Mark K. Dodson

Maternal morbidity in cases of placenta accreta managed by a multidisciplinary care team compared with standard obstetric care.

OBJECTIVE: To compare maternal morbidity in cases of placenta accreta managed by a multidisciplinary care team with similar cases managed by standard obstetric care. METHODS: This was a retrospective cohort study of all cases of placenta accreta identified in the State of Utah from 1996 to 2008. Cases of placenta accreta were identified using International Classification of Diseases (ICD-9) codes for placenta accreta, placenta previa, and cesarean hysterectomy. Maternal morbidity was compared for cases managed by a multidisciplinary care team in two tertiary care centers and similar cases managed at 26 other hospitals using multivariable logistic regression analysis. RESULTS: One-hundred forty-one cases of placenta accreta were identified including 79 managed by a multidisciplinary care team and 62 cases managed by standard obstetric care. Women managed by a multidisciplinary care team were less likely to require large-volume blood transfusion (4 or more units of packed red blood cells) (43% compared with 61%, P=.031) and reoperation within 7 days of delivery for bleeding complications (3% compared with 36%, P<.001) compared with women managed by standard obstetric care. Women with suspected placenta accreta managed by a multidisciplinary team were less likely to experience composite early morbidity (prolonged maternal admission to the intensive care unit, large-volume blood transfusion, coagulopathy, ureteral injury, or early reoperation) than women managed by standard obstetric care (47% compared with 74%, P=.026). The odds ratio of composite early morbidity in women managed by a multidisciplinary team was 0.22, (95% confidence interval, 0.07–0.70) in the multivariable model. CONCLUSION: Maternal morbidity is reduced in women with placenta accreta who deliver in a tertiary care hospital with a multidisciplinary care team. LEVEL OF EVIDENCE: II

Elevated cyclooxygenase-2 expression correlates with diminished survival in carcinoma of the cervix treated with radiotherapy

PURPOSE The purpose of this study was to examine the relationship between overall survival and prognostic factors in carcinoma of the cervix treated with radiation therapy. A clinicopathologic study was performed on 24 patients. METHODS AND MATERIALS Formalin-fixed, paraffin-embedded tumor biopsies were stained for Cyclooxygenase-2 (COX-2), Topoisomerase I, Topoisomerase II, and p53. Clinical factors such as stage, grade, tumor size, pre- and post-treatment hemoglobin level, and radiotherapy dose were also evaluated. RESULTS Median follow-up was 75 months for living patients. The only immunohistochemical or clinical factor that was associated with improved survival was decreased COX-2 distribution staining. High COX-2 distribution staining was associated with decreased overall survival (p = 0.021) and decreased disease-free survival (p = 0.015) by log-rank comparison of Kaplan-Meier survival curves. The 5-year overall survival rates for tumors with low vs. high COX-2 distribution values were 75% and 35%, respectively. COX-2 staining intensity was found to correlate positively with tumor size (p = 0.022). CONCLUSION These findings indicate that increased expression of COX-2 portends a diminished survival in patients with invasive carcinoma of the cervix treated with radiotherapy. Because COX-2 is an early-response gene involved in angiogenesis and inducible by different stimuli, these data may indicate opportunity to intervene with specific inhibitors of COX-2 in carcinoma of the cervix.

Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) negatively affect overall survival in carcinoma of the cervix treated with radiotherapy.

PURPOSE The purpose of this study was to examine a variety of biomarkers in carcinoma of the cervix to better characterize (1). the natural history of the disease, (2). response to radiotherapy (RT), and (3). potential for new therapeutic strategies. MATERIALS AND METHODS Fifty-five patients with Stage IB-IVA carcinoma of the cervix, treated with definitive intent RT, and on whom tumor tissue blocks were available were included in this study. Charts were reviewed for clinical parameters and disease status. Immunohistochemistry was performed for epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), CD34, topoisomerase II alpha (topo-II), and cyclooxygenase-2 (COX-2). Univariate and multivariate Cox proportional hazards modeling was performed with disease-free survival (DFS) and overall survival (OS) as the end points. Biomarkers were evaluated for correlation between various prognostic factors. RESULTS In this series of 55 patients with carcinoma of the cervix treated with definitive RT, only stage was significant on univariate analysis for DFS (p < 0.0001). On univariate analysis, increasing FIGO stage (p < 0.0001) and membranous staining of EGFR (p < 0.037) indicated diminished OS. On multivariate analysis for DFS, COX-2, VEGF, and stage were significant (p = 0.012, p = 0.014, and p = 0.03, respectively), with increased expression indicating a worse prognosis. For OS, multivariate analysis revealed that VEGF, EGFR, and FIGO stage were significant (p = 0.005, p = 0.011, and p < 0.0001, respectively). Significant direct correlations were identified between VEGF and CD34 (p = 0.04), COX-2 and topo-II (p = 0.04), COX-2 and grade (p = 0.04), and tumor size and clinical stage (p = 0.04). CONCLUSION Multivariate analysis revealed that increased staining for VEGF and COX-2 indicated diminished DFS, and VEGF and EGFR identified patients at increased risk of death. A significant direct correlation between VEGF and CD34 implicates the process of angiogenesis. Topo-II is a proliferative marker and it correlated directly with COX-2, indicating that expression of COX-2 may be greater in more proliferative tumors. Increased expression of EGFR, VEGF, and COX-2 has identified patients with a worse prognosis in cancer of the cervix. These data support the investigation of therapeutics that target these proteins in carcinoma of the cervix.

Phosphatidylinositol 3-kinase inhibition by LY294002 radiosensitizes human cervical cancer cell lines

Purpose: The phosphatidylinositol 3-kinase (PI3K) catalytic subunit is amplified in cervical cancers, implicating PI3K in cervical carcinogenesis. We evaluated the radiosensitizing effect of PI3K inhibition by LY294002 on clonogenic survival, growth characteristics, and gene expression in cervical cancer cell lines (HeLa and CaSki). Experimental Design: Cervical cancer cells were treated separately and concurrently with the PI3K inhibitor LY294002 (10 μmol/L) and radiation (2 Gy) with serial analysis of cell count, apoptosis, and flow cytometry. PI3K inhibition was assessed by protein analysis of phosphorylated Akt. Clonogenic assays were done with varying doses of radiation and LY294002 and varied time points of administration of LY294002 proximate to the radiation dose. Surviving fractions and dose modification factors (DMF) were calculated. Each experiment was done in triplicate and analyzed using ANOVA regression analysis and Dunnetts t Test. Microarray gene expression analysis was done on the HeLa cell line. Results: PI3K inhibition with LY294002 alone did not decrease cell survival. However, treatment with LY294002 significantly radiosensitized HeLa and CaSki cell lines with DMFs (1 log cell kill) of 1.95 and 1.37, respectively. Compared with post-irradiation, pretreatment produced more radiosensitization (P < 0.0001). DMFs were 2.2, 2.0, 2.0, and 1.2 for LY294002 added at 6, 2, and 0.5 hours before irradiation and 6 hours after irradiation, respectively. LY294002 pretreatment in irradiated HeLa cells led to altered gene expression. Conclusions: Although LY294002 alone did not produce cytotoxic effects, PI3K inhibition with LY294002 produced significant radiosensitization, showed significant time-dependent effects, increased apoptosis, and altered gene expression. These findings support future investigation of PI3K inhibitors in combination with radiation therapy for carcinoma of the cervix.

Complications associated with optical-access laparoscopic trocars

OBJECTIVE To investigate the number and type of serious complications associated with optical‐access trocars reported by sources other than the medical literature. METHODS Optical‐access trocars, first introduced in 1994, were designed to decrease the risk of injury to intra‐abdominal structures by allowing the surgeon to visualize abdominal wall layers during placement. To date, very few complications with their use have been reported in the medical literature. MEDLINE, the Food and Drug Administrations Medical Device Reporting, and the Manufacturer and User Facility Device Experience databases were searched for reports of complications occurring during the use of optical‐access trocars for laparoscopic access. RESULTS Only two serious complications resulting from the use of optical‐access trocars (vena cava injuries) have been reported in the medical literature. However, 79 serious complications using these techniques have been cited in the Medical Device Reporting and Manufacturer and User Facility Device Experience databases since 1994. These include 37 major vascular injuries involving aorta, vena cava, or iliac vessels, 18 bowel perforations, 20 cases of significant bleeding from other sites, three liver lacerations, and one stomach perforation. Four of these complications resulted in patient deaths. CONCLUSION Optical‐access trocars may be associated with significant injuries despite having the ability to visualize tissue layers during insertion.

Subtotal hysterectomy in modern gynecology: A decision analysis

OBJECTIVE Our purpose was to compare the risks and benefits of subtotal (supracervical) hysterectomy with those of total hysterectomy in women at low risk for cervical cancer. STUDY DESIGN A decision analysis was performed. Baseline probabilities for operative and postoperative morbidity, mortality, and long-term quality of life were established for subtotal and total hysterectomy. RESULTS Operative complication rates and ranges for total abdominal hysterectomy were infection 3.0% (3.0% to 20.0%), hemorrhage 2.0% (2.0% to 15.4%), and adjacent organ injury 1.0% (0.7% to 2.0%). Those for subtotal hysterectomy were infection 1.4% (1.0% to 5.0%), hemorrhage 2.0% (0.7% to 4.0%), and adjacent organ injury 0.7% (0.6% to 1.0%). Operative mortality, the risk for development of cervicovaginal cancer, and long-term adverse effects on sexual or vesicourethral function were low in both groups. CONCLUSIONS Recently proposed benefits from subtotal hysterectomy are not well proven. Total hysterectomy remains the procedure of choice for most women.

Prognostic significance of histology and positive lymph node involvement following radical hysterectomy in carcinoma of the cervix

Objective:Lymph node (LN) metastasis portends a poor outcome in women with carcinoma of the uterine cervix. We queried a large database to analyze the importance of number of positive LN and histology in relation to survival after radical hysterectomy and lymphadenectomy. Methods:Data were collected from the Surveillance, Epidemiology, and End Results Program on women who had primary surgery for the years 1988 to 2003 (n = 4559). Statistical analyses were performed using conventional methods. Results:The median number of LNs examined per patient has significantly declined in recent years (P = 0.003). The 5-year rates of cause specific and overall survival were 94% and 91%, 76% and 69%, 62% and 58%, and 41% and 35%, for 0, 1 to 2, 3 to 9 and ≥10 positive LNs, respectively. Pathologic LN involvement was associated with higher grade, higher stage, larger tumor size, and squamous cell histology. Predictors for both cause specific and overall survival on multivariate analysis included number of involved LN, histology, tumor grade, tumor size, disease stage, and pelvis or paraaortic lymphatic involvement. Conclusions:Adenocarcinoma histology independently predicted for a more aggressive phenotype, particularly in women with LN involvement. The number of LNs examined did not independently predict for survival when adjusted for patient and disease characteristics, providing context for the investigation of sentinel node biopsy or other sampling methods. LN positive disease in carcinoma of the cervix predicts a prognosis that is inversely related to the number of involved nodes. Tumor grade, size, and FIGO stage were associated with increasing risk for lymph node metastases.

Impact of comorbid conditions on survival in endometrial cancer.

Objectives:To evaluate the contribution of multiple medical comorbidities on the overall survival of endometrial cancer patients. Methods:The study evaluated 490 endometrial cancer patients stages I to IV who were treated between 1992 and 2008 with a hysterectomy with or without radiation therapy (RT). Hazard ratios (HR) were calculated for multiple variables including: diabetes mellitus (DM), hypertension (HTN), body mass index, smoking, RT, and years of estrogen exposure and then recalculated with an adjustment for age and grade as potential confounders. Results:In this study, 47% of patients had HTN, 26% had DM, 11% were smokers, 64% were stage I, 39% were grade 1, and 36% received RT. The presence of DM and HTN on univariate analysis resulted in decreased survival with [HR 1.70; 95% confidence interval (CI), 1.18-2.46] and (HR 1.66; 95% CI, 1.17-2.36), respectively. On multivariate analysis after correction for stage, age, and grade, DM and HTN continued to show a reduced survival rate (HR 1.58; 95% CI, 1.07-2.33 and HR 1.51; 95% CI, 1.06-2.15, respectively). Body mass index, smoking, parity, age at menarche, and years of estrogen exposure did not affect survival before or after correction for stage, age, and grade. Conclusions:In this study, DM and HTN adversely effected survival. Given the favorable survival rate for most patients with endometrial cancer, attention to comorbid conditions, and particularly DM and HTN, is becoming more relevant for its implications on current health care and policy.

Fertility-sparing management of endometrial adenocarcinoma

Approximately 15% of patients with endometrial cancer are premenopausal. Previous studies largely support the conservative treatment of endometrial cancer in women desiring future fertility. From these studies, 75% to 80% of patients demonstrate a complete response to progestin therapy and the average recurrence rate is 30% to 35%. Conservative therapy should be reserved for women with International Federation of Gynecology and Obstetrics grade I tumors. Before conservative management, patients should be informed of the elevated risk (11%–29%) of concurrent ovarian cancer in cases of premenopausal endometrial cancer, and screening and ongoing surveillance during the treatment period is mandatory. A suggestion of myometrial invasion or metastatic disease is a contraindication to conservative management. Individuals meeting criteria for Lynch syndrome testing should be referred to genetic counseling. Fertility treatment should be individualized, and close surveillance is required during treatment. Staging hysterectomy is recommended after the completion of the childbearing period. Target Audience: Obstetricians & Gynecologists, Family Physicians Learning Objectives: After participating in this activity, physicians should be better able to select appropriate candidates with endometrial cancer for fertility-sparing treatment. Educate patients with endometrial cancer regarding the risks and benefits of standard of care therapy and conservative therapy and screen appropriate patients for lynch syndrome.

Familial clustering of endometrial cancer in a well-defined population

OBJECTIVE Using a genealogical database, we examined risk of endometrial cancer among family members of individuals with endometrial cancer. METHODS We identified endometrial cancer cases in the Utah Population Database (UPDB), a computerized archive of genealogy data linked to the Utah Cancer Registry. We tested for excess relatedness and estimated relative risks (RR) among first-, second-, and third-degree relatives of endometrial cancer cases and stratified analyses by tumor histology and body mass index (BMI). RESULTS We identified 3911 cases; 3546 were Type I cancers and 365 Type II cancers. The RR for all endometrial cancer cases and for cases with type I histology was significantly increased for first-, second-, and third-degree relatives. An almost three-fold risk was observed among first-degree relatives of individuals with Type I cancers and a 2.24-fold risk among second-degree relatives of Type I morbidly obese cases. The magnitude of endometrial cancer risk among relatives appeared to increase with case BMI. CONCLUSIONS The elevated risks for endometrial cancer among first-, second-, and third-degree relatives support a genetic contribution to predisposition to endometrial cancer. The increased risk appears to be limited to Type I endometrial cancer. We observed increased risks for endometrial cancer among relatives of obese and morbidly obese Type I cases, which may be indicative of a synergistic relationship between underlying genetic propensity and shared environment. This study quantifies risk of developing cancer among relatives of patients with disease and provides the basis for further analysis of high risk pedigrees and gene identification for genetic etiologies of endometrial cancer.