DNA damage and mutagenesis induced by procarbazine in lambda lacZ transgenic mice: evidence that bone marrow mutations do not arise primarily through miscoding by O6-methylguanine

The DNA damaging and mutagenic activities of procarbazine, a methylating drug employed in cancer chemotherapy and suspected of causing therapy-related leukaemia, were investigated in the liver and bone marrow of lambda lacZ transgenic mice (MutaMouse). The drug was administered using two different protocols, a 'high-dose' one involving 5 daily doses of 200 mg/kg, expected to cause depletion of the repair enzyme O6-alkylguanine-DNA alkyltransferase (AGT) and thus favour the selective accumulation of the premutagenic lesion O6-methylguanine (O6- meG) relative to other adducts, and a 'low-dose' one involving 10 daily doses of 20 mg/kg procarbazine. Substantial accumulation of O6-meG was observed in both tissues examined 6 h after the end of the 'high-dose' treatment, with the liver accumulating somewhat higher levels than the bone marrow (28.0 +/- 1.8 fmol/microg DNA and 18.5 +/- 1.1 fmol/microg DNA respectively). However, significant increases in mutant frequency 10 days after the end of treatment were observed only in the bone marrow, reaching a 16-fold increase over background following the 5 x 200 mg/kg treatment. Sequence analysis of the mutations induced after this treatment revealed a mixed spectrum, in which G:C-->A:T transitions (characteristic of O6-meG miscoding) were only a secondary feature: Among 20 mutants analysed, only six such mutations were found, including three at CpG sites, which might have arisen from deamination of 5-methylcytosine. The other mutations observed included 1 A:T-->G:C transition, five transversions (one G:C-->T:A, one double G:C-->C:G, two A:T-->T:A, one A:T-->C:G), five deletions and three insertions. The mechanistic and clinical significance of these findings is discussed.      

Hypofractionated irradiation for inoperable non-small cell lung cancer

A policy of palliative intent thoracic irradiation was prospectively evaluated in 38 consecutive patients referred for treatment of inoperable non-small cell lung cancer at a single institution. A target dose of 1700cGy in two fractions 1 week apart was delivered. Characteristics of the treatment group revealed most (87%; 33/38) to be of good-excellent performance status with minimal weight loss before irradiation. Although three patients (8%) had initial metastatic disease, ail had symptoms referable to the thorax with cough (71%), dyspnoea (55%), haemoptysis (39%), and chest wall pain (34%) being dominant. Following treatment, the relative risk of maintaining complete response with regard to each of these symptoms was 0.91, 0.40, 0.92 and 0.78, respectively. Overall 70% of patients maintained complete symptomatic response to time of death or last review. Uncorrected median survival was 35 weeks and was comparable to best international end-results for either palliative intent or curative intent radiation schedules. We conclude that the radiation regimen employed is safe, efficacious and eminently resource conscious. Recognition of patient groups who overwhelmingly derive no benefit from conventional fractionation schedules will streamline access to radiotherapy services of patients suitable for radical treatment.     

CC2 Cost of Preventable Adverse Drug Events in Emergency Department Patients

1–4% of all visits to emergency rooms are due to adverse drug events (ADEs), but data about preventability and cost due to preventable ADEs in this setting are limited.
OBJECTIVE: To determine the incidence of ADEs associated with emergency department (ED) visits and subsequent hospital admissions; to assess their preventability and to estimate the costs of preventable ADEs to our institution, a 750 bed university tertiary care center.
METHODS: All patients who visited the ED from October 1995 to March 1996 were prospectively-evaluated. Recorded data included: medical and medication history, laboratory data, serum drug concentrations, ED procedures, intervention therapy, and characteristics and outcome of ADEs. Patients admitted as a result of the ADE were followed to collect information of invasive and non invasive procedures, therapy, length of stay, and intensive care. Preventable ADEs were analyzed to identify the associated factors. A cost analysis was performed.
RESULTS: From a total of 33,975 visits to the ED, 766 (2.25%) were due to ADEs. A total of 336 (43.9%) ADEs were assessed as preventable; these resulted in 121 hospital admissions, 1,575 stays, 121 ICU days, and 15 deaths. Inappropiate dose prescribed and inadequate monitoring of drug therapy accounted for 46% and 31% of preventable ADEs; 17% preventable ADEs were due to automedication. The estimated hospital annual cost for all ADEs was $1.42 million and for preventable ADEs was almost $1 million.
CONCLUSIONS: Many ADES seen in ED patients are preventable and contribute substantially to hospital costs. At a time when much emphasis is put on the limitation of health expenses, here is a domain where expense-cutting could probably be done reasonably easily, while increasing quality of care.     

Characterization of a monoclonal antibody having selective reactivity with normal and neoplastic plasma cells

A myeloma cell-reactive monoclonal antibody (MoAb), MM4, was generated from BALB/c mice immunized with alternate injections of cells from two human multiple myeloma (MM) cell lines. Screening by the enzyme-linked immunosorbent assay (ELISA) technique showed that MM4 reacted with human MM cell lines (7 of 7 positive), as well as bone marrow aspirates from MM patients (4 of 4 cases positive). MM4 did not react with marrow aspirates from control patients (3 cases), or with peripheral blood mononuclear (PBM) cells from normal subjects, lymphocytic (12 cases) and myelogenous (8 cases) leukemia patients. In addition, MM4 was negative with polymorphonuclear leukocytes and RBCs from normal donors. By means of the immunoperoxidase technique, the MM4-reactive antigen was detected in paraffin-embedded, Zenker formalin-fixed bone marrow biopsies of MM (12 of 12 cases positive), Waldenstrom's macroglobulinemia (2 of 2 cases positive), asymptomatic plasma cell dyscrasia (4 of 4 cases positive), and certain lymphomas (2 of 5 cases positive). Marrow biopsies from lymphocytic (5 cases) and myelogenous (5 cases) leukemias were uniformly negative. The MM4-reactive antigen also was expressed on plasma cells generated from pokeweed mitogen (PWM)-stimulated normal PBM cultures. The pattern of reactivity of MM4 with lymphocytes of B origin was similar to that of the plasma cell MoAb PCA-1. Competitive binding studies showed, however, that these two MoAbs recognized distinct antigenic determinants. These observations suggest that MM4 may be useful for the study of human plasma cell dyscrasias.     

Upper airway obstruction in infants and children: evaluation with ultrafast CT

The diagnostic accuracy of ultrafast computed tomography (CT) was evaluated prospectively in 25 infants and children with suspected airway obstruction. All examinations were conducted in spontaneously breathing, nonsedated children. Scan acquisition times were 0.05 or 0.1 second. CT examinations, completed in an average of 10 minutes, routinely included localizing, contiguous sections through the trachea followed by serial images obtained at a rate of 17 per second through regions of interest. Imaging results were correct in 24 of 25 examinations as judged from clinical and surgical data. Ultrafast CT data permitted diagnosis of dynamic changes in airway caliber, small intraluminal polyps, focal tracheal atresia, compressive mediastinal masses, and foreign body obstructions of the major bronchi. Dose measurements showed a maximum skin exposure of 245 mR (0.06 mC/kg) per 0.05-second image. Ultrafast CT provides an accurate, minimally invasive method for dynamic imaging of the airway in nonsedated children.