The use of acellular dermal allograft for vulvovaginal reconstruction.

BACKGROUND: Many different techniques that require the surgeon to harvest autologous tissue to create a neovagina have been described in the literature. TECHNIQUE: We describe a technique for creating a neovagina with the use of an acellular dermal allograft as a replacement for split-thickness skin graft. Three patients are presented who had a successful creation of a neovagina with this technique. The indications for vaginoplasty include vaginal agglutination from lichen planus, squamous cell carcinoma of the vagina, and vaginal agenesis. CONCLUSION: The creation of a neovagina using an acellular dermal allograft can be successfully accomplished in patients undergoing constructive and exenterative procedures. The use of an acellular dermal allograft decreases operative time and decreases the incidence of postoperative morbidity because harvesting autologous tissue for the neovagina is not required.

Prognostic factors for stage I ovarian carcinoma.

Stage I ovarian carcinoma is relatively uncommon, and data on prognostic factors are conflicting. The clinical and pathologic features of 51 International Federation of Gynecology and Obstetrics stage I ovarian carcinomas were analyzed. There were 22 stage IA, 1 stage IB, and 28 stage IC cases. The mean follow-up was 6.1 years. The 5-year and 10-year disease-specific survival rates for the entire cohort were 92% and 78%, respectively. Among 51 patients, there were 6 tumor deaths, and 1 patient died of unrelated causes. All patients who died of disease were stage IC. Significant adverse prognostic factors were serous histology [relative risk (RR) 5.4, 95% confidence interval (CI) 1.3-22.0] and stage IC (RR 1.3, 95% CI 1.1-1.5). Among factors associated with stage IC, only positive washings or ascites affected survival (RR 9.25, 95% CI 1.9-44.4). The 5-year survival rates for stages IA and IC were 100% and 83%, respectively (P<0.025, log rank test). For comprehensively staged patients, the 5-year survival rate was 96% as compared with 72% for all others (P<0.025, log rank test). Tumor rupture, surface involvement, histologic grade and clear cell histology were not of adverse prognostic significance. Serous histology and positive washings or ascites are adverse prognostic factors in stage I. The prognostic importance of tumor grade, rupture, surface involvement and clear cell histology remains unclear. Patients who are International Federation of Gynecology and Obstetrics stage I on the basis of comprehensive surgical staging have an excellent prognosis.

Cervical biopsy and excision procedure specimens lack sufficient predictive value for lymph-vascular space invasion seen at hysterectomy for cervical cancer.

OBJECTIVE: The purpose of this study was to determine whether lymph-vascular space invasion (LVSI) that is discovered in cervical biopsy and excision specimens is associated with LVSI in the hysterectomy specimen of patients with cervical cancer. STUDY DESIGN: A retrospective pathologic review to determine the presence of LVSI in cervical biopsy specimens, cold-knife cone biopsy (CKC biopsy), and loop electrical excision procedure (LEEP) specimens that contained cervical cancer was performed if subsequent hysterectomy results were available for review. Data were analyzed with chi-square analysis testing. RESULTS: One hundred six patients were identified. The negative predictive value of the biopsy is lower at 0.45 than either the CKC biopsy (0.83) or LEEP (0.57); however, the positive predictive value (0.83) is higher than either CKC biopsy (0.50) or LEEP (0.75). LVSI, when present in cervical biopsy (odds ratio, 4.13; 95% CI, 0.414-98.446), CKC biopsy (odds ratio, 4.8; 95% CI, 0.542-46.280), and LEEP (odds ratio, 4.0; 95% CI, 0.439-43.793) specimens, is associated with a statistically insignificant increased risk of LVSI in the hysterectomy specimen. CONCLUSION: Cervical biopsy and excision specimens lack sufficient negative predictive value for the detection of LVSI in the hysterectomy specimen.

The ability of endometrial biopsies with atypical complex hyperplasia to guide surgical management.

OBJECTIVE: This study was undertaken to determine the clinical relevance of "qualifying comments" on pathology reports of complex atypical endometrial hyperplasia. STUDY DESIGN: A retrospective review of endometrial biopsy specimens with atypical hyperplasia at our institutions was performed if subsequent hysterectomy results were available for review. Endometrial biopsy results were graded on an ordinal scale (complex atypical endometrial hyperplasia vs atypical endometrial hyperplasia "cannot rule out a more severe lesion") and compared with pathology obtained at hysterectomy. Data were analyzed by using Fisher's exact test. RESULTS: Endometrial biopsy specimens were associated with carcinoma in 37.5% (18/48) of complex atypical endometrial hyperplasia cases and in 60% (18/30) of atypical endometrial hyperplasia-cancer cases. Atypical endometrial hyperplasia-cancer on biopsy was associated with an increased risk of discovering a malignancy at intermediate/high-risk for lymph node involvement (odds ratio 4.71, P = .0256). CONCLUSION: Biopsy specimens that show atypical endometrial hyperplasia-cancer are associated with an increased risk of finding a cancer at intermediate or high risk for nodal metastasis.

Overexpression of folate binding protein and mesothelin are associated with uterine serous carcinoma.

PURPOSE: Folate receptor alpha (FOLR1) is a membrane bound receptor involved in the transport of folate as well as other regulatory cellular processes. The purpose of this study was to examine the expression of FOLR1 in uterine cancers and to identify changes in gene expression that are associated with overexpression of FOLR1. EXPERIMENTAL DESIGN: Fifty-eight frozen uterine cancer specimens were stained for FOLR1 using immunohistochemistry and results were correlated with transcript expression noted on quantitative PCR. Total RNA from 16 cases of uterine serous carcinoma (USC) was analyzed for gene expression using the Affymetrix HG-U133A and HG-U133B GeneChip set. USCs overexpressing FOLR1 were compared to cancers with an absence of FOLR1 using binary comparison and template matching of data was used to identify genes that correlate with FOLR1 expression. Selected targets from this analysis were evaluated by quantitative PCR as well as in an independent set of USC represented in quadruplicate on a tissue microarray (TMA). RESULTS: Overexpression of FOLR1 was observed in 11/16 (69%) of USC and 0/10 normal endometrium cases using frozen tissue specimens. Binary comparison between FOLR1 positive and negative cases identified 121 genes altered by 2-fold at p<0.01 of which 45 are well correlated with FOLR1 expression pattern. Using quantitative PCR, both mesothelin (MSLN) and PTGS1 (COX1) were significantly increased in FOLR1 overexpressing tumors (p=0.014 and p=0.006 respectively). TMA confirmed that overexpression of FOLR1 and MSLN respectively occurred in 23/48 (48%) and 17/54 (32%) of pure USC. CONCLUSION: Both FOLR1 and MSLN are cell surface targets that are co-expressed at high levels in USC and are appealing targets for biologic therapy.

A phase I trial of oxaliplatin and topotecan in recurrent ovarian carcinoma.

OBJECTIVE: Oxaliplatin and topotecan have demonstrated activity as single agents against recurrent platinum-sensitive and -resistant ovarian cancer, as well as synergy in vitro. This was a dose-finding study of combination therapy with weekly topotecan and alternating-week oxaliplatin in patients with recurrent epithelial ovarian cancer. METHODS: Eligible patients had a diagnosis of recurrent ovarian or primary peritoneal carcinoma, a performance status of 0-2, and normal bone marrow, renal, and hepatic function. On days 1 and 15 of a 28-day cycle, patients received a fixed dose of oxaliplatin (85 mg/m2) via intravenous infusion. On days 1, 8, and 15, patients received an escalating dose of intravenous topotecan (2.0-4.0 mg/m2). Five dose levels were planned with a minimum cohort of 3 patients at each level. RESULTS: Thirteen patients were enrolled and received a total of 50 cycles of chemotherapy. The maximum tolerated dose was 85 mg/m2 of oxaliplatin and 3.0 mg/m2 of topotecan, and grade 3 neutropenia was the dose-limiting toxicity. Four of nine (44%) evaluable patients had stable disease or a partial response to the drug combination as assessed by cancer antigen-125 levels. CONCLUSIONS: A 28-day schedule of oxaliplatin and topotecan is safe and well tolerated. Because of the in vitro synergy observed between topoisomerase I inhibitors and platinum derivatives and the tolerability reported in the current study, this regimen warrants further investigation.

Sustained response to bevacizumab in refractory well-differentiated ovarian neoplasms.

BACKGROUND: Bevacizumab has demonstrated activity against a variety of solid tumors, including ovarian carcinoma. However, there have not been reproducible prognostic features associated with its activity. CASES: One patient each with recurrent, refractory well-differentiated serous-endometrioid ovarian carcinoma, micropapillary serous carcinoma of the ovary, and primary peritoneal micropapillary serous carcinoma were treated with single agent bevacizumab (15 mg/kg [DOSAGE ERROR CORRECTED] intravenously every 3 weeks). All three have had dramatic sustained responses of 15, 15, and 22 months' duration. CONCLUSION: Bevacizumab may have significant activity against well-differentiated ovarian carcinoma and micropapillary serous carcinomas of the ovary or peritoneum. Since these tumors are generally indolent and not responsive to adjuvant therapy, further investigation is warranted.

Cost-effectiveness analysis of liquid-based cytology and human papillomavirus testing in cervical cancer screening.

OBJECTIVE: To compare the outcomes of several cervix cancer screening strategies in a military population using a model that considers both direct and indirect costs of health care. METHODS: A Markov model of the natural history of cervical cancer was used to simulate an age-stratified cohort of 100,000 active duty women in the U.S. Army. Total costs and incremental cost-effectiveness ratios were estimated for different modalities of screening: liquid-based cytology with testing for human papillomavirus (HPV) irrespective of cytologic results compared with liquid-based cytology with HPV detection for cytologic results of atypical cells of undetermined significance (reflex HPV). The costs and outcomes of these screening methods were evaluated separately as well as in combination (liquid-based cytology and reflex HPV before age 30 years and DNA and Pap test every 3 years thereafter). Each of these screening methods was evaluated at 1-, 2-, and 3-year intervals. RESULTS: A screening strategy of liquid-based cytology and reflex HPV every 2 or 3 years is the least costly strategy among active duty women irrespective of age, especially when accounting for time costs associated with screening, diagnosis, and treatment of cervix cancer. A strategy of liquid-based cytology and HPV testing irrespective of cytology results is the most effective strategy; however, it is also the most costly of the strategies tested, even when performed in patients older than 30 years of age. CONCLUSION: In the U.S. Army, cervix cancer screening performed with liquid-based cytology and reflex HPV testing of atypical squamous cells of undetermined significance performed every 2 years is cost-effective, especially when indirect costs are considered.

Prediction of lymph node metastasis in patients with endometrioid endometrial cancer using expression microarray.

PURPOSE: To characterize the gene expression profiles of endometrioid endometrial cancers associated with lymph node metastasis in an effort to identify genes associated with metastatic spread. EXPERIMENTAL DESIGN: Tumors from 41 patients with endometrioid endometrial cancer grossly confined to the uterine cavity were evaluated. Positive lymph nodes were noted in 12 of 41 patients. RNA was analyzed for gene expression using the Affymetrix HG133A and HG133B GeneChip set, representing 45,000 array features covering >28,000 UniGene clusters. Data analysis was done using multidimensional scaling, binary comparison, and hierarchical clustering. Gene expression for several differentially expressed genes was examined using quantitative PCR. RESULTS: Gene expression data was obtained from 30,964 genes that were detected in at least 5% of the cases. Supervised analysis of node-positive versus node-negative cases indicated that 450 genes were significantly differentially expressed between the two classes at P < 0.005, 81 of which were differentially expressed by at least 2-fold at P < 0.005. Overexpressed genes included two cell cycle checkpoint genes, CDC2 and MAD2L1, which have previously been described in association with lymph node metastasis in other cancer types. The ZIC2 zinc finger gene was overexpressed in endometrial cancers with positive nodes versus those with negative nodes. CONCLUSION: Gene expression profiling of the primary tumors in patients with endometrioid endometrial cancers seems promising for identifying genes associated with lymph node metastasis. Future studies should address whether the status of nodal metastasis can be determined from the expression profiles of preoperative tissue specimens.

Spontaneous pregnancy following cytoreduction with peritonectomy and hyperthermic intraperitoneal chemotherapy.

BACKGROUND: Spontaneous pregnancy is rare after radical cytoreduction and intraperitoneal chemotherapy. CASE: We present a case of a 28-year-old female with extensive, bulky malignant peritoneal epitheliod mesothelioma who underwent optimal cytoreduction with peritonectomy followed by intraoperative hyperthermic cisplatin and postoperative intraperitoneal paclitaxel and fluorouracil. Fourteen months after the conclusion of her therapy, she spontaneously conceived, resulting in an uneventful term pregnancy and spontaneous vaginal delivery. CONCLUSION: Fertility may be preserved in select patients after radical cytoreduction and hyperthermic intraperitoneal chemotherapy.

The prevalence of HR-HPV DNA in ASC-US Pap smears: A military population study.

OBJECTIVE: To determine the prevalence of HR-HPV DNA in ASC-US Pap smears following implementation of the Bethesda 2001 classification system. METHODS: A computer database of Pap smears obtained within Department of the Army medical facilities was queried for the study period August 2002 to June 2004. All ASC-US Pap smears that underwent reflex testing for HR-HPV DNA were included. Additional clinical and demographic data were obtained from facilities within the US northeast region to evaluate the differences in ASC-US and SIL rates between the current and former Bethesda classification systems. RESULTS: 550,000 Pap smears were collected during the study period. The HR-HPV prevalence was 40.8% (95% confidence interval [CI] = 40.3 to 41.3) among 40,870 patients with ASC-US Pap smears. Within the northeast region, the HR-HPV prevalence in ASC-US Pap smears decreased from 61.2% (95% CI = 57.4 to 64.8%) in patients 18-22 years old to 24.9% (95% CI = 23.1 to 26.8%) in patients age 29 and older. When comparing the two classification systems, significant increases in both ASC-H and SIL and decreases in ASC-US were appreciated after the institution of Bethesda system 2001. CONCLUSION: In our large, diverse cohort, the implementation of the Bethesda II system has resulted in a decrease in ASC-US Pap smear results. Additionally, the prevalence of HR-HPV in the ASC-US population was 40.8%, significantly lower than the rate noted in the ALTS trial under the Bethesda I classification system.

Markedly elevated beta-hCG levels in a normal singleton gestation with hyperreactio luteinalis.

BACKGROUND: Human chorionic gonadotropin (hCG) is produced by the trophoblast early in pregnancy and peaks at a level of approximately 100,000 IU/liter around the ninth week of gestation. Abnormally high levels are usually noted in association with multiple gestation, molar gestation, and specific ovarian or gestational malignancies. CASES: A multiparous patient in the second trimester was referred for evaluation after a maternal triple marker screen was incalculable due to a beta-hCG level of 2.1 million IU/L. Targeted sonography revealed bilateral complex adnexal masses with a solid component of the left ovary, a normal fetus, and normal placenta. The patient underwent an exploratory laparotomy at 18 weeks' gestational age. A left oophorectomy was performed. Pathology confirmed hyperreactio luteinalis. The remainder of the pregnancy was remarkable for preterm labor and delivery at 35 weeks' gestational age. At delivery, the hCG level was noted to be 24,210 IU/L, and the fetus and placenta were normal. CONCLUSION: Markedly elevated hCG levels rarely occur in normal singleton pregnancy and can be associated with hyperreactio luteinalis. When noted, a work-up to evaluate possible malignancy, molar gestation, and multiple gestation should be pursued.