The analysis of the variation of the surface proteins of leukemic lymphocytes of B-chronic lymphocytic leukemia patients by high performance liquid chromatography.

Surface phenotypes of leukemic lymphocytes are analyzed by high performance liquid chromatography of the vectorially iodinated surface proteins and the variation of the phenotypes of B-chronic lymphocytic leukemia (B-CLL) lymphocytes from different individuals is studied. A number of surface molecules show a coordinated variation between patients in their level of expression. Some of these molecules belong to recognized clusters of differentiation, e.g., CD45 and CD21 and their variation can be confirmed by flow cytometry. But the HPLC also reveals other components that have not been assigned to known clusters, e.g., a component of Mr of around 300 kD. Two types of B CLL lymphocytes can be recognized by this set of molecules and the patients ranked according to the level of expression of these markers on their leukemic cells. The effects of TPA treatment on expression suggests that these molecules represent a maturational sequence and that the leukemias are derived from progressive stages along this process.

Single versus triplicate measurements of blood pressure and heart rate.

The mean of rapidly repeated duplicate or triplicate measurements is often used in studies of antihypertensive drugs. Forty patients with hypertension had triplicate measurements of blood pressure and heart rate on two occasions, 1 week apart, during placebo treatment. The average difference between the first measurement and the mean of the triplicate measurements was -0.3 mm Hg. The average coefficient of variation for supine and standing, systolic and diastolic blood pressures was 8.4% for the single measurements and 8.0% for the mean of triplicate measurements. The correlations between the first measurements and the mean of triplicate measurements ranged from 0.90 to 0.98 (all p less than 0.01). The average difference between the two visits for all four blood pressure parameters was -0.6 mm Hg for the single measurements and -0.5 mm Hg for the mean of triplicate measurements (all p = NS). These results indicate that 1) blood pressure does not change further after 1 week of placebo treatment, and 2) use of the mean of triplicate measurements of blood pressure and heart rate gives the same result as use of single measurements, and the results are no less variable.

Effects of ketorolac tromethamine on hemostasis in volunteers.

Ketorolac tromethamine, an analgesic agent with prostaglandin synthetase--inhibiting activity, is more active than aspirin in vitro in inhibiting collagen- or arachidonic acid-induced platelet aggregation. In this randomized, double-blind study, 26 volunteers received ketorolac, 30 mg intramuscularly four times a day for 5 days, and placebo, two capsules orally four times a day for at the last 2 study days. The effects of this treatment were compared with those of intramuscular placebo and oral aspirin, two 325 mg capsules, given on the same schedule to eight volunteers. Aspirin at a mean serum concentration of 84 micrograms/ml did not affect prothrombin time, partial thromboplastin time, platelet count, or bleeding time. Ketorolac produced a modest prolongation of the bleeding time, from 4.9 +/- 1.1 minutes (mean +/- SD) to 7.8 +/- 4.0 minutes (p less than 0.005). Ketorolac did not affect the prothrombin time or partial thromboplastin time but was associated with clinically insignificant change in the platelet count from 303 +/- 57 X 10(3)/m3 to 277 +/- 56 X 10(3)/mm3.

CHOP-based chemotherapy is as effective as alternating PEEC/CHOP chemotherapy in a randomised trial in high-grade non-Hodgkin's lymphoma. Scotland and Newcastle Lymphoma Group.

The aim of this study was to test whether survival for patients with high-grade non-Hodgkin's lymphoma (NHL) can be improved with a non-cross-resistant regimen as compared to a CHOP-based regimen. This is a multicentre study comprising 325 adult patients, median age 58 years, with high-grade non-Hodgkin's lymphoma: patients of any age and performance status were eligible provided they were able to receive the drugs in the regimens. Patients were randomised to either B-CHOP-M (bleomycin, cyclophosphamide, doxorubicin, vincristine, prednisolone and methotrexate) or PEEC-M (methylprednisolone, vindesine, etoposide, chlorambucil and methotrexate) alternating with B-CHOP-M. At a median follow-up of 9 years, there was no significant difference in overall survival or disease-free survival between the two arms. Toxicities for the two regimens were equivalent. This study confirms that for relatively unselected patients with high-grade non-Hodgkin's lymphoma, an alternating multidrug regimen does not improve upon the results obtained with B-CHOP-M.

Prospective study of the safety and financial benefit of ketoconazole as adjunctive therapy to cyclosporine after heart transplantation.

In a prospective study of the relative safety and potential benefit of concomitant ketoconazole and cyclosporine after heart transplantation, 15 transplant recipients were followed up for up to 1 year (mean, 10.7 months) after ketoconazole was added to their immunosuppressive regimen of cyclosporine, prednisone, and azathioprine, and these patients were compared with a matched cohort over the same time. There was an 88% reduction in the mean (+/- SD) dose of cyclosporine, from 394 (115) mg/day to 47 (21) mg/day (p less than 0.0005) in the ketoconazole group, compared with an insignificant change in the control group. The projected annual cost of cyclosporine was reduced by 88%, with a 72% reduction in the projected cost of immunosuppressive drugs and prophylactic antifungal therapy, from a mean of $6800 to $1862 per year per transplant recipient in the ketoconazole-treated group. Other beneficial effects found over the study period included a significant reduction in the mean and diastolic systemic arterial pressure and a significant reduction in serum cholesterol. The mean total serum cholesterol fell from 265 (44) to 204 (38) mg/dl in the ketoconazole group but did not change significantly in the control group (p less than 0.005). Low-density lipoprotein cholesterol also fell from a mean of 167 (32) mg/dl to 112 (28) mg/dl (p less than 0.005). Renal function was not significantly affected by ketoconazole when compared with the control group. Ketoconazole and other drugs of potential use in organ transplant recipients should be evaluated for financial as well as for other potential clinical benefits in the long-term management of these patients.

Fibronectin in blood products--an in vitro and in vivo study.

The concentration of fibronectin was assessed in a variety of coagulation factor preparations. Highest concentrations of fibronectin were found in the intermediate purity factor VIII concentrates. Significant amounts were found in cryoprecipitate but high purity factor VIII concentrates contained only small amounts. For practical purposes factor IX concentrates contained no fibronectin. Qualitative estimation of fibronectin showed the presence of an abnormal slow migrating peak on 2 DIEP which was not found in normal plasma. In vivo recovery infused fibronectin was relatively low for all products studied (30-54%). The plasma half life (17-25 h) did not differ significantly depending on whether cryoprecipitate or a factor VIII concentrate was used as a source of fibronectin. No enhancement of plasma fibronectin concentrations was obtained following DDAVP infusion, venous occlusion and exercise. Plasma fibronectin concentrations and 2 DIEP patterns were unaltered following prolonged storage.

Marrow involvement with T cell lymphoma initially presenting as abnormal myelopoiesis.

Three cases of T cell lymphoma affecting the marrow, in which initial bone marrow appearances were misleading, occurred. In each case the initial clinical presentation was related to cytopenia, but the marrow abnormalities at this time suggested an abnormal myeloid proliferative state, with no evidence of a malignant lymphoid proliferation. Later in the course of the disease, however, the characteristic pattern of marrow infiltration by mature post-thymic T cells became evident. The consequent delay (two to 36 months) in diagnosis was noted.

Distribution of fibronectin and laminin in normal and pathological lymphoid tissue.

Forty six lymph nodes were examined with the indirect immunoperoxidase technique for the distribution of fibronectin and laminin. Fibronectin was present in the framework of the tissue and the basal lamina of blood vessels, giving a clear outline of nodal architecture. Intracellular fibronectin was observed in cases of reactive sinus histiocytosis, when about a third of macrophages exhibited strong positivity. Mast cells were positive. A pronounced increase in extracellular fibronectin was seen in nodular sclerosing Hodgkin's disease, although heavily hyalinised areas exhibited only superficial positivity. Reed-Sternberg and mononuclear Hodgkin's cells were consistently negative for fibronectin. Laminin staining was localised to vascular and marginal sinus basement membranes. No cellular positivity was evident. The distribution of laminin indicated a pronounced increase in vascularity in nodular sclerosing Hodgkin's disease, which was especially prevalent within the dense fibrous trabeculae. In contrast, however, examination of the other Rye subtypes showed a lesser degree of vascularity with numbers of vessels similar to those observed in reactive follicular hyperplasia. Laminin was found to be more efficient than factor VIII related antigen as a vascular marker.

Yersinia enterocolitica septicaemia from transfusion of red cell concentrate stored for 16 days.

Two cases of transfusion transmitted Yersinia enterocolitica biotype 3, serotype 09 infection occurred in south east Scotland within four months of each other. In one case, a 79 year old man died the day after receiving a unit of red cell concentrate that had been stored for 29 days after donation. In the second case a 78 year old man died three days after transfusion of a unit of red cell concentrate that had been collected 16 days before transfusion. The donors of both units had no symptoms attributed to gastrointestinal infection. Early outdating of blood for transfusion after three weeks of storage is unlikely to eradicate Y enterocolitica associated fatalities from blood transfusion, and alternative methods should be considered.

8;21 translocation with duplication of the der(21) in a patient with myelomonocytic leukemia.

An 8;21 translocation with duplication of the der(21) is described in a 72-year-old man who presented with features of chronic myelomonocytic leukemia. Progression to acute myelomonocytic leukemia occurred within one month of diagnosis. The possible prognostic significance of the t(8;21) with duplicated der(21) in myelodysplasia is discussed.

The development of targeted chemotherapy for CNS lymphoma-a pilot study of the IDARAM regimen.

PURPOSE: We have developed and evaluated a CNS-targeted chemotherapy regimen based on the pharmacokinetic properties of the individual drugs in the combination. PATIENTS AND METHODS: In a twin-track study, 16 patients with secondary CNS lymphoma (SCNSL) and 8 with primary CNS lymphoma (PCNSL) were treated with IDARAM which comprised idarubicin 10 mg/m(2) i.v., days 1 and 2; dexamethasone 100 mg, 12-h infusion, days 1, 2 and 3; cytosine arabinoside (ARA-C) 1.0 g/m(2), 1-h infusion, days 1 and 2; methotrexate 2.0 g/m(2), 6-h infusion, day 3 (with folinic acid rescue); and cytosine arabinoside 70 mg plus methotrexate 12 mg, intrathecally, days 1 and 8. Two cycles were delivered at 3-weekly intervals. After response assessment, patients received adjuvant cranial radiotherapy (40 Gy over 20 fractions). RESULTS: The series comprised 24 patients, 11 male and 13 female. Their median age was 53 years (range 21 to 73 years). Grade 4 neutropenia and thrombocytopenia occurred in the majority of patients treated. Of the eight PCNSL patients, seven achieved complete remission (CR). Four remained in CR at the time of this report with a median duration of follow-up of 25 months (range 11 to 42 months). Of the 16 SCNSL patients, 12 achieved CR. Seven patients remained in CR at the time of this report with a median duration of follow-up of 24 months (range 18 to 57 months). CONCLUSION: This study suggests that IDARAM is an effective regimen in both PCNSL and SCNSL and is suitable for further development and evaluation.

A numerical prognostic index for clinical use in identification of poor-risk patients with Hodgkin's disease at diagnosis. The Scotland and Newcastle Lymphoma Group (SNLG) Therapy Working Party.

The aim of this study was to assess the feasibility of using objective data obtained at the time of diagnosis of Hodgkin's disease to predict those patients who were likely to die of progressive disease within four years. Ninety-two consecutive patients from one centre (Newcastle upon Tyne) were used to construct a numerical index based on disease stage (Ann Arbor), age, haemoglobin and absolute lymphocyte count. Weight was assigned according to a predictive value from univariate and multivariate analyses based on survival. The index produced was then validated on a separate patient set (455) from other centres within the Scotland and Newcastle Lymphoma Group (SNLG) on whom the same prospective information was available. The index produced provided a useful separation of those patients destined to die of disease. In 101 patients with index > 0.5, 62 (61.4%) were dead at four years, whereas with index < 0.5, 61 (18%) of 336 patients were dead at four years. The index includes Ann Arbor stage but possesses additional practical prognostic value which allows identification of patients with early stage destined to die of disease. Of 149 patients with Stage IA and IIA disease 15 patients had index > 0.5, and 10 (60%) have died, whereas the remaining patients had survival of 90% and 85% respectively. This numerical index has now been strengthened by an added factor for bulk disease > 10 cms and in the SNLG it has replaced Ann Arbor staging for selection of patients requiring aggressive therapy. A randomized study of chemotherapy versus chemotherapy plus autotransplant in first remission using high dose melphalan and VP16 is currently in progress.

Monocyte procoagulant activity in breast cancer.

Abnormalities of blood coagulation associated with neoplasia may be important in the pathogenesis of tumour spread. Most patients with advanced malignancy have evidence of activated coagulation, but the mechanisms underlying this are unclear. We have examined in vitro monocyte procoagulant activity and compared this to plasma levels of fibrinopeptide A, in 52 patients with clinically localised breast cancer. Patients with localised breast cancer and activated coagulation displayed a strong positive correlation between monocyte procoagulant activity and level of fibrinopeptide A(r = +0.86, p less than 0.001). No such relationship was demonstrated in a smaller number of patients with metastatic breast cancer. It is concluded that monocyte procoagulant activity plays an important role in coagulation activation in patients with localised breast cancer. The implications of this for adjuvant anticoagulant therapy in breast cancer are discussed.

Elastase-alpha 1 antitrypsin complexes in acute leukaemia.

30 consecutive patients with acute leukaemia were studied prior to commencement of treatment in order to assess the incidence and significance of raised elastase (ELP) - alpha 1 antitrypsin complex level. In addition the reliability of detecting low factor XIII subunit levels as an indicator of in vivo release of ELP was evaluated. While 15 patients had raised levels of ELP alpha 1 antitrypsin complex levels, only 4 of these had reduced levels or factor XIII subunits A and S. In addition increased levels of ELP- alpha 1 antitrypsin complex were not associated with any marked disturbance of routine coagulation tests. Patients with raised ELP- alpha 1 antitrypsin complex levels had significantly higher circulating white cell and blast cell counts as compared to those patients with normal levels of this complex. In patients entering remission the levels of ELP- alpha 1 antitrypsin complex returned to normal.

An anterior cervical mass due to infection with absidia.

Absidiosis , diagnosed after biopsy of an anterior cervical mass, is described in a patient who was in remission from acute myeloid leukaemia.

Forty years of randomised trials in the New Zealand Medical Journal.

AIM: To identify all randomised trials published in the New Zealand Medical Journal, to document the basic characteristics of these trials and to count the number that were detectable on medline. METHODS: All issues of the New Zealand Medical Journal between 1943 and 1995 were systematically hand-searched. All trials identified were characterised and compared against the trials identified using an optimal medline search strategy. RESULTS: The handsearch identified 152 randomised controlled trials, the first published in 1955. Half the trials recruited less than 34 participants and more than 90% were of pharmaceutical interventions. Only 18% of studies reported on the method of randomisation and 13% provided evidence that final analyses were conducted on an intention to treat basis. Fifty one percent of trials employed a placebo control group and 28% involved a crossover design. Since 1966, when Medline became available, 143 trials were published of which 89 (62%) were identified by the Medline search. CONCLUSIONS: Two of the major difficulties that face those preparing systematic reviews were illustrated by this survey. First, important information on design and analysis is often missing from reports of trials. Second, a large proportion of published randomised trials are not identifiable on Medline. Standard formats for reporting the results of trials and inclusion of trials identified by hand-searching on the Cochrane Collaboration's International Register of Randomised Controlled Trials of Health Care will facilitate the future production of reliable systematic reviews.

Fletcher Challenge-University of Auckland Heart & Health Study: design and baseline findings.

AIMS: The aims of this prospective observational study are to determine the relationship of sociodemographic factors, psychological factors and several factors measured in blood, with the risk of coronary heart disease (CHD) in a New Zealand population. METHODS: Participants were recruited from two sources: employees of the Fletcher Challenge Group and individuals listed on the general electoral roll for the Auckland region. Baseline and follow up risk factor data were obtained from a questionnaire, blood samples and a simple physical examination. Outcome data on deaths and hospitalisations due to coronary heart disease will be obtained primarily through linkage of participant identifiers to data collected nationally by the New Zealand Health Information Service. RESULTS: A total of 10,529 individuals agreed to participate (8011 from Fletcher Challenge and 2518 from the electoral roll), representing a response rate of 74%. Within the study population, there was a broad distribution of sociodemographic characteristics including ethnicity-10% of participants were Maori and 5% were of Pacific Islands origin. There was also wide heterogeneity of coronary heart disease risk as judged from the distributions of established risk factors at baseline-5% of participants had evidence of existing coronary heart disease, a quarter were current smokers, a sixth were nondrinkers, almost a half were overweight, a fifth had blood pressure > or = 150/95 mmHg or were receiving antihypertensive treatment and a sixth had cholesterol levels > or = 6.5 mmol/L. CONCLUSIONS: This is the first, large scale prospective observational study of the determinants of coronary heart disease in a New Zealand population. The study participants represent a broad cross section of society, with wide variation in sociodemographic characteristics and coronary heart disease risk. Initial results concerning the relationships of primary interest should be available within 5 years when sufficient coronary heart disease events have been documented to allow reliable analyses.