Michael Quinn

Should the standard dimethyl sulfoxide concentration be reduced? Results of a European Group for Blood and Marrow Transplantation prospective noninterventional study on usage and side effects of dimethyl sulfoxide.

Dimethyl sulfoxide (DMSO) is essential for the preservation of liquid nitrogen–frozen stem cells, but is associated with toxicity in the transplant recipient.

RAGE regulates immune cell infiltration and angiogenesis in choroidal neovascularization

Purpose RAGE regulates pro-inflammatory responses in diverse cells and tissues. This study has investigated if RAGE plays a role in immune cell mobilization and choroidal neovascular pathology that is associated with the neovascular form of age-related macular degeneration (nvAMD). Methods RAGE null (RAGE−/−) mice and age-matched wild type (WT) control mice underwent laser photocoagulation to generate choroidal neovascularization (CNV) lesions which were then analyzed for morphology, S100B immunoreactivity and inflammatory cell infiltration. The chemotactic ability of bone marrow derived macrophages (BMDMs) towards S100B was investigated. Results RAGE expression was significantly increased in the retina during CNV of WT mice (p<0.001). RAGE−/− mice exhibited significantly reduced CNV lesion size when compared to WT controls (p<0.05). S100B mRNA was upregulated in the lasered WT retina but not RAGE−/− retina and S100B immunoreactivity was present within CNV lesions although levels were less when RAGE−/− mice were compared to WT controls. Activated microglia in lesions were considerably less abundant in RAGE−/− mice when compared to WT counterparts (p<0.001). A dose dependent chemotactic migration was observed in BMDMs from WT mice (p<0.05–0.01) but this was not apparent in cells isolated from RAGE−/− mice. Conclusions RAGE-S100B interactions appear to play an important role in CNV lesion formation by regulating pro-inflammatory and angiogenic responses. This study highlights the role of RAGE in inflammation-mediated outer retinal pathology.

The finding of reduced estimated glomerular filtration rate is associated with increased mortality in a large UK population

BACKGROUND CKD as defined by KDIGO/KDOQI has been shown to affect ~ 8.5% of the UK population. The prevalence of CKD in the UK is similar to that in the USA, yet incident dialysis rates are dramatically different. This retrospective cohort study investigates the association between reduced kidney function and mortality in a large UK population. METHODS All serum creatinine results covering Northern Irelands 1.7 million population were collected between 1 January 2001 and 31 December 2002. Estimated glomerular filtration rates (eGFR) were calculated for all serum creatinine measurements using four-variable MDRD equation (IDMS aligned). Patients were followed up for both all-cause and cardiovascular mortality data until the end of December 2006. Patients on renal replacement therapy were excluded. Subgroup analysis in the 75,345 subjects enrolled within a parallel primary care study permitted additional survival analysis with adjustment for traditional cardiovascular risk factors. RESULTS A total of 1,967,827 serum creatinine results from 533,798 patients were collected. During the period of follow-up, 59,980 deaths occurred. In multivariate survival analysis, using eGFR as a time-varying covariate, a graded association between CKD (defined by eGFR) and all-cause mortality was identified. Compared with participants with an eGFR of > 60 mL/min/1.73 m(2), the adjusted hazard ratios (and 95% confidence intervals) for participants with an eGFR of 45-59 mL/min/1.73 m(2) was 1.02 (0.99-1.04), an eGFR of 30-44 mL/min/1.73 m(2) was 1.44 (1.40-1.47), an eGFR of 15-29 mL/min/1.73 m(2) was 2.12 (2.05-2.20) and an eGFR of < 15 mL/min/1.73 m(2) was 3.46 (3.24-3.70). Significantly, increased all-cause mortality was associated with an eGFR < 45 mL/min/1.73 m(2) following adjustment for age and gender. The association between cardiovascular mortality and reduced renal function continued to be significant for participants with an eGFR of 45-65 mL/min/1.73 m(2). Subgroup analysis in 75,345 individuals with more detailed clinical information available confirmed this association following adjustment for traditional cardiovascular risk factors in addition to age and gender. CONCLUSIONS This study demonstrates a graded association between reduced renal function as represented by eGFR and mortality in a UK population. The all-cause and cardiovascular mortality risk increases sharply when estimated GFR falls < 45 mL/min/1.73 m(2). The association between an eGFR measured between 45 and 65 mL/min/1.73 m(2) and cardiovascular mortality persists in this cohort and highlights the ongoing uncertainty in accurately categorizing renal dysfunction.

Optimizing the management of patients with spinal myeloma disease

Myeloma is one of the most common malignancies that results in osteolytic lesions of the spine. Complications, including pathological fractures of the vertebrae and spinal cord compression, may cause severe pain, deformity and neurological sequelae. They may also have significant consequences for quality of life and prognosis for patients. For patients with known or newly diagnosed myeloma presenting with persistent back or radicular pain/weakness, early diagnosis of spinal myeloma disease is therefore essential to treat and prevent further deterioration. Magnetic resonance imaging is the initial imaging modality of choice for the evaluation of spinal disease. Treatment of the underlying malignancy with systemic chemotherapy together with supportive bisphosphonate treatment reduces further vertebral damage. Additional interventions such as cement augmentation, radiotherapy, or surgery are often necessary to prevent, treat and control spinal complications. However, optimal management is dependent on the individual nature of the spinal involvement and requires careful assessment and appropriate intervention throughout. This article reviews the treatment and management options for spinal myeloma disease and highlights the value of defined pathways to enable the proper management of patients affected by it.

Patterns of hospitalisation before and following initiation of haemodialysis: a 5 year single centre study

Background The utilisation of healthcare resources by prevalent haemodialysis patients has been robustly evaluated with regard to the provision of outpatient haemodialysis; however, the impact of hospitalisation among such patients is poorly defined. Minimal information is available in the UK to estimate the health and economic burden associated with the inpatient management of prevalent haemodialysis patients. The aim of this study was to assess the pattern of hospitalisation among a cohort of haemodialysis patients, before and following their initiation of haemodialysis. In addition the study sought to assess the impact of their admissions on bed occupancy in a large tertiary referral hospital in a single region in the UK. Methods All admission episodes were reviewed and those receiving dialysis with the Belfast City Hospital Programme were identified over a 5 year period from January 2001 to December 2005. This tertiary referral centre provides dialysis services for a population of approximately 700 000 and additional specialist renal services for the remainder of Northern Ireland. The frequency and duration of hospitalisation, and contribution to bed day occupancy of haemodialysis patients, was determined and compared to other common conditions which are known to be associated with high bed occupancy. In addition, the pattern and timing of admissions in dialysis patients in relation to their dialysis initiation date was assessed. Results Over the 5 year study period, 798 haemodialysis patients were admitted a total of 2882 times. These accounted for 2.5% of all admissions episodes; the median number of admissions for these patients was 3 (2–5) which compared with 1 (1–2) for non-dialysis patients. The majority of first hospitalisations (54%) were within 100 days before or after commencement of maintenance dialysis therapy. In all clinical specialties the median length of stay for haemodialysis patients was significantly longer than for patients not on haemodialysis (p=0.004). In multivariate analysis with adjustment for age, gender, and other clinically relevant diagnostic codes, maintenance haemodialysis patients stayed on average 3.75 times longer than other patient groups (ratio of geometric means 3.75, IQR 3.46–4.06). Conclusions Maintenance haemodialysis therapy is an important risk factor for prolonged hospitalisation regardless of the primary reason for admission. Such patients require admission more frequently than the general hospital population, particularly within 100 days before and after initiation of their first dialysis treatment.

Re‐transplantation after bortezomib‐based therapy

Whilst the use of high dose alkylating agents and autologous stem cell transplantation (ASCT) has a fundamental role in consolidating initial anti-tumour induction therapy, its role in salvage therapy consolidation remains to be determined. Bortezomib has been shown to be an effective agent at first and subsequent relapse, with responses equivalent or better than the response to previously used conventional therapies in first-line therapy (Richardson et al, 2005; Laubach et al, 2009). Combining bortezomib re-induction with a second ASCT after maximal anti-tumour response is, therefore, an attractive concept. Accordingly, we undertook a retrospective review of patients proceeding to a second ASCT after bortezomib-based re-induction therapy. Patients undergoing a second ASCT after progression from an initial ASCT and subsequent bortezomib re-induction therapy in 12 centres were identified (n = 40). Detailed information on the patients was obtained through anonymized clinical data retrieval forms, capturing critical patient and disease-specific factors including response to initial induction therapy, response to first ASCT, time to progression, subsequent therapies, bortezomib-based re-induction therapy and response to second ASCT (including the type of transplant and stem cell source). Response to therapy was categorized according to the International Myeloma Working Group criteria (Durie et al, 2006). Kaplan Meier plots were made using the Statistical Package for the Social Sciences (spss) IBM, Chicago, Illinois, USA. There were insufficient cytogenetic data for analysis. A total of 40 patients were identified in this retrospective study. Two patients had planned reduced intensity allogeneic (RIC-Allo) transplants after their second autologous transplant and weren excluded from further analysis. Patient characteristics including age, sex, type of myeloma, therapy prior to their first and second transplants are shown in Table Ia. One patient who relapsed 10 months after their bortezomib therapy was transplanted in relapse. All other patients were transplanted prior to disease progression. Twenty-six patients were treated with a combination of bortezomib and dexamethasone, eight patients had PAD chemotherapy (bortezomib, adriamycin and dexamethasone (Oakervee et al, 2005). Two patients had bortezomib monotherapy, one patient had bortezomib plus intravenous melphalan and one patient had bortezomib plus cyclophosphamide, dexamethasone and idarubicin. The median number of cycles of bortezomib therapy was 4 (range 2–12). Patients receiving PAD chemotherapy also had a median of four cycles

UK consensus statement on the use of plerixafor to facilitate autologous Peripheral Blood Stem Cell collection to support high‐dose chemoradiotherapy for patients with malignancy

Plerixafor is a CXC chemokine receptor (CXCR4) antagonist that mobilizes stem cells in the peripheral blood. It is indicated (in combination with granulocyte‐colony stimulating factor [G‐CSF]) to enhance the harvest of adequate quantities of cluster differentiation (CD) 34+ cells for autologous transplantation in patients with lymphoma or multiple myeloma whose cells mobilize poorly. Strategies for use include delayed re‐mobilization after a failed mobilization attempt with G‐CSF, and rescue or pre‐emptive mobilization in patients in whom mobilization with G‐CSF is likely to fail. Pre‐emptive use has the advantage that it avoids the need to re‐schedule the transplant procedure, with its attendant inconvenience, quality‐of‐life issues for the patient and cost of additional admissions to the transplant unit. UK experience from 2 major centers suggests that pre‐emptive plerixafor is associated with an incremental drug cost of less than £2000 when averaged over all patients undergoing peripheral blood stem cell (PBSC) transplant. A CD34+ cell count of <15 µl−1 at the time of recovery after chemomobilization or after four days of G‐CSF treatment, or an apheresis yield of <1 × 106 CD34+ cells/kg on the first day of apheresis, could be used to predict the need for pre‐emptive plerixafor.

The Impact of Admissions for the Management of End-stage renal disease on hospital bed occupancy

Background: End-stage renal disease (ESRD) is increasingly prevalent but the inpatient costs associated with this condition are poorly defined due to limitations with data extraction and failure to differentiate between hospitalisation for renal and non-renal disease reasons. The impact of admissions primarily for the management of ESRD on hospital bed utilisation was assessed over a 5-year period in a large teaching hospital. Methods: All admission episodes were reviewed and the ESRD group was identified by a primary International Classification of Diseases code for ESRD or a non-specific primary renal failure code with a secondary code for ESRD. The frequency and duration of hospitalisation and contribution to bed day occupancy of this group with ESRD was determined. Results: There were 70,808 patients responsible for a total of 116,915 admissions and 919,212 bed days over the study period. Of these, 988 (1.4%) patients were admitted for the management of ESRD, accounting for 2,387 (2.0%) of admissions and utilisation of 23,011 (2.5%) bed days. After adjustment for age and gender, those admitted for ESRD management were significantly more likely to have a prolonged admission exceeding 30 days (odds ratio 1.46, 95% confidence interval 1.23–1.72, p < 0.001). When the admission was an emergency rather than an elective event, the patient was 4.6 times more likely to be hospitalised for over 30 days. Conclusions: Persons admitted for ESRD management are hospitalised more frequently and for longer than the overall inpatient population, occupying a substantial number of bed days.