Outcomes of adolescents with acute lymphoblastic leukaemia.

INTRODUCTION: Compared with young children who have acute lymphoblastic leukaemia (ALL), adolescents with ALL have unfavourable disease profiles and worse survival. However, limited data are available regarding the characteristics and outcomes of adolescents with ALL who underwent treatment in clinical trials. The aim of this study was to investigate the causes of treatment failure in adolescents with ALL. METHODS: We retrospectively analysed the outcomes of 711 children with ALL, aged 1-18 years, who were enrolled in five clinical trials of paediatric ALL treatment between 1993 and 2015. RESULTS: Among the 711 children with ALL, 530 were young children (1-9 years at diagnosis) and 181 were adolescents (including 136 younger adolescents [10-14 years] and 45 older adolescents [15-18 years]). Compared with young children who had ALL, adolescents with ALL were less likely to have favourable genetic features and more likely to demonstrate poor early response to treatment. The 10-year overall survival and event-free survival rates were significantly lower among adolescents than among young children (77.9% vs 87.6%, P=0.0003; 69.7% vs 76.5%, P=0.0117). There were no significant differences in the 10-year cumulative incidence of relapse, but the 10-year cumulative incidence of treatment-related death (TRD) was significantly greater among adolescents (7.2%) than among young children (2.3%; P=0.002). Multivariable analysis showed that both younger and older adolescents (vs young children) had worse survival and greater incidence of TRD. CONCLUSION: Adolescents with ALL had worse survival because they experienced a greater incidence of TRD. There is a need to investigate optimal treatment adjustments and novel targeted agents to achieve better survival rates (without excessive toxicity) among adolescents with ALL.

Association between HLA-B*58:01 allele and severe cutaneous adverse reactions with allopurinol in Han Chinese in Hong Kong.

BACKGROUND: Allopurinol has been reported as a common cause of severe cutaneous adverse reactions (SCARs). Recent studies in various populations suggest that HLA-B*58:01 is a strong genetic marker for allopurinol-induced SCAR, especially in populations with a high frequency of HLA-B*58:01. OBJECTIVES: To confirm the association link between HLA-B*58:01 and hypersensitivity reactions attributed to allopurinol use in Han Chinese patients in Hong Kong. METHODS: We performed a case-control study to investigate whether the HLA-B*58:01 allele predisposes to allopurinol-induced SCAR in Han Chinese patients in Hong Kong. The HLA-B*58:01 genotyping was performed in 20 patients with allopurinol-induced SCAR or erythema multiforme major (EMM; n = 1) and in 30 patients tolerant to allopurinol. RESULTS: All of the 19 patients with allopurinol-induced SCAR examined but not the patient with EMM carried HLA-B*58:01 whereas only four (13%) of the control patients had this allele. The positive rate of the HLA-B*58:01 was significantly higher in the cases than in the allopurinol-tolerant control group [odds ratio (OR) 123·5, 95% confidence interval (CI) 12·8-1195·1; P < 1 × 10(-4) ] and was even higher after removal of the patient with EMM (OR 229·7, 95% CI 11·7-4520·4). The sensitivity and specificity of the HLA-B*58:01 allele for prediction of allopurinol-induced SCAR were 100% and 86·7%, respectively. CONCLUSIONS: This study confirmed the strong association between the HLA-B*58:01 and allopurinol-induced SCAR in Hong Kong Han Chinese patients. A screening test for the HLA-B*58:01 allele should effectively reduce the risk for allopurinol-induced SCAR in Chinese populations.

Inhibition of c-Met downregulates TIGAR expression and reduces NADPH production leading to cell death.

c-Met represents an important emerging therapeutic target in cancer. In this study, we demonstrate the mechanism by which c-Met tyrosine kinase inhibition inhibits tumor growth in a highly invasive Asian-prevalent head and neck cancer, nasopharyngeal cancer (NPC). c-Met tyrosine kinase inhibitors (TKIs; AM7 and c-Met TKI tool compound SU11274) downregulated c-Met phosphorylation, resulting in marked inhibition of NPC cell growth and invasion. Strikingly, inhibition of c-Met resulted in significant downregulation of TP53-induced Glycolysis and Apoptosis Regulator (TIGAR) and subsequent depletion of intracellular NADPH. Importantly, overexpression of TIGAR ameliorated the effects of c-Met kinase inhibition, confirming the importance of TIGAR downregulation in the growth inhibitory activity of c-Met TKI. The effects of c-Met inhibition on TIGAR and NADPH levels were observed with two different c-Met TKIs (AM7 and SU11274) and with multiple cell lines. As NADPH provides a crucial reducing power required for cell survival and proliferation, our findings reveal a novel mechanistic action of c-Met TKI, which may represent a key effect of c-Met kinase inhibition. Our data provide the first evidence linking c-Met, TIGAR and NADPH regulation in human cancer cells suggesting that inhibition of a tyrosine kinase/TIGAR/NADPH cascade may have therapeutic applicability in human cancers.

Narcolepsy in Southern Chinese patients: clinical characteristics, HLA typing and seasonality of birth.

OBJECTIVE: To report clinical characteristics, human leukocyte antigen (HLA) typing and seasonality of birth of a series of 54 Southern Chinese patients suffering from narcolepsy. METHODS: All subjects underwent detailed medical and psychiatric interviews and a standardised nocturnal polysomnogram followed by a daytime Multiple Sleep Latency Test. Each subject also completed a set of sleep questionnaires. HLA typing was performed in 91% of subjects. RESULTS: A total of 78% and 22% of patients were diagnosed with suffering from cataplectic and non-cataplectic narcolepsy, respectively. The majority (n = 47, 87%) of patients were referred to our sleep clinic for excessive daytime sleepiness (EDS). The cataplectic narcolepsy differed from non-cataplectic narcolepsy by having more rapid eye movement (REM)-related clinical symptoms (more sleep paralysis and sleep-related hallucination) and sleep disturbances (shorter REM latency), as well as tighter association with HLA DQB1*0602. A bi-modal peak pattern was observed at 11 and 39 years old. A similar bi-modal pattern also occurred for EDS and cataplexy. Excess winter births were observed for this series of patients. 81% of patients with cataplectic narcolepsy were DQB1*0602-positive. There were no differences between early- and late-onset cases in the association with positive DQB1*0602 (71.4% vs 60%). Narcolepsy had prominent pernicious effects on various social, academic, family and mental aspects in our patients. CONCLUSIONS: In our Southern Chinese narcolepsy series, bi-modal peak pattern of age of onset, excess winter birth and tight association of HLA DQB1*0602 with cataplectic narcolepsy were found.

Increase in circulating Foxp3+CD4+CD25(high) regulatory T cells in nasopharyngeal carcinoma patients.

Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus-associated disease with high prevalence in Southern Chinese. Using multiparametric flow cytometry, we identified significant expansions of circulating naïve and memory CD4+CD25(high) T cells in 56 NPC patients compared with healthy age- and sex-matched controls. These were regulatory T cells (Treg), as they overexpressed Foxp3 and GITR, and demonstrated enhanced suppressive activities against autologous CD4+CD25- T-cell proliferation in functional studies on five patients. Abundant intraepithelial infiltrations of Treg with very high levels of Foxp3 expression and absence of CCR7 expression were also detected in five primary tumours. Our current study is the first to demonstrate an expansion of functional Treg in the circulation of NPC patients and the presence of infiltrating Treg in the tumour microenvironment. As Treg may play an important role in suppressing antitumour immunity, our findings provide critical insights for clinical management of NPC.

End-stage renal disease risk equations for Hong Kong Chinese patients with type 2 diabetes: Hong Kong Diabetes Registry.

AIMS/HYPOTHESIS: The objective of the study was to investigate risk factors and develop risk equations for end-stage renal disease (ESRD) in Chinese patients with type 2 diabetes. SUBJECTS AND METHODS: A prospective cohort of 4,438 patients with type 2 diabetes mellitus and without ESRD (median observation period 2.9 years, interquartile range 1.6-4.1 years) was included in the analysis. The end-point (ESRD) was defined by: (1) death due to diabetes with renal manifestations or renal failure; (2) hospitalisation due to renal failure; (3) estimated GFR (eGFR) <15 ml min(-1) 1.73 m(-2). Cox proportional hazards regression was used to develop risk equations. The data were randomly and evenly divided into the training data for development of the risk equations and the test data for validation. The validation was performed using the area under the receiver operating characteristic curve (aROC), which takes into account follow-up time and censoring. RESULTS: During the observation period, 159 patients or 12.45 per 1,000 person-years (95% CI 10.52-14.37 per 1,000 person-years) developed ESRD. Known duration of diabetes, systolic blood pressure, log(10) total cholesterol:HDL cholesterol ratio and retinopathy were significant predictors of ESRD. After further adjusting for eGFR, log(10) spot albumin:creatinine ratio (ACR) and haematocrit, only eGFR, haematocrit and log(10) ACR remained as independent predictors of ESRD. The risk equation derived from these three independent predictors had good discrimination, with an aROC of 0.97. CONCLUSIONS/INTERPRETATION: Estimated GFR, haematocrit and ACR were independent predictors of ESRD and the derived risk equation performed well in Chinese patients with type 2 diabetes.

Improved outcome of acute lymphoblastic leukaemia treated by delayed intensification in Hong Kong children: HKALL97 study.

OBJECTIVE: To study the outcome of children with acute lymphoblastic leukaemia who were treated using a protocol including one or two delayed intensifications. DESIGN: Prospective single-arm multicentre study. SETTING: Five designated children cancer units of the Hospital Authority of Hong Kong. PATIENTS: Children aged between 1 and 17.9 years with newly diagnosed acute lymphoblastic leukaemia seen from November 1997 to December 2002. INTERVENTION: Chemotherapy was modified from a German Berlin-Frankfurt-Muenster 95 (BFM95) protocol that included a delayed intensification similar to the induction phase repeated 5 months after diagnosis. High-risk patients were given double delayed intensification. MAIN OUTCOME MEASURES: Overall survival and event-free survival of the whole group and the three risk groups (standard-, intermediate-, and high-risk groups), and comparison with historical controls. RESULTS: A total of 171 patients were recruited with a median age at diagnosis of 5.57 years (range, 1.15-17.85 years). The induction remission rate was 95.3% and non-leukaemia mortality during remission was 2.3%. At 4 years, the relapse rate of this (HKALL97) study was significantly lower than that of the HKALL93 study (15.7 vs 37.3%; P<0.001). The 4-year overall survival of HKALL97 and HKALL93 studies were 86.5% and 81.8%, respectively (P=0.51). The 4-year event-free survival for HKALL97 and HKALL93 studies were 79% and 65%, respectively (P=0.007). Nonetheless the difference of event-free survival was most remarkable in the intermediate-risk group: 75.6% and 53.1% for HKALL97 and HKALL93 studies, respectively (P=0.06). CONCLUSION: A more intensive delayed consolidation phase improved the outcome for children with acute lymphoblastic leukaemia by reducing relapses at 4 years. The early treatment complications were manageable and non-leukaemia mortality during remission remained low.

Specific epitopes of the structural and hypothetical proteins elicit variable humoral responses in SARS patients.

BACKGROUND: Severe acute respiratory syndrome (SARS) is an infectious disease which was caused by a novel coronavirus (SARS-CoV). SARS has caused an outbreak in the world during 2003 and 2004, with 8098 individuals being infected and a death toll of 774 in 28 regions around the world. Specific humoral responses to viral infection remain unclear. OBJECTIVE: To analyse the antigenicity of the SARS-CoV genome and identify potential antigenic epitopes in the structural proteins. METHODS: Potential antigenic epitopes were identified in the structural proteins (nucleocapsid, membrane, spike, and small envelope proteins) and hypothetical proteins (SARS3a, 3b, 6, 7a, and 9b) that are specific for SARS-CoV. A peptide chip platform was created and the profiles of antibodies to these epitopes were investigated in 59 different SARS patients' sera obtained 6-103 days after the onset of the illness. Serial sera from five additional patients were also studied. RESULTS: Epitopes at the N-terminus of the membrane protein and the C-terminus of nucleocapsid protein elicited strong antibody responses. Epitopes on the spike protein were only moderately immunogenic but the effects were persistent. Antibodies were also detected for some putative proteins, noticeably the C-termini of SARS3a and SARS6. CONCLUSIONS: Important epitopes of the SARS-CoV genome that may serve as potential markers for the viral infection are identified. These specific antigenic sites may also be important for vaccine development against this new fatal infectious disease.

Use of convalescent plasma therapy in SARS patients in Hong Kong.

In order to evaluate the efficacy of convalescent plasma therapy in the treatment of patients with severe acute respiratory syndrome (SARS), 80 SARS patients were given convalescent plasma at Prince of Wales Hospital, Hong Kong, between 20 March and 26 May 2003. Good outcome was defined as discharge by day 22 following the onset of SARS symptoms. Poor outcome was defined as death or hospitalization beyond 22 days. A higher day-22 discharge rate was observed among patients who were given convalescent plasma before day 14 of illness (58.3% vs 15.6%; P<0.001) and among those who were PCR positive and seronegative for coronavirus at the time of plasma infusion (66.7% vs 20%; P=0.001).

Hematological findings in SARS patients and possible mechanisms (review).

Severe acute respiratory syndrome (SARS) is a new human infectious disease. The causative agent of SARS is a novel coronavirus (SARS-CoV). This report summarizes the hematological findings in SARS patients and proposes the possible mechanisms of SARS-CoV related abnormal hematopoiesis. Hematological changes in patients with SARS are common and include lymphopenia, thrombocytopenia and occasionally leukopenia. A significant decrease was also observed in peripheral CD4+ and CD8+ T lymphocyte subsets and it was related to onset of SARS. A number of potential mechanisms may be involved. The development of auto-immune antibodies or immune complexes triggered by viral infection may play a major role in inducing lymphopenia and thrombocytopenia. Moreover, SARS-CoV may also directly infect hematopoietic stem/progenitor cells via CD13 or CD66a inducing their growth inhibition and apoptosis. The receptor for group I and III CoV is aminopeptidase N (CD13). CD13 has been identified in human bone marrow CD34+ cells, platelets, megakaryocytes, myeloid cells, and erythroid cells, but not in lymphocytes. The common receptor for group II CoV is CEACAM1a (CD66a). CD66a is an adhesion molecule expressed on bone marrow CD34+ cells, platelets, granulocytes and activated lymphocytes. In addition, glucocorticoids could induce lymphopenia and the use of steroids may account for the decrease of lymphocytes in some SARS patients. The increased consumption of platelets and/or the decreased production of platelets in the damaged lungs are a potential alternative but often overlooked mechanism that can contribute to thrombocytopenia in severe critical pulmonary conditions.

Retrospective comparison of convalescent plasma with continuing high-dose methylprednisolone treatment in SARS patients.

Treatment of severe acute respiratory syndrome (SARS) is experimental, and the effectiveness of ribavirin-steroid therapy is unclear. Forty SARS patients with progressive disease after ribavirin treatment and 1.5 g of pulsed methylprednisolone were given either convalescent plasma (n = 19) or further pulsed methylprednisolone (n = 21) in a retrospective non-randomised study. Good clinical outcome was defined as discharge by day 22 following the onset of symptoms. Convalescent plasma was obtained from recovered patients after informed consent. Patients in the plasma group had a shorter hospital stay (p 0.001) and lower mortality (p 0.049) than the comparator group. No immediate adverse effects were observed following plasma infusion.

Unrelated umbilical cord blood transplantation in children: experience of the Hong Kong Red Cross Blood Transfusion Service.

OBJECTIVE: To review the outcome of unrelated umbilical cord blood transplantation in children using cord blood from the Hong Kong Red Cross Blood Transfusion Service. DESIGN: Retrospective study. PATIENTS: Records of eight patients who received unrelated umbilical cord blood transplants between 1999 and 2003 were reviewed. MAIN OUTCOME MEASURES: Engraftment of haematopoietic cells and graft-versus-host disease after transplantation. RESULTS: The median age of the patients was 4.9 years (range, 1.0-9.4 years). Five patients had acute leukaemia, one had non-Hodgkin's lymphoma, one had X-linked adrenoleukodystrophy, and one had mucolipidosis. The infused umbilical cord blood units contained a median of 6.7 x 10(7) /kg nucleated cells and 4.0 x 10(5) /kg CD34-positive cells. Neutrophil engraftment was achieved at a median of 13 days (range, 11-19 days) and, for seven patients, platelet engraftment was achieved at a median of 39 days (range, 24-98 days). Acute graft-versus-host disease occurred in all patients (grades I to III). One of the patients died because of encephalitis; of the other seven, five developed chronic graft-versus-host disease of the skin. At a median follow-up of 2 years, the four patients with leukaemia and the one with non-Hodgkin's lymphoma remained in continuous complete remission; the patient with adrenoleukodystrophy showed stabilisation of neurological condition. CONCLUSION: The Hong Kong Red Cross Blood Transfusion Service Cord Blood Bank stored cord blood units of good quality for transplantation, the outcome of which was comparable to that of bone marrow transplantation.

Lymphocyte subsets and natural killer cell cytotoxicity after laparoscopically assisted resection of rectosigmoid carcinoma.

BACKGROUND: Laparoscopically assisted resection of colorectal carcinoma is technically feasible and minimally invasive. Postoperative immunosuppression also may be reduced. This study compared the lymphocyte subsets and natural killer (NK) cell cytotoxicity in patients after laparoscopically assisted resection with those after open resection of rectosigmoid carcinoma. METHODS: In this study, 40 patients with rectosigmoid carcinoma, but no evidence of metastasis, were randomized to receive either laparoscopically assisted or conventional open resection of the tumor. Blood was collected before the operation, then 24 h, 72 h, and 8 days after the operation for studies of lymphocyte subsets and NK cell cytotoxicity. RESULTS: The lymphocyte subsets and NK cell cytotoxicity of both groups showed typical suppression after surgery. The suppression of T cell activation and NK-like T cells was significantly less after laparoscopically assisted resection than in after open resection, whereas the difference in other lymphocyte subsets and NK cell cytotoxicity was not significant. CONCLUSION: This study showed that some cellular components of the immune system are less suppressed after laparoscopically assisted than after conventional open resection of rectosigmoid carcinoma. This may have implications for tumor recurrence and long-term patient survival.

Implication of maternal-cell contamination in the clinical banking of umbilical cord blood.

BACKGROUND: The increasing utilization of human UC blood (UCB) in transplantation has drawn attention to the need for rationalization of selection, collection, processing, testing, banking and release of UCB. However, the issue of maternal blood contamination has not been well addressed. There are concerns that maternal T cells might elicit GvHD post-UCB transplant. METHODS: Maternal T cells in 58 male UCB allografts were enumerated using fluorescent in situ hybridization and flow cytometry. Obstetric factors, preceding labor, multi-parity and gestational age, were also analyzed. RESULTS: Levels of maternal cells of 0.75-5.25% were found in 15.5% (9/58) UCB. There was no association of maternal-cell contamination with preceding labor [25% (2/8) with previous delivery versus 35.4% (17/48) first born, P = 0.702], nor any correlation with multi-parity [37.5% (3/8) para > or = 3 versus 16.7% (8/48) para < 3, P = 0.181]. Gestation age of newborns also exhibited no association with maternal-cell contamination (39.47 weeks in newborn UCB with maternal cells, versus 39.58 weeks without: P = 0.674). The extrapolated maternal T cells/kg in nine UCB transplants were 1.05 x 10(5) +/- 1.12 x 10(5) (3.40 x 10(4) - 3.18 x 10(5)). DISCUSSION: In relation to the arbitrary threshold of 1 x 10(5) T cells/kg in HLA-mismatched transplants utilizing T-cell depleted BM, 22.2% (2/9) of UCB transplants having maternal-cell contamination might be at risk of GvHD. Data support the need for testing for maternal blood in UCB, and evaluating the clinical relevance of GvHD in patients post-UCB transplant. The establishment of guidelines and standards for release of such UCB collections would be advisable in evidence-based UCB transplantation.