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The molecular mechanisms underlying the development and evolution of myelodysplastic syndrome (MDS) are largely unknown. The increasing number of blast cells in the bone marrow correlate with poor prognosis and risk of developing acute leukemia. Such progression is frequently associated with increasing chromosomal abnormalities and genetic mutations. A cohort of 75 MDS patients were investigated for RAS, FMS and p53 mutations, and these molecular findings were related to cytogenetics, clinical status, transformation to acute leukemia, prognostic scores and survival. A mutation incidence of 57% (43/75) was found, with 48% (36/75) RAS mutations, 12% (9/75) FMS mutations and 8% (4/50) p53 mutations. The mutation status for RAS and FMS was related to MDS subgroup, increasing with poor-risk disease. The highest incidence was in the chronic myelomonocytic leukemia (CMML) subgroup. The most frequent RAS mutations were of codon 12 and a predominance of FMS codon 969 mutations was observed. A statistically significant increased frequency of transformation to AML was observed in MDS patients harboring RAS or FMS mutations (P Ͻ 0.02). Patients with oncogene mutations had a significantly poorer survival compared with those without mutations at 2 years and at the end of the period of follow-up (P Ͻ 0.02). Multivariate analysis including mutation, age, gender, diagnosis (FAB), cytogenetics and International score shows that the International score and mutation and age is the best predictive model of a poor outcome, (P Ͻ0.0001). When the analysis was undertaken without the International score, mutation and gender was the best predictor of poor survival (P = 0.005). This study shows that oncogene mutation, indicative of genetic instability, is associated with disease progression and poor survival in MDS.

Objective-To determine the causes of nonattendance at new outpatient appointments.Design-Case-control study of non-attenders and attenders.Setting-Outpatient department of a general hospital.Subjects-All non-attenders (n= 277) for first outpatient appointments in six specialties during a three month period were included. Controls (n= 135) were the attenders who followed every second nonattender; thus they attended the same consultant on the same day that the non-attenders were expected.Interventions -None. Measurements and main results-Information on the clinical problem, difficulties in attending the hospital, and reasons for non-attendance from the questionnaire were coded and classified. Nonattenders had received shorter notice of their appointment than attenders (14% v 1% had received three days' notice or less). There were small differences in the seriousness of patients' clinical condition.Conclusions-Client factors are less important than aspects of the service in explaining nonattendance at outpatient appointments. IntroductionOutpatient departments are at the critical interface between primary care and hospital practice. Here is perhaps the greatest opportunity to influence the use of resources in the pursuit of efficient health care. Nonattendance at outpatient departments may lead to inefficient use of facilities and result in unnecessary costs and delays in assessing patients. Given the concern expressed by managers, planners, and politicians over the consequences of non-attendance' it is surprising how few studies have been reported on this problem as it is experienced in the NHS. This contrasts with the number of studies reported from the United States. The difference in emphasis may reflect the differing economic consequences of nonattendance in the two countries rather than any difference in the scale of the problem.Studies have concentrated on the social and medical characteristics of non-attenders. Those of lower social class23 and from certain ethnic groups4' are less likely to attend, though not all studies have found such associations.67 The dominant assumption in reports as well as in the perceptions of those concerned with managing outpatient care is that non-attendance is primarily a problem of compliance. Such a view begs the question that this study addresses, for it is also possible that the problem is one of non-invitation by the hospital. Accordingly we attempted to answer the more general question "Why do appointments fail?" to avoid the assumptions underlying the usual question

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Summary Resistance to cytotoxic agents may be encountered during the treatment of acute myeloblastic leukaemia (AML). P-glycoprotein encoded by the MDR-] gene has been implicated as a potential drug resistance mechanism in leukaemic cells. In recent years, many data have been accrued concerning the expression of P-glycoprotein in leukaemia, and several studies have been published which A significant limiting factor in the successful treatment of haematological malignancies is the phenomenon of drug resistance to cytotoxic agents. The refractory nature of these diseases may be evident at presentation, i.e. intrinsic resistance, or conversely the tumour may be initially chemosensitive but acquire resistance at relapse. Most cancers are treated with multiagent regimens and so resistant disease is associated with a loss of chemosensitivity to a wide spectrum of structurally unrelated cytotoxic drugs. This phenomenon was first observed in vitro by Biedler and Riehm (1970), and the term 'multidrug resistance' (MDR) was coined. Cellular acquisition of the MDR phenotype results in resistance to the vinca alkaloids, anthracyclines and epipodophyllotoxins. The advent of molecular biological techniques has led to the discovery that there exists within the mammalian genome a family of MDR genes. In man, there are two MDR genes, MDR-J and MDR-3. The function of the protein encoded by the MDR-3 gene is unknown. The MDR-J gene encodes for a transmembranous glycoprotein (P-170). Transfection of the MDR-1 DNA into drug-sensitive cells confers the MDR phenotype (Chen et al., 1986;Ueda et al., 1987). P-170 acts as an ATP-dependent efflux pump, leading to a decreased intracellular concentration of drugs and cell survival in the presence of normally lethal doses of cytotoxic agents (Juliano & Ling, 1976). Much in vitro evidence has accumulated supporting the role of P-170 as a drug resistance mechanism in tumour cells (Bradley et al., 1988).In the last 5 years, investigators have looked for evidence of P-170 in clinical samples. In that time, many data have been amassed, on both solid tumours and leukaemias (Nooter & Herweijer, 1991). Particular attention has focused on acute leukaemia, since a homogeneous population of blast cells is readily obtained from peripheral blood and bone marrow.Theoretically, any malignant cell can attain a drugresistant state by either a quantitative or qualitative change in P-170. To date, there have been no convincing reports of MDR-J gene amplification in human leukaemia. Although the number of leukaemic cases studied is small, there have been no reports of point mutations within the gene (Gekeler et al., 1991;Holmes et al., 1992). In contrast, several studies have identified MDR-J RNA up-regulation or increased P-170 expression in acute myeloblastic leukaemia (AML) and, in addition, have attempted to relate these parameters to outcome in AML (see Table I). in conferring drug resistance in AML is unclear. The purpose of this article is to review those studies which have investigated the prognostic s...

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Patients with myelodysplastic syndromes (MDS) have high frequencies of cytogenetic abnormalities and evidence is accumulating of associations between exposure history and primary MDS. The objective of this article is to examine the relationship between histories of occupational or environmental exposure and presence of cytogenetic abnormalities. A case control study of MDS patients estimated lifetime exposure to more than 90 potential hazards in 400 age, sex, and area of residence matched patient and control pairs. A parallel cytogenetics study undertaken at time of diagnosis, independently of any knowledge of exposure history, identified 75 cytogenetically abnormal and 139 normal (186 not studied). Odds ratios of MDS patients and their matched controls were compared for 3 groups: cytogenetically abnormal, normal, and not known. The odds ratios for all exposures combined were possibly higher among cytogenetically abnormal 2.0 (95% confidence interval 0.8-5.9) than among normal 1.0 (0.6-1.8). This pattern was observed for exposure to semimetals, abnormal 4.0 (0.4-195.1) and normal 0.5 (0.1-1.0) and inorganic dusts, 1.6 (0. 6-3.8) and 0.4 (0.1-1.4) respectively. The pattern was principally in abnormalities in chromosomes 5 and 7. For organic chemicals and radiation, the odds ratios for both cytogenetically abnormal and normal were marginally raised: organic 1.8 (0.6-6.0) and 1.3 (0.6-2.9), respectively, and radiation 1.7 (0.5-5.6) and 1.3 (0.4-4.7) respectively. For radiation, abnormalities were mostly in chromosome 8. This study of association between exposures and cytogenetics in primary MDS complements those previously reported in secondary MDS and may provide some insight into pathogenetic mechanisms that lead to development of MDS.