Philadelphia chromosome unmasked as a secondary genetic change in acute myeloid leukemia on imatinib treatment.
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Acute Disease↗
Biomedical subjects
L C Chan
Publications and source records attributed to L C Chan.
The Mll-Een knockin fusion gene enhances proliferation of myeloid progenitors derived from mouse embryonic stem cells and causes myeloid leukaemia in chimeric mice.
Rearrangement of the mixed lineage leukaemia (MLL) gene with extra eleven nineteen (EEN) was previously identified in an infant with acute myeloid leukaemia. Using homologous recombination, we have created a mouse equivalent of the human MLL-EEN allele and showed that when Mll(Een/+) embryonic stem (ES) cells were induced to differentiate in vitro into haemopoietic cells, there was increased proliferation of myeloid progenitors with self-renewal property. We also generated Mll(Een/+) chimeric mice, which developed leukaemia displaying enlarged livers, spleens, thymuses and lymph nodes owing to infiltration of Mll(Een/+)-expressing leukemic cells. Immunophenotyping of cells from enlarged organs and bone marrow (BM) of the Mll(Een/+) chimeras revealed an accumulation of Mac-1+/Gr-1- immature myeloid cells and a reduction in normal B- and T-cell populations. We observed differential regulation of Hox genes between myeloid cells derived from Mll(Een/+) ES cells and mouse BM leukemic cells which suggested different waves of Hox expression may be activated by MLL fusion proteins for initiation (in ES cells) and maintenance (in leukemic cells) of the disease. We believe studies of MLL fusion proteins in ES cells combined with in vivo animal models offer new approaches to the dissection of molecular events in multistep pathogenesis of leukaemia.
Amino Acid Sequence↗
Trisomy 4 as sole karyotypic abnormality in acute lymphoblastic leukemia: different clinical features and treatment response between B and T phenotypes?
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Burkitt Lymphoma↗
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.
Adolescent↗
Can all neonatal resuscitation be managed by nurse practitioners?
AIM: To assess the ability of nurse practitioners to manage the care of all babies requiring resuscitation at birth in a unit without on site medical assistance. METHOD: A prospective review, and selective external audit, of the case records of all 14 572 babies born in a maternity unit in the north of England during the first eight years after nurse practitioners replaced resident paediatric staff in 1996. RESULTS: Every non-malformed baby with an audible heart beat at the start of delivery was successfully resuscitated. Twenty term babies and 41 preterm babies were intubated at birth. Eight term babies only responded after acidosis or hypovolaemia was corrected following umbilical vein catheterisation; in each case the catheter was in place within six minutes of birth. Early grade 2-3 neonatal encephalopathy occurred with much the same frequency (0.12%) as in other recent studies. Independent external cross validated review found no case of substandard care during the first hour of life. CONCLUSION: The practitioners successfully managed all the problems coming their way from the time of appointment. There was no evidence that their skill decreased over time even though, on average, they only found themselves undertaking laryngeal intubation once a year. It remains to be shown that this level of competence can be replicated in other settings.
Apnea↗
Cultivating psychological well-being in Hong Kong's future doctors.
There has been much recent attention on psychological well-being and pastoral care for medical students. This study examines psychological morbidity (depression, anxiety and stress) in Hong Kong medical students, as well as their concerns, coping mechanisms and their help-seeking. Medical students in Hong Kong reported a higher level of psychological morbidity as compared with other tertiary education students. Their main concerns include examinations, stress, career, adjusting to the new medical curriculum and commitment to the course. The coping skills adopted were largely adaptive. Maladaptive coping skills like 'denial', 'self-blame' and 'behavioural disengagement' were highly correlated with depression, anxiety and stress scores. Most of the students concerned wanted support services that were specifically tailored to their needs and at least partly provided by people who had been through medical training themselves. The faculty at the University of Hong Kong is establishing a Programme for Effective Transition and Student Support (PETSS) to provide a multi-faceted support system for its medical students. The findings in this study help to ensure that the services provided will be relevant, accessible and acceptable to the students.
Adaptation, Psychological↗
Pathogenesis of jumping translocations: a molecular cytogenetics study.
BACKGROUND/AIMS: Jumping translocations are rare cytogenetic aberrations in haematological malignancies, the pathogenesis of which remains to be fully characterised. We investigated the mechanism of formation of jumping translocations in a case of adult common acute lymphoblastic leukaemia (ALL) positive for the Ph translocation. METHODS: Interphase and metaphase fluorescence in situ hybridisation (FISH) was performed using several probe systems. Results were correlated with findings on conventional cytogenetics. Granulocytes, T-cells and leukaemic B-cells in peripheral blood were sorted by immunomagnetic method and the terminal restriction fragment (TRF) length of these cellular populations was determined by Southern blot analysis. RESULTS: Duplicated BCR-ABL fusion signals were found on a dic(14;22)der(22)t(9;22) chromosome. Clonal jumping translocations, existing as evolutionary changes, involved the donor chromosomal segment distal to 1q12 jumping onto the telomere ends of 11q, 15p, 19p and 20p. Telomere length was decreased in the neoplastic B-cell population and contributed to the formation of the dicentric chromosome that showed absence of telomere repeats at fusion ends. Subsequent pericentromeric heterochromatin decondensation of chromosome 1q occurred, and this donor segment was randomly fused to the shortened telomere ends of non-homologous chromosomes. CONCLUSIONS: Both telomere shortening and pericentromeric heterochromatin decondensation contribute to the formation of jumping translocations, which is most probably a multi-stage process.
Antigens, CD↗
Chloramphenicol succinate, a competitive substrate and inhibitor of succinate dehydrogenase: possible reason for its toxicity.
From our previous study [Eur. J. Clin. Pharmacol. 56 (2000) 405] we hypothesized that chloramphenicol succinate (CAPS) may be a competitive substrate for succinate dehydrogenase (SDH). It may be oxidized by SDH to release chloramphenicol (CAP), which may inhibit SDH by feed back mechanism. The present ex-vivo/in vitro study was aimed to investigate this possibility by using human tissues (bone marrow and liver samples) and animal tissues (rat liver and kidney). The effect of different SDH activators and specific inhibitors was studied on CAPS metabolism by SDH. The metabolites and reduction products were detected by using HPLC. In marrow samples, CAPS was slowly oxidized to form CAP. The formation of CAP (oxidation product) was enhanced by FAD and low malonate and inhibited by high malonate and 3-NPA. Similar results were obtained with mitochondria from human and rat tissues. These studies suggest that CAPS could be a competitive oxidative substrate and the metabolite CAP could be an inhibitor at the reduction site. Therefore, SDH could be a target molecule responsible for CAPS induced toxicity.
Animals↗
Atypical fluorescence in situ hybridisation pattern in chronic myeloid leukaemia due to cryptic insertion of BCR at 9q34.
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Bone Marrow↗
Clinical phenotype of haemoglobin Q-H disease.
Seven patients of Chinese origin who had haemoglobin (Hb) Q-H disease were studied. They were found to have a similar clinical phenotype to that of patients with deletional Hb H disease, who have a near identical genotypic configuration. The complete absence of Hb A in Hb Q-H disease and the similar clinical phenotype to deletional Hb H disease lends support to the observation that Hb Q-Thailand shares similar functional properties with Hb A.
Adolescent↗
Investigation of MYCN status in neuroblastoma by fluorescence in situ hybridization.
Neuroblastoma, a form of neuroblastic tumor, is one of the most common neoplasms seen in early childhood. The diverse clinical behavior of this tumor is most probably explainable by the heterogeneity in the associated genetic changes. We investigated 12 neuroblastoma patients for MYCN amplification and chromosome 2 aneusomy by fluorescence in situ hybridization (FISH) and results were correlated with conventional cytogenetics. Samples from both primary tumor tissue and bone marrow metastasis were available in two cases. The copy number of MYCN oncogene paralleled that of chromosome 2 in 10 cases, whereas two cases (16.7%) showed numerous distinct signals within the nuclei of the tumor cells, consistent with MYCN amplification as double minute (dmin). The morphology of dmin in one case was of an extremely small type and might potentially be missed by conventional chromosome analysis. Discordant cytogenetics and FISH results was observed between primary tumor and metastasis disease in one case, with loss of chromosome 2 tetrasomic and pentasomic cells as well as over-representation of chromosome 2 disomic cells harboring MYCN amplification in bone marrow deposits. Our study reaffirmed the need for MYCN status to be determined in light of chromosome 2 copy number, as recommended by published guidelines. We also showed that genetic heterogeneity might occur between primary tumor and bone marrow metastasis. Finally, atypical dmin morphology when encountered would need confirmation by FISH study.
Child↗
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.
Adolescent↗
Deletion 9q as the sole karyotypic abnormality in myelocytic disorders: a new case of myelodysplastic syndrome and its prognostic implications in acute myelocytic leukemia.
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Aged↗
Prevalence and specificity of clinically significant red cell alloantibodies in Chinese women during pregnancy--a review of cases from 1997 to 2001.
Guidelines for the prevention and management of red cell alloantibodies during pregnancy, related to anti-D in particular, are well established in Caucasian populations. However, because of the racial difference of the blood group distribution, applicability to Chinese is unknown as a result of insufficient data on the prevalence and their outcome. In a retrospective review of 28,303 (21,327 Chinese) antenatal attendances from 1997 to 2001, 213 (0.79%) women were found to have a total of 230 irregular antibodies. About 137 (0.64%) were ethnic Chinese, and a total of 160 irregular antibodies were identified in their blood samples. About 58 of these Chinese women (0.27%) were found to have 66 clinically significant antibodies. There was only one case of anti-D detected in an Rh(D)-negative subject. Our study shows the overall prevalence of clinically significant antibodies in Chinese women, which was not different from that of the Western population. However, the specificities of the antibodies differ with the commonest antibodies encountered; these being anti-Mi (57.6%), anti-E (19.7%), anti-S (10.6%) and anti-c (7.6%). Neonatal jaundice was observed in 37 babies and 10 of them required phototherapy. The findings support the previous recommendation that routine antenatal antibody screening for Chinese women may not be worthwhile except in Rh(D)-negative subjects or those with an antecedent history of haemolytic disease of the newborn (HDN). The relative high incidence of anti-Mi in the present study and the local population, in general, may warrant a large-scale prospective study of pregnancy outcome in these subjects, especially in the light of the previous case reports of HDN because of anti-Mi.
Adult↗
Derivative chromosome 9 deletions in chronic myeloid leukaemia: interpretation of atypical D-FISH pattern.
BACKGROUND/AIMS: New molecular cytogenetic techniques are increasingly applied as a routine investigative tool in haematological malignancies, both at diagnosis and subsequent monitoring. This report describes the interpretation of atypical signal patterns encountered using BCR-ABL dual colour dual fusion fluorescence in situ hybridisation (D-FISH) translocation probes in chronic myeloid leukaemia (CML). METHODS: Interphase FISH experiments were carried out using BCR-ABL D-FISH probes in 46 patients with CML at diagnosis and during subsequent disease monitoring. Atypical hybridisation signal patterns were characterised by molecular cytogenetic techniques and correlated with conventional karyotyping. RESULTS: Two patients showed atypical interphase D-FISH patterns with one orange, one green, and one fusion (1O1G1F) signal. The presence of BCR-ABL gene fusion was documented by a dual colour single fusion (S-FISH) probe. The submicroscopic deletion of the ABL-BCR fusion gene on the derivative chromosome 9 in these cases was subsequently characterised by metaphase FISH on relocated G banded metaphases. CONCLUSIONS: Atypical interphase D-FISH patterns should not be interpreted in isolation and should be considered in conjunction with other cytogenetic or molecular genetic investigations.
Adult↗
Venous thromboembolism in the Chinese population-experience in a regional hospital in Hong Kong.
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Hong Kong↗
Fatal diffuse alveolar damage complicating acute myeloid leukemia with abnormal eosinophils and trisomy X.
We describe a case of acute myeloid leukemia (AML) with abnormal eosinophils in a 44-year-old Chinese woman that was complicated by diffuse alveolar damage (DAD) and pulmonary hemorrhage (PH) shortly after induction chemotherapy. Cytogenetic study of bone marrow cells at diagnosis showed a rare aberration of trisomy X (+X) as the sole acquired karyotypic abnormality. We speculate that tissue damage by cellular constituents of the abnormal eosinophils that were released on cell lysis after chemotherapy might be etiologically linked to the occurrence of fatal pulmonary complications.
Acute Disease↗
Two balanced and novel chromosomal translocations in myeloid malignancies. characterization by multiplex fluorescence in situ hybridization.
We describe two novel chromosomal translocations in two cases of leukemia in which these translocations were further characterized as the sole acquired karyotypic abnormality by mutliplex fluorescence in situ hybridization (M-FISH). They comprised a case of acute myeloid leukemia with t(6;10)(q21;p12) and a case of chronic myelomonocytic leukemia with t(5;12)(q34;q24). To the best of our knowledge, these two balanced translocations are novel and are hitherto unrecognized in hematologic malignancies. While the clinical and pathogenic significance of these translocations remains to be defined, the present report illustrates that M-FISH technology contributes to the exclusion of subtle or cryptic translocations in sole karyotypic aberrations and the confirmation of novel chromosomal arrangements in neoplastic disorders.
Chromosome Mapping↗