HLA-matched sibling transplantation for severe aplastic anemia: impact of HLA DR15 antigen status on engraftment, graft-versus-host disease, and overall survival

The HLA class II DRB1 antigen DR15 (common alleles *1501, *1502) is an important marker in the pathobiology of severe aplastic anemia (SAA). We studied 1204 recipients of HLA-matched sibling bone marrow transplantation for SAA to determine whether HLA DR15 status (as determined by allele-level typing) affected hematopoietic recovery, graft-versus-host disease (GVHD), or overall survival (OS). In multivariate analysis, secondary graft failure rate at 2 years was lower in patients who were HLA DR15+ (hazard ratio = 0.46, P = .01). However, neutrophil recovery at day -28, platelet recovery at day -100, acute GVHD, chronic GVHD, and overall mortality were independent of DR15 status. The 5-year probabilities of OS, after adjusting for age, race, performance score, transplant-conditioning regimen, and year of transplantation, were 78% and 81% for patients who were HLA DR15+ and HLA DR15-, respectively (P = .35). In conclusion, DR15 status is associated with secondary graft failure after HLA-matched sibling bone marrow transplantation for SAA but has no significant impact on survival.     

Demographic study of leukaemia presenting within the first 3 months of life in the Northern Health Region of England

AIMS: To determine the incidence and outcome of congenital leukaemia. METHODS: Retrospective population based study of putative leukaemia arising during the first 3 months of life over an 18 year period within the Northern Health Region of England. RESULTS: Nine infants with putative leukaemia were identified. Five had acute leukaemia and four had transient myeloproliferative disorder (TMD). Trisomy 21, either as Down's syndrome or perhaps restricted to proliferating marrow cells, was present in all four infants with TMD. The incidence of congenital acute leukaemia was 8.6/10(6) live births/year, but would be less than half this value if only patients presenting within 4 weeks of birth were counted. Remission was induced in three of the five patients with acute leukaemia. One patient, who presented at birth, remains well five years after diagnosis. All four patients with TMD survive. CONCLUSIONS: Congenital leukaemia is very rare but is not inevitably fatal. Finding trisomy 21 in spontaneously dividing blood or bone marrow cells of an infant with putative acute leukaemia, particularly within 3 months of birth, should encourage a cautious clinical approach and suggests that the diagnosis might be TMD.     

Evolution of transcatheter closure of perimembranous ventricular septal defects in a single centre

Objectives : To describe the evolution of transcatheter closure of perimembranous ventricular septal defects (PMVSD) using either the Amplatzer membranous or muscular occluders in a single centre. Methods : Retrospective analysis of all patients referred for transcatheter PMVSD closure from December 2003 to December 2007. All patients met unit criteria for surgical closure. Results : There were 27 procedures on 25 patients (11 male) with a preprocedure diagnosis of a PMVSD. Median age was 9.6 years (1.8–32.8). Median weight was 28 kg (10.2–86). Defect size on TOE ranged from 5 to 12 mm. Median Qp:Qs was 1.6:1. A muscular occluder was used in six patients. Median procedure time was 93.5 min (51–214). Implantation was ultimately successful in 23 patients (92%). Acute aortic incompetence resulting in occluder removal occurred in two cases, one requiring surgical removal. Another patient had an aborted attempt but had subsequent successful closure in another unit. Median follow‐up is 19.5 months (1–42). Five patients (22%) have trivial/mild residual leak across the occluder at their latest assessment, the majority of which had an aneurysmal perimembranous septum (n = 4). Two patients (8%) developed new trivial to mild aortic incompetence. To date, none of the patients in our group have developed complete heart block. Conclusions : Transcatheter closure of PMVSD is evolving and should be considered an acceptable alternative to surgery in selected subgroups. Avoidance of oversized occluders and use of muscular occluders in those with aneurysmal defects may help to avoid heart block and aortic regurgitation. Muscular occluders may however interfere with tricuspid valve function. © 2009 Wiley‐Liss, Inc.     

The Two-Week Referral System for colorectal cancer—not fit for purpose

Purpose

The UK government target expects all suspected colorectal cancer (CRC) patients to be seen within the Two-Week Referral (TWR) system made by general practitioners. These guidelines originally derived from only level 5 evidence. However, this has significant impact on the workload for colorectal surgeons. The aim of the study is to investigate the effectiveness of this colorectal service and whether the referral criteria are predictive of CRC.

Methods

A retrospective study of all patients referred under the TWR guidance in 2010 was assessed. The first 573 TWRs were piloted for analysis. Clinical information from each patient was collected regarding TWR criteria and additional colorectal symptoms or risk factors. Multiple regression analysis was performed to determine which symptoms independently correlated with CRC.

Results

One hundred twenty-six CRCs were diagnosed via all methods of referral in 2010. There were 940 patients referred under the TWR guidelines in that year, when 50 CRC patients were identified. Amongst the 573 patients, 32 CRCs were diagnosed. Multiple regression analysis revealed tenesmus to be independently associated with CRC (p?=?0.003, Pearson’s r?=?0.09185). None of the individual TWR criteria confidently predicted CRC.

Conclusion

Our preliminary results suggest that the current TWR guidelines cannot effectively predict CRC. There is an urgent need for an evidence-based approach to referral criteria for suspected CRC.     

Fenofibrate represses interleukin-17 and interferon-gamma expression and improves colitis in interleukin-10-deficient mice

BACKGROUND & AIMS: Interleukin-10 knockout (IL-10(-/-)) mice spontaneously develop colitis characterized by T-helper cell type 1-polarized inflammation. We tested the possible therapeutic activity of the peroxisome proliferator-activated receptor alpha (PPARalpha) ligand fenofibrate, and the PPARdelta ligand GW0742, in IL-10(-/-) mice and investigated the cellular/molecular mechanisms for fenofibrate action. METHODS: The effect of fenofibrate or GW0742 on the progression of colitis in C3H.IL-10(-/-) mice was evaluated. Effects of fenofibrate on cytokine and chemokine gene expression were studied in cultured splenocytes, pathogenic T cells isolated from C3H/HeJBir mice, and HT-29 colorectal cancer cells. RESULTS: Treatment of C3H.IL-10(-/-) mice with fenofibrate delayed the onset of colitis, decreased the colonic histopathology score, and decreased colonic expression of genes encoding the inflammatory cytokines interferon-gamma and interleukin (IL)-17. The target for fenofibrate, PPARalpha, was expressed in lymphocytes, macrophages, and crypt and surface epithelial cells of the colon. The mean number of lymphocytes was decreased by more than 75% in colonic sections of fenofibrate-treated as compared with control IL-10(-/-) mice, and fenofibrate repressed interferon-gamma and IL-17 expression in isolated T cells. Fenofibrate also repressed the expression of the genes encoding 3 chemokines, CXCL10, CCL2, and CCL20, and repressed CXCL10 gene promoter activity in tumor necrosis factor-alpha-treated HT-29 cells. In contrast to the beneficial effect of fenofibrate, the PPARdelta ligand GW0742 accelerated the onset of colitis in IL-10(-/-) mice. CONCLUSIONS: The immunopathology observed in IL-10(-/-) mice resembles that seen in Crohn's disease. The novel therapeutic activity of fenofibrate in this mouse model suggests that it may also have activity in Crohn's disease.