A phase I study of lapatinib in combination with carboplatin in women with platinum sensitive recurrent ovarian carcinoma.

OBJECTIVES: To determine the maximum tolerated dose (MTD), spectrum of toxicities, clinical activity, and pharmacokinetics of carboplatin given in combination with lapatinib in women with a first recurrence of platinum sensitive epithelial ovarian carcinoma. METHODS: Patients with measurable, platinum sensitive recurrent epithelial ovarian carcinoma were eligible. Cohorts of 3-6 patients were to receive up to 6 cycles of intravenous carboplatin AUC of 6 every 21 days in combination with escalating dosages of oral lapatinib (starting at a dose of 750 mg daily). Toxicity was assessed using NCI CTC for Adverse Events. Clinical response was monitored using RECIST criteria. Pharmacokinetic (PK) analysis was performed for the second cohort of patients. RESULTS: Twelve patients were enrolled. No dose limiting toxicity was noted. Two of 6 patients in the first cohort had unanticipated excessive delays in treatment due to non-dose limiting G3 neutropenia. Therefore, the study was modified to reduce the carboplatin dose in the second cohort. The median number of courses administered to the 11 evaluable patients in these two cohorts was 2.8 (range 1-6). Drug-related grade 3 or 4 toxicities included non-dose limiting G4 thrombocytopenia (n=1), and non-dose limiting G3 neutropenia (n=3). Of the 11 patients who received >or=1 course of therapy, 3 (27%) had a partial response, and 3 (27%) had stable disease. The pharmacokinetics of carboplatin were not significantly altered by concomitant administration of lapatinib. CONCLUSIONS: This regimen of lapatinib and carboplatin was associated with unacceptable non-dose limiting toxicities, excessive treatment delays and limited clinical responses.

Bowel resection at the time of primary debulking for epithelial ovarian carcinoma: outcomes in patients treated with platinum and taxane-based chemotherapy.

BACKGROUND: Our goal was to determine the morbidity, disease-free survival, and overall survival of patients with bowel resection at primary cytoreductive surgery for advanced epithelial ovarian carcinoma in the era of platinum and taxane chemotherapy. STUDY DESIGN: We performed a retrospective study of patients undergoing bowel resection at the time of primary cytoreduction for advanced epithelial ovarian carcinoma, who subsequently received platinum and taxane chemotherapy, from 1996 to 2001. Data collected included demographics, stage, histology, debulking status, surgical morbidity, recurrence, and survival. Survival analysis and comparisons were performed using the Kaplan-Meier method and log-rank test. RESULTS: Of 48 patients (45 stage III; 3 stage IV), 25 patients (52%) were optimally debulked to < 1 cm of residual disease; the remaining 23 patients had residual disease > 1 cm. Four-year disease-free survival in the optimally debulked group was 24% versus 12% in the suboptimally debulked group (p=0.009). Four-year overall survival was 81% in the optimally debulked group versus 54% in the suboptimally debulked group (p=0.162). Five patients (10%) experienced a major postoperative complication including stroke, small bowel obstruction, anastomotic leak, entercutaneous fistula, and pelvic abscess. Two perioperative deaths occurred in the suboptimally debulked group. CONCLUSIONS: Patients with advanced epithelial ovarian carcinoma who undergo bowel resection as part of optimal cytoreduction and receive platinum and taxane chemotherapy have improved disease-free survival and a trend toward improved overall survival. Bowel resection at the time of primary cytoreductive surgery is associated with acceptable perioperative morbidity.

Surgical staging in endometrial cancer.

Early presentation of endometrial cancer permits effective management with excellent clinical outcome. The addition of hysteroscopy to dilatation and curettage (D&C) in the evaluation of postmenopausal bleeding adds little to the detection of malignancy. Imaging studies such as computed tomography, magnetic resonance imaging, and positron-emission tomography may be of use in determining the presence of extrauterine disease in patients medically unfit for surgical staging. However, these studies are not sufficiently sensitive to replace surgical staging and have little role in routine preoperative evaluation. Clinical staging alone is clearly inadequate, as 23% of preoperative clinical stage I/II patients are upstaged with comprehensive surgical staging. Preoperative tumor grade from D&C or office biopsy may be inaccurate and lead to an underestimate of tumor progression if used to determine which patients should be surgically staged. Clinical estimation of depth of invasion, with or without frozen section, is inaccurate and may lead to underestimation of disease status when surgical staging is not performed. The practice of resecting only clinically suspicious nodes should be discouraged as it is no substitute for comprehensive surgical staging. Comprehensive surgical staging provides proper guidance for postoperative adjuvant therapy, avoiding needless radiation in 85% of clinical stage I/II patients. Finally, resection of occult metastasis with surgical staging may improve survival.

A fiber-modified, secretory leukoprotease inhibitor promoter-based conditionally replicating adenovirus for treatment of ovarian cancer.

PURPOSE: The use of conditionally replicating adenoviruses (CRAD) is dependent on molecular differences between tumor cells and nontumor cells. Transcriptional targeting of CRAD replication via tumor-specific promoters is an effective way to control replication regulation. Genetic fiber pseudotyping is an approach for circumventing low expression of the primary adenovirus serotype 5 (Ad5) receptor by using the distinct adenovirus serotype 3 (Ad3) receptor for entry into and subsequent killing of ovarian cancer cells. EXPERIMENTAL DESIGN: In this study, we constructed a fiber-modified CRAD containing the secretory leukoprotease inhibitor (SLPI) promoter to control viral replication via the E1A gene (Ad5/3SLPI). To evaluate the liver toxicity of chimeric 5/3 fiber-modified CRADs, we compared Ad5/3SLPI with Ad5/3Cox-2L, a CRAD with E1A under control of the Cox-2 promoter, and Ad5/3Delta24, a CRAD that replicates in cancer cells inactive in the retinoblastoma/p16 pathway by use of an in vivo hepatotoxicity model and by a model system that uses slices of human liver. RESULTS: We show efficient viral replication and oncolysis of Ad5/3SLPI in both multiple ovarian cancer cell lines and primary tumor cell spheroids as well as therapeutic efficacy in an orthotopic mouse model of peritoneal carcinomatosis. Ad5/3SLPI showed significantly decreased liver toxicity compared with other 5/3 fiber-modified control vectors examined. CONCLUSIONS: In summary, Ad5/3SLPI is a promising vector candidate for treating metastatic ovarian cancer and showed robust virus replication, oncolysis, and in vivo therapeutic efficacy. Ad5/3SLPI showed comparatively low liver toxicity and therefore holds potential for patient use in the clinic.

A novel ex vivo model system for evaluation of conditionally replicative adenoviruses therapeutic efficacy and toxicity.

PURPOSE: Current animal tumor models are inadequate for the evaluation of toxicity and efficacy of conditionally replicative adenoviruses. A novel model system is needed that will provide insight into the anticipated therapeutic index of conditionally replicative adenoviruses preclinically. We endeavored to show a novel model system, which involves ex vivo evaluation of conditionally replicative adenovirus toxicity and therapeutic efficacy in thin, precision-cut slices of human primary tumor and liver. EXPERIMENTAL DESIGN: The Krumdieck thin-slice tissue culture system was used to obtain and culture slices of tumor xenografts of ovarian cancer cell lines, human primary ovarian tumors, and human liver. We determined the viability of slices in culture over a period of 36 to 48 hours by ([3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxphenyl-2-(4-sulfophenyl)-2H-tetrazolium, inner salt)]) (MTS) assay. In vitro Hey cells, slices of Hey xenografts, and human ovarian tumor or human liver slices were infected with 500vp/cell of either replication competent wild-type adenovirus (Ad5/3wt), conditionally replicative adenovirus (Ad5/3cox-2), or the replication deficient adenovirus (Ad5/3luc1). At 12-, 24-, and 36-hour intervals, the replication of adenoviruses in these slices was determined by quantitative reverse transcription-PCR of adenoviral E4 copy number. RESULTS: Primary tumor slices were able to maintain viability for up to 48 hours after infection with nonreplicative virus (Ad5luc1). Infection of Hey xenografts with Ad5/3cox-2 showed replication consistent with that seen in Hey cells infected in an in vitro setting. Primary tumor slices showed replication of both Ad5/3wt and Ad5/3cox over a 36-hour time period. Human liver slices showed replication of Ad5/3wt but a relative reduction in replication of Ad5/3cox-2 indicative of conditional replication "liver off" phenotype, thus predicting lower toxicity. CONCLUSIONS: The thin-slice model system represents a stringent method of ex vivo evaluation of novel replicative adenoviral vectors and allows assessment of human liver replication relative to human tumor replication. This is the first study to incorporate this system for evaluation of therapeutic efficacy and replicative specificity of conditionally replicative adenoviruses. Also, the study is the first to provide a valid means for preclinical assay of potential conditionally replicative adenovirus-based hepatotoxicities, thus providing a powerful tool to determine therapeutic index for clinical translation of conditionally replicative adenoviruses.

Immunotherapy of ovarian cancer.

Epithelial ovarian cancer remains the leading cause of death due to gynaecological malignancy. Although patients with advanced ovarian cancer have a good response to surgery and platinum-based chemotherapy, long-term survival remains poor. Immunotherapy techniques currently under investigation for treatment of recurrence include antitumour monoclonal and bispecific antibodies. Antibodies to ovarian cancer antigens have also been combined with radioisotopes, immunotoxins and chemotherapeutic drug conjugates to provide improved targeting of these agents. Anti-idiotypic antibodies and vaccines have also been developed to initiate humoral and cellular immune responses against ovarian cancer. Cytokines have been administered alone as well as in combination with other immunotherapy agents in patients with ovarian cancer. Finally, antigen-presenting cells are being modified by a variety of methods to stimulate an antitumour immune response. This review summarises the latest published clinical data and highlights promising areas of research in this exciting field.

Gene therapy for ovarian cancer: progress and potential.

Gene therapy remains a promising therapeutic modality for ovarian cancer. Yet much work remains to be done to see gene therapy realize its full potential in elucidating the complex genetic interactions of delivered genes within target cancer cells and in the development of improved vector systems. Because most neoplasms involve multiple mutations, the targeting of a single mutation is unlikely to achieve total tumor control: gene therapy strategies that target multiple cellular processes or invoke various antitumor approaches need to be investigated. Additionally, current vector systems do not transduce ovarian cancer cells efficiently and are hampered by immune responses that further limit their efficacy. Additionally, limitations in vector specificity lead to transduction of normal cells and subsequent toxicity. Investigators are developing refinements to current gene therapy approaches that would address these limitations and that are soon to be incorporated into clinical trials. It is hoped that these advances will lead to improvements in the therapeutic index for ovarian cancer gene therapy and provide another effective therapeutic tool for this deadly disease.

A prospective evaluation of a simulator-based laparoscopic training program for gynecology residents.

BACKGROUND: To determine prospectively if simulator-based laparoscopic training could improve laparoscopic skills of gynecology residents. STUDY DESIGN: Twenty-six gynecology residents were enrolled in a laparoscopy training curriculum involving didactics, self-paced learning modules, and graded simulator-based laparoscopic training modules. Six simulator tasks were developed to introduce incremental levels of difficulty. Residents were tested on bead/peg manipulation, passing of a specially designed "key," cutting of lines and circles on a two-layer latex glove, and laparoscopic suturing followed by both intra- and extracorporeal knot tying. Times for each task and penalties for errors were assessed at baseline and after 3 months of training. RESULTS: Twenty-six residents completed initial baseline and 3-month evaluations. Average summary time (including 30-seconds penalties for each error) at baseline was 64 minutes and 36 minutes at 3-month evaluation (p < 0.001). For PGY1 baseline summary times averaged 83 minutes compared with 50 minutes at 3 months (p = 0.006). For PGY4 baseline summary times averaged 49 minutes compared with 28 minutes at 3 months (p = 0.05). All individual tasks demonstrated substantial improvement (p < 0.001) from baseline to 3-month evaluation. Baseline summary scores demonstrated correlation between PGY training year and overall score (p < 0.001) consistent with earlier ability and training. Three-month scores demonstrated equalization of skill level across PGY2 through PGY4. CONCLUSIONS: A dedicated simulator-based laparoscopic training curriculum has the ability to improve basic laparoscopic skills in a gynecologic residency, as measured by timed and scored simulator tasks. Construct validity was demonstrated by measuring substantial improvement in performance with increasing residency training, and with practice.

Lipoxygenase pathway receptor expression in ovarian cancer.

OBJECTIVE: To determine the expression of lipoxygenase (LOX) pathway receptors in ovarian cancer as a potential target for anti-LOX-based therapy. STUDY DESIGN: Paraffin-embedded tumor samples from epithelial ovarian cancer patients were used to construct tissue microarrays to stain for the proposed sites of inhibition of a LOX inhibitor (5-LOX, LTB4-BLT1, and LTB4-BLT2). RESULTS: 245 samples were available for interpretation. Strong expression was demonstrated in 45%, 34%, and 6% of ovarian cancer for LTB4-BLT2, LTB4-BLT1, and 5-LOX, respectively. Expression of LTB4-BLT2 correlated with advanced stage III/IV disease (P = .05), suboptimal debulking (P = .07), and platinum resistance (P = .03). No correlation was seen with regard to disease-free survival. CONCLUSIONS: LOX pathway receptor expression was found in the majority of cancers evaluated. Additionally, LTB4-BLT2 expression portends worse clinical parameters for ovarian cancer. Thus, further investigation on the role of LOX pathway in ovarian cancer is warranted.

Autoclave sterilization of instruments used on women with cervical neoplasia is an effective method of eradicating residual human papillomavirus DNA: a polymerase chain reaction-based evaluation.

OBJECTIVE: To determine whether autoclave sterilization eradicates human papillomavirus (HPV) DNA on specula and instruments used to treat women with cervical neoplasia. METHODS: Specula and instruments used in two referral colposcopy clinics were evaluated to determine the PGMY9/11 primer system's ability to amplify residual HPV DNA. Each speculum and instrument was sampled with a Dacron swab and stored in PreservCyt solution (Cytyc Corporation, Marlborough, MA) at 4 degrees C. DNA amplification was performed under standard conditions with appropriate controls followed by HPV typing using the reverse line blot test (Roche Molecular Systems, Alameda, CA). Once validated, the same polymerase chain reaction method was used on autoclave-sterilized specula and biopsy instruments and heated glass bead- and Cidex bath (Johnson & Johnson, New Brunswick, NJ)-sterilized instruments. All results, with appropriate positive and negative controls, were confirmed in triplicate. RESULTS: A total of 140 instruments (70 used and 70 autoclaved) were sampled for residual HPV DNA. Five samples in the contaminated specula arm were excluded from analysis secondary to insufficient sampling. Of the remaining samples, 52.3% (34/65) of contaminated instruments-both specula and biopsy instruments-had detectable HPV DNA. Fifty-five percent of contaminated biopsy instruments (11/20) were positive and 51.1% of contaminated specula (23/45) were positive. All 70 autoclaved samples (50 specula and 20 biopsy instruments) were negative for residual HPV DNA or beta-globin. One instrument in the glass bead and Cidex group that was presumed sterile was positive for HPV 16 DNA. CONCLUSIONS: The PGMY9/11 primer system is an effective method to detect residual HPV DNA. Autoclave sterilization appears to eradicate HPV DNA to levels undetectable with this sensitive assay, whereas heated glass beads followed by Cidex bath appears to be inadequate methods. These results suggest that autoclave sterilization is effective when using nondisposable instruments and should be the method of choice in studies using polymerase chain reaction-based amplification of HPV DNA.

Recurrent basosquamous cell carcinoma of the vulva.

BACKGROUND: Basosquamous cell carcinoma (BSC) of the vulva is a rare entity with interesting prognostic and therapeutic implications. Currently, there is no definitive treatment due to its low incidence. CASE: A case of recurrent BSC of the vulva treated with unilateral radical vulvectomy and unilateral lymph node dissection is reported. CONCLUSION: BSC is a rare disorder of the vulva. The metastatic potential of this tumor is not fully understood, but likely is intermediate between squamous cell carcinoma and basal cell carcinoma. Local recurrence is common and close follow-up is warranted.

A case report of rhabdomyosarcoma of the uterus associated with uterine inversion.

BACKGROUND: Alveolar rhabdomyosarcoma is an uncommon malignant soft tissue tumor rarely found in the genital tract. This tumor is associated with a poor prognosis, especially in the adult population. Equally as rare are non-puerperal uterine inversions secondary to sarcomas. CASE: A 21-year-old obese woman was initially evaluated with excessive vaginal bleeding. On exam, a large pedunculated mass protruding from the cervix was seen and biopsy of this mass revealed an alveolar rhabdomyosarcoma. The patient was treated with adjuvant chemotherapy consisting of VAC (Vincristine, Actinomycin, and Cyclophosphamide) for a presumed cervical rhabdomyosarcoma. After five cycles of chemotherapy the patient underwent a total abdominal hysterectomy and bilateral salpingo-oophorectomy, at which time a complete uterine inversion was noted with the tumor located at the fundus of the uterus. Final pathology showed alveolar rhabdomyosarcoma of the uterus. The patient then received additional postoperative VAC regimen for a total of 10 treatments and remains in good health with no evidence of disease 20 months from diagnosis. CONCLUSION: This case report describes the only reported case of uterine inversion secondary to alveolar rhabdomyosarcoma of the uterus and discusses current therapeutic options for adults.

Gamma mode of infiltration associated with poor prognosis in malignant teratoma of the ovary: A case report.

BACKGROUND: Although mature cystic teratoma is the most common tumor of the ovary, squamous cell carcinoma arising from a mature teratoma is a rare event. Prognosis depends on clinical stage, grade, and recently described mode of tumor infiltration. CASE: This case involves a 52-year-old woman with stage II squamous cell carcinoma arising in a mature cystic teratoma of the left ovary. Final pathology demonstrated poorly differentiated squamous cell carcinoma with gamma mode of tumor infiltration. The patient completed adjuvant chemotherapy and subsequently died of progressive disease. CONCLUSION: Squamous cell carcinoma arising from a benign cystic teratoma is a rare event. Studies have shown stage, grade, and mode of infiltration to be predictors of recurrence and prognosis. This case supports the growing evidence linking the mode of tumor infiltration with overall prognosis of survival.

Predictors of outcomes for women with cervical carcinoma.

BACKGROUND: To determine the impact of race and other factors on the management and outcomes of women treated for cervical cancer in a rural state. METHODS: Following IRB approval, a retrospective review identified 434 eligible women treated for cervical cancer from 1994 to 2000. Collected data included: demographics, clinicopathologic data, primary and adjuvant therapy, recurrence, and survival. Statistical analyses were performed with the Chi-square test, Kaplan-Meier method, and Cox regression. RESULTS: 304 (70%) of the women were white and 130 (30%) were non-white. Non-whites were more likely to present with advanced stage disease [Stage IIB-IVB] (25% vs. 13%; P < 0.01). Whites were more likely to smoke, be married, be employed, and have private insurance. Non-whites were more likely to have medical co-morbidities such as diabetes and hypertension. Although whites with early stage disease were more likely to undergo surgery as their primary therapy than non-whites (93% vs. 84%; P < 0.01), survival was similar. Survival outcomes for advanced stage disease were similar between groups. CONCLUSIONS: Non-whites diagnosed with cervical cancer are more likely to present with advanced stage disease than whites; however, overall survival was similar between groups. Non-whites with early stage disease were more likely to receive primary radiation therapy than whites. The decision to use radiation therapy vs. surgery does not appear to have a detrimental effect on overall survival, but may impact quality of life.

A prospective evaluation of "see and treat" in women with HSIL Pap smear results: is this an appropriate strategy?

OBJECTIVE: The evaluation of abnormal cervical cytologic results is time consuming and costly. Most patients with high-grade squamous intraepithelial lesion (HSIL)-cervical intraepithelial neoplasia 3 (CIN 3) Pap smear results require an excisional procedure for diagnostic or therapeutic reasons. "See and treat" is a surgical procedure that involves a loop electrosurgical excisional procedure (LEEP) simultaneously to diagnose and to treat premalignant cervical disease in one visit. This procedure eliminates a second visit that typically is required for treatment. Data is lacking on the incidence of CIN 2 and CIN 3 in patients with an HSIL (CIN 2) Pap smear result. The objective of this study was to determine the incidence of CIN 2 and CIN 3 in patients with an HSIL (CIN 2) Pap smear using a see-and-treat protocol. METHODS: Women referred from local health departments to our university-based colposcopy clinic for evaluation of an HSIL (CIN 2) Pap smear result were evaluated for inclusion in a see and treat protocol. All eligible patients underwent colposcopy to rule out an obvious cervical carcinoma followed by an immediate LEEP to remove the transformation zone. A colposcopic impression was made using the Reid colposcopic index. Pathologic specimens were analyzed for the presence of CIN and the incidence of CIN 2 and CIN 3 was determined. RESULTS: To date, 51 patients have been enrolled in the study. Exclusion criteria included age less than 19 years, pregnancy, or medical contraindications. The mean age of the patients was 26 years (range, 19-45 years). Forty-seven percent were white, 47% were black, and 6% were Hispanic. Of the 51 patients who underwent LEEP, 43 of 51 (85%) had satisfactory colposcopy and no patient had a lesion suspicious for cervical carcinoma. The average Reid colposcopic index was 3.5. Of the 51 LEEP specimens, 4 of 51 had no evidence of CIN (8%), 4 of 51 (8%) had CIN 1, 18 of 51 (35%) had CIN 2, and 25 of 51 (49%) had CIN 3. Eighty-four percent of patients had either CIN 2 or CIN 3, resulting in an overtreatment rate (CIN 1 or less) of 16%. CONCLUSIONS: The use of a see and treat protocol for patients with HSIL (CIN 2) Pap smear results may be an acceptable treatment option because of a high incidence of CIN 2 and CIN 3.

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.

High-risk human papillomavirus and cervical intraepithelial neoplasia at time of atypical squamous cells of undetermined significance cytologic results in a population with human immunodeficiency virus.

OBJECTIVE: Little information exists regarding high-risk human papillomavirus (HPV) subtypes in human immunodeficiency virus (HIV) patients with atypical squamous cells of undetermined significance (ASCUS) cytologic results. This study aimed to characterize further HPV prevalence and high-grade cervical intraepithelial neoplasia (CIN) in this sub-population of patients. MATERIALS AND METHODS: This is a secondary analysis of a prospective HPV natural history study involving 200 HIV-sero-positive patients. We analyzed 102 patients from this cohort with a cervical cytologic diagnosis of ASCUS for high-risk and low-risk HPV prevalence, clearance of HPV infection, progression or regression of cervical cytologic abnormality, and prevalence of CIN 2 or worse at the time of indicated colposcopy. Pap smears were slide-based and HPV testing was performed using nested polymerase chain reaction. RESULTS: Overall prevalence of ASCUS in the HIV population was 20% (40 of 200 patients). Despite a high prevalence of all HPV subtypes (74 of 102 subtypes; 73%), high-risk subtypes were present in only 32% of patients (33 of 102 patients) with ASCUS cytologic results. In 5 of 42 patients (12%) undergoing colposcopy within 6 months of ASCUS cytologic results, CIN 2 or worse was found. Sensitivity, specificity, positive predictive value, and negative predictive value of a high-risk or intermediate-risk HPV test for CIN 2,3 were 100%, 70%, 31%, and 100%, respectively. Progression to high-grade intraepithelial lesion cytologic results after ASCUS was rare (5/64 evaluable patients; 8%) but persistence of low-grade cytologic results (ASCUS or low-grade intraepithelial lesion) was common (43/64 evaluable patients; 67%). CONCLUSIONS: Despite a high rate of HPV infection in the HIV population with ASCUS Pap results, high-risk HPV subtypes represent a minority of patients and are significantly associated with presence of high-grade CIN at colposcopy. High-risk HPV testing should be investigated further in the HIV population.

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.

A pilot study of ovarian cancer chemoprevention using medroxyprogesterone acetate in an avian model of spontaneous ovarian carcinogenesis.

OBJECTIVE: Our previous studies have documented the feasibility of using the laying hen, Gallus domesticus, as a model of spontaneous ovarian carcinogenesis. This study was performed to determine the ability of medroxyprogesterone acetate (Depo-Provera) to reduce the frequency of spontaneously developing reproductive tract adenocarcinoma in the avian model. METHOD: Four hundred 3-year-old hens were in a two-arm trial designed to determine the frequency of epithelial reproductive tract adenocarcinomas. Animals were designated to receive three injections of 100 mg Depo-Provera versus no injection over a 16-month period. Both groups were subjected to two induced molts 12 months apart. Egg counts were obtained and decreased egg production was documented in the treated hens due to Depo-Provera. At the end of 16 months surviving animals were sacrificed and the frequency of reproductive tract adenocarcinoma was determined histologicically. RESULTS: Histologic information was obtained from the 293 hens that completed the full prescribed course of study. At the time of necropsy, multiple hens had evidence of carcinomatosis and massive ascites consistent with metastatic reproductive tract adenocarcinomas. Of the tissues examined from the informative cases gathered at the time of sacrifice, there was evidence of a reduction of reproductive tract adenocarcinoma observed in the Depo-Provera group (45/127-35%) when compared to the control group (69/166-42%). A risk reduction of 15% is observed in the treatment group (risk ratio 0.85: 95% confidence interval 0.63-1.15). CONCLUSION: The high rate of reproductive tract adenocarcinoma observed in this study supports the avian hen as a valid model of spontaneous ovarian carcinogenesis in which to test chemoprevention strategies and provides a unique opportunity for investigating the pathogenesis of ovarian carcinoma. The current histologic findings are consistent with the theory that a reduction of ovulatory events may prevent the development of ovarian adenocarcinoma.

Gene transfer to cervical cancer with fiber-modified adenoviruses.

Successful adenoviral (Ad) vector-mediated strategies for cancer gene therapy mandate gene-delivery systems that are capable of achieving efficient gene delivery in vivo. In many cancer types, in vivo gene-transfer efficiency remains limited due to the low or highly variable expression of the primary Ad receptor, the coxsackie Ad receptor (CAR). In this study, we evaluated the expression of CAR on cervical cancer cells as well as CAR-independent targeting strategies to integrins (Ad5.RGD), heparan sulfate proteoglycans (Ad5.pK7) or both (Ad5.RGD.pK7). We used a panel of established cervical cancer cell lines and primary cervical cancer cells isolated from patients to quantify the expression of CAR mRNA and to evaluate the gene-transfer efficiency of fiber-modified Ads. Of the fiber-modified vectors, Ad5.pK7 and Ad5.RGD.pK7 displayed significantly enhanced gene-transfer efficiency in vitro. Gene-delivery efficiency in vivo was evaluated using an s.c. cervical cancer mouse model. Ad5.RGD.pK7 significantly improves tumor targeting in vivo, resulting in a significantly improved tumor/liver ratio in mice. Our results suggest that the double-modified Ad5.RGD.pk7 vector enhances gene transfer to clinically relevant cervical cancer substrates, while the infectivity of nontarget cells in the mouse is not increased and comparable to Ad5. The fiber-modified virus described here can help achieve higher clinical efficacy of cervical cancer gene therapy.