Raymond Siu Ming Wong

Haematological manifestations in patients with severe acute respiratory syndrome: retrospective analysis

Abstract Objectives To evaluate the haematological findings of patients with severe acute respiratory syndrome (SARS). Design Analysis of the demographic, clinical, and laboratory characteristics of patients with SARS. Setting Prince of Wales Hospital, Hong Kong. Subjects All patients with a diagnosis of SARS between 11 March and 29 March 2003 who had no pre-existing haematological disorders. Main outcome measures Clinical end points included the need for intensive care and death. Univariate and multivariate analyses were performed to examine factors associated with adverse outcome. Results 64 male and 93 female patients were included in this study. The most common findings included lymphopenia in 153 (98%) of the 157 patients, neutrophilia in 129 (82%), thrombocytopenia in 87 patients (55%), followed by thrombocytosis in 77 (49%), and isolated prolonged activated partial thromboplastin time in 96 patients (63%). The haemoglobin count dropped by more than 20 g/l from baseline in 95 (61%) patients. Four patients (2.5%) developed disseminated intravascular coagulation. Lymphopenia was shown in haemato-lymphoid organs at postmortem examination. Multivariate analysis showed that advanced age and a high concentration of lactate dehydrogenase at presentation were independent predictors of an adverse outcome. Subsets of peripheral blood lymphocytes were analysed in 31 patients. The counts of CD4 positive and CD8 positive T cells fell early in the course of illness. Low counts of CD4 and CD8 cells at presentation were associated with adverse outcomes. Conclusions Abnormal haematological variables were common among patients with SARS. Lymphopenia and the depletion of T lymphocyte subsets may be associated with disease activity.

Phase 3 Study of Recombinant Factor IX Fc Fusion Protein in Hemophilia B

BACKGROUND Prophylactic factor replacement in patients with hemophilia B improves outcomes but requires frequent injections. A recombinant factor IX Fc fusion protein (rFIXFc) with a prolonged half-life was developed to reduce the frequency of injections required. METHODS We conducted a phase 3, nonrandomized, open-label study of the safety, efficacy, and pharmacokinetics of rFIXFc for prophylaxis, treatment of bleeding, and perioperative hemostasis in 123 previously treated male patients. All participants were 12 years of age or older and had severe hemophilia B (endogenous factor IX level of ≤2 IU per deciliter, or ≤2% of normal levels). The study included four treatment groups: group 1 received weekly dose-adjusted prophylaxis (50 IU of rFIXFc per kilogram of body weight to start), group 2 received interval-adjusted prophylaxis (100 IU per kilogram every 10 days to start), group 3 received treatment as needed for bleeding episodes (20 to 100 IU per kilogram), and group 4 received treatment in the perioperative period. A subgroup of group 1 underwent comparative sequential pharmacokinetic assessments of recombinant factor IX and rFIXFc. The primary efficacy end point was the annualized bleeding rate, and safety end points included the development of inhibitors and adverse events. RESULTS As compared with recombinant factor IX, rFIXFc exhibited a prolonged terminal half-life (82.1 hours) (P<0.001). The median annualized bleeding rates in groups 1, 2, and 3 were 3.0, 1.4, and 17.7, respectively. In group 2, 53.8% of participants had dosing intervals of 14 days or more during the last 3 months of the study. In groups 1, 2 and 3, 90.4% of bleeding episodes resolved after one injection. Hemostasis was rated as excellent or good during all major surgeries. No inhibitors were detected in any participants receiving rFIXFc; in groups 1, 2, and 3, 73.9% of participants had at least one adverse event, and serious adverse events occurred in 10.9% of participants. These events were mostly consistent with those expected in the general population of patients with hemophilia. CONCLUSIONS Prophylactic rFIXFc, administered every 1 to 2 weeks, resulted in low annualized bleeding rates in patients with hemophilia B. (Funded by Biogen Idec; ClinicalTrials.gov number, NCT01027364.).

Relationship Between Patients’ Warfarin Knowledge and Anticoagulation Control:

OBJECTIVE To evaluate patients’ knowledge of warfarin and its relationship to anticoagulation control. METHODS From January to March 1999, 122 patients attending the warfarin clinic of the Prince of Wales Hospital in Hong Kong were interviewed. Their knowledge of warfarin therapy and adherence to medical advice were tested by 9 questions. A score (maximum 1.0) was calculated for each patient. The number of international normalized ratios (INRs) that was within the target range in the 4 most recent clinic visits was noted. RESULTS Fifty-six men and 66 women participated in the study (mean ± SD age 58.0 ± 13.0, duration of treatment 43.1 ± 39.8 mo). Patients’ warfarin knowledge was poor, with an overall score of 0.48 ± 0.18. Participants generally knew the colors of their warfarin tablets and took them regularly. They almost always informed their physicians and dentists of their warfarin therapy. Only 40–45% of patients knew the strengths of their warfarin tablets, the reason for taking warfarin, and its effect on the body. Their deficiencies in knowledge were even more obvious with respect to the possible consequences of under- or over-anticoagulation, drugs and medicated oils that might interact with warfarin, and management of a missed dose. Knowledge was related to age (r −0.43; p < 0.001) and duration of therapy (r 0.18; p = 0.044). Sixty patients (49.2%) had read the information booklet on warfarin and had better knowledge than those who had not (0.53 ± 0.20 vs. 0.42 ± 0.20; p < 0.001). Illiteracy was the main reason for not reading the booklet. There was a positive correlation between patients’ warfarin knowledge and the number of INR values that was within the target range in the 4 most recent clinic visits (r 0.20; p = 0.024). CONCLUSIONS Patients’ warfarin knowledge, a determinant of anticoagulation control, was generally poor. More attention should be given to the education of elderly and illiterate patients.

Plasma DNA tissue mapping by genome-wide methylation sequencing for noninvasive prenatal, cancer, and transplantation assessments

Significance Plasma consists of DNA released from multiple tissues within the body. Using genome-wide bisulfite sequencing of plasma DNA, we obtained a bird’s eye view of the identities and contributions of these tissues to the circulating DNA pool. The tissue contributors and their relative proportions are identified by a bioinformatics deconvolution process that draws reference from DNA methylation signatures representative of each tissue type. We validated this approach in pregnant women, cancer patients, and transplant recipients. This method also allows one to identify the tissue of origin of genomic aberrations observed in plasma DNA. This approach has numerous research and diagnostic applications in prenatal testing, oncology, transplantation monitoring, and other fields. Plasma consists of DNA released from multiple tissues within the body. Using genome-wide bisulfite sequencing of plasma DNA and deconvolution of the sequencing data with reference to methylation profiles of different tissues, we developed a general approach for studying the major tissue contributors to the circulating DNA pool. We tested this method in pregnant women, patients with hepatocellular carcinoma, and subjects following bone marrow and liver transplantation. In most subjects, white blood cells were the predominant contributors to the circulating DNA pool. The placental contributions in the plasma of pregnant women correlated with the proportional contributions as revealed by fetal-specific genetic markers. The graft-derived contributions to the plasma in the transplant recipients correlated with those determined using donor-specific genetic markers. Patients with hepatocellular carcinoma showed elevated plasma DNA contributions from the liver, which correlated with measurements made using tumor-associated copy number aberrations. In hepatocellular carcinoma patients and in pregnant women exhibiting copy number aberrations in plasma, comparison of methylation deconvolution results using genomic regions with different copy number status pinpointed the tissue type responsible for the aberrations. In a pregnant woman diagnosed as having follicular lymphoma during pregnancy, methylation deconvolution indicated a grossly elevated contribution from B cells into the plasma DNA pool and localized B cells as the origin of the copy number aberrations observed in plasma. This method may serve as a powerful tool for assessing a wide range of physiological and pathological conditions based on the identification of perturbed proportional contributions of different tissues into plasma.

Siltuximab for multicentric Castleman's disease: a randomised, double-blind, placebo-controlled trial

BACKGROUND Multicentric Castlemans disease is a rare lymphoproliferative disorder driven by dysregulated production of interleukin 6. No randomised trials have been done to establish the best treatment for the disease. We assessed the safety and efficacy of siltuximab-a chimeric monoclonal antibody against interleukin 6-in HIV-negative patients with multicentric Castlemans disease. METHODS We did this randomised, double-blind, placebo-controlled study at 38 hospitals in 19 countries worldwide. We enrolled HIV-negative and human herpesvirus-8-seronegative patients with symptomatic multicentric Castlemans disease. Treatment allocation was randomised with a computer-generated list, with block size six, and stratification by baseline corticosteroid use. Patients and investigators were masked to treatment allocation. Patients were randomly assigned (2:1) to siltuximab (11 mg/kg intravenous infusion every 3 weeks) or placebo; all patients also received best supportive care. Patients continued treatment until treatment failure. The primary endpoint was durable tumour and symptomatic response for at least 18 weeks for the intention-to-treat population. Enrolment has been completed. The study is registered with ClinicalTrials.gov, number NCT01024036. FINDINGS We screened 140 patients, 79 of whom were randomly assigned to siltuximab (n=53) or placebo (n=26). Durable tumour and symptomatic responses occurred in 18 (34%) of 53 patients in the siltuximab group and none of 26 in the placebo group (difference 34·0%, 95% CI 11·1-54·8, p=0·0012). The incidence of grade 3 or more adverse events (25 [47%] vs 14 [54%]) and serious adverse events (12 [23%] vs five [19%]) was similar in each group despite longer median treatment duration with siltuximab than with placebo (375 days [range 1-1031] vs 152 days [23-666]). The most common grade 3 or higher were fatigue (five vs one), night sweats (four vs one), and anaemia (one vs three). Three (6%) of 53 patients had serious adverse events judged reasonably related to siltuximab (lower respiratory tract infection, anaphylactic reaction, sepsis). INTERPRETATION Siltuximab plus best supportive care was superior to best supportive care alone for patients with symptomatic multicentric Castlemans disease and well tolerated with prolonged exposure. Siltuximab is an important new treatment option for this disease. FUNDING Janssen Research & Development.

Early risk stratification of patients with major trauma requiring massive blood transfusion

BACKGROUND There is limited evidence to guide the recognition of patients with massive, uncontrolled hemorrhage who require initiation of a massive transfusion (MT) protocol. OBJECTIVE To risk stratify patients with major trauma and to predict need for MT. DESIGNS Retrospective analysis of an administrative trauma database of major trauma patients. A REGIONAL TRAUMA CENTRE: A regional trauma centres in Hong Kong. PATIENTS Patients with Injury Severity Score ≥ 9 and age ≥ 12 years were included. Burn patients, patients with known severe anemia and renal failure, or died within 24h were excluded. MAIN OUTCOME MEASURES Delivery of ≥ 10 units of packed red blood cells (RBC) within 24h. RESULTS Between 01/01/2001 and 30/06/2009, 1891 patients met the inclusion criteria. 92 patients required ≥ 10 units RBC within 24h. Seven variables which were easy to be measured in the ED and significantly predicted the need for MT are heart rate ≥ 120/min; systolic blood pressure ≤ 90 mm Hg; Glasgow coma scale ≤ 8; displaced pelvic fracture; CT scan or FAST positive for fluid; base deficit >5 mmol/L; hemoglobin ≤ 7 g/dL; and hemoglobin 7.1-10 g/dL. At a cut off of ≥ 6, the overall correct classification for predicting need for MT was 96.9%, with a sensitivity of 31.5% and specificity of 99.7%, and an incidence of MT of 82.9%. The area under the curve was 0.889. CONCLUSION A prediction rule for determining an increased likelihood for the need for massive transfusion has been derived. This needs validation in an independent data set.

Potential Clinical and Economic Outcomes of CYP2C9 and VKORC1 Genotype‐Guided Dosing in Patients Starting Warfarin Therapy

The US Food and Drug Administration has updated the label information for warfarin to encourage the use of genetic information before initiating treatment with the drug. We used decision‐tree modeling to simulate the outcomes of CYP2C9 and vitamin K epoxide reductase complex 1 (VKORC1) genotype–guided dosing in patients in whom warfarin therapy is to be initiated. The inputs for the model were derived from the literature. The incremental costs per unit outcome improved (ICERs) were US

Safety of bosutinib versus imatinib in the phase 3 BELA trial in newly diagnosed chronic phase chronic myeloid leukemia

347,059 per quality‐adjusted life‐year (QALY) gained,

Cost-Effectiveness of Dabigatran versus Genotype-Guided Management of Warfarin Therapy for Stroke Prevention in Patients with Atrial Fibrillation

170,192 per adverse event averted, and

The potential clinical and economic outcomes of pharmacogenetics-oriented management of warfarin therapy - a decision analysis

1,106,250 per life saved. The outcomes of 10,000 Monte Carlo simulations demonstrate that the ICER per QALY gained was >