Assessment of various continual reassessment method models for dose-escalation phase 1 oncology clinical trials: using real clinical data and simulation studies.

BACKGROUND: The continual reassessment method (CRM) identifies the maximum tolerated dose (MTD) more efficiently and identifies the true MTD more frequently compared to standard methods such as the 3 + 3 method. An initial estimate of the dose-toxicity relationship (prior skeleton) is required, and there is limited guidance on how to select this. Previously, we compared the CRM with six different skeletons to the 3 + 3 method by conducting post-hoc analysis on a phase 1 oncology study (AZD3514), each CRM model reduced the number of patients allocated to suboptimal and toxic doses. This manuscript extends this work by assessing the ability of the 3 + 3 method and the CRM with different skeletons in determining the true MTD of various "true" dose-toxicity relationships. METHODS: One thousand studies were simulated for each "true" dose toxicity relationship considered, four were based on clinical trial data (AZD3514, AZD1208, AZD1480, AZD4877), and four were theoretical. The 3 + 3 method and 2-stage extended CRM with six skeletons were applied to identify the MTD, where the true MTD was considered as the largest dose where the probability of experiencing a dose limiting toxicity (DLT) is ≤33%. RESULTS: For every true dose-toxicity relationship, the CRM selected the MTD that matched the true MTD in a higher proportion of studies compared to the 3 + 3 method. The CRM overestimated the MTD in a higher proportion of simulations compared to the 3 + 3 method. The proportion of studies where the correct MTD was selected varied considerably between skeletons. For some true dose-toxicity relationships, some skeletons identified the true MTD in a higher proportion of scenarios compared to the skeleton that matched the true dose-toxicity relationship. CONCLUSION: Through simulation, the CRM generally outperformed the 3 + 3 method for the clinical and theoretical true dose-toxicity relationships. It was observed that accurate estimates of the true skeleton do not always outperform a generic skeleton, therefore the application of wide confidence intervals may enable a generic skeleton to be used. Further work is needed to determine the optimum skeleton.

PATRIOT: A phase I study to assess the tolerability, safety and biological effects of a specific ataxia telangiectasia and Rad3-related (ATR) inhibitor (AZD6738) as a single agent and in combination with palliative radiation therapy in patients with solid tumours.

PATRIOT is a phase I study of the ATR inhibitor, AZD6738, as monotherapy, and in combination with palliative radiotherapy. Here, we describe the protocol for this study, which opened in 2014 and is currently recruiting and comprises dose escalation of both drug and radiotherapy, and expansion cohorts.

Systems Pharmacology Modeling of Prostate-Specific Antigen in Patients With Prostate Cancer Treated With an Androgen Receptor Antagonist and Down-Regulator.

First-in-human (FIH) studies with AZD3514, a selective androgen receptor (AR) down-regulator, showed decreases of >30% in the prostate-specific antigen (PSA) in some patients. A modeling approach was adopted to understand these observations and define the optimum clinical use hypothesis for AZD3514 for clinical testing. Initial empirical modeling showed that only baseline PSA correlated significantly with this biological response, whereas drug concentration did not. To identify the mechanistic cause of this observation, a mechanism-based model was first developed, which described the effects of AZD3514 on AR protein and PSA mRNA levels in LNCaP cells with and without dihydrotestosterone (DHT). Second, the mechanism-based model was linked to a population pharmacokinetic (PK) model; PSA effects of clinical doses were subsequently simulated under different clinical conditions. This model was used to adjust the design of the ongoing clinical FIH study and direct the backup program.

AZD3514, an oral selective androgen receptor down-regulator in patients with castration-resistant prostate cancer - results of two parallel first-in-human phase I studies.

BACKGROUND: AZD3514 is a first-in-class, orally bio-available, androgen-dependent and -independent androgen receptor inhibitor and selective androgen-receptor down-regulator (SARD). METHODS: In study 1 and 2, castration-resistant prostate cancer (CRPC) patients (pts) were initially recruited into a once daily (QD) oral schedule (A). In study 1, pharmacokinetic assessments led to twice daily (BID) dosing (schedule B) to increase exposure. Study 2 explored a once daily schedule. RESULTS: In study 1, 49 pts were treated with escalating doses of AZD3514 (A 35 pts, B 14 pts). Starting doses were 100 mg (A) and 1000 mg (B). The AZD3514 formulation was switched from capsules to tablets at 1000 mg QD. 2000 mg BID was considered non-tolerable due to grade (G) 2 toxicities (nausea [N], vomiting [V]). No adverse events (AEs) met the dose-limiting toxicity (DLT) definition. Thirteen pts received AZD3514 in study 2, with starting doses of 250 mg QD. The most frequent drug-related AEs were N: G1/2 in 55/70 pts (79 %); G3 in 1 pt (1.4 %); & V: G1/2 in 34/70 pts (49 %) & G3 in 1 pt (1.4 %). PSA declines (≥50 %) were documented in 9/70 patients (13 %). Objective soft tissue responses per RECIST1.1 were observed in 4/24 (17 %) pts in study 1. CONCLUSION: AZD3514 has moderate anti-tumour activity in pts with advanced CRPC but with significant levels of nausea and vomiting. However, anti-tumour activity as judged by significant PSA declines, objective responses and durable disease stabilisations, provides the rationale for future development of SARD compounds.

Assessment of diurnal changes and confounding factors that affect circulating cell death biomarker levels: a short communication.

There is increasing use of circulating cell death biomarkers in patients and clinical trials. Knowledge of the potential noise and confounders in assays are vital for biomarker interpretation. The daily and diurnal variability and effect of menstruation and exercise on nucleosomal DNA (nDNA), total cytokeratin 18 (tK18) and apoptotic specific cytokeratin 18 (cK18) were assessed in 3 cohorts of healthy volunteers; 12 pre-menopausal women to establish the effect of menstruation, 12 men to perform exercise and 12 post-menopausal women. All 36 subjects were evaluated to establish daily and diurnal variability. Estimates of variability were derived in a linear mixed effects model and presented as the back transformed coefficient of variation (%CV). Minimal variation was seen in cK18 (11%CV) and tK18 (11%CV) but higher variability was seen in nDNA (85%CV). K18 results appeared stable throughout the day but a possible peak in nDNA was seen at 15:00. Menstruation had minimal effects but exercise led to immediate short-lived elevations in cell death biomarkers. There is no evidence of significant daily variability in K18 assays. We recommend subjects should not exercise for 6h before blood sampling.

A pilot study to explore circulating tumour cells in pancreatic cancer as a novel biomarker.

BACKGROUND: Obtaining tissue for pancreatic carcinoma diagnosis and biomarker assessment to aid drug development is challenging. Circulating tumour cells (CTCs) may represent a potential biomarker to address these unmet needs. We compared prospectively the utility of two platforms for CTC enumeration and characterisation in pancreatic cancer patients in a pilot exploratory study. PATIENTS AND METHODS: Blood samples were obtained prospectively from 54 consenting patients and analysed by CellSearch and isolation by size of epithelial tumour cells (ISET). CellSearch exploits immunomagnetic capture of CTCs-expressing epithelial markers, whereas ISET is a marker independent, blood filtration device. Circulating tumour cell expression of epithelial and mesenchymal markers was assessed to explore any discrepancy in CTC number between the two platforms. RESULTS: ISET detected CTCs in more patients than CellSearch (93% vs 40%) and in higher numbers (median CTCs/7.5 ml, 9 (range 0-240) vs 0 (range 0-144)). Heterogeneity observed for epithelial cell adhesion molecule, pan-cytokeratin (CK), E-Cadherin, Vimentin and CK 7 expression in CTCs may account for discrepancy in CTC number between platforms. CONCLUSION: ISET detects more CTCs than CellSearch and offers flexible CTC characterisation with potential to investigate CTC biology and develop biomarkers for pancreatic cancer patient management.

Circulating melanoma cells and survival in metastatic melanoma.

A validated assay for the enumeration of circulating melanoma cells (CMCs) may facilitate the development of more effective therapies for metastatic melanoma patients. In this study CD146+ cells were immunomagnetically enriched from 7.5 ml of blood. Isolated cells were fluorescently stained with DAPI, anti-molecular weight melanoma-associated antigen (HMW-MAA), anti-CD45 and CD34 and Ki67. CMCs were identified as CD146+, HMW-MAA+, CD45-, CD34-, Ki67-/+ cells. Eighty-eight percent of spiked SK-MEL28 cells in 7.5 ml blood were recovered. In all 55 healthy donors ≤1 CMCs were detected in 7.5 ml of blood. A retrospective analysis was conducted comparing CMC counts and overall survival in 79 blood samples from 44 melanoma patients. CMCs ranged from 0 to 8,042 per 7.5 ml. Two or more CMCs were detected in 18 (23%) of the patients and 30-100% (mean 84%) of the CMCs expressed the proliferation marker Ki67. Patients with ≥2 CMCs per 7.5 ml of whole blood, as compared with the group with <2 CMCs, had a shorter overall survival (2.0 months vs. 12.1 months, P=0.001).

Long-term effects of anastrozole on bone mineral density: 7-year results from the ATAC trial.

BACKGROUND: This 'Arimidex', Tamoxifen, Alone or in Combination (ATAC) trial sub-study examined the effects of anastrozole and tamoxifen on bone mineral density (BMD) following 5 years of treatment. PATIENTS AND METHODS: Lumbar spine and total hip BMD were assessed at years 6 and 7 in a total of 71 eligible patients. In total, 50 patients had evaluable data. RESULTS: Following anastrozole treatment, the lumbar spine median BMD increased by 2.35% (P=0.04) and 4.02% (P=0.0004) at years 6 and 7, while total hip median BMD increased by 0.71% (P=0.3) and 0.5% (P=0.8). After tamoxifen treatment, lumbar spine median BMD decreased by 0.79% (P=0.2) and 0.30% (P=0.9) at years 6 and 7, while total hip median BMD decreased by 2.09% (P=0.0003) and 2.52% (P=0.0002). Patients with a normal BMD or who were osteopenic at 5 years did not become osteoporotic. CONCLUSIONS: Anastrozole treatment-related bone loss did not continue into the off-treatment follow-up period. The recovery in lumbar spine BMD and absence of further loss at the hip is consistent with the reduction in the annual rate of fracture observed after treatment cessation in the main ATAC trial.

The ATAC adjuvant breast-cancer trial: six-year results of the endometrial subprotocol.

Postmenopausal women with localised, early breast cancer (n = 285) were enrolled in a prospective subprotocol of the 'arimidex, tamoxifen, alone or in combination' (ATAC) trial to assess gynaecological abnormalities arising during treatment with anastrozole (1 mg/day) or tamoxifen (20 mg/day). After 6 years' follow-up, there appeared to be non-significantly fewer endometrial abnormalities with anastrozole than with tamoxifen (12.4% vs 20.2%, odds ratio 0.52; 95% confidence intervals 0.20, 1.32; p = 0.17). The time to first endometrial abnormality was non-significantly longer for patients receiving anastrozole compared with tamoxifen (hazard ratio 0.57; 95% confidence intervals 0.26, 1.22; p = 0.15), with most abnormalities occurring within the first year of treatment. Fewer patients treated with anastrozole appeared to require medical intervention for endometrial abnormalities, compared with patients on tamoxifen. This study showed that there was no significant difference in endometrial pathology between anastrozole and tamoxifen treatment groups.

Current status and future potential of somatic mutation testing from circulating free DNA in patients with solid tumours.

Genetic alterations can determine the natural history of cancer and its treatment response. With further advances in DNA sequencing technology, multiple novel genetic alterations will be discovered which could be exploited as prognostic, predictive and pharmacodynamic biomarkers in the development and use of cancer therapeutics. As such, the importance in clinical practice of efficient and robust somatic mutation testing in solid tumours cannot be overemphasized in the current era of personalized medicine. However, significant challenges remain regarding the testing of genetic biomarkers in clinical practice. Reliance on archived formalin fixed, paraffin embedded tumour, obtained from diagnostic biopsies, for testing somatic genetic alterations could restrict the scientific community in asking relevant questions about a patient's cancer biology. Problems inherent with using formalin fixed, archival tissue are well recognized and difficult to resolve. It could be argued that to achieve rapid and efficient incorporation of genetic biomarkers into clinical practice, somatic mutation testing in cancer patients should be simpler, less invasive using a readily available clinical sample, whilst maintaining robustness and reproducibility. In this regard, use of circulating free DNA (cfDNA) from plasma or serum as an alternative and/or additional source of DNA to test cancer specific genetic alterations is an attractive proposition. In light of encouraging results from recent studies, this mini review will discuss the current role and future potential of somatic mutation testing from circulating or cell free DNA derived from the blood of patients with solid tumours.

Src inhibitors in early breast cancer: a methodology, feasibility and variability study.

Early clinical trials of anticancer agents may be enriched by robust biomarkers of activity. Surrogate measures used in trials of cytotoxic agents, such as tumor size regression, may not be informative when investigating targeted agents that act principally to inhibit invasion or proliferation. This study aimed to determine the validity of invasion-related biomarkers of activity for AZD0530, a potent Src inhibitor currently in clinical development. Focal adhesion kinase (FAK) and paxillin are downstream phosphorylation substrates of Src and mediate tumor cell adhesion and invasiveness. These were therefore selected as biologically relevant markers of Src inhibition. Early breast cancer was chosen as a model as multiple samples can be collected during standard treatment and there is an intervening period in which experimental intervention can be applied. Tumor tissue was collected from diagnostic core biopsies and subsequent surgical tumor excision samples in 29 women with early breast cancer attending a single center. Protein levels were assessed quantitatively by Luminex and qualitatively by immunohistochemistry. AZD0530 inhibited tumor growth in a manner independent of dose and inhibited phosphorylation of FAK and paxillin in a dose-dependent manner in a Calu-6 xenograft model. In the clinical study, agreement of within-visit and also of between-visit measurements was high and the estimated number of patients required to detect a drug effect would be low enough to allow use of these markers as endpoints in future dose selection studies.

A prototypical process for creating evidentiary standards for biomarkers and diagnostics.

A framework for developing evidentiary standards for qualification of biomarkers is a key need identified in the Food and Drug Administration's Critical Path Initiative. This article describes a systematic framework that was developed by Pharmaceutical Research and Manufacturers of America (PhRMA) committees and tested at a workshop in collaboration with the Food and Drug Administration and academia. With some necessary refinements, this could be applied to create an appropriately individualized evidentiary standard for any biomarker purpose.

The ATAC ('Arimidex', Tamoxifen, Alone or in Combination) adjuvant breast cancer trial: first results of the endometrial sub-protocol following 2 years of treatment.

BACKGROUND: Tamoxifen treatment results in a doubling of the risk of endometrial cancer after 1-2 years of treatment and a quadrupling after 5 years. Anastrozole, a third-generation aromatase inhibitor, with superior efficacy to tamoxifen, may also offer tolerability benefits in terms of effects on the endometrium. METHODS AND RESULTS: A sub-protocol of the ATAC trial compared the incidence/type of intrauterine changes following treatment with these agents in a subgroup of patients (n = 285) from the main trial. After 2 years anastrozole treatment, endometrial thickness remained

The ATAC ('Arimidex', Tamoxifen, Alone or in Combination) adjuvant breast cancer trial: baseline endometrial sub-protocol data on the effectiveness of transvaginal ultrasonography and diagnostic hysteroscopy.

BACKGROUND: The 'Arimidex', Tamoxifen, Alone or in Combination (ATAC) trial is a randomized, double-blind trial comparing anastrozole ('Arimidex'), alone or in combination with tamoxifen, relative to tamoxifen alone as 5 year adjuvant treatment for post-menopausal women with early breast cancer. Since tamoxifen is associated with endometrial pathology, the ATAC endometrial sub-protocol was initiated to establish the background prevalence of intrauterine pathology, and to assess prospectively the incidence and nature of intrauterine changes following endocrine therapy. Another aim was to provide data from which advice could be generated on the best endometrium screening method for patients receiving tamoxifen. METHODS: Patients underwent endometrial assessments at entry to the sub-protocol. The baseline investigations comprised transvaginal ultrasound scanning (TVUS), a hysteroscopy and an endometrial biopsy. RESULTS: A total of 285 gynaecologically asymptomatic women from 31 centres in 10 countries entered the endometrial sub-protocol. The mean uterine volume was 47.7 cm3. The median endometrial thickness overall was 3 mm. Twenty-four histologically confirmed, pathological changes were observed. Twenty-three pathologies were confirmed by TVUS, and 21 were identified by hysteroscopy and confirmed by histopathology. Women with or without intrauterine pathology had median endometrial thickness of 5 and 3 mm respectively. CONCLUSIONS: The presence of pathology was associated with increased endometrial thickness. The relative sensitivity and specificity of hysteroscopy and endometrial thickness for the diagnosis of endometrial pathology was comparable to other studies. If screening of the endometrium prior to treatment is appropriate, this study supports the use of an endometrial thickness of 3 mm, as assessed by TVUS, as a threshold for needing further investigation. This study demonstrates that if the endometrial thickness is >3 mm, hysteroscopy and biopsy is the optimal method of detecting intrauterine pathology in women with breast cancer who are about to commence endocrine treatment.

The ATAC adjuvant breast cancer trial in postmenopausal women: baseline endometrial subprotocol data.

OBJECTIVE: The ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial is a randomised, double-blind trial comparing 'Arimidex' (anastrozole), alone or in combination with tamoxifen, relative to tamoxifen alone as a five year adjuvant treatment for postmenopausal women with early breast cancer. Because tamoxifen is associated with endometrial pathology, the ATAC endometrial subprotocol was initiated to establish the background prevalence of pathology, and to assess prospectively the incidence and nature of intrauterine changes before and following endocrine therapy. SETTING: International. POPULATION AND STUDY DESIGN: Two hundred and eighty-five women entered the subprotocol: the mean age was 60 years (range 44-80 years); 113 women (40%) had taken hormone replacement therapy prior to randomisation, and 238 women were parous (84%). The age at onset of the menopause was 32-58 years, with the majority becoming menopausal between 46 and 55 years of age. Two hundred and seventy-two women had a hysteroscopy before they commenced trial medication. Hysteroscopy was performed successfully in 265 women. In six women, failure of hysteroscopy at baseline led to withdrawal from the study. Three of the women who withdrew had a pipelle biopsy taken. Therefore, the total number of endometrial biopsies at baseline was 268. MAIN OUTCOME MEASURES: To assess the demographic characteristics of women entering the endometrial subprotocol and their hysteroscopic and histological findings before commencing trial medication. RESULTS: At hysteroscopy, there was a diagnosis of endometrial polyps in 34 women (13%), fibroids in 16 women (6%) and one case of suspicious endometrium, which was confirmed as a polyp on histology. Only 21 of the 34 polyps seen hysteroscopically were proven histologically (62% accuracy of hysteroscopy). Final histology found the prevalence of endometrial diagnostic categories as follows: 123 inactive endometrium (46%), 20 benign polyps (7%), 17 secretory endometrium (6%), 7 proliferative endometrium (3%), 3 atypical hyperplasia (2 in a polyp), 1 simple hyperplasia (in a polyp) and 1 fibroid. The remaining women had pipelle samples with insufficient tissue obtained, indicating a normal endometrial cavity. CONCLUSION: This is the first study of such size in gynaecologically asymptomatic breast cancer patients. This paper describes the findings in individual patients before any trial treatment was given. In this baseline group, 82% (219/268) of women had a normal endometrial cavity; 18% (49/268) had endometrial activity (proliferative or secretory endometrium in 9%) or an intracavity abnormality (hyperplasia, polyps and a fibroid in 9%). In total, 36% of biopsies had insufficient tissue for diagnosis, which in combination with a normal hysteroscopy was classed as normal. The appearance of a polyp hysteroscopically in this group was not proven histologically in approximately 40% of cases. The development of uterine pathology over time in the ATAC study will subsequently be assessed against the findings of this baseline paper.

The development of a more equitable approach to resource allocation and manpower planning for undergraduate teaching in a UK medical school.

CONTEXT: Resource allocation and manpower planning in the clinical faculty of a UK medical school. PURPOSE: To design a model, which is perceived to be fair, to determine indicative undergraduate teaching budgets to departments within the school from university resources and to specialty care groups of the main university hospital from service increment for teaching (SIFT) resources, and to aid manpower planning. METHOD: The student load for each department is measured in full-time-equivalent student numbers (FTEs) for each specialty and compared with the total load for the whole curriculum to derive each department's percentage share of available undergraduate teaching resources. Data on staff numbers available for teaching, both from the school and NHS, are also included. Student load and teaching capacity are then compared. RESULT: Undergraduate teaching resources relate to student load in the resource allocation process, and changes to the course are automatically reflected. Staff data, when compared with student load, facilitate rational planning of establishment levels to meet the teaching needs of the undergraduate curriculum. Of the respondents to a survey of heads of departments and the faculty's management board, 88% agreed that it was a better approach to resource allocation than the previous historical basis. PRESENT LIMITATIONS AND SCOPE FOR DEVELOPMENT: Data are currently entered manually but will be transmitted electronically in the future via the Web. Further consideration will be given to the possible inclusion in the model of weighting factors for different types of teaching and to how appropriate measures of quality may be incorporated into the resource allocation process. CONCLUSION: The model, despite some limitations, is a cost-effective and pragmatic management tool.

A randomized, open, parallel-group trial to compare the endocrine effects of oral anastrozole (Arimidex) with intramuscular formestane in postmenopausal women with advanced breast cancer.

BACKGROUND: This study provides a direct randomized comparison of a new-generation, non-steroidal aromatase inhibitor, anastrozole (Arimidex), with a steroidal aromatase inhibitor (formestane) with respect to oestrogen (oestradiol, oestrone, and oestrone sulphate) suppression and tolerability. PATIENTS AND METHODS: Sixty postmenopausal women with advanced breast cancer were randomized to receive either anastrozole 1 mg once daily orally (n = 29), or formestane 250 mg once every two weeks by intramuscular injection (n = 31). Treatment was continued until progression of disease or withdrawal from the study. The primary endpoints of this study were oestradiol suppression and tolerability. The secondary endpoints included oestrone and oestrone sulphate suppression. All laboratory analyses were conducted 'blind' of the randomized drug treatment. RESULTS: Anastrozole produced a greater and more consistent suppression of oestradiol levels compared with formestane. Based on two- and four-week measurements, the mean fall from baseline (pre-dose) in oestradiol level was 79% and 58% in the anastrozole and formestane groups, respectively (P = 0.0001). After four weeks of treatment, oestrone and oestrone sulphate levels were also suppressed to a greater extent by anastrozole compared with formestane (oestrone: 85% versus 67%, respectively, P = 0.0043; oestrone sulphate: 92% versus 67%, respectively, P = 0.0007). No statistical differences were seen between the two drugs in the incidence of adverse events. CONCLUSIONS: Anastrozole provides a more consistent and significantly more effective suppression of oestradiol compared with formestane. Similar results were observed for oestrone and oestrone sulphate. The clinical significance of these differences in total oestrogen suppression remains to be established.

Service increment for teaching (SIFT): a review of its origins, development and current role in supporting undergraduate medical education in England and Wales.

OBJECTIVES: To describe the ways in which total resources available for the Service Increment for Teaching (SIFT) have been determined and related to numbers of undergraduate medical students; and the development and current arrangements for allocating SIFT to the providers of service support for teaching. DESIGN: The derivation of SIFT from excess costs of teaching hospitals over general hospitals is described. The official principles of organizing SIFT to reimburse the service costs of teaching undergraduate medical students are explained. The crucial development that is examined is the change from SIFT being a global subsidy to being related to educational contracts. This development has facilitated both the specification of standards and innovative uses of SIFT. These are illustrated with examples. SETTING: Hospital and Community Health Services and Primary Care in the National Health Service (NHS) in England and Wales. SUBJECTS: Medical students. RESULTS: There is often confusion caused by SIFT being intended to cover the service costs of teaching but not having been derived in this way. This causes problems in deciding what providers should be paid through contracts for teaching of different kinds. CONCLUSIONS: The new contractual basis has enabled medical schools to use contracts to improve the clinical teaching of undergraduate medical students in the NHS. These developments may offer useful models for other countries.

Gender differences in medical graduates' assessment of their personal attributes.

CONTEXT: As part of the planning process for a new undergraduate curriculum for King's, a profile of the type of doctor which the Medical School wishes to produce was defined. OBJECTIVE: To investigate, in a sample of medical graduates, their perceptions of the personal attributes they had developed by the time of qualification which the Curriculum Steering Group had identified as being 'desirable' in a doctor. SUBJECTS: Five cohorts of doctors who had qualified from the King's College School of Medicine and Dentistry between 1985/86 and 1989/90 (n = 478). METHOD: Postal questionnaire survey. RESULTS: 371 replied, a response rate of 78%. In most cases the respondents felt they had acquired the attributes at least partially, by qualification. Gender differences in responses were found for nine of the sixteen attributes. The men felt better equipped with 'leadership potential', 'spirit of curiosity', 'tolerance of ambiguity and uncertainty' compared to the women who felt more confident in their 'ability to inspire confidence in others', 'ability to listen', 'ability to work in a team', 'caring and compassionate nature', 'motivation' and 'satisfactory at interpersonal relationships in professional life'. There were no significant differences for 'ability to recognize own limitations and strengths', 'capacity for self-audit', 'excitement with the subject of medicine', 'open-mindedness' and 'perseverance'. Most graduates agreed these attributes were 'desirable' in a doctor, the women feeling more strongly than the men about 'open-mindedness'. CONCLUSIONS: The findings are consistent with current theories which relate to personality differences between men and women and socialization during early upbringing.

Medical graduates evaluate the effectiveness of their education.

In response to the General Medical Council's 1991 Consultative Document proposing changes to medical curricula, the King's College School of Medicine and Dentistry, London, established a steering group to plan a new curriculum. As part of this process a postal survey was undertaken of five cohorts of King's graduates to ascertain how well the medical course they had undertaken had equipped them for practice. The questionnaire explored the level of factual content, the adequacy of their skills training, and the development of personal attributes during the course. A total of 371 graduates replied, a response rate of 78%. Over 70% indicated that their education had satisfactorily equipped them for their medical practice. Significant differences were found, however, between those now practising in primary care and those in hospital medicine regarding the importance attached to different subjects within the curriculum, and also with respect to the personal attributes the graduates felt they had acquired. Both groups identified deficiencies in virtually all aspects of their skills training: clinical, analytical, communication, management and technical. This feedback from some of the 'consumers' of medical education is now being used to assist the planning of the new King's curriculum.