Steven A. Vasilev

Prognostic significance of human papillomavirus DNA in vulvar carcinoma

Objective To determine the histopathologic, epidemiologic, and prognostic significance of human papillomavirus (HPV) DNA in primary invasive vulvar cancer. Methods From December 1981 through October 1992, primary tumor tissue from 55 newly diagnosed vulvar cancers was evaluated for the presence of HPV DNA. The DNA was extracted from tumor tissue and subjected to the polymerase chain reaction (PCR) using highly conserved consensus L1 primers that detect 25 different HPV genotypes and primers specific for HPV type 6/E6, type 16/E7, and type 18/E6 gene sequences. All PCR products were hybridized to type-specific radiolabeled probes. The association between the presence of HPV DNA and histologic, epidemiologic, and clinical characteristics was analyzed. Results Thirty-three (60%) tumors contained HPV DNA. Patients younger than 70 years of age or who smoked were more likely to have HPV-positive vulvar cancers. Twentyone (95%) of 22 tumors classified as basaloid, warty, or verrucous contained HPV DNA, whereas 12 (39%) of 31 typical squamous tumors contained HPV (P < .001). Two adenocarcinomas were negative for HPV. Tumors with or without HPV DNA did not differ with respect to International Federation of Obstetricians and Gynecologists stage (size and nodal status), tumor grade, or therapy. Using life-table analysis, the absence of HPV DNA and the presence of regional nodal metastasis were predictive of recurrence and death from vulvar cancer. When controlling for lesion size, age, tumor grade, and nodal metastasis using the Cox proportional hazards model, only HPV status remained an independent prognostic factor. Conclusion Human papillomavirus DNA is more common in vulvar cancers of young women who smoke than in older nonsmokers. patients with HPV-negative tumors are at an increased risk of recurrence and death from vulvar cancer.

Bowel resection at the time of primary cytoreduction for epithelial ovarian cancer.

BACKGROUND The purpose of this study was to determine the morbidity and survival associated with bowel resection at the time of primary cytoreductive surgery for ovarian cancer. STUDY DESIGN We reviewed all patients undergoing bowel resection by gynecologic oncology faculty at the time of primary cytoreduction for advanced epithelial ovarian cancer diagnosed between 1983 and 1995. RESULTS There were 105 patients meeting the above criteria. The median age was 65 years (range 34 to 85 years). There were 76 stage III and 25 stage IV cancers. The primary indication for bowel resection was tumor debulking in 92% of the patients. Seventy patients had segmental resection of the colon only, and 22 patients underwent resections that included the large and small bowels. Mean operating time was 260 minutes and mean estimated blood loss was 1,447 mL. Thirty-three (31%) patients were optimally cytoreduced to less than 1 cm residual disease. Ten patients experienced major complications directly related to bowel resection, including bowel fistula (4 patients), early postoperative bowel obstruction (5 patients), and stomal hernia (1 patient). Other morbidity included ileus for more than 10 days (18 patients), cardiac complications (17 patients), pneumonia (8 patients), sepsis (5 patients), and thromboembolism (4 patients). Six patients died and five patients required reexploration within 30 days of operation. Patients with preoperative bowel obstruction and suboptimal residual disease were more likely to have postoperative morbidity. Median survival in the optimally debulked patients was 35 months compared with 18 months in patients suboptimally cytoreduced (p = 0.006). Multivariate analysis demonstrated that optimal debulking (p = 0.009) and platinum chemotherapy (p = 0.00006) were independently associated with improved survival. Age, International Federation of Gynecologia Oncologists stage, American Society of Anesthesiologists class, and paclitaxel chemotherapy did not influence survival. CONCLUSIONS In patients undergoing bowel resection at the time of primary cytoreduction for ovarian cancer, optimal cytoreduction to less than 1 cm residual disease results in improved survival. Morbidity is common but is comparable to other published series of ovarian cancer patients undergoing primary cytoreductive surgery without bowel resection. Additionally, patients with preoperative bowel obstruction and suboptimal residual disease are more likely to have serious morbidity.

Pelvic radiation improves local control after hysterectomy for uterine leiomyosarcoma: a 20-year experience.

Background: Uterine leiomyosarcoma (LMS) is associated with high rate of recurrence after surgical resection. The role of adjuvant radiation therapy in improving survival in women with uterine LMS is unclear. Methods: All cases of LMS treated from 1985 to 2005 at 11 regional medical centers were identified. Kaplan-Meier survival curves were constructed and compared with log-rank testing. Multivariate analysis was performed to account for the potential influence of confounding factors. Results: One hundred forty-seven patients with LMS were identified. The median age of diagnosis was 51 years with the stage distribution of stage I (n = 87), II (n = 9), III (n = 25), IV (n = 25), and unknown (n = 1). One hundred forty-three underwent total abdominal hysterectomy and bilateral salpingoophorectomy. Twenty-four (17%) of these patients received adjuvant pelvic irradiation, and 63 (44%) received adjuvant and/or palliative chemotherapy. With a median follow-up of 24 months (range, 1-249 months), the median survival for the entire group was 37 months. Cox proportional hazards modeling demonstrated the presence of high tumor grade and advanced stage adversely affected survival. Although the 5-year survival for patients who received adjuvant radiotherapy was significantly higher than those who did not (70% vs 35%), this survival advantage was not sustained as the curves crossed at 90-month follow-up. Pelvic recurrence rate was lower in the radiation group (18% vs 49%; P = 0.02). Conclusions: Adjuvant radiation therapy was associated with decreased pelvic failure and a modest improvement in 5-year survival, but did not impact overall survival with extended follow-up.

Comparison of the polymerase chain reaction and Southern blot analysis in detecting and typing human papilloma virus deoxyribonucleic acid in tumors of the lower female genital tract

To conduct studies on the clinical and pathologic significance of human papilloma virus (HPV) in genital malignancies. accurate detection and typing of the virus in clinical material are essential. Currently. Southern blotting and the polymerase chain reaction (PCR) are two of the most commonly used methods to identify HPV This study was undertaken to compare these techniques in the detection and typing of HPV in 242 invasive malignancies of the lower female genital tract. BamHI and PstI restriction digests of tumor DNA were hybridized to ,32PTabeled probes for HPV types 6. 16. and‘ 18 at Tm - 20°C after Southern transfer. Blots were then washed at Tm −20°C and Tm −9°C. The DNA was also amplified by PCR using both highly conserved consensus LI primers that detect 25 different HPV genotypes and primers specific for HPV 6 E6. 16 E7. and 18 E6. All PCR products were hybridized to type-specific radiolabeled probes. In 202 of the 242 (83%) samples. HPV was detected, including 189 of 218 (87%) cervical cancers. 11 of the 20 (55%) vulvar cancers, and two of four tumors from the vagina, urethra. or anus. In 67% of the specimens, there was agreement between the Southern blot technique and both methods of PCR (consensus and type-specific primers), including 121 of the 202 HPV-positive specimens and 40 HPV-negative specimens. Of the 141 tumors with HPV detected by Southern blot analysis, the same HPV type was detected by PCR in 121 (86%). The discrepant typing for HPV in the tumors positive by Southern blot included four tumors negative by PCR. 10 tumors with a mixture of HPV types by PCR, five tumors positive by PCR with the consensus primers but negative with the corresponding type-specific primers: and, in one case, the Southern blot was read as HPV 16. whereas PCR showed the tumor to contain HPV 18. Of the 101 cases negative for HPV by Southern blot, HPV was detected in 61 (60%) cases by PCR. Forty-two cases were positive with both sets of primers, 15 cases were positive only with the consensus primers, and four cases were positive only with type-specific primers. Comparison of PCR detection of HPV by consensus and type-specific primers showed that 191 cases were positive with the consensus primers, 170 with the type-specific primers, and 163 positive using both sets of primers. In conclusion. PCR was more sensitive for detection of HPV in tumor tissue than Southern blot analysis, and consensus primers detected more HPV types than type-specific primers. There was good agreement between typing HPV by Southern blot and PCR when the Southern blot was positive. We concluded that PCR using both consensus and type-specific primers is optimal for detection of HPV in genital tumors.

Histopathologic effects of tamoxifen on the uterine epithelium of breast cancer patients: analysis by menopausal status

We evaluated the histopathologic changes of the uterine epithelium in 73 breast cancer patients with tamoxifen stratified by menopausal status. Clinicopathologic data at the time of breast cancer diagnosis and endometrial sampling were analyzed and compared with 122 breast cancer patients not receiving the drug. The incidence of endocervical and/or endometrial polyps was increased in tamoxifen-treated postmenopausal patients compared with untreated patients, 43% (25 of 58) and 24% (16 of 68), respectively (odds ratio=2.46, P=0.02). In contrast, there was no increase in polyps in premenopausal tamoxifen-treated patients. This finding suggests that the effects of tamoxifen on the endometrium may vary with menopausal status.

Highly elevated CA125 and tubo-ovarian abscess mimicking ovarian carcinoma

Elevated serum CA125 levels may be caused by any condition which produces peritoneal irritation as well as by the presence of various malignancies. This report of a case with atypical presentation of tubo-ovarian abscess and CA125 level of 1,160 U/ml serves to re-emphasize cautious operative planning in patients desirous of reproductive capability in the face of findings highly consistent with probable malignancy. This is the highest reported serum CA125 level in a reproductive age woman with well-documented reversible benign disease.

Role of adjuvant chemotherapy in patients with early stage uterine papillary serous cancer

Objective: Uterine papillary serous carcinoma (UPSC) is an aggressive subtype of endometrial cancer. We studied survival outcomes in patients with stages I/II UPSC. Materials: A retrospective, multi-institutional study of patients with stages I/II UPSC was conducted. Patients underwent surgical staging followed by observation, adjuvant platinum-based chemotherapy (CT), or radiation therapy (RT). Continuous variables were compared via Wilcoxon rank sum test; Fisher exact test was used for the unordered categorical variables. Kaplan-Meier curves were used to estimate survival. Results: Thirty-nine women were diagnosed with stage I (n = 30) or II (n = 9) UPSC, with a median follow-up of 52 months. Of the 26 patients who did not receive adjuvant CT, 9 developed recurrences and 8 died of their disease. Of the 10 patients with no myometrial invasion who did not receive adjuvant CT, 3 developed recurrences and died. Of the 7 patients who underwent RT, 2 developed distant recurrences and died. Of the 13 patients who underwent CT, 1 developed vaginal recurrence. The 5-year overall (OS) and progression-free survival (PFS) rates for the adjuvant CT group were 100% and 92%, respectively, compared with 69% and 65% for those who did not receive CT (P = 0.002 OS, P = 0.002 PFS). The 5-year OS and PFS rates for RT group were both 71%. Conclusions: Patients with stages I/II UPSC are at significant risk for distant recurrence and poor survival. Platinum-based adjuvant CT may decrease recurrence rate and improve survival in women with early and well-staged UPSC.

Phase II trial of carboplatin and infusional cyclosporine with alpha-interferon in recurrent ovarian cancer: A California Cancer Consortium Trial

The purpose of this study was to estimate the response rate of 26-h continuous infusion cyclosporine A (CSA) combined with carboplatin (CBDCA) and subcutaneous alpha-interferon (IFN), in recurrent ovarian cancer (OC), and to measure their effects on CBDCA pharmacokinetics. OC patients relapsing following platinum-based chemotherapy received CBDCA area under the curve (AUC 3) with CSA and IFN, every 3 weeks. The pharmacokinetics of CSA and CBDCA were determined in a subset of patients. Thirty patients received 84 courses of therapy. Three partial responses were observed. Nine patients were stable for >4 months. Toxicity was similar to that observed in our previously reported phase I study and consisted of myelosuppression, nausea, vomiting, and headache. The mean end of infusion CSA level (high-performance liquid chromatographic assay [HPLC]) was 1109 ± 291 μg/mL (mean ± SD). CBDCA pharmacokinetics revealed a measured AUC of 3.61 versus a targeted AUC of 3, suggesting a possible effect of IFN on CBDCA levels versus errors in the estimation of CBDCA clearance using measured creatinine clearance. Steady-state levels of >1 μg/mL CSA (HPLC assay) are achievable in vivo. Insufficient clinical resistance reversal was observed in this study to warrant further investigation of this combination.

Phase II trial of high-dose intravenous doxorubicin, etoposide, and cyclophosphamide with autologous stem cell support in patients with residual or responding recurrent ovarian cancer

This study was performed in order to evaluate the toxicities, progression-free and overall survival of patients with responsive residual or recurrent ovarian cancer treated with high-dose chemotherapy. Twenty-seven patients were treated. Doxorubicin, 165 mg/m2 over 96 h (days −12 to −8), etoposide 700 mg/m2 every day ×3 (days −6 to −4), and cyclophosphamide 4.2 g/m2 on d −3 was followed by stem cells and granulocyte colony-stimulating factor. The median days of granulocyte count <500/μl was 14 (range 10–42) and platelets <20 000/μl was 13 (range 2–80). Median numbers of red cell and platelet transfusions were 15 (5–16) and 14 (4–103). Toxicity included mucositis requiring narcotic analgesia in all patients. Asymptomatic decreases in ejection fraction to values <50% were observed in four patients. No clinical congestive heart failure was observed. One death due to sepsis was observed. Median progression-free survival is 7.5 months (1.0–56 months); five patients remain alive, two of whom remain progression-free at 19.5 and 24.5 months post transplant. Median overall survival is 14.0 months (1–68 months). We conclude that high-dose anthracyclines may be safely administered to ovarian cancer patients. The short overall and progression-free survivals observed in our population suggest that this combination is not optimal. Bone Marrow Transplantation (2001) 28, 859–863.

Gynecologic oncology : evidence-based perioperative and supportive care

Foreword to the Second Edition ix Contributors xi Part One General Principles 1. Introduction 1 Steven A. Vasilev and Scott E. Lentz 2. Evidence-Based Medicine and Decision Support 11 Steven A. Vasilev 3. Vascular Access and Other Invasive Procedures 43 Paul Koonings and Scott E. Lentz 4. Fluids, Electrolytes, and Nutrition 69 Howard Silberman and Matthew Powers Part Two Perioperative Management of Gynecologic Surgery 5. Preoperative Evaluation 145 Devansu Tewari 6. Postoperative Surveillance and Perioperative Prophylaxis 161 Harriet O. Smith and Lejla Delic 7. Perioperative Infections: Prevention and Therapeutic Options 235 Amy Stenson 8. Intraoperative and Perioperative Considerations in Laparoscopy 261 Steven A. Vasilev and Scott E. Lentz Part Three Oncologic Perioperative Decision Making 9. Cervical Carcinoma 299 Fidel A. Valea 10. Endometrial Cancer 329 R. Wendel Naumann 11. Pelvic Masses and Ovarian Carcinoma 361 Margarett C. Ellison 12. Molar Gestation 377 Allison E. Axtell and Steven A. Vasilev 13. Perioperative Issues in the Management of Vulvar Cancer 389 Kathryn F. McGonigle and Maliaka W. Amneus Part Four Complimentary Medicine/Supportive Care 14. Perioperative Psychosocial Considerations 419 Judith McKay and Steven A. Vasilev 15. Pain Management in Gynecologic Oncology 443 Laszlo Z. Galffy and Clayton A. Varga 16. Fertility Preservation in the Gynecologic Cancer Patient 469 Nicole Fleming 17. Perioperative Herbal and Supplement Use 487 Alexander Vasilev and Steven Vasilev 18. End-of-Life Decision Making 509 Scott E. Lentz Index 539