The association between allogeneic perioperative blood transfusion on tumour recurrence and survival in patients with advanced ovarian cancer.

OBJECTIVE: To evaluate the association between perioperative blood transfusion on the recurrence and survival of patient with advanced ovarian cancer. BACKGROUND: Cytoreductive surgery for ovarian cancer can be an extensive procedure often requiring allogeneic blood transfusions. Blood transfusions can have detrimental effects on immune function which can lead to a decrease in the organism ability to detect and destroy metastasis. METHODS: The study was a retrospective cohort investigation. Patients with advanced ovarian cancer (stage III) undergoing cytoreductive surgery were stratified by the need for perioperative blood transfusion. Allogeneic transfusions were non-leucodepleted. Primary outcome included time to recurrence and survival. Data were extracted from the gynaecology oncology database at Northwestern University. Times to event outcomes were evaluated by constructing Kaplan-Meyer curves and Cox regression. RESULTS: The charts of 136 subjects were evaluated. Seventy-six received blood transfusion. Median [95% confidence interval (CI)] time to recurrence for the non-transfusion group was longer, i.e. 17 (6-27) months, compared to 11 (8-14) months for the transfused group (P = 0.03). Median (95% CI) survival following surgery was longer in the non-transfused group, i.e. 58 (43-73) months, compared to 36 (28-44) months for the transfused group (P = 0.04). Cox regression showed that transfused subjects had shorter median times to recurrence and mortality after adjusting for age and tumour grade. CONCLUSIONS: There is an association between ovarian cancer recurrence and allogeneic perioperative blood transfusion in patients with advanced ovarian cancer undergoing cytoreductive surgery. These findings may have important implications in the perioperative management of those patients.

Malignant melanoma of the vulva: an extension of cutaneous melanoma?

OBJECTIVE: To determine the prognostic significance of the 2002 revisions of the American Joint Committee on Cancer (AJCC) Staging System for cutaneous melanoma in melanoma of the vulva and review the current surgical utilized for treatment of this neoplasm. METHODS: Demographic, surgical and outcomes data were obtained from the records of vulvar melanoma patients treated from 1990 to 2006 at five academic medical centers. The 2002 modifications of the AJCC staging system for cutaneous melanoma, Breslow thickness and Clark level, were applied to all subjects. Kaplan-Meier Modeling and Linear Regression analysis were utilized for data analysis. Statistics were performed with SAS v 9.1. RESULTS: Seventy-seven patients were identified with a median age of 62 years. 73% had Stage I/II disease. Surgical radicality did not impact recurrence rates or survival. Breslow thickness was associated with recurrence (p=0.002) but not survival. Only the 2002 modified AJCC staging criteria were predictive of overall survival (p=0.006) in patients with malignant melanoma of the vulva. CONCLUSIONS: In the largest multi-site series of vulvar melanoma, the AJCC-2002 staging system for cutaneous malignant melanoma appears to be applicable to primary vulvar melanoma. Moreover, surgical radicality was associated with significant morbidity but not with improvement in survival. Utilization of standard operative staging and resection principles in cutaneous melanoma should be used for all vulvar melanoma patients. Moreover, these patients should also be considered for enrollment in cutaneous melanoma clinical trials.

Saline contrast sonohysterography and directed extraction, resection and biopsy of intrauterine pathology using a Uterine Explora Curette.

OBJECTIVE: To assess the utility of an endometrial sampling device, the Uterine Explora Curette, with concomitant saline contrast sonohysterography (SCSH) for ultrasound-directed extraction, resection and biopsy of endometrial pathology. METHODS: Use of the Uterine Explora Curette was prospectively evaluated in 20 women with either infertility (n = 14), recurrent miscarriage (n = 2) or peri-/postmenopausal bleeding (n = 4). Findings on SCSH were compared with those on pathological analysis. RESULTS: In all 20 cases the Uterine Explora Curette was used successfully during SCSH to treat endometrial filling defects. The procedure was well tolerated, with an average time from start to finish of 10 (range, 2-23) min. It was without complications, and appeared to remove or biopsy adequately endometrial filling defects in most patients, obviating the need for hysteroscopy. CONCLUSIONS: In properly selected patients, directed extraction, resection and biopsy using the Uterine Explora Curette during SCSH appears to be an effective and easy method for treating intrauterine pathology and provides a cost-effective alternative to operative hysteroscopy.

Liquid-based cytologic specimen studies to screen for cervical dysplasia in rural El Salvador.

OBJECTIVE: To evaluate an alternative tool (ThinPrep; Cytye Corporation, Boxborough, Mass, USA) for cervical cancer screening in rural El Salvador. METHODS: Cervical samples were obtained from 471 women attending health fairs in rural El Salvador. The samples were read by American and Salvadoran pathologists after a 1-week training course in liquid-based cytologic studies in the United States. RESULTS: The system evaluated detected a significantly higher number of high-grade and above lesions than conventional cytologic studies (P=0.01). There were 0.4% and 1.7% of high-grade lesions and above detected with conventionally prepared slides in the United States and El Salvador, respectively, and 3.2% and 3.8% of such lesions detected with liquid-based samples in the United States and El Salvador. Intra-observer agreement among the pathologists reading the samples was substantial for the ThinPrep system, with a kappa value of 0.6. CONCLUSION: A short workshop is effective in training pathologists to use ThinPrep. In the studied population, liquid-based studies appear to offer significant advantages over conventional cytologic studies for detecting high-grade lesions.

A pilot study of whole body hyperthermia and carboplatin in platinum-resistant ovarian cancer.

The aim of this study was to determine whether the addition of whole body hyperthermia (WBH) to carboplatin (CBDCA) can induce responses in patients with platinum-resistant ovarian cancer. 16 pretreated patients with platinum-resistant ovarian cancer were entered on a Systemic Hyperthermia Oncological Working Group (SHOWG) study; (14 patients were eligible with 14 evaluable for toxicity and 12 for response). The patients were treated with WBH (Aquatherm) 41.8 degrees C x 60 min in combination with carboplatin (CBDCA) (area under the curve (AUC) of 8) every 4 weeks. Disease status was evaluated every two cycles. Patients were treated for a maximum of six cycles. One patient had a complete response (CR) and 4 had a partial response (PR). 4 patients had stable disease (SD). 3 patients had progressive disease (PD). 2 patients were unevaluable: 1 had a bowel obstruction shortly after her first treatment; the second patient achieved a CR, but only had one treatment secondary to an idiosyncratic reaction to sedative drugs. 2 patients entered on study were ineligible, as they did not meet criteria for platinum resistance; 1 entered a CR and 1 had SD. Dose-limiting toxicity, which required CBDCA dose reductions, was grade 4 thrombocytopenia. Other toxicities included neutropenia (grade 3/4), and nausea and/or vomiting. Consistent with preclinical modelling, these results suggests that 41.8 degrees C WBH can overcome platinum resistance in ovarian cancer. These observations suggest further investigation of the therapeutic potential of WBH in a group of patients who historically fail to respond to salvage therapies is warranted.

Outpatient taxol and carboplatin chemotherapy for suboptimally debulked epithelial carcinoma of the ovary results in improved quality of life: an Eastern Cooperative Oncology Group Phase II Study (E2E93).

PURPOSE: The combination of a platinum compound and paclitaxel is a standard treatment for ovarian cancer. In this cooperative group trial, paclitaxel and carboplatin were combined in an outpatient schedule to determine the clinical benefit, toxicities, and effect on quality of life. PATIENTS AND METHODS: Women with International Federation of Gynecology and Obstetrics stage II to IV epithelial ovarian cancer with suboptimal residual disease (> 1 cm) were eligible. Paclitaxel, 150 mg/m2, was given over 3 hours, followed by carboplatin (area under the curve, 5). This was repeated every 4 weeks for six cycles. Quality of life was assessed using the Functional Assessment of Cancer Therapy-Ovarian Cancer scale. Fifty-nine patients were enrolled, 38 with measurable disease and 21 with evaluable disease. RESULTS: The response rate (complete response + partial response) was 72%. The progression-free interval for patients with measurable disease was 17.5 months and for patients with evaluable disease was 11.1 months. Median survivals were 30.1 months (measurable) and 25.7 months (evaluable). Toxicities were modest. Quality-of-life scores improved significantly during therapy. DISCUSSION: This regimen is ideal for most women with advanced ovarian cancer because it is convenient and well tolerated, with response and survival comparable to those of more aggressive regimens. Overall quality-of-life scores and physical well-being scores improved throughout this outpatient treatment regimen for most patients.

Exfoliative cytology of primary poorly differentiated (small-cell) neuroendocrine carcinoma of the uterine cervix in ThinPrep material: a case report.

Poorly differentiated neuroendocrine (small-cell) carcinoma of cervical origin is a rare neoplasm that frequently metastasizes. Although the cytologic features have been described for conventional cervical smears, we know of no reports of its appearance in ThinPrep (TP) material. Therefore, we present a TP case of primary, small-cell carcinoma arising in a 46-yr-old female, confirmed by histologic and immunohistochemical analysis. Similar to conventional smears, the neoplastic cells occurred either individually or in small clusters. The cells were relatively monomorphic, with stippled chromatin and minimal amounts of cytoplasm. Unlike conventional smears, nuclear molding was not prominent (although overlap was observed), and nuclear smearing was not identified. The features are compared to TP cases of squamous-cell carcinoma, small-cell type, and endometrioid adenocarcinoma, which are close mimics of small-cell carcinoma. We conclude that correct diagnosis of small-cell carcinoma in TP is difficult, requiring a high degree of suspicion and immunohistochemical confirmation.

High-dose-rate versus low-dose-rate brachytherapy in the treatment of cervical cancer: analysis of tumor recurrence--the University of Wisconsin experience.

PURPOSE: To retrospectively compare the clinical outcome for cervical cancer patients treated with high-dose-rate (HDR) vs. low-dose-rate (LDR) brachytherapy. METHODS AND MATERIALS: One hundred ninety-one LDR patients were treated from 1977 to 1988 and compared to 173 HDR patients treated from 1989 to 1996. Patients of similar stage and tumor volumes were treated with identical external beam fractionation schedules. Brachytherapy was given in either 1 or 2 LDR implants for the earlier patient cohort, and 5 HDR implants for the latter cohort. For both patient groups, Point A received a minimum total dose of 80 Gy. The linear-quadratic formula was used to calculate the LDR dose-equivalent contribution to Point A for the HDR treatments. The primary endpoints assessed were survival, pelvic control, relapse-free survival, and distant metastases. Endpoints were estimated using the Kaplan-Meier method. Comparisons between treatment groups were performed using the log-rank test and Cox proportional hazards models. RESULTS: The median follow-up was 65 months (2 to 208 months) in the LDR group and 22 months (1 to 85 months) in the HDR group. For all stages combined there was no difference in survival, pelvic control, relapse-free survival, or distant metastases between LDR and HDR patients. For Stage IB and II HDR patients, the pelvic control rates were 85% and 80% with survival rates of 86% and 65% at 3 years, respectively. In the LDR group, Stage IB and II patients had 91% and 78% pelvic control rates, with 82% and 58% survival rates at 3 years, respectively. No difference was seen in survival or pelvic control for bulky Stage I and II patients combined (>5 cm). Pelvic control at 3 years was 44% (HDR) versus 75% (LDR) for Stage IIIB patients (p = 0.002). This difference in pelvic control was associated with a lower survival rate in the Stage IIIB HDR versus LDR population (33% versus 58%, p = 0.004). The only major difference, with regard to patient characteristics, between the Stage IIIB patients was the incidence of hydronephrosis in the HDR vs. LDR group--28% vs. 12%, respectively (p = 0.05). For Stage IIIB patients treated with HDR, our analysis suggested that pelvic control rates improved when the first brachytherapy insertion was performed after the majority of external beam radiotherapy had been delivered. CONCLUSION: Similar outcome was observed for Stage IB and II patients treated with either HDR or LDR brachytherapy-regardless of tumor volume. However, poorer survival and pelvic control rates were observed for Stage IIIB patients treated with HDR brachytherapy. If HDR is used for Stage IIIB patients, our results suggest the majority of external beam radiotherapy should be delivered prior to initiating the brachytherapy to allow for adequate tumor regression. HDR brachytherapy is more convenient for patients, decreases the radiation exposure for health care workers, and should be considered a standard therapy for women with Stage I or II cervical cancer.

Paclitaxel, carboplatin, and hexamethyl-melamine (taxchex) as first-line therapy for ovarian cancer.

BACKGROUND: The addition of hexamethylmelamine to therapy with cisplatin, cyclophosphamide, and doxorubicin significantly enhanced outcomes of patients with advanced ovarian cancer. Hexamethylmelamine, also known as altretamine, has potent antineoplastic activity when used as a single agent in patients who have failed to respond to both platinum-based and paclitaxel therapy. We have conducted a pilot study to evaluate the efficacy and safety of adding this drug to the popular ovarian cancer regimen of paclitaxel plus carboplatin. METHODS: Patients with advanced ovarian, fallopian tube, or primary peritoneal cancer (International Federation of Gynecology and Obstetrics stages IIA, IIIC, and IV) were prospectively enrolled to receive six cycles, repeated every 4 weeks, of paclitaxel (150 mg/m2 i.v., day 1), carboplatin (AUC 5.0 i.v., day 1), and hexamethylmelamine (150 mg/m2 p.o., days 2-15). Colony stimulating factors were prohibited. Response and toxicity were monitored by use of Eastern Cooperative Oncology Group criteria. RESULTS: Twenty patients were enrolled, 18 with ovarian cancer, one with fallopian tube cancer, and one with peritoneal cancer; 17 of these patients were evaluable for response and toxicity. At a median follow-up of 6.5 months, 13 of the patients had a complete response (76%), and four had progressive disease. Three of those with a complete response had a recurrence within 1 year of completing treatment. Toxicity was acceptable, with myelosuppression the most severe adverse effect; one patient had grade 3 anemia, one patient had grade 4 thrombocytopenia, and 12 patients had grade 4 neutropenia. Quality of life showed improvement over the course of therapy, particularly in the physical well-being subscale. CONCLUSION: The addition of hexamethylmelamine to paclitaxel and carboplatin is a well-tolerated multidrug combination for women with advanced ovarian cancer that deserves further testing in a phase III study.

Familial ovarian germ cell cancer: report and review.

Ovarian germ cell cancers are rare malignancies accounting for less than 5% of all ovarian cancers. We present a family in which three closely related women were diagnosed with ovarian germ cell malignancies. This family's cancer history prompted a family history investigation of women treated for ovarian germ cell malignancies in the Gynecologic-Oncology Clinic at the University of Wisconsin. One of the eight patients whose family histories were reviewed had an uncle who had been diagnosed with testicular germ cell cancer. A review found six other previously reported families in which more than one relative had been diagnosed with a malignant ovarian germ cell tumor. Additionally, several cases of families with both males and females diagnosed with germ cell cancers have been documented. The low incidence of ovarian germ cell cancers suggests that multiple occurrences in the same family may not be due to chance. Rather, it is possible that a gene conferring susceptibility to ovarian germ cell cancers, and possibly to germ cell tumors in males as well, is present in at least some of these families.

Current initial therapy of stage III and IV ovarian cancer: challenges for managed care.

Patients with advanced ovarian cancer (International Federation of Gynecology and Obstetrics stage III or stage IV) have improved their long-term prognosis, but the majority will still die of their disease. The current standard therapy, which involves aggressive cytoreductive surgery (removal of all visible tumor) followed by platinum/paclitaxel chemotherapy, has increased 5-year survival rates considerably over the last three decades. The choice of treatment for patients with stage III or IV disease in the managed care setting must consider survival rates, patient quality of life, and cost-effectiveness. Two chemotherapy combinations, cisplatin/paclitaxel and carboplatin/paclitaxel, appear comparable in efficacy in advanced disease, but are currently being investigated in clinical trials to compare side effects, quality-of-life parameters, and cost-effectiveness. The results of these trials may determine which chemotherapy combination becomes the standard of care for first-line treatment. Managed care organizations and patients can also benefit from a multidisciplinary approach to cancer care that includes additional support, such as risk assessment programs, the use of specialists (gynecologic oncologists), and psychosocial counseling. As the search for more effective agents and other therapeutic modalities continues, the focus of future research may be to find specific biomarkers of ovarian cancer, which will help detect disease at its earliest stages.

Methotrexate sequestration in an ovarian cyst.

OBJECTIVE: Methotrexate has been documented to accumulate in pleural effusions and ascitic fluid, resulting in severe local and systemic toxicity. In the following case report, we publish results of intraoperative measurements of methotrexate levels in serum and an ovarian cyst and attempt to determine if ovarian cysts similarly act as a depot for methotrexate. METHODS: After determining intraoperative measurements of serum and ovarian cystic levels of methotrexate, we compared demonstrated pharmacokinetics to those expected by using pharmacokinetic systems analysis software. RESULTS: Intraoperative measurement of methotrexate levels on day 3 of a 5-day methotrexate regimen revealed a serum methotrexate concentration of 1.6 x 10(-7) M and a concentration of 3.1 x 10(-7) M within the 166.4 ml ovarian cyst. CONCLUSIONS: The measured levels demonstrate that methotrexate is sequestered within an ovarian cyst resulting in higher local drug levels. Our pharmacokinetic analysis suggests that methotrexate doses less than 100 mg/m2 can be safely administered to patients with small ovarian cysts. However, computed simulations support the possibility of local and systemic toxicity arising from large ovarian cysts when using high doses of methotrexate.

Outpatient vaginal cuff brachytherapy for endometrial cancer.

Petereit DG, Tannehill SP, Grosen EA, Hartenbach EM, Schink JC. Outpatient vaginal cuff brachytherapy for endometrial cancer. The objective of this study was to determine the efficacy and complications of postoperative high-dose-rate (HDR) vaginal-cuff brachytherapy (VCB) in patients with endometrial carcinoma. Between August 1989 to September 1997, 191 patients were treated postoperatively after a total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH/BSO) with outpatient adjuvant HDR VCB for low-risk endometrial cancer (IB-84%, grade 1 or 2-96%). Patients were treated with 2 HDR fractions, delivered one week apart while under conscious sedation (16.2 Gy X 2 to the vaginal surface). All clinical endpoints were calculated using the Kaplan Meier method. The median time in the brachytherapy suite was 60 min in which no acute complications were observed. The 30-day morbidity and mortality rates were both 0%. With a median follow-up of 38 months (12-82 months), the 4-year survival, relapse-free survival, and vaginal-control rates were 95%, 98%, and 100%, respectively. One patient developed a colo-vaginal fistula at 5 years. Adjuvant HDR VCB in 2 outpatient insertions produced 100% vaginal control rates with minimal morbidity. The advantages of high dose-rate compared to low dose-rate vaginal brachytherapy include patient convenience, markedly shorter treatment times (1 h per insertion), and reduction in the cost and potential morbidity of hospitalization. HDR brachytherapy approach is a cost-effective alternative to either low-dose-rate brachytherapy or whole pelvic radiotherapy in carefully selected patients.

Resection of a giant aggressive angiomyxoma in the Philippines.

INTRODUCTION: Medicine for Humanity is a multidisciplinary team of health care professionals, travelling to developing areas throughout the world on medical missions. The following is one of many technically challenging and unique cases presented for treatment. CASE: A 38-year-old woman gradually developed a giant mass arising from the right labium majus, extending into the retroperitoneum. Surgical resection was performed by abdominal and perineal teams. Intraoperative blood loss was approximately 10,000 ml, requiring 18 units of whole blood transfusion-including 6 units acutely donated by members of the surgical team. A "pack and go back" technique was used for hemostasis. The tumor weighed 19.8 kg. Final histology confirmed an aggressive angiomyxoma. CONCLUSION: This patient had the largest, histologically confirmed, aggressive angiomyxoma described to date. The surgical management of this case followed the principles in treating hemorrhagic shock, but required modifications based on availability of resources in Cebu City, Philippines.

Phase I study of continuous-infusion L-S,R-buthionine sulfoximine with intravenous melphalan.

BACKGROUND: Increased intracellular glutathione has long been associated with tumor cell resistance to various cytotoxic agents. An inhibitor of glutathione biosynthesis, L-S,R-buthionine sulfoximine (BSO), has been shown to enhance the cytotoxicity of chemotherapeutic agents in vitro and in vivo. We performed a phase I study of BSO administered with the anticancer drug melphalan to determine the combination's safety/tolerability and to determine clinically whether BSO produced the desired biochemical end point of glutathione depletion (<10% of pretreatment value). METHODS: Twenty-one patients with advanced cancers received an initial 30-minute infusion of BSO totaling 3.0 g/m2 and immediately received a continuous infusion of BSO on one of the following schedules: 1) 0.75 g/m2 per hour for 24 hours (four patients); 2) the same dose rate for 48 hours (four patients); 3) the same dose rate for 72 hours (10 patients); or 4) 1.5 g/m2 per hour for 48 hours (three patients). During week 1, the patients received BSO alone; during weeks 2 or 3, they received BSO plus melphalan (15 mg/m2); thereafter, the patients received BSO plus melphalan every 4 weeks. Glutathione concentrations in peripheral blood lymphocytes were determined for all patients; in 10 patients on three of the administration schedules, these measurements were made in multiple sections from tumor biopsy specimens taken before, during, and after continuous-infusion BSO. RESULTS: Continuous-infusion BSO alone produced minimal toxic effects, although BSO plus melphalan produced occasional severe myelosuppression (grade 4) and frequent low-grade nausea/vomiting (grade 1-2). This treatment also produced consistent, profound glutathione depletion (<10% of pretreatment value). The degree of glutathione depletion in peripheral lymphocytes was considerably less than that observed in tumor sections. CONCLUSIONS: Continuous-infusion BSO is relatively nontoxic and results in depletion of tumor glutathione.

Infiltrating ductal carcinoma of the vulva.

The eleventh case of primary infiltrating ductal carcinoma of the vulva is reported with a review of the literature. The infiltrating tumor is associated with an intraductal component as well as noninvolved mammary-like glandular tissue (ectopic breast tissue) and metastases to inguinal lymph nodes. Estrogen receptor and progesterone receptor immunohistochemical staining is negative utilizing the HSCORE method. The treatment regimen is patterned after approach to node-positive breast carcinoma.

The genetics of ovarian cancer: concepts in testing and counseling.

The discovery and sequencing of the BRCA1 gene is an exciting breakthrough for women and health care providers. BRCA1 is associated with inherited breast and ovarian cancer and the body of scientific information regarding its role in ovarian cancer is growing rapidly. The impact of this knowledge on counseling women with a family history of breast or ovarian cancer is profound. This review provides information about familial ovarian cancer syndromes and the emerging role of genetic testing in women with an inherited susceptibility for cancer.

Phase 1 trial of intraperitoneal AD-32 in gynecologic malignancies.

AD-32 (N-trifluoroacetyladriamycin-14-valerate), an analogue of doxorubicin, was examined for intraperitoneal (ip) administration in a phase 2 trial involving 25 patients with advanced gynecologic malignancies. At an AD-32 dose of 600 mg/m2, the limiting toxicity was grade 4 neutropenia (64% of patients), while severe abdominal pain was relatively uncommon (12%). Intraperitoneal AD-32 administration was associated with a 200-fold pharmacokinetic advantage for cavity exposure, compared to the systemic compartment. At the 600 mg/m2 dose level, 4 of 9 patients (44%) with ascites experienced control of malignant fluid reaccumulation. Based on the results of this phase 1 trial, further exploration of a possible role for the ip administration of AD-32 in individuals with gynecological malignancies appears indicated, particularly in patients with either small volume residual disease after initial systemic chemotherapy or in those with intractable ascites.