Enhanced c-erbB-2/neu expression in human ovarian cancer cells correlates with more severe malignancy that can be suppressed by E1A.

Amplification or overexpression of c-erbB-2/neu protooncogene, or both, occur frequently in many different types of human cancers and have been shown to correlate with decreased survival in ovarian cancer patients. We have previously found that the ovarian carcinoma cell line SK-OV-3 overexpresses c-erbB-2/neu mRNA. To further study the biological effect of c-erbB-2/neu overexpression in SK-OV-3 cells, we injected such cells i.p. into female nu/nu mice and found that this cell line forms extensive abdominal tumors and ascites. From the ascites in an injected mouse, we established the SKOV3.ip1 cell line and found that it expressed 2-fold more c-erbB-2/neu-encoded p185 proteins than the parental SK-OV-3 cells. When transformation phenotypes of SK-OV-3 and SKOV3.ip1 cells were compared, SKOV3.ip1 cells showed higher cell growth and DNA synthesis rates, formed more colonies in soft agar, produced larger s.c. tumors, and resulted in shorter survival of nu/nu mice after i.p. injection. These data indicate that the level of c-erbB-2/neu overexpression may correlate with the degree of malignancy in these ovarian carcinoma cells. Since we had previously shown that the adenovirus 5 E1A gene product can suppress transformation and metastatic properties induced by mutation-activated rat neu oncogene in mouse embryo fibroblast cells, we further examined whether E1A can abrogate malignancy in c-erbB-2/neu-overexpressing human ovarian cancer cells. We introduced the E1A gene into c-erbB-2/neu-overexpressing SKOV3.ip1 cells and found that the E1A-expressing ovarian cancer cell lines had decreased c-erbB-2/neu-encoded p185 expression and reduced malignancy, including a decreased ability to induce tumors in nu/nu mice. Therefore, we concluded that E1A is a tumor suppressor gene for c-erbB-2/neu-overexpressing human ovarian cancer cells and may be useful in developing therapeutic reagents for these human cancers.

Cationic liposome-mediated E1A gene transfer to human breast and ovarian cancer cells and its biologic effects: a phase I clinical trial.

PURPOSE: Preclinical studies have demonstrated that the adenovirus type 5 E1A gene is associated with antitumor activities by transcriptional repression of HER-2/neu and induction of apoptosis. Indeed, E1A gene therapy is known to induce regression of HER-2/neu-overexpressing breast and ovarian cancers in nude mice. Therefore, we evaluated the feasibility of intracavitary injection of E1A gene complexed with DC-Chol cationic liposome (DCC-E1A) in patients with both HER-2/neu-overexpressing and low HER-2/neu-expressing breast and ovarian cancers in a phase I clinical trial. PATIENTS AND METHODS: An E1A gene complexed with DCC-E1A cationic liposome was injected once a week into the thoracic or peritoneal cavity of 18 patients with advanced cancer of the breast (n = 6) or ovary (n = 12). RESULTS: E1A gene expression in tumor cells was detected by immunohistochemical staining and reverse transcriptase-polymerase chain reaction. This E1A gene expression was accompanied by HER-2/neu downregulation, increased apoptosis, and reduced proliferation. The most common treatment-related toxicities were fever, nausea, vomiting, and/or discomfort at the injection sites. CONCLUSION: These results argue for the feasibility of intracavitary DCC-E1A administration, provide a clear proof of preclinical concept, and warrant phase II trials to determine the antitumor activity of the E1A gene.

Adenovirus-mediated expression of p53 or p21 in a papillary serous endometrial carcinoma cell line (SPEC-2) results in both growth inhibition and apoptotic cell death: potential application of gene therapy to endometrial cancer.

Papillary serous endometrial carcinoma is an aggressive tumor characterized by late-stage presentation, i.p. spread, and poor prognosis. It is histologically similar to serous papillary carcinoma of the ovary. Preclinical studies have shown that adenovirus-mediated expression of p53 in ovarian cancer cell lines causes growth inhibition and apoptosis in vitro and in vivo. Such studies provide the rationale for Phase I Adp53 gene therapy clinical trials in ovarian cancer. In the present study, we compared the efficacy of adenoviral vectors containing p53 (Adp53) or p21 (Adp21) in a papillary serous endometrial tumor cell line (SPEC-2) that contains mutated p53. Growth assays revealed that both Adp53 and Adp21 were efficacious in decreasing cell proliferation as assessed by anchorage-dependent and anchorage-independent growth assays. However, as compared with Adp53, the effects of Adp21 tended to be more transient and less marked. Strikingly, Adp21, but not Adp53, induced a G1 arrest in SPEC-2 endometrial adenocarcinoma cells. In contrast, as assessed by induction of hypodiploid peaks, free DNA ends detected by a terminal deoxynucleotidyl transferase-based assay, and annexin V positivity, p53 was more effective than p21 in inducing cell death by apoptosis. Compatible with the more efficient induction of apoptosis, Adp53, but not Adp21, induced a marked increase in expression of the preapoptotic molecule BAX without a concomitant change in expression of the antiapoptotic mediator Bcl-2. The differential effects of Adp53 and Adp21 on cell cycle progression and apoptosis may be related to the reversibility of p21-induced cell cycle arrest and the irreversibility of p53-induced apoptosis. Thus, at least in the papillary serous endometrial carcinoma cell line SPEC-2, Adp53 may be more effective than Adp21 as a gene therapeutic. Nevertheless, these preclinical studies suggest that papillary serous endometrial carcinoma is a potential target for p53- or p21-mediated gene therapy.

In vitro and in vivo adenovirus-mediated p53 and p16 tumor suppressor therapy in ovarian cancer.

PURPOSE: The objectives of this study were to determine the effects of adenovirus-mediated p16 and p53 on growth and apoptosis in ovarian cancer cells and on survival in nude mice implanted with human ovarian cancer cells. EXPERIMENTAL DESIGN: SKOV-3 ip1 (p53 and p16 null), 2774 (p53 and p16 mutant), and OVCA 420 (p53 and p16 wild-type) cells were used for in vitro studies. SKOV-3 ip1, 2774, and Hey A8 (p53 and p16 wild-type) cells were used in the nude mouse studies. The E1-deleted adenoviruses containing p53, p16, or beta-galactosidase cDNA were transfected into the different cell types or inoculated into the nude mice after injection with ovarian cancer cells. RESULTS: Cell counting, microtetrazolium, and anchorage-independent growth assays on transfected cells demonstrated that p16 and the p16/p53 combination suppressed growth, whereas p53 did not (except in the anchorage-independent growth assay). Although cells infected with the p16/p53 combination had decreased growth compared with cells infected with either tumor suppressor alone, the difference was only statistically significant compared with p53. p16, p53, and the p16/p53 combination all increased apoptosis in the cells. In the nude mice, p16 treatment resulted in the longest survival for all three models, although it only reached statistical significance for the 2774 and SKOV-3 ip1 groups. CONCLUSIONS: Overall, p16 demonstrated greater growth inhibition than p53 both in vivo and in vitro. The p16/p53 combination demonstrated a consistent trend toward increased growth suppression and apoptosis over p16 or p53 alone. Adenovirus-mediated p16 may be a viable future treatment for ovarian cancer.

Adenovirus E1A expression enhances the sensitivity of an ovarian cancer cell line to multiple cytotoxic agents through an apoptotic mechanism.

The introduction of adenovirus 5 E1A into the SKOV3ip1 ovarian cancer cell line was shown previously to suppress HER2/neu expression and reduce the malignant potential of these cells (Yu et al., Cancer Res., 53: 891-898, 1993). In this report, we show that reduction of p185 in cells stably expressing E1A protein was coincident with increased sensitivity to cytotoxic agents. The LD50 of cisplatin was reduced 6-fold, and the LD50 of paclitaxel and doxorubicin was reduced 10-fold in E1A-expressing cells compared with control cells. The growth of SKOV3ip1 and control cells was unchanged in the presence of 150 ng/ml of tumor necrosis factor-alpha, whereas the growth of E1A-expressing cells was reduced by 30 to 40%. When we used a physiologically obtainable concentration of paclitaxel (0.5 microM), DNA laddering consistent with apoptotic cell death was seen after a 24-h exposure in the E1A-expressing cells, whereas laddering and DNA fragmentation were only detected in DNA from control cells after longer exposure (48 h) at a 20-fold higher concentration of paclitaxel. The SKOV3ip1 cells do not express p53 protein; hence, the induction of apoptosis by paclitaxel is through a p53-independent pathway. Despite their diverse mechanisms of action, the cytotoxic effects of cisplatin, doxorubicin, paclitaxel, and tumor necrosis factor-alpha were enhanced by the expression of E1A proteins in the SKOV3ip1 ovarian cancer cells. This suggests that these agents share a common final pathway of cell killing, which may represent a potential therapeutic target in resistant ovarian cancers.

Analysis of 96 patients with advanced ovarian carcinoma treated with high-dose chemotherapy and autologous stem cell transplantation.

The purpose of this study was to identify characteristics significant to survival and progression-free survival in patients with advanced ovarian cancer receiving high-dose chemotherapy. In all, 96 patients received autologous stem cell transplantation. Regimens included paclitaxel with carboplatin (PC), topotecan, melphalan, cyclophosphamide (TMC) and cyclophosphamide, BCNU, thiotepa (CBT). At the time of transplantation, 43% of patients were in clinical CR, 34% were in clinical PR, 18% had progressive disease and 5% had stable disease. There were no treatment-related deaths. The 6-year survival by Kaplan-Meier was 38%. For patients who received transplantation for remission consolidation, the 6-year survival was 53% with a PFS of 29%. On univariate analysis, the CBT regimen, clear cell histology and disease status other than CR prior to treatment were statistically significant adverse prognostic factors. This analysis has demonstrated that patients in clinical remission are most likely to benefit from autologous transplantation, with the exception of patients with clear cell histology. The TMC combination appeared to be superior to the PC and CBT combinations. Comparative studies of different consolidation approaches will be necessary to determine if autologous transplantation is the preferred treatment for this patient population.

Adenocarcinoma in situ of the cervix: significance of cone biopsy margins.

OBJECTIVE: To evaluate the treatment and outcome of patients with adenocarcinoma in situ of the cervix, with special emphasis on cone biopsy margins. METHODS: Sixty-one women with adenocarcinoma in situ of the cervix treated between April 1984 and December 1993 were identified. Medical records and histologic material were reviewed. Mixed lesions with both adenocarcinoma in situ and squamous cervical intraepithelial neoplasia (CIN) were included. RESULTS: The mean age of the patients was 35.9 years. Fifty-five of the 61 (90%) patients had cone biopsies, and 44 of these 55 (80%) subsequently had hysterectomies. Eight women (13%) had associated invasive cancer. Among 50 patients in whom the status of the margins was confirmed, 23 (46%) had positive margins and 27 (54%) had negative margins. Of 23 women with positive margins, 19 had hysterectomies and ten of the 19 (53%) had residual disease in the uterus. Of 27 patients with negative cone margins, 21 had hysterectomies, and seven of the 21 (33%) had residual disease in the uterus. Two women with negative margins who did not have hysterectomies developed recurrent disease. Fifty-five of the total series of 61 patients followed-up for a median of 57 months (range 17-132) had no evidence of disease at last follow-up. CONCLUSION: Women with adenocarcinoma in situ of the cervix often have residual disease in the uterus, regardless of whether the margins on cone biopsy are positive or negative.

Distinctive karyotypes and growth patterns in nude mice reveal cross-contamination in an established human cancer cell line.

A human cancer cell line was found to be heterogeneous for expression of the epidermal growth factor receptor (EGFR). Clones and variants of this cell line were separated on the basis of EGFR expression level, and those expressing high EGFR had different growth characteristics, in vitro and in vivo, than variants expressing low levels of EGFR. Karyotype analysis revealed that the heterogeneity was the result of mixing of two lines, the 2774 ovarian cancer cell line, and the SW620 colon cancer cell line. Our results reinforce the necessity for accurate identification of cell lines. Also, that measurement of gene expression on a single cell level, for example by flow cytometric analysis, can be more informative than measurements of cell lysates, since the initial indication of heterogeneity would not have been detected by northern or western blotting. The different cell types retained characteristic growth patterns when injected i.p. in nude mice, i.e. peritoneal carcinomatosis and ascites formation by the 2774 ovarian cancer cells, and liver metastasis and growth of discrete abdominal tumors by the SW620 colon cancer.

Epidermal growth factor receptor (EGFR) antisense transfection reduces the expression of EGFR and suppresses the malignant phenotype of a human ovarian cancer cell line.

An EGFR-expressing clone of the human ovarian cancer line 2774 was transfected with an antisense construct of EGFR to test how suppression of this gene modulates the malignant phenotype. Transfected clones were screened for EGFR expression by Western blot and FACS analysis. Anchorage-independent growth was used to assess the effect of reduced EGFR on the malignant behavior of the cells. Several transfected clones with decreased EGFR (40-50% reduction) were identified. A correlation was noted between reduced EGFR and decreased anchorage-independent growth, with the transfected clones losing the ability to grow in agarose and responsiveness to exogenous EGF. These results suggest that EGFR may be an important factor in the malignant behavior of this ovarian cancer cell line.

Adenoviral-mediated gene therapy with Ad5CMVp53 and Ad5CMVp21 in combination with standard therapies in human breast cancer cell lines.

Our objective was to determine the efficacy of adenoviral-mediated gene therapy with wild-type p53 or p21 in human breast cancer cells and investigate interactions with radiation and chemotherapy. Two human breast cancer cell lines, MDA-MB-231 and MDA-MB-435, both with p53 mutations, were transduced with adenoviral vectors containing wild-type p53 (Ad5CMV-p53) or p21/WAF1/Cip1 (Ad5CMV-p21), and the effects on growth were determined. Infection was combined with low-dose (1.4 - 3.7 Gy) irradiation to see if this would improve transduction efficiency and enhance numbers of cells killed. Transduction with either vector resulted in expression of p21WAF1/cip1 and growth inhibition, although Ad5CMV-p53 transduction produced greater growth inhibition than did Ad5CMV-p21. The cell lines differed in sensitivity to the vectors. The Ad5CMV-p53 vector in a multiplicity of infection (MOI) of 125 resulted in 50% to 80% inhibition of MDA-MB-231, while MOI 250 of the same vector resulted in 27% inhibition of MDA-MB-435. Infection with Ad5CMV-p21 produced modest growth inhibition in both cell lines (< or = 40% at MOI 200), although protein expression was detected at lower viral doses. Low dose gamma-irradiation (1.4 to 3.7 Gy) was used to try and improve the rate of gene transfer. Modest increases in transduction efficiency and duration of expression of a vector containing beta-galactosidase occurred in irradiated breast cancer cells. Radiation 24 hr before transduction with Ad5CMV-p53 increased the proportions of apoptotic MDA-MB-231 cells. The cells transduced with Ad5CMV-p21 were arrested in G1, yet when they were irradiated before adenoviral transduction, the overexpression of p21 protected the cells from the cytotoxic effects of the radiation. Clonogenic assays showed that Ad5CMV-p21 reduced the sensitivity of MDA-MB-231 to VP-16 and paclitaxel. Combining these drugs with Ad5CMV-p53 did not consistently or significantly decrease clonogenic survival.

High-risk gestational trophoblastic neoplasia with brain metastases: individualized multidisciplinary therapy in the management of four patients.

PURPOSE: To report our recent experience managing four patients with brain metastases of gestational trophoblastic neoplasia (GTN), coordinating systemic chemotherapy with early neurosurgical intervention or stereotactic radiosurgery and intensive supportive care during initial therapy to prevent early mortality. MATERIALS AND METHODS: A series of four consecutive patients with brain metastases from high-risk Stage IV GTN managed at our institution in 2003 and 2005. Patients were assigned FIGO stage and risk score prospectively. Because of concern for chronic toxicity resulting from concurrent moderate dose methotrexate and whole brain radiation, an individualized multidisciplinary approach was used to manage patients. RESULTS: All four women presented with brain and pulmonary metastases; one had multiple liver metastases. Neurological symptoms at presentation included grand mal seizures in 2 patients, left upper extremity hemiparesis and headache each in 1 patient, while 1 patient was asymptomatic. Index pregnancies were term pregnancies in all patients with interval from prior delivery ranging from 2 weeks to 4 years. Two had received prior chemotherapy for postmolar GTN prior to the index pregnancy with incomplete follow-up. Initial hCG values ranged from 26,400 to 137,751 mIU/ml; FIGO risk scores were > or =16 for all patients. Systemic combination chemotherapy was initiated with etoposide and cisplatin followed by moderate/high-dose (500-1000 mg/m(2)) methotrexate combinations. Craniotomy was used before or during the first chemotherapy cycle to extirpate solitary lesions in 3 patients, while stereotactic radiosurgery was administered after the first cycle to treat two brain lesions in the remaining patient. None received whole brain radiation or intrathecal methotrexate. In one patient, selective angiographic embolization was used to control hemorrhage from multiple liver metastases. Two patients required ventilator support early in treatment to allow stabilization from intrathoracic hemorrhage and neutropenic sepsis with respiratory distress syndrome, respectively. Hysterectomy was performed in one patient after completion of salvage chemotherapy. All have completed maintenance chemotherapy and are in prolonged remission (12-24 months). Neurologic sequelae include persistent left upper extremity dyskinesia and weakness in one patient, and episodic grand mal seizures and pseudoseizures in a second patient with a pre-existing seizure disorder. CONCLUSION: This case series documents the utility for a multidisciplinary approach to the treatment of brain metastases from GTN. Using early craniotomy or stereotactic radiosurgery combined with etoposide-cisplatin and moderate/high-dose methotrexate combination chemotherapy, we were able to stabilize patients early in their treatment and avoid whole brain radiation therapy or intrathecal chemotherapy.

Phase II study of tirapazamine plus cisplatin in patients with advanced or recurrent cervical cancer.

The aim of this study was to evaluate the activity and toxicity of a tirapazamine (TPZ)/cisplatin drug combination in patients with stage IV or recurrent cervical cancer. The chemotherapy was administered for a maximum of eight cycles every 21 days. TPZ was administered intravenously at 330 mg/m(2) over a 2-h infusion, followed 1 h later by cisplatin intravenously at 75 mg/m(2) over 1 h on day 1. All patients received antiemetics including dexamethasone, ondansetron, and lorazepam. Subsequent doses were unchanged, reduced, or omitted according to observed toxicity and protocol guidelines. Response evaluation was performed every two cycles. Thirty-six patients with stage IV or recurrent cervical cancer were treated. Ninety-four percent of patients had prior radiotherapy. Two patients had prior chemotherapy. There were two complete responses and eight partial responses (27.8%). An additional 11 patients (30.6%) had stable disease as their best response. Response rate was greater in tumors outside of the previously radiated field (44.4% vs 11.1%). The median time to progression was 32.7 weeks. The most frequent grade 3 or 4 adverse events were nausea, vomiting, and fatigue, which occurred in 30.6%, 25%, and 22% of subjects, respectively. Anemia was the most frequent grade 3 or 4 hematologic toxicity at 8.3%. We conclude that the combination of cisplatin and TPZ was reasonably well tolerated in patients with recurrent or advanced cervical cancer. Further evaluation of this drug combination may be warranted.

The molecular biology of cervical cancer.

Cervical cancer remains a major worldwide health problem, especially in developing countries. Over the last few decades many advancements have been made in determining the molecular genetics of the development of cancer. This paper attempts to summarize the major disturbances in cellular function known to date to play a role in the development of cervical cancer. The role of human papillomavirus (HPV) infection in the development of cervical cancer is a major player in the genetic abnormalities described thus far. The effects of HPV E6 and E7 on important cell cycle genes are discussed. As oncogenes and tumor suppressor genes have been described in the different types of cancer, their possible role in cervical cancer has been investigated. The possible role of angiogenesis and angiogenic factors is described. Because of the importance of HPV infection in the development of cervical cancer, the role of the body's immune function in this cancer is also under study, and the results of these findings are summarized. Although a complete paradigm of the development of cervical cancer from normal cervical epithelium is not yet known, continued study in this area will hopefully lead to a defined progression of molecular and immunologic abnormalities that cause the disease. The goal would be to use this information to help prevent and/or treat cervical cancer in the future.

Low-grade ovarian cancer in an adolescent patient.

BACKGROUND: Ovarian tumors in the pediatric population are most likely to be of germ cell origin. However, serous tumors have also been reported in adolescent patients. CASE: A 14-year-old girl was diagnosed with stage IIIc low-grade ovarian cancer. Her serum CA-125 was elevated preoperatively and was a marker for recurrence of disease. Five months after completing standard chemotherapy, she developed recurrent disease, which progressed despite hormonal therapy. She then developed toxicity on liposomal doxorubicin (Doxil) and is now receiving hospice care. CONCLUSION: Low-grade serous adenocarcinoma of the ovary can present as advanced disease and should be considered in the differential diagnosis of an ovarian mass in an adolescent patient.

Laparoscopic port-site metastases in patients with gynecological malignancies.

OBJECTIVE: The purpose of this study is to review all reported cases of laparoscopic port-site metastases in patients with gynecological malignancies. Potential etiologies as well as options for prevention are discussed. METHODS: We searched the Medline database for English-language articles presenting raw data on laparoscopic port-site metastases in patients with gynecological malignancies. RESULTS: We found 31 articles describing port-site metastases in 58 patients. Forty patients had low malignant potential (seven patients) or invasive ovarian carcinoma (33 patients). The median age of these patients was 50 years (range: 22-79), and 83% had advanced (stage III or IV) disease. Seventy-one percent of the patients (24 of 34) had ascites, and 97% (29 of 30) had carcinomatosis. Seventy-five percent of the laparoscopic procedures in this group were performed for diagnosis. Median time to diagnosis of port-site metastases was 17 days (range: 4-730). Seventy-one percent of port-site recurrences (15 of 21) were isolated to a tissue-manipulating port. Twelve patients had port-site metastases after laparoscopy for cervical cancer. The median age was 44 years (range: 31-74). Eighty percent of cases were squamous cell carcinoma. In 75% of the patients, laparoscopy was performed for therapeutic purposes. The median time to diagnosis of port-site metastases was 5 months (range: 1.5-19). Four patients had port-site metastases after laparoscopy for uterine cancer. The median age was 63 years (range: 56-72). The median time to diagnosis of metastases was 13.5 months (range: 6-21). Half of the recurrences were in the tissue-manipulating port. Port-site metastases after laparoscopy were reported for one patient each with a diagnosis of fallopian tube carcinoma and vaginal carcinoma. CONCLUSIONS: Laparoscopic port-site metastases are a potential complication of laparoscopy in patients with gynecological malignancies, even in patients with early-stage disease.

Groin dissection practices among gynecologic oncologists treating early vulvar cancer.

OBJECTIVE: To survey the surgical practice of gynecologic oncologists regarding the extent of groin dissection for early vulvar cancer. METHODS: A 14-item questionnaire was developed and presented to the Annual Meeting of the Felix Rutledge Society. Gynecologic oncologists were asked to describe in descriptive, categorical, and visual terms the groin procedure that they perform as part of management of early vulvar cancers. Three ink-line drawings were created by a medical illustrator for the purpose. Fifty returned surveys were evaluable. RESULTS: The most commonly performed procedures were removal of the lymph nodes above the cribriform fascia and those medial to the femoral vein (40%), removal of lymph nodes above the cribriform fascia (34%), and removal of all nodes above and below the cribriform fascia (22%). Respondents performing the first procedure termed it "superficial inguinal lymphadenectomy" (40%), "inguinal femoral lymphadenectomy" (25%) and a variety of other names (35%). Respondents performing the second two procedures were much more consistent in the figure and name that they matched with their description of the nodes removed. When respondents were asked to match the figures with categorical definitions based on their understanding of the literature, the figure depicting Scarpa's triangle following removal of the superficial inguinal and medial femoral nodes was named superficial inguinal lymphadenectomy by 24% despite the fact that the femoral vein was clearly visible and labeled. CONCLUSIONS: We conclude that (1) among this group of gynecologic oncologists superficial inguinal and medial femoral lymphadenectomy is the most commonly performed procedure for women with early vulvar cancer and that the procedure is frequently called superficial inguinal lymphadenectomy; (2) publications and protocols on this topic must provide complete descriptions of procedures performed, and investigators must assure that individual surgeons are performing the same procedure; and (3) treatment results with superficial inguinal and medial femoral lymphadenectomy are poorly described and a fertile area for further study.

Hypersensitivity reactions and the utility of oral and intravenous desensitization in patients with gynecologic malignancies.

OBJECTIVES: The aims of this study were to characterize hypersensitivity reactions to chemotherapy in patients with gynecologic malignancies and to determine the utility of oral and intravenous desensitization. METHODS: We retrospectively reviewed patients with hypersensitivity reactions identified by direct physician query and by review of charts with ICD9 code E933.1 (Adverse Effect Anti-Neoplastic). RESULTS: Thirty-two patients were identified: 27 with ovarian cancer, 4 with primary peritoneal cancer, and 1 with cervical cancer. Nine patients experienced hypersensitivity reactions during the primary regimen and 23 during chemotherapy for recurrent disease. Hypersensitivity occurred following an average of nine courses. Hypersensitivity occurred secondary to paclitaxel (10) carboplatin (16), cisplatin (4), bleomycin (1), and paclitaxel/carboplatin combination therapy (1). Patients had previously received the agent in 93.8% of carboplatin reactions, in 54.5% of paclitaxel reactions, and in all other agent reactions. Hypersensitivity reactions most commonly included flushing, dyspnea/bronchospasm, back pain, chest discomfort, pruritus, erythema, and nausea and occasionally included alterations in blood pressure or pulse rate. Reactions were successfully treated in 96.9% of patients by interrupting the infusion and administering steroids, antihistamines, benzodiazepines, nebulized beta-agonists, and/or pressors. Seventeen patients underwent desensitization, one to two agents, with 94% success. Nine of ten patients had successful iv desensitization, and 8/10 patients had successful oral desensitization. One failure on the oral regimen had previous successful iv desensitization. CONCLUSIONS: Hypersensitivity reactions to chemotherapeutic agents do not necessarily require exclusion of a compound from the treatment regimen. Intravenous and oral desensitization protocols are useful for successful and safe administration of paclitaxel and platinum compounds in patients with prior hypersensitivity reactions.

Sigmoid perforation following radiation therapy in patients with cervical cancer.

OBJECTIVE: We describe the clinical presentation, evaluation, management, and outcome of patients experiencing sigmoid perforation following radiation therapy for cervical cancer. METHODS: A database consisting of over 5000 patients with stage IB-IIIB cervix cancer treated between 1963 and 1992 revealed 35 patients with sigmoid perforation. Twenty-seven were diagnosed and managed at one institution, and they form the study group. RESULTS: The median age at the time of perforation was 50 years, and the median follow-up care was 78 months (range 6-396). The median time from completion of radiotherapy to perforation was 13 months (range 3-98). The mean interval from the first documented complaint to the index admission was 90 days. Nine (33%) of 27 patients were treated with high-dose radiation therapy. The most common complaint was abdominal pain in 25 (93%) patients, nausea occurred in 12 (44%) patients, weight loss in 12 (44%) patients, and vomiting in 10 (37%) patients. The pain was described as mild in 16 (73%) of 22 patients. Only 5 (18.5%) of 27 patients had physical signs of acute peritonitis, 8 (30%) of 27 patients had some form of tenderness, and 11 (41%) of 27 had a benign exam. A total of 20 (74%) patients had an abdominal radiograph, and 12 (44%) patients had a contrast enema for evaluation. Evidence of perforation was present in 5 (25%) of 20 plain abdominal radiographs and 1 (8%) of 12 contrast enemas. Following admission, 17 (63%) patients were observed initially with subsequent surgery after symptoms either failed to resolve or worsened. The median duration under observation was 4 days (range 1-23). Surgery was performed immediately in 8 patients (30%), and 2 (7%) were observed without operation. In these 2 patients, perforation was diagnosed postmortem. Seventeen (68%) of 25 patients had a localized abscess. Three of the patients who underwent immediate exploration and 7 who had surgery after a period of observation died postoperatively (10/25, 40%). Five (55%) of 9 patients in the group who received high-dose radiation therapy died because of sigmoid perforation. When the time frame of presentation was evaluated, we noted that 10 (50%) of 20 patients died between 1960 and 1979 and 1 (14%) of 7 died between 1980 and 1992. CONCLUSIONS: Sigmoid perforation following pelvic radiation for cervical cancer does not usually present with the typical signs of a ruptured viscus. A high degree of suspicion remains a priority in the care of radiated patients who present with abdominal pain given the atypical presentation of perforation in this group.

Ovarian serous borderline tumors with invasive peritoneal implants.

BACKGROUND: The objective of the current study was to update the authors' experience with patients with ovarian serous borderline tumors with invasive peritoneal implants to gain additional insight into the biologic behavior of these tumors and a better understanding of the effect of postoperative treatment. METHODS: Thirty-nine patients with ovarian serous borderline tumors with invasive peritoneal implants were identified through a retrospective review. Major endpoints selected for analysis were surgicopathologic response, time to recurrence, type of recurrence, progression free survival, and overall survival. Univariate and multivariate regression analyses also were performed. RESULTS: Median follow-up time was 111 months. Four of 7 evaluable patients who had second-look surgery (57%) had a response to chemotherapy. Twelve of 39 patients (31%) either developed progressive disease or had a recurrence. The median time from date of diagnosis to recurrence was 24 months. In 10 of these 12 patients with a recurrence, tissue was available; 9 had invasive low grade serous carcinoma and 1 had a recurrent borderline tumor. Macroscopic residual disease was the only factor studied that had a significant effect on survival; patients with no macroscopic residual tumor had a significantly better survival than those with any macroscopic residual tumor (P < 0.01). In univariate regression analysis, macroscopic residual disease and the presence of frankly invasive implants were significant predictors of progression free survival. Platinum-based chemotherapy was associated with a significantly shorter progression-free survival. Only macroscopic residual tumor was a significant predictor of survival. CONCLUSIONS: Greater than 30% of patients with ovarian serous borderline tumors with invasive peritoneal implants will develop progressive or recurrent tumor, most commonly serous carcinoma. The presence of macroscopic residual disease appears to be the major predictor of recurrence and survival. However, in this study, the authors were unable to elucidate the role of postoperative therapy or the criteria for selection of patients for such therapy.