Red cell and platelet transfusion burden following myeloablative allogeneic haemopoietic stem cell transplantation.

BACKGROUND: Adult allogeneic haemopoietic stem cell transplant (HSCT) usually requires blood transfusion support of red cells and platelets. There are few studies describing transfusion burden after allogeneic HSCT. AIMS: This study aims to quantify and identify determinants of transfusion burden after allogeneic HSCT to improve planning, inventory management and patient counselling. METHODS: A retrospective audit of blood use (red cells and platelets) of all adult HSCT (n = 169) was performed over an 8-year period extracted from pathology and hospital databases. ABO compatibility, graft type, conditioning regimens and patient factors were analysed for up to 12 months post transplant. RESULTS: Transfusion burden was lower than expected and lower than reported by other groups. The median number of units transfused was four red cells and four platelets by day 30, and six red cells and six platelets by day 365. The median time to transfusion independence was 12 days for red cells and 16 days for platelets. Factors associated with increased red cell use included sex, disease stage, graft type (cord blood) and ABO compatibility. Disease stage and graft type (cord blood) were associated with increased platelet transfusion. CONCLUSIONS: Donor and patient characteristics are associated with transfusion burden after allogeneic HSCT. Determining transfusion burden in HSCT and identifying determinants of increased transfusion use assist in inventory planning and patient information.

Cord blood transplantation in Western Australia.

BACKGROUND/AIMS: Thirty-one umbilical cord blood transplants performed in Western Australia were retrospectively examined in order to document local experience and relevant prognostic factors. Three cord units were from human leucocyte antigen-matched siblings and the remainder were unrelated single (n= 22) or double (n= 6) cord blood transplants. METHODS: Twenty patients were transplanted for malignant conditions and 11 for non-malignant conditions. Cord units contained a median of 5.6 × 107 total nucleated cells/kg and 1.4 × 105 CD34+ cells/kg. Cumulative incidence of neutrophil engraftment was 76% at day 60. RESULTS: Of those who did not engraft, two patients remain alive following subsequent allogeneic bone marrow transplant. There were no deaths caused by graft-versus-host disease. Overall survival at median follow up of 28 months was 62%. Two year overall survival was influenced by type of disease (non-malignant = 91 ± 9% vs malignant = 41 ± 13%, P= 0.005), total nucleated cell dose (>3.5 × 107/kg = 87 ± 9% vs <3.5 × 107/kg = 34 ± 15%, P= 0.01) and CD34 dose (>1.7 × 105/kg = 92% vs <1.7 × 105/kg = 46%, P= 0.04). Age and human leucocyte antigen match did not influence survival. Four relapses occurred, all of which were fatal. CONCLUSION: Cord blood transplantation for malignant and non-malignant disease is practised in Western Australia and outcomes are satisfactory. Trends and techniques in cord blood transplantation in this state are comparable with those observed nationally and overseas. Although numbers are small, cell dose appears to be predictive of overall survival

Safety and efficacy results from an international expanded access programme to bortezomib for patients with relapsed and/or refractory multiple myeloma: a subset analysis of the Australian and New Zealand data of 111 patients.

BACKGROUND: Bortezomib has been shown to be a safe and efficacious for the treatment of relapsed and refractory multiple myeloma (MM). Here we report a subset analysis of Australian and New Zealand data from the International Extended Access Programme for bortezomib. METHODS: Patients with more than or equal to two prior lines of therapy were given bortezomib 1.3 mg/m(2) (i.v. bolus days 1, 4, 8, 11) for up to eight 21-day cycles (C). Dexamethasone, 20 mg/day p. o. on the day of, and day after, bortezomib was added after C2 for progressive disease or after C4 for stable disease. Efficacy was assessed using modified Southwest Oncology Group criteria in the intent-to-treat group. Results were compared between the Australian and New Zealand and international cohort. RESULTS: One hundred and eleven patients from 16 centres (55% men, median age 61.9 years) had a median of 5.2 +/- 2.8 treatment cycles of bortezomib. Among them, 82% had > or =3 prior therapies. Grade 3-4 treatment-related adverse events were reported in 57 patients (52%); the most common were thrombocytopenia (25.7%), anaemia (8.3%), peripheral neuropathy (7.3%) and diarrhoea (7.3%). Responses were evaluable in 106 patients: 22% achieved a best response of complete response/response and 20% partial response (overall response rate of 42%). Median times to first and best responses were 42 days and 69 days, respectively. Compared with the international cohort, the cohorts from Australian and New Zealand showed inferior overall response rates (54 vs 42%, P = 0.001), possibly due to heavier pretreatment (82% greater than or equal to three prior therapies vs 68%, P < 0.001). CONCLUSION: Our analysis confirms that bortezomib is safe and effective in relapsed and refractory MM in a real-life clinical setting.

Skill mix - a paradigm shift?

Skill mix is a term that has drifted effortlessly into the dental vocabulary over the last few years, but what does it mean to you, and perhaps more importantly what bearing might it have on your dental career? This article and the associated session at the 2016 British Dental Conference and Exhibition will explore dental skill mix from a variety of viewpoints. This includes the historical and wider health care context, challenges and opportunities for clinicians, practices and their patients, and what its significance may be in terms of benefitting oral health at a population level.

Variable kappa gene rearrangement in lymphoproliferative disorders: an analysis of V kappa gene usage, VJ joining and somatic mutation.

We have studied a diverse group of lymphoproliferative disorders (acute lymphoblastic leukaemia (ALL), chronic lymphocytic leukaemia (CLL), non-Hodgkin lymphoma (NHL) and myeloma) to determine if V kappa gene use is random or disease-specific and whether somatic mutations (a late event in B-cell differentiation) can provide additional information on the type of B cell involved in the neoplastic clone. In this group of disorders V kappa gene selection is not random and some members of each V kappa family are preferentially rearranged. V kappa genes from the distal portion of the locus are seldom used, possibly because rearrangement of the proximal locus by deletion is more efficient than rearrangement of the distal locus by inversion. Although pseudogenes account for 46% of the V genes in the kappa locus none were ever rearranged, even in non-functional rearrangements of lambda-producing leukemias, suggesting the existence of a mechanism which down-regulates the rearrangement of pseudogenes. N regions were noted at the VJ junction in 20% of alleles (in six CLL, three NHL, two ALL and one myeloma) possibly the result of kappa-chain recombination during the early period of B-cell maturation in which TdT is expressed. Nucleotide addition or imprecise joining at the VJ junction, resulting in a shift in the reading frame, were the commonest causes of non-functional rearrangement. The occurrence of somatic mutation broadly correlated with the stage of B-cell maturation from which the different disorders are thought to arise. However, there was no strict association and somatic mutations were demonstrated in 'typical CLL' while V kappa genes were germline in some follicular lymphomas; these findings suggest either heterogeneity in the stage of B-cell maturation at which these disorders arise or some variability in the process of somatic mutation.

Correlation of bone marrow minimal residual disease and apparent isolated extramedullary relapse in childhood acute lymphoblastic leukaemia.

We have used a polymerase chain reaction (PCR) technique capable of detecting one leukaemic cell in 10(5) normal cells to monitor minimal residual disease (MRD) in a retrospective study of childhood ALL. We were particularly interested in comparing MRD findings in patients in long-term remission, bone marrow relapse and apparent isolated extramedullary relapse (EMR). Archival slides were initially studied from 21 patients. However, on subsequent analysis, only 15 patients were informative at the molecular level. All seven patients with EMR had evidence of MRD in the bone marrow at the time of relapse. Five of the seven also had evidence of bone marrow MRD prior to EMR. In one of the seven patients, MRD was not detected in a bone marrow sample studied 5 months prior to EMR. The remaining EMR patient was not studied prior to EMR. Of five patients who remained in long-term remission (mean 144 months), three did not have detectable MRD at the end of induction therapy (2 months) and all five were MRD-negative at the end of treatment (36 months). This contrasts with the three patients who relapsed in the bone marrow at 8, 15 and 88 months post-treatment and who had evidence of MRD at the end of therapy.

Molecular detection of minimal residual disease in adult and childhood acute lymphoblastic leukaemia reveals differences in treatment response.

Immunoglobulin heavy chain gene (IgH gene) rearrangements are found in the majority of patients with B lineage acute lymphoblastic leukaemia (ALL). Two hundred and three bone marrow samples from 54 patients (33 adults and 21 children) were analysed by PCR within specific time-points after diagnosis (ie 1, 2-3, 4-6 and 7-12 months) using FR1 and JH primers (fingerprinting with a sensitivity > or =1:5 x 10[3]). CDR3-derived allele specific oligoprimers (ASO to achieve a sensitivity between 1:10[4] and 1:10[5]) were applied to 12 children and 18 adults, while size of CDR3 region, oligoclonality and background problems prevented their application to the remaining patients. All patients were followed clinically for > or =24 months. Thirty adults and 16 children presented as newly diagnosed ALL, while the remaining eight patients were analysed in first or subsequent relapse. Patients destined to relapse showed a higher proportion of positive tests (> or =50%), particularly after 1 month, than in the remission group, irrespective of age. Among patients staying in remission, a decrease in MRD-positive tests occurred during the first 12 months in both age groups. However, the proportion of positive tests dropped below 15% at a later stage in adults (4-6 months) than in children (2-3 months). Among children, only patients destined to relapse were MRD positive beyond 1 month, with the exception of only one patient, still positive at 2-3 months in the remission group. The difference in MRD positivity between relapse and remission patients was statistically significant in children (P < 0.03) at any time of testing, but only at 4-6 months in adults (P < 0.01). These data suggest that resolution of MRD in ALL occurs more rapidly in children compared to adults, particularly within the first 6 months. Children and adults, studied in first or subsequent relapse, showed a higher proportion of positive tests during reinduction compared to newly diagnosed patients.

Effects of glycosylated recombinant human granulocyte colony-stimulating factor after high-dose cytarabine-based induction chemotherapy for adult acute myeloid leukaemia.

The Australian Leukaemia Study Group (ALSG) investigated whether G-CSF would accelerate haemopoietic recovery after induction treatment for acute myeloid leukaemia (AML) intensified with high-dose cytarabine, and therefore improve response rates and survival. Patients were randomised to receive lenograstim (glycosylated recombinant human G-CSF) 5 microg per kg body weight subcutaneously daily from day 8 after starting chemotherapy, or no cytokine, following chemotherapy with cytarabine 3 g/m2 every 12 h on days 1, 3, 5, and 7, together with idarubicin 9 or 12 mg/m2 on days 1, 2, and 3, plus etoposide 75 mg/m2 on days 1 to 7 inclusive. Patients had untreated AML, and were aged 16 to 60 years. Overall, 54 evaluable patients were randomised to receive lenograstim and 58 to no cytokine. Patients in the lenograstim arm had a significantly shorter duration of neutropenia <0.5 x 10(9)/l compared to patients in the no cytokine arm (median 18 vs 22 days; P = 0.0005), and also shorter duration of total leucopenia <1.0 x 10(9)/l (17 vs 19 days; P = 0.0002), as well as a reduction in duration of treatment with therapeutic intravenous antibiotics (20 vs 24 days; P= 0.015) and a trend to reduced number of days with fever >38.0 degrees C (9 vs 12 days; P = 0.18). There were no differences between the two groups in platelet recovery, red cell or platelet transfusions, or non-haematological toxicities. For patients achieving CR after their first induction course, a reduction in the time to the start of the next course of therapy was observed in the lenograstim arm, from a median of 40.5 days to a median of 36 days (P = 0.082). The overall complete response rates to chemotherapy were similar, 81% in the lenograstim arm vs 75% for the no cytokine arm (P = 0.5), and there was no significant difference in the survival durations. We conclude that the granulopoietic stimulating effect of G-CSF is observed after induction therapy for AML intensified by high-dose cytarabine, resulting in an improvement in a number of clinically important parameters with no major adverse effects.

Delivery of postgraduate dental education to meet the needs of general dental practice --a case study.

In order for dental practices to gain the maximum benefit from an educational opportunity such as a course or workshop, it is important that the training received meets the needs of these practices and is delivered appropriately. This paper provides an account of an educational initiative undertaken within the Eastern deanery in 2003 and 2004, 'Essex Promoting Infection Control' (EPIC), which set out to establish training needs in infection control within general dental practices across Essex and then to design and deliver learning events to meet these needs.

Unrelated donors selected prospectively by block-matching have superior bone marrow transplant outcome.

Previous retrospective studies have demonstrated improved outcome in patients whose donors were matched for non-HLA markers in the MHC as well as for HLA genes. Forty patients receiving transplants from unrelated donors were typed prospectively for HLA and non-HLA markers. Non-HLA markers near HLA-B (beta-block markers) and in the DRB1 introns (delta-block markers) were used to assess MHC match between donors and recipient. Patients whose donors were matched at the beta- and delta-blocks had improved event free survival (63%) compared to patients whose donors were mismatched at one or both blocks (25%) (p < 0.05). Patients whose donors were matched at the beta-block had significantly less severe acute graft versus host disease (p < 0.05). In order to investigate the basis for improved outcome block matching was correlated with HLA matching as determined by DNA sequencing. Beta-block matching was highly correlated with matching for exons 2 and 3 of HLA-B but less so for HLA-C. Delta-block matching was highly correlated with matching for exon 2 of HLA DRB1. It is concluded that matching for non-HLA markers in the MHC improves matching for HLA genes. Further studies are required to determine whether matching for non-HLA markers improves outcome to a greater extent than matching for the HLA genes alone.

Urate metabolism during bone marrow transplantation.

We studied urate metabolism in 36 patients undergoing both allogeneic and autologous bone marrow transplantation (BMT) without allopurinol. Most patients had low tumour burdens. Three different preparative regimens were used; busulphan/cyclophosphamide (BUCY); BCNU, etoposide, ara-C and melphalan (BEAM) and cyclophosphamide/total body irradiation (CY/TBI). Urate excretion rose during each of the regimens but the pattern of excretion varied with each regimen. Urate excretion remained elevated 72 h after completion of BEAM and BUCY, possibly reflecting the prolonged action of some of the agents used, e.g. melphalan, busulphan and etoposide. Urinary urate concentrations were unchanged compared with pre-chemotherapy levels reflecting the adequacy of the hydration protocol. No significant rise in creatinine was seen and no cases of tumour lysis syndrome occurred. Serum uric acid levels were a poor reflection of urate production, falling in most patients, and are an unreliable end-point for decisions regarding prophylaxis. BMT can be safely undertaken in patients with low tumour loads without allopurinol if an adequate urine volume is maintained. In this series, high levels of urate excretion often persisted for 72 h after the completion of conditioning and adequate hydration should be ensured during this period.

Infections in patients managed at home during autologous stem cell transplantation for lymphoma and multiple myeloma.

A group of 51 patients with multiple myeloma, non-Hodgkin's lymphoma or Hodgkin's disease receiving high-dose chemotherapy and autologous peripheral blood stem cell rescue received chemotherapy and clinical care in the peritransplant period at home. This group was compared with 88 cases with the same diagnoses, receiving the peripheral stem cell transplant over the same time period as an inpatient in a high efficiency particulate air filtered bone marrow transplant unit. Patients were treated at home based on choice, geographic accessibility, availability of an educated care giver and a clean home environment, and comprehension of the concepts of infection and aseptic techniques. Febrile neutropenia and sepsis were not increased in the home group and no episodes of septic shock were seen in this group. Patients at home received prophylactic oral ciprofloxacin and roxithromycin during the phase when the absolute neutrophil count was < 1 x 10(9)/l. Fewer gram-negative infections, but no diminution in gram-positive infections or in the rate of fever were seen in patients at home. Empiric therapy with a third generation cephalosporin, teicoplanin and tobramycin was instituted in 31 patients who developed a fever greater than 38.5 degrees C. Of this group of 31, 18 required admission to hospital, 12 because of febrile neutropenia which persisted or was considered unsuitable for management at home due to sepsis. The remaining 13 with febrile neutropenia remained at home throughout, as did the 20 cases not developing neutropenic fever. This study demonstrates the feasibility of managing carefully selected patients in their home environment when at risk from febrile neutropenia or other septic complications following autologous peripheral stem cell support.

A phase II study of Rituximab in rheumatoid arthritis patients with recurrent disease following haematopoietic stem cell transplantation.

Haematopoietic stem cell transplantation (HSCT) has been used recently as an effective therapy in patients with resistant rheumatoid arthritis (RA). Although disease control occurs in the majority of cases, recurrence is common, often coinciding with B-cell reconstitution. We hypothesized that Rituximab, a monoclonal anti-CD20 antibody, would have activity in this group of patients. We treated 10 RA patients (8F:2M, median age 46.5 years), who had recurrent disease post HSCT. All patients received two doses of Rituximab 1 g, 2 weeks apart with no major adverse sequelae and were followed for 12 months. A total of eight out of 10 patients experienced major clinical responses as measured by the American College of Rheumatology (ACR) criteria, with 50-70% improvement in disease parameters. Responses were equivalent to previous responses attained with HSCT. Disease responses were maximal at 4-8 months post Rituximab and correlated with B-cell lymphopenia and a reduction of rheumatoid factor titre. Disease recurrence occurred in 6/9 responders within 12 months and four patients were subsequently retreated, with major responses again attained. This study provides further evidence that B-cell depletion leads to a significant improvement in disease activity in patients with severe RA and provides data for future trials of HSCT and Rituximab therapy.

Mycobacterial central venous catheter tunnel infection: a difficult problem.

We report our experience of non-tuberculous mycobacterial infection associated with the tunnel of Hickman-Broviac central venous catheters in immunosuppressed patients with haematological malignancies undergoing high-dose chemotherapy supported by BMT. The problem is rare and difficult to treat. Our cases are unique in developing tunnel site mycobacterial infection well after the tunnelled catheters were removed. We diagnosed one case of Mycobacterium chelonae, which is a well-documented cause of such infections, and two cases of Mycobacterium haemophilum, which are the first reported cases in this setting. Early wide surgical excision of the infected tunnel site and prolonged antibiotic therapy is necessary. Despite these measures recurrence occurred in two cases. Close liaison with the microbiology laboratory is needed to ensure the appropriate culture media and conditions are used for these fastidious organisms. Empiric antibiotic regimens should be based on the likely organism. Drugs active against M. chelonae and M. haemophilum should be included.

Investors in people: what is it all about?

Recently, there has been a proliferation of press releases from organizations recognized as Investors in People including the BDTA, the DPB, the BDA and many individual dental practices. Indeed, the number of dental practices recognized as Investors in People has more than doubled in the last six months. What is this sudden interest in Investors in People within the dental profession all about? This article is a guide to what the Investors in People (IiP) standard is, what relevance it has to dental practice and what benefits can be gained from working towards this standard. I have used my own experiences in gaining the standard in our dental practice to act as an example throughout the article.

Fludarabine Melphalan reduced-intensity conditioning allotransplanation provides similar disease control in lymphoid and myeloid malignancies: analysis of 344 patients.

This was an Australasian Bone Marrow Transplant Recipient Registry (ABMTRR)-based retrospective study assessing the outcome of Fludarabine Melphalan (FluMel) reduced-intensity conditioning between 1998 and 2008. Median follow-up was 3.4 years. There were 344 patients with a median age of 54 years (18-68). In all, 234 patients had myeloid malignancies, with AML (n=166) being the commonest indication. There were 110 lymphoid patients with non-hodgkins lymphoma (NHL) (n=64) the main indication. TRM at day 100 was 14% with no significant difference between the groups. OS and disease-free survival (DFS) were similar between myeloid and lymphoid patients (57 and 50% at 3 years, respectively). There was no difference in cumulative incidence of relapse or GVHD between groups. Multivariate analysis revealed four significant adverse risk factors for DFS: donor other than HLA-identical sibling donor, not in remission at transplant, previous autologous transplant and recipient CMV positive. Chronic GVHD was associated with improved DFS in multivariate analysis predominantly due to a marked reduction in relapse (HR:0.44, P=0.003). This study confirms that FluMel provides durable and equivalent remissions in both myeloid and lymphoid malignancies. Disease stage and chronic GVHD remain important determinants of outcome for FluMel allografting.

Evaluation of the end user (dentist) experience of undertaking clinical audit in the post April 2001 general dental services (GDS) scheme.

INTRODUCTION: A mandatory scheme for clinical audit in the general dental services (GDS) was launched in April 2001. No evaluation of this mandatory scheme exists in the literature. This study provides an evaluation of this scheme. More recently a new dental contract was introduced in the general dental services (GDS) in April 2006. Responsibility for clinical audit activities was devolved to primary care trusts (PCTs) as part of their clinical governance remit. METHODS: All GDPs within Essex were contacted by letter and invited to participate in the research. A qualitative research method was selected for this evaluation, utilising audio-taped semi-structured research interviews with eight general dental practitioners (GDPs) who had taken part in the GDS clinical audit scheme and who fitted the sampling criteria and strategy. The evaluation focused on dentists' experiences of the scheme. RESULTS: The main findings from the analysis of the GDS scheme data suggest that there is clear evidence of change following audit activities occurring within practices and for the benefit of patients. However, often it is the dentist only that undertakes a clinical audit project rather than the dental team, there is a lack of dissemination of project findings beyond the individual participating practices, very little useful feedback provided to participants who have completed a project and very limited use of formal re-auditing of a particular topic. CONCLUSIONS: This study provides evaluation of the GDS clinical audit scheme. Organisations who propose to undertake clinical audit activities in conjunction with dentistry in the future may benefit from incorporating and/or developing some findings from this evaluation into their project design and avoiding others.