Molecular tools for companion diagnostics

The heterogeneous nature of cancer results in highly variable therapeutic responses even among patients with identical stages and grades of a malignancy. The move towards personalised medicine in cancer therapy has therefore been motivated by a need to customise therapy according to molecular features of individual tumours. Companion diagnostics serves to support early drug development, it can provide surrogate markers in clinical trials, and also guide selection of individual therapies and monitoring of responses in routine clinical care. The era of companion diagnostics can be said to have begun with the introduction of the HercepTest - a first-of-a-kind diagnostic tool developed by DakoCytomation in 1998 to select patients for therapy with the anticancer drug Herceptin (trastuzumab). Herceptin and the paired test proved that companion diagnostics can help guide patient-tailored therapies. We will discuss herein technologies to analyse companion diagnostics markers at the level of DNA, RNA or protein, focusing on a series of methods developed in our laboratory that can facilitate drug development and help stratify patients for therapy.     

Guest Lecture 9.45–10.30 Wednesday 17 September 2003

The success of the Cervical Screening Programme (CSP) is due in part to its management being underpinned by Quality Assurance. These measures ensure uniform standards across the country. Since 1992 Colposcopy Guidelines have been in place; these were updated in 1997 and have just been redefined. It is entirely consistent with the National CSP that colposcopy is governed by Guidelines.
The aim of clinical practice guidelines is to raise the standard of care and improve outcomes. The objectives are, therefore:

The credibility of guidelines is crucial to their adoption and this depends far more on the demonstration of an evidence base than that the authors are 'experts'. Development by a professional group or body who are seen as having a legitimate role is very important as is involvement of all 'stakeholders' in ensuring acceptability.
In terms of their nature, guidelines should be valid i.e. they will achieve what they are intended to achieve, and they should be robust i.e. they will work when implemented by different individuals in different settings. Colposcopy lends itself well to guidelines because it is largely a routine practice, but substandard care can have serious consequences.
In previous years there has been a set of Guidelines for Practice ^{1, 2} and a set of Quality Standards ³ . On this occasion these two components have been put together in a simple publication.
It needs to be borne in mine that the new guidelines were being developed in the context of a number of potential changes which could interact with each other and impact on the Guidelines. These include:
 

     

Progress in melanoma treatment: Patient's perspectives

Upon the 20th Anniversary of the Society for Melanoma Research, we highlight the perspectives of patients aiming to help improve future experiences, outcomes, and their quality of life over the next 20 years. Five melanoma patients generously shared their inspiring and enlightening stories of diagnosis, treatment, and outcomes. Many patients had excellent medical teams that synergistically worked together to provide an accurate diagnosis, effective treatment options, and supportive care. However, it is clear that health inequities persist in communities where people of color are predominant, affecting early detection, patient experience, and outcomes. These stories shed light on the unique challenges faced by patients and how the lack of melanoma awareness and adequate resources, especially in communities of color or low socioeconomic status, can contribute to disparate outcomes in melanoma care. We expect that these stories will raise awareness about the progress in melanoma treatment but also the existent disparities in melanoma diagnosis and treatment and the importance of early detection and prevention.     

Urea-cycle disorders as a paradigm for inborn errors of hepatocyte metabolism

Urea-cycle disorders (UCDs) are a group of inborn errors of hepatocyte metabolism that are caused by the loss of enzymes involved in the process of transferring nitrogen from ammonia to urea, via the urea cycle (UC). Recent genetic analyses of inherited disorders that present with hyperammonemia demonstrate the function of cellular transporters that regulate the availability of UC intermediates. The regulation of UC intermediates, such as arginine, could have far reaching implications on nitric-oxide synthesis and vascular tone. Hence, each UCD and UC-related disorder constitutes a unique gene-nutrient interaction that is crucial for postnatal homeostasis. Recent advances in the diagnosis and management of UCDs include the application of in vivo metabolic-flux measurements. Cumulative morbidity is still high despite dietary and pharmacological therapies and, hence, both cell and gene therapies are being pursued as possible long-term corrective treatments. Although gene-replacement therapy has suffered recent clinical setbacks, new vector developments offer hope for the treatment of cell-autonomous defects of hepatocyte metabolism.     

Guest Lecture 9.45–10.30 Wednesday 17 September 2003. Csp Colposcopy Guidelines

The success of the Cervical Screening Programme (CSP) is due in part to its management being underpinned by Quality Assurance. These measures ensure uniform standards across the country. Since 1992 Colposcopy Guidelines have been in place; these were updated in 1997 and have just been redefined. It is entirely consistent with the National CSP that colposcopy is governed by Guidelines. The aim of clinical practice guidelines is to raise the standard of care and improve outcomes. The objectives are, therefore:

• a) to develop evidence based guidelines;
• b) to ensure the guidelines are widely adopted.

The credibility of guidelines is crucial to their adoption and this depends far more on the demonstration of an evidence base than that the authors are ‘experts’. Development by a professional group or body who are seen as having a legitimate role is very important as is involvement of all ‘stakeholders’ in ensuring acceptability. In terms of their nature, guidelines should be valid i.e. they will achieve what they are intended to achieve, and they should be robust i.e. they will work when implemented by different individuals in different settings. Colposcopy lends itself well to guidelines because it is largely a routine practice, but substandard care can have serious consequences. In previous years there has been a set of Guidelines for Practice ^1, 1Duncan 1992 ² 2Duncan 1995 and a set of Quality Standards ³ 3Luesley 1996 . On this occasion these two components have been put together in a simple publication. It needs to be borne in mine that the new guidelines were being developed in the context of a number of potential changes which could interact with each other and impact on the Guidelines. These include: The process for the development of the Guidelines included an Editor, an editorial group, and a group of contributors to produce a draft set of evidence based guidelines across 18 areas. New areas covered included HIV +ve women, immuno suppressed women, and working practice. The draft has been available for comment for several months and amendments have been made. Clearly there are areas where evidence is lacking and where different views are expressed. The most contentious area not surprisingly is in the topic of managing mild dyskaryosis; controversy in this has persisted for many years. The quality standards are either attainable or within attainment and are a driver for rising standards. These programme practice guidelines and standards have earned UK colposcopy international respect. They provide a benchmark for QA assessment and will continue to require amendment as new developments come into being.     

The effects of clinical practice guidelines on patient outcomes in primary care: a systematic review

OBJECTIVE: To assess the evidence for the effectiveness of clinical practice guidelines (CPGs) in improving patient outcomes in primary care. DATA SOURCES: A search of the MEDLINE, HEALTHPLAN, CINAHL and FAMLI databases was conducted to identify studies published between Jan. 1, 1980, and Dec. 31, 1995, concerning the use of guidelines in primary medical care. The keywords used in the search were "clinical guidelines," "primary care," "clinical care," "intervention," "randomized controlled trial" and "effectiveness." STUDY SELECTION: Studies of the use of CPGs were selected if they involved a randomized experimental or quasi-experimental method, concerned primary care, were related to clinical care and examined patient outcomes. Of 91 trials of CPGs identified through the search, 13 met the criteria for inclusion in the critical appraisal. DATA EXTRACTION: The following data were extracted, when possible, from the 13 trials: country and setting, number of physicians, number of patients (and the proportion followed to completion), length of follow-up, study method (including random assignment method), type of intervention, medical condition treated and effect on patient outcomes (including clinical and statistical significance, with confidence intervals). DATA SYNTHESIS: The most common conditions studied were hypertension (7 studies), asthma (2 studies) and cigarette smoking (2 studies). Four of the studies followed nationally developed guidelines, and 9 used locally developed guidelines. Six studies involved computerized or automated reminder systems, whereas the others relied on small-group workshops and education sessions. Only 5 of the 13 trials (38%) produced statistically significant results. CONCLUSION: There is very little evidence that the use of CPGs improves patient outcomes in primary medical care, but most studies published to date have used older guidelines and methods, which may have been insensitive to small changes in outcomes. Research is needed to determine whether the newer, evidence-based CPGs have an effect on patient outcomes.     

Practice patterns of mitochondrial disease physicians in North America. Part 2: treatment,care and management

Mitochondrial medicine is a young subspecialty. Clinicians have limited evidence-based guidelines on which to formulate clinical decisions regarding diagnosis, treatment and management for patients with mitochondrial disorders. Mitochondrial medicine specialists have cobbled together an informal set of rules and paradigms for preventive care and management based in part on anecdotal experience. The Mitochondrial Medicine Society (MMS) assessed the current state of clinical practice including diagnosis, preventive care and treatment, as provided by various mitochondrial disease providers in North America. In this second of two reports, we present data related to clinical practice that highlight the challenges clinicians face in the routine care of patients with established mitochondrial disease. Concerning variability in treatment and preventative care approaches were noted. We hope that sharing this information will be a first step toward formulating a set of consensus criteria and establishing standards of care.     

Die Effektivität psychologischer Behandlungsansätze zur Verbesserung der Stoffwechselkontrolle bei Patienten mit Diabetes mellitus

Various reviews have highlighted that despite an increased awareness that psychological care is needed to help optimize diabetes self care, there are difficulties in interpreting the current evidence and translating it into the clinical setting but there seems to be most evidence for CBT techniques delivered by experienced therapists and family interventions for children and adolescents. In the coming years, combining qualitative and quantitative research methodologies should help to refine the techniques, identify what works for whom and for which outcome(s).     

Disseminating the best available evidence: New challenges in public reporting of health care

As a direct benefit of the Health Care Reform Act (2010), concerted effort has been deployed to define and characterize the process by which the best available evidence for diagnosis or treatment intervention prognosis can be obtained. The science of research synthesis in health care has established the systematic research protocol by which randomized clinical trials and other clinical studies must be reviewed and compared for the level and quality of the evidence presented, as well as the consensus of the best available evidence synthesized and shared. This process of systematic review yields a reliable and valid approach in comparing different interventions and strategies to prevent, diagnose, treat and monitor health conditions in terms of efficacy, and or of effectiveness. The resulting bioinformation outcome of comparative effectiveness and efficacy research review of the available clinical data is expressed as a consensus of the best available evidence, which finds its way in evidence-based clinical practice guidelines, standards of care and eventually, in policies: hence, the acronym CEERAP (comparative effectiveness and efficacy review and policy). The methodological and the procedural criteria that determine and regulate the public reporting dissemination of this sort of bioinformation, and the extent of benefit to the patient's health literacy, which have remained a bit more elusive to this date, are investigated and discussed in this paper.     

Guidelines for the Management of Helicobacter pylori Infection in Japan: 2009 Revised Edition

Background:  Over the past few years, the profile of Helicobacter pylori infection has changed in Japan. In particular, the relationship between H. pylori and gastric cancer has been demonstrated more clearly. Accordingly, the committee of the Japanese Society for Helicobacter Research has revised the guidelines for diagnosis and treatment of H. pylori infection in Japan.
Materials and Methods:  Four meetings of guidelines preparation committee were held from July 2007 to December 2008. In the new guidelines, recommendations for treatment have been classified into five grades according to the Minds Recommendation Grades, while the level of evidence has been classified into six grades. The Japanese national health insurance system was not taken into consideration when preparing these guidelines.
Results:  Helicobacter pylori eradication therapy achieved a Grade A recommendation, being useful for the treatment of gastric or duodenal ulcer, for the treatment and prevention of H. pylori -associated diseases such as gastric cancer, and for inhibiting the spread of H. pylori infection. Levels of evidence were determined for each disease associated with H. pylori infection. For the diagnosis of H. pylori infection, measurement of H. pylori antigen in the feces was added to the tests not requiring biopsy. One week of proton-pump inhibitor-based triple therapy (including amoxicillin and metronidazole) was recommended as second-line therapy after failure of first-line eradication therapy.
Conclusion:  The revised Japanese guidelines for H. pylori are based on scientific evidence and avoid the administrative restraints that applied to earlier versions .     

Designing and reporting case series in plastic surgery

The case series is the most prevalent type of clinical research in the plastic surgery literature. However, this is a lower level study design in the hierarchy of evidence. The case series is nevertheless a useful hypothesis generator for future studies. These in turn can be tested with more robust study designs such as the randomized controlled trial. Because the case series remains the most common study design used to communicate our new innovations, there is a need to improve its reporting so that readers will know why the study was undertaken, what the results were, and how the results affect patient care. The authors provide a guide to help future investigators improve the conduct and the reporting of their case series.     

Physicians' participation in establishing criteria for hypertension management in the office: will patient outcomes be improved?

We designed this study to determine whether an intensive 1-day educational workshop involving family physicians in establishing essential criteria for hypertension management would significantly affect the short-term outcomes of hypertensive patients in their practices. Forty randomly selected physicians were separated into three groups: those who would be involved in establishing the criteria (15), those who would receive the criteria by mail (15) and those who would act as controls and not be aware of the criteria (10). We found no significant difference between the three groups in the number of hypertensive patients whose condition remained uncontrolled after the intervention. We conclude that physicians'' participation in the establishment of standards of care for conditions such as hypertension or their awareness of such standards does not independently result in significantly better patient outcomes. Consequently, we recommend that physicians and health care planners concerned with improving outcomes not rely on any single intervention strategy when planning change.     

Medical practice guidelines: lessons from the United States.

Clinical guidelines, or protocols, have been devised by many different groups, often with differing aims. Some aim to reduce variations in care by using guidelines, while others seek to improve outcomes. Guidelines have long been used in the United States to try to control the behaviour of the medical profession--and the cost of health care. The "effectiveness initiative," run by the Agency for Health Care Policy and Research spawned much activity among other groups, including the American Medical Association and the American College of Physicians. The experience of the Americans in analysing data to gauge effectiveness and then in disseminating good practice may help British moves in this direction. In particular, it is often hard to get guidelines adopted in practice; doctors have to be exposed to the same message in different forms. Also guidelines must not be unrealistic: those devised by senior doctors away from the realities of day to day practice are likely to fail.     

American Association of Clinical Endocrinologists/American College of Endocrinology Clinical Practice Guidelines for the Diagnosis and Treatment of Postmenopausal Osteoporosis— 2020 Update Executive Summary

Objective: The development of these guidelines is sponsored by the American Association of Clinical Endocrinologists (AACE) Board of Directors and American College of Endocrinology (ACE) Board of Trustees and adheres with published AACE protocols for the standardized production of clinical practice guidelines (CPGs).Methods: Recommendations are based on diligent reviews of the clinical evidence with transparent incorporation of subjective factors, according to established AACE/ACE guidelines for guidelines protocols.Results: The Executive Summary of this 2020 updated guideline contains 52 recommendations: 21 Grade A (40%), 24 Grade B (46%), 7 Grade C (14%), and no Grade D (0%). These detailed, evidence-based recommendations allow for nuance-based clinical decision-making that addresses multiple aspects of real-world care of patients. The evidence base presented in the subsequent Appendix provides relevant supporting information for the Executive Summary recommendations. This update contains 368 citations: 123 (33.5%) evidence level (EL) 1 (highest), 132 (36%) EL 2 (intermediate), 20 (5.5%) EL 3 (weak), and 93 (25%) EL 4 (lowest). New or updated topics in this CPG include: clarification of the diagnosis of osteoporosis, stratification of the patient according to high-risk and very-high-risk features, a new dual-action therapy option, and transitions from therapeutic options.Conclusion: This guideline is a practical tool for endocrinologists, physicians in general, regulatory bodies, health-related organizations, and interested laypersons regarding the diagnosis, evaluation, and treatment of post-menopausal osteoporosis.     

Clinical Audit of COPD Patients Requiring Hospital Admissions in Spain: AUDIPOC Study

BACKGROUNDS: AUDIPOC is a nationwide clinical audit that describes the characteristics, interventions and outcomes of patients admitted to Spanish hospitals because of an exacerbation of chronic obstructive pulmonary disease (ECOPD), assessing the compliance of these parameters with current international guidelines. The present study describes hospital resources, hospital factors related to case recruitment variability, patients' characteristics, and adherence to guidelines. METHODOLOGY/PRINCIPAL FINDINGS: An organisational database was completed by all participant hospitals recording resources and organisation. Over an 8-week period 11,564 consecutive ECOPD admissions to 129 Spanish hospitals covering 70% of the Spanish population were prospectively identified. At hospital discharge, 5,178 patients (45% of eligible) were finally included, and thus constituted the audited population. Audited patients were reassessed 90 days after admission for survival and readmission rates. A wide variability was observed in relation to most variables, hospital adherence to guidelines, and readmissions and death. Median inpatient mortality was 5% (across-hospital range 0-35%). Among discharged patients, 37% required readmission (0-62%) and 6.5% died (0-35%). The overall mortality rate was 11.6% (0-50%). Hospital size and complexity and aspects related to hospital COPD awareness were significantly associated with case recruitment. Clinical management most often complied with diagnosis and treatment recommendations but rarely (<50%) addressed guidance on healthy life-styles. CONCLUSIONS/SIGNIFICANCE: The AUDIPOC study highlights the large across-hospital variability in resources and organization of hospitals, patient characteristics, process of care, and outcomes. The study also identifies resources and organizational characteristics associated with the admission of COPD cases, as well as aspects of daily clinical care amenable to improvement.     

General practitioner's perceptions of the route to evidence based medicine: a questionnaire survey.

OBJECTIVES: To determine the attitude of general practitioners towards evidence based medicine and their related educational needs. DESIGN: A questionnaire study of general practitioners. SETTING: General practice in the former Wessex region, England. SUBJECTS: Randomly selected sample of 25% of all general practitioners (452), of whom 302 replied. MAIN OUTCOME MEASURES: Respondents'' attitude towards evidence based medicine, ability to access and interpret evidence, perceived barriers to practising evidence based medicine, and best method of moving from opinion based to evidence based medicine. RESULTS: Respondents mainly welcomed evidence based medicine and agreed that its practice improves patient care. They had a low level of awareness of extracting journals, review publications, and databases (only 40% knew of the Cochrane Database of Systematic Reviews), and, even if aware, many did not use them. In their surgeries 20% had access to bibliographic databases and 17% to the world wide web. Most had some understanding of the technical terms used. The major perceived barrier to practising evidence based medicine was lack of personal time. Respondents thought the most appropriate way to move towards evidence based general practice was by using evidence based guidelines or proposals developed by colleagues. CONCLUSION: Promoting and improving access to summaries of evidence, rather than teaching all general practitioners literature searching and critical appraisal, would be the more appropriate method of encouraging evidence based general practice. General practitioners who are skilled in accessing and interpreting evidence should be encouraged to develop local evidence based guidelines and advice.     

Life- and person-centred help in Mecklenburg-Western Pomerania, Germany (DelpHi): study protocol for a randomised controlled trial

ABSTRACT: BACKGROUND: The provision of appropriate medical and nursing care for people with dementia is a major challenge for the healthcare system in Germany. New models of healthcare provision need to be developed, tested and implemented on the population level. Trials in which collaborative care for dementia in the primary care setting were studied have demonstrated its effectiveness. These studies have been conducted in different healthcare systems, however, so it is unclear whether these results extend to the specific context of the German healthcare system. The objective of this population-based intervention trial in the primary care setting is to test the efficacy and efficiency of implementing a subsidiary support system on a population level for persons with dementia who live at home. Methods and study design The study was designed to assemble a general physician-based epidemiological cohort of people above the age of 70 who live at home (DelpHi cohort). These people are screened for eligibility to participate in a trial of dementia care management (DelpHi trial). The trial is a cluster-randomised, controlled intervention trial with two arms (intervention and control) designed to test the efficacy and efficiency of implementing a subsidiary support system for persons with dementia who live at home. This subsidiary support system is initiated and coordinated by a dementia care manager: a nurse with dementia-specific qualifications who delivers the intervention according to a systematic, detailed protocol. The primary outcome is quality of life and healthcare for patients with dementia and their caregivers. This is a multidimensional outcome with a focus on four dimensions: (1) quality of life, (2) caregiver burden, (3) behavioural and psychological symptoms of dementia and (4) pharmacotherapy with an antidementia drug and prevention or suspension of potentially inappropriate medication. Secondary outcomes include the assessment of dementia syndromes, activities of daily living, social support health status, utilisation of health care resources and medication. DISCUSSION: The results will provide evidence for specific needs in ambulatory care for persons with dementia and will show effective ways to meet those needs. Qualification requirements will be evaluated, and the results will help to modify existing guidelines and treatment paths. Trial registration NCT01401582.     

Contemporary practice patterns in the management of newly diagnosed hypertension

OBJECTIVE: To determine what proportion of patients with hypertension are managed in accordance with guidelines established by the Canadian Hypertension Society. DESIGN: Retrospective medical record review. SETTING: Outpatients seen in primary care offices and internal medicine referral clinics in Edmonton. PATIENTS: All 969 adults who presented with a new diagnosis of essential hypertension from Sept. 1, 1993, to Dec. 31, 1995. OUTCOME MEASURES: Initial laboratory tests performed, advice concerning nonpharmacologic treatment given, antihypertensive drugs prescribed and any contraindications to thiazide diuretics or beta-adrenergic blocking agents documented. RESULTS: The mean age of the 969 patients in the sample was 52.5 years; 129 (13%) of the patients were older than 70 years of age; and 500 (52%) were women. Most of the patients (704, 73%) had mild or moderate diastolic hypertension. In the 617 patients who underwent laboratory tests related to hypertension, the creatinine level was determined in 466 (76%), the cholesterol level in 372 (60%), a urinalysis was conducted in 378 (61%), the serum potassium level was checked in 343 (56%), the sodium level in 323 (52%) and an electrocardiogram was performed in 303 (49%). Liver function tests, which are not recommended in the guidelines, were performed in 338 patients (55%). Although there were differences in prescribing among physicians in the 711 patients given first-line therapy, most (238, 34%) were prescribed angiotensin-converting-enzyme (ACE) inhibitors. Lifestyle modification, without drug therapy, was suggested for 180 (25%) of the patients. Although the guidelines recommend their use for first-line drug therapy, only 82 patients (12%) were given beta-adrenergic blocking agents and only 75 (11%) were given thiazide diuretics. Of the patients who were prescribed an antihypertensive other than a thiazide or beta-adrenergic blocking agent as first-line drug therapy, only 161 (43%) had a documented contraindication to thiazides or beta-adrenergic blocking agents. CONCLUSIONS: There is variation in the contemporary care of patients with hypertension. Further studies are required to determine the reasons underlying physicians'' noncompliance with the evidence-based guidelines established by the Canadian Hypertension Society.     

The impact of adherence to screening guidelines and of diabetes clinics referral on morbidity and mortality in diabetes

Despite the heightened awareness of diabetes as a major health problem, evidence on the impact of assistance and organizational factors, as well as of adherence to recommended care guidelines, on morbidity and mortality in diabetes is scanty. We identified diabetic residents in Torino, Italy, as of 1st January 2002, using multiple independent data sources. We collected data on several laboratory tests and specialist medical examinations to compare primary versus specialty care management of diabetes and the fulfillment of a quality-of-care indicator based on existing screening guidelines (GCI). Then, we performed regression analyses to identify associations of these factors with mortality and cardiovascular morbidity over a 4 year-follow-up. Patients with the lowest degree of quality of care (i.e. only cared for by primary care and with no fulfillment of GCI) had worse RRs for all-cause (1.72 [95% CI 1.57-1.89]), cardiovascular (1.74 [95% CI 1.50-2.01]) and cancer (1.35 [95% CI 1.14-1.61]) mortality, compared with those with the highest quality of care. They also showed increased RRs for incidence of major cardiovascular events up to 2.03 (95% CI 1.26-3.28) for lower extremity amputations. Receiving specialist care itself increased survival, but was far more effective when combined with the fulfillment of GCI. Throughout the whole set of analysis, implementation of guidelines emerged as a strong modifier of prognosis. We conclude that management of diabetic patients with a pathway based on both primary and specialist care is associated with a favorable impact on all-cause mortality and CV incidence, provided that guidelines are implemented.