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To determine whether measurement of the levels of multiple tumor markers in the preoperative serum of women presenting with a pelvic mass distinguished benign from malignant disease better than the assay of CA 125 alone, sera from 429 patients, 192 of whom had malignant histology, were assayed for 8 different markers: CA 125, macrophage colony-stimulating factor, OVX1, lipid-associated sialic acid (LASA), CA15-3, CA72-4, CA19-9, and CA54/61. The sensitivity and specificity of CA 125 alone (> 35 U/ml) was 78.1 and 76.8%, respectively. A panel consisting of CA 125, OVX1, LASA, CA15-3, and CA72-4 had a sensitivity of 83.3% and specificity of 84.0% when two or more markers were elevated. Using the concentrations of these five markers, logistic regression analysis had a sensitivity of 85.4% and a specificity of 83.1%. Considering the values of markers in different sequences, classification and regression tree analysis substantially improved the sensitivity to 90.6% and the specificity to 93.2%. When applied in clinical practice this approach could improve the management of women presenting with a pelvic mass and may also have application in screening for ovarian cancer.

Early detection of ovarian cancer might substantially improve results of therapy. After careful surgical staging, 90% of patients with stage I disease and 70% of patients with stage II disease can be cured with currently available therapy. Epithelial ovarian cancer may be one of the malignancies that lends itself to early detection with a blood test. Antigens shed from the ovarian surface into the peritoneal cavity are taken up by diaphragmatic lymphatics and pass through the alternative thoracic duct into the venous circulation. In early work by Knauf and Urbach [1] the OCA antigen could be detected in 70% of patients with early stage disease. OCA was also found in approximately 10% of healthy individuals, precluding its use in screening. This observation did, however, suggest that shed tumor products could be found in the circulation in an early stage of disease.

The initiation of translation in eukaryotes is promoted by multi-protein eukaryotic initiation factor complexes (eIFs). While several eIF subunits are overexpressed in cancer, very few have been conclusively implicated as drivers of human cancer phenotypes. Through a transcriptomic analysis of human bladder cancer our studies suggested that eIF3b, considered to be the major scaffolding subunit within the eIF3 complex, is elevated compared to normal urothelium. We went on to functionally evaluate eIF3b in human bladder cancer by siRNA depletion in UMUC3 and lul2 human bladder cancer lines. This reveled that expression of eIF3b was important for anchorage dependent and independent cell growth and G1 to S cell cycle transition. Depletion of eIF3b also inhibited cell migration in vitro and this was associated with disruption of actin cytoskeleton organization and focal adhesion formation through integrin [[Unsupported Character - Symbol Font ]]5, which in turn decreased FAK phosphorylation and downstream Akt phosphorylation. We also observed the similar results from PC3 prostate cancer cells. In vivo, UMUC3 and lul2 cells depleted of eIF3b formed smaller tumors that grew more slowly following subcutaneous inoculation and these cells formed fewer lung metastases following intravenous inoculation. This data provides the first demonstration of a causal role of eIF3b in human cancer cell phenotypes in vitro and in vivo. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4200. doi:1538-7445.AM2012-4200

Identification of the antigens (Ags) recognized by CD8+ T cells specific for melanoma and other types of cancer cells has been motivated by the expectation that they will serve as the basis for a therapeutic vaccine or will be useful for the stimulation of more effective CD8+ CTL for adoptive immunotherapy. Few of the currently identified Ags are derived from source proteins directly associated with transformation or metastasis, and many are self-Ags which may be subject to tolerance mechanisms. We have defined a new array of phosphorylated peptides presented by HLA-A1, -A2, -A3, -B7, -B44 and HLA-B27 that are presented on melanomas from multiple patients at >1 copy per cell and derived from source proteins associated with tumorigenesis and metastasis. We evaluated the immunogenicity of several of the HLA-A2-restricted phosphopeptide Ags in an HLA-transgenic murine model system and in vitro human T cell cultures, evaluated the presence of the phosphorylated source protein or display of the phosphorylated epitope on cancers of different histological types, and investigated the ability of phosphopeptide-specific CD8+ T cells to prevent outgrowth of cancer cells in a xenogenic model. Evaluation of metastatic melanoma tissue microarrays and cancer cell lysates demonstrated that the phosphorylated source proteins for β-catenin (Ser33-phosphorylated), Breast cancer anti-estrogen resistance −3 (BCAR3; Thr130-phosphorylated), and Insulin receptor substrate-2 (IRS2; Ser1100-phosphorylated) were broadly expressed in melanomas and other cancers but not normal tissues. In addition, these epitopes can be utilized to elicit phosphopeptide-specific T cells in both murine HLA-A2 transgenic mice in vivo and human in vitro culture. The phospho-β-catenin, phospho-IRS2 and phospho-BCAR3-specific-T cells that were generated differentiate between the phosphorylated and non-modified forms of their respective peptides and recognize the endogenously processed and presented phosphopeptide on the surface of cancer cells. Finally, adoptive transfer of these phosphopeptide-specific T cells slowed outgrowth of melanoma tumors implanted in immunodeficient NOD.SCID.IL2Rα-/- mice. Thus, we have defined a new set of post-translationally modified epitopes derived from source proteins associated with tumorigenesis and metastasis that are immunogenic and capable of slowing tumor outgrowth in a xenograft model. Based on these results, we are currently planning a clinical trial utilizing these HLA-A2-restricted phosphopeptides in melanoma patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1584. doi:1538-7445.AM2012-1584

OBJECTIVE: Our purpose was to determine whether protein tyrosine phosphatase 1B is overexpressed in ovarian cancers, possibly altering the balance of intracellular tyrosine phosphorylation. STUDY DESIGN: The expression of protein tyrosine phosphatase 1B was assayed in frozen sections from 54 human ovarian carcinomas and seven normal ovaries by immunochemical staining with monoclonal antibody AE4-2J, which is specific for protein tyrosine phosphatase 1B. The expression of protein tyrosine phosphatase 1B - specific messenger ribonucleic acid in tumors was determined by Northern analysis. The results were analyzed statistically by means of Fisher's exact test. RESULTS: Minimal staining was observed in normal ovarian epithelium. In contrast, 43 of 54 (79.6%) tumors displayed increased protein tyrosine phosphatase 1B expression, which is statistically associated with malignancy. Overexpression was associated with the expression of the p185 c- erb B-2 , p170 EGFR , and p165 mCSFR growth factor receptor protein tyrosine kinases. Protein tyrosine phosphatase 1B messenger ribonucleic acid expression was inconsistently increased in tumor cells. CONCLUSION: Increased expression of protein tyrosine phosphatase 1B in ovarian cancers that also express protein tyrosine kinases suggests that protein tyrosine phosphatase 1B may play a role in the growth regulation of ovarian cancers. (AM J OBSTET GYNECOL 1994;170:1177-83.)

BACKGROUND During the past 3 years, there has been a highly publicized debate concerning the potential medical complications of silicone breast implants. There have been no studies that have addressed the effect of this controversy on women with a history of breast cancer who have undergone breast reconstruction with silicone implants. PURPOSE This study was undertaken to understand the concerns of such women regarding their breast reconstructions and to assess what impact the silicone implant controversy had on them. METHODS One hundred seventy-four randomly selected women who had undergone reconstructive surgery with silicone implants subsequent to mastectomy for treatment of breast cancer were interviewed by telephone from February through May 1992. (A moratorium on use of silicone breast implants, imposed by the Food and Drug Administration, extended from January through April 1992.) These women, a subset of 359 mastectomy/reconstruction patients of one university-based plastic surgeon, had their first permanent prostheses placed between 1985 and 1990. The interview included questions designed to elicit information about women's experiences with reconstruction and reactions to the controversy. RESULTS All study participants were aware of the controversy surrounding silicone implants. Seventy-six percent stated that breast reconstruction helped them cope with cancer, and only 16% had regrets about reconstruction. Many respondents had misconceptions about the nature of possible complications from silicone implants. Fifty-five percent were worried about the implants, yet only 13% considered having them removed as a result of the controversy. Only 27% indicated they would be completely likely to choose silicone implants again. The majority of women were unwilling to accept substantial risks of complications from implants, but there was variability in the level of risk that respondents would tolerate. CONCLUSIONS A majority of women who have had breast reconstruction using silicone implants after treatment of breast cancer believe that implants helped them cope with the cancer. However, a sizeable proportion of such women are worried about possible medical complications that may develop as a consequence of silicone breast implants. Many would likely not choose these implants today. IMPLICATIONS The true risks associated with silicone implants will ultimately be known. In the meantime, health care providers need to address patients' concerns about these implants. Information and guidance regarding the potential benefits and risks of breast implant devices should be provided to women with breast cancer who are considering treatment options.

The authors tested the hypothesis that giving women control over the compression portion of the mammography examination results in a less painful experience, greater overall patient satisfaction, and a radiographic image as good as that produced by means of technologist-controlled compression. One hundred nine women undergoing screening mammography at a hospital-based outpatient clinic were studied. Each underwent two-view, screen-film mammography performed in routine fashion except that, by random assignment, one breast was compressed by the technologist and the other breast, by the patient. Patient-controlled compression was significantly (P = .003) less painful than technologist-controlled compression. Overall patient satisfaction (96% [105 of 109]) and willingness to repeat the experience were extremely high. The majority of images (93.5% [202 of 216]) were rated as having good to excellent compression. With minimal patient education, self-compression resulted in an image at least as good as that produced with technologist-applied compression. Further study of this technique is warranted.

RalA and RalB are members of the Ras family of monomeric G proteins that are 83% identical in amino acid sequence, but have paralog-specific effects on cancer cell proliferation, metastasis and apoptosis. Using in vitro kinase assays and phosphosite specific antibodies, here we show paralog-specific phosphorylation of RalA by PKA and RalB by PKC. Mutagenesis identified Ser194 as the single PKA phosphorylation site in RalA and S198 as the primary PKC phosphorylation site in RalB. Phorbol ester treatment of human bladder carcinoma cells induced phosphorylation of S198 in both stably expressed FLAG-RalB and endogenous RalB. Compared to activated RalB(G23V) that localized at plasma membrane, phosphosite mutant RalB(G23V-S198A) colocalized with GFP-Rab11, a recycling endosome marker. Phorbol ester treatment enhanced anchorage independent growth of UMUC3 human bladder carcinoma cells stably transfected with wild type RalB or activated RalB(G23V), but not with phosphosite mutants RalB(S198A) or RalB(G23V-S198A). Furthermore, UMUC3 cells transfected with RalB(G23V) exhibited enhanced subcutaneous tumor growth compared to vector transfected cells, but cells expressing RalB(G23V-S198A) had growth indistinguishable from the controls. Our data demonstrate that RalA and RalB are specifically phosphorylated by different kinases, and RalB phosphorylation regulates its intracellular localization and in vivo tumor growth promotion. Phosphorylation of RalA and RalB by different kinases may contribute to the biological specificity of these closely related proteins. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 311.

This paper develops a conceptual framework for examining the process of immunisation and explores the sociodemographic determinants of vaccination in Zambia. About 300 mothers with children under 3 years of age were interviewed in urban Lusaka. The analyses suggest that sociostructural, as well as cultural, processes influence the attrition process and immunisation programmes should focus on the uniqueness of each stage. In addition, programmes to improve women's education and to reduce male gender preferences are needed.Data from 277 low income mothers in Lusaka, Zambia were analyzed to determine the effect certain biosocial variables had on immunization coverage of 3-year old children. About 90% began the immunization schedule but the % fell consistently up to DPT3. Only about 48% were fully immunized. 70% of infants in each birth cohort received all the vaccinations except for measles. The largest dropout percentage occurred before the measles shot. The 1985 birth cohort represented the largest percentage not immunized against measles (about 35%), but they had the highest overall rates of immunization. The 1986 birth cohort had the lowest immunization rates. Increased educational levels of mothers increased the chances of immunization. In addition, all children of mothers working outside the home were vaccinated against some diseases compared with 12./5% of children of mothers who do not work outside the home who received no vaccinations. Among children with some immunization, boys tended to have received more vaccinations than girls. Girls were 2.32 times more likely to have received the BCG than boys, but were also more likely to stop at this stage this stage than boys. Boys were more likely than girls to stop at the 3rd stage. Other than the 2nd stage, attrition rates for girls were always lower than for boys. Further lower attrition rates were tied in with higher levels of education. Younger mothers were more likely to have their children who had received a BCG vaccination return for the DPT1 vaccination than older mothers, but age did not influence immunization converge at other stages. These results suggest that immunization programs should focus on improving the chance of vaccination at each stage, especially the last stage. They also highlight the need for these programs to improve women's education and reduce son preferences.

ContextDespite evidence that patients with acute lung injury (ALI) have pulmonary surfactant dysfunction, trials of several surfactant preparations to treat adults with ALI have not been successful. Preliminary studies in children with ALI have shown that instillation of a natural lung surfactant (calfactant) containing high levels of surfactant-specific protein B may be beneficial.ObjectiveTo determine if endotracheal instillation of calfactant in infants, children, and adolescents with ALI would shorten the course of respiratory failure.Design, Setting, and PatientsA multicenter, randomized, blinded trial of calfactant compared with placebo in 153 infants, children, and adolescents with respiratory failure from ALI conducted from July 2000 to July 2003. Twenty-one tertiary care pediatric intensive care units participated. Entry criteria included age 1 week to 21 years, enrollment within 48 hours of endotracheal intubation, radiological evidence of bilateral lung disease, and an oxygenation index higher than 7. Premature infants and children with preexisting lung, cardiac, or central nervous system disease were excluded.InterventionTreatment with intratracheal instillation of 2 doses of 80 mL/m2 calfactant or an equal volume of air placebo administered 12 hours apart.Main Outcome MeasuresVentilator-free days and mortality; secondary outcome measures were hospital course, adverse events, and failure of conventional mechanical ventilation.ResultsThe calfactant group experienced an acute mean (SD) decrease in oxygenation index from 20 (12.9) to 13.9 (9.6) after 12 hours compared with the placebo group’s decrease from 20.5 (14.7) to 15.1 (9.0) (P = .01). Mortality was significantly greater in the placebo group compared with the calfactant group (27/75 vs 15/77; odds ratio, 2.32; 95% confidence interval, 1.15-4.85), although ventilator-free days were not different. More patients in the placebo group did not respond to conventional mechanical ventilation. There were no differences in long-term complications.ConclusionsCalfactant acutely improved oxygenation and significantly decreased mortality in infants, children, and adolescents with ALI although no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was observed.

The aim of the study was to evaluate the health of children with cerebral palsy (CP) using a global assessment of quality of life, condition-specific measures, and assessments of health care use. A multicenter population-based cross-sectional survey of 235 children, aged 2 to 18 years, with moderate to severe impairment, was carried out using Gross Motor Function Classification System (GMFCS) levels III (n = 56), IV (n = 55), and V (n = 122). This study group scored significantly below the mean on the Child Health Questionnaire (CHQ) for Pain, General Health, Physical Functioning, and Impact on Parents. These children used more medications than children without CP from a national sample. Fifty-nine children used feeding tubes. Children in GMFCS level V who used a feeding tube had the lowest estimate of mental age, required the most health care resources, used the most medications, had the most respiratory problems, and had the lowest Global Health scores. Children with the most severe motor disability who have feeding tubes are an especially frail group who require numerous health-related resources and treatments. Also, there is a relationship among measures of health status such as the CHQ, functional abilities, use of resources, and mental age, but each appears to measure different aspects of health and well-being and should be used in combination to reflect children's overall health status.

PURPOSE: Approximately 40,000 men die each year of hormone-refractory prostate cancer (HRPC). The results of treatment with chemotherapy have been disappointing to date, with no trials demonstrating a benefit with respect to survival duration. Corticosteroids and mitoxantrone each have been shown to be active agents in this disease. The purpose of this study was to demonstrate an advantage of mitoxantrone and hydrocortisone (M+H) over hydrocortisone alone with respect to survival duration. PATIENTS AND METHODS: Two hundred forty-two patients with HRPC were randomized to receive either M+H or hydrocortisone alone. Patients were monitored for survival, time to disease progression, time to treatment failure, response, and quality-of-life (QOL) parameters. RESULTS: Treatment in both arms was well tolerated. Although there was a delay in time to treatment failure and disease progression in favor of M+H over hydrocortisone alone, there was no difference in overall survival (12.3 months for M+H v 12.6 months for hydrocortisone alone). There was an indication that QOL was better with M+H, in particular with respect to pain control. CONCLUSION: M+H generated more frequent responses and a delay in both time to treatment failure and disease progression compared with hydrocortisone alone. In addition, there was a possible benefit of M+H with respect to pain control over hydrocortisone alone. No improvement in survival was observed. Although M+H could be viewed as a palliative option for patients with HRPC, new drugs and novel strategies are needed to improve survival for this disease.

In this paper we propose methods for designing phase II trials that allow for a trade-off between treatment safety and antitumor activity, where safety and antitumor activity are measured as binary endpoints. The designs can be carried out either in a single stage or can be conducted in two stages, with an interim analysis to assess whether the treatment appears sufficiently safe and effective to warrant continuing. The emphasis is on the derivation of stopping rules for phase II trials that require the enrollment of a small number of patients and are based on enumerating the exact distribution of the proposed test statistic. We illustrate the methods with a recent study that required the use of a group sequential design to monitor antitumor activity and toxicity.

In this paper we propose methods for designing group sequential phase II trials with two dependent binary endpoints. The emphasis is on the derivation of stopping rules for phase II trials which require the enrollment of a small number of patients. The methods are based on enumerating the exact distribution for the binary endpoints. We illustrate the methods with a recent study which required the use of group sequential design to monitor antitumor activity and toxicity.

This paper uses causal models for nonresponse (Fay, 1986, Journal of the American Statistical Association 81, 354-365) to extend the conditional likelihood procedure for repeated categorical outcome variables to allow for nonrandomly missing data. The extension based on causal models is similar to the log-linear approach presented by Conaway (1992, Journal of the American Statistical Association, 87, 817-824), but has the advantage that the parameters are directly interpretable in terms of the distribution of the outcome variables. As with log-linear model approach, all of the computations can be done with standard statistical software. The methods are first described in terms of a simple example with three binary responses with no covariates and then are applied to a more complicated example. A simulation study evaluates the properties of the estimates based on the proposed method.

SUMMARY This paper presents an analysis of time-ordered categorical variables with incomplete data. The models allow for either an ignorable or a non-ignorable non-response model and take into account the time ordering of the categorical variables. All the necessary computations can be done with standard statistical software. In addition, we present a Bayesian analysis which uses information from previous years in the priors. The methods are presented in the context of an example, using data from the National Crime Survey. Although this paper deals with two-way tables, the methods are readily extended to higher dimensional tables.

SUMMARY This paper presents a method based on maximizing the marginal likelihood for analyzing binary data with random effects. With the assumption of a parametric family that allows for a wide variety of shapes for the distribution of the random effects, the marginal likelihood can be computed without numerical integrations. The method uses local independence models as well as those that incorporate additional dependence among the responses. Two examples, a panel study with binary responses and an analysis of item-response data, will be used to illustrate the method.