Multidisciplinary Management of Phyllodes Tumours and Breast Sarcoma: A Cross-sectional Survey of Clinical Practice across the UK and Ireland.

AIMS: Phyllodes tumours and breast sarcomas are uncommon tumours and their rarity poses significant challenges in diagnosis and management. This cross-sectional study was conducted to evaluate the multidisciplinary clinical practice for these tumours across the UK and Ireland, with the aim of identifying gaps in knowledge and providing direction for establishing national guidelines. MATERIALS AND METHODS: An international survey was adapted and circulated to breast and/or sarcoma surgeons and oncologists in the UK and Ireland through national organisations. Multidisciplinary team (MDT) responses were analysed anonymously. RESULTS: Twenty-eight MDTs participated in this study, predominately from high-volume units (85.5%). Although only 43% of the surveyed units were part of a trust that holds a sarcoma MDT, 68% of units managed malignant phyllodes and angiosarcoma, whereas 64.5% managed soft-tissue sarcoma of the breast. Across all subtypes, axillary surgery was recommended by 14-21% of the MDTs and the most recommended resection margins for breast surgery were 'no tumour on ink' in benign phyllodes (39%) and 10 mm in the remaining subtypes (25-29%). Immediate breast reconstruction was supported by 11-18% of MDTs for breast sarcoma subtypes, whereas 36% and 32% advocated this approach in benign and borderline phyllodes tumours, respectively. Adjuvant radiotherapy and chemotherapy were recommended by up to 29% and 11% of the MDTs, respectively. CONCLUSION: The results of this study demonstrate a wide variation in clinical practice across the surveyed MDTs. As only 28 MDTs participated in our study, with under-representation from low-volume units, our results might be an underestimation of the variability in practice across the UK and Ireland. This multi-institutional study sheds light on controversial aspects in the management of phyllodes tumours and breast sarcoma, identifies the need for national guidelines to inform best practice, and calls for the centralisation of the management of breast sarcoma within specialist centres.

Expression, methylation and chromatin structure of the p53 gene in untransformed and human T-cell leukemia virus type I-transformed human T-lymphocytes.

p53 is a nuclear protein associated with cellular transformation and normal cellular proliferation. Some transformed cells have been found to have one or several quantitative or qualitative abnormalities of p53. We studied expression, kinetics, phosphorylation, DNA methylation and chromatin structure of p53 in resting and proliferating untransformed T-lymphocytes and in human T-cell leukemia virus type I transformed T-lymphocytes from the same individuals. p53 expression is indistinguishable in transformed compared to untransformed proliferating T-lymphocytes by: (1) p53 mRNA levels, (2) rate of synthesis and stability of p53 protein, (3) change in protein stability after exposure to an inhibitor of protein synthesis, (4) presence of phosphorylation of the p53 protein. Resting T-lymphocytes from these same individuals did not express p53. No difference in DNA methylation and chromatin structure of the p53 gene was observed in either resting or proliferating untransformed, or virally transformed T-lymphocytes. The gene was fully methylated and resistant to DNAase I over its entire coding region but was demethylated and contained DNAase I hypersensitive sites in a distinct region 5' of the site of initiation of transcription.

The deliberate self-harm syndrome.

Recent research has differentiated several distinct classes of self-destructive behavior. This paper describes the clinical characteristics of one class, the deliberate self-harm syndrome. Analysis of 56 published case reports of self-harm revealed a typical pattern of onset in late adolescence, multiple recurrent episodes, low lethality, harm deliberately inflicted upon the body, and extension of the behavior over many years. Since the clinical characteristics of the deliberate self-harm syndrome differ substantially from those of other classes of self-destructive behavior, the authors propose that DSM-IV classify deliberate self-harm as a separate diagnostic syndrome.

Molecular analysis of the cyclin-dependent kinase inhibitor genes, p15, p16, p18 and p19 in the myelodysplastic syndromes.

The myelodysplastic syndromes (MDS) are a heterogeneous group of clonal blood disorders characterized by dyshematopoiesis with a frequent evolution to acute leukemia. Chromosomal deletions rather than translocations are the predominant karyotypic abnormalities in MDS, suggesting a recessive mechanism in the pathogenesis of MDS, such as inactivation of tumor suppressor genes. A group of cyclin-dependent kinase inhibitors, p15 (INK4B), p16 (INK4A), p18 (INK4C) and p19 (INK4D), are candidate tumor suppressor genes. To determine whether genetic alterations of these genes play an important role in the development and/or progression of MDS, we examined 46 samples from MDS patients by Southern blotting, single-strand-conformation polymorphism (SSCP) using polymerase chain reaction (PCR) and sequencing of DNA. These samples included 13 refractory anemias (RA), four refractory anemias with ringed sideroblasts (RARS), 16 refractory anemias with an excess of blasts (RAEB), eight refractory anemias with an excess of blasts in transformation (RAEB-T) and five chronic myelomonocytic leukemia (CMMoL) samples. Except for allelic polymorphisms or silent point mutations, no alterations of coding regions of these four CDKI genes were identified. In summary, genetic abnormalities of the p15, p16, p18 and p19 genes are rare events in the development and/or progression of MDS.

Sensitivity and specificity of the RAND/UCLA Appropriateness Method to identify the overuse and underuse of coronary revascularization and hysterectomy.

There is no empirical evidence on the sensitivity and specificity of methods to identify the possible overuse and underuse of medical procedures. To estimate the sensitivity and specificity of the RAND/UCLA Appropriateness Method. Parallel three-way replication of the RAND/UCLA Appropriateness Method for each of two procedures, coronary revascularization and hysterectomy. Maximum likelihood estimates of the sensitivity and specificity of the method for each procedure. These values were then used to re-calculate past estimates of overuse and underuse, correcting for the error rate in the appropriateness method. The sensitivity of detecting overuse of coronary revascularization was 68% (95% confidence interval 60-76%) and the specificity was 99% (98-100%). The corresponding values for hysterectomy were 89% (85-94%) and 86% (83-89%). The sensitivity and specificity of detecting the underuse of coronary revascularization were 94% (92-95%) and 97% (96-98%), respectively. Past applications of the appropriateness method have overestimated the prevalence of the overuse of hysterectomy, underestimated the prevalence of the overuse of the coronary revascularization, and provided true estimates of the underuse of revascularization. The sensitivity and specificity of the RAND/UCLA Appropriateness Method vary according to the procedure assessed and appear to estimate the underuse of procedures more accurately than their overuse.

Decreasing the burden in families caring for a relative with a dementing illness. A controlled study.

The purpose of this study was to investigate the efficacy of a specifically designed group support program for relatives of patients with Alzheimer's disease and related disorders. The group program included educational/supportive activities and used basic principles of the cognitive-behavioral approach. Twenty-two subjects participated in an eight-session program. Eighteen control subjects received no treatment. Measures of family burden, levels of depression, and knowledge of dementia were obtained. Experimental subjects showed a significant decrease in total family burden, whereas control subjects actually showed a significant increase, experimental subjects also showed reduction in their levels of depression. Experimental subjects showed a significantly greater improvement than did control subjects on knowledge of dementia. The acquisition of new knowledge was an important ingredient in reducing perception of burden and levels of depression, but other facets of the intervention also accounted for the improvement. Results indicated that a relatively short but intensive support experience can have a positive effect in reducing some of the burden and depression associated with the care of a demented relative.

Guideline adherence rates and interprofessional variation in a vignette study of depression.

OBJECTIVE: To assess the appropriateness of and variation in intention-to-treat decisions in the management of depression in the Netherlands. DESIGN: Mailed survey with 22 paper cases (vignettes) based on a population study. SETTING: A random sample from four professional groups in the Dutch mental healthcare system. SUBJECTS: 264 general practitioners, psychiatrists, psychotherapists, and clinical psychologists. MAIN OUTCOME MEASURES: Each vignette contained information on a number of patient characteristics taken from three national depression guidelines. The distribution of patient characteristics was based on data from a population study. Respondents were asked to choose the best treatment option and the best treatment setting. For each vignette we examined which of the selected treatments was appropriate according to the recommendations of the three published Dutch clinical guidelines and a panel of experts. RESULTS: 31% of all intention-to-treat decisions were not consistent with the guidelines. Overall, less severe depression, alcohol abuse, psychotic features, and lack of social resources were related to more inappropriate judgements. There was considerable variation between the professional groups: psychiatrists made more appropriate choices than the other professions although they had the highest rate of overtreatment. CONCLUSIONS: There is sufficient variation in the intentions to treat depression to give it priority in quality assessment and guideline development. Efforts to achieve appropriate care should focus on treatment indications, referral patterns, and overtreatment.

European criteria for the appropriateness and necessity of coronary revascularization procedures.

OBJECTIVES: Large variations in the use of coronary revascularization procedures have led many countries to apply the RAND appropriateness method to develop specific criteria describing patients who should be offered these procedures. The method is based on the work of a multidisciplinary expert panel that reviews a synthesis of the scientific evidence and rates the appropriateness of a comprehensive list of indications for the procedure being studied. Previous studies, however, have all involved single-country panels. We tested the feasibility of carrying out a multinational panel to rate the appropriateness and necessity of coronary revascularization, thereby producing recommendations for common European criteria. METHODS: Using the RAND methodology, a multispecialty (interventional cardiologists, non-interventional cardiologists and cardiovascular surgeons), multinational (The Netherlands, Spain, Sweden, Switzerland and the United Kingdom) panel rated the appropriateness and necessity of indications for percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass graft surgery (CABG). A synthesis of the evidence and list of indications for PTCA and CABG were sent to 15 panelists, three from each country, who performed their ratings in three rounds. RESULTS: For PTCA, 24% of the indications were appropriate and necessary, 16% were appropriate, 43% were uncertain and 17% were inappropriate. The corresponding values for CABG were 33% appropriate and necessary, 7% appropriate, 40% uncertain and 20% inappropriate. The proportion of indications rated with disagreement was 4% for PTCA and 7% for CABG. CONCLUSION: Multinational panels appear to be a feasible method of addressing issues concerning the appropriateness and necessity of medical procedures in western European countries. The criteria produced provide a common tool that can be used to measure the overuse and underuse of medical procedures and to guide decision-making.

Coronary angiography and revascularization: defining procedural indications through formal group processes. The Canadian Revascularization Panel, the Canadian Coronary Angiography Panel.

OBJECTIVES: To summarize the process and extent of interphysician agreement within two panels convened to derive indications for the appropriate use of coronary angiography and for coronary revascularization procedures. PARTICIPANTS: Two panels, each with nine practitioners. METHODS: Panelists rated the appropriateness of intervention for a comprehensive set of indications for each procedure. Indications were brief profiles created by combining and permuting clinical characteristics pertinent to case selection for intervention. Ratings were first made at home, with a second round at the panel meeting following open discussion. Final rankings of indications as 'appropriate', 'uncertain' or 'inappropriate' were based on the pattern of panelists' responses on a nine-point scale, including the median rating and extent of agreement among panelists. Agreement was defined as at least seven panelists' ratings within the three-point region containing the median rating. Panelists were later mailed a much-reduced list of indications for which there was agreement on appropriateness. These were re-rated on a necessity scale. A procedure was rated 'necessary' only if a physician was ethically obligated to recommend it as the preferred treatment option. RESULTS: For appropriateness of angiography, agreement occurred in 38.2% of indications in round 1 and 64.4% in round 2 (P < 0.0001). For coronary artery bypass graft (CABG) versus medical therapy, the corresponding increase was from 43.5 to 54.0% (P < 0.0001). Agreement on necessity of angiography occurred for 44.3% of scenarios. For indications where CABG alone was appropriate, agreement on necessity was 56%. However, for indications where percutaneous transluminal coronary angioplasty (PTCA) could be regarded as the first-line intervention, agreement on necessity was only 5%. CONCLUSIONS: A two-step panel process permitted considerable convergence of panelists' ratings, highlighting the importance of formal panel methods in setting utilization management criteria. However, the extent of continuing disagreement on ratings underscores the need to avoid a forced consensus; instead, divergent opinions should be taken as indicative of uncertainty about the appropriateness of intervention. Interpanelist agreement on necessity ratings was modest, but may help in setting benchmarks to assess possible underprovision of invasive cardiac services in Canada.

Thienamycin, a new beta-lactam antibiotic. I. Discovery, taxonomy, isolation and physical properties.

A new beta-lactam antibiotic, named thienamycin, was discovered in culture broths of Streptomyces MA4297. The producing organism, subsequently determined to be a hitherto unrecognized species, is designated Streptomyces cattleya (NRRL 8057). The antibiotic was isolated by adsorption on Dowex 50, passage through Dowex 1, further chromatography on Dowex 50 and Bio-Gel P2, and final purification and desalting on XAD-2. Thienamycin is zwitterionic, has the elemental composition C11H16N2O4S (M.W. = 272.18) and possesses a distinctive UV absorption (lambda max = 297 nm, epsilon = 7,900). Its beta-lactam is unusually sensitive to hydrolysis above pH8 and to reaction with nucleophiles such as hydroxylamine, cysteine and, to a lesser degree, the primary amine of the antibiotic itself. The latter reaction results in accelerated inactivation at high antibiotic concentrations.

Dissemination of effectiveness and outcomes research.

Effectiveness and outcomes research seeks to improve patients' health outcomes by improving the quality of the health care they receive. Dissemination of the findings of such research is a necessary step in that process. This paper reviews what is known about designing and disseminating effective information packages aimed at health care providers (mainly physicians), where effectiveness means promoting behavior change on the part of practitioners that leads to better patient care. Practice-relevant research information is delivered to providers through publication of results from randomized clinical trials, dissemination of consensus recommendations, development and use of computer-based aids to clinical decision making, and provision of continuing medical education. Each of these areas offers numerous examples of the exceedingly modest behavioral response that can be expected from the mere provision of information. The literature also offers some principles that may improve the chances for success, including the desirability of techniques that involve face-to-face interaction, promoting the active involvement of the learner, repeating the message, making recommendations explicit and relevant to clinical practice, and making use of opinion leaders and peer influence. Little basic research has been done on providers' motivations and actual decision-making processes. Research aimed at furthering a behavioral science of providers could yield new insights on effective dissemination strategies as well.

Measuring the clinical consistency of panelists' appropriateness ratings: the case of coronary artery bypass surgery.

OBJECTIVE: To assess the clinical consistency of expert panelists' ratings of appropriateness for coronary artery bypass surgery. DESIGN: Quantitative analysis of panelists' ratings. PARTICIPANTS: Nine physicians (three cardiothoracic surgeons, four cardiologists, and two internists) convened by RAND to establish criteria for the appropriateness of coronary artery bypass surgery. MAIN OUTCOMES MEASURES: Percentage of indication-pairs given clinically inconsistent ratings (i.e. higher rating assigned to one member of an indication-pair when rating should have been equal or lower). RESULTS: In the final round of appropriateness ratings, among 1785 pairs of indications differing only on a single clinical factor (e.g., three-vessel vs. two-vessel stenosis), 6.6% were assigned clinically inconsistent ratings by individual panelists, but only 2.7% received inconsistent ratings from the panel as a whole (using the median panel rating as the criterion). Internists on the panel provided fewer inconsistent ratings (4.6%) than either cardiologists (7.8%) or cardiothoracic surgeons (6.3%) (p < 0.001). More inconsistencies were noted when the factor distinguishing otherwise identical indications was symptom severity (inconsistency rate, 13.2%) or intensity of medical therapy (13.2%) than when it was number of stenosed vessels (3.8%) or proximal left anterior descending (PLAD) involvement (1.9%). Contrary to expectations, panelists' inconsistency rates increased between the initial and final rounds of appropriateness ratings (from 3.9 to 6.6%, p < 0.001). Panelists' mean ratings across indications were only weakly correlated with individual inconsistency rates (r = 0.18, p = ns). CONCLUSIONS: The RAND/UCLA method for assessing the appropriateness of coronary revascularization generally produces criteria that are clinically consistent. However, research is needed to understand the sources of panelists' inconsistencies and to reduce inconsistency rates further.

The appropriateness of treatment of benign prostatic hyperplasia: a comparison of Dutch and multinational criteria.

Over the last decade, a number of organisations have developed clinical guidelines, typically at a national level, in order to increase appropriate health care. This raises the question as to whether it is possible to develop guidelines, applicable on the national level, at an international level. In order to examine this, we compared the appropriateness criteria for the treatment of benign prostatic hyperplasia ratings developed by two panels, one a single-nationality (Dutch) panel, the other a multinational (European) panel. The panels, both consisting of experienced urologists, used a modified Delphi process to rate 1152 indications for the most common treatments (surgery, alpha-blocker, finasteride and watchful waiting) on a nine-point scale. This article describes the similarities and differences between the ratings produced by the panels. The appropriateness ratings were identical for 84% of the indications (kappa=0.76). The difference in the scores for individual indications was zero in 41% of indications and less than or equal to two in 99% of indications. This study provides strong evidence that a multinational panel can deliver essentially the same appropriateness ratings for BPH as a national panel. Developing appropriateness criteria on an international level may result in significant savings and may help contribute to the reduction of undesirable practice variation.

Panellist consistency in the assessment of medical appropriateness.

Where information about the appropriateness of a surgical procedure is lacking, expert panels have been used to establish guidelines for medical practitioners. Such a panel was convened to assess the appropriateness of percutaneous transluminal coronary angioplasty and coronary artery bypass graft surgery in the Netherlands. The panel, consisting of interventional cardiologists and cardiothoracic surgeons, used a modified Delphi process to rate 1126 clinical indications over two rounds. This article describes the degree of change in both agreement amongst members and in the appropriateness ratings over the two rounds, and examines the internal consistency of the ratings of individual panellists. Over the two rounds, agreement increased. Although most appropriateness ratings remained unchanged, there was significant movement from equivocal ratings to determinate ratings. While individual members showed some degree of inconsistency in their scoring, the panel as a whole scored very consistently. The observed changes in appropriateness were consistent with expectations, showing that the appropriateness method is used logically and consistently by panellists.

Effect of panel composition on physician ratings of appropriateness of abdominal aortic aneurysm surgery: elucidating differences between multispecialty panel results and specialty society recommendations.

OBJECTIVE: To investigate how the composition of multispecialty physician panels is associated with both the summary ratings assigned by such panels and the agreement of such panels with the recommendations of specialty societies. DATA SOURCES/STUDY SETTING: We examined the final ratings assigned by a nine-member multispecialty RAND Corporation physician panel regarding indications for abdominal aortic aneurysm surgery and the recommendations of a specialty society representing vascular surgeons who perform the same surgery. STUDY DESIGN: The panel was retrospectively divided into two sub-panels, one composed of the three vascular surgeons on the panel and the other composed of the six remaining physicians. We analyzed the two sub-panels' rating patterns with respect to each other and with respect to concurrent guidelines generated by the Joint Council of the Society of Vascular Surgery and the North American Chapter of the International Society for Cardiovascular Surgery. PRINCIPAL FINDINGS: Of the 782 indications considered by the panel for appropriateness, the vascular surgeons had an average of mean ratings for appropriateness of 5.1, significantly higher than the 4.5 average of the other physicians. Across the 221 indications considered by the panel for necessity, the vascular surgeons had an average of mean necessity ratings of 6.8, significantly higher than the 5.8 average of the other physicians. The vascular surgeons' rankings of agreement with the guidelines of the Joint Council were significantly higher than those of the physician panelists from other specialties. CONCLUSIONS: statements of clinical appropriateness and necessity produced by summarizing ratings assigned to indications by expert panel members may disguise marked underlying disagreements among well-defined groups of practitioners within these panels. In the case of abdominal aortic aneurysm management, these disagreements within the RAND panel explain the marked discrepancy between the RAND multidisciplinary panel ratings and the recommendations issued by vascular surgeon professional societies.

Proposal for a distinctive diagnosis: the deliberate self-harm syndrome (DSH).

Self-destructive behavior is a major clinical problem in psychiatry. A review of the literature reveals the existence of enough clinical data to identify a diagnostic entity, "The Deliberate Self-Harm Syndrome" (DSH). The authors present a diagnostic formulation of the DSH syndrome (in the DSM-III format) which consists of four essential clinical features, a group of associated features, clinical features, a group of associated features, a clinical course of typical onset in late adolescence, with multiple recurrent episodes, with multiple methods of low lethality physical self-injury, extending over many years. On the basis of relatively exclusive association of clinical signs and symptoms a heuristic clinical entity is proposed.

Food and Drug Administration regulation of medical device biotechnology, and food and food additive biotechnology.

The Food and Drug Administration (FDA) is facing a flurry of new products coming to market over the next few years that will be based on biotechnology. The agency will have to deal with state-of-the-art drugs and devices utilizing biotechnology as the developmental base. Also, many universities and companies are exploring the potential uses of biotechnology in developing new foods and food additives. This article will examine how the FDA is presently regulating medical device, and food and food additive biotechnology and the challenges confronting the agency in these areas in the future.

Cumulative industrial trauma as an etiology of seven common disorders in the foot and ankle: what is the evidence?

The concept of cumulative industrial trauma as an etiology of orthopaedic disease has recently generated considerable attention in both the medical and legal communities. To clarify the current state of knowledge about the issue as applied to the foot and ankle, we critically reviewed the literature on the etiology of seven foot and ankle disorders commonly involved in compensation litigation in the practice of the senior author: hallux valgus, interdigital neuroma, tarsal tunnel syndrome, lesser toe deformity, heel pain, adult acquired flatfoot, and foot and ankle osteoarthritis. Koch's postulates were appropriately modified and used as a logistic framework to analyze the potential for cumulative industrial trauma to cause foot pathology. In none of the disorders analyzed could cumulative industrial trauma reasonably satisfy even one of Koch's three postulates. We conclude there is currently no unequivocal literature support upon which to invoke cumulative industrial trauma as a clear etiology of these disorders of the adult foot and ankle. The superb evolutionary adaptation of the human foot to prolonged ambulation and the absence of industrial demands that significantly differ from this task likely account for this dramatically reduced vulnerability of the foot to industrial repetitive motion disorders compared to the upper extremity.