Outcome of patients with myelodysplastic syndromes: experience from a single institution in South Australia.

AIMS: To study disease characteristics of adult patients with myelodysplastic syndromes (MDS) in South Australia and to analyse their outcome and survival. METHODS: One hundred and eight adult patients with confirmed MDS from marrow biopsies in the 76-month period before April 2006 were retrospectively included in an MDS database. RESULTS: The median age at diagnosis of this cohort was 70 years, with skewing of refractory anaemia with excess blasts and refractory cytopenia with multilineage dysplasia in the younger patients. Clonal cytogenetic abnormalities were present in 42% of patients. Median survival was 48 months, and secondary transformation to acute myeloid leukaemia was seen in 27%. Survival, according to the World Health Organization subtypes in ascending order, was refractory anaemia with excess blasts, refractory anaemia, refractory anaemia with ringed sideroblast, refractory cytopenia with multilineage dysplasia and del(5q). The International Prognostic Scoring System score stratified MDS patients into different risk groups and effectively discriminated significantly different survivals, ranging from a median 4 months for high-risk patients to 72 months for low-risk patients. CONCLUSION: An MDS database provides useful information regarding the disease characteristics and survival of MDS patients in South Australia and confirms the prognostic usefulness of the International Prognostic Scoring System. The future prospective collection of results will be invaluable in evaluating the effect of novel therapies on patient prognosis.

Angioedema, lymphoproliferative disorder and angiotensin-converting enzyme inhibitors: masking of diagnosis by corticosteroids.

Angioedema is a relatively common clinical disorder. Although most cases are idiopathic, the use of angiotensin-converting enzyme inhibitors is a well recognized cause of angioedema and a further rare but important diagnostic consideration is acquired C1 inhibitor deficiency. We discuss the diagnosis of C1 inhibitor deficiency in angioedema, with reference to a case in which the diagnosis was initially masked by the use of corticosteroids, which normalized the C1 inhibitor level.

Clinical audit of the use of fresh-frozen plasma and platelets in a tertiary teaching hospital and the impact of a new transfusion request form.

AIM: To carry out an audit of the appropriateness of fresh-frozen plasma (FFP) and platelets (Plt) transfusion with reference to the Australian National Health and Medical Research Council/Australian Society of Blood Transfusion Clinical Practice Guidelines, and to assess the impact of a self-educating transfusion request form. METHODS: A prospective review of the clinical indications and laboratory data in all transfusion episodes of FFP and Plt occurring in a tertiary teaching hospital in South Australia in two 2-month periods of the years 2002 and 2003. RESULTS: Reversal of warfarin has emerged as the major indication to transfuse FFP (34%). More than 72% FFP and 88% Plt were prescribed in an appropriate manner, and the majority were monitored adequately. The transfusion request form further improved the appropriate uses and was met with a satisfactory compliance. Further grounds for improvement are in FFP usage by the haematology unit and in cardiac bypass surgery, and Plt by surgical units. CONCLUSION: Clinical transfusion audit helps to identify current pattern of usage and areas of improvement. A self-educating transfusion specific request form is also beneficial.

Selected CD34 blood cell allografts for older patients: low transplant-related mortality, graft failure and acute GvHD.

BACKGROUND: Early transplant mortality is related to acute GvHD, which this study in older patients (40 to 60 years) decreased by reducing the graft T-cell number while maintaining a high CD34 cell number--by positive CD34 cell selection. Potential increased risk of relapse is addressed by giving donor leucocyte infusion (DLI) post-transplant. METHODS: CD34 cells selected by Isolex devices from leukophereses obtained from Filgrastim-treated matched sibling donors were transplanted and DLI given later if there was no GvHD. RESULTS: Selection of CD34 cells achieved a median of 5.2 million cells/kg, with minimum target for transplantation achieved in 17 of 21 donors. Median CD3 cell number was 0.24 million/kg. Engraftment was rapid and graft failure rare. Transplant-related mortality was low (6% at 3 months). Acute GvHD of >or=Grade 2 occurred in only two patients (12.5%). DLI were given to only six patients who had resolved Grade 1 or no GvHD. Eight of the 17 patients relapsed, including three of the six who had DLI. Extensive chronic GvHD developed in six of 12 evaluable patients, two of these had received DLI. Seven of the 17 patients (41%) are alive at median follow-up of 56 months. CONCLUSION: CD34 selection allows transplantation of high numbers of CD34 cells with low CD3 cell count, reducing early mortality in patients 40-60 years old because of rapid hemopoietic reconstitution and low acute GvHD incidence. Administration of DLI was often precluded by low-grade acute GvHD.

Nitrous oxide flux from landfill leachate-sawdust nitrogenous compost.

Composted nitrogenous waste has the potential to produce excessive amounts of nitrous oxide (N2O), a potent greenhouse gas that also contributes to stratospheric ozone depletion. In this laboratory study, sawdust was irrigated with varying amounts of landfill leachate with high NH4+-N content (3950 mg l(-1)). Physicochemical properties, including the amount of N2O produced, were monitored during the composting process over 28 days. A rapid decline in NH4+-N in the first 4 days and increasing NO3--N for 11 days was followed by lower but stabilized levels of available-N, even with repeated leachate irrigation. Less than 0.03% of the leachate-applied N was lost as N2O. Higher leachate applications as much as tripled N2O production, but this represented a lesser proportion overall of the total nitrogen. Addition of glucose to the composting process had no significant effect on N2O production. The derived sawdust-leachate compost supported healthy growth of Sesbania rostrata. It is concluded that compost can be produced from sawdust irrigated with landfill leachate without substantial emission of N2O, although excessive flux of N2O remains about high application rates over longer time periods.

Pulmonary nocardiosis re-visited: experience of 35 patients at diagnosis.

Pulmonary infection by Nocardia is an uncommon opportunistic infection in humans. Thirty-five patients with pulmonary nocardiosis were identified in two tertiary referral hospitals. A retrospective review of the patient characteristics, clinical and laboratory features including antimicrobial susceptibility at diagnosis was carried out. Radiological features derived from chest radiographs and CT scans were also documented. In our population, the predominant risk factors were immuno-compromised state, corticosteroid therapy, and underlying pulmonary pathology. The presenting features were similar to those previously described but disseminated infection was not common. The radiological changes were diverse and non-specific. Nocardia asteroides was the commonest species. Most Nocardia isolates were susceptible to imipenem, ceftriaxone, amikacin, and cotrimoxazole. Co-existing microbial agents are common and reflect the underlying complex disorders.

Successful peripheral blood stem cell mobilisation with filgrastim in patients with chronic myeloid leukaemia achieving complete cytogenetic response with imatinib, without increasing disease burden as measured by quantitative real-time PCR.

Imatinib mesylate (Glivec) is a selective inhibitor of bcr-abl tyrosine kinase, the product of the Philadelphia chromosome, which is the hallmark of chronic myeloid leukaemia (CML). With imatinib, complete cytogenetic response (CCR) can be achieved in over 70% of newly diagnosed patients with CML. However, the optimal long-term management of patients who achieve CCR after imatinib is unknown. With longer follow-up, it is anticipated that some patients are likely to progress and become candidates for autologous transplantation. We studied filgrastim (r-metHuG-CSF) mobilisation of peripheral blood stem cells (PBSC) in 32 patients who have achieved CCR with imatinib. Our data demonstrate that (1) the target CD34(+) cell yields of >/=2.0 x 10(6)/kg were attained with filgrastim 10 microg/kg/day, in 9/18 (50%) of patients during uninterrupted imatinib therapy, and in 10/14 (70%) when imatinib was temporarily withheld. The median CD34(+) cell yield per aphaeresis was 0.70 x 10(6)/kg (range 0.14-2.18) and 2.90 x 10(6)/kg (range 0.15-8.71) in the two groups, respectively (P&<0.005). (2) The cell yields did not correlate with the duration of imatinib administration. (3) There was no impact of the mobilisation procedure on the level of leukaemia as measured by serial blood bcr-abl levels using real-time quantitative PCR with either protocol. (4) bcr-abl remained detectable at low levels in the harvests in most but not all patients. In conclusion, filgrastim can safely be used to mobilise PBSC in patients who have achieved CCR with imatinib, but CD34(+) cell yields are significantly improved when imatinib is temporarily withheld.

Successful salvage of RAEB/AML relapsing early post allograft with FLAG-Ida conditioned mini-allograft: a report of two cases.

Management options are often limited for patients with AML or high grade myelodysplasia (MDS) relapsing within a year of allogeneic transplantation. We report, in two such patients, the use of re-induction with FLAG-Ida chemotherapy, followed by the infusion of GCSF-mobilized blood stem cells from the same HLA-matched donor. Both patients achieved durable complete remissions with good quality of life and longer disease-free survival than after the first myeloablative allografts. This mini-allograft approach offers a practical, well-tolerated salvage and a potentially curative treatment for relapsed AML/high grade MDS patients failing a first conventional myeloablative allogeneic transplants.

Combination of stem cell factor and granulocyte colony-stimulating factor mobilizes the highest number of primitive haemopoietic progenitors as shown by pre-colony-forming unit (pre-CFU) assay.

Fifty-two patients with poor prognosis carcinoma of the breast underwent peripheral blood stem cell (PBSC) mobilization using five different regimens. The yields of primitive haemopoietic progenitors were quantified by a recently described pre-colony-forming unit (pre-CFU) assay using limiting dilution analysis (LDA). Results of days 14 and 35 pre-CFU were also correlated with conventional CD34+ cell enumeration, CFU-GM (granulocyte-macrophage) and long-term culture-initiating cell (LTCIC) assays. The yield of pre-CFUs with the combination of granulocyte colony-stimulating factor (G-CSF) and stem cell factor (SCF) was significantly higher than with G-CSF alone, cyclophosphamide (Cyclo) and granulocyte-monocyte colony-stimulating factor (GM-CSF), interleukin (IL)-3 and GM-CSF, or Cyclo alone. No significant correlation between neutrophil engraftment and pre-CFU could be demonstrated. Furthermore, CFU-GM was shown to bear a stronger correlation with pre-CFU and LTCIC than CD34+ cell measurement; thus, CFU-GM remains a useful biological tool for haemopoietic stem cell assay. We conclude that the combination of G-CSF and SCF mobilizes the highest number of pre-CFUs as measured by functional pre-CFU assay, which provides an alternative measurement of primitive haemopoietic progenitors to the LTCIC assay.

Peripheral Stem Cells in Bone Marrow Transplantation. Future prospects.

Mobilized peripheral blood cells are emerging to be the main haematopoietic progenitor cell sources in both autologous and allogeneic transplantation. The superior engraftment kinetics make high-dose therapy (HDT) safer and more cost-effective. Advances in mobilization protocols will enable an adequate, efficacious and predictable progenitor cell yield for most patients, and may even permit differential mobilization of normal and tumour cells. Peripheral blood stem cell transplantation is going to make an impact on tumour control by allowing dose escalation through multiple HDT and rescues, promoting various purging manoeuvres and facilitating immunomodulatory approaches to enhance graft-versus-tumour responses. Technological advances in ex vivo expansion and manipulation of haematopoietic progenitor cell grafts will add to our armamentarium of new therapeutic approaches and broaden our dimensions in the use of peripheral blood stem cell transplantation.

Granulocyte colony-stimulating factor (G-CSF) dose-dependent efficacy in peripheral blood stem cell mobilization in patients who had failed initial mobilization with chemotherapy and G-CSF.

For 10 consecutive patients in our unit who did not show a significant rise in blood progenitor cells within 14 days following chemotherapy and G-CSF, we increased the G-CSF dose from 5 to 10 microg/kg/day (n = 9) or from 10 to 15 microg/kg/day (n = 1). As a result, there were significant increases in total yield as well as yield per apheresis of mononuclear cells, CD34+ cells and CFU-GM (P < 0.025, <0.01 and <0.005, respectively). After G-CSF dose escalation, six of the 10 patients had sufficient CD34+ cells for performing transplantation. These results demonstrate a dose-dependent response of progenitor cell mobilization by G-CSF when used in combination with chemotherapy. Moreover, increasing the dose of G-CSF as late as the third week of mobilization may still provide sufficient cell yield even with patients who did not show a significant mobilization with conventional doses of G-CSF.

Clinicopathological features of megaloblastic anaemia in Hong Kong: a study of 84 Chinese patients.

Megaloblastic anaemia is uncommon in Hong Kong. Eighty-four consecutive Chinese patients with megaloblastic anaemia were studied. There were 48 males and 36 females, with a median age at presentation of 67 years. Vitamin B12 deficiency was found in all cases, with none of the patients showing folate deficiency. The frequency of pernicious anaemia in our patients was higher than in other south-east Asian series but comparable with western ones. When compared with patients in the West, our cases showed the following main differences: virtual absence of folate deficiency, even in alcoholics; absence of associated gastric malignancies; and a high frequency of tuberculosis.

Unique risk factors for bacteraemia in allogeneic bone marrow transplant recipients before and after engraftment.

A study of the risk factors associated with bacteraemia in 191 allogeneic bone marrow transplant (BMT) recipients (1991-1996) was performed. In contrast to risk factors commonly cited for cancer chemotherapy, mucositis, degree of conditioning toxicity of the gut and lungs, duration of neutropenia, and severity of neutropenia and monocytopenia were not associated with bacteraemia in the pre-engraftment period, during which the only significant risk factor was late stage underlying disease (P < 0.05). After engraftment, Hickman catheter infection, and severe acute and chronic graft-versus-host disease (GVHD) were found to be independently associated with bacteraemia by multivariate analysis (P < 0.001, <0.05 and <0.05, respectively). This might be explained by intense antimicrobial prophylaxis, early empirical treatment, and non-routine use of haemopoietic growth factors. No significant difference in mortality was detected between bacteraemic and non-bacteraemic patients in both periods. Allogeneic BMT recipients are therefore a group of patients distinct from other cancer patients receiving chemotherapy at risk of developing bacteraemia. The study findings prompt consideration of a management protocol incorporating early and routine use of haemopoietic growth factors before engraftment in high-risk patients with late stage underlying malignancies, routine antimicrobial prophylaxis for acute GVHD with intense immunosuppression, and intravenous immunoglobulin therapy for chronic GVHD. Further cost-benefit analyses are warranted.

Clinical outcome of HIV-infected haemophiliac patients in Hong Kong.

About half of the haemophiliacs in Hong Kong have been infected by human immunodeficiency virus (HIV). This study aimed to determine their clinical course of progression. Forty-seven adult patients with congenital coagulation factor deficiency being followed up regularly from January 1992 onward in the Department of Medicine of Queen Mary Hospital, Hong Kong, were included in this study. Twenty were positive for HIV antibody and the remaining 27 were negative. Three other HIV-positive patients who died before 1992 were excluded. From January 1992 to June 1996, the 47 patients included in the study were followed up in the clinic every 3-6 months with regular CD4, CD8 lymphocyte counts and ß2 microglobulin levels. At the initiation of the study in January 1992, the HIV-infected patients had already a lower mean CD4 count (360.4 µL(-1) versus 658.8 µL(-1) , P<0.01), a reversed CD4/CD8 ratio (0.53) and a higher mean serum ß2 microglobulin level (1.853 µg mL(-1) versus 1.315 µg mL(-1) , P>0.05). On regular follow-up, HIV-positive patients had a more significant progressive fall in their mean CD4 count (301.6 µL(-1) versus 360.4 µL(-1) , P<0.01) and rise in their mean serum ß2 microglobulin level (2.60 µg mL(-1) , versus 1.853 µg mL(-1) , P<0.05). The CD4 and CD8 counts of HIV-positive patients were falling at a rate of 1.44 µL(-1) month(-1) and 4.03 µL(-1) month(-1) respectively. During the follow-up period, two of the 20 HIV-positive patients developed clinical acquired immunodeficiency syndrome (AIDS) at 15 and 36 months from the initiation of the study. Both patients had typical features of AIDS with a low CD4 count, reversed CD4/CD8 ratio and elevated ß2 microglobulin level. The former patient eventually died of fungal brain abscess. The remaining 18 HIV-positive patients so far remained clinically asymptomatic. Eleven patients were put on antiretroviral drug therapy when their CD4 counts fell below 200 µL(-1) . Only two of the 20 HIV-infected patients developed AIDS during the observation period of 4 years; this figure of 10% is relatively slow. Two of our patients died of AIDS before the study was initiated in 1992. Even if they were included, still only 17.4% had progressed. The figure is in the lowest rate of progression expected from Western experience. Although our study population is small, it remains unclear why our HIV-infected Chinese haemophiliacs have a slow rate of progression to AIDS.

Expression of an abnormal sized c-kit transcript in Hong Kong Chinese acute lymphoblastic leukaemia patients.

Blast cells from a majority of acute myelogenous leukaemia (AML) patients express c-kit mRNA. However, c-kit expression has not been observed in patients with acute lymphoblastic leukaemia (ALL) and lymphoproliferative disease. We report here the detection of an abnormal sized c-kit mRNA in two Hong Kong Chinese patients with pre-B ALL and common ALL.

'Superwarfarin' poisoning leading to prolonged coagulopathy.

An elderly Chinese was admitted for haemetemesis. Investigations revealed markedly prolonged clotting times that recurred every few days despite administration of fresh frozen plasma and vitamin K. The derangement in coagulation lasted more than 3 months. In view of the absence of liver disease or malabsorption syndromes, long-acting anticoagulant ('superwarfarin') ingestion was suspected. The diagnosis of rodenticide poisoning was hampered by the lack of available assays. Diagnosis of brodifacoum intoxication using HPLC was confirmed only months after prolonged treatment with high dose vitamin K1. Superwarfarin poisoning should be suspected in cases of deranged coagulation refractory to treatment since these over-the-counter rodenticides are easily available.