A randomized study (WOS MM1) comparing the oral regime Z-Dex (idarubicin and dexamethasone) with vincristine, adriamycin and dexamethasone as induction therapy for newly diagnosed patients with multiple myeloma.

Whilst infusional vincristine, adriamycin and dexamethasone (VAD) is an effective treatment for patients with multiple myeloma (MM), administration may be complicated by line-associated infections and thromboses. The oral regime, Z-Dex (idarubicin and dexamethasone) has been shown to be efficacious in MM. We conducted a randomized study comparing Z-Dex with VAD as induction therapy in newly diagnosed MM patients. A total of 106 patients (median age, 56 years; range: 37-73; Durie-Salmon stage II/III) were randomized to receive four to six cycles of Z-Dex or VAD. Central line complications were reported in 38 patients on 57 cycles, primarily because of infection. Neutropenia (all grades) was more common in the Z-Dex arm (P = 0.009) although grade III/IV neutropenia was not significantly different between the treatment groups (P = 0.06). Infections (all grades) were more commonly seen in the VAD arm (P = 0.001) although grade III/IV infections were not significantly different between the two groups (P = 0.081). The responses to therapy (complete/partial response) in evaluable patients were: VAD 74% vs. Z-Dex 58%, with an estimated difference in response of 16% (95% CI -2-33, P = 0.075). VAD recipients (15%) suffered early treatment-related mortality compared with 12% of Z-Dex recipients. Overall, 45 patients have died: disease progression (Z-Dex n = 13, VAD n = 10), regimen-related toxicity (Z-Dex n = 2, VAD n = 2), infection (Z-Dex n = 0, VAD n = 3), other causes (Z-Dex n = 7, VAD n = 2), unknown (Z-Dex n = 3, VAD n = 2). This study demonstrated that Z-Dex might be a suitable oral alternative to VAD for treating newly diagnosed MM patients, although definitive evidence for equivalence is not provided.

Report on slide session, British Society for Haematology, 43rd Annual Scientific Meeting, Glasgow, 2003.

Seven patients who had a diagnostic problem were presented at the British Society for Haematology, Annual Scientific Meeting in 2003. The likely diagnosis was discussed on the basis of a synopsis of the history and blood film and trephine biopsy features and forms the basis of this report. Diagnostic problems dealt with included lymphoproliferative and myeloproliferative disorders and haemolytic anaemia.

ChlVPP/EVA hybrid versus the weekly VAPEC-B regimen for previously untreated Hodgkin's disease.

PURPOSE: To test the hypothesis that a chemotherapy regimen of relatively low toxicity and 11 weeks' duration (doxorubicin, cyclophosphamide, etoposide, vincristine, bleomycin, and prednisolone [VAPEC-B]) is at least as effective in terms of disease control as 6 months' treatment with chlorambucil, vinblastine, procarbazine, and prednisone/etoposide, vincristine, and doxorubicin (ChlVPP/EVA hybrid), which is associated with a high risk of permanent sterility. PATIENTS AND METHODS: Two hundred eighty-two patients with previously untreated Hodgkin's disease, clinical stages I/II (plus mediastinal bulk and/or B symptoms) and clinical stages III/IV were randomized at three United Kingdom and one Italian center to receive either six monthly cycles of ChlVPP/EVA hybrid or 11 weekly cycles of VAPEC-B. After chemotherapy and a restaging evaluation, radiotherapy was administered to sites of previous bulk or residual radiographic abnormality before patients were observed off treatment. RESULTS: Further accrual to the trial was halted at the planned third interim analysis in September 1996. After a median follow-up of 4.9 years, freedom from progression (FFP), event-free survival (EFS), and overall survival (OS) are all significantly better in the population treated with ChlVPP/EVA than VAPEC-B, where the comparative 5-year results are 82% and 62% (FFP), 78% and 58% (EFS), and 89% and 79% (OS), respectively. The superiority of ChlVPP/EVA was seen in both low-risk and intermediate/high-risk patients, although subset analysis suggested that ChlVPP/EVA and VAPEC-B produce equivalent results in the best-prognosis patients (Hasenclever score

Spontaneous fracture of the outlet catheter of a totally implanted catheter system (Port-A-Cath).

A case of spontaneous fracture of the outlet catheter of a totally implanted catheter system (Port-A-Cath) is presented. The outlet catheter was fractured at the entrance into the left subclavian vein twenty-one weeks after insertion and the distal part was embolized in the right ventricle. The embolized catheter fragment was retrieved by a 'goose-neck' snare via the right femoral vein. The awareness of a possible spontaneous fracture of the outlet catheter of a totally implanted catheter system (Port-A-Cath) is important to prevent accidental spillage of potent cytotoxic substances.

Use of plasma ferritin concentration to diagnose iron deficiency in elderly patients.

AIMS: To determine a concentration of ferritin below which the possibility of iron deficiency should be considered in elderly patients. METHODS: Consecutive new referrals to a geriatric unit (n = 472) were studied prospectively. Full blood count, ferritin, serum vitamin B12 and red cell folate were measured for all patients. A blood film was assessed independently by three haematologists for features of iron deficiency. For those with ferritin of 12-45 ng/ml, bone marrow aspirates were performed and examined for the presence of stainable iron. When possible, a trial of oral iron was given to those with ferritin of < or = 45 ng/ml and response was determined by re-measurement of full blood count and ferritin after a minimum of three weeks of treatment. RESULTS: Bone marrow examination was performed in 32 patients with ferritin of 12-45 ng/ml, of whom 27 (84%) had absent stainable iron, suggesting that most elderly patients with ferritin in this range have iron deficiency. Compared with those with ferritin of 100-299 ng/ml, in whom iron stores were presumed to be normal, patients with ferritin of 12-45 ng/ml had a significantly lower mean haemoglobin and mean red blood cell volume. Furthermore, patients with ferritin up to 75 ng/ml had a significantly higher mean red cell distribution width, and were more likely to have an iron deficient blood film. CONCLUSION: Iron deficient erythropoiesis can occur in elderly patients with ferritin up to 75 ng/ml. This is much higher than the lower limit of the "normal" range usually quoted for younger subjects; this difference should be taken into account when ferritin concentrations are interpreted in elderly patients.

Should hyposplenic patients receive prophylaxis against bacterial infection?

The risk of overwhelming septicaemia, most commonly due to encapsulated organisms, is well recognised post-splenectomy. Although a similar risk is documented in hyposplenic patients, many physicians do not routinely give prophylaxis here. We report the case of a 41 year old woman with adult onset coeliac disease who developed pneumococcal meningitis resulting in severe residual disability and suggest that prophylaxis should be given to such individuals who have evidence of reduced splenic function.

Mixed colony formation in vitro by the heterogeneous compartment of multipotential progenitors in human bone marrow.

The physiology of the human haemopoietic primitive progenitor populations can be studied in normal and disease states by clonal in vitro cultures in which the primitive progenitor cells proliferate and differentiate to form mixed colonies. For many applications it is essential that such assays detect a high proportion of primitive progenitor cells. We describe an in vitro assay which detects a high incidence of human CD34+ multipotential progenitor cells. Bone marrow mononuclear cells (MNC) or selected CD34+ cells were plated at low cell concentrations in semisolid agar cultures with synergizing growth factor combinations. The optimum growth factor combination of conditioned medium from Mia PaCa-2 cells (Mia-CM), recombinant granulocyte-macrophage colony-stimulating factor and recombinant stem cell factor (SCF) supported the formation of macroscopic (> or = mm) colonies (97% of which were multilineage), at an average incidence of 250/10(5) MNC. The colony-forming cells (human colony-forming unit, type A) detected, showed a low cycling status (7.3%) and the macroscopic colonies had a high replating efficiency (46%), reflecting their probable primitive nature. This assay should prove invaluable, for studies on the regulation of proliferation of the multipotential compartment and in studies involving the assessment of these cells in transplantation and neoplastic disease.

Use of the erythrogram in the diagnosis of iron deficiency in elderly patients.

In elderly patients the diagnosis of iron deficiency from full blood count indices is often difficult. We assessed an automated technique (numerical data of the erythrogram; Technicon H*1) by which the proportions of microcytic (< 60 fl) and/or hypochromic (< 28 g.dl-1) red blood cells are determined. Of 472 elderly patients investigated, 100 (21%) were found to have iron deficiency (plasma ferritin < or = 45 ng.ml-1). Less than two-thirds of patients with iron-deficient erythropoiesis (anaemia or microcytosis) had increased proportions of hypochromic and/or microcytic red blood cells. Furthermore, the erythrogram was not sensitive in detecting latent or early iron deficiency. The erythrogram also lacked specificity for iron deficiency anaemia as many patients with mild normocytic anaemia associated with chronic inflammatory disease had increased proportions of hypochromic and/or microcytic red blood cells. Although patients with iron deficiency had increased proportions of hypochromic normocytic (p < 0.01) and normochromic microcytic red blood cells (p < 0.05) compared to those with chronic inflammatory disease and normal or raised iron stores (ferritin > or = 100 ng.ml-1, n = 32), there was a large overlap between these two groups, and the grossly elevated erythrogram results in patients with iron deficiency were almost always associated with a mean cell volume (MCV) < 80 fl, whereas none of the patients with chronic inflammatory disease and normal or raised iron stores had an MCV < 80 fl. Thus the erythrogram does not appear to be of value in the routine assessment of iron status in elderly patients.

The prognostic significance of the CD34 antigen in acute myeloid leukaemia.

The prognostic value of CD34 expression on leukaemic blast cells was assessed in 38 patients with acute myeloid leukaemia. Nineteen patients had more than 10% CD34 positive blast cells. Median survival for the CD34 positive patients was 125 days and for the CD34 negative patients the median survival has not yet been reached at day 575 (p = 0.06). Of those patients who received intensive chemotherapy, CD34 positive patients (n = 13) had a median survival of 150 days while for CD34 negative patients (n = 14) the median survival has not yet been reached (p = 0.01). Adjustment for age and pre-existing myelodysplastic syndrome did not affect the correlation of CD34 positivity with survival (p = 0.02). Over the period of observation (median 10 months, range 2-19 months) the relative risk of death was 5 times greater for the CD34 positive patients. This study suggests that CD34 expression is an adverse prognostic marker, independent of age and pre-existing myelodysplasia.

Immunohistochemical and functional studies of glycoprotein 60 (gp60) in platelets.

We showed by immunofluorescence, immunoelectron microscopy and Western blot analysis that the plasma glycoprotein (gp60), an Fc gamma binding protein which inhibits complement-mediated prevention of immune precipitation, is present in platelets. The gp60 content of platelets in normal individuals and patients with rheumatoid arthritis was similar (mean 0.028 and 0.024 fg/platelet respectively). Immunoelectron microscopic studies showed that gp60 was present in the cytoplasm and the surface connecting structures but not in the alpha granules, dense granules or lysosomes. Using this technique gp60 was also found on platelet membranes, an observation which was confirmed by immunofluorescence. Activation of platelets with thrombin, calcium ionophore, and immune complexes (IC) resulted in the release of the contents of the alpha granules (beta-thromboglobulin), dense granules (5-hydroxytryptamine) and lysosomes (beta-glucuronidase) but did not induce gp60 secretion. The inability of Fab anti-gp60 to inhibit IC-mediated platelet aggregation and of F(ab')2 anti-gp60 to produce platelet aggregation suggested that IC-mediated platelet aggregation did not occur as a result of the interaction of IC with platelet gp60. However, as the preincubation of IC with purified gp60 produced dose-dependent inhibition of the ability of IC to aggregate platelets it is possible that fluid-phase plasma gp60 modulates the interaction of IC with platelets.

Recovery of CD3+ and CD5- lymphocyte subpopulation after autologous bone marrow transplantation and chemotherapy.

Although most circulating T cells in normal subjects express both CD3 and CD5 antigens on the cell surface, a small number lack the CD5 antigen. Recipients of allogeneic bone marrow transplants develop increased numbers of CD3+ CD5- cells, particularly those who develop graft versus host disease (GVHD). This CD3+ CD5- population may rise transiently in patients who have received an autologous bone marrow transplant (BMT) and in patients following completion of intensive chemotherapy for acute myeloid leukaemia (AML). These findings suggest that these CD3+ CD5- cells are a normal component of the regenerating lymphoid system after BMT or chemotherapy.

CD5-T lymphocytes in renal transplant recipients.

The CD3+CD5--subpopulation of T cells has been shown to be increased in patients following allogeneic bone marrow transplantation, and a statistical association has been found with graft-versus-host disease (GVHD). We studied this population in renal transplant recipients. There was no correlation with rejection episodes but we found an increase in this CD3+CD5--population in patients on cyclosporin, and we suggest that these cells may be involved in the mechanism of action of this drug. In patients on azathioprine the absolute number of CD3+CD5--lymphocytes is reduced, along with other lymphoid subpopulations.

Acute Cardiotoxicity After Daunorubicin in Acute Myeloid Leukaemia.

Use of the anthracycline antibiotics daunorubicin and adriamycin as antineoplastic agents is limited by dose-dependent, late cardiac toxicity. We describe a patient who developed fatal cardiogenic shock after comparatively low dose daunorubicin early in the treatment of acute myeloid leukaemia (A.M.L.). She was young with no previous cardiac history: investigations for an infectious aetiology were negative and at post-mortem there was no evidence of leukaemic infiltration. This unusual case demonstrates that standard doses of daunorubicin in A.M.L. may be followed early in the treatment by severe cardiac damage.

Angiotropic B-cell lymphoma (malignant angioendotheliomatosis): failure of systemic chemotherapy.

A 65-year-old female with angiotropic B-cell lymphoma is reported. Despite the absence of systemic involvement on formal staging and the favourable response of the cutaneous lesions to triple systemic chemotherapy with prednisolone, vincristine and cyclophosphamide, postmortem findings showed that death was due to widespread disease dissemination.

Radon and Acute Lymphoblastic Leukaemia.

The incidence of Acute Lymphoblastic Leukaemia (A.L.L.) in an L.R.P. data collection survey has been compared with the indoor radon and gamma-ray exposure in 22 administrative counties in England and Wales. There is a strong correlation (r = 0.56, p < 0.01) for the incidence of childhood A.L.L. and indoor radon concentration. Weaker correlations were present in adults and no correlation with gamma-rays were obtained. A weak negative association of Hodgkin's Disease with indoor gamma-rays was found. This data adds to the accumulating evidence suggesting an association between indoor radon and acute leukaemia.

Endotoxaemia, fever and clinical status in immunosuppressed patients: a preliminary study.

A prospective study was performed in order to find out whether endotoxaemia assays are clinically relevant in neutropenic patients. In a group of 10 immunocompromised patients, serial haematological, bacteriological and clinical investigations were done in parallel with serial plasma endotoxin assays. The chromogenic modification of the Limulus amoebocyte lysate (LAL) assay for endotoxin used in this study had a sensitivity of less than 10 pg endotoxin per ml plasma. It was found that endotoxaemia was associated with Gram-negative bacteraemia but infection with Gram-negative bacteria did not always produce endotoxaemia. Furthermore, infections with Gram-positive bacteria and administration of blood products may lead to raised endotoxin values. Endotoxin assays may be of value for elucidating mechanisms of fever in immunocompromised patients but it seems unlikely that routine assays of endotoxin will help in the clinical management of these patients.