinical data were collected, including smoking history and anthropometric measurements. Body mass index (BMI) was categorized according to World Health Organization criteria. Logistic regression and Wilcoxon rank sum analyses were performed. Results Two hundred ninety-eight women had complete follow-up data at 3 years. The median age at diagnosis was 43.5 years (range, 17.6–87.1 years). At diagnosis, 31.9% had a normal BMI, 28.2% were overweight, and 34.6% were obese compared with 31.7%, 21.1%, and 30.2% at 3 years, respectively. Of the 51 women whose BMI categorization changed, 33 (64.7%) had weight gain, and 18 (35.3%) had weight loss. By paired analyses, increase in BMI was significant over the 3-year interval (P < 0.001). Seventy patients actively smoked at diagnosis. Compared with nonsmokers, current smokers had a greater odds of referral to the pain service (odds ratio [OR], 6.56; confidence interval [CI], 6.26–16.43; P < 0.001), physical therapy (OR, 4.74; CI, 1.29–17.36; P = 0.02), and gastroenterology (OR, 2.25; CI, 1.14–4.24; P = 0.02). Conclusions Obesity and smoking are significant comorbidities that may complicate care in cervical cancer survivors. Interventions aimed at modifying these risk factors should be routinely undertaken in this population.

Ethics Consultation on a Gynecologic Oncology Service: An Opportunity for Physician Education

The purpose of this study is to understand the features of gynecologic oncology patients who receive ethics consults in order to identify areas for physician education and improve patient care. A review of ethics consults for gynecologic oncology patients from 1993 to 2008 was performed. Information on all gynecologic oncology patients treated during the study interval was also collected to define a base population for comparison. Forty-one consults were performed. Compared to the base population, a greater proportion of consult patients had pregnancy-related malignancies (7.9% vs. 0.8%, p < 0.0001) and were African American (33.3% vs. 10.9%, p < 0.0001). The most common clinical case types involved identifying levels of appropriate treatment. Support of the health care team and complex family dynamics were key underlying issues. Ethics consultation provides a substantial resource in identifying relevant issues experienced by gynecologic oncology patients upon which physician educational initiatives may be based.

Cytomegalovirus reactivation following chemoradiation for invasive cervical carcinoma

► Cytomegalovirus is an uncommon infectious agent in gynecologic cancer patients. ► Viral causes should be considered in women on chemotherapy with persistent fever.

Survival after intestinal perforation: Can it be predicted?

OBJECTIVE Intestinal perforation is associated with high morbidity and mortality in gynecologic oncology patients. We investigated potential factors associated with survival after perforation which may influence treatment recommendations. METHODS A retrospective review of all gynecologic oncology patients experiencing intestinal perforation between 1993 and 2007 was performed. Demographics, cancer history, presenting symptoms, vital signs, laboratory values, and management of perforation were collected, and Acute Physiology and Chronic Health Evaluation II (APACHE II) scores were calculated for each patient. Factors affecting survival from the time of perforation were analyzed using Kaplan-Meier method and univariate and multivariate Cox proportional hazard models. Students t-test and chi(2) analysis were also utilized to evaluate potential associations. RESULTS Fifty-three patients met the inclusion criteria. No difference in survival was found based on disease site, history of radiation therapy, presenting symptoms, smoking history, or presence of bowel procedures performed during the most recent abdominal surgery prior to perforation. APACHE II score, disease status, body mass index, and treatment method of perforation were found to be significant prognostic factors for survival. After multivariate Cox regression analysis, only APACHE II scores remained significantly associated with an increased risk of death. Median survival of patients with APACHE II scores <15 was 28.13 months compared to 2.90 months in patients with scores> or =15 (P<0.0001). CONCLUSION Many factors must be examined when determining the management of intestinal perforation in gynecologic oncology patients. Clinicians should consider the APACHE II score in their assessment to assist risk stratification and treatment planning of these patients.

Obstetric and Gynecologic Emergencies in Cancer Patients

Gynecologic emergencies in cancer patients can be significant, and knowledge of the approach to treatment of these emergencies is crucial to optimizing the patient’s oncologic and gynecologic care. This chapter outlines the basic principles of diagnosis and treatment of obstetric and gynecologic emergencies in cancer patients.