Predictive Value of Clinical Judgment of Tumour Progression in Phase II Trials

Background

The diagnosis of tumour progression or progressive disease (PD) is a key element for designing and interpreting contemporary phase II trials. In some cases, PD is stated by the physician and is not formally confirmed by imaging.

Purpose

In this study, we intend to analyze the value of the PD based on clinical judgment and the risk of overestimating the occurrence of PD by clinical judgment.

Methods

We have conducted a single-centre retrospective study to analyse the diagnostic accuracy of this clinical judgment compared to planned imaging including all patients enrolled in our institution in phase II trials investigating systemic treatments for advanced solid tumours between January 2008 and November 2010.

Results

The positive predictive value (PPV) and the specificity of clinical judgment of PD was very high (>90%).

Conclusions

According to this study, the clinical judgment of PD is highly predictive of radiological PD as assessed, for example, by RECIST. Physicians do not overestimate PD occurence. Clinical judgment of PD could be taken into account in the definition of PD.     

Perceived Impeding Factors for Return-to-Work after Long-Term Sickness Absence Due to Major Depressive Disorder: A Concept Mapping Approach

Objective

The purpose of the present study was to explore various stakeholder perspectives regarding factors that impede return-to-work (RTW) after long-term sickness absence related to major depressive disorder (MDD).

Methods

Concept mapping was used to explore employees'', supervisors'' and occupational physicians'' perspectives on these impeding factors.

Results

Nine perceived themes, grouped in three meta-clusters were found that might impede RTW: Person, (personality / coping problems, symptoms of depression and comorbid (health) problems, employee feels misunderstood, and resuming work too soon), Work (troublesome work situation, too little support at work, and too little guidance at work) and Healthcare (insufficient mental healthcare and insufficient care from occupational physician). All stakeholders regarded personality/coping problems and symptoms of depression as the most important impeding theme. In addition, supervisors emphasized the importance of mental healthcare underestimating the importance of the work environment, while occupational physicians stressed the importance of the lack of safety and support in the work environment.

Conclusions

In addition to the reduction of symptoms, more attention is needed on coping with depressive symptoms and personality problems in the work environment support in the work environment and for RTW in mental healthcare, to prevent long term sickness absence.     

Regrets associated with providing healthcare: qualitative study of experiences of hospital-based physicians and nurses

Background

Regret is an unavoidable corollary of clinical practice. Physicians and nurses perform countless clinical decisions and actions, in a context characterised by time pressure, information overload, complexity and uncertainty.

Objective

To explore feelings associated with regretted clinical decisions or interventions of hospital-based physicians and nurses and to examine how these regrets are coped with.

Method

Qualitative study of a volunteer sample of 12 physicians and 13 nurses from Swiss University Hospitals using semi-structured interviews and thematic analysis

Results

All interviewees reported at least one intense regret, which sometimes led to sleep problems, or taking sickness leave. Respondents also reported an accumulation effect of small and large regrets, which sometimes led to quitting one''s unit or choosing another specialty. Respondents used diverse ways of coping with regrets, including changing their practices and seeking support from peers and family but also suppression of thoughts related to the situation and ruminations on the situation. Another coping strategy was acceptance of one''s limits and of medicine''s limits. Physicians reported that they avoided sharing with close colleagues because they felt they could lose their credibility.

Conclusions

Since regret seems related to both positive and negative consequences, it is important to learn more about regret coping among healthcare providers and to determine whether training in coping strategies could help reduce negative consequences such as sleep problems, absenteeism, or turnover.     

A Clinical Index to Predict Progression from Mild Cognitive Impairment to Dementia Due to Alzheimer's Disease

Background

Mild cognitive impairment is often a precursor to dementia due to Alzheimer''s disease, but many patients with mild cognitive impairment never develop dementia. New diagnostic criteria may lead to more patients receiving a diagnosis of mild cognitive impairment.

Objective

To develop a prediction index for the 3-year risk of progression from mild cognitive impairment to dementia relying only on information that can be readily obtained in most clinical settings.

Design and Participants

382 participants diagnosed with amnestic mild cognitive impairment enrolled in the Alzheimer''s Disease Neuroimaging Initiative (ADNI), a multi-site, longitudinal, observational study.

Main Predictors Measures

Demographics, comorbid conditions, caregiver report of participant symptoms and function, and participant performance on individual items from basic neuropsychological scales.

Main Outcome Measure

Progression to probable Alzheimer''s disease.

Key Results

Subjects had a mean (SD) age of 75 (7) years and 43% progressed to probable Alzheimer''s disease within 3 years. Important independent predictors of progression included being female, resisting help, becoming upset when separated from caregiver, difficulty shopping alone, forgetting appointments, number of words recalled from a 10-word list, orientation and difficulty drawing a clock. The final point score could range from 0 to 16 (mean [SD]: 4.2 [2.9]). The optimism-corrected Harrell''s c-statistic was 0.71(95% CI: 0.68–0.75). Fourteen percent of subjects with low risk scores (0–2 points, n = 124) converted to probable Alzheimer''s disease over 3 years, compared to 51% of those with moderate risk scores (3–8 points, n = 223) and 91% of those with high risk scores (9–16 points, n = 35).

Conclusions

An index using factors that can be obtained in most clinical settings can predict progression from amnestic mild cognitive impairment to probable Alzheimer''s disease and may help clinicians differentiate between mild cognitive impairment patients at low vs. high risk of progression.     

Profiling dizziness in older primary care patients: an empirical study

Background

The diagnostic approach to dizzy, older patients is not straightforward as many organ systems can be involved and evidence for diagnostic strategies is lacking. A first differentiation in diagnostic subtypes or profiles may guide the diagnostic process of dizziness and can serve as a classification system in future research. In the literature this has been done, but based on pathophysiological reasoning only.

Objective

To establish a classification of diagnostic profiles of dizziness based on empirical data.

Design

Cross-sectional study.

Participants and Setting

417 consecutive patients of 65 years and older presenting with dizziness to 45 primary care physicians in the Netherlands from July 2006 to January 2008.

Methods

We performed tests, including patient history, and physical and additional examination, previously selected by an international expert panel and based on an earlier systematic review. We used the results of these tests in a principal component analysis for exploration, data-reduction and finally differentiation into diagnostic dizziness profiles.

Results

Demographic data and the results of the tests yielded 221 variables, of which 49 contributed to the classification of dizziness into six diagnostic profiles, that may be named as follows: “frailty”, “psychological”, “cardiovascular”, “presyncope”, “non-specific dizziness” and “ENT”. These explained 32% of the variance.

Conclusions

Empirically identified components classify dizziness into six profiles. This classification takes into account the heterogeneity and multicausality of dizziness and may serve as starting point for research on diagnostic strategies and can be a first step in an evidence based diagnostic approach of dizzy older patients.     

The Potential Biomarker Panels for Identification of Major Depressive Disorder (MDD) Patients with and without Early Life Stress (ELS) by Metabonomic Analysis

Objective

The lack of the disease biomarker to support objective laboratory tests still constitutes a bottleneck in the clinical diagnosis and evaluation of major depressive disorder (MDD) and its subtypes. We used metabonomic techniques to screen the diagnostic biomarker panels from the plasma of MDD patients with and without early life stress (ELS) experience.

Methods

Plasma samples were collected from 25 healthy adults and 46 patients with MDD, including 23 patients with ELS and 23 patients without ELS. Furthermore, gas chromatography/mass spectrometry (GC/MS) coupled with multivariate statistical analysis was used to identify the differences in global plasma metabolites among the 3 groups.

Results

The distinctive metabolic profiles exist either between healthy subjects and MDD patients or between the MDD patients with ELS experience (ELS/MDD patients) and the MDD patients without it (non-ELS/MDD patients), and some diagnostic panels of feature metabolites'' combination have higher predictive potential than the diagnostic panels of differential metabolites.

Conclusions

These findings in this study have high potential of being used as novel laboratory diagnostic tool for MDD patients and it with ELS or not in clinical application.     

Clinical and Organizational Issues in the Management of Surviving Breast and Colorectal Cancer Patients: Attitudes and Feelings of Medical Oncologists

Background

The fast growing demand and the shortage of resources are pushing toward more efficient models of survivorship care delivery. The Associazione Italiana di Oncologia Medica (AIOM) established an interdisciplinary working group with the purpose of promoting organizational improvements at the national level. A survey aimed at assessing attitudes and feelings of oncologists was considered preliminary to further initiatives.

Methods

A 25-item questionnaire, sent to the mailing list of the Society, explored the following issues on the practice of breast and colorectal cancer patients'' follow up: 1) organization; 2) clinical features; 3) feelings about the different meanings of follow-up.

Results

Ninety-one oncologists of 160 institutions (57%) answered to the questionnaire. Although follow up is considered a distinct oncological activity in 68%, a fully shared organization between specialists is not common and communications with Primary Care Physicians are not structured in the majority of the cases. Fifty-five and 30% of the oncologists follow breast and colorectal cancer patients indefinitely. In case of discharge a survivorship care plan is delivered in only 9%. The majority of respondents do not hold a role of follow up in mortality reduction.

Conclusions

Although survivorship care represents a significant part of the oncologists'' workload, an “oncology-centered” model is largely adopted and established care pathways are still incomplete. Survivorship care needs to be put at the center of an educational policy and of a widespread organizational effort, directed at improving appropriateness and quality.     

Screening Primary-Care Patients Forgoing Health Care for Economic Reasons

Background

Growing social inequities have made it important for general practitioners to verify if patients can afford treatment and procedures. Incorporating social conditions into clinical decision-making allows general practitioners to address mismatches between patients'' health-care needs and financial resources.

Objectives

Identify a screening question to, indirectly, rule out patients'' social risk of forgoing health care for economic reasons, and estimate prevalence of forgoing health care and the influence of physicians'' attitudes toward deprivation.

Design

Multicenter cross-sectional survey.

Participants

Forty-seven general practitioners working in the French–speaking part of Switzerland enrolled a random sample of patients attending their private practices.

Main Measures

Patients who had forgone health care were defined as those reporting a household member (including themselves) having forgone treatment for economic reasons during the previous 12 months, through a self-administered questionnaire. Patients were also asked about education and income levels, self-perceived social position, and deprivation levels.

Key Results

Overall, 2,026 patients were included in the analysis; 10.7% (CI95% 9.4–12.1) reported a member of their household to have forgone health care during the 12 previous months. The question “Did you have difficulties paying your household bills during the last 12 months” performed better in identifying patients at risk of forgoing health care than a combination of four objective measures of socio-economic status (gender, age, education level, and income) (R² = 0.184 vs. 0.083). This question effectively ruled out that patients had forgone health care, with a negative predictive value of 96%. Furthermore, for physicians who felt powerless in the face of deprivation, we observed an increase in the odds of patients forgoing health care of 1.5 times.

Conclusion

General practitioners should systematically evaluate the socio-economic status of their patients. Asking patients whether they experience any difficulties in paying their bills is an effective means of identifying patients who might forgo health care.     

Concordance between Patient Self-Reports and Claims Data on Clinical Diagnoses,Medication Use,and Health System Utilization in Taiwan

Purpose

The aim of this study was to evaluate the concordance between claims records in the National Health Insurance Research Database and patient self-reports on clinical diagnoses, medication use, and health system utilization.

Methods

In this study, we used the data of 15,574 participants collected from the 2005 Taiwan National Health Interview Survey. We assessed positive agreement, negative agreement, and Cohen''s kappa statistics to examine the concordance between claims records and patient self-reports.

Results

Kappa values were 0.43, 0.64, and 0.61 for clinical diagnoses, medication use, and health system utilization, respectively. Using a strict algorithm to identify the clinical diagnoses recorded in claims records could improve the negative agreement; however, the effect on positive agreement and kappa was diverse across various conditions.

Conclusion

We found that the overall concordance between claims records in the National Health Insurance Research Database and patient self-reports in the Taiwan National Health Interview Survey was moderate for clinical diagnosis and substantial for both medication use and health system utilization.     

Electromyographic activity of hand muscles in a motor coordination game: effect of incentive scheme and its relation with social capital

Background

A vast body of social and cognitive psychology studies in humans reports evidence that external rewards, typically monetary ones, undermine intrinsic motivation. These findings challenge the standard selfish-rationality assumption at the core of economic reasoning. In the present work we aimed at investigating whether the different modulation of a given monetary reward automatically and unconsciously affects effort and performance of participants involved in a game devoid of visual and verbal interaction and without any perspective-taking activity.

Methodology/Principal Findings

Twelve pairs of participants were submitted to a simple motor coordination game while recording the electromyographic activity of First Dorsal Interosseus (FDI), the muscle mainly involved in the task. EMG data show a clear effect of alternative rewards strategies on subjects'' motor behavior. Moreover, participants'' stock of relevant past social experiences, measured by a specifically designed questionnaire, was significantly correlated with EMG activity, showing that only low social capital subjects responded to monetary incentives consistently with a standard rationality prediction.

Conclusions/Significance

Our findings show that the effect of extrinsic motivations on performance may arise outside social contexts involving complex cognitive processes due to conscious perspective-taking activity. More importantly, the peculiar performance of low social capital individuals, in agreement with standard economic reasoning, adds to the knowledge of the circumstances that makes the crowding out/in of intrinsic motivation likely to occur. This may help in improving the prediction and accuracy of economic models and reconcile this puzzling effect of external incentives with economic theory.     

Use of Electrical Impedance Tomography to Monitor Regional Cerebral Edema during Clinical Dehydration Treatment

Objective

Variations of conductive fluid content in brain tissue (e.g. cerebral edema) change tissue impedance and can potentially be measured by Electrical Impedance Tomography (EIT), an emerging medical imaging technique. The objective of this work is to establish the feasibility of using EIT as an imaging tool for monitoring brain fluid content.

Design

a prospective study.

Setting

In this study EIT was used, for the first time, to monitor variations in cerebral fluid content in a clinical model with patients undergoing clinical dehydration treatment. The EIT system was developed in house and its imaging sensitivity and spatial resolution were evaluated on a saline-filled tank.

Patients

23 patients with brain edema.

Interventions

The patients were continuously imaged by EIT for two hours after initiation of dehydration treatment using 0.5 g/kg intravenous infusion of mannitol for 20 minutes.

Measurement and Main Results

Overall impedance across the brain increased significantly before and after mannitol dehydration treatment (p = 0.0027). Of the all 23 patients, 14 showed high-level impedance increase and maintained this around 4 hours after the dehydration treatment whereas the other 9 also showed great impedance gain during the treatment but it gradually decreased after the treatment. Further analysis of the regions of interest in the EIT images revealed that diseased regions, identified on corresponding CT images, showed significantly less impedance changes than normal regions during the monitoring period, indicating variations in different patients'' responses to such treatment.

Conclusions

EIT shows potential promise as an imaging tool for real-time and non-invasive monitoring of brain edema patients.     

Living with a crucial decision: a qualitative study of parental narratives three years after the loss of their newborn in the NICU

Background

The importance of involving parents in the end-of-life decision-making-process (EOL DMP) for their child in the neonatal intensive care unit (NICU) is recognised by ethical guidelines in numerous countries. However, studies exploring parents'' opinions on the type of involvement report conflicting results. This study sought to explore parents'' experience of the EOL DMP for their child in the NICU.

Methods

The study used a retrospective longitudinal design with a qualitative analysis of parental experience 3 years after the death of their child in four NICUs in France. 53 face-to-face interviews and 80 telephone interviews were conducted with 164 individuals. Semi-structured interviews were conducted to explore how parents perceived their role in the decision process, what they valued about physicians'' attitudes in this situation and whether their long-term emotional well being varied according to their perceived role in the EOL DMP.

Findings

Qualitative analysis identified four types of perceived role in the DMP: shared, medical, informed parental decision, and no decision. Shared DM was the most appreciated by parents. Medical DM was experienced as positive only when it was associated with communication. Informed parental DM was associated with feelings of anxiousness and abandonment. The physicians'' attitudes that were perceived as helpful in the long term were explicit sharing of responsibility, clear expression of staff preferences, and respectful care and language toward the child.

Interpretation

Parents find it valuable to express their opinion in the EOL DMP of their child. Nonetheless, they do need continuous emotional support and an explicit share of the responsibility for the decision. As involvement preferences and associated feelings can vary, parents should be able to decide what role they want to play. However, our study suggests that fully autonomous decisions should be misadvised in these types of tragic choices.     

Clinical use of biomarkers of survival in pulmonary fibrosis

Background

Biologic predictors or biomarkers of survival in pulmonary fibrosis with a worse prognosis, more specifically in idiopathic pulmonary fibrosis would help the clinician in deciding whether or not to treat since treatment carries a potential risk for adverse events. These decisions are made easier if accurate and objective measurements of the patients'' clinical status can predict the risk of progression to death.

Method

A literature review is given on different biomarkers of survival in interstitial lung disease, mainly in IPF, since this disease has the worst prognosis.

Conclusion

Serum biomarkers, and markers measured by medical imaging as HRCT, pertechnegas, DTPA en FDG-PET are not ready for clinical use to predict mortality in different forms of ILD. A baseline FVC, a change of FVC of more than 10%, and change in 6MWD are clinically helpful predictors of survival.     

Clinical utility of diagnostic guidelines and putative biomarkers in lymphangioleiomyomatosis

Background

Lymphangioleiomyomatosis is a rare disease occurring almost exclusively in women. Diagnosis often requires surgical biopsy and the clinical course varies between patients with no predictors of progression. We evaluated recent diagnostic guidelines, clinical features and serum biomarkers as diagnostic and prognostic tools.

Methods

Serum vascular endothelial growth factor-D (VEGF-D), angiotensin converting enzyme (ACE), matrix metalloproteinases (MMP) -2 and -9, clinical phenotype, thoracic and abdominal computerised tomography, lung function and quality of life were examined in a cohort of 58 patients. 32 healthy female controls had serum biomarkers measured.

Results

Serum VEGF-D, ACE and total MMP-2 levels were elevated in patients. VEGF-D was the strongest discriminator between patients and controls (median = 1174 vs. 332 pg/ml p < 0.0001 with an area under the receiver operating characteristic curve of 0.967, 95% CI 0.93-1.01). Application of European Respiratory Society criteria allowed a definite diagnosis without biopsy in 69%. Adding VEGF-D measurement to ERS criteria further reduced the need for biopsy by 10%. VEGF-D was associated with lymphatic involvement (p = 0.017) but not the presence of angiomyolipomas.

Conclusions

Combining ERS criteria and serum VEGF-D reduces the need for lung biopsy in LAM. VEGF-D was associated with lymphatic disease but not lung function.     

Oral Doxycycline Reduces Pterygium Lesions; Results from a Double Blind,Randomized, Placebo Controlled Clinical Trial

Purpose

To determine whether oral doxycycline treatment reduces pterygium lesions.

Design

Double blind, randomized, placebo controlled clinical trial.

Participants

98 adult patients with primary pterygium.

Methods

Patients were randomly assigned to receive 100 mg oral doxycycline twice a day (49 subjects), or placebo (49 subjects), for 30 days. Photographs of the lesion were taken at the time of recruitment and at the end of the treatment. Follow-up sessions were performed 6 and 12 months post-treatment. Statistical analyses for both continuous and categorical variables were applied. p values of less than 0.05 were considered to indicate statistical significance.

Main Outcome Measures

The primary endpoint was the change in lesion size after 30 days of treatment.

Results

The primary endpoint was not met for the whole population but subgroup analysis showed that doxycycline was effective in patients of Caucasian origin while other ethnicities, mostly Hispanic, did not respond to the treatment. Moreover, there was a correlation between age and better response (p = 0.003). Adverse events were uncommon, mild, and in agreement with previous reports on short doxycycline treatments.

Conclusions

Oral doxycycline was superior to placebo for the treatment of primary pterygia in older Caucasian patients. These findings support the use of doxycycline for pterygium treatment in particular populations.

Trial Registration

European Union Clinical Trials Register EudraCT 2008-007178-39     

Autoantibodies and Sjogren’s Syndrome in Multiple Sclerosis,a Reappraisal

Background

Rheumatologic diseases may cause neurologic disorders that mimic multiple sclerosis (MS). A panel of serum autoantibodies is often obtained as part of the evaluation of patients suspected of having MS.

Objectives

To determine, in light of recently revised diagnostic criteria for MS, neuromyelitis optica, and Sjogren’s Syndrome, if testing for autoantibodies in patients with a confirmed diagnosis of MS would reveal a frequency or demonstrate a clinical utility divergent from previous reports or lead to identification of undiagnosed cases of Sjogren’s Syndrome.

Methods

Convenience sample cross-sectional study of MS patients recruited from the OHSU Multiple Sclerosis Center.

Results

Autoantibodies were detected in 38% (35/91) of patients with MS and were not significantly associated with disease characteristics or severity. While four patients had SSA antibodies, none met diagnostic criteria for Sjogren’s Syndrome.

Conclusions

Rheumatologic autoantibodies are frequently found in MS patients and are not associated with disease severity or systemic rheumatologic disease. Our demonstration of the low specificity of these autoantibodies suggests that the diagnostic utility and cost-effectiveness of testing is not supported when there is strong clinical suspicion of MS and low clinical suspicion of rheumatologic disease.     

Performance of Thirteen Clinical Rules to Distinguish Bacterial and Presumed Viral Meningitis in Vietnamese Children

Background and Purpose

Successful outcomes from bacterial meningitis require rapid antibiotic treatment; however, unnecessary treatment of viral meningitis may lead to increased toxicities and expense. Thus, improved diagnostics are required to maximize treatment and minimize side effects and cost. Thirteen clinical decision rules have been reported to identify bacterial from viral meningitis. However, few rules have been tested and compared in a single study, while several rules are yet to be tested by independent researchers or in pediatric populations. Thus, simultaneous test and comparison of these rules are required to enable clinicians to select an optimal diagnostic rule for bacterial meningitis in settings and populations similar to ours.

Methods

A retrospective cross-sectional study was conducted at the Infectious Department of Pediatric Hospital Number 1, Ho Chi Minh City, Vietnam. The performance of the clinical rules was evaluated by area under a receiver operating characteristic curve (ROC-AUC) using the method of DeLong and McNemar test for specificity comparison.

Results

Our study included 129 patients, of whom 80 had bacterial meningitis and 49 had presumed viral meningitis. Spanos''s rule had the highest AUC at 0.938 but was not significantly greater than other rules. No rule provided 100% sensitivity with a specificity higher than 50%. Based on our calculation of theoretical sensitivity and specificity, we suggest that a perfect rule requires at least four independent variables that posses both sensitivity and specificity higher than 85–90%.

Conclusions

No clinical decision rules provided an acceptable specificity (>50%) with 100% sensitivity when applying our data set in children. More studies in Vietnam and developing countries are required to develop and/or validate clinical rules and more very good biomarkers are required to develop such a perfect rule.     

The Influence of Clinical Information in the Histopathologic Diagnosis of Melanocytic Skin Neoplasms

Background

We tested the relevance of clinical information in the histopathologic evaluation of melanocytic skin neoplasm (MSN).

Methods

Histopathologic specimens from 99 clinically atypical MSN were circulated among ten histopathologists; each case had clinical information available in a database with a five-step procedure (no information; age/sex/location; clinical diagnosis; clinical image; dermoscopic image); each step had a histopathologic diagnosis (D1 through D5); each diagnostic step had a level of diagnostic confidence (LDC) ranging from 1 (no diagnostic certainty) to 5 (absolute diagnostic certainty). The comparison of the LDC was employed with an analysis of variance (ANOVA) for repeated measures.

Findings

In D1 (no information), 36/99 cases (36.3%) had unanimous diagnosis; in D5 (full information available), 51/99 cases (51.5%) had unanimous diagnosis (p for difference between proportions <0.001). The observer agreement expressed as kappa increased significantly from D1 to D5. The mean LDC linearly increased for each observer from D1 through D5 (p for linear trend <0.001). On average, each histopathologist changed his initial diagnosis in 7 cases (range: 2–23). Most diagnostic changes were in D2 (age/sex/location).

Interpretation

The histopathologic criteria for the diagnosis of MSN can work as such, but the final histopathologic diagnosis is a clinically-aided interpretation. Clinical data sometimes reverse the initial histopathologic evaluation.