Upper abdominal cytoreduction and thoracoscopy for advanced epithelial ovarian cancer: unanswered questions and the impact on treatment.

Gynaecological oncologists, by conducting Phase II and III chemotherapy trials, have sought to improve survival in women with epithelial ovarian cancer. The greatest impact on survival has been the use of intraperitoneal chemotherapy in women who have had all visible disease removed. No change in drug regimen has had an impact on survival equivalent to that associated with complete cytoreduction or the use of intraperitoneal chemotherapy. Interestingly, these two treatment modalities (complete cytoreduction and intraperitoneal chemotherapy) have not been universally adopted. Most often it is the inability to achieve optimal cytoreduction in the upper abdomen that defines the limit of the cytoreductive effort, and ultimately the integration of intraperitoneal chemotherapy. The importance of identifying disease outside the abdominal cavity, along with achieving complete cytoreduction, is paramount, if the use of intraperitoneal chemotherapy is to be logically integrated in treatment algorithms for women with advanced-stage epithelial ovarian cancer. This report summarises pertinent literature on upper abdominal cytoreduction, discusses surgical techniques and introduces new data on women with epithelial ovarian cancer undergoing thoracoscopy, suggesting consideration of its incorporation into the surgical management of advanced epithelial ovarian cancer.

Carbonic anhydrase IX (CA-IX) and high-risk human papillomavirus (H-HPV) as diagnostic biomarkers of cervical dysplasia/neoplasia in Japanese women with a cytologic diagnosis of atypical glandular cells (AGC): a Gynecologic Oncology Group (GOG) Study.

BACKGROUND: High-risk human papillomavirus (H-HPV) infection is linked to cervical neoplasia but its role in detecting cervical glandular lesions (GLs) is unclear. Carbonic anhydrase IX (CA-IX) is a hypoxic biomarker that is highly expressed in neoplastic cervical GLs. The diagnostic utility of these biomarkers was evaluated by the Gynecologic Oncology Group in Japanese women with a cytological diagnosis of atypical glandular cells. METHODS: Immunostaining was used to detect CA-IX in a conventional Pap smear. Immunoreactivity of CA-IX was interpreted by a panel of pathologists blinded to the histological diagnosis. Polymerase chain reaction was used to detect H-HPV in a liquid-based cytology specimen. RESULTS: Significant cervical lesions (SCLs), defined as cervical intraepithelial neoplasia (CIN2, CIN3), adenocarcinoma in situ or invasive carcinoma, were observed in 37/88 (42%) of women. CA-IX testing alone (n=88) had a sensitivity of 89, 100 or 73% for SCLs, GLs or significant squamous lesions (SLs), respectively, with a false negative rate (FNR) of 14%. Testing for H-HPV (n=84) had a sensitivity of 65, 53 or 80% for SCLs, GLs or SLs, respectively, with a FNR of 22%. The combination of CA-IX and H-HPV testing had a sensitivity of 97, 100 or 93% for SCLs, GLs or SLs, respectively, with a FNR of 5%. Among eight H-HPV-negative GLs, six (75%) had a diagnosis of lobular endocervical glandular hyperplasia (LEGH). CONCLUSION: The combination of CA-IX and HPV testing improved the diagnostic accuracy. The low rate of H-HPV positivity in the GLs was associated with coexisting LEGH independent of H-HPV.

Tumor heterogeneity in ovarian cancer as demonstrated by in vitro chemoresistance assays.

OBJECTIVE: Tumor heterogeneity has been demonstrated in solid tumors. In vitro assays were developed in an effort to predict in vivo tumor response to therapy. We compare the in vitro assay results from multiple synchronous tumor samples in primary and recurrent ovarian cancers. METHODS: 38 patients underwent surgery for primary (18) or recurrent (20) ovarian cancer. Two (22) or three (16) samples were obtained per patient and tested using the EDR assay (Oncotech, Inc.). The percentage of Extreme (E), Intermediate (I) and Low (L) drug resistance for each chemotherapy was compared between synchronous specimens. RESULTS: A total of 92 samples were collected and 787 drug assays were performed. Tumor heterogeneity was seen in 22.4% of all cases, including 18.6% primary and 26.1% recurrent diseases (p=0.01). Two category differences (L vs. E) were seen in 4.1% primary and 11.3% recurrent cases (7.8% of all cases). Overall, an increased frequency in EDR was seen in recurrent disease as compared to primary for all agents tested (22.9% primary vs. 31.6% recurrent, p=0.006). Marked heterogeneity of the drug resistance profiles was seen with paclitaxel as compared with cisplatin/gemcitabine (p=0.03), taxotere (p=0.04) or topotecan (p=0.04). No association was demonstrated between assay results and clinicopathologic parameters collected in this cohort. CONCLUSIONS: Treatment failure is often attributed to the development of chemoresistance. These results suggest that tumor heterogeneity may play an equally important role in treatment failure. Recurrent lesions exhibit greater heterogeneity and more frequent EDR. These data can influence therapeutic strategy i.e., multiple samples, sequential, or consolidation therapy.

Phase II trial of intraperitoneal paclitaxel in carcinoma of the ovary, tube, and peritoneum: a Gynecologic Oncology Group Study.

PURPOSE: To determine the response rate of intraperitoneal (i.p.) paclitaxel in patients with small-volume residual carcinomas of the ovary, fallopian tube, or peritoneum. PATIENTS AND METHODS: Eligibility criteria included patients with one of the cancers noted above, with the largest residual disease 0.5 cm or less in maximum diameter at the end of second-look surgery, and prior treatment with systemic paclitaxel was permitted. The treatment plan was paclitaxel 60 mg/m2 i.p. weekly for 16 weeks, followed by surgical evaluation in patients without evidence of disease progression. RESULTS: Of 80 patients entered onto the study, 76 were eligible, of whom 86% were considered to be potentially cisplatin-sensitive. Although five patients (7%) did not complete the first course of therapy because of catheter leakage or blockade, 53 patients (70%) received all 16 planned courses. Only 14 patients (18%) received fewer than 11 courses. Treatment was well tolerated, which included only moderate abdominal pain (grade 2, 12 patients; grade 3, one patient) and minimal neutropenia (grade 2, three patients; grade 3, one patient). Of 28 assessable patients with microscopic disease at the start of i.p. therapy, 17 patients (61%) achieved a surgically defined complete response (CR). Only one of 31 patients (3%) with any macroscopic disease achieved a CR. Of the eligible patients, 18 of 76 (24%) achieved a CR. CONCLUSION: Salvage i.p. paclitaxel is tolerable and active in patients with microscopic residual disease. The impact of this treatment strategy on survival remains to be assessed in a phase III trial.

Whole abdominal radiotherapy versus combination chemotherapy with doxorubicin and cisplatin in advanced endometrial carcinoma (phase III): Gynecologic Oncology Group Study No. 122.

Although localized endometrial cancer is effectively treated with surgery and radiation therapy, the treatment of advanced disease remains problematic. With increasing utilization of primary surgical staging and therapy, the early identification of patients with tumor spread beyond the uterus is becoming routine. The impact of adjuvant radiotherapy and/or chemotherapy in these patients remains to be demonstrated. In several institutions, whole abdominal radiation therapy has been used with some success as adjuvant treatment in selected patients with advanced disease. The Gynecologic Oncology Group (GOG) has completed a phase II trial of the whole abdominal radiotherapy in this patient population. Although data analysis is not complete, the regimen employed appears to be tolerable and shows some evidence of efficacy. In previous GOG trials, cisplatin and doxorubicin have shown single-agent activity in patients with measurable, advanced endometrial cancer. Subsequently, the response rate with the combination of cisplatin and doxorubicin was found to be superior to that with doxorubicin alone. Because approximately 30%-50% of patients with extrauterine disease have systemic failure, the evaluation of combination chemotherapy with doxorubicin and cisplatin in the adjuvant setting seemed warranted. The current ongoing prospective, randomized trial (GOG No. 122) compares the survival and the progression-free interval and treatment failure patterns in patients with endometrial carcinoma of stage III or IV with up to 2 cm of residual disease when treated with either whole abdominal radiotherapy or a combination of doxorubicin and cisplatin. The incidence and type of acute and late adverse events observed with the two treatment regimens were determined and compared.

Chemotherapy, early surgical reassessment, and hyperfractionated abdominal radiotherapy in stage III ovarian cancer: results of a gynecologic oncology group study.

PURPOSE: To determine outcomes and treatment toxicities in patients with optimal (< or = 1 cm residual) Stage III ovarian carcinoma treated with three courses of cisplatin-cyclophosphamide, surgical reassessment (SRA), and hyperfractionated whole abdominal irradiation (WAI). METHODS AND MATERIALS: Forty-two eligible patients entered this prospective Phase II study conducted by the Gynecologic Oncology Group (GOG). Disease characteristics were as follows: age range, 32-76 years (median 58); Stage IIIA (n = 1, 2%), IIIB (n = 2, 5%), IIIC (n = 39, 93%); histology-serous papillary (n = 21, 50%); other (n = 21, 50%); Grade 1 (n = 1, 2%); 2 (n = 14, 33%); 3 (n = 27, 54%); residual disease after initial surgery (present: n = 23, 55%; absent: n = 19, 45%). Five patients progressed while on chemotherapy, could not be effectively cytoreduced, and were not eligible for WAI. Of the remaining 37 patients, 35 received WAI. Surgical reassessment was not performed in five patients. RESULTS: Of 37 patients with known SRA status after chemotherapy, 21 (57%) were grossly positive, 4 (11%) were microscopically positive, and 12 (32%) were negative. Based on measurements recorded following initial laparotomy and surgical reassessment, progression during chemotherapy was noted in 40%, stage disease in 37%, and objective response in 23%. Toxicity during hyperfractionated WAI was limited and reversible. No patient beginning WAI failed to complete or required a significant treatment break. Following WAI, six patients underwent laparotomies for abdominal symptoms; five had recurrent disease. Five additional patients were managed conservatively for small bowel obstruction (SBO) or malabsorption, of whom three subsequently developed recurrence. Twenty-two patients having pelvic boosts were significantly more likely to require management for gastrointestinal morbidity (p = 0.0021). Considering all eligible patients, median disease-free and overall survivals were 18.5 and 39 months, respectively. Considering patients completing chemotherapy and WAI, median disease-free and overall survivals were 24 and 46 months, respectively. CONCLUSIONS: (a) Disease progression occurred within three cycles of cisplatin and cyclophosphamide chemotherapy in 40% of patients with optimal (< or = 1 cm residual) Stage III ovarian carcinoma. (b) Following limited chemotherapy, hyper-fractionated WAI was acutely well tolerated. (c) Late radiation-related toxicity was observed in only three patients (8.6%) in the absence of recurrent disease. Late gastrointestinal morbidity was significantly associated with the administration of a pelvic radiotherapy (RT) boost. (d) Short duration chemotherapy followed by SRA and hyperfractionated WAI without a pelvic boost is a promising management option for patients with optimal Stage III ovarian cancer. A Phase III trial will be necessary to determine how this treatment strategy compares with chemotherapy or RT alone in this patient population.

Autologous rectus sheath grafts. V. Growth in aortic grafts.

Experiments were designed to test autologous rectus sheath as a replacement for the thoracic aorta in the growing dog. Adequacy of graft function was determined by angiography at 4 month intervals; stress-strain measurements and microscopic examination were made at the time of autopsy. A 3 cm tubular graft of rectus sheath tissue was employed as an aortic graft in 13 mongrel puppies. Nine puppies (70%) were long-term survivors and were put to death between 6 and 22 months postoperatively. No deaths were due to graft failure. Angiographic studies demonstrated patency of the graft without development of pressure gradients. An increase in diameter of the aorta (21.25%) and the rectus sheath graft %22.87%) were demonstrated in all cases. During the time of observation, the compliance of the growing aorta (93,120 dynes/cm2) decreased to one fourth that of the control aortic tissue (24,800 dynes/cm2), whereas the compliance of the rectus sheath graft (547,1000 dynes/cm2) decreased to only one eighth that of the control rectus sheath (47,400 dynes/cm2). Tensile strength is maintained in both the growing aorta (4.5 x 10(7) dynes/cm2) and the rectus sheath graft (4.7 x 10(7) dynes/cm2; p less than 0.05). Microscopic examination showed no calcification, thinning, or weakness. Vascularization of the graft had occurred, with cellular proliferation and development of more than 30 lamellar-like units in the media and an adventitia-like surface.

Laparoscopic staging of the patient with incompletely staged early adenocarcinoma of the endometrium.

OBJECTIVE: To determine the feasibility of laparoscopic staging in patients with presumed early stage but incompletely surgically staged adenocarcinoma of the endometrium. METHODS: Thirteen patients with incompletely staged adenocarcinoma of the endometrium underwent laparoscopic staging. The women ranged in age from 36-74 years (mean age 64) and weighed 132-201 lb (mean 147.5). The interval between hysterectomy and laparoscopic staging ranged from 14-63 days, for an average of 47. All patients underwent inspection of the entire intraperitoneal cavity, procurement of pelvic washings, and/or pelvic or para-aortic lymphadenectomy, and two patients had remaining ovaries removed. RESULTS: Extrauterine disease was found in three patients: One had intraperitoneal washings positive for adenocarcinoma, and two had pelvic lymph nodes positive for microscopic carcinoma. The average number of lymph nodes removed was 17.5. There were no intraoperative complications. Estimated blood loss averaged less than 50 mL, and the mean hospital stay was 1.5 days. CONCLUSION: Our initial experience indicates that this is a safe, effective procedure that offers a short hospital stay. We consider laparoscopic staging an attractive option for some patients with incompletely staged early adenocarcinoma of the endometrium.

Resumption of ovulation after ectopic pregnancy.

Forty-four patients with ectopic pregnancies were followed with serial serum progesterone determinations for up to 40 days after surgery. Seven patients (16%) failed to show luteal function during the study. Thirty-seven (84%) demonstrated luteal activity (serum progesterone at least 3 ng/mL): in six patients by days 17-19, in 50% by day 24, and in 72% by day 30. Because hormonal contraception delayed until the first postoperative office visit would miss the onset of folliculogenesis in approximately three-quarters of ectopic pregnancies, contraception should be begun immediately after surgery.

Sarcoid-like lesions associated with epithelial ovarian adenocarcinoma.

A woman with poorly differentiated endometrioid adenocarcinoma of the ovary had sarcoid-like lesions in the bone marrow. Sarcoid-like lesions may be misinterpreted as metastatic disease, resulting in inappropriate modification of therapy.

A critical evaluation of the endocervical curettage.

A prospective study was undertaken to critically evaluate the endocervical curettage. The study group consisted of 261 patients with colposcopically identifiable cervical lesions that had not been previously biopsied and were not macroscopically suspicious for invasive cancer. In 210 patients, the entire lesion, transformation zone, and squamocolumnar junction were visible (satisfactory colposcopy), and in 51 patients, the full extent of the lesion was not visualized colposcopically (unsatisfactory colposcopy). We used a method of examination not previously described. Colposcopy was performed before and after the endocervical curettage, but before the ectocervical biopsy. This method of examination allowed us to identify potentially contaminated endocervical curettages and to test the null hypothesis that a positive endocervical curettage in patients with satisfactory colposcopy is not the result of contamination. Twenty of 210 endocervical curettages in patients with satisfactory colposcopy were potentially contaminated, as suggested by an ectocervical lesion disrupted by the endocervical curettage. No patient with a positive endocervical curettage had an intact ectocervical lesion. Therefore, the null hypothesis was rejected (P less than .005). Of the 51 patients with unsatisfactory colposcopy, 39 (76%) underwent cone biopsy. Invasive cancer was diagnosed by cone biopsy in two patients when both ectocervical biopsy and endocervical curettage demonstrated only dysplasia. We also confirmed that patients with unsatisfactory colposcopy occasionally benefit from having an endocervical curettage. However, basing the treatment plan for any lesion short of invasive cancer solely on the results of colposcopy, ectocervical biopsy, and/or endocervical curettage could lead to significant undertreatment of some patients.

The clinical significance of blood transfusion at the time of radical hysterectomy.

A retrospective review was conducted to evaluate the clinical implications of perioperative blood transfusion in the surgical management of stage IB cervical cancer. The investigation focused on 126 patients treated with radical hysterectomy and retroperitoneal lymph node dissection who were found to have clear surgical margins, negative retroperitoneal lymph nodes, and no lymph-vascular space involvement in the hysterectomy specimen, and who had no perioperative radiation therapy, no history of immunosuppression with medication, and at least 18 months of follow-up. The distributions of age, weight, operative time, nodal yields, mean lesion diameters, median depths of invasion, and histologic subtypes were not statistically different between the transfused and untransfused groups. The average estimated blood loss among the transfused patients was 1104 mL, compared with 764 mL among the untransfused patients (P = .015). Among the 68 who received blood perioperatively, there were ten recurrences (14.7%), compared with two (3.4%) among the 58 patients who did not receive blood (P = .035). In this select population of patients, in which perioperative transfusion was isolated as a variable, transfusion adversely affected the outcome of surgical therapy.

Pseudocorpus luteum insufficiency: a study of cytosol progesterone receptors in human endometrium.

This prospective, controlled study of 38 women was designed to compare the number of endometrial cytosol progesterone receptor (PRc) binding sites in infertile women with documented luteal phase defect with those of similar women without luteal phase defect. A 25% reduction in PRc binding sites was observed in women with luteal phase defect (P less than .05). Considerable overlap was noted between luteal phase defect and control groups; thus, no definite range of binding site numbers was predictive of luteal phase defect. The results of this study, therefore, suggest that an end-organ receptor defect may exist in some women with luteal phase abnormalities.

Chest tube drainage of pleural effusion correcting abdominal ascites in a patient with severe ovarian hyperstimulation syndrome: a case report.

OBJECTIVE: To describe a patient with severe ovarian hyperstimulation syndrome (OHSS) demonstrating a beneficial result of reduction in abdominal ascites with a chest tube placed for bilateral pleural effusions. DESIGN: Case report. SETTING: Academic hospital. PATIENT: A 28-year-old white female with primary infertility on hMG (Pergonal; Serono Laboratories, Randolph, MA) therapy. INTERVENTIONS: Intravenous fluids, lasix, and albumin were administered for correction of laboratory abnormalities, including hemoconcentration, hypoalbuminemia, and leukocytosis. A chest tube was placed for treatment of pleural effusions. MAIN OUTCOME MEASURES: Laboratory values of hematologic measures and electrolytes. Resolution of pleural effusions and abdominal ascites as determined by chest roentgenogram and physical examination. RESULTS: Treatment of OHSS with intravenous fluids, lasix, and albumin corrected the hemoconcentration, hypoalbuminemia, and leukocytosis associated with OHSS. Placement of a chest tube corrected the pleural effusions and abdominal ascites. CONCLUSION: This case report demonstrates a beneficial result of reduction in abdominal ascites by a chest tube placed for pleural effusions.

Correlation and comparison of Nb2 lymphoma cell bioassay with radioimmunoassay for human prolactin.

Serum samples from groups of men and women with normal and elevated prolactin (PRL) levels were assayed by radioimmunoassay (RIA) and by Nb2 lymphoma cell bioassay (BA) for the presence of PRL. Because the Nb2 lymphoma cells respond to both PRL and growth hormone, BA for PRL activity was carried out before and after neutralization of growth hormone in the serum samples. There were excellent correlations between RIA and BA both in euprolactinemic (r = 0.7587; P less than 0.002) and hyperprolactinemic (r = 0.9558; P less than 0.001) subjects. On an absolute basis, RIA and BA values were similar in the euprolactinemic group (6.6 +/- 0.8 versus 6.2 +/- 1.0), whereas in the hyperprolactinemic group, RIA values were significantly higher than the BA results (89.41 +/- 22.4 versus 62.1 +/- 21.2). The two assay systems also appeared to correlate better in women who were hyperprolactinemic, with obvious menstrual cycle disturbances, than in hyperprolactinemic women without menstrual cycle disturbances.

Lithokelyphos. A case report and literature review.

Retained abdominal pregnancy is an extremely rare complication of pregnancy. A patient presented with an intraabdominal pregnancy that had been retained for 29 years.