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.

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.

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.

Breast self-examination and breast examination by a health care provider: prevalence and predictors of screening in a randomly selected sample of Australian women.

Professional organizations recommend the practice of monthly breast self-examination (BSE), and examination of the breasts by a health care provider every three years for women up to the age of 40 and annually thereafter. These practices were examined in a randomly selected sample of 1454 women. Only 39% (95% confidence interval [CI], 36%-42%) of the sample reported monthly BSE. Women were more likely to examine their breasts each month if they had found a breast lump, believed they were likely to get breast cancer, were not single, or were frequent users of general practitioners. Only 51% (95% CI, 45%-53%) of women under the age of 40 reported receiving three-yearly breast examinations; of those women aged 40 or more, 31% (CI, 27%-35%) of those with no additional risk factors and 35% (95% CI, 27%-42%) of those with at least one additional risk factor reported annual examinations. Women were more likely to have received a breast examination in the past three years if they had previously had a breast lump, were not single, had reached a higher educational level, were more frequent users of general practitioners, had private health insurance, or were described as other than ill or retired. There was a substantial association between BSE and breast examination by a health care provider with 25% (95% CI, 23%-27%) practising BSE and being screened by a health care provider. Thirty-five per cent (95% CI, 32%-38%) of women were not being screened by either method. The implications of the results for health education campaigns are discussed.

The effectiveness of two smoking cessation programmes for use in general practice: a randomised clinical trial.

OBJECTIVE: To evaluate a structured, behavioural change, smoking cessation intervention designed for use within general practice. DESIGN: Randomised controlled clinical trial. SETTING: General practices in Newcastle, Australia. PATIENTS: 311 Patients identified as smokers by a screening question were enrolled in the study. Of these, 101 were assigned to a structured behavioural change programme, 104 to a simple advice programme adapted from previous research, and 106 to a control group. No significant differences were found between groups for demographic and smoking related variables before the study. INTERVENTIONS: Patients in the simple advice group received a brief statement of advice from the general practitioner as well as three pamphlets; those in the structured intervention group were given strategies which included attitude and behavioural change programmes as well as techniques to aid compliance. The amount of smoking in all groups was assessed by self reports with validation by measurement of salivary cotinine concentrations. MAIN OUTCOME MEASURE: Significant increase in cessation rates. CONCLUSIONS: Significant differences between controls and the structured behavioural change group were found at the one month follow up, but only for self reported abstinence. The simple advice programme did not produce any significant differences over the control group. General practitioner evaluation of the structured programme highlighted difficulties in relation to the duration of the intervention. Overall the structured programme in its present form did not appear to be an effective programme for use within general practice.

General practitioners and the provision of Papanicolaou smear-tests: current practice, knowledge and attitudes.

General practitioners are the main providers of Papanicolaou smear-tests yet, given the current suboptimal rates of cervical screening, it is clear that their full potential as screening providers is not being realized. To date, no information has been available concerning the possible barriers to the provision of Papanicolaou smear-tests by general practitioners. The present study assessed the views of a random sample of NSW general practitioners regarding the value of smear-tests, the most appropriate providers, the recommended screening protocol, and factors that were thought to influence both practitioners' provision and women's utilization of screening. The results indicate a number of changes to the current system which could counter screening barriers such as educational programmes for general practitioners, more female providers and the investigation of alternative services, consensus screening guide-lines, and screening registers and recall systems.

A study of intranasally administered interferon A (rIFN-alpha 2A) for the seasonal prophylaxis of natural viral infections of the upper respiratory tract in healthy volunteers.

The efficacy of interferon A (rIFN-alpha 2A), an Escherichia coli-derived interferon, in the prophylaxis of acute upper respiratory tract infection, was evaluated in a community-based double-blind placebo-controlled study in the Australian winter of 1985. The trial population of 412 healthy volunteers (190 males and 222 females, aged 18-65 years) self-administered 1.5, 3.0 and 6.0 megaunits (MU) of interferon A per day or a placebo, intranasally for 28 days. The period of study coincided with an outbreak of H3N2 influenza A (detected in 35 of the 107 acute specimens) as well as substantial numbers of respiratory syncytial virus and adenovirus infections. Rhinoviruses were isolated from only three specimens. In many cases, subjects had laboratory and clinical evidence of having had more than one respiratory tract infection during the period of the study. Viruses were detected in 54 or 107 acute specimens (49%). No statistically significant differences were noted between the various treatment groups in the incidence of laboratory-proven viral infection (virus isolation and/or antibody response). Analysis of reported symptoms indicated that blood-tinged mucus and nasal stuffiness occurred more frequently with higher doses of interferon. There appeared to be no clinical benefit from the use of interferon A in the amelioration of symptoms.