Circulating pre-treatment T-cell receptor repertoire as a predictive biomarker in advanced or metastatic non-small-cell lung cancer patients treated with pembrolizumab alone or in combination with chemotherapy.

BACKGROUND: The circulating T-cell receptor (TCR) repertoire is a dynamic representation of overall immune responses in an individual. MATERIALS AND METHODS: We prospectively collected baseline blood from patients treated with first-line pembrolizumab monotherapy or in combination with chemotherapy. TCR repertoire metrics were correlated with clinical benefit rate (CBR), progression-free survival (PFS), overall survival (OS) and immune-related adverse events (irAEs). We built a logistic regression classifier by fitting all four TCR-ß repertoire metrics to the immune checkpoint inhibitor (ICI) CBR data. In the subsequent receiver operating characteristic (ROC) analysis of the resulting logistic regression model probabilities, the best cut-off value was selected to maximise sensitivity to predict CBR to ICI. RESULTS: We observed an association between reduced number of unique clones and CBR among patients treated with pembrolizumab monotherapy (cohort 1) [risk ratio = 2.86, 95% confidence interval (CI) 1.04-8.73, P = 0.039]. For patients treated with pembrolizumab plus chemotherapy (cohort 2), increased number of unique clones [hazard ratio (HR) = 2.96, 95% CI 1.28-6.88, P = 0.012] and Shannon diversity (HR = 2.73, 95% CI 1.08-6.87, P = 0.033), and reduced evenness (HR = 0.43, 95% CI 0.21-0.90, P = 0.025) and convergence (HR = 0.41, 95% CI 0.19-0.90, P = 0.027) were associated with improved PFS, while only an increased number of unique clones (HR = 4.62, 95% CI 1.52-14.02, P = 0.007) were associated with improved OS. Logistic regression models combining the TCR repertoire metrics improved the prediction of CBR (cohorts 1 and 2) and were strongly associated with PFS (cohort 1, HR = 0.38, 95% CI 0.19-0.78, P = 0.009) and OS (cohort 2, HR = 0.20, 95% CI 0.05-0.76, P < 0.0001). Reduced TCR conversion was associated with increased frequency of irAEs needing systemic steroid treatment. CONCLUSION: Combined pre-treatment circulating TCR metrics might serve as a predictive biomarker for clinical outcomes among patients with advanced non-small-cell lung cancer treated with pembrolizumab alone or in combination with chemotherapy.

Markers of circulating tumour cells in the peripheral blood of patients with melanoma correlate with disease recurrence and progression.

BACKGROUND: Multimarker quantitative real-time polymerase chain reaction (qRT-PCR) represents an effective method for detecting circulating tumour cells in the peripheral blood of patients with melanoma. OBJECTIVES: To investigate whether the phenotype of circulating melanoma cells represents a useful indicator of disease stage, recurrence and treatment efficacy. METHODS: Peripheral blood was collected from 230 patients with melanoma and 152 healthy controls over a period of 3years and 9months. Clinical data and blood samples were collected from patients with primary melanoma (early stages, 0-II, n=154) and metastatic melanoma (late stages, III-IV, n=76). Each specimen was examined by qRT-PCR analysis for the expression of five markers: MLANA, ABCB5, TGFß2, PAX3d and MCAM. RESULTS: In total, 212 of the patients with melanoma (92%) expressed markers in their peripheral blood. Two markers, MLANA and ABCB5, had the greatest prognostic value, and were identified as statistically significant among patients who experienced disease recurrence within our study period, being expressed in 45% (MLANA) and 49% (ABCB5) of patients with recurrence (P=0·001 and P=0·031, respectively). For patients administered nonsurgical treatments, MCAM expression correlated with poor treatment outcome. CONCLUSIONS: Circulating tumour cells were detectable at all stages of disease and long after surgical treatment, even when patients were considered disease free. Specifically, expression of ABCB5 and MLANA had significant prognostic value in inferring disease recurrence, while MCAM expression was associated with poor patient outcome after treatment, confirming multimarker qRT-PCR as a potential technique for monitoring disease status.

A community based, patient-centred, longitudinal medical curriculum.

The School of Rural Health is an initiative of the Australian Commonwealth Government, the University of New South Wales, Australia, and the Greater Murray Area Health Service. The school was established in February 2000 to facilitate the recruitment of doctors to and their retention in rural areas. The school is responsible for providing an education program for half of the three-year clinical component of the six-year undergraduate course. This article outlines the educational philosophies and methodologies employed in the development of a community-based, patient-centred, longitudinal approach to medical education. Although developed for and delivered in a rural setting, the curriculum could easily be adapted for implementation in an urban setting. The article presents a synopsis of experiences during the initial implementation of the curriculum, and it provides recommendations for future developments.

Randomized controlled trial of a computer strategy to increase general practitioner preventive care.

BACKGROUND: Previous interventions targeting primary care practitioners with the aim of increasing preventive care delivery have demonstrated limited effectiveness. The primary aim of this study was to assess the effectiveness of a computerized continuing medical education program to increase rates of three screening behaviors (cholesterol, blood pressure, and cervical screening) and to identify three risk behaviors (smoking, alcohol consumption, benzodiazepine use) in general practice. METHODS: Nineteen general practitioners were randomly allocated to intervention or control conditions. Those given the intervention received a computerized feedback system. The intervention was delivered using a touch-screen computer located in the surgery waiting area. The preventive behaviors of interest were patient smoking, alcohol use, benzodiazepine use, and blood pressure, cholesterol and cervical screening using the Papanicolou test. Differences in performance by group in each of the outcomes was measured at baseline and 3-month follow-up. Logistic regression analyses with generalized estimating equations were conducted as the main analyses. RESULT: At 3-month follow-up, statistically significant differences were evident in the following outcome measures: accurate classification of benzodiazepine users (z = 2.8540, P < 0.05); accurate classification of non-benzodiazepine users (z = 2.7339, P < 0.05); accurate classification of hazardous or harmful alcohol drinkers (z = 2.3079, P < 0.02); blood pressure screening (z = 3.4136, P < 0.001); and cholesterol screening (z = 6.6313, P < 0.001). CONCLUSION: A computerized system of performance-specific feedback was effective at increasing some preventive care services in general practice.

General practitioner screening for melanoma: sensitivity, specificity, and effect of training.

OBJECTIVE: To measure the performance of trained and untrained general practitioners (GPs) in screening men and women aged 50 or more for melanomas. METHODS: GPs trained in melanoma diagnosis, untrained GPs, and skin cancer specialists examined groups of volunteers, each of which included a small number of subjects with prediagnosed suspicious pigmented lesions (SPLs) that were subsequently excised for histopathological examination. RESULTS: Trained and untrained GPs achieved mean sensitivities of 0.73 and 0.71, and mean predictive values of 0.40 and 0.37, respectively, for the detection of prediagnosed SPLs. When the SPLs had been excised and examined histopathologically, reanalysis showed mean sensitivities of 0.98 and 0.95, mean specificities of 0.52 and 0.49, and mean positive predictive values of 0.24 and 0.22 for the detection of subjects with melanomas by trained and untrained GPs respectively. Trained GPs were significantly better than untrained GPs at diagnosing as melanomas SPLs that subsequently proved to be melanomas (p = 0.04). CONCLUSIONS: GPs in this study achieved high sensitivities in screening older Australian men and women for melanomas, but at the cost of low specificities and positive predictive values. Training in melanoma diagnosis had no significant effect on sensitivity, specificity, and positive predictive value for screening. Data from the study were tested in a model of population screening for melanomas, and costs per life year saved for men aged 50-70 ranged from $A11,852 to $A40,259 depending upon the screening interval and whether the GPs excised the SPLs diagnosed, or referred all patients to skin cancer specialists; this would be as cost effective as cervical cancer screening.

Understanding our patients. An anthropological approach.

OBJECTIVE: To provide an accurate description of the views of a suburban population on health, disease and its causes and the provision of medical and other forms of care. A specific purpose of this paper is to draw attention to the relevance of this research methodology and its similarity to general practice. METHOD: An ethnographic study. A discrete Australian coastal suburb with a broad socio-demographic mix. RESULTS: The health beliefs of the population and their views on the delivery of care are briefly summarised. A fuller report is available from the General Practice Evaluation Program--Grant No. 275. CONCLUSIONS: The application of ethnographic methods of Australian suburbia provides new, valid and reliable information which is needed if the health messages and care provided to people are to be relevant.

An evaluation of the effectiveness of a consultation-liaison psychiatry service in general practice.

OBJECTIVE: This study evaluated the 6-month outcome of patients referred by their general practitioner (GP) to a consultation-liaison (C-L) psychiatry service provided to eight group general practices. METHOD: Over a 12-month period, there were 307 referrals to the C-L psychiatry service of whom 86 consented to take part in an outcome study. Two different control groups were examined comprising patients seen by the same GPs but not referred to the C-L service, who were matched with the C-L referrals on the basis of either demographic characteristics (n = 86) or initial symptomatology (n = 59). Clinical interviews were conducted at recruitment to the outcome study using the Composite International Diagnostic Interview (CIDI), while postal questionnaires were used at both the initial and 6-month assessments. RESULTS: Data reported include DSM-III-R clinical audit and CIDI diagnoses, changes in current symptomatology (SCL-90-R) and changes in global ratings of physical health, emotional health, social relationships and ability to perform everyday duties. Consultation-liaison referrals without symptom-matched controls (n = 27), being patients with higher levels of symptoms initially, were more likely to be referred to other psychiatric services for treatment. They also showed more marked improvement over time on the selected outcome measures. However, there were no significant differences in the patterns of change over time between symptom-matched C-L referrals and their non-referred controls. CONCLUSIONS: The findings from the 6-month outcome study raise doubts about the overall benefit of the current C-L service relative to usual GP care. Improving the quality of psychiatric care in general practice is likely to require a range of interrelated strategies, including C-L psychiatry services, GP education and well-functioning links with public mental health services.

Consultation-liaison psychiatry in general practice.

OBJECTIVE: This paper describes the characteristics of 303 consecutive referrals, over a 12-month period, to a consultation-liaison (C-L) psychiatry service provided to eight group general practices in Newcastle, Australia. METHOD: A purpose designed service audit form was used throughout the evaluation period to collect information about demographic characteristics, reasons for referral, service contacts, psychiatric diagnoses and clinical management. In addition, patients were invited to participate in a separate, prospective outcome evaluation study, which involved structured interviews and questionnaires. RESULTS: The most common reasons for referral were: depression (33%); anxiety (12%); diagnostic assessment (9%); and impaired relationships (8%). The most common psychiatric diagnoses were: mood disorders (29%); mild, transient conditions (29%); anxiety (14%); and substance abuse disorders (12%). Following the psychiatric consultation(s), GPs were actively involved in patients' treatment in 53% of cases. However, there was a higher than expected rate of referral (44%) to another mental health agency. Selected comparisons are also reported between patients referred to the C-L service (n = 303) and a sample of non-referred GP attenders (n = 535). CONCLUSIONS: As expected, the diagnostic profiles of patients attending the C-L service differed in several respects from those using similar services in general hospitals. There were comparatively low rates of organic brain syndromes, suicide risk evaluations, and problems of differential diagnosis of somatic symptoms. Greater emphasis needs to be placed on more formal psychiatric education for GPs, on ways of screening out from the referral process those patients with mild, transient conditions who do not require specialist expertise, and on the development of strategies to help GPs manage such conditions.

Seeking solutions for mental health problems in general practice.

Mental health counsellors could provide one component of an integrated solution to the structural problems now inherent in the primary care of patients with mental health problems. Further training of general practitioners in interview and counselling skills is also essential.

A study of respiratory infections in a healthy adult population during the 1987 Australian winter.

During the 1987 Australian winter, respiratory illness patterns were studied in a population of 454 healthy adults, aged 18-59, over a period of 45 days. These patterns were matched with data obtained from laboratory diagnoses for respiratory viruses, Mycoplasma pneumoniae and bacteria. Influenza B/1/86 was by far the most prevalent pathogen but other viruses including influenza A, paramyxoviruses, respiratory syncytial virus and coronavirus OC-43 were also present, either alone or in combination during the sampling period. Overall, 92 males and 101 females experienced one episode, 12 males and 22 females experienced two episodes and four females experienced three episodes. However, there were only 52 instances of viral or M. pneumoniae infections, of which 37 had a defined aetiology, while the remainder were clinically silent. No bacterial pathogens could be detected from throat swabs taken from 15 of 37 volunteers in whom a viral infection was detected, or from 43 of 70 volunteers who did not experience such infections. The study indicates that major deficiencies in our understanding of the aetiology of respiratory viral illness are probably due to methodological problems in obtaining laboratory diagnoses for many respiratory viruses, and that great difficulties exist in establishing an aetiology for respiratory infections based upon clinical symptoms alone.

Detection of alcohol-related problems in general practice.

While primary care has considerable potential as a site for detecting and intervening for alcohol-related problems, few doctors currently identify these problems. The judgments of eight primary care physicians about alcohol-related problems in 371 of their patients were compared with the patients' responses to the Short Michigan Alcoholism Screening Test (SMAST) and the CAGE. The CAGE classified 11.4% of the patients as alcoholics and the SMAST identified 23.9% as probable alcoholics. However, the doctors identified only a small proportion (7.0%) of their patients as having any level of alcohol-related problem. The doctors did not identify 65.0% of CAGE-defined alcoholics and 82.3% of those patients classified by the SMAST as probable alcoholics. The discrepancy between primary care physician's judgments and the SMAST and CAGE may be attributable to the doctor's failure to identify patients with alcohol-related problems. An alternative explanation is that the SMAST and CAGE are inappropriate screening tools for use in Australian primary care. The findings are discussed in terms of the implications for training doctors and for the development of better measures of alcohol-related problems for use within a primary care context.

Early detection of colorectal cancer: a profile of current practice.

This study examines the prevalence of colorectal cancer screening among individuals in the general community. The survey was undertaken as part of a large scale general population survey of health practices and attitudes. A sample of 1090 people aged 40 years and over with no previous history of colorectal cancer or other predisposing condition was interviewed. Only 56% of this group reported that they regularly checked their bowel movements, the toilet bowl, or the toilet paper for signs of rectal bleeding. Only 13% could recall a doctor ever advising them to check for rectal bleeding; and 21% could recall a doctor asking them if they had ever noticed blood in their bowel movements. More involved practitioner-based procedures, such as digital rectal examination, fecal occult blood testing, endoscopy, and barium enema, were reported by only a minority of participants. Analysis of screening rates in the 9.3% of people who reported a family history of colorectal cancer revealed that this higher risk group was no more likely to be screened than those at average risk.

Training medical practitioners in information transfer skills: the new challenge.

Traditionally, undergraduate medical education has concentrated on teaching students how to gather information or take medical histories from their patients. However, research increasingly indicates that there is a need for medical practitioners to improve their skills in information transfer in a way which will increase the probability that patients are active collaborators in their treatment. Consequently, Newcastle Medical School has sought to develop training packages for medical students in information transfer skills. This paper describes the resulting training programme with particular emphasis on the areas selected for training, the methods by which students are taught, the necessary interactional skills and the assessment procedures which are applied.