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.

Diffuse laminar endocervical glandular hyperplasia: a case report.

BACKGROUND: Diffuse laminar endocervical glandular hyperplasia is extremely rare with only 14 cases reported in the literature. Diffuse laminar endocervical glandular hyperplasia is a benign lesion that is easily confused with malignancy. CASE REPORT: We present a 22-year-old woman referred to our gynecologic oncology service with a 2.0 x 4.0-cm exophytic cervical mass. Colposcopic-directed cervical biopsies were diagnosed as adenocarcinoma, suggestive of minimal deviation adenocarcinoma. Computed tomographic scans of the abdomen and the pelvis failed to reveal any metastatic foci. A radical abdominal hysterectomy with pelvic and para-aortic lymph node sampling was performed without complications. Final pathology revealed diffuse laminar endocervical glandular hyperplasia. CONCLUSIONS: Diffuse laminar endocervical glandular hyperplasia is an uncommon histological type of pseudoneoplastic glandular lesions that may be found in the cervix, and this entity should be considered in the differential diagnosis of a potentially malignant endocervical glandular lesion.

Final analysis of a phase I/IIa trial of the folate-binding protein-derived E39 peptide vaccine to prevent recurrence in ovarian and endometrial cancer patients.

BACKGROUND: E39, an HLA-A2-restricted, immunogenic peptide derived from the folate-binding protein (FBP), is overexpressed in multiple malignancies. We conducted a phase I/IIa trial of the E39 + GM-CSF vaccine with booster inoculations of either E39 or E39' (an attenuated version of E39) to prevent recurrences in disease-free endometrial and ovarian cancer patients(pts). Here, we present the final 24-month landmark analysis. PATIENTS AND METHODS: HLA-A2 + patients receiving E39 + GM-CSF were included in the vaccine group (VG), and HLA-A2- pts (or HLA-A2 + patients refusing vaccine) were followed as the control group (CG). VG group received 6 monthly inoculations as the primary vaccine series (PVS) and were randomized to receive either E39 or E39' booster inoculations. Demographic, safety, immunologic, and disease-free survival (DFS) data were collected and evaluated. RESULTS: Fifty-one patients were enrolled; 29 in the VG and 22 in the CG. Fourteen patients received <1000 µg and 15 received 1000 µg of E39. There were no clinicopathologic differences between VG and CG or between dose groups. E39 was well tolerated. At the 24 months landmark, DFS was 55.5% (VG) vs 40.0% (CG), P = 0.339. Patients receiving 1000 µg and boosted patients also showed improved DFS (P < 0.03). DFS was improved in the 1000 µg group after treatment of primary disease (90.0% vs CG:42.9%, P = 0.007), but not in recurrent patients. In low-FBP expressing patients, DFS was 100.0% (1000 µg), 50.0% (<1000 µg), and 25.0% (CG), P = 0.029. CONCLUSIONS: This phase I/IIa trial reveals that E39 + GM-CSF is safe and may be effective in preventing recurrence in high-risk ovarian and endometrial cancer when optimally dosed (1000 µg) to FBP low patients being treated for primary disease.

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 (5.7±1.5 mm vs 10.3±3.0 mm, p = 0.06) in the VG, and increased more in the 1000mcg group (3.8±2.0 mm vs 9.5±3.5 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.

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.

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.

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.

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.

Normal endometrial cells in liquid-based cervical cytology specimens in women aged 40 or older.

OBJECTIVE: The 2001 Bethesda System consensus statement directs the reporting of endometrial cells on cervical cytologic preparations in women aged 40 years or older. Our objective was to assess the significance of endometrial cells on cervical liquid-based cytology (LBC) specimens in this population. METHODS: The population included women aged 40 years or older in whom endometrial cells were identified in otherwise normal LBC specimens from December 2001 through June 2005, and who subsequently underwent endometrial sampling within a 12-month period. Patient age, menopausal status, hormonal use, the presence or absence of co-incident symptoms and endometrial sampling results were recorded. RESULTS: Endometrial cells were identified on LBC specimens in 2494 women during the study period, for an incidence of 0.4%. Of these, 370 women underwent endometrial sampling within 12 months of the incident LBC preparation and met inclusion criteria. In asymptomatic premenopausal women, sampled solely due to the presence of endometrial cells, 2.1% were identified with significant endometrial pathology, compared to 2.6% of symptomatic premenopausal women. In menopausal women, only those with symptoms (mainly bleeding) had significant pathology on subsequent sampling (25%); none of the asymptomatic menopausal women were found to have hyperplasia or carcinoma. No significant differences were identified in premenopausal women according to the time of sampling during the menstrual cycle or use of oral contraceptives. CONCLUSION: Endometrial cells on LBC preparations, even in the absence of symptoms in premenopausal women aged 40 years or older, are associated with significant uterine pathology.

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.

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.

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.

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.

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.

Lower urinary tract reconstruction with ileum in the treatment of gynecologic malignancies.

INTRODUCTION: Advanced or recurrent gynecologic malignancies can invade or obstruct the lower urinary tract. If extirpation is necessary for cytoreduction or repair of radiation sequelae, treatment has typically involved creation of either an ileal conduit or a cutaneous continent urinary diversion. As an alternative, a more limited resection with urinary tract reconstruction using ileum for interposition or augmentation may allow for the preservation of urethral voiding. CASES: We describe the use of ileal segments for lower urinary tract reconstruction in the treatment of ten patients with advanced or recurrent gynecologic malignancies. The clinical history, surgical technique, and patient outcomes are reviewed. DISCUSSION: These cases demonstrate that limited bladder or ureteral resection with reconstruction using ileal segments may offer select patients preservation of urethral voiding.

The impact of converting to liquid-based cervical cytology in a military population.

OBJECTIVE: The liquid-based cytology Pap test was adopted as the exclusive collection method for cervical cytology in military treatment facilities within the National Capital Area in 2001. We sought to determine the impact of converting from conventional to liquid-based cervical cytology. METHODS: A retrospective population-based study was performed to analyze the cervical cytology results from the National Capital Area for fiscal years 1999, 2000, 2002, and 2003. Using a computer database, the results of 78,738 conventional and 76,675 liquid-based cervico-vaginal cytology examinations were reviewed. All cytology samples during the study period were collected with the same collection device and were processed in a single laboratory. RESULTS: An increase of 116% (P < 0.005) in the mean rate of LSIL detection and a 38% (P < 0.005) increase in HSIL detection were noted with conversion to liquid-based cytology. A 65% (P < 0.005) decrease in the mean rate of atypical glandular cell detection was also observed. However, a mean increase of 46% (P < 0.005) per year was noted in the unsatisfactory rate with conversion to liquid-based cytology. The incidence of cervical carcinoma did not change during the study period. CONCLUSIONS: Consistent with previous reports, conversion from conventional to liquid-based Pap testing in this population resulted in a significant increase in the detection rates of both LSIL and HSIL. Contrary to earlier studies, we noted an almost 50% increase in the number of unsatisfactory samples after conversion. Further studies are warranted to determine the potential etiology of these findings to include the role of collection devices.

The utility of hand-assisted laparoscopy in ovarian cancer.

INTRODUCTION: The traditional approach to patients with ovarian cancer is cytoreductive surgery and surgical staging through a vertical midline laparotomy. While laparoscopy has become an integral part of gynecologic surgery, debulking procedures have not been feasible to date with standard minimally invasive techniques. METHODS AND MATERIALS: Twenty-five patients with ovarian carcinoma underwent surgical staging and cytoreduction using hand-assisted laparoscopy. We review the surgical technique and clinical outcomes. RESULTS: Twenty-five patients were managed during this study time frame with hand-assisted laparoscopy. Six patients had apparent advanced stage ovarian cancer at the time of referral, and 17 patients had apparent early-stage ovarian cancer. Of the 19 patients with presumed early-stage disease, 5 patients were upstaged based on retroperitoneal lymph node involvement, 3 with disease to other pelvic structures, and 2 patients had microscopic disease in the omentum. Twenty-two patients had their surgeries completed via hand-assisted laparoscopy, and three cases required conversion to laparotomy for completion of debulking surgery. Complication rates were low with three complications requiring reoperation or hospitalization. The mean hospital stay was 1.8 days for the 22 patients who had a successful hand-assisted laparoscopic evaluation. Operating times were variable and ranged from 81 to 365 min. CONCLUSION: Hand-assisted laparoscopy may be employed in the initial management of early and advanced stage ovarian carcinoma. This approach allows for thorough evaluation of peritoneal and retroperitoneal structures and surgical cytoreduction while retaining the advantages of minimally invasive surgery.

Novel techniques to improve split-thickness skin graft viability during vulvo-vaginal reconstruction.

BACKGROUND: Split-thickness skin grafts are often utilized for vulvo-vaginal reconstruction. Unfortunately, infection and sloughing may occur in up to 22% of patients with standard techniques especially at irradiated recipient sites. CASES: We report seven cases of vulvo-vaginal reconstruction using split-thickness skin grafts. In this series, we used fibrin tissue adhesives with and without vacuum-assisted closure devices to augment graft adherence and viability. We briefly describe the clinical history, surgical techniques, and outcomes of the cohort. CONCLUSION: Fibrin tissue adhesives and wound vacuum-assisted closure devices may improve the viability of split-thickness skin grafts during vulvo-vaginal reconstruction.