Next-generation sequencing with a myeloid gene panel in core-binding factor AML showed KIT activation loop and TET2 mutations predictive of outcome.

Clinical outcome and mutations of 96 core-binding factor acute myeloid leukemia (AML) patients 18-60 years old were examined. Complete remission (CR) after induction was 94.6%. There was no significant difference in CR, leukemia-free-survival (LFS) and overall survival (OS) between t(8;21) (N=67) and inv(16) patients (N=29). Univariate analysis showed hematopoietic stem cell transplantation at CR1 as the only clinical parameter associated with superior LFS. Next-generation sequencing based on a myeloid gene panel was performed in 72 patients. Mutations in genes involved in cell signaling were associated with inferior LFS and OS, whereas those in genes involved in DNA methylation were associated with inferior LFS. KIT activation loop (AL) mutations occurred in 25 patients, and were associated with inferior LFS (P=0.003) and OS (P=0.001). TET2 mutations occurred in 8 patients, and were associated with significantly shorter LFS (P=0.015) but not OS. Patients negative for KIT-AL and TET2 mutations (N=41) had significantly better LFS (P<0.001) and OS (P=0.012) than those positive for both or either mutation. Multivariate analysis showed that KIT-AL and TET2 mutations were associated with inferior LFS, whereas age ⩾40 years and marrow blast ⩾70% were associated with inferior OS. These observations provide new insights that may guide better treatment for this AML subtype.

Genetic predisposition of white matter infarction with protein S deficiency and R355C mutation.

BACKGROUND: The association between protein S deficiency (PSD) and ischemic stroke is controversial and warrants further investigation. METHODS: We conducted a genotype and MRI correlation study in a Chinese family in which hereditary PSD cosegregated with premature ischemic strokes. Six out of 11 family members inherited PSD type III in an autosomal dominant manner. RESULTS: Among all PSD members, a novel missense mutation 1063C→T in exon 10 of protein S alpha (PROS1) was identified, which encoded a substitution of arginine to cysteine at position 355 (R355C) in the first globular domain of laminin A of protein S. Wild-type PROS1 sequences were retained in non-PSD members. MRI detected deep white matter infarctions predominantly distributed in the borderzone regions. The infarct topography was homogeneous in all adult mutant carriers. By contrast, cerebral infarction was absent in nonmutant carriers. Extensive investigation in the family did not reveal any confounding stroke risk. Haplotype analysis with high-density single nucleotide polymorphism markers revealed a 6.1-Mb minimally rearranged region (rs12494685 to rs1598240) in 3q11.2, lod = 3.0. Among the 7 annotated genes in this region, PROS1 is known to be associated with thrombotic disorders. MRI screening in an additional 10 PSD families without R355C showed no cerebral infarction. CONCLUSIONS: PROS1 R355C mutation cosegregated with PSD type III and premature white matter infarctions in the index family. The findings substantiate an association between PSD and stroke. Study of the mechanism underlying this association may improve our understanding of premature cryptogenic white matter infarction.

Organ-specific hemosiderosis and functional correlation in Chinese patients with thalassemia intermedia and hemoglobin H disease.

We performed MRI assessment in 37 adult Chinese patients with thalassemia intermedia and hemoglobin H disease. Despite abnormal ferritin and liver T2*, only 5% of patients had cardiac hemosiderosis. The two patients with reduced ejection fraction had normal cardiac T2*. Half of the cases showed pituitary and pancreatic iron loading. Subclinical endocrine abnormalities (HOMA, insulin growth factor) showed correlation with pancreatic, pituitary, and cardiac MRI values. Prospective data with serial functional and imaging monitoring is needed to verify the utility for chelation to improve cardiac and endocrine function in this group of patients.

Longitudinal study of Chinese patients with pernicious anaemia.

BACKGROUND: The survival of whites who have been treated for pernicious anaemia (PA) is unaffected, apart from incurring a greater risk of gastric cancers. The long term outcome of PA in Chinese is unknown. METHODS: A hospital based prospective longitudinal study of Chinese PA patients was conducted. Patients with known cancers were excluded. RESULTS: From 1994 to 2007, 199 intrinsic factor antibody (IFA) positive and 168 IFA negative patients were recruited. Both cohorts had similar baseline characteristics, except the IFA positive patients had more severe haematological findings and more thyrogastric immune features; also more IFA negative patients had type 2 diabetes mellitus and gastrointestinal (GI) disease or GI surgery. Both cohorts had a good haematological response but an unsatisfactory neurological response to treatment. Hypothyroidism developed in patients of both cohorts during follow-up. 24 IFA positive patients and 7 IFA negative patients developed cancers (p = 0.007) during follow-up. 20% of all cancers were gastric carcinoma. Mean survival of both cohorts was similar. Mean survival of IFA positive patients with and without cancers was 64 and 129 months, respectively (p<0.001), and that of IFA negative patients 36 and 126 months, respectively (p<0.001). Death rates were 31% in the IFA positive cohort and 21% in the IFA negative cohort (p = 0.028). Cancer related death rates of IFA positive and IFA negative cohorts were 37% and 14%, respectively (p = 0.014). CONCLUSION: The survival period of Chinese with PA who have received treatment is good, but there is an increased risk of gastric cancers. IFA positive patients have a higher risk of developing all types of cancers and cancer related deaths than IFA negative patients.

Candida tropicalis arthritis of the knee in a patient with acute lymphoblastic leukaemia: successful treatment with caspofungin.

Candida arthritis in patients with a haematological malignancy is rare. We report a case of Candida tropicalis arthritis of the knee that occurred in a patient with acute lymphoblastic leukaemia during the recovery phase of post-chemotherapy neutropenia. Although the Candida tropicalis isolates from synovial fluid and synovial tissue were sensitive to fluconazole in vitro, a 6-week course of oral treatment failed to produce clinical improvement. The arthritis resolved after 7 weeks of combination therapy with caspofungin, a new echinocandin class of antifungal agent that acts primarily on the cell wall. Eleven other reports of Candida arthritis in patients with a haematological malignancy were reviewed.

Trisomy 21 and other chromosomal abnormalities in acute promyelocytic leukemia.

We describe a case of acute promyelocytic leukemia (APL) with t(15;17)(q22;q12) and trisomy 21 as an additional change in a patient who died at relapse after achieving complete remission (CR) for the duration of 20 months. A survey of 42 cases of APL with cytogenetic study performed at our institutionover the past 10 years showed 12 cases (28.6%) having chromosomal changes in addition to t(15;17). Trisomy 8 and trisomy 21 as additional changes were noted in 4 and 2 cases, respectively, with one patient showing both trisomies simultaneously. Two cases showed t(15;17) in hyperdiploid clones. Among the 10 patients with follow-up data, all eventually relapsed and none achieved continuous complete remission 1. Survival analysis performed in APL patients with adequate follow-up data showed no significant difference in overall and disease free survival between those with and without additional cytogenetic changes. After excluding cases with one induction death, the overall survival was significantly in favor of the group without additional cytogenetic abnormalities (P = 0.022). Late relapses may therefore be significantly more common in APL patients with additional cytogenetic abnormalities, and may not be reflected by analysis focused at three-year survival only. As APL is now considered a curable disease, any confirmed long-term survival impact of additional cytogenetic changes is expected to have important management implications.

Venous thromboembolism in the Chinese population--experience in a regional hospital in Hong Kong.

OBJECTIVE: To estimate the incidence and determine the characteristic features of venous thromboembolism in the Hong Kong Chinese population. DESIGN: Retrospective study. SETTING: Regional hospital, Hong Kong. SUBJECTS AND METHODS: Data were collected during a period of four years (1997-2000). Patients with duplex doppler ultrasonography or venography-documented venous thromboembolism and new episodes of deep vein thrombosis were identified from Department of Diagnostic Radiology records. Patients with high-probability ventilation-perfusion scans were identified from Department of Nuclear Medicine records and these scans were taken as evidence of pulmonary embolism. Patients with intermediate-probability ventilation-perfusion scans, with pulmonary embolism documented by either pulmonary angiography or spiral computed tomography scan, were also included in the study. Patients with autopsy-verified fatal pulmonary embolism were identified from Department of Pathology records. Patients with deep vein thrombosis at other sites were sought from patient discharge diagnostic coding data. Medical records were reviewed for patient characteristics and conditions associated with the development of venous thromboembolism. RESULTS: Three hundred and seventy-six Chinese patients had venous thromboembolism during the study period. Of these, 352 had peripheral deep vein thrombosis, five had deep vein thrombosis at other sites (cerebral sinus and portal vein thrombosis), 40 had pulmonary embolism (26 had concomitant deep vein thrombosis), and six had fatal pulmonary embolism shown at autopsy. CONCLUSION: The calculated annual incidence of venous thromboembolism in Hong Kong Chinese people was estimated at 16.6 events per 100,000 population, which is lower than incidence rates reported in Caucasians. The four conditions most commonly associated with venous thromboembolism were medical illness, malignancy, orthopaedic surgery, and intravenous drug use. Conditions associated with venous thromboembolism in patients younger than 45 years included intravenous drug use, thrombophilia, pregnancy, and the use of oral contraceptives.

Chromosomal abnormalities in T-cell large granular lymphocyte leukaemia: report of two cases and review of the literature.

Cytogenetic information on T-cell large granular lymphocyte leukaemia (T-LGL; large granular lymphocytosis) is limited. We report two cases of T-LGL with unusual karyotypic aberrations. The first case showed a novel inv(7)(p15q22) as the sole chromosomal abnormality, while the second case showed an inv(14)(q11q32) with evidence of clonal evolution. The breakpoints 7p14-p15 and 14q11 coincide with the T-cell receptor (TCR)-gamma and TCR-alpha/TCR-delta gene loci respectively. This is the first report describing the possible involvement of T-cell receptor genes in karyotypic aberrations in T-LGL.