Diagnosis and management of hepatic ectopic pregnancy.

BACKGROUND: We present a case in which an adnexal mass caused symptoms that eventually lead to the identification of a primary hepatic pregnancy. CASE: A young woman presented with abdominal pain, a positive hCG test result, an empty uterus, and a pelvic mass. Diagnostic laparoscopy revealed a cystic adnexal mass. An exploratory laparotomy with ovarian cystectomy identified a mature teratoma but no evidence of pregnancy in the pelvis. Because the patient's quantitative hCG level continued to increase without evidence of an intrauterine pregnancy, a dilation and curettage was performed which yielded no products of conception. An ultrasound examination and magnetic resonance imaging identified an 11-week ectopic pregnancy with fetal cardiac activity located in the maternal liver. This was treated with fetal injections of methotrexate and potassium chloride under ultrasound guidance and subsequent maternal intramuscular injection of methotrexate. The patient tolerated these interventions well, and subsequent ultrasound examinations showed absent fetal cardiac activity and decreasing fetal size. Serial hCG tests were followed up to zero, and the patient's liver enzyme levels remained normal. CONCLUSION: With persistently rising hCG levels and no pregnancy identified in the uterus or pelvis, there should be a thorough evaluation of the entire pelvis and abdomen. Magnetic resonance imaging is a useful tool for locating such an ectopic pregnancy. Once identified, decisions regarding surgical versus medical management must take risk of adverse outcomes into consideration. This report reveals an 11-week hepatic pregnancy managed conservatively with fetal potassium chloride and maternal methotrexate administration.

Outcomes of Stage I/II vulvar cancer patients after negative superficial inguinal lymphadenectomy.

OBJECTIVES: To investigate the patterns of recurrence associated with superficial inguinal lymphadenectomy (SupIL) and vulvectomy for patients with Stage I/II vulvar cancer. METHODS: A retrospective chart review identified patients from 1990-2001 with Stage I/II vulvar cancer that underwent SupIL and vulvectomy. Survival was analyzed using the Kaplan-Meier method with Fisher Exact and Chi-square tests for comparisons between groups. RESULTS: 65 patients with Stage I/II vulvar cancer with a pathologically negative SupIL were identified (30 Stage I, 35 Stage II). Three patients recurred in the inguinal region, (4.6%) and 11 patients (16.9%) recurred on the vulva. Two of the 11 patients died of disease, six patients are alive without evidence of disease after additional therapy. Five-year disease-free survival and overall survival were 66% and 97%, respectively. Risk of recurrence was not associated with smoking status, stage, or margin status. CONCLUSIONS: SupIL and vulvectomy for Stage I/II vulvar cancer have a low recurrence rate in the inguinal region when nodes are negative. The local recurrence rate (17%) is acceptable, and overall survival is good using this conservative approach.

Retrospective analysis of weekly topotecan as salvage therapy in relapsed ovarian cancer.

OBJECTIVE: To retrospectively investigate the safety and efficacy of weekly topotecan in heavily pretreated patients with ovarian cancer. METHODS: Data were collected by retrospective review of patient records. Eligible patients had received > or =2 prior regimens for ovarian cancer before treatment with weekly topotecan. Efficacy was determined by measurable disease or CA 125 levels. Adverse event and growth factor support data were also collected. RESULTS: Fifty patients (median age, 61 years) were evaluable for safety and received a total of 244 4-week cycles of therapy (median, 3; range, 1-21 cycles). Most patients (84%) had measurable disease, and 30% had performance status of > or =2. Patients had received two to six prior treatments for ovarian cancer. Median weekly dose per patient was topotecan 3.7 mg/m(2). Grade 4 hematologic toxicities (generally manageable) occurred in 4% of patients. One patient had febrile neutropenia. Grade 3/4 nonhematologic toxicities were fatigue in two (4%) patients. Forty-two patients were evaluable for response. Of 35 evaluable patients with measurable disease, 11 (31%) had a partial response (median duration, 3 months), and 15 (43%) patients had stable disease (median duration, 3.5 months). Of 41 evaluable patients with elevated CA 125 (median, 154 U/l; range, 47-7200 U/l), 11 (27%) had > or =50% decreases or normalization of CA 125 levels. Median time to progression in all patients with stable disease has not been reached (follow-up range, 1.5-17.3 months). CONCLUSIONS: Weekly topotecan is active and well tolerated in heavily pretreated patients with relapsed ovarian cancer. Prospective studies of this regimen are warranted.

Inter-patient variation in efficacy of five oncolytic adenovirus candidates for ovarian cancer therapy.

BACKGROUND: Gene therapy offers a new strategy for cancer treatment. Adenoviruses represent the most widely used gene therapy vector and feature an excellent safety record. Conditionally replicative adenoviruses (CRAds) effect solid tumor penetration and tumor selective oncolysis and consequently offer potential efficacy for metastatic disease treatment. We evaluated five CRAds as candidate clinical agents for ovarian cancer therapy: RGDCRADcox-2R, Ad5VEGFE1, Ad5/3VEGFE1, Ad5-Delta24RGD, and Ad5/3-Delta24. METHODS: DNA replication by these five CRAds, wild-type adenovirus, and an E1-deleted control was measured in purified primary ovarian cancer cell spheroids by quantitative PCR. CRAd-mediated oncolysis was quantified in ovarian cancer cell monolayers and three-dimensional spheroids by cellular viability assays. The therapeutic efficacy of each CRAd was tested by intraperitoneal administration in mice with peritoneally disseminated human ovarian cancer. RESULTS: An increase in viral DNA was noted in primary tumor cell spheroids for all replicative viruses tested. Variation was noted in viral DNA replication between patient samples. All five CRAds induced remarkable oncolysis. They also prolonged survival in vivo compared with the wild-type control group. CONCLUSIONS: All five CRAds tested showed robust DNA replication, oncolysis, and in vivo therapeutic efficacy. Each virus has potential for clinical testing, and such further testing will ultimately determine its safety and relative usefulness. Variation of CRAd DNA replication between different patient samples suggests that target tissue features, such as surface receptors and endogenous transcription factors, may affect CRAd infectivity and replicativity. Evaluation of such factors may become important to optimize cancer therapy for individual patients.

The impact of aborted radical hysterectomy in patients with cervical carcinoma.

OBJECTIVE: To determine the impact of an aborted radical hysterectomy on morbidity and overall survival in patients undergoing surgical treatment for early stage cervical carcinoma. METHODS: Following IRB approval, a computerized database identified 304 women treated with radical surgery for early stage cervical carcinoma from 1994 to 2000 of which 23 (8%) had an aborted radical hysterectomy. RESULTS: Of the 23 patients, 17 patients had a IB(1) lesion, 4 patients had a IB(2) lesion, and 2 patients had a IIA lesion. Median age was 42 years (range 28-60). Twenty-one patients had squamous cell carcinoma and two patients had adenocarcinoma. Radical hysterectomy was aborted for the following reasons: 11 patients had pelvic extension, seven had positive pelvic nodes, and five patients had positive paraaortic nodes. All 23 patients received postoperative radiation therapy; additionally, 12 patients received concurrent chemotherapy consisting of platinum with or without 5-FU. There were four operative complications (17%) including deep vein thrombosis, wound infection, blood transfusion, and an ileus. Four patients (17%) had radiation-associated complications. Six of 23 (26%) patients experienced a recurrence. The 5-year overall survival was 83% with a median follow-up of 59 months (range 12-107 months). CONCLUSIONS: A small percentage of patients (8%) with early stage cervical carcinoma will have an aborted radical hysterectomy for pelvic extension or positive nodes. Fortunately, these patients still have a favorable prognosis with postoperative radiation therapy. Aborted radical surgery does not significantly increase overall complications.

Novel therapies for recurrent ovarian cancer management.

The search for novel therapies has resulted in a number of biologic agents that target cellular processes and molecules involved in ovarian carcinogenesis. These drugs include cytokines, monoclonal antibodies, vaccines, protease inhibitors and gene replacement systems. Many of these have been evaluated in Phase I/II trials and are currently being investigated in Phase III trials. This paper will review the progress of and ongoing clinical studies evaluating the potential utility of these new agents in patients affected with ovarian cancer. Further development and investigation of these agents may eventually lead to a combination of treatments that ultimately results in improved survival for patients with ovarian cancer.

Expression of sperm protein 17 (Sp17) in ovarian cancer.

Sperm protein 17 (Sp17) is an antigenic protein highly expressed in spermatozoa. Sp17 expression was demonstrated recently in multiple myeloma, suggesting that it may be a novel cancer-testis antigen. Expression of Sp17 mRNA and protein was examined in human ovarian tumors. Sp17 mRNA was evaluated by reverse transcription-polymerase chain reaction (RT-PCR) and Northern blot analysis of RNA derived from epithelial ovarian tumors and normal tissues. RT-PCR analysis detected Sp17 transcripts in 15 of 18 (83%) primary ovarian tumors. The transcript was not detected in RNA derived from normal uterus or cervix, whereas weak expression was noted in some normal ovarian tissue samples. Northern blot analysis showed no detectable Sp17 mRNA expression in normal tissues, including normal ovary, but showed Sp17 expression in 17 of 25 ovarian tumors (68%). To evaluate protein expression, mouse monoclonal antibodies were produced against recombinant Sp17 protein and used in Western blot and immunohistochemical analyses of normal reproductive tissue and primary ovarian tumor samples. Sp17 protein was detected by Western blot analysis in normal spermatozoa and in 8 of 19 ovarian tumor samples. Immunohistochemical studies showed Sp17 expression in spermatozoa, ciliated cells of the female reproductive tract, and most ovarian tumors evaluated. Tumors showed a predominantly nuclear localization of Sp17 expression, with some cytoplasmic staining. These results demonstrate that Sp17, a protein with restricted expression in somatic tissues, is expressed in ovarian tumors. Because Sp17 is immunogenic, it may represent a novel target for immunotherapeutic interventions for ovarian cancer patients.

The role of radical parametrectomy in the treatment of occult cervical carcinoma after extrafascial hysterectomy.

OBJECTIVES: To assess the morbidity and efficacy of radical parametrectomy (RP) performed following extrafascial hysterectomy in patients with occult cervical carcinoma. METHODS: An IRB approved retrospective chart review identified 23 patients that underwent RP with pelvic and/or para-aortic lymphadenectomy and upper vaginectomy. Data were collected on demographics, tumor stage, grade, histology, indication for hysterectomy, surgical findings, complications, recurrence, and survival. RESULTS: Of the 23 patients, 2 patients had a stage IA(2) lesion while 21 patients had a stage IB(1) lesion. There were 5 patients with a grade 1 tumor, 10 with grade 2, 4 with grade 3, and 4 with unknown grade. Median age was 41 years (range 27-59). The most common indication (48%) for extrafascial hysterectomy was CIS of the cervix. Four patients (17%) had metastasis to pelvic nodes or evidence of tumor at the margin at the time of RP. Three of these 4 patients with a positive specimen received adjuvant radiation and all are alive (mean follow-up 66 months). One patient declined radiation and is alive at 42 months. There were 7 (30%) operative complications: Most notably 4 patients received blood transfusions. Two of 19 patients (11%) with no residual tumor in RP specimen recurred and 1 patient was salvaged with radiation (follow-up 103 months). With a median follow-up of 61 months (range 9-103), overall 5-year survival is 96%. CONCLUSIONS: RP is an acceptable option for patients diagnosed with an occult cervical carcinoma at the time of extrafascial hysterectomy. Careful selection of RP for patients unlikely to have residual tumor will obviate the need for radiation in most instances.

The secretory leukoprotease inhibitor (SLPI) promoter for ovarian cancer gene therapy.

BACKGROUND: Adenoviruses allow efficient transduction of dividing and non-dividing cells and their safety for the treatment of cancer has been established in clinical trials. However, one disadvantage is their promiscuous tropism. In this regard, tissue-specific promoters (TSPs) could be useful for directing transgene expression to target tissues and for reducing adverse effects in non-target tissues. We hypothesize that selective adenovirus-mediated transgene expression could be achieved through the use of the secretory leukoprotease inhibitor (SLPI) promoter in the context of ovarian cancer. METHODS: Adenoviruses containing the SLPI promoter driving reporter and suicide gene expression were created and tested in ovarian cancer cell lines and primary tumor cells isolated from patients. To evaluate the in vivo activation of the SLPI promoter in comparison to a ubiquitous promoter, intraperitoneal delivery was performed in tumor-bearing mice, followed by analysis of survival or gene expression in normal organs and tumor. RESULTS: The SLPI promoter retained its fidelity in an adenoviral context and was activated in both cell lines and primary cancer cells. The SLPI promoter was induced to a high degree in ovarian cancer cells while showing significantly reduced activity in normal tissues. The therapeutic efficacy of SLPI promoter-controlled gene expression was similar to the ubiquitous promoter in vitro and in an orthotopic murine model of peritoneally disseminated ovarian cancer, with higher activity than controls. CONCLUSIONS: The SLPI promoter is a potentially useful TSP for ovarian cancer and facilitates further development of targeting strategies for improved gene therapy of ovarian carcinomas.

Gene transfer to ovarian cancer versus normal tissues with fiber-modified adenoviruses.

Adenovirus serotype 5 (Ad5) displays unparalleled gene transfer efficacy to cells with high coxsackie-adenovirus receptor (CAR) expression. Unfortunately, cells isolated from clinical human cancers, both ovarian and other types, express highly variable and often low levels of CAR. Fortunately, native Ad5 tropism can be modified to circumvent CAR deficiency and to enhance infectivity. Ad5/3luc1 incorporates the serotype 3 fiber knob and binds to a receptor distinct from CAR, while the fiber of Ad5lucRGD is modified with an RGD-4C motif, allowing CAR-independent binding to integrins. We studied the liver tropism and blood clearance of these viruses after intravenous (i.v.) injection, and biodistribution after intraperitoneal (i.p.) injection to tumor-bearing mice. To estimate efficacy, we assessed gene transfer to purified human primary ovarian cancer cells, and in a mouse model of ovarian cancer. Ad5/3luc1 achieved improved gene transfer over Ad5lucRGD, and both infectivity-enhanced viruses were superior to the isogenic control with an unmodified Ad5 capsid. In the presence of malignant ascites, gene transfer was improved with both Ad5/3luc1 and Ad5lucRGD. Thus, retargeting to the Ad3 receptor enhances gene transfer to clinically relevant ovarian cancer substrates, while the mouse toxicity and biodistribution profile of both fiber-modified Ad vectors is comparable to Ad5.