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Background Quality of life and patient reported outcome measures (PROMs) are important secondary endpoints and incorporated in most contemporary clinical trials. There have been deficiencies in their assessment and reporting in ovarian cancer clinical trials, particularly in trials of maintenance treatment where they are of particular importance. The Gynecologic Cancer InterGroup (GCIG) symptom benefit committee (SBC) recently convened a brainstorming meeting with representation from all collaborative groups to address questions of how to best incorporate PROMs into trials of maintenance therapies to support the primary endpoint which is usually progression free survival (PFS). These recommendations should harmonize the collection, analysis and reporting of PROM's across future GCIG trials. Methods Through literature review, trials analysis and input from international experts, the SBC identified four relevant topics to address with respect to promoting the role of PROMs to support the PFS endpoint in clinical trials of maintenance treatment for OC. Results The GCIG SBC unanimously accepted the importance of integrating PROM's in future maintenance trials and developed four guiding principles to be considered early in trial design. These include 1) adherence to SPIRIT-PRO guidelines, 2) harmonization of selection, collection and reporting of PROM's; 3) combining Health Related Quality of Life (HRQL) measures with clinical endpoints and 4) common approaches to dealing with incomplete HRQL data. Conclusions Close attention to incorporating HRQL and PROM's is critical to interpret the results of ovarian cancer clinical trials of maintenance therapies. There should be a consistent approach to assessing and reporting patient centered benefits across all GCIG trials to enable cross trial comparisons which can be used to inform practice.

Body image disturbance has been highlighted as a common characteristic within the development and maintenance of clinical eating disorders (EDs), represented by alterations in an individual’s bodily experience. However, whilst the perceptual stability of the sense of body ownership has been investigated in ED patients, the stability of the sense of body agency in those with ED is yet to be examined. Therefore, body ownership and body agency were investigated using the moving rubber hand illusion, alongside measures of explicit and implicit body satisfaction. Furthermore, with evidence demonstrating a direct link between perceptual and cognitive-affective components of body image in the healthy population, the relationship between measures of body perception and body satisfaction was investigated. Results showed that both ED and healthy individuals displayed a similar subjective experience of illusory ownership and agency towards the fake hand, following voluntary movement. However, whilst both groups initially overestimated their own hand width prior to the illusion, the ED group displayed a significant reduction in hand size estimation following the illusion, which was not matched to the same degree in healthy individuals. In addition, ED individuals displayed a significantly lower body satisfaction compared with healthy females, on both an explicit and implicit level. Such implicit outcomes were shown to be driven specifically by a weaker association between the self and attractiveness. Finally, a significant relationship was observed between specific perceptual measures and implicit body satisfaction, which highlights the important link between perceptual and cognitive-affective components of one’s body image. Together, such findings provide a useful foundation for further research to study the conditions in which these two components relate with regard to body image and its disturbance, particularly in relation to the prognosis and treatment of EDs.

The Eating Disorder Examination Questionnaire (EDE-Q) is a widely used assessment of eating disorder psychopathology; however, EDE-Q norms are yet to be provided within a nonclinical U.K. adult sample. Second, there is considerable disagreement regarding the psychometric properties of this measure. Several alternative factor structures have been previously proposed, but very few have subsequently validated their new structure in independent samples and many are often confined to specific subpopulations. Therefore, in the current study, we provide norms of the original four-factor EDE-Q structure, and subsequently assess the psychometric properties of the EDE-Q in females and males using a large nonclinical U.K. sample (total N = 2459). EDE-Q norms were consistently higher in females compared with males across all samples. Initial confirmatory factor analyses (CFA) did not support the original 4-factor structure for females or males (Phase 1). However, subsequent exploratory factor analyses (EFA) revealed a 3-factor structure as being the optimal fit for both females and males, using an 18-item and 16-item model, respectively (Phase 2). For females, the newly proposed 18-item structure was validated within an independent student sample and further validated in an additional nonstudent sample. The 16-item 3-factor male structure was also validated within an independent nonstudent sample, but was marginally below accepted fit indices within an independent student sample (Phase 3). Taken together, the above findings suggest that the EDE-Q factor structure may require further reassessment, with greater focus on the qualitative differences in interpretation of EDE-Q items between females and males. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

In the late nineteenth and early twentieth century, the Peruvian Andes ranked as a key international destination for those afflicted with one of the world’s most deadly diseases, tuberculosis. Physicians, scientists, policy makers, and patients believed that high-elevation mountain climates worldwide would help cure the disease. Historical processes driving the creation of Andean health resorts, which are understudied in the historiography, uncover an important story in the history of tuberculosis, and also reveal how global health initiatives and disease treatment played out within the global South, where national forces and local environmental conditions influenced the trajectory of science and medicine. Jauja, Peru, became an internationally recognized health resort for tuberculosis treatment not only through science and medicine but also through national political integration campaigns, transportation initiatives, economic development agendas, social (race and class) relations, cultural perspectives of the Andean landscape, and the impact of the physical environment. This historical case about the evolution of Jauja reveals how science and medicine are shaped by distinct spatial forces that illuminate a geography of science in the postcolonial setting, as well as the ways in which climate is culturally constructed in specific sites, by different peoples, and at distinct points in time.

Recent research suggests visuo-tactile binding is temporally extended in autism spectrum disorders (ASD), although it is not clear whether this specifically underlies altered body representation in this population. In the current study children and adolescents with ASD, and typically developing controls, placed their hand into mediated reality system (MIRAGE) and saw two identical live video images of their own right hand. One image was in the proprioceptively correct location (veridical hand) and the other was displaced to either side. While visuo-tactile feedback was applied via brushstroke to the participant’s (unseen) right finger, they viewed one hand image receiving synchronous brushstrokes and the other receiving brushstrokes with a temporal delay (60, 180 and 300 ms). After brushing, both images disappeared from view and participants pointed to a target, with direction of movement indicating which hand was embodied. ASD participants, like younger mental aged-matched controls, showed reduced embodiment of the spatially incongruent, but temporally congruent, hand compared to chronologically age-matched controls at shorter temporal delays. This suggests development of visuo-tactile integration may be delayed in ASD. Findings are discussed in relation to atypical body representation in ASD and how this may contribute to social and sensory difficulties within this population. Keywords: Autism spectrum disorder, Temporal binding window, Visuo-tactile processing, Embodied action

Aberrations in oncogenes and tumor suppressors frequently affect the activity of critical signal transduction pathways. To analyze systematically the relationship between the activation status of protein networks and other characteristics of cancer cells, we did reverse phase protein array (RPPA) profiling of the NCI60 cell lines for total protein expression and activation-specific markers of critical signaling pathways. To extend the scope of the study, we merged those data with previously published RPPA results for the NCI60. Integrative analysis of the expanded RPPA data set revealed five major clusters of cell lines and five principal proteomic signatures. Comparison of mutations in the NCI60 cell lines with patterns of protein expression showed significant associations for PTEN, PIK3CA, BRAF, and APC mutations with proteomic clusters. PIK3CA and PTEN mutation enrichment were not cell lineage-specific but were associated with dominant yet distinct groups of proteins. The five RPPA-defined clusters were strongly associated with sensitivity to standard anticancer agents. RPPA analysis identified 27 protein features significantly associated with sensitivity to paclitaxel. The functional status of those proteins was interrogated in a paclitaxel whole genome small interfering RNA (siRNA) library synthetic lethality screen and confirmed the predicted associations with drug sensitivity. These studies expand our understanding of the activation status of protein networks in the NCI60 cancer cell lines, demonstrate the importance of the direct study of protein expression and activation, and provide a basis for further studies integrating the information with other molecular and pharmacological characteristics of cancer. Mol Cancer Ther; 9(2); 257–67

Purpose: It is critical to develop methods to quantify the early pharmacodynamic effects of targeted therapeutics in vivo to make drug development more efficient and ensure biologically relevant dosing. Furthermore, an ability to identify patients likely to respond to targeted therapeutics would decrease the size, duration, and cost of clinical trials, resulting in more efficient translation to improved patient outcomes. Recent studies suggest that perifosine inhibits the phosphatidylinositol-3′-kinase (PI3K) pathway by preventing cell membrane recruitment of the AKT pleckstrin homology domain. Experimental Design: A novel functional proteomics technology, reverse phase protein array, was used to establish and quantify pharmacodynamic markers of perifosine efficacy. Results: Perifosine selectively prevents AKT recruitment to the membrane and blocks activation of downstream effectors. Perifosine inhibited breast, ovarian, and prostate cancer models. Growth inhibition was associated with apoptosis. Activation of AKT as a consequence of genomic aberrations predicted perifosine efficacy. In cell lines and xenografts, there was a highly statistically significant correlation between the degree of antitumor efficacy of different perifosine doses and quantified down-regulation of phosphorylation of AKT and of its downstream targets, particularly S6. Conclusions: Because of a strong correlation between proportional modulation of PI3K pathway biomarkers and quantified perifosine efficacy, it is likely that early measurement of such pharmacodynamic biomarkers with reverse phase protein array will optimize selection of responding patients and guide perifosine dosing. Furthermore, PI3K pathway activation status may allow baseline selection of patients most likely to respond to perifosine alone or in combination with other therapies.

Objective. Our goal was to evaluate, using a retrospective cohort study design, the management and outcome of 403 women with a colposcopic biopsy of cervical intraepithelial neoplasia grade 1 (CIN1). Methods. Patients were identified from a database of 3,782 new colposcopy patients from 1990 to 1996. CIN1 on initial biopsy was identified in 505 women, and inclusion criteria were met by 403. Management and follow-up information was retrieved from the colposcopy record and computerized pathology information system. Results. Management consisted of immediate treatment for 112 women (cone biopsy, 4; cryotherapy, 26; laser ablation, 79; loop electrosurgical excision, 3) and follow-up for 291 women (colposcopy follow-up, 192; cytology follow-up by family doctor, 99). In patients with a CIN1 biopsy and an index Papanicolaou smear no more serious than atypia, 78% had follow-up only. If the index cytology showed CIN1, 51% had immediate treatment. Conclusion. Conservative management of patients with biopsy-proven CIN1 appears to be appropriate, as 64.6% of patients with follow-up reverted to benign cytology. However, compliance with follow-up must be ensured, as the failure rate of immediate treatment is not insignificant at 21%.

The management of trauma patients has become increasingly nonoperative, especially for solid abdominal organ injuries. However, the Residency Review Committee (RRC) still requires an operative trauma experience deemed essential for graduating general surgical residents. The purpose of this study was to review the trauma volume and mix of patients at two trauma centers and determine the major operative trauma cases available to residents involved in the care of these patients.A retrospective chart review was conducted at the two trauma centers used by the Michigan State University surgery residency. Both of the trauma centers are American College of Surgeons verified. Surgical residents are involved with the care of every trauma patient at each of the hospitals. Cumulative data were collected and analyzed from January 1, 1997, through December 31, 1999. Age, gender, mechanism of injury (blunt vs. penetrating), Injury Severity Score, length of stay, operative interventions, and patients managed nonoperatively were reviewed.There were 434 patients selected for this study from 2,340 patients admitted to the trauma services. Male patients accounted for 66% of patients and female patients accounted for 34% of patients. Blunt trauma was the mechanism in 89% of patients, with penetrating trauma accounting for the other 11% of patients. Of the total number of patients, motor vehicle crashes accounted for the majority of cases, 325 of 434 (75%). Overall, 85% (370 of 434) of patients were managed without an index trauma surgical procedure according to RRC guidelines. Only 14.7% (64 of 434) of patients underwent operative intervention that qualified as index trauma surgical cases identified by the RRC. The spleen and small bowel were the two most commonly injured organs found at laparotomy. Nonoperative intervention of many patients with solid abdominal organ injuries did not meet the operation requirements expected by the RRC.Our residency program had 10 graduating chief residents over the 3-year time period. With only 64 operative trauma cases, this yields an average of 6.4 trauma cases per resident. This falls significantly short of the 16-case minimum requirement in trauma surgery established by the RRC. The operative trauma requirements established by the RRC for graduating residents may be unattainable in many residency programs because of the high incidence of blunt trauma and the changing patterns of trauma management.

Purpose: To examine the androgen receptor (AR) levels in breast cancer and to assess the impact of AR expression on patient outcomes. Experimental Design: Reverse-phase protein arrays were used to measure AR levels and a mass spectroscopy–based approach was used to detect PIK3CA mutations. Means and SDs were generated for AR levels. Linear regression models were used to determine if AR levels differed by tumor subtype and PIK3CA mutation status. Two-sample t tests were used to identify pair-wise differences. Survival probabilities were estimated with the use of the Kaplan-Meier product and log-rank test. Results: The median age was 59 years (23-89 years). Significant differences in AR levels existed among different breast tumor subtypes (highest in estrogen receptor–positive and/or progesterone receptor–positive tumors) as well as by PIK3CA mutation status (P < 0.0001 for both). AR levels were significantly higher in breast tumors with kinase domain PIK3CA mutations versus tumors that are wild type or with PIK3CA helical mutations (P = 0.017 and P < 0.0001, respectively). In 347 patients, dichotomized AR level by the median was a significant prognostic factor of recurrence-free survival (P = 0.0002) and overall survival (P = 0.004). High AR levels were associated with a significantly improved recurrence-free survival in 207 patients with early-stage estrogen/progesterone receptor–positive tumors after adjuvant hormonal therapy. A trend (P = 0.07) was found toward higher AR expression in PIK3CA mutant versus PIK3CA wild-type triple-negative breast tumors. Conclusions: AR levels may represent a prognostic marker in breast cancers and may provide a valuable tool for selecting treatment. There was an association of PIK3CA mutation (kinase domain) with increased AR levels.

The present investigation was performed to study the kinetics of tissue distribution and deposition of Escherichia coli and endotoxin translocating from the intestine after thermal injury. Escherichia coli was grown in the presence of 14C glucose and both labeled bacteria and endotoxin prepared from the labeled bacteria were used as translocation probes. Escherichia coli (10(8) to 10(10) bacteria) and E. coli endotoxin (100 micrograms per animal) were gavaged into the stomach immediately before a 30% burn injury was inflicted in mice. Animals were killed 1, 4 and 24 hours after burn injury. Translocation occurred extensively within 1 hour after burn injury. Expressed as amount of radioactivity per gram of tissue, translocation was greatest in the mesenteric lymph node (MLN) followed by spleen, lung, and liver. Translocation of endotoxin was similar to translocation of intact bacteria, with the exception that less radioactivity could be found in the peritoneal cavity and more in the liver. Both intact E. coli and endotoxin translocated directly through the intact bowel wall. Killing of bacteria was greatest in the MLN and spleen, approximating 95% to more than 99% of translocating bacteria. Killing efficiency was lowest in the lungs. It is concluded that estimation of translocation by viable bacterial counts in tissues grossly underestimates the extent of translocation of bacteria and ignores the extent of translocation of endotoxin. Translocation of endotoxin may have biologic significance that is independent of and in addition to translocation of intact bacteria.

In a typical two-stage design employed in a phase II cancer clinical trial for efficacy screening, a fixed number of patients are initially enrolled. The trial may be terminated for lack of clinical efficacy of treatment if the observed number of treatment successes after the first stage is too small. Otherwise, an additional fixed number of patients are enrolled to accumulate additional information on efficacy. Simon's optimal design and minimax design have often been applied to designing phase II clinical trials. Other designs have largely been ignored. In this paper, we introduce a graphical method to search for a good design that is a compromise between the optimal and the minimax designs.

Wounds that were measured precisely 4 x 5 cm in size were created over the dorsal surfaces of rats. The defects were grafted with the use of either the microskin or Chinese technique of intermingled auto/allograft with an expansion ratio of 10:1. The size of the grafted wound of each rat was recorded on the fifth graft day after grafting and then weekly for 11 weeks. The extent of scar contracture on each rat was calculated weekly as a percentage of the original size. The results showed that the scar contracture associated with the Chinese type of intermingled auto/allograft transplantation was less than that associated with the microskin technique. The healing process in both forms of grafting was uneventful.

Introduction: Germline mutations in DNA repair genes BRCA1/2 increase the risk of developing breast and ovarian cancer. Germline BRCA1/2 mutations occur in 8.6-13.7% of unselected epithelial ovarian cancers, somatic mutations are also frequent. BRCA1/2 mutated or dysfunctional cells may be sensitive to PARP inhibition by synthetic lethality, the inhibition of two major DNA repair pathways. Therefore, there is a need to characterize ovarian cell lines for their BRCA1/2 status for in vitro studies of novel drugs. Methods: The BRCA1/2 genes were sequenced in 43 ovarian cell lines, mRNA expression of BRCA1/2 and gene methylation of BRCA1 were also examined. The cytotoxicity of PARP inhibitors olaparib and veliparib was examined in 10 cell lines. Results: Sequencing of BRCA1/2 revealed 18 and 33 different alterations respectively, mostly non-pathogenic polymorphisms. The cell line SNU-251 has a deleterious BRCA1 mutation at 5564G>A and is the only deleterious BRCA1/2 mutant in the panel. Two cell lines (UPN-251 and PEO1) had deleterious mutations as well as additional reversion mutations which restore the function of the protein. BRCA1 was methylated in three cell lines (A1847, OVCAR8, EF021) and there was a corresponding decrease in gene expression in these cell lines. The deleterious mutant SNU-251 was relatively resistant to PARP inhibition, compared to wild-type cells. However, the methylated cell lines A1847 and OVCAR8 were more sensitive to PARP inhibition than wild-type cells. Conclusions: The incidence of BRCA1/2 deleterious mutations 1/43 cell lines (2.3%) is much lower than the population incidence. The reversion mutations suggest that there is a selective pressure against BRCA1/2 mutations in cell culture. PARP inhibitors may be useful in patients with BRCA1 methylation and reduced gene expression in their ovarian tumour. 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 78. doi:1538-7445.AM2012-78

The failure of three consecutive treatment protocols to significantly increase the complete remission rate for poor prognosis newly diagnosed patients with acute myelocytic leukemia led to a detailed investigation of the causes of treatment failure. In the majority of cases treatment failure was attributable to "clinical resistance" to therapy. Upon close examination two types of "clinical resistance" were discernible: the failure of chemotherapy to produce adequate cytotoxic effects ("classical" drug resistance), and treatment failure attributed to the rapid regrowth of leukemia cells subsequent to the substantial killing of leukemia cells by cytotoxic therapy ("biological" resistance). Each form of resistance accounted for one-half of the treatment failures.

ContextSore throat is a common complaint, and identifying patients with group A β-hemolytic streptococcal pharyngitis (strep throat) is an important task for clinicians. Previous reviews have not systematically reviewed and synthesized the evidence.ObjectiveTo review the precision and accuracy of the clinical examination in diagnosing strep throat.Data SourceMEDLINE search for articles about diagnosis of strep throat using history-taking and physical examination.Study SelectionLarge blinded, prospective studies (having ≥300 patients with sore throat) reporting history and physical examination data and using throat culture as the reference standard were included. Of 917 articles identified by the search, 9 met all inclusion criteria.Data ExtractionPairs of authors independently reviewed each article and used consensus to resolve discrepancies.Data SynthesisThe most useful findings for evaluating the likelihood of strep throat are presence of tonsillar exudate, pharyngeal exudate, or exposure to strep throat infection in the previous 2 weeks (positive likelihood ratios, 3.4, 2.1, and 1.9, respectively) and the absence of tender anterior cervical nodes, tonsillar enlargement, or exudate (negative likelihood ratios, 0.60, 0.63, and 0.74, respectively). No individual element of history-taking or physical examination is accurate enough by itself to rule in or rule out strep throat. Three validated clinical prediction rules are described for adult and pediatric populations.ConclusionsWhile no single element of history-taking or physical examination is sufficiently accurate to exclude or diagnose strep throat, a well-validated clinical prediction rule can be useful and can help physicians make more informed use of rapid antigen tests and throat cultures.