Combination chemotherapy for metastatic or recurrent adenocarcinoma of the cervix.

Twenty-four patients with recurrent or widespread adenocarcinoma of the cervix were treated with combination chemotherapy. The drugs used were 5-fluorouracil (5-FU) (500 to 800 mg/m2), doxorubicin (40 to 50 mg/m2), and cisplatin (50 to 60 mg/m2). The chemotherapy was administered as a 76-hour continuous infusion via a silastic central venous catheter and repeated every 28 days. The total response rate was 42% (25% complete and 17% partial). Median duration of response was 7 months. Areas of response were usually lung and lymph node metastases. Toxicity, mainly neutropenia, was acceptable. All patients relapsed. This combination chemotherapy results in a modest response rate for a malignancy about which there is little information regarding the treatment of disseminated disease. Future studies should determine the activity of this combination administered in a bolus fashion.

Management of uncorrected exstrophy of the bladder in women.

A 28-year-old Hispanic woman presented with uncorrected exstrophy of the bladder and accompanying defects of the external genitalia. These defects were corrected in a single operation. The objectives of the operation and the rationale for choosing the specific methods used are discussed in detail.

The management of diaphragmatic lesions in ovarian carcinoma.

Cytoreduction is currently an essential feature of the treatment of carcinoma of the ovary. Occasionally, optimal reduction is achieved except for localized diaphragmatic lesions. Two patients who were treated with primary cytoreduction for epithelial ovarian carcinoma had localized full-thickness diaphragmatic metastasis. Often resection is avoided because of concern about pneumothorax. A safe and easy method is described for removing peritoneal and diaphragmatic muscular metastasis without the need for a thoracostomy tube. These patients were cytoreduced without morbidity. The first patient is currently free of disease at 17 months after surgery. The second patient had a 13-month disease-free interval before her abdominal recurrence.

Major morbidity after pelvic exenteration: a seven-year experience.

Thirty-eight patients underwent pelvic exenteration at the University of South Florida during the last seven years. The majority of the operations were performed for recurrent carcinoma of the cervix, and the operative mortality was 5.3%. Twenty-one patients developed major morbidity in the postoperative period, and 11 with complications involving the gastrointestinal or urinary tract required reoperation. Multivariate logistic regression analysis demonstrated a correlation between the amount of pelvic radiation, type of pelvic floor, type of pelvic drain, amount of blood loss, race, and the occurrence of serious postoperative morbidity. Strategies to avoid serious postoperative morbidity are discussed.

Aspirin effects on endometrial cancer cell growth.

OBJECTIVE: To find whether aspirin (acetylsalicylic acid, ASA) inhibits the growth of endometrial cancer cells in vitro in a way similar to that in colorectal cancer cells and to investigate the mechanisms by which aspirin might lead to growth inhibition. METHODS: Ishikawa human endometrial tumor cells were grown in the presence of ASA (1-5 mM) for 96 hours. Controls were treated with vehicle (absolute ethanol). Cell proliferation was assessed by 3-(4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide assay. Apoptosis was determined by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay. Analysis of cell-cycle distribution and bcl-2 expression was assessed by flow cytometry. RESULTS: Acetylsalicylic acid induced a dose-dependent inhibition of Ishikawa cells in vitro. The percentage of growth inhibition was 21-88% at concentrations of 1-5 mM. It also induced apoptosis and reduced bcl-2 expression in Ishikawa cells in a dose-dependent manner. Control cells and cells treated with the lowest concentration of ASA exhibited 2% apoptosis and more than 60% of the population expressed bcl-2. Apoptosis levels increased as levels of ASA increased from 2 to 5 mM (7-58%) with a concommitant decrease in bcl-2 expression from 46% at 2 mM to 2% at 5 mM. Acetylsalicylic acid concentrations of 3 mM or greater induced a shift from the resting phase (G0/G1) to S phase of the cell cycle. CONCLUSION: Acetylsalicylic acid inhibited Ishikawa cell growth in vitro in a dose-dependent manner. Apoptosis is one of the mechanisms involved in the response, which can be mediated in part by downregulation of bcl-2.

Cervical conization with frozen section before planned hysterectomy.

OBJECTIVE: To report our institutional experience with the accuracy and usefulness of cervical conization with frozen section before planned hysterectomy. METHODS: One hundred fifty-nine patients who planned to have hysterectomies for or with a concomitant diagnosis of cervical intraepithelial neoplasia (CIN) underwent preliminary cone biopsies with frozen section. The frozen and permanent pathologic diagnoses were compared retrospectively. Detailed analysis was directed at the indications for cone biopsy and the patients who were found to have invasive cancer. RESULTS: Among 108 patients with negative specimens or CIN, the frozen section was accurate within one degree of CIN in 106. Cone biopsy for a positive endocervical curettage, unsatisfactory colposcopy, or discrepant cytology did not contribute to the diagnosis of invasive cancer but did lead to an ultimate diagnosis of CIN III. One of 12 women with a frozen-section diagnosis of microinvasion had deeper invasion on permanent sections. CONCLUSIONS: Frozen-section evaluation of a cone biopsy carries a degree of accuracy that enables the surgeon to make an immediate decision about definitive therapy. Exact indications, use during pregnancy, and accuracy for the diagnosis of microinvasion require further study.

Atrial natriuretic factor in gynecologic malignancy.

OBJECTIVE: To determine whether plasma atrial natriuretic factor (ANF) levels are different in patients with gynecologic malignancy compared with those in healthy, nonpregnant women, and if differences do exist, whether chemotherapy plays a role. METHODS: We compared the plasma levels of ANF in nonpregnant women free of malignancy (group 1, n = 25) and in patients with malignancy receiving at least one course of platinum-based chemotherapy (group 2, n = 32). To differentiate the contributory role of chemotherapy, another group of patients (group 3, n = 18) was studied before the initiation of chemotherapy. RESULTS: The ANF values (mean +/- standard error [SE]) in groups 1, 2, and 3 were 7.3 +/- 0.3, 13.8 +/- 0.8, and 14.6 +/- 1.8 fmol/mL of plasma, respectively. Significant differences (P < or = .001) occurred between groups 1 and 2 and 1 and 3, but not between 2 and 3. In comparing groups 2 and 3 for a specific type of cancer, there were no significant differences. The respective values (mean +/- SE) for endometrial, ovarian, and cervical cancer before chemotherapy were 9.9 +/- 1.7, 15.05 +/- 2.6, and 18.5 +/- 4.3 fmol/mL. After chemotherapy, the values remained at 9.3 +/- 1.5, 15.03 +/- 1.06, and 14.6 +/- 2.2 fmol/mL, respectively. CONCLUSION: Plasma ANF levels in gynecologic cancer patients were significantly higher than those in healthy, nonpregnant women. Levels were higher before chemotherapy started, thus negating the idea that chemotherapy may initiate the production and release of ANF.

Accuracy of lymph node palpation to determine need for lymphadenectomy in gynecologic malignancies.

OBJECTIVE: To assess the accuracy of intraoperative lymph node palpation for identifying lymph node metastasis in gynecologic malignancies. METHODS: We prospectively evaluated 126 women who had lymphadenectomies for staging of various gynecologic malignancies from August 1995 to June 1997. Surgeries were done by obstetrician-gynecologists with subspecialty certification in gynecologic oncology from the American Board of Obstetrics and Gynecology, who had practiced gynecologic oncology for at least 5 years. Data were collected on gynecologic oncologists' opinions of lymph node status by palpation. Nodes believed to be positive were sent separately. We recorded operating time for lymphadenectomies, and intraoperative and postoperative complications. RESULTS: Mean (range) patient age was 55 (18-83) years. Mean (range) operating time was 188 (85-435) minutes. The mean (range) lymphadenectomy time was 46 (5-150) minutes. The total number of lymph nodes dissected was 2138. One hundred seven of 2138 (5%) nodes were positive for malignancy. Thirty-eight of 107 (36%) positive lymph nodes were missed by palpation. Fifty-six of 2031 (3%) negative lymph nodes were selected as positive. Sixty-nine of 107 (64%) positive lymph nodes were identified correctly. Sensitivity and specificity of palpation were 72% and 81%, respectively. The positive and negative predictive values of lymph node palpation were 56% and 89%, respectively. CONCLUSION: Intraoperative lymph node palpation has low sensitivity and positive predictive value even when done by experienced board-certified gynecologic oncologists.

Percutaneous nephrostomy and ureteral stenting in gynecologic malignancies.

OBJECTIVE: To identify the indications, complications, and efficacy of percutaneous nephrostomies and ureteral stents in women with gynecologic cancer. METHODS: In a retrospective study, 40 women underwent urinary diversion with percutaneous nephrostomy and ureteral stents. Nine had ureteral stenosis on initial presentation, 18 had persistent or recurrent cancer, nine had no evidence of disease, and four had operative ureteral damage. Of the nine who were without disease, seven had a urinary conduit. RESULTS: Thirty-five patients had ureteral stenosis, which was bilateral in 24, and five had a ureteral fistula. Sixteen had a unilateral and 22 had bilateral percutaneous nephrostomies, with two cases having stents only. The most common complication was hematuria. Thirteen women were later hospitalized for pyelonephritis. Twenty-nine (72.5%) had ureteral stents, which were bilateral in 12. Renal function was abnormal in 26, but improved in 14 and returned to normal in six. Five fistulas were managed with ureteral stents alone and four were closed. The median time to death (N = 22) was 5.5 months, 12 months in primary cases versus 5.5 months in recurrent cases. Twelve of the remaining 18 were alive without evidence of disease at a median of 38 months, five were alive with disease at a median of 16 months, and one was lost to follow-up. CONCLUSIONS: These techniques are safe and often improve renal function. The procedures have different roles in women with primary and recurrent gynecologic cancer, in those without evidence of recurrent disease, and in those with urinary conduits.

Interleukin-12 synergizes with interleukin-2 to generate lymphokine-activated killer activity in peripheral blood mononuclear cells cultured in ovarian cancer ascitic fluid.

OBJECTIVES: The ascites-associated lymphocytes in ovarian cancer have altered immunologic function, and cell-free ascitic fluid has immunomodulating properties. We determined (1) whether interleukin (IL)-2 could induce lymphokine-activated killer (LAK) activity in normal peripheral blood mononuclear cells (PBMC) cultured in ovarian cancer ascitic fluid, and (2) whether IL-12 could synergize with IL-2 to generate LAK activity in normal PBMC cultured in ascitic fluid. METHODS: Normal PBMC were cultured in control medium and in media consisting of 50% ascitic fluid (ascitic medium), with and without IL-2 and IL-12. Cell activation to assess LAK activity (cell lysis) was determined in a 51Cr-release assay with the tumor cell lines FMEX and SKOV3 as target cells. To determine a possible mechanism for any synergistic effect, the expression of perforin, a pore-forming protein, was determined by Northern blot analysis. RESULTS: Interleukin-2 alone could not induce LAK activity in normal PBMC cultured in 50% ascitic fluid for up to 3 days. Interleukin-12 did mediate some or minimal LAK activity after 1, 2, or 3 days of incubation in control medium or in 50% ascitic fluid. When IL-2 and IL-12 were used in combination, PBMC cultured for 3 days in 50% ascitic fluid had remarkably high lytic activity against FMEX and SKOV3 tumor cells. In some experiments, this cytotoxicity was greater than that in PBMC cultured in control medium with IL-2 and IL-12. Lower concentrations of IL-12 (1 U/mL) with IL-2 (100 U/mL) were as effective as, and often more effective than, higher doses of IL-12 with IL-2. Very low-dose IL-12 (0.01-0.03 U/mL) in combination with IL-2 also induced a range of cytotoxicities. Only the combination of IL-2 and IL-12 up-regulated expression of perforin mRNA in ascitic medium. CONCLUSIONS: The cytotoxicity responses of PBMC cultured in ascitic fluid in the presence of IL-2 and IL-12 are complex. Low-dose IL-2 and IL-12 can overcome the inhibitory property of ascitic fluid on LAK generation and can restore and enhance cytotoxic activity, possibly by reconstituting the expression of perforin. These findings may have therapeutic potential.

Expression of interleukin-2 receptor alpha (IL-2R alpha) mRNA and protein in advanced epithelial ovarian cancer.

Advanced epithelial ovarian cancer has recently been identified by us to be associated with elevated serum and ascitic levels of the soluble Interleukin-2 receptor alpha (sIL-2R alpha). To determine the cellular source of sIL-2R alpha, the expression of IL-2R alpha was assessed at the mRNA and protein level in peripheral blood mononuclear cells (PBMC), in ovarian cancer ascitic cell infiltrates and in primary and metastatic epithelial ovarian cancer lesions by immunochemistry, by flow cytometric analysis and by in situ hybridization (ISH). Normal PBMC and the PBMC from ovarian cancer patients had a low or undetectable level of IL-2R alpha mRNA and of IL-2R alpha cell-surface protein expression. Flow cytometric analysis of the heterogeneous ascitic infiltrates revealed few cells positively expressing cell-surface IL-2R alpha. By immunocytochemistry, 1-2% of leukocytes in the ascitic infiltrates were IL-2R alpha+. Cytologically these IL-2R alpha+ cells were lymphocytes. Frozen sections of primary and metastatic ovarian cancer lesions showed sparse lymphocytic infiltration and very small numbers of these tumour infiltrating lymphocytes (TIL) were IL-2R alpha+. In situ hybridization demonstrated that although less than 2% of leukocytes in the ascitic infiltrate had detectable levels of IL-2R alpha mRNA, there was a wide range in the level of mRNA expression in these positive cells. The cells expressing IL-2R alpha mRNA had the cytologic characteristics of lymphocytes. Similarly, in the frozen sections of the solid tumours, there was a range in the level of IL-2R alpha mRNA expression in the few TIL that expressed IL-2R alpha. Importantly, ovarian cancer cells and mesothelial cells did not express IL-2R alpha mRNA or IL-2R alpha protein. Our observations lead us to conclude that lymphocytes are the main, if not the only, source of sIL-2R alpha in ovarian cancer patients. Although cells expressing IL-2R alpha were relatively few in number, as the source of the high levels of sIL-2R alpha, they may contribute to the immunosuppression of ascitic lymphocytes in advanced epithelial ovarian cancer.

Recent modifications in the treatment of invasive squamous cell carcinoma of the vulva.

The curative potential of therapy should not be sacrificed. However, an effort must be made to determine methods that will reduce the morbidity while at least retaining the curative potential. Modifications which potentially may reduce the morbidity of regional nodal management include deletion of the inguinal lymphadenectomy or use of superficial inguinal lymphadenectomy in selected early lesions, the use of separate groin incisions, the selected use of unilateral inguinal lymphadenectomy, and the use of primary radiation therapy to the inguinal and/or pelvic nodal areas. Modifications which potentially may reduce the morbidity of the primary tumor management include wide local excision for superficial lesions, modified radical vulvectomy for regionalized lesions, the use of skin flaps in selected cases, the development of more sophisticated plastic surgical procedures for the management of posterior lesions, and the use of combined treatment modalities in the management of locally advanced disease.

Ovarian Sertoli-Leydig cell tumor: success with salvage therapy.

A case of metastatic ovarian Sertoli-Leydig cell tumor is presented. The patient achieved a complete pathologic response with four courses of cisplatin, vinblastine and bleomycin chemotherapy. Recurrence of the tumor was detected with elevated serum alpha-fetoprotein. After surgical debulking, the recurrence was treated with intra-arterial cisplatin and intravenous etoposide with pelvic radiation therapy followed by intravenous doxorubicin and cyclophosphamide. The patient is alive and disease free 75 months after initial diagnosis, 4 years after salvage therapy.

Continuous intra-arterial cisplatin combined with radiotherapy in locally advanced squamous carcinoma of the cervix: a Gynecologic Oncology Group pilot study.

The high local failure rate in patients with locally advanced carcinoma of the cervix treated with standard radiation has spurred interest in radiosensitization. Cisplatin is the most active single chemotherapeutic agent in squamous carcinoma of the cervix, and is considered to be a radiosensitizer. Based on a previous single-institution study looking at continuous low-dose intra-arterial cisplatin given throughout planned radiation therapy in patients with advanced carcinoma of the cervix, the Gynecologic Oncology Group initiated a limited access pilot study to assess the feasibility of this treatment method for a group-wide study. Patients with locally advanced squamous carcinoma of the cervix and surgically documented negative periaortic lymph nodes were eligible for the study. During surgical staging, the catheters of a totally implantable pump were placed in the internal iliac arteries. The pump was filled with cisplatin which was delivered at 4.5-6.5 mg day-1 continuously throughout both external radiation and brachytherapy. Drug distribution through the catheters was determined using radiolabelled macro-aggregated albumin particles. Three of nine evaluable patients were free of disease at follow-up. Drug distribution was less than optimal through 4.6% of the pump catheters. Five patients had premature discontinuation of the cisplatin for various reasons. These problems resulted in low accrual and subsequent closure of the study. This treatment method is not feasible for a phase III evaluation on a group-wide basis.

Ultraradical surgery for advanced carcinoma of the vulva: an update.

From July 1, 1955 to March 31, 1989 24 patients with locally advanced vulvar cancer underwent ultraradical resection. Three patients had received prior radiotherapy. Seventeen of the 24 patients underwent posterior exenteration, four underwent anterior exenteration, and the remaining three required a total pelvic exenteration. One patient died 3 months postoperatively of fulminating infection considered to be a complication of the operation. Three other patients experienced serious complications, including postoperative hemorrhage, severe urinary sepsis, and colostomy stoma necrosis. Eleven (46%) of the 24 patients have remained alive without evidence of recurrent cancer for at least 3 years. Of the 10 patients known to have died of recurrent cancer, nine had positive lymph nodes at the time of surgery. It may be reasonable to utilize ultraradical surgery in patients with clearly resectable lesions who have negative or perhaps 1 or 2 microscopically positive regional lymph nodes.

Use of local flaps in the preservation of fecal continence following resection of perianal neoplasias.

The feasibility of achieving curative resection of perianal pre-invasive and invasive lesions with preservation of fecal continence was studied prospectively. Resection of these lesions involved excision of as much as the anterior third of the external anal sphincter. Twenty-two patients had invasive cancer and nine had extensive carcinoma in situ suspicious for invasive disease on preoperative assessment. Anal reconstruction consisted of plication of the external anal sphincter and plication of the puborectalis muscles. The perianal/perineal defects were closed using bilateral rhomboid flaps in 21 patients, unilateral rhomboid flaps in five patients and local advancement flaps in five patients. Twenty-eight patients were ultimately continent of feces, although two required further surgery for incontinence. Two of the three incontinent patients had fecal incontinence before surgery. Two patients had recurrence of invasive cancer, neither of which was perineal or perianal. Curative surgery of selected perianal lesions with preservation of fecal continence can be achieved with local resection and reconstruction with the use of local full thickness skin flaps.

Does ligation of the hypogastric artery at the time of radical hysterectomy and lymphadenectomy decrease blood loss? Results of a prospective randomized trial.

A prospective, randomized study of patients undergoing radical hysterectomy for gynecologic malignancies was undertaken from 10/95 to 11/96 to determine if ligation of the hypogastric arteries at the time of radical hysterectomy decreases blood loss. Patients were randomized to either ligation of the hypogastric artery (Group 1) or no ligation (Group 2) prior to a standard Piver type III radical hysterectomy. Surgeries were performed by Board certified gynecologic oncologists with gynecologic oncology fellows and/or OB/GYN residents. Patients were analyzed for demographic characteristics and intraoperative and postoperative parameters. Statistical analysis was performed with independent samples t-test, Mann-Whitney rank sum test, Chi square and Fisher exact test. Twenty-one patients were randomized to group 1 and 22 to group 2. Groups were similar with respect to demographics and preoperative parameters except for age. There were no differences among the groups with respect to intraoperative and postoperative parameters. The mean estimated blood loss for group 1 was 600 ml and 550 ml for group 2 (P = NS). Hypogastric artery ligation (HAL) at the time of radical hysterectomy for gynecologic malignancy does not reduce blood loss.

Organ blood flow redistribution in response to hypoxemia in neonatal piglets.

This study was designed to determine the effects of severe hypoxemia on newborn piglet visceral blood flow. While the hemodynamic effects of a severe hypoxemic insult are well characterized in newborn animals, its impact on organ perfusion in premature infants is not well characterized. Cannulas were placed in the femoral vessels and left atrium of term (1-14 days old) and prematurely delivered (cesarean section at 90% of term gestation) piglets. After stabilization, some animals were subjected to 1 h of ventilator-controlled hypoxia (yielding PaO2 approximately = 30-40 torr) followed by 30 min of reoxygenation; the remaining animals served as unchallenged controls. Radiolabeled microspheres were injected in all animals at times 0 min (baseline), 5 and 60 min (hypoxia), and 90 min (reoxygenation). Blood flows (mL/min/g tissue) to organs were determined using reference organ techniques. Control animals displayed no alterations in any of the variables monitored. Throughout the experimental period, organ blood flows were almost uniformly lower (p<.05, ANOVA) in premature versus term animals. The trend toward increased cerebral and cardiac blood flows during hypoxia observed in the premature piglets was similar to that of term animals, but of lower magnitude. In term piglets, hypoxia produced an immediate and significant (*p<.05) decline in small-intestinal blood flow followed by autoregulatory escape (2.02+/-0.17 mL/min/g at time 0, 1.56+/-0.15 mL/min/g at 5 min hypoxia, 1.88+/-0.18 mL/min/g at 60 min hypoxia, 2.26+/-0.19 mL/min/g at 30 min reoxygenation), an effect not readily observed in the premature piglets (0.48+/-0.10 mL/min/g at time 0, 0.44+/-0.07 mL/min/g at 5 min hypoxia, 0.46+/-0.10 mL/min/g at 60 min hypoxia, 0.42+/-0.08 mL/min/g at 30 min reoxygenation). However, mucosal blood flows measured in these younger animals declined throughout the experimental period to almost 50% of baseline, compared to a complete restoration to baseline blood flow observed following reoxygenation of term piglets. Intestinal blood flow in premature infants is small when compared to term animals, and alterations in small intestinal blood mucosal flow induced by hypoxia appear less well tolerated by the premature animals. Taken together, this may in part account for the increased risk of developing intestinal ischemic diseases in premature infants who are even temporarily exposed to a severe hypoxic challenge.

Development of a protocol to provide prolonged general anesthesia to pregnant sows.

This study was designed to determine whether a pregnant sow could be maintained under conditions of prolonged general anesthesia in order to provide access to prematurely delivered piglets for purposes of acute experimentation. Fifteen time-dated pregnant (90% of gestation) sows were preanesthetized with intramuscular xylazine (Rompun Mobay Pharmaceutical, Shawnee, KS)/ketamine (Aveco Pharmaceutical, Fort Dodge, IA). After anesthesia was induced with intravenous sodium thiopental, the animals underwent tracheotomy and mechanical ventilation. The electrocardiogram was monitored externally; systemic arterial pressure was supervised by the insertion of a brachial artery cannula; and urine output was determined by inserting a cystostomy tube. A surgical plane of anesthesia was achieved by the "balanced" technique: an inhalant, isoflurane, supplemented by intravenous doses of sufentanil citrate, propofol (Stuart Pharmaceuticals, Wilmington, DE), and vecuronium. Sows were maintained under general anesthesia for an average of 12 h; piglets were delivered, one or two at a time, by a modified cesarean section technique. No sows or piglets were lost to anesthetic complications. It is concluded that, with appropriate precautions, pregnant sows can be anesthetized for a prolonged period of time, and provide viable premature neonates for acute experimentation.

Redistribution of organ blood flow after hemorrhage and resuscitation in full-term piglets.

Newborn piglets (aged 1 to 2 days and 7 to 14 days) were used to study (1) the redistribution of organ blood flow after a 25% acute blood loss and (2) the response to resuscitation with shed blood (20 mL/kg), crystalloid (normal saline [NS] or lactated Ringer's [LR]; 60 mL/kg), and colloid (Dextran-40, 20 mL/kg). Hemodynamic parameters showed little differences in the response to hemorrhage and resuscitation. The two age groups had no significant differences in parameters or blood flow (results combined). The animals maintained flow to the heart and central nervous system (CNS) and had significantly decreased flow to the kidneys and splanchnic organs. In the gastrointestinal tract, the small intestine was affected most severely, with a significant decrease in blood flow, especially to the mucosa. In all organ systems, Dextran 40 restored blood flow to levels significantly above the baseline. Shed blood and crystalloid restored flow to organs sustaining decreased flow, but crystalloid did not restore flow to the baseline level in the kidney and all segments of the gastrointestinal tract.