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BACKGROUND: This study was performed to determine whether 24-h paclitaxel plus doxorubicin and filgrastim was superior to cisplatin plus doxorubicin in patients with endometrial cancer with respect to response, progression-free survival (PFS) and overall survival (OS). PATIENTS AND METHODS: Eligible chemotherapy-naïve patients were randomly assigned to doxorubicin 60 mg/m2 intravenously (i.v.) followed by cisplatin 50 mg/m2 i.v. (arm 1, n=157) or doxorubicin 50 mg/m2 i.v. followed 4 h later by paclitaxel 150 mg/m2 i.v. over 24 h plus filgrastim 5 microg/kg on days 3-12 (arm 2, n=160). Starting doses were reduced for prior pelvic radiotherapy and age > 65 years. Both regimens were to be repeated every 3 weeks for a maximum of seven cycles. RESULTS: There was no significant difference in response rate (40% versus 43%), PFS (median 7.2 versus 6 months) or OS (median 12.6 versus 13.6 months) for arm 1 and arm 2, respectively. Toxicities were primarily hematological, with 54% (arm 1) and 50% (arm 2) of patients experiencing grade 4 granulocytopenia. Gastrointestinal toxicities were similar in both arms. CONCLUSIONS: Doxorubicin and 24-h paclitaxel plus filgrastim was not superior to doxorubicin and cisplatin in terms of response, PFS or survival in advanced endometrial cancer.

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OBJECTIVE: We have previously reported on the feasibility of weekly topotecan as single-agent therapy in previously treated patients with ovarian cancer. The objective of this study was to assess the maximum tolerated dose (MTD) of weekly bolus intravenous (IV) topotecan combined with weekly paclitaxel in a comparable patient population. METHODS: Previously treated ovarian cancer patients with measurable disease and/or elevated cancer antigen 125 (CA-125) received (as second-line or third-line therapy) weekly 30-min bolus IV topotecan starting at 2 mg/m(2) combined with weekly paclitaxel starting at a dose of 60 mg/m(2). In this intrapatient dose-escalation study, topotecan and paclitaxel were escalated in parallel until the MTD was reached, defined as the first dose level at which >or= 2 of 6 patients experienced dose-limiting toxicity. RESULTS: Twenty-one of 26 patients were evaluable for toxicity and received a total of 306 weeks of therapy (median, 13 weeks; range, 5 to 33 weeks). No significant dose-limiting toxicity was observed up to a weekly bolus IV topotecan dose of 3 mg/m(2) and a concurrent paclitaxel dose of 80 mg/m(2). The MTD was topotecan 3.5 mg/m(2) plus 90 mg/m(2) paclitaxel. The dose-limiting toxicities included anemia and fatigue, with 10 of 21 patients receiving epoetin alfa for grade 3 or 4 anemia; only 1 patient required a blood transfusion. Two patients had a treatment delay of at least 1 week and only 1 patient required a dose reduction to maintain the weekly schedule. CONCLUSIONS: Based on the results of this study, the recommended initial dose for this novel regimen is topotecan 3 mg/m(2) and paclitaxel 80 mg/m(2). Further investigation of the efficacy of weekly topotecan plus paclitaxel in less heavily pretreated patients is warranted.

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OBJECTIVE: Topotecan is an established topoisomerase I inhibitor for the treatment of relapsed ovarian cancer. Myelotoxicity and suboptimal patient convenience associated with daily topotecan, however, have prompted investigators to explore alternate regimens, including a weekly regimen of topotecan. The objective of this study was to determine the maximum tolerated dose (MTD) of topotecan given as a weekly bolus in previously treated ovarian cancer patients. METHODS: Second- and third-line ovarian cancer patients with measurable disease or elevated cancer antigen 125 received weekly bolus topotecan intravenously starting at 1.5 mg/m(2). Topotecan was escalated in dose increments of 0.5 mg/m(2) every 21 days as tolerability allowed. Dose-limiting toxicity was defined as grade 3/4 neutropenia or thrombocytopenia. RESULTS: Thirty-two of 35 patients were evaluable for safety and tolerability. No notable toxicity was observed with weekly topotecan doses < 4 mg/m(2). Additionally, there was an absence of dose-limiting myelotoxicity and thrombocytopenia with weekly topotecan. The MTD of weekly topotecan without the use of granulocyte colony-stimulating factor support was 4 mg/m(2), with grade 2 anemia, chronic fatigue, and grade 2 gastrointestinal toxicity limiting further dose escalation. Weekly topotecan also demonstrated antitumor activity at doses >2 mg/m(2). CONCLUSIONS: The establishment of a well-tolerated, weekly regimen of topotecan (4 mg/m(2), with a maximum recommended dose of 6 mg/m(2)) provides the basis for further investigation in phase II studies of single-agent and combination regimens in previously treated ovarian cancer patients.

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Endometrial carcinoma associated with pregnancy is uncommon. In case 1, a 40-year-old gravida 2, para 2, was diagnosed with focal well-differentiated papillary adenocarcinoma 4 months postpartum. In case 2, a 35-year-old gravida 1, para 0, was diagnosed with a well-differentiated papillary adenocarcinoma of the endometrium after a D&C for an incomplete abortion at 7 weeks gestation. In case 3, a 32-year-old gravida 2, para 1, was diagnosed with a moderately differentiated adenocarcinoma with squamous metaplasia 4 months postpartum. All are without evidence of disease more than 2 years after therapy. A literature review shows 24 previous cases of pregnancy associated with endometrial cancer. These cases demonstrate the importance of endometrial sampling for abnormal postpartum bleeding despite the protective effects of pregnancy.

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A patient with respiratory failure from metastatic choriocarcinoma was treated with mechanical ventilation while receiving chemotherapy with etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine. The patient recovered from respiratory failure with the assistance of standard mechanical ventilation using low tidal volumes. The patient has sustained clinical remission with normal respiratory function. Mechanical ventilation with low tidal volumes and a pressure-targeted approach should be considered in the patient who develops early respiratory failure from metastatic choriocarcinoma.

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The retinoblastoma (RB) gene was the first defined tumor suppressor gene. While originally described in retinoblastoma, more recently alterations in RB have been described in a number of other human neoplasms and there has been a suggestion that alteration of RB may play a significant role in the development of endometrial carcinoma. We examined RB protein expression by immunohistochemistry in a series of cases including normal endometrium, endometrial hyperplasia, and endometrial carcinoma. A relatively homogeneous pattern of staining was observed in proliferative endometrium, while weak or absent reactivity was noted in secretory endometrium. A heterogeneous pattern of reactivity was observed in 10/10 cases of hyperplasia, 66/70 cases of endometrial adenocarcinoma, and 7/7 cases of uterine carcinosarcoma. An altered pattern of reactivity was observed in the remaining 4/70 cases of adenocarcinoma. All of the cases with altered reactivity were high grade neoplasms. We conclude that alteration of RB protein expression is uncommon in endometrial adenocarcinoma and when it does occur, it may represent a late event in carcinogenesis.

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PURPOSE: Cisplatin, mitolactol (dibromodulcitol), and ifosfamide have been the most active single agents in squamous carcinoma of the cervix identified so far by the Gynecologic Oncology Group (GOG). Combinations of cisplatin plus ifosfamide and cisplatin plus mitolactol are prospectively compared with cisplatin alone. PATIENTS AND METHODS: Patients were randomized to receive cisplatin 50 mg/m2 or the same dose of cisplatin plus mitolactol (C + M) 180 mg/m2 orally on days 2 to 6, or cisplatin plus ifosfamide (CIFX) 5 g/m2 given as a 24-hour infusion plus mesna 6 g/m2 during and for 12 hours after the ifosfamide infusion, every 3 weeks for up to six courses. Of 454 patients entered, 438 were eligible and analyzed for response and survival. RESULTS: CIFX had a higher response rate (31.1% v 17.8%, p = .004) and longer progression-free survival (PFS) time (P = .003) compared with cisplatin alone. The median times to progression or death were 4.6 and 3.2 months, respectively. C + M showed no significant improvement in these parameters compared with cisplatin alone. Survival was associated with initial performance score (PS; 0 was more favorable; P < .001) and with age (younger was unfavorable, P = .025). There was no significant difference in overall survival between cisplatin and either of the combinations. Leukopenia, renal toxicity, peripheral neurotoxicity, and CNS toxicity were more frequent with CIFX (P < .05). CONCLUSION: CIFX improved the response rate and PFS duration in advanced cervix cancer compared with cisplatin alone, but at the cost of greater toxicity and with no improvement in survival.

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The bcl-2 gene codes for a protein which functions to inhibit apoptotic cell death. bcl-2 overexpression was originally described in follicular lymphoma, but more recently bcl-2 expression has been observed in a variety of other human neoplasms. In this study we used immunohistochemistry to examine bcl-2 protein expression in endometrial hyperplasia and carcinoma. bcl-2 protein was observed in 4/4 cases of complex hyperplasia, 1/4 cases of complex atypical hyperplasia, and 10/29 cases of carcinoma. The staining observed in the cases of complex atypical hyperplasia and carcinoma was focal and less intense than the reactivity of normal proliferative endometrium. We conclude that bcl-2 protein is seldom overexpressed in complex atypical hyperplasia or carcinoma of the endometrium. Rather, in many cases of endometrial carcinoma bcl-2 expression appears to be decreased.

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Twenty-eight patients with advanced, persistent or recurrent leiomyosarcoma of the uterus not previously exposed to cytotoxic drugs were entered into a study of single-agent intravenous etoposide 100 mg/m2 daily for 3 days every 3 weeks. No complete or partial responses were observed. Thirteen patients demonstrated stable disease, while 15 exhibited increasing disease. Median progression-free interval was 2.1 months, median survival 9.2+ months. The most frequent and severe adverse effects were the result of myelosuppression and manifested primarily as leukopenia and neutropenia. Based on the absence of activity, no further study of intravenous etoposide in leiomyosarcoma of the uterus at the dose and schedule tested is planned.

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We reported the characterization of three serine proteases (granzymes 1, 2, and 3) from human cytotoxic T lymphocytes. In this study, human granzymes 1, 2, and 3 were purified from the cytoplasmic granules of lymphokine activated killer (LAK) cells by gel filtration and cation exchange chromatography. Human perforin was purified by phenyl superose and heparin-agarose chromatography. Each purified granzyme was used with purified perforin to study DNA fragmentation in target cells of both human and murine origin. As measured by agarose gel electrophoresis and [125I]dUrd assay, the granzymes induced oligonucleosomal DNA fragmentation and [125I]dUrd release respectively from various target cells. Murine target cells were generally more susceptible to nuclear DNA release than were human targets. Both enzyme activity and nuclear DNA breakdown were significantly inhibited by 3,4-dichloroisocoumarin (DCI) or by heat inactivation of each granzyme. Perforin alone or granzyme alone failed to fragment nuclear DNA in various target cells. We conclude that human granzymes are an important family of effector molecules that with perforin induce DNA fragmentation in susceptible target cells.

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OBJECTIVE: The purpose of this investigation was to determine the pattern of loss of heterozygosity in multiple tumor sites from familial ovarian cancer cases. If ovarian cancer arises focally in one ovary and then metastasizes to other sites, a similar pattern should be seen in all tumor sites. However, if ovarian cancer arises multifocally throughout the peritoneal cavity, a different pattern of loss would be expected among the different sites. STUDY DESIGN: The presence or absence of loss of specific alleles for 9 loci on chromosomes 1, 6, 11, 13, 16, and 17 was determined in multiple tumor sites from 12 familial ovarian cancer cases. RESULTS: The frequency of loss of heterozygosity was as follows: chromosome 17 (100%), chromosome 13 (82%), chromosome 6 (80%), chromosome 16 (73%), chromosome 1 (57%), and chromosome 11 (22%). In every case an identical pattern was present for at least one locus. In four cases loss of the same allele was present in tumor from the ovary and all metastatic sites for all informative loci. In the remaining eight cases loss of the same allele for one to five (mean three) loci was detected. CONCLUSIONS: The pattern of loss of heterozygosity in the 12 familial ovarian cancers included in this investigation favors a unifocal origin of disease. A dual primary origin could not be absolutely excluded in 3 cases. High frequencies on chromosomes 17q and 13 suggest that loss of whole or part of these chromosomes is important in ovarian carcinogenesis.

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BACKGROUND: Since the 1980s, there have been isolated reports of a toxic shock syndrome associated with Clostridium sordellii necrotizing subcutaneous infections during the puerperium. Relatively localized fascial and muscle necrosis is noted at the surgical incision sites. However, circulating toxins produce marked edema, resulting in shock and cardiovascular collapse. Despite aggressive surgical and supportive therapy, all postpartum cases thus far have been fatal. CASE: A 24-year-old primipara developed an episiotomy infection which progressed to involve the underlying fascia and muscle. Despite early and adequate debridement of the devitalized tissue, she developed anasarca, marked leukocytosis, refractory hypotension, hypothermia, and a persistent coagulopathy, and expired on postpartum day 5. The cultures from the excised tissue grew C. sordellii All blood cultures were negative. CONCLUSION: Treatment modalities aimed solely at the eradication of the microbe and removal of necrotic tissue, although essential components of therapy, have proved inadequate. Future efforts should be directed toward neutralization or elimination of the circulating exotoxins responsible for the systemic shock.

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Splenectomy is sometimes necessary to achieve optimal cytoreduction or manage iatrogenic injury in the surgical management of epithelial ovarian cancer (EOC) and related conditions. To determine the place of splenectomy in cytoreductive surgery a retrospective review was made of patient hospital records. Between April 1989 and August 1994, 18 patients were found to have undergone a splenectomy as a component of their surgery leading to optimal debulking. Morbidity attributable to the splenectomy was minimal, with no significant increase in operative time or blood loss. The morbidity attributable to the splenectomy was as follows: atelectasis and/or effusion (8), pancreatic tail injury (4), thrombocytosis > 10(6)/microliters (3), pancreatic pseudocyst (1), partial left adrenalectomy (1), and pulmonary embolism (1). There were no instances of overwhelming postsplenectomy infection. Five patients were anticipated to require splenectomy and may have benefitted from preoperative vaccination against potential pathogens. Three patients were found to have splenic parenchymal metastases. Consistent with the international literature, these patients had other features consistent with stage IV disease, recurrent disease, or poor survival. Consideration should be given to expanding the FIGO stage IV classification to include splenic parenchymal disease. Splenectomy is a feasible and safe procedure to facilitate optimal tumor debulking; however, the potential associated morbidity mitigates against this procedure if significant, suboptimal residual disease is left elsewhere.

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Recurrent ovarian cancer after negative findings at second-look laparotomy is common. A retrospective review of 57 patients who developed recurrent tumor after a negative second-look laparotomy was undertaken to evaluate treatment efficacy and prognostic factors. All patients received primary platinum-based chemotherapy. Recurrences occurred in the abdomen or pelvis (40 patients), lymph nodes (7), liver (4), lungs (3), and vagina (3). Recurrent disease was diagnosed at a mean interval of 20 months after second-look surgery. Of the 38 patients who underwent laparotomy for recurrence, 36 (95%) had > 0.5 cm disease. After cytoreductive surgery 14 patients (37%) were left with minimal (< 0.5 cm) residual disease. Intestinal resection or bypass was performed on 10/38 patients (26%) with one requiring a colostomy. There was no operative mortality and one complication (small bowel obstruction). Treatment after recurrence consisted of platinum-based chemotherapy (88%), with the remaining patients receiving irradiation or hormonal therapy. At a mean follow-up from recurrence for the entire group of 20 months, 18/38 (47%) explored patients are alive. All 19 patients who were not explored died with a median survival time from recurrence of 9 months. Patients who underwent a laparotomy and patients with < 0.5 cm residual disease had a significant survival advantage (P < 0.0001). Initial stage, grade, disease-free interval, and disease found at laparotomy did not influence survival. Recurrent ovarian carcinoma after platinum-based chemotherapy is associated with a grave prognosis when the patient is deemed inoperable or when distant metastasis are found. Patients with disease reduced to < 0.5 cm showed a significant survival advantage.

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Incorporating effective screening into preventive health care for women would theoretically eliminate the diagnosis of cervical cancer in pregnancy. Until this goal is reached, our management decisions are limited by the relatively small and retrospective studies that form the basis for our pertinent knowledge and the ethical issues that would complicate randomized trials of treatment in pregnancy. Limited data suggest that radical hysterectomy with pelvic lymphadenectomy might carry a more favorable therapeutic index than radiation therapy in early-stage disease. In general, improvements in neonatal management may allow earlier intervention, shortening the time between diagnosis and treatment in hope of improving maternal outcome. The actual survival impact of this information remains to be demonstrated. An algorithm has been provided in Figure 3 which summarizes the salient features of the clinical management of significantly abnormal cervical cytology in pregnancy. At many institutions the rate of "atypical" or other nonspecified cytologic abnormalities exceeds 10%, and low-grade dysplastic changes are common and less threatening. These conditions place the responsibility for cervical cancer detection firmly upon the clinician and his or her index of suspicion that a significant abnormality exists. Those directing prenatal care must remain compulsive in the proper use of cytologic screening and careful clinical examination. A diagnosis should be rapidly and vigorously pursued when a diagnosis of cancer is suspected, with timely referral when needed. These practices may have the most immediate impact upon both maternal and fetal outcome when facing cervical cancer in pregnancy.

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BACKGROUND: Intraperitoneal chemotherapy is an established treatment for abdominal and pelvic malignancies. Several catheter-related complications have been reported. We report a case of abnormal distribution of intraperitoneal chemotherapy into the pleural cavity. CASE: A patient receiving intraperitoneal cisplatin developed shortness of breath. A pleural effusion was diagnosed and was evacuated by thoracentesis. Abnormal distribution of instilled fluid was responsible for her distress. CONCLUSION: Communications exist between the peritoneal and pleural cavities. The use of intraperitoneal chemotherapy or radioactive material may lead to respiratory complications if abnormal distribution occurs.

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The absence of a reliable noninvasive means of detecting persistent clinically occult ovarian cancer is the basis for performing repetitive operative procedures, usually called a second-look. Although controversy persists regarding whether second-look surgery contributes to an improved survival, it is well established that the second-look findings are of prognostic value. Patients with no pathologic evidence of tumor at second-look surgery (negative second-look) are much more likely to experience a prolonged disease-free interval than are patients with evidence of gross tumors at second-look (macroscopic positive second-look). Likewise, patients without gross tumor but with pathologic or cytologic disease (microscopic positive second-look) tend to survive longer than patients with a macroscopic positive second-look, but they do more poorly than patients with a negative second-look. It is also well known, however, that there are other prognostic features that influence clinical outcomes. For example, patients who have a negative second-look after treatment for a stage IIIC, grade 3 epithelial ovarian carcinoma should be considered at higher risk (50%) for an earlier clinical relapse than patients with low-grade tumors (grade 1 or low malignant potential) who have microscopic or small-volume gross tumors at second-look surgery. Much attention has been directed to whether second-look surgery has a favorable impact on survival. Unfortunately, no blind randomized trials have addressed this question. The conduct of a trial to evaluate the impact of second-look surgery on survival would be most difficult and essentially impossible because of an inability to standardize or control the treatment for recurrent tumors. Even measuring the interval of progression-free disease from completion of primary chemotherapy would be a challenging clinical trial to execute.

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Tumor-infiltrating lymphocytes (TIL) from human ovarian tumors of low malignant potential (LMP) were studied in situ by immunohistology and characterized functionally after isolation from tumors. In comparison to ovarian carcinomas, borderline (LMP) ovarian tumors contained significantly fewer infiltrating leukocytes. Phenotypically, TIL from LMP tumors contained significantly fewer activated (HLA-DR+ or CD25+) lymphocytes than did fresh TIL from ovarian carcinomas. Also, percentages of CD3-CD56+ natural killer cells were higher in LMP than in ovarian carcinomas. TIL obtained from LMP tumors proliferated well in vitro in the presence of interleukin 2 (IL2) and tumor necrosis factor alpha (TNF alpha) but did not show a selective enrichment in CD3+CD8+T lymphocytes generally observed with TIL from ovarian carcinomas. Antitumor cytotoxicity against a panel of tumor cell targets of cultured TIL from LMP tumor did not parallel that of effectors generated from autologous peripheral blood lymphocytes. However, no significant enrichment in reactivity against autologous tumor cells was observed in long-term cultures of TIL from LMP tumors. Thus, considerable differences were observed between phenotypic and functional characteristics of lymphoid cells infiltrating LMP tumors and invasive ovarian carcinomas.

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Carcinosarcoma of the uterus is an uncommon tumor composed of epithelial and mesenchymal components. The incidence is higher in blacks and increases with age. It most commonly presents with postmenopausal bleeding or as a prolapsing, polypoid uterine mass. When clinically limited to the uterus, this tumor will be surgically upstaged in 20% to 30% of cases, usually because of its propensity for nodal metastasis. Treatment of choice consists of total abdominal hysterectomy, bilateral salpingo-oophorectomy, and complete surgical staging. Surgical findings determine further therapy. Retrospective studies have shown a decrease in local recurrence after pelvic irradiation, which also is beneficial in the control of localized recurrences or advanced disease. Chemotherapy has been limited to advanced or recurrent disease, although its role in the adjuvant setting is currently under investigation. The most active single agents are ifosfamide and cisplatin.

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Tumor-infiltrating lymphocytes (TIL) freshly isolated from human ovarian carcinomas were phenotyped (up to 75% CD3+ HLA-DR+ cells) and cultured in the presence of recombinant interleukin 2 and tumor necrosis factor alpha. In short-term cultures, an initial outgrowth of CD3+ CD8+ T lymphocytes resulted in the enrichment of autotumor cytotoxicity under these culture conditions. The early peak of autotumor cytotoxicity was accompanied by interleukin 1 beta and interferon gamma production. The RNA message for interferon gamma was detected by in situ hybridization in TIL induced with interleukin 2 and tumor necrosis factor alpha but not in freshly isolated TIL. A combination of interleukin 2 and tumor necrosis factor alpha was also advantageous for selective outgrowth of CD3+ CD8+ T lymphocytes with autotumor reactivity in long-term cultures of ovarian TIL. At days 30-40 of growth, total lytic units of autotumor cytotoxicity per culture increased from a mean of 59 to 2155, and the percentage of CD3+ CD8+ T lymphocytes rose to 98% in some of the cultures. Thus, the combination of interleukin 2 and tumor necrosis factor alpha provided conditions favorable for sustained growth of autotumor-reactive CD3+ CD8+ TIL in vitro.

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