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.

Total registration of non-Hodgkin's lymphoma and Hodgkin's disease in Scotland: effect of deprivation and caseload on outcome.

All cases S16 years of age with a histological diagnosis of non-Hodgkin's lymphoma (NHL) and Hodgkin's disease (HD) presented in Scotland between 1 January 1994 and 31 December 1996 were registered prospectively in the Scotland and Newcastle Lymphoma Group database by a process of total registration. The census population of Scotland in 1996-1997 was 5.1 million. One thousand seven hundred and sixty three patients were registered with NHL and 350 patients with HD. These patients have been followed up for a median of 47 months in the case of NHL and 51 months for HD cases. Actuarial 5-year survival for adult NHL was 35% and for HD, 75%. Outcome for both NHL and HD was particularly poor in the population over 60 years with median survival of 18 months for NHL and 27 months for HD. When analysis of survival was related to degree of material deprivation using the Carstairs score a significantly poorer survival was seen for NHL with increasing deprivation that could not be explained by a different pattern of age or stage at presentation. Deprivation had no impact on incidence or survival in HD. Analysis of impact of caseload of the physician initiating therapy showed no significant difference in 5-year survival.

A multicentre, open, non-comparative phase II study of a combination of fludarabine phosphate, cytarabine and granulocyte colony-stimulating factor in relapsed and refractory acute myeloid leukaemia and de novo refractory anaemia with excess of blasts in transformation.

The primary objective of this study was to determine the complete remission (CR) rate achieved with the FLAG (fludarabine phosphate, cytarabine and granulocyte colony-stimulating factor) regimen in patients with relapsed or refractory acute myeloid leukaemia (AML) or de novo refractory anaemia with excess of blasts in transformation (RAEB-t). Secondary objectives were to evaluate survival and toxicity. Induction treatment consisted of between one and two courses of FLAG. Patients achieving CR received between one and two courses of consolidation treatment. Eighty-three of the 89 patients entering the study were eligible for assessment. CR rates were: 17 out of 21 (81%) in late relapse AML (Group 1), 13 out of 44 (30%) in early relapse/refractory AML (Group 2), and 10 out of 18 (56%) in de novo RAEB-t (Group 3). Thirty-four of the 40 responders (85%) achieved CR after one induction course. Median survival times were 1.4 years, 3 months and 1.6 years in Groups 1, 2 and 3 respectively. Other than myelosuppression, the FLAG regimen was not generally associated with clinically significant toxicity and was well tolerated by most patients including the elderly. The FLAG regimen offers a very effective alternative treatment for CR induction in poor prognosis adult patients with either relapsed or refractory AML or de novo RAEB-t. FLAG delivers high-dose treatment without increasing overall toxicity, an approach which is of particular value in older patients, who constitute the majority in these diseases. It is therefore an important advance in developing new treatment options for these patients.

Rapid detection of BCR/ABL and PML/RARA using fluorescence in situ hybridization in cytospin preparations.

Fluorescence in situ hybridization (FISH) is increasingly used as an adjunct to conventional cytogenetic analysis in the diagnosis of haematological malignancies and in monitoring minimal residual disease. FISH, however, is generally performed on slides prepared after short-term sample incubation and therefore, whilst faster than conventional cytogenetics, still requires a minimum of 2 days for a result to be obtained. A simplification of the FISH procedure is reported using uncultured cytospin preparations of bone marrow or peripheral blood for the rapid diagnosis of the BCR-ABL and PML-RARa gene rearrangements. It demonstrates that culturing has no effect on the ratio of normal to abnormal cells in the nondividing population. Data is presented from an analysis of 24 cases in whom unequivocal results were obtained in less than 12 h and in complete concordance with results obtained by conventional cytogenetics and/or interphase FISH.

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.

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.

Use of whole gut perfusion to investigate gastrointestinal blood loss in patients with iron deficiency anaemia.

Iron deficiency anaemia may be due to occult bleeding into the gut. However, although clinical investigations may show a high frequency of gastrointestinal tract disease in these patients, the cause-effect relationship between the lesions detected and anaemia remain uncertain. This study aimed to establish whether lesions detected by endoscopy or imaging of the gastrointestinal tract in patients with unexplained iron deficiency anaemia are bleeding continuously. Routine clinical tests were performed in 42 patients with unexplained iron deficiency anaemia referred to this unit. Whole gut lavage and assay of haemoglobin in the gut perfusate were also performed. The main outcome measures were clinical diagnoses (by imaging and endoscopy of the upper gastrointestinal tract and colon); the concentration of haemoglobin in whole gut lavage fluid; and the calculated gastrointestinal blood loss per day. There were 73 clinical, dietary, or iatrogenic factors of possible aetiological importance in the 42 patients--poor diet (10), gross gastrointestinal abnormality (34 in 28 patients), malabsorption (14), coagulation problems (6), and NSAID use (9). The gut lavage test showed, however, that at the time the test was performed, only eight patients were losing more than 2 ml blood daily into the gut, including all four with colonic cancer, one with diffuse gastric vascular ectasia, and one with severe ulcerative oesophagitis. It is concluded that occult gastrointestinal bleeding sufficient to cause anaemia was evident in only 19% of 42 patients. There was a high frequency of other potential causes of iron deficiency in the remainder, suggesting that most of the gastrointestinal diseases and lesions detected in them were probably coincidental. Factors other than blood loss should be considered and treated in patients referred for anaemia assessment.

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.

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.

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.

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.

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 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.

Prognostic subgroups in B-cell chronic lymphocytic leukemia defined by specific chromosomal abnormalities.

BACKGROUND AND METHODS: Specific chromosomal abnormalities have been shown to affect the overall survival of patients with acute leukemia, but the possibility that specific chromosomal defects may influence the course of B-cell chronic lymphocytic leukemia (CLL) is controversial. We assessed this possibility as follows: blood mononuclear cells from 433 patients with B-cell CLL in five European centers were cultured with B-cell mitogens, and banded metaphases were studied. RESULTS: Three hundred ninety-one patients could be evaluated cytogenetically, and 218 had clonal chromosomal changes. The most common abnormalities were trisomy 12 (n = 67) and structural abnormalities of chromosome 13 (n = 51; most involving the site of the retinoblastoma gene) and of chromosome 14 (n = 41). Patients with a normal karyotype had a median overall survival of more than 15 years, in contrast to 7.7 years for patients with clonal changes. Patients with single abnormalities (n = 113) did better than those with complex karyotypes (P less than 0.001). Patients with abnormalities involving chromosome 14q had poorer survival than those with aberrations of chromosome 13q (P less than 0.05). Among patients with single abnormalities, those with trisomy 12 alone had poorer survival than patients with single aberrations of chromosome 13q (P = 0.01); the latter had the same survival as those with a normal karyotype. A high percentage of cells in metaphase with chromosomal abnormalities, indicating highly proliferative leukemic cells, was associated with poor survival (P less than 0.001). Cox proportional-hazards analysis identified age, sex, the percentage of cells in metaphase with chromosomal abnormalities, and the clinical stage of the disease (Binet classification system) as independent prognostic variables. CONCLUSIONS: Chromosomal analysis provides prognostic information about overall survival in addition to that supplied by clinical data in patients with B-cell CLL.

Relationship between age and the cardiovascular response to meals.

In 82 healthy normotensive and hypertensive subjects aged 19-79, blood pressure and heart rate were measured for 1 hour before and 2 hours after a meal. Mean blood pressure decreased from 147/93 to 139/83 mmHg supine and from 148/101 to 142/94 mmHg standing (all p less than .001). Older subjects had higher premeal blood pressures. There were significant correlations between age and the reductions in supine systolic and diastolic blood pressures and standing systolic blood pressure, i.e., older patients had greater reductions. However, after statistical correction for premeal blood pressure, there was no longer any significant relationship between age and the cardiovascular response to meals. The greater blood pressure reduction after meals in older patients may be due to decreased baroreflex sensitivity in association with higher arterial pressures. The changes in blood pressure due to meals may confound the diagnosis of hypertension and interfere with the interpretation of the response to antihypertensive treatment.

Molecular evidence for a single clonal origin in biphenotypic concomitant chronic lymphocytic leukemia and multiple myeloma.

To establish the clonal origin of a case of concomitant B-cell chronic lymphocytic leukemia (IgM kappa) and multiple myeloma (IGA lambda), we analyzed the immunoglobulin (Ig) gene rearrangements in the patient's blood and bone marrow. Despite the different isotypes, pretreatment investigation of the heavy chain gene (JH) revealed a germline fragment and two identical rearrangements in the blood and marrow. Both kappa and lambda light-chain genes were rearranged in the blood, suggesting peripheral blood lymphocyte involvement in the myeloma. Analysis of the Ig genes after chemotherapy demonstrated no change in the JH or CK rearrangements; however, the lambda genes were now in a germline configuration. Our results suggest that in this patient both chronic lymphocytic leukemia and myeloma originated from the same B-cell progenitor.

The role of cell maturation in the generation of phenotypic heterogeneity in B-cell chronic lymphocytic leukaemia.

B-chronic lymphocytic leukaemia (B-CLL) patients can be ranked along a progression of phenotypes characterized by a decreasing surface expression of CD20, CD21, CD22 and membrane immunoglobulin and a gradual replacement of the high molecular weight (MW) glycoproteins of the leucocyte-common antigen (LC) CD45RA by the lower MW components, including the CD45RO determinant. As CD20, CD21, CD22 and membrane immunoglobulin change during or after B-cell activation, and the CD45RA/CD45RO inversion is implicated in T-cell maturation, the possibility that the phenotypic differences are generated by a maturational diversity of the CLL clones has been investigated by testing the effects of TPA treatment of the leukaemic cells. TPA reduces the level of expression of CD20, CD21, mIg and CD45RA and increases CD45RO binding, thereby minimizing the phenotypic heterogeneity of the CLL clones and causing them to converge towards one end of the natural range. We propose that the phenotypic diversity in CLL is, at least in part, a consequence of maturational diversity where lymphocyte development is disrupted at different stages in different patients.

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.

Effects of tamoxifen on blood coagulation.

Sixteen patients with clinically localized breast carcinoma who had been receiving tamoxifen 20 mg twice daily for between 3 and 38 months (median, 14 months) were studied. Several parameters of coagulation (antithrombin III, protein C, fibrinopeptide A and in vitro monocyte procoagulant activity) were investigated in this group and compared to a group of 15 patients with clinically localised breast carcinoma not given tamoxifen. Tamoxifen did not induce significant changes in these parameters to account for the reported thromboembolic events associated with this therapy. The reduced antithrombin III activity previously described in patients receiving tamoxifen for metastatic breast cancer may reflect disease activity rather than a direct effect of tamoxifen on blood coagulation.