Liver complications of haemoglobin H disease in adults.

Haemoglobin H (HbH) disease is a type of non-transfusion-dependent thalassaemia. This cross-sectional study aimed at determining the prevalence and severity of liver iron overload and liver fibrosis in patients with HbH disease. Risk factors for advanced liver fibrosis were also identified. A total of 80 patients were evaluated [median (range) age 53 (24-79) years, male 34%, non-deletional HbH disease 24%]. Patients underwent 'observed' T2-weighted magnetic resonance imaging examination for liver iron concentration (LIC) quantification, and transient elastography for liver stiffness measurement (LSM) and fibrosis staging. In all, 25 patients (31%) had moderate-to-severe liver iron overload (LIC ≥7 mg/g dry weight). The median LIC was higher in non-deletional than in deletional HbH disease (7·8 vs. 2.9 mg/g dry weight, P = 0·002). In all, 16 patients (20%) had advanced liver fibrosis (LSM >7.9 kPa) and seven (9%) out of them had probable cirrhosis (LSM >11.9 kPa). LSM positively correlated with age (R = 0·24, P = 0·03), serum ferritin (R = 0·36, P = 0·001) and LIC (R = 0·28, P = 0·01). In multivariable regression, age ≥65 years [odds ratio (OR) 4·97, 95% confidence interval (CI) 1·52-17·50; P = 0·047] and moderate-to-severe liver iron overload (OR 3·47, 95% CI 1·01-12·14; P = 0·01) were independently associated with advanced liver fibrosis. The findings suggest that regular screening for liver complications should be considered in the management of HbH disease.

Intrathecal chemotherapy for hematologic malignancies: drugs and toxicities.

Intrathecal (IT) chemotherapy is an important component of the prophylaxis or treatment of hematologic malignancies in the central nervous system (CNS), especially in patients with acute lymphoblastic leukemia and aggressive lymphomas. Different regimens of IT chemotherapies have been formulated, often in conjunction with systemic high-dose chemotherapy leading to penetration of the drugs into the cerebrospinal fluid (CSF). The three commonest IT drugs are methotrexate, cytosine arabinoside (Ara-C), and corticosteroids. The CSF half-lives of methotrexate and Ara-C are much prolonged, a factor to be considered if these drugs are also administered systemically in high doses. Neurotoxicities attributed to IT chemotherapy have been reported, including spinal cord lesions, seizures, and encephalopathy. Spinal cord lesions, manifesting as tetraplegia, paraplegia, and cauda equina syndrome, are the commonest neurotoxicity. It is mostly related to combined IT methotrexate and Ara-C, or Ara-C as the sole IT agent when given at high doses or as a slow-release preparation. Cord lesions rarely recover and patients are left with motor deficits, bowel and urinary disabilities. Seizures and encephalopathy are reported in relatively fewer patients, with variable manifestations and prognosis. Knowledge of the pharmacokinetics, dosing schedules and potential toxicities of IT chemotherapeutic drugs is important in the design of CNS prophylaxis and treatment in hematologic malignancies.

4q loss is potentially an important genetic event in MM tumorigenesis: identification of a tumor suppressor gene regulated by promoter methylation at 4q13.3, platelet factor 4.

In this study, we have elucidated the chromosomal imbalances in the multistep pathogenesis and delineated several critical tumor suppressor gene (TSG) loci in multiple myeloma (MM). By using comparative genomic hybridization, allelotyping, and multicolor interphase fluorescence in situ hybridization, 5 MM cell lines and bone marrow CD138+ plasma cells from 88 Chinese patients with monoclonal gammopathy of undetermined significance (MGUS) and early and advanced stages of MM were investigated. In all MGUS and MM samples, chromosome copy number abnormalities were detected. A higher number of chromosomal imbalances and specific genetic alterations are involved in MGUS to MM transition (-6q, +3p, and +1p) and MM progression (+2p and +9q). In addition to -13q, we first found high frequencies (42% to 46%) of -4q involving high percentages (70% to 74%) of clonal plasma cells in both MGUS and MM, suggesting that inactivation of TSG in this region is also a potentially critical genetic event in MM tumorigenesis. By high-resolution allelotyping, we defined a common deletion region on 4q13.3 and found that a candidate TSG, platelet factor 4, was frequently silenced by promoter hypermethylation in MM (15 of 28) and MM cell lines (5 of 5). These data have opened up a new approach in the molecular targeting therapy and provide novel insights into MM tumorigenesis.

Use of the oral chelator deferiprone in the treatment of iron overload in patients with Hb H disease.

Seventeen non-transfusion-dependent Chinese haemoglobin H (Hb H) disease patients (age 29-76 years) with serum ferritin >900 microg/l were treated with deferiprone for up to 18 months. One patient withdrew and data from 16 patients were analysed. Sixteen other Hb H patients with ferritin <900 microg/l, matched for age and genotype, acted as controls. Treatment was well tolerated except for mild arthralgia. Serum ferritin fell with treatment, reaching significance at 6 and 18 months (from 1492.3 +/- 901.4 to 519.4 +/- 405.4 microg/l at 18 months, P = 0.0008). Nine of 16 patients had levels below 397 microg/l before 18 months. Serum ferritin remained stable 6 months after stopping treatment. In contrast, there was no change in ferritin levels in the control group. Magnetic resonance imaging was used for measurement of liver iron content. Spin echo T(1)-signal intensity ratio (T(1)-SIR) and gradient echo T(2)-signal intensity ratio (T(2)-SIR) increased with treatment. T(2)-SIR rose from 0.17 +/- 0.08 pretreatment to 0.58 +/- 0.50 at 2 years (P = 0.0055). Improvement occurred in 12 of 16 patients, reaching normal in three patients. Using echocardiography, peak early diastolic : late diastolic blood flow (E/A) remained unchanged with treatment, but isovolumic relaxation time (IVRT) was prolonged at 2 years indicating mild impairment of diastolic function. All systolic function parameters were normal. A longer treatment period is desirable to demonstrate improvement in cardiac function.

Alterations of RAS signalling in Chinese multiple myeloma patients: absent BRAF and rare RAS mutations, but frequent inactivation of RASSF1A by transcriptional silencing or expression of a non-functional variant transcript.

The methylation status, mutation and expression of RASSF1A, and mutations of RAS and BRAF were studied in 52 patients with multiple myeloma (MM), one plasma cell leukaemia (PCL) patient and four MM-derived cell lines. Aberrant methylation of RASSF1A was found in nine of 32 MM patients and in one of four MM cell lines (U266), where the associated loss of transcription was reversible by demethylation treatment. RASSF1A transcription was further investigated on anti-CD138-sorted plasma cell-enriched bone marrow samples from 10 MM, one PCL and three reactive plasmacytosis patients. While the wild-type RASSF1A transcript was detected in all three reactive plasmacytosis and the PCL samples, we found no detectable wild-type transcripts in six of 10 MM samples studied. In two MM samples, only the non-functional variant transcript was detected, whereas the other four showed loss of transcription. In great contrast to western data, RAS mutations were identified in only four of 31 (13%) MM patients. While no RASSF1A or BRAF mutation (V599E) was detected in any of the primary MM studied (n = 21), the latter was found in the U266 cell line. Taken together, these data indicate that alterations of RAS signalling are critical in MM pathogenesis. In our current studies of Chinese MM patients, these alterations involved frequent RASSF1A inactivation (60%) as a result of transcriptional silencing or expression of a non-functional variant transcript.