John C. Elkas

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. LEVEL OF EVIDENCE: III

Gynecologic malignancies in women aged less than 25 years

OBJECTIVE: To describe the epidemiologic characteristics of gynecologic malignancies in patients 25 years of age or younger. METHODS: The Automated Central Tumor Registry (ACTUR), the cancer registry for the Department of Defense, was used to identify children, adolescents, and young adults diagnosed with gynecologic malignancies. Specifically, primary ovarian, uterine, cervical, vaginal, and vulvar malignancies diagnosed between 1990 and 2002 were included in the analysis. Data from the Department of Defense tumor registry were then compared with results obtained from the national Surveillance, Epidemiology, and End Report (SEER) program database. RESULTS: Two hundred fifty-one cases were identified in the Department of Defense tumor registry. The most common primary site was ovary, with 116 cases (46%), followed by cervix, with 108 cases (43%). The most common histological types were germ cell (35%) for ovary, squamous cell (52%) for cervix, choriocarcinoma (18%) for uterus, and squamous cell (30%) for vulva/vagina. The 21- to 25-year-old age group had the greatest number of cases for the entire cohort (23%). Most patients had only local disease at time of diagnosis, and the 5-year survival percentage was 86% (95% confidence interval 80–91) for all patients with ovarian and cervical carcinoma. Data from the SEER program demonstrated a similar distribution and incidence pattern. CONCLUSION: The ovary and cervix are the most common primary sites of gynecologic malignancies in patients 25 years of age or younger. Health maintenance programs for patients in this age group should continue to include pelvic exams and Pap test screening. LEVEL OF EVIDENCE: II-2

Modulation of endometrial steroid receptors and growth regulatory genes by tamoxifen.

Objective We investigated tamoxifens effects on the expression of growth regulatory genes in the endometrium to identify the mechanism by which tamoxifen induces proliferation. Methods Using immunohistochemical techniques, we analyzed 39 endometrial specimens for expression of Ki-67, lactoferrin, transforming growth factor-α, tumor necrosis factor receptor-II, adrenomedullin, estrogen receptors, and progesterone receptors. Twenty specimens were obtained from postmenopausal breast cancer patients treated with tamoxifen (20 mg/day) for at least 6 months to include two endometrial adenocarcinoma specimens. Five secretory phase, three proliferative phase, and seven atrophic endometrial specimens were used as controls. In addition, four endometrial adenocarcinoma specimens were reviewed from patients not treated with tamoxifen. Intensity of immunostaining was quantified using digitized imaging techniques. Results Overexpression of both estrogen receptors and progesterone receptors, and an elevated proliferative index were the most consistent effects observed in benign endometrial specimens from tamoxifen-treated patients compared with atrophic controls (P < .003). This staining pattern was also evident in adenocarcinomas from patients who received tamoxifen. Benign endometrium from tamoxifen-treated patients also expressed transforming growth factor-α, tumor necrosis factor receptor-II, lactoferrin, and adrenomedullin at levels comparable with those found in proliferative endometrial specimens. Conclusion These data provide further documentation that the uterotropic effects of tamoxifen may be due, at least in part, to the induction of estrogen receptors and progesterone receptors, as well as other genes associated with the proliferative phase. Furthermore, analysis of estrogen receptors, progesterone receptors, and Ki-67 may be useful in identifying postmenopausal individuals on tamoxifen, who are at increased risk for developing endometrial cancer.

Novel hormone treatment of benign metastasizing leiomyoma: an analysis of five cases and literature review.

OBJECTIVEnTo evaluate novel hormonal therapies in patients with unresectable benign metastasizing leiomyoma (BML) disease.nnnDESIGNnCase series.nnnSETTINGnNational Institutes of Health (NIH).nnnPATIENT(S)nFive subjects with the diagnosis of BML based on imaging and/or histopathologic diagnosis.nnnINTERVENTION(S)nFour patients were treated with single or combination therapy of leuprolide acetate and/or an aromatase inhibitor. One patient was treated with an antiprogestin (CDB-2914).nnnMAIN OUTCOME MEASURE(S)nResponse to therapy was measured by tumor burden on cross-sectional imaging employing RECIST (Response Evaluation Criteria in Solid Tumors) 1.1 guidelines.nnnRESULT(S)nFour patients treated with single or combination therapy of leuprolide acetate and/or an aromatase inhibitor demonstrated stable disease with reduction in tumor burden. The fifth patient treated with antiprogestin (CDB-2914) had degeneration of her tumor, progression of its size, and an improvement in symptoms.nnnCONCLUSION(S)nHormone treatment with GnRH agonist and/or aromatase inhibition may be a therapeutic option to reduce tumor burden in unresectable BML disease or for those patients who wish to avoid surgical intervention. RECIST 1.1 guidelines, while traditionally used to evaluate tumor response to cancer therapeutics, may be useful in evaluating BML tumor burden response to hormone therapy.

Is atypical squamous cells that cannot exclude high-grade squamous intraepithelial lesion clinically significant?

Objective. To determine the cumulative risk of cervical intraepithelial neoplasia (CIN) 2 or 3 in patients with atypical squamous cells, cannot exclude HSIL (ASC-H). Methods. A retrospective analysis was performed to identify patients referred to the dysplasia clinic with ASC-H. Initial evaluation included colposcopy, endocervical curettage, and an ectocervical biopsy, when indicated, in all the patients. A follow-up evaluation was performed at 6 and 12 months. Cumulative histological diagnosis of CIN 2 or 3 at 12 months served as the clinical end point. Results. Two hundred twenty-nine patients with ASC-H and with a mean age of 32.8 years were evaluated. At the time of initial colposcopy, only 10.0% (23/229; 95% CI = 6.5%-15%) of the patients had histological evidence of CIN 2 or 3. The cumulative risk of CIN 2 or 3 was 12.2% (95% CI = 8%-17%). Conclusions. Evaluation of patients with ASC-H with colposcopy does lead to the detection of CIN 2 or 3 but perhaps at a rate lower than previously reported.

Conservative management of extra-adrenal pheochromocytoma during pregnancy.

BACKGROUND: Extra-adrenal pheochromocytomas are catecholamine-secreting tumors that arise from chromaffin cells of the paraganglion sympathetic system. All of the previously reported cases have described surgical resection during the antepartum period. CASE: At 14 weeks of gestation, a multiparous patient was diagnosed with an extra-adrenal dopaminergic pheochromocytoma. A decision was made to delay surgical intervention until the postpartum period. Phenoxybenzamine, 10 mg per day, was subsequently started. At 35 + 2 weeks of gestation, the patient delivered a 2,600 g infant via an uncomplicated cesarean. Three weeks later, the extra-adrenal pheochromocytoma was removed, and she also underwent total abdominal hysterectomy, bilateral salpingo-oophorectomy, and rectosigmoid resection with end-to-end colostomy. CONCLUSION: Conservative management of dopaminergic-secreting extra-adrenal pheochromocytomas can result in favorable maternal and fetal outcomes.

Hematologic changes after splenectomy for cytoreduction: implications for predicting infection and effects on chemotherapy

Postsplenectomy leukocytosis and thrombocytosis are common findings in trauma patients. The intent of this study is to describe postsplenectomy hematologic changes in gynecological oncology surgery and subsequent chemotherapy. We performed a retrospective record review of gynecological oncology patients at our institutions. Postsurgical hematologic changes, infectious morbidity, and pre- and post-chemotherapy hematologic changes were noted. Data were analyzed using repeated measures analysis of variance. We identified 27 patients who underwent cytoreductive surgery with splenectomy. Thirteen patients with splenectomy had postoperative chemotherapy data available, and we matched these patients with 13 control patients who underwent cytoreduction surgery without splenectomy and postoperative chemotherapy. Nine of the 27 splenectomy patients had documented infectious morbidity. There was a significant difference in postoperative platelet counts between the infected and the noninfected splenectomy patients (P= 0.037), and a significant difference between splenectomy and control patients for white blood cell (WBC) counts (P= 0.007). Patients with splenectomy had higher precycle WBC, absolute neutrophil count (ANC), platelet counts, and higher postcycle nadir levels in all cycles compared to control patients. There was a significant overall difference between splenectomy patients and controls with regard to WBC (P= 0.001), ANC (P= 0.005), and platelet counts (P= 0.016) during chemotherapy cycles. Median postchemotherapy nadir WBC was 4.4 (range: 3.4–4.8) for the splenectomy group versus 2.8 (range: 2.5–3.0) for the control group. Median postchemotherapy nadir ANC was 1800 (range: 1320–2450) for the splenectomy group and 1001 (range: 864–1064) for the control group. Median postchemotherapy nadir platelet count was 222 (range: 181–277) for the splenectomy patients and 169 (range 164–215) for the control patients. In conclusion, the patients who undergo splenectomy as part of cytoreductive surgeries have a statistically significant leukocytosis and insignificant thrombocytosis relative to the control patients. Leukocytosis alone is not an accurate indicator of infection. Splenectomy is not associated with an increased risk of chemotherapy-related neutropenia and thrombocytopenia.

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.

Interim analysis of a phase I/IIa trial assessing E39+GM-CSF, a folate binding protein vaccine, to prevent recurrence in ovarian and endometrial cancer patients

BACKGROUND Folate binding protein(FBP) is an immunogenic protein over-expressed in endometrial(EC) and ovarian cancer(OC). We are conducting a phase I/IIa trial of E39 (GALE 301)+GM-CSF, an HLA-A2-restricted, FBP-derived peptide vaccine to prevent recurrences in disease-free EC and OC patients. This interim analysis summarizes toxicity, immunologic responses, and clinical outcomes to date. METHODS HLA-A2+ patients were vaccinated(VG), and HLA-A2- or -A2+ patients were followed as controls(CG). Six monthly intradermal inoculations of E39+250mcg GM-CSF were administered to VG. Demographic, safety, immunologic, and recurrence rate(RR) data were collected and evaluated. RESULTS This trial enrolled 51 patients; 29 in the VG and 22 in the CG. Fifteen patients received 1000mcg E39, and 14 received <1000mcg. There were no clinicopathologic differences between groups(all p = 0.1). E39 was well-tolerated regardless of dose. DTH increased pre- to post-vaccination (5.71.5 mm vs 10.33.0 mm, p = 0.06) in the VG, and increased more in the 1000mcg group (3.82.0 mm vs 9.53.5 mm, p = 0.03). With 12 months median follow-up, the RR was 41% (VG) vs 55% (CG), p = 0.41. Among the 1000mcg patients, the RR was 13.3% vs 55% CG, p = 0.01. Estimated 2-year DFS was 85.7% in the 1000mcg group vs 33.6% in the CG (p = 0.021). CONCLUSIONS This phase I/IIa trial reveals that E39+GM-CSF is well-tolerated and elicits a strong, dose-dependent in vivo immune response. Early efficacy results are promising in the 1000 mcg dose cohort. This study proves the safety and establishes the dose of E39 for a larger prospective, randomized, controlled trial in HLA-A2+ EC and OC patients to prevent recurrence.

The use of acellular dermal graft for vulvovaginal reconstruction in a patient with lichen planus.

BACKGROUND: Vulvovaginal lichen planus is an inflammatory dermatosis that can progress to an erosive form with scarring of the vulva, resorption of the labia minora, vaginal synechiae, and vaginal obliteration secondary to desquamative vaginitis. Traditionally, conservative medical therapy has consisted of topical corticosteroids and immunosuppressants. CASE: A 61-year-old woman with a history of refractory erosive vulvovaginal lichen planus presented with complete obliteration of the vaginal vault. The patient failed both medical and conservative surgical management and desired definitive management. After performing a skinning vulvectomy and simple vaginectomy, acellular dermal graft was used for grafting the vulva and creating a neovagina. CONCLUSION: Acellular dermal graft is a suitable graft material for vulvar and vaginal reconstruction in select patients, and it avoids the postoperative pain associated with graft harvest sites.