Prognostic gene expression signature for high-grade serous ovarian cancer.

BACKGROUND: Median overall survival (OS) for women with high-grade serous ovarian cancer (HGSOC) is ∼4 years, yet survival varies widely between patients. There are no well-established, gene expression signatures associated with prognosis. The aim of this study was to develop a robust prognostic signature for OS in patients with HGSOC. PATIENTS AND METHODS: Expression of 513 genes, selected from a meta-analysis of 1455 tumours and other candidates, was measured using NanoString technology from formalin-fixed paraffin-embedded tumour tissue collected from 3769 women with HGSOC from multiple studies. Elastic net regularization for survival analysis was applied to develop a prognostic model for 5-year OS, trained on 2702 tumours from 15 studies and evaluated on an independent set of 1067 tumours from six studies. RESULTS: Expression levels of 276 genes were associated with OS (false discovery rate < 0.05) in covariate-adjusted single-gene analyses. The top five genes were TAP1, ZFHX4, CXCL9, FBN1 and PTGER3 (P < 0.001). The best performing prognostic signature included 101 genes enriched in pathways with treatment implications. Each gain of one standard deviation in the gene expression score conferred a greater than twofold increase in risk of death [hazard ratio (HR) 2.35, 95% confidence interval (CI) 2.02-2.71; P < 0.001]. Median survival [HR (95% CI)] by gene expression score quintile was 9.5 (8.3 to -), 5.4 (4.6-7.0), 3.8 (3.3-4.6), 3.2 (2.9-3.7) and 2.3 (2.1-2.6) years. CONCLUSION: The OTTA-SPOT (Ovarian Tumor Tissue Analysis consortium - Stratified Prognosis of Ovarian Tumours) gene expression signature may improve risk stratification in clinical trials by identifying patients who are least likely to achieve 5-year survival. The identified novel genes associated with the outcome may also yield opportunities for the development of targeted therapeutic approaches.

Diagnosis and treatment of temporomandibular disorders: an ethical analysis of current practices.

The defining characteristic of a profession - and especially a health-care profession - is that the behaviour of its members is proscribed by a formal code of ethics. The main purpose of such codes is to guide practitioners' interactions with patients, assuring that patient interests are protected. In other words, the ethical code requires practitioners to place their patients' needs for proper diagnosis and appropriate treatment ahead of their own needs for income and advancement. The dental profession has a code of ethics that was developed by the American Dental Association many years ago; in most clinical situations, determination of proper behaviour is self-evident. However, the field of temporoman-dibular disorders (TMDs) has been the subject of considerable controversy for over half a century, and many people have argued that this makes it impossible to evaluate various approaches to treatment of TMDs within an ethical framework. In this article, the authors argue that the large volume of scientific evidence in the contemporary TMD literature provides an ethical framework for the diagnosis and treatment of patients with TMDs within a biopsychosocial medical model. They present a summary of the research with contemporary scientific integrity, which has produced that information over a period of many years. Based on that research, they conclude that dentists may provide conservative and reversible treatments that will be successful for most TMDs and in doing so will comply with the profession's code of ethics. Conversely, the authors claim that those dentists who continue to follow the older mechanistic models of TMD aetiology and treatment are not only out of step scientifically, but are placing their patients' welfare at risk by providing unnecessary irreversible bite-changing and jaw-repositioning interventions. Therefore, debate of these issues should not be solely focused on scientific merit, but also upon the compelling ethical obligations that dentists have as a result of the contemporary scientific literature regarding TMDs.

Dental occlusion: a critical reflection on past, present and future concepts.

For nearly a century, the diversity of concepts about 'normal' and 'ideal' dental occlusal relationships has led to confusion in trying to describe the occlusion of any individual patient. In addition, a similar controversy arises when trying to formulate treatment plans for patients who need extensive dental restorations or orthodontic treatment. And finally, the application of occlusal concepts to patients with temporomandibular pain and dysfunction has created a third area of debate. Over the past few decades, however, an appreciable part of the tenacious dogmatic heritage of this topic has been challenged. As a result, the acceptance of morphological and functional variability of the stomatognathic system has gained increasing support, and this change has important consequences for modern dental practice. In this article, the past, present and future of the subject of occlusion will be considered.

The etiology of temporomandibular disorders: implications for treatment.

This article begins by reviewing the history of etiologic thinking in the field of temporomandibular disorders (TMD). I conclude from this review that not only are the old mechanistic etiologic concepts incorrect, but also that 2 of the most popular current concepts (biopsychosocial and multifactorial) are seriously flawed. Therefore, what we really have at the individual TMD patient level is nearly always an idiopathic situation--we simply do not know enough, or cannot measure enough, or cannot precisely determine why each patient has a TMD. In addition, we do not understand the host resistance factors that ultimately determine why one person gets sick while another does not. The issue of "why" (etiology) must be differentiated from the issue of "how" (pathophysiology), both semantically and intellectually, to discuss all of this properly. However, our current inability to precisely identify etiologies in TMD patients does not prevent us from providing sensible (and often successful) treatment for most of these patients. Many health conditions currently are treated by physicians and dentists with either incomplete or flawed understanding of their etiology, but the availability of empirical data about treatment outcomes permits some level of appropriate care to be given. Fortunately, a large number of comparative studies have been done in the field of TMD therapy, providing us with a basis for selecting initial therapies as well as for dealing with treatment failures. Even in the absence of a perfect understanding of etiology, we still can provide good conservative care, and we should avoid aggressive and irreversible treatments, especially when they are based on flawed concepts of etiology. The article concludes by discussing current basic science research activities in the field of TMD and orofacial pain. I propose that these ongoing studies of the molecular and cellular mechanisms of joint disease, muscle pain, and chronic pain are the most likely avenues to future progress in this field, as specific countermeasures are developed to become the basis for more precisely targeted therapies.

Temporomandibular disorders and science: a response to the critics.

This article was prepared by the above authors and submitted to members of the TMD academic community for their endorsement. A total of 120 people signed an endorsement; their names are available on request.

Pancraniosynostosis after surgery for single sutural craniosynostosis.

Three children who developed pancraniosynostosis after surgery to correct nonsyndromic single suture synostosis (2 sagittal, 1 unilateral coronal) were noted on prolonged follow-up to have a decreased rate of head growth, and beaten copper findings on plain radiographs of the skull. All had elevated intracranial pressure as recorded by lumbar puncture. The children were reoperated, and then cranial growth resumed, and the radiographic abnormalities resolved. Because of the risk of pancraniosynostosis after surgery for single suture craniosynostosis, extended neurosurgical follow-up for patients with craniosynostosis is warranted.

Temporomandibular disorders and science: a response to the critics.

This article was prepared and submitted to members of the TMD academic community for their endorsement. A total of 120 people signed an endorsement; their names are available on request.

Predictive value of letters of recommendation vs questionnaires for emergency medicine resident performance.

OBJECTIVE: To evaluate the predictive value of standard letters of recommendation (LORs) vs preprinted questionnaires (PPQs) for resident performance at one emergency medicine (EM) residency program. METHODS: A retrospective association of LORs and PPQs with in-training residents performance ratings was done at one EM residency program. The residency application files of EM residents who completed the program were reviewed to locate files that had LORs and PPQs written by the same author. Seventeen resident files contained 32 LOR/PPQ pairs. These LORs and PPQs were submitted in a blinded fashion to 3 outside EM residency directors. Each LOR and PPQ was evaluated for the applicant's suitability for the specialty of EM, medical knowledge, procedural skills, interpersonal skills, motivation, and overall rank. The scores given by the outside reviewers were compared with resident performance ratings determined by 5 EM attending physicians who evaluated the residents along the same 6 dimensional ratings. RESULTS: Statistically, no differences were found between the LORs and PPQs in predicting resident performance. CONCLUSIONS: PPQs may substitute for LORs in the evaluation of resident applicants.

Etiology of temporomandibular disorders.

This article discusses the subject of causation (etiology) as it has been applied to the field of temporomandibular disorders (TMD). These disorders have been the focus of considerable disagreement about what constitutes proper diagnosis and treatment, and it is clear that the main basis for these controversies has been conflicting views about the etiology of the various disorders. Many earlier theories emphasized dental morphological factors of malocclusion, occlusal dysharmony, and bad mandibular alignment as being primarily responsible for the development of TMD symptoms. Certain versions of these dental/skeletal concepts have long been a part of the belief system of the orthodontic specialty, leading to some special orthodontic protocols for managing TM disorders. Today, it is generally agreed that the etiology of TM disorders includes a multifactorial combination of physical and psychosocial factors, with some of them being either poorly understood or difficult to assess. In most cases, there are no special occlusal or orthodontic factors to be considered, and therefore occlusion-changing procedures are not generally required for successful treatment. This means that contemporary orthodontists must face the same challenge as all their other dental colleagues: to learn about modern concepts of diagnosis and treatment for all types of orofacial pain patients, and then to use currently recommended protocols for pain management and musculoskeletal therapy for those patients who have temporomandibular disorders.

Temporomandibular disorders in the geriatric population.

Contrary to popular assumptions that temporomandibular disorders may become more prevalent with increasing age, a review of the literature shows that this is clearly not the case. Instead, it seems that most objective "signs" of temporomandibular disorders, namely clicking, tender joints and muscles, crooked opening, limited movement, and so forth, are found either less often in the elderly or at approximately the same rate in all adult age groups. Subjective complaints, however, decrease as populations get older, and the demand for treatment declines accordingly.

A quantitative computer-assisted analysis of disc displacement in patients with internal derangement using sagittal view magnetic resonance imaging.

Forty patients diagnosed clinically as having internal derangement of one or both temporomandibular joints underwent magnetic resonance imaging. Seventy-three films were obtained: 26 films from 13 patients with bilateral symptoms; 40 films from 20 patients with unilateral symptomatic joints; and seven films from only the symptomatic joint in the remaining seven patients. Disc positions were evaluated in all of these films, and also in 17 films obtained from 10 asymptomatic volunteers. A system for quantitative measurement of disc position relative to the condyle in the closed-mouth position was used in two ways: manually, with an operator locating reference points and measuring them; and computer-assisted, with a special program developed to locate and measure these points. There was no significant difference in the results produced by these two methods. Important findings of this study were as follows: 1) 35% of the joints in the asymptomatic volunteers were found to have moderately or severely displaced discs; 2) only 75% of the joints diagnosed clinically as having an internal derangement were found to have significant disc displacement, which suggests that the other 25% must have had a different pathologic basis for the symptoms; and 3) the contralateral disc in the unilateral patients was found to be displaced as often as the disc on the symptomatic side (75%).

The origins, benefits, harms, and implications of emergency medicine clinical policies.

Emergency physicians desire to provide their patients with care that is of the highest quality and is cost effective. Any tool that promotes these aims is good and should be used. Clinical policies have been proposed as a new method of prompting physicians to provide better care. While there is no direct evidence that emergency medicine clinical policies improve care, there is indirect evidence that they may be useful. ACEP has initiated a process for the development and evaluation of selected clinical policies. We anxiously await information that sheds light on the value of policies in enhancing the clinical practice of emergency medicine.