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Background: The increased exposure to heparin products for thromboprophylaxis against VTE in hospitalized patients raises concerns for an increase in the incidence of heparin-induced thrombocytopenia(HIT).Methods: We analyzed, among 90,875 patients exposed to heparin products between 2005 and 2009, the number of hematologic consultations for thrombocytopenia, requests for heparin induced antibodies by enzyme-linked immunosorbent assay, and cases given a diagnosis of HIT by the hematology consult service.Results: We observed that despite a doubling in the number of patients receiving pharmacoprophylaxis with heparin, there was no significant increase in the number of consultations for thrombocytopenia,the number of requests for HIT tests, the number of positive HIT test results, or the number of HIT diagnoses. The number of cases of HIT was low and represented < 0.1% of patients exposed to heparin.Conclusions: We conclude that concerns about HIT should not be a limiting factor for the systematic implementation of heparin-based VTE prophylaxis. [ABSTRACT FROM AUTHOR]

Carcinosarcomas (CSs) of the endometrium are biphasic malignancies, composed of high-grade carcinomatous and sarcomatous components. Surgical stage and pathologic characteristics are the most important prognostic findings, with a 5-yr survival of 15% to 30% in advance stage disease. Folate receptor alpha (FRA) overexpression has been observed in endometrial carcinomas and not yet studied in CSs. This study evaluates semiquantitative expression of FRA in both carcinomatous and sarcomatous components of CSs on whole tissue sections. Immunohistochemistry for FRA expression was performed and extent and intensity of staining were recorded for each case for both histologic components. A total of 46 cases were stained for FRA. The majority of these (40/46, 87%) showed FRA staining at variable intensity in the carcinomatous component, stronger in serous carcinomas and high-grade endometrioid, while only a small subset of tumors demonstrated weak staining in the sarcomatous component (2/46, 4.35%). CS is known to be associated with poor prognosis and adjuvant therapy is recommended even in low stage disease. Serous and high-grade endometrioid carcinomas are the most common carcinomatous components of CSs and are known to show consistently high FRA expression. Folate plays a role in tumor cell migration and loss of cellular adhesion, which are key steps in epithelial-mesenchymal transition, the process by which CS develops from carcinoma cells. Our study shows expression of FRA in the carcinomatous component of almost all CS cases (87%), further favoring FRA as a target for adjuvant treatment. While expression of FRA in the sarcomatous component was rarely observed, the carcinomatous component being associated with metastatic potential underscores the importance of anti-FRA therapy for systemic disease control., Competing Interests: The authors declare no conflict of interest., (Copyright © 2020 by the International Society of Gynecological Pathologists.)

Introduction: Treatment of advanced stage ovarian carcinoma is challenging, and despite surgical treatment and chemotherapy, the 5-year survival rate is estimated around 30%. Early recurrence and resistance to platinum-based chemotherapy are associated with poor prognosis and limited response to available second-line chemotherapy. The relative incidence of endocervical adenocarcinoma (EAC) compared with squamous cell carcinoma is increasing. Although the first-line treatment modality for early stage EAC is surgical resection, for locally advanced disease chemoradiation or neoadjuvant chemotherapy is used. Recently, folate along with its receptor alpha (FRA) has been studied as a potential target in gynecologic malignancy. The objective of this study was to elucidate FRA expression in chemotherapy resistant ovarian cancer and primary EAC., Methods: FRA expression was evaluated in tissue samples in an epithelial ovarian tumor microarray and 2 study groups: platinum resistant ovarian cancer and primary EAC. Staining intensity was analyzed with a semiquantitative staining algorithm., Results: FRA expression was positive in 32 of 40 (80%) ovarian tumors in the control group. In the platinum resistant ovarian cancer group, FRA was expressed in all 30 samples with moderate to strong staining. None of the EAC samples stained positive for FRA expression., Conclusions: FRA expression occurs frequently in epithelial ovarian cancer. Our data supports that FRA expressions are maintained after chemotherapy treatment. Folate targeted therapies may be most useful in patients with chemotherapy resistant disease based on high levels of FRA expression in these tumors. There is likely no benefit to folate therapy as an adjuvant treatment in EAC.

Importance: Unsolicited patient observations are associated with risk of medical malpractice claims. Because lawsuits may be triggered by an unexpected adverse outcome superimposed on a strained patient-physician relationship, a question remains as to whether behaviors that generate patient dissatisfaction might also contribute to the genesis of adverse outcomes themselves., Objective: To examine whether patients of surgeons with a history of higher numbers of unsolicited patient observations are at greater risk for postoperative complications than patients whose surgeons generate fewer such unsolicited patient observations., Design, Setting, and Participants: This retrospective cohort study used data from 7 academic medical centers participating in the National Surgical Quality Improvement Program and the Vanderbilt Patient Advocacy Reporting System from January 1, 2011, to December 31, 2013. Patients older than 18 years included in the National Surgical Quality Improvement Program who underwent inpatient or outpatient operations at 1 of the participating sites during the study period were included. Patients were excluded if the attending surgeon had less than 24 months of data in the Vanderbilt Patient Advocacy Reporting System preceding the date of the operation. Data analysis was conducted from June 1, 2015, to October 20, 2016., Exposures: Unsolicited patient observations for the patient's surgeon in the 24 months preceding the date of the operation., Main Outcomes and Measures: Postoperative surgical or medical complications as defined by the National Surgical Quality Improvement Program within 30 days of the operation of interest., Results: Among the 32 125 patients in the cohort (13 230 men, 18 895 women; mean [SD] age, 55.8 [15.8] years), 3501 (10.9%) experienced a complication, including 1754 (5.5%) surgical and 2422 (7.5%) medical complications. Prior unsolicited patient observations for a surgeon were significantly associated with the risk of a patient having any complication (odds ratio, 1.0063; 95% CI, 1.0004-1.0123; P = .03), any surgical complication (odds ratio, 1.0104; 95% CI, 1.0022-1.0186; P = .01), any medical complication (odds ratio, 1.0079; 95% CI, 1.0009-1.0148; P = .03), and being readmitted (odds ratio, 1.0088, 95% CI, 1.0024-1.0151; P = .007). The adjusted rate of complications was 13.9% higher for patients whose surgeon was in the highest quartile of unsolicited patient observations compared with patients whose surgeon was in the lowest quartile., Conclusions and Relevance: Patients whose surgeons have large numbers of unsolicited patient observations in the 24 months prior to the patient's operation are at increased risk of surgical and medical complications. Efforts to promote patient safety and address risk of malpractice claims should continue to focus on surgeons' ability to communicate respectfully and effectively with patients and other medical professionals.

Background: Clear cell carcinoma of cervix (CCCC) is a rare cervical neoplasm that is usually associated with diethylstilbestrol (DES) exposure in utero as a primary risk factor. Advanced stage disease typically has poor outcomes and no evidence-based approach exists to guide clinicians in treating this rare disease., Case: The authors report a case of locally advanced CCCC in a 37-year-old Caucasian female. She underwent chemoradiation therapy that included 109 courses of paclitaxel chemotherapy until no disease could be detected on imaging studies. She is now disease-free 13 years after discontinuing chemotherapy., Conclusion: A prolonged course of single agent paclitaxel after completing standard radiation therapy was successful in achieving remission in a patient with this rare disease.

Purpose of Investigation: Because of rarity, consensus on adjuvant therapies for Type II endometrial cancers (BC) remains undefined. Reporting their institutional outcomes, the present authors assessed the impact of adjuvant therapies on recurrence and overall survival in women with 2009 FIGO Stage I-III Type II BC., Material and Methods: The authors identified 108 women, treated with definitive surgery between 2000-2013, with pathologically-confirmed Type II EC (non-endometrioid [NEM, n=801 and high grade endometrioid [G3EEC, n=28]) Cox proportional hazard models were used to assess the effect of prognostic variables on disease-free (DFS) and overall survival (OS). Kaplan-Meier method was used to assess survival., Results: Of the 108 women, 83 (77%) were African American (AA). Fifty-nine (55%), 12 (11%), and 37 (34%) were Stage I, II, and III, respectively. Ninety-seven patients received adjuvant therapy: 52 (radiation only), four (chemotherapy only), and 40 (combined). During follow-up (median 41 months), 44 patients (41%) recurred. Five-year DFS was 53% overall (48% [NEM], 80% [G3EEC]). Five-year OS was 75% overall (68% [NEM], 95% [G3EEC]). On multivariate analysis, lower stage and adjuvant radiation improved DFS. Higher stage, NEM, and increasing age were poor prognostic indicators of OS., Conclusion: Representing a large single institutional cohort for Type II BC, the present study's observed sur- vival rates are consistent with previous studies, despite the relatively high frequency of carcinosarcoma and Stage III/nodal disease. The protective effect on recurrence was not lost when radiation was delayed for chemotherapy. The present results support a multimodal adjuvant approach for treating all stages of invasive NEM EC.

Surgery is the primary treatment for vulvar cancer as well as early-stage carcinoma of the cervix. This article reviews the significance of margin status after surgery on overall survival, need for further surgical intervention, and role for possible adjuvant therapy. It summarizes the abundant literature on margin status in vulvar cancer and highlights the need for further investigation on the prognostic significance of margins in cervical cancer. In addition, it reviews other important operative considerations., (© 2016 Wiley Periodicals, Inc.)

Pediatric cervicovaginal clear cell adenocarcinoma (CCA) is rare but continues to occur in the postdiethylstilbestrol era. Ideal management is unclear. We report a case of locally advanced, node-negative CCA in a 14-year-old girl without a history of diethylstilbestrol exposure. The patient's disease was FIGO stage IIIA, involving the cervix, vagina, and parametrium. She was treated with concurrent cisplatin and external beam radiation, followed by interstitial low-dose rate brachytherapy. The patient has no evidence of disease after 2 years of follow-up. These findings support the use of definitive chemoradiation as a treatment option for adolescents with locally advanced CCA.

Background: Recommendations for high-risk human papillomavirus (HR-HPV) testing as an adjunct to cytology for cervical cancer screening differ by age group, because HR-HPV tests lack adequate specificity in women aged <30. Here, we assess age-group differences in HPV types and other risk factors for cervical intraepithelial neoplasia (CIN) grade 3 or worse (CIN3+) versus CIN0-2 in women from four colposcopy clinics., Methods: Women ages 18 to 69 (n = 1,658) were enrolled and completed structured interviews to elicit data on behavioral risk factors prior to their examinations. HPV genotyping was done on exfoliated cervical cell samples. We estimated relative risks (RR) for HPV types and cofactors for CIN3+, overall and stratified by age group., Results: After 2 years of follow-up, we identified 178 CIN3+, 1,305 CIN0-2, and 175 indeterminate outcomes. Nonvaccine HR-HPV types were only associated with CIN3+ among women ≥ 30 (RR = 2.3, 95% CI: 1.5-3.4; <30: RR = 0.9). Among all HR-HPV-positive women, adjusting for age, significant cofactors for CIN3+ included current smoking (RR = 1.5), former smoking (RR = 1.8), regular Pap screening (RR = 0.7), current regular condom use (RR = 0.5), and parity ≥ 5 (RR = 1.6, P(trend) for increasing parity = 0.07). However, the parity association differed by age group (≥ 30: RR = 1.8, P(trend) = 0.008; <30: RR = 0.9; P(trend) =.55)., Conclusion: Subgroup variation by age in the risk of CIN3+ points to the importance of the timing of exposures in relation to CIN3+ detection., Impact: Future screening strategies need to consider natural history and secular trends in cofactor prevalence in the pursuit of appropriately sensitive and specific screening tools applied to appropriate age groups.

Previous screening trials for early detection of ovarian cancer in postmenopausal women have used the standard CA125 cut-point of 35 U/mL, the 98th percentile in this population yielding a 2% false positive rate, whereas the same cut-point in trials of premenopausal women results in substantially higher false positive rates. We investigated demographic and clinical factors predicting CA125 distributions, including 98th percentiles, in a large population of high-risk women participating in two ovarian cancer screening studies with common eligibility criteria and screening protocols. Baseline CA125 values and clinical and demographic data from 3,692 women participating in screening studies conducted by the National Cancer Institute-sponsored Cancer Genetics Network and Gynecologic Oncology Group were combined for this preplanned analysis. Because of the large effect of menopausal status on CA125 levels, statistical analyses were conducted separately in pre- and postmenopausal subjects to determine the impact of other baseline factors on predicted CA125 cut-points on the basis of 98th percentile. The primary clinical factor affecting CA125 cut-points was menopausal status, with premenopausal women having a significantly higher cut-point of 50 U/mL, while in postmenopausal subjects the standard cut-point of 35 U/mL was recapitulated. In premenopausal women, current oral contraceptive (OC) users had a cut-point of 40 U/mL. To achieve a 2% false positive rate in ovarian cancer screening trials and in high-risk women choosing to be screened, the cut-point for initial CA125 testing should be personalized primarily for menopausal status (50 for premenopausal women, 40 for premenopausal on OC, and 35 for postmenopausal women)., (©2011 AACR.)

Curcumin, a component of turmeric, has been reported to exhibit potential antitumor activities. This study assessed the effects of a novel synthetic curcumin analog, EF24, on proliferation, apoptosis, and vascular endothelial growth factor (VEGF) regulation in platinum-sensitive (IGROV1) and platinum-resistant (SK-OV-3) human ovarian cancer cells. EF24 time- and dose-dependently suppressed the growth of both cell lines and synergized with cisplatin to induce apoptosis. Although treatment with EF24 had no significant effect on VEGF messenger RNA (mRNA) expression,VEGF protein secretion into conditioned media was dose-dependently reduced with EF24 demonstrating ∼8-fold greater potency than curcumin (P < .05). EF24 significantly inhibited hydrogen peroxide (H(2)O(2))-induced VEGF expression, as did the phenolic antioxidant tert-butylhydroquinone (t-BHQ). EF24 upregulated cellular antioxidant responses as observed by the suppression of reactive oxygen species (ROS) generation and activation of antioxidant response element (ARE)-dependent gene transcription. Given its high potency, EF24 is an excellent lead candidate for further development as an adjuvant therapeutic agent in preclinical models of ovarian cancer.

Purpose: This study evaluated efficacy of single-agent trastuzumab against advanced or recurrent HER2-positive endometrial carcinoma (EC), and explored predictors for HER2 amplification., Patients and Methods: Eligible patients had measurable stage III, IV, or recurrent EC. There was no limit on prior therapy although total prior doxorubicin dose was limited to 320 mg/m(2). Tumors were required to have HER2 overexpression (2+ or 3+ immunohistochemical staining) or HER2 amplification (FISH HER2/CEP 17 ratio >2.0). Trastuzumab was administered intravenously at a dose of 4 mg/kg in week 1, then 2 mg/kg weekly until disease progression. The primary endpoint was tumor response., Results: Of the 286 tumors centrally screened by LabCorp, 33 (11.5%) were HER2-amplified. Three of 8 clear (38%) cell carcinomas and 7 of 25 serous carcinomas (28%) screened exhibited HER2 amplification compared with 7% (2/29) of endometrioid adenocarcinomas. HER2 overexpression was correlated with HER2 amplification (r=0.459; p<0.0001). Thirty-four women were enrolled; 1 was excluded (refused treatment); and 18 had tumors with known HER2 amplification. No major tumor responses were observed. Twelve women experienced stable disease, 18 had increasing disease, and 3 were indeterminate for tumor response. Neither HER2 overexpression nor HER2 amplification appeared to be associated with progression-free survival or overall survival., Conclusion: Trastuzumab as a single agent did not demonstrate activity against endometrial carcinomas with HER2 overexpression or HER2 amplification, although full planned accrual of women with HER2 amplified tumors was not achieved due to slow recruitment. Serous and clear cell endometrial carcinomas appear to be more likely to demonstrate HER2 amplification.

Introduction: Discovery of positive lymph nodes (LNs) in patients with cervix cancer is important prognostically, may direct adjuvant therapy, and may have therapeutic benefit. The purpose of this Surveillance Epidemiology and End Results (SEER) analysis was to assess the value of lymphadenectomy (LND) in patients with cervical cancer., Methods: The 17-registry SEER database was searched for patients treated for cervical cancer between 1988 and 1998. Observed survival (OS) and expected survival (ES) were reported with a minimum of 5-year follow-up. Chi-square analysis and log-rank test were used to compare OS and ES., Results: Between 1988 and 1998, 4,059 of 12,882 patients underwent LND for cervical cancer and were registered. By stage, 2,653 of 7,621 stage I, 341 of 2,042 stage II, 814 of 1,986 stage III, 251 of 1,233 stage IV, and 28 of 226 stage IVA patients underwent LND. Of these, 778 stage III and 210 stage IV patients had a +LN. Patients who underwent LND had improved OS (P = 0.001). OS was significantly increased for each stage after LND. OS increased based on number of nodes resected. OS increased up to 15 nodes resected (P = 0.01)., Conclusion: This SEER analysis of 12,882 patients suggests that LND benefited patients with cervical cancer and OS was improved., ((c) 2009 Wiley-Liss, Inc.)

Purpose: To assess the role of radiotherapy (RT) in women with Stage IIIC endometrial cancer., Methods and Materials: The 17-registry Survival, Epidemiology, and End Results (SEER) database was searched for patients with lymph node-positive non-Stage IV epithelial endometrial cancer diagnosed and treated between 1988 and 1998. Two subgroups were identified: those with organ-confined Stage IIIC endometrial cancer and those with Stage IIIC endometrial cancer with direct extension of the primary tumor. RT was coded as external beam RT (EBRT) or brachytherapy (BT). Observed survival (OS) was reported with a minimum of 5 years of follow-up; the survival curves were compared using the log-rank test., Results: The therapy data revealed 611 women with Stage IIIC endometrial cancer during this period. Of these women, 51% were treated with adjuvant EBRT, 21% with EBRT and BT, and 28% with no additional RT (NAT). Of the 611 patients, 293 had organ-confined Stage IIIC endometrial cancer and 318 patients had Stage IIIC endometrial cancer with direct extension of the primary tumor. The 5-year OS rate for all patients was 40% with NAT, 56% after EBRT, and 64% after EBRT/BT. Adjuvant RT improved survival compared with NAT (p <0.001). In patients with organ-confined Stage IIIC endometrial cancer, the 5-year OS rate was 50% for NAT, 64% for EBRT, and 67% for EBRT/BT. Again, adjuvant RT contributed to improved survival compared with NAT (p = 0.02). In patients with Stage IIIC endometrial cancer and direct tumor extension, the 5-year OS rate was 34% for NAT, 47% for EBRT, and 63% for EBRT/BT. RT improved OS compared with NAT (p <0.001). Also, in this high-risk subgroup, adding BT to EBRT was superior to EBRT alone (p = 0.002)., Conclusion: Women with Stage IIIC endometrial cancer receiving adjuvant EBRT and EBRT/BT had improved OS compared with patients receiving NAT. When direct extension of the primary tumor was present, the addition of BT to EBRT was even more beneficial.

Numerous molecular biomarkers have been suggested for early detection of cervical cancer, but their usefulness in routinely collected exfoliated cells remains uncertain. We used quantitative reverse transcription-PCR to evaluate expression of 40 candidate genes as markers for high-grade cervical intraepithelial neoplasia (CIN) in exfoliated cervical cells collected at the time of colposcopy. Samples from the 93 women with CIN3 or cancer were compared with those from 186 women without disease matched (1:2) for age, race, and high-risk human papillomavirus status. Normalized threshold cycles (C(t)) for each gene were analyzed by receiver operating characteristics to determine their diagnostic performance in a split sample validation approach. Six markers were confirmed by an area under the curve >0.6 in both sample sets: claudin 1 (0.75), minichromosome maintenance deficient 5 (0.71) and 7 (0.64), cell division cycle 6 homologue (0.71), antigen identified by monoclonal antibody Ki-67 (0.66), and SHC SH2-domain binding protein 1 (0.61). The sensitivity for individual markers was relatively low and a combination of five genes to a panel resulted in 60% sensitivity with 76% specificity, not positively increasing this performance. Although the results did not indicate superiority of RNA markers for cervical cancer screening, their performance in detecting disease in women referred for colposcopy suggests that the genes and pathways they highlight could be useful in alternative detection formats or in combination with other screening indicators.

Purpose: Based on the activity and tolerability of liposomal doxorubicin in platinum- and paclitaxel-resistant ovarian carcinoma, we conducted a phase I trial of pegylated liposomal doxorubicin with paclitaxel and carboplatin to determine the maximum tolerated dose (MTD) in chemotherapy naive ovarian, peritoneal and tubal carcinoma patients., Methods: Three schedules were studied: paclitaxel, carboplatin and pegylated liposomal doxorubicin every 28 days; paclitaxel and carboplatin every 21 days with liposomal doxorubicin every 42 days; and weekly paclitaxel, carboplatin (AUC=5) every 21 days and liposomal doxorubicin every 42 days. The paclitaxel dose was 175 mg/m(2) over 3 h on an every 3-4 week schedule and 60 mg/m(2) when administered weekly. Based on the frequency of neutropenic sepsis, grade 4 thrombocytopenia and > or =grade 3 non-hematologic toxicity, the starting dose of liposomal doxorubicin of 20 mg/m(2) was escalated to determine the MTD., Results: A total of 210 (21-day) cycles were administered to 37 patients. Dose-limiting toxicity (DLT) occurred when liposomal doxorubicin was administered at 40 mg/m(2). Because of treatment-related delays resulting in decreased paclitaxel/carboplatin dose intensity, administration was modified to be given every 21 days, with liposomal doxorubicin given every 42 days. Since neutropenia was the DLT of this schedule, the schema was further modified to administer paclitaxel weekly; however, weekly administration was inconsistent because of toxicity., Conclusion: Paclitaxel 175 mg/m(2), carboplatin (AUC=5) and pegylated liposomal doxorubicin 30 mg/m(2) are tolerable without supportive therapy. The usual dose intensity of paclitaxel/carboplatin was maintained by administering liposomal doxorubicin every other cycle.

Background: Embryonal rhabdomyosarcoma is a rare sarcoma which characteristically occurs in non genitourinary sites in children., Case: We present a case of uterine embryonal rhabdomyosarcoma in a postmenopausal patient who presented with increasing abdominal girth, early satiety, weight loss, and pelvic pain., Conclusion: Embryonal rhabdomyosarcoma does not commonly originate from the uterine corpus, and it is rarely seen in postmenopausal patients. A review of the literature confirms the unique nature of this case.

Disabled-2 (Dab2) is a phosphoprotein involved in cellular signal transduction and endocytic trafficking. The expression of Dab2 is frequently lost or suppressed in several epithelial tumors, and studies of its cellular function and growth suppressive activity when re-expressed in cancer cells led to the suggestion that Dab2 is a tumor suppressor. A role for Dab2 in epithelial cell positioning organization was derived from study of knockout mice: homozygous deletion of dab2 results in early embryonic lethality due to the disorganization of the primitive endoderm, the first epithelium in early embryos. We now report that dab2 heterozygous mice develop uterine hyperplasia and ovarian preneoplastic morphological changes at a high frequency. Crossing into a p53(-/-) background unexpectedly produced few female dab2(+/-):p53(-/-) mice, while the male dab2(+/-):p53(-/-) were born at the expected Mendelian frequency. The tumor-prone phenotype of dab2(+/-) mice provides additional support for a role of human Dab2 as a tumor suppressor, and the sex-biased embryonic lethality suggests a genetic interaction between p53 and dab2 genes in female mice.

Objective: To analyze the impact of patient and organizational characteristics on surgical treatment patterns for patients with uterine fibroids., Methods: Unadjusted means and percentages were calculated from a population-based inpatient sample (HCUPNIS). Multiple logistic regression analysis was used to estimate the prevalence odds ratios for the association of uterine fibroid treatments and covariates of interest., Results: More than 1.2 million patients with a primary diagnosis of uterine fibroids were treated from 1998 to 2002. Of these, 84.4% received a hysterectomy and 12.3% received a myomectomy. Total abdominal hysterectomy was the most common procedure. The number of supracervical hysterectomies increased 18.1% over the five-year period. Black women and Asians/Pacific Islanders were more likely than white women to receive a myomectomy. All types of hysterectomies were more common in Medicaid patients compared with private/HMO patients. With the exception of patients in ZIP codes with a median income of <$25,000 per year, an inverse relationship was identified between income and hysterectomy rates., Conclusions: The management of uterine fibroids appears to differ across a variety of socioeconomic factors and institutional characteristics. This study suggests that additional research should be conducted to assess the impact of nonclinical factors on treatment decisions for patients with uterine fibroids.

The introduction of cytokine antibody arrays has added a new approach for investigators to simultaneously measure multiple cytokine levels in biological samples. Several different platforms have been developed. The ability to measure hundreds of cytokine levels with high specificity and sensitivity within a very limited amount of samples is a powerful tool. Many investigators worldwide have applied this novel technology in their biomedical research, particularly in drug discovery. Undoubtedly, the technology will continue to be improved and the application increased in the next several years.

While infection with high-risk HPV is the most important risk factor for cervical cancer, HPV alone is insufficient. Our purpose was to identify viral and epidemiologic factors associated with cervical disease in HPV-16 DNA-positive women referred to colposcopy. We used a standardized interview to collect epidemiologic data from consenting women. Total nucleic acids from exfoliated cervical cells were used for all viral assays (HPV detection and typing using L1 consensus PCR with line probe hybridization, variant classification by sequencing, viral load and transcript copy determination by quantitative PCR and transcript pattern by nested RT-PCR). Cervical disease was based on colposcopic biopsy. Logistic regression was used to calculate ORs with 95% CIs. There were 115 HPV-16 positive women among 839 enrollees. By univariate analyses, age >25 years (OR = 3.05, 95% CI 1.20-7.76), smoking (OR = 3.0, 95% CI 1.19-7.56), high viral load (OR = 5.27, 95% CI 2.05-13.60), detection of both E6 and E6*I transcripts (OR = 10.0, 95% CI 2.1-47.58) and high transcript copies (OR = 5.56, 95% CI 2.05-13.60) were significant risk factors for CIN III with reference to No CIN/CIN I. Less than a third of the women (31.5%) had prototype HPV-16 detected, and variants showed no association with disease, viral load or transcription. Viral DNA and transcript copies were highly correlated, and the ratio of transcript copies to DNA copies was not changed with disease status. While viral load, transcript copies and transcript pattern were statistically associated with CIN III, none of these measures effectively discriminated between HPV-16 women with disease requiring treatment and those who could be followed. Cellular proliferation and differentiation pathways affected by HPV should be investigated as biomarkers for cervical cancer screening., ((c) 2005 Wiley-Liss, Inc.)

Purpose: The purpose of this study is to develop a high-throughput approach to detect protein expression from hundreds and thousands of samples and to apply this technology to profile circulating angiogenic factor protein levels in patients with gynecological tumors., Experimental Design: Analytes containing a mixture of protein are immobilized onto antibody-coated surface of support in array format. The presence of protein in analytes is detected with biotin-labeled antibody coupled with an enhanced chemiluminescence or fluorescence detection system. The exact amount of protein can be quantitatively measured. The expression levels of five angiogenic factors (angiogenin, interleukin 8, vascular endothelial growth factor, platelet-derived growth factor, and epidermal growth factor) from 157 samples were quantitatively measured using this novel protein array technology and were statistically analyzed. The expression patterns of angiogenic factors were analyzed using two-way hierarchical cluster analysis approach., Results: A novel protein array technology, which can simultaneously and quantitatively measure few protein levels from hundreds and thousands of samples was developed. Only minute amounts of sample are required for the assay. This approach also features high sensitivity and specificity. Using this novel protein array approach, we analyzed the plasma expression levels of five angiogenic factors in 137 patients diagnosed with a tumor and 20 controls. Statistical analysis reveals different expression levels of angiogenic factors between patients and controls. Cluster analysis suggests a possible classification of normal subjects from patients., Conclusions: Enhanced protein profiling arrays provide a high-throughput and sensitive system to detect one or few protein from hundreds and thousands of samples. Such an approach should have broad application in biomedical discovery.

Background: Growing evidence suggests that cytokines not only are associated with ovarian cancer development, drug resistance and metastasis, but also may provide valuable markers for ovarian cancer diagnosis and prognosis. Here, we determined the expression profiles of 43 plasma cytokines in ovarian cancer patients using this high throughput protein array technology developed in our laboratory., Materials and Methods: The expression of 43 cytokines from 13 ovarian cancer patients and 12 normal women was determined simultaneously using human cytokine antibody microarray technology. The differential expression of cytokines was analyzed using the Student's t-test and two-way hierarchical cluster analysis approach., Results: Our data showed that 22 cytokines were significantly increased in the plasma of ovarian cancer patients compared to normal women (t-test, two-tailed, p<0.05). The results from cytokine antibody array assays were in agreement with the published data, but also revealed a new group of cytokines whose expression levels were altered in ovarian cancer. Cluster analysis suggested an interesting link between cytokine profile and ovarian cancer., Conclusion: Human cytokine antibody arrays are a valuable tool to profile cytokine expression from patients' specimen. The cytokine profile may prove to be of diagnostic and prognostic significance in ovarian cancer., (Copyright© 2004 International Institute of Anticaner Research (Dr. John G. Delinassios), All rights reserved.)

Purpose: To evaluate the feasibility, toxicity, and efficacy of single-agent monoclonal antibody therapy targeting the human epidermal growth factor receptor 2 (HER2)/neu receptor in ovarian and primary peritoneal carcinoma., Patients and Methods: Eligible patients had measurable persistent or recurrent epithelial ovarian or primary peritoneal carcinoma with 2+ or 3+ HER2 overexpression documented by immunohistochemistry. Intravenous trastuzumab was administered initially at a dose of 4 mg/kg, then weekly at 2 mg/kg. Patients without progressive disease or excessive toxicity could continue treatment indefinitely. Those with stable or responding disease at 8 weeks were offered treatment at a higher weekly dose (4 mg/kg) at time of progression. Patient sera were analyzed for the presence of the soluble extracellular domain of HER2, host antibodies against trastuzumab, and trastuzumab pharmacokinetics., Results: A total of 837 tumor samples were screened for HER2 expression, and 95 patients (11.4%) exhibited the requisite 2+/3+ expression level. Forty-five patients, all of whom received prior chemotherapy, were entered, and 41 were deemed eligible and assessable. There were only mild expected toxicities and no treatment-related deaths. Although an elevated level of the soluble extracellular domain of HER2 was detected in eight of 24 patients, serum HER2 was not associated with clinical outcome. There was no evidence of host antitrastuzumab antibody formation. Serum concentrations of trastuzumab gradually increased with continued therapy. An overall response rate of 7.3% included one complete and two partial responses. Median treatment duration was 8 weeks (range, 2 to 104 weeks), and median progression-free interval was 2.0 months., Conclusion: The clinical value of single-agent trastuzumab in recurrent ovarian cancer is limited by the low frequency of HER2 overexpression and low rate of objective response among patients with HER2 overexpression.

Cervical carcinoma is prevented easily with proper screening. Unfortunately, many women in industrialized countries continue to have poor access to adequate medical care. In many third-world countries, cervical cancer is one of the top malignancies diagnosed. Screening should be provided for all women to prevent or diagnose cervical cancer at an early, treatable stage.

Angiogenesis plays an important role in neovascularization in tumors. Glycodelin, a hormone-responsive protein, has been detected in tumors of reproductive organs and is found in high levels in the plasma of subjects with gynecological malignancies. Glycodelin is also found in the endothelial cells of the umbilical cord and in the blood vessels of tumors. In this study, we tested whether glycodelin-rich amniotic fluid and a synthetic peptide derived from the sequence of glycodelin peptide (Gp) might promote angiogenic response by examining the migration and tube formation in human umbilical cord vein endothelial cells (HUVECs). Increased migration and tube formation of HUVECs were found in the presence of amniotic fluid and Gp, and this increase was blocked by antibody to Gp and by an anti-vascular endothelial growth factor (VEGF) antibody, suggesting that the angiogenic effects of glycodelin might be mediated by VEGF. The results also showed that Gp significantly increased the release of VEGF protein and mRNA expression in HUVECs, RL-95 (human endometrial carcinoma cells), OVCAR-3 (human ovarian adenocarcinoma cells), EM42 (human endometrial epithelial cells), THP-1 (human monocyte), and MCF-7 and MDA-MB-231 (human breast adenocarcinoma cells) cell lines. VEGF receptor Fit-1 mRNA expression in HUVECs was also increased in the presence of Gp. These findings, together with the suggestion from the literature that glycodelin may have immunosuppressive properties, suggest that glycodelin might play an important role in neovascularization during embryogenesis and tumor development.

Glycodelin, an immunosuppressive protein with contraceptive properties, is synthesized by a variety of tissues and cell types. The ability of reproductive tissues to synthesize glycodelin is of major interest in pregnancy and disease conditions. We studied glycodelin levels in subjects with malignant gynecological tumors and in control subjects. Using a polyclonal glycodelin antibody against the synthetic glycodelin peptide sequence, an enzyme-linked immunosorbent assay (ELISA) was devised to measure plasma glycodelin levels. The assay detected as much as 5 ng/ml of glycodelin. There was a significant increase in plasma glycodelin levels in endometrial > ovarian > cervical cancer subjects when compared to those of controls. Strong expression of mRNA and protein were found in the ovarian and endometrial tumor tissues. Given glycodelin's immunosuppressive abilities, increased level of glycodelin may facilitate tumor growth in gynecological malignancies.

Purpose: Given the activity of prolonged oral etoposide in platinum and paclitaxel-resistant ovarian carcinoma, a phase I trial was conducted that combined increasing days of oral etoposide therapy with paclitaxel and carboplatin in chemotherapy-naive patients with ovarian peritoneal and tubal carcinoma to establish a maximum-tolerated dose (MTD) of this combination., Patients and Methods: Paclitaxel at 175 mg/m(2) given over 3 hours and carboplatin at an area under the curve of 5 were administered on day 1 followed by oral etoposide 50 mg/m(2)/d beginning on day 2. The number of days of etoposide therapy was escalated on the basis of toxicity. Toxicity end points included neutropenic sepsis, grade 4 thrombocytopenia, or grade 3 neutropenia or thrombocytopenia during etoposide administration. Cycles were repeated every 21 days for a maximum of six courses. Due to hematologic toxicity, the duration of the paclitaxel infusion was decreased to 1 hour for a second stage of accrual., Results: Of 52 patients studied, 29 were in the first stage of accrual. Dose-limiting toxicity occurred with 8 days of oral etoposide, making the MTD six days of therapy. Twenty-three patients were entered into the second stage of accrual. Dose-limiting toxicity occurred at 12 days of oral etoposide, making the MTD 10 days of therapy. Three patients developed acute myeloid leukemia 16, 27, and 35 months after receiving a cumulative dose of 200 mg/m(2), 1,200 mg/m(2), and 2,400 mg/m(2), respectively., Conclusion: One-hour paclitaxel, carboplatin, and oral etoposide at 50 mg/m(2)/d for 10 days is tolerable without supportive therapy. The leukemogenic potential is cause for concern and precludes its use in chemotherapy-naive ovarian carcinoma.

Epithelial ovarian cancer (EOC) continues to be an academically challenging and clinically problematic disease. Even with recent advances, the overall 5-year survival is still 31% to 42% in various studies. Deaths from EOC outnumber those due to cervical, vulvar, and endometrial carcinomas combined. Screening for EOC has shown limited success in early detection. The Pap smear is not a dependable tool in EOC screening, though at times it can be the first evidence of ovarian disease. We report a case of EOC that was diagnosed during evaluation of an abnormal Pap smear. On completion of evaluation, stage IIIA endometrioid-type adenocarcinoma of the ovary was diagnosed. Occult EOC should be considered in patients with abnormal findings on cervical cytology after cervical and uterine carcinomas are ruled out.

Objective: To explore whether HIV types 1 and 2 and CD4 cell count affect cervical neoplasia independent of human papillomavirus (HPV) in women with high or low numbers of sexual partners residing in Abidjan, Côte d'Ivoire., Methods: The study population and methods are described in the companion paper. Additional methods include a Papanicolaou smear for cytological diagnosis and statistical analysis., Results: In maternal women, both HIV-1 and high risk HPV were significant independent risk factors for squamous intraepithelial lesions (SIL) (adjusted odds ratio (OR) 11.0 (95% CI 1.1-112) and 5.4 (1.5-18.8), respectively). Only high levels of HPV DNA in the lavage were associated with SIL (OR 13.2 (3.6-47.8)) in the maternal group. In female sex workers, high risk HPV was significantly associated with SIL (OR 23.7 (4.4-126)); HIV seropositivity was not. Any positive level (high or low amounts) of HPV DNA was significantly associated with SIL in sex workers (ORs 15.9 (3.3-76) and 12.7 (3.6-44), respectively). There was no association of SIL with CD4 cell counts < or = 500 x 10(6)/l in HIV seropositive women from either group., Conclusion: HPV or HIV-1 infection independently affect cervical neoplasia in women with low numbers of sex partners.

Objective: To explore whether HIV serostatus (HIV-1, HIV-2, and dual (HIV-D) reactivity) and CD4 cell count affect human papillomavirus (HPV) in two groups of women from Côte d'Ivoire., Methods: We conducted a cross sectional study of two groups of women. One group had low numbers of lifetime sex partners (maternal women, n = 258) and were enrolled based on HIV serostatus. The other group had high numbers of sex partners (female sex workers, n = 278) and all consenting self identified sex workers were admitted to this study. We collected epidemiological and clinical data, and cervicovaginal lavage for HPV testing., Results: The groups had different distributions of HIV seroreactivity, but the rates of HPV DNA detection were similar. Most of the HPV DNAs detected in both groups were high risk types. A strong association of high risk HPV DNA and HIV-1 seropositivity was found in both maternal women (adjusted odds ratio (OR) 7.5 (95% CI 3.2-17.4)) and in sex workers (OR 5.0 (2.1-12.0)). The maternal group also showed an association of high risk HPV DNA detection with HIV-2 (OR 3.7 (1.6-8.5)) and HIV-D (OR 12.7 (4.3-37.5)) that was not observed in the sex workers. In addition, the association of high risk HPV DNA with HIV-1 in the maternal group was independent of low CD4 cell count, while in the sex workers the association depended on CD4 cell counts < or = 500 x 10(6)/l., Conclusions: We found that an association between HPV and HIV varied depending on the sexual behaviour and CD4 cell count of the population examined.

Objective: Our goal was determine the correlation between serum colony stimulating factor-1 levels, cervical human papillomavirus infection, and dysplasia., Study Design: Serum samples were obtained from control subjects from the United States and from a group of Panamanian women. Members of the latter group fell into 3 categories: those who serve as Panamanian control subjects and who test negative for human papillomavirus (n = 10); those who are high risk by history and test positive for human papillomavirus types 16/18 and 30s (n = 10); and those with the same high-risk history with biopsy-proven cervical intraepithelial neoplasia (n = 8). Serum colony-stimulating factor-1 levels were determined using enzyme-linked immunosorbent assay. Data were analyzed with the Student-Newman-Keuls and t tests., Results: Mean serum colony-stimulating factor-1 levels of patients with a positive test result for human papillomavirus (1166 +/- 949 pg/mL) and cervical intraepithelial neoplasia (1295 +/- 314 pg/mL) were higher than those of control subjects from the United States (584 +/- 237 pg/mL) and those of Panamanian control subjects (520 +/- 229 pg/mL). Statistical analysis revealed the concentration of colony-stimulating factor in patients with positive test results for human papillomavirus or cervical intraepithelial neoplasia were significantly higher than in control groups. In addition, combining patients with human papillomavirus with those who have cervical intraepithelial neoplasia results in a group that has significantly higher colony-stimulating factor levels compared with control subjects., Conclusions: Both high-grade cervical dysplasia and high-risk human papillomavirus infection are associated with higher mean serum colony-stimulating factor levels, suggesting a possible role for colony-stimulating factor-1 in cervical neoplasia. Further studies are needed to understand the mechanism of colony- stimulating factor activation in human papillomavirus infection. This may assist in designing therapeutic approaches for the management of this disease.

This case report describes a 31-year-old woman at 8 weeks' gestation with large arteriovenous malformation of the uterus involving bilateral uterine and ovarian arteries. She had a history of multiple pregnancy losses, as well as spontaneous copious vaginal hemorrhage. The patient underwent an embolization procedure followed by total abdominal hysterectomy and bilateral salpingo-oophorectomy. The uterus was very small (30 g) despite its gravid status, and the overall microscopic findings indicated Müllerian system hypoplasia in addition to vascular malformation.

Purpose: To test the hypothesis that prolonged infusion of paclitaxel (96 hours) might overcome resistance to shorter infusion schedules (3 or 24 hours) in ovarian cancer., Patients and Methods: A total of 30 patients with advanced ovarian cancer (24 patients), primary carcinoma of the peritoneum (four patients), or fallopian tube cancer (two patients) who previously had received paclitaxel administered on either a 3-hour or 24-hour schedule were treated with the agent delivered as a 96-hour infusion (30 to 35 mg/m2/d x 4 days) on an every 3-week program., Results: Although the regimen generally was well tolerated, no objective responses were observed., Conclusion: In patients with ovarian cancer who have shown resistance to shorter paclitaxel infusion schedules, ninety-six hour infusional paclitaxel is an inactive treatment strategy. This makes it less likely that protracted infusion of paclitaxel will improve outcome when used as part of primary therapy of ovarian cancer. An ongoing randomized study will answer that question.

This study reviewed a high-risk population of inner-city women with FIGO (International Federation of Gynecologists and Obstetricians) stage Ib cervical cancer diagnosed and treated at a single institution between 1986 and 1993. The patient age at diagnosis averaged 49 years, and most of the patients were black (83%). Squamous carcinomas predominated (75%). Radiotherapy was the most frequent treatment modality (49%), followed by surgery (38%) and combined radiation/surgery (13%). The Kaplan-Meier estimated 4-year survival for all patients completing treatment was 81%. Increased survival was significantly associated with therapy. The Kaplan-Meier estimated survival at 26 months (the time of the last death in radiotherapy patients) was 66% for radiotherapy patients and 100% for those treated with surgery. Radiotherapy patients differed from surgery patients in age, tumor size, and pelvic lymph node status, indicating that treatment selection bias could explain the observed difference in survival. Age, race, histology, and cervical lesion size were not significantly associated with survival.