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Biomedical subjects

K Chun

Publications and source records attributed to K Chun.

At least 19 recordsLinked to original sources
PubMed2005

Treatment of elderly patients with acute lymphoblastic leukemia--evidence for a benefit of imatinib in BCR-ABL positive patients.

All patients with acute lymphoblastic leukemia (ALL) over age 60 years seen at Princess Margaret Hospital over an 11-year period were analysed retrospectively. Of 53 patients, 45 received multiagent induction chemotherapy using a variety of regimens. There were 13 BCR-ABL positive patients, 9 of who received imatinib mesylate, either during induction or post-remission therapy. The overall complete remission (CR) rate of all 45-induction patients was 56%, with a 27% induction-related mortality rate. The CR rate was not influenced by induction regimen, age, initial WBC, LDH or BCR-ABL status. The median overall survival of the induction patients was 9 months, while the median progression-free survival (PFS) of the patients achieving CR was 10 months. The estimated overall survival (OS) at 3 years was 18.4% (95% CI: 9.8-34.3%). Age and initial WBC did not significantly predict for OS when evaluating the entire group of induction patients. However, there was a strong trend for BCR-ABL status to favorably predict for PFS, and for OS when only patients treated after July 2000 (when imatinib became available) were evaluated. The results indicate that ALL remains a poor prognosis disease in elderly patients, and that aggressive induction regimens designed for younger patients are very toxic for these patients. These data suggest that BCR-ABL+ ALL is becoming a relatively more favorable prognosis disease in the elderly, likely due to the influence of imatinib therapy. Further regimens should explore the use of less aggressive regimens in elderly patients and should evaluate the optimal way of combining imatinib with conventional agents in BCR-ABL+ patients.

Aged↗
PubMed2005

Assessment of the downstream portion of the mitochondrial pathway of caspase activation in patients with acute myeloid leukemia.

Most chemotherapeutic agents used in the treatment of acute myeloid leukemia (AML) induce apoptosis by triggering the mitochondrial pathway of caspase activation. To investigate the downstream portion of the mitochondrial pathway of caspase activation in patients with AML, cytosolic lysates were stimulated with cytochrome c and dATP and hydrolysis of Ac-DEVD-AFC by effector caspases was measured. Defects in the distal mitochondrial pathway were more common in samples from patients with AML that relapsed rapidly after induction chemotherapy compared to samples from treatment naïve patients. The incidence of blocked pathways did not differ based on response to induction chemotherapy, as even nonresponders generally had an intact pathway. When the distal mitochondrial pathway was blocked, defects were usually at the level of the effector caspases. Thus, functional defects in the distal portion of the mitochondrial pathway of caspase activation may help explain the nature of response and relapse after treatment.

Adenosine Triphosphate↗
PubMed2004

The role of allogeneic bone marrow transplantation in adult patients below the age of 55 years with acute lymphoblastic leukemia in first complete remission: a donor vs no donor comparison.

The role of allogeneic bone marrow transplantation (alloBMT) in adults with acute lymphoblastic leukemia (ALL) in first complete remission (CR1) remains controversial. At our institution, the policy is to offer alloBMT to ALL patients in CR1 up to the age of 55 years if a related donor is available. In addition, unrelated donor transplants are offered to patients with Philadelphia (Ph+) ALL. We report the results on 92 patients with ALL treated according to this policy from September 1992 to October 2001. Of the 87 patients achieving CR1, the comparison of patients with (n=48) or without donors (n=39) was done using an intention-to-treat approach. Of the 48 patients with donors (39 related and nine unrelated), 35 (73%) received alloBMT in CR1. No significant difference in 3-year event-free survival (EFS) (40 vs 39%, P=0.74) or overall survival (OS) (46 vs 58%, P=0.41) was seen in 'donor' vs 'no-donor' groups. For Ph+ patients, 3-year EFS and OS in 'donor' group were 46 and 57%, respectively, none of the patients in 'no-donor' group survived beyond 3 years. With our treatment strategy, 3-year OS of Ph+ patients was equivalent to Ph-negative (Ph-) patients (51 vs 52%, P=0.77). In conclusion, our data show that the policy of performing alloBMT if a sibling donor is available has not resulted in better outcome in Ph- patients.

Adolescent↗
PubMed2003

Quantitative PCR identifies a minimal deleted region of 120 kb extending from the Philadelphia chromosome ABL translocation breakpoint in chronic myeloid leukemia with poor outcome.

Fluorescence in situ hybridization (FISH) analysis has shown previously that 10-15% of chronic myeloid leukemias (CML) have hemizygous deletions of variable sizes affecting regions that flank the ABL and BCR translocation breakpoints on the derivative chromosome 9, and these patients have a poor outcome. FISH studies using large commercial genomic probes have previously suggested that haploinsufficiency of sequences flanking either ABL or BCR modify the disease process of CML and lead to an unfavorable prognosis. In this present study, real-time quantitative PCR (Q-PCR) analysis was used to identify and map much smaller hemizygous microdeletions in a subset of CML patients that were not deleted using large genomic FISH probes. Microdeletions were identified by Q-PCR in 25 of 71 patients selected based on less favorable outcome (chronic phase duration of less than 96 months and a survival time of less than 84 months). In contrast, no microdeletion was detected in any of 18 CML samples selected from a group with a more favorable outcome. Detailed mapping of the 25 Q-PCR microdeletions showed that the minimal deleted region extended approximately 120 kb from the 5' end of the ABL gene in the centromeric direction on the derivative chromosome 9, and the region 3' to BCR on chromosome 22 was excluded. Of the four ESTs and/or genes that map to the 120 kb region, the putative tumor suppressor PRDM12 is the strongest candidate gene. The potential role for each sequence in modifying the clinical behavior of CML is presented.

Chromosome Breakage↗
PubMed2001

Methodology for miniaturized CE and insulation on a silicon substrate.

We have developed a synchronously switched cyclic capillary electrophoresis (CE) separator that is fabricated on a silicon substrate and glass. Au electrodes were also integrated on the chip that could be wire bonded to the printed circuit board (PCB). The advantage of using a cyclic separator is that it has the high resolution and the ability to separate each sample to the designated reservoir from mixed samples. This approach makes it possible to reduce the supplied voltage and the total chip size. Another goal of this work was to introduce the methodology of electroosmotic flow (EOF) on the silicon substrate and to separate DNA samples using a modified double-T injector.

Journal Article↗
PubMed2001

Isochromosome (17)(q10) and translocation (4;12)(q12;p13) in a child with acute myeloid leukemia.

Isochromosome 17q is a commonly observed cytogenetic aberration in hematologic malignancies. Isolated isochromosome 17q usually presents as a marker of a chronic myeloid disorder, with a high propensity for transformation into acute nonlymphoblastic leukemia (ANLL). t(4;12)(q11-12;p13) is a recently described translocation, associated with ANLL, predominantly in adults. In this article, we present a case of acute myeloblastic leukemia (AML) in a 14-year-old female in which i(17q) and t(4;12)(q12;p13) were found in the leukemic clone at diagnosis. We briefly review the literature and hypothesize as to the significance of the coexistence of these cytogenetic changes.

Adolescent↗
PubMed2001

A case of PDH-E1 alpha mosaicism in a male patient with severe metabolic lactic acidosis.

We have characterized a novel mutation in a male patient that affects the coding sequence of PDH-E1 alpha gene and changes arginine-141 to a leucine. This nucleotide substitution was found in about 75% of the studied DNA (fibroblasts, liver and muscle), a scenario that would indicate a case of E1 alpha mosaicism in a male patient. When the mutant E1 alpha protein was expressed in human skin fibroblasts with zero endogenous pyruvate dehydrogenase complex activity and E1 alpha protein expression, no significant restoration of activity was recorded, in contrast to the wild-type cDNA. even though both wild-type and mutant protein levels were comparable. We concluded that the R141L mutation is a severe one and that it must have occurred in one of the E1 alpha alleles during early embryogenesis.

Acidosis, Lactic↗
PubMed2000

The use of remifentanil for Cesarean section in a parturient with recurrent aortic coarctation.

PURPOSE: To illustrate the clinical utility of a short acting opioid (remifentanil) based general anesthetic for Cesarean section in a parturient with compromised cardiac function. CLINICAL FEATURES: A 23-yr-old primigravida, complicated by a recurrent aortic coarctation with an approximate 50% narrowing of the aortic arch, presented for elective Cesarean section at 37 wk gestational age. Initially asymptomatic, her clinical condition had deteriorated as the pregnancy progressed, with worsening episodes of mild chest pain and shortness of breath. A semi-elective Cesarean section under general anesthesia was planned at 37 wk to minimize the potential for aortic complications associated with the hemodynamic stress of labour. Remifentanil was infused at 0.05 to 0.1 microg x kg(-1) x min(-1) with good sedation and analgesia for the placement of invasive monitors. The infusion was increased to 0.2 microg x kg(-1) x min(-1) for induction, and combined with isoflurane 0.4 to 0.6% for maintenance of anesthesia. The patient maintained stable hemodynamics throughout and her trachea was extubated without difficulty at the end of the procedure. The newborn did not require tracheal intubation, mask ventilation or naloxone and was in excellent condition upon transfer to the well baby nursery. CONCLUSION: Remifentanil, when used as part of an opioid-based general anesthetic for Cesarean section, can provide maternal hemodynamic stability with minimal neonatal respiratory depression and should allow for immediate postoperative tracheal extubation of the mother.

Adult↗
PubMed1999

Achondroplasia-hypochondroplasia complex in a newborn infant.

We describe the case of an 8-month-old girl with achondroplasia-hypochondroplasia complex. The diagnosis was suggested antenatally when obstetrical ultrasonography at 27 weeks of gestation showed short limbs, small chest, and macrocephaly. The father has achondroplasia due to the common G1138A (G380R) mutation in the fibroblast growth factor receptor 3 (FGFR3) gene, while the mother has hypochondroplasia due to the C1620G (N450K) mutation in the FGFR3 gene. Neither had had genetic counseling or molecular testing prior to the pregnancy. Antenatal ultrasound study at 29 weeks of gestation showed a large head, very short limbs, and a small chest; the findings were more severe than in achondroplasia or hypochondroplasia alone. The patient was born by cesarean section at 37 weeks of gestation and had rhizomelic shortness of limbs with excess skin creases, large head, and small chest, diagnostic of achondroplasia. Radiographs showed shortness of the long bones and flaring of the metaphyses. She had mild hypoplasia of lungs. Molecular testing showed both the G1138A and the C1620G mutations in FGFR3, confirming the diagnosis of achondroplasia-hypochondroplasia complex. At 8 months, she has disproportionate shortness of the long bones and a large head with frontal bossing and a depressed nasal bridge. Her chest remains small, and she is on home oxygen at times of respiratory stress. She has a large gibbus. She is delayed in her motor development and has significant head lag. To our knowledge, there is only one previously published report of achondroplasia-hypochondroplasia complex.

Abnormalities, Multiple↗
PubMed1999

Compound heterozygosity for the Achondroplasia-hypochondroplasia FGFR3 mutations: prenatal diagnosis and postnatal outcome.

We report on a male newborn infant, a compound carrier of heterozygous mutations in the FGFR3 gene causing achondroplasia and hypochondroplasia. The mother has achondroplasia and carries the common G1138 (G380R) mutation in the FGFR3 gene; the father has hypochondroplasia due to the C1620A (N540K) mutation in the same gene. The fetus was found to carry both mutations diagnosed prenatally by amniocentesis at 17.6 weeks of gestation, following maternal serum screening which showed an increased risk for Down syndrome (1:337). Detailed fetal ultrasound studies showed a large head, short limbs, and a small chest at 22 weeks of gestation. The changes were more severe than those of either achondroplasia or hypochondroplasia. The patient was born by cesarean section at 38 weeks of gestation and had rhizomelic shortness of the upper and lower limbs with excess skin folds, large head, enlarged fontanelles, frontal bossing, lumbar gibbus, trident position of the fingers, and a narrow chest with a horizontal line of demarcation at the narrowest area of the chest. Skeletal radiographs showed shortness of the long bones and flare of metaphyses. He had respiratory difficulties and was treated with nasal prongs. Seizures developed on day 2 of life and recurred on day 9 and responded to treatment with phenobarbital. Brain computed tomographic scan showed possible grey matter heterotopia, partial agenesis of the corpus callosum, and cortical dysplasia. To our knowledge, there are only two previously published cases of compound heterozygous achondroplasia-hypochondroplasia patients. The diagnosis was confirmed by DNA mutation analysis of the FGFR3 gene in both cases.

Abnormalities, Multiple↗
PubMed1998

FGFR2 mutation associated with clinical manifestations consistent with Antley-Bixler syndrome.

The Antley-Bixler syndrome (ABS) is a rare syndrome with synostosis of cranial sutures and elbow joints as minimal diagnostic criteria. The inheritance has been suggested to be autosomal recessive based on two families with sib recurrence with both sexes being affected, and two cases born to consanguineous parents. We report the first case of ABS associated with an apparent dominant de novo mutation in the fibroblast growth factor receptor 2 (FGFR2) gene. The patient was found to be heterozygous for a C-->G transversion at nucleotide 1064, which predicts a Ser351Cys amino acid substitution in the IgIII domain of FGFR2. Apart from the craniosynostosis and elbow ankylosis, our patient also presented with severe spinal dysraphism, the first report of such a finding in association with ABS. This suggests that FGFR2 is expressed as early as the fourth week of embryogenesis when somite formation occurs. We propose that the Antley-Bixler syndrome is an autosomal dominant condition with possible gonadal mosaicism. Alternatively, there may be two types of ABS: an autosomal dominant form and an autosomal recessive form. In light of our findings, FGFR mutations should be looked for in other craniosynostosis patients with elbow synostosis.

Abnormalities, Multiple↗
PubMed1998

Expression of normal and mutant pyruvate dehydrogenase complex E1 alpha cDNAs in cultured human lymphoblasts.

Transfection of PDH E1 alpha cDNAs into human normal (3781) and PDH-deficient (4787) lymphoblast cell lines was performed to study the expression of different E1 alpha cDNAs. Transfection of normal human E1 alpha cDNA into a severely PDH-deficient cell line with 10% residual activity resulted in a fivefold increase in residual PDH complex activity. Transfection of the normal cDNA into the normal cell line did not affect the residual enzyme activity. Transfection of three known human PDH E1 alpha mutations (A875T, C787G, and a 13-bp insertion at nucleotide 981) into the normal cell line resulted in a decrease of PDH complex activity. Expression of these same mutations in the deficient cell line resulted in an increase of PDH complex activity, with the C787G mutation causing the greatest increase in enzyme activity. The increase in activity seen with A875T expressed in the mutant cell line suggested that interallelic complementation had occurred.

Cells, Cultured↗
PubMed1997

Scrotoschisis associated with contralateral meconium periorchitis.

Scrotoschisis, a congenital defect of the scrotal wall associated with extracorporeal testicular ectopy, has been previously reported only twice. Meconium periorchitis is another rare scrotal anomaly indicative of an antenatally healed gastrointestinal perforation. The authors present a third case of scrotoschisis and the first associated with meconium periorchitis. Several hours after birth of an otherwise-normal term baby boy, a scrotal exploration was performed with orchidopexy and primary closure of the scrotal wall defect. At 4 months of age the baby underwent a contralateral inguino-scrotal exploration with excision of a paratesticular mass of calcified meconium. The role of a normally developed scrotum in testicular descent and causes of calcified scrotal masses in infants are discussed.

Humans↗
PubMed1996

Naive murine neonatal T cells undergo apoptosis in response to primary stimulation.

The cellular mechanisms controlling deficient immune responses in newborn animals are not well understood. Our earlier studies showed that developmental regulation of Th cell activity may be one of the major causes of immunodeficiency in neonatal animals. Naive murine neonatal T cells showed poor Th1 activity but robust Th2 activity in response to primary stimulation in vitro. Although they produced high levels of IL-4, neonatal T cells proliferated poorly, suggesting that neonatal T cell survival in primary cultures may be limited. We show here that, unlike adult T cells, naive neonatal T cells undergo apoptosis in response to primary TCR-mediated stimulation. Ligation of the TCR alone, in the absence of accessory cell costimulation, is sufficient to induce apoptosis. Moreover, CD4+ and CD8+ T cells show equivalent levels of apoptosis. Lastly, this apoptosis can be prevented by the addition of excess IL-2 or by conditions promoting a high level of IL-2 production (TCR-independent stimulation, anti-CD28 mAb, or exogenous IL-6) by neonatal T cells. However, IL-2 alone is not sufficient to support functional rescue from apoptosis; only IL-6 supports the ability of these cells both to survive and to mount vigorous secondary responses. The identification of conditions allowing functional rescue from apoptosis in vitro has important implications for enhancing vaccine responsiveness in vivo.

Animals↗
PubMed1996

Disorders of pyruvate carboxylase and the pyruvate dehydrogenase complex.

The most common defect associated with deficiency of the pyruvate dehydrogenase (PDH) complex occurs in the E1 component, specifically due to mutations in the X-linked E1 alpha gene. Clinical sequelae of these mutations, which range from severe neonatal lactic acidosis to carbohydrate-sensitive ataxia, can be different in males and females depending on the nature of the mutation and, in the case of females, on the X-inactivation pattern in different tissues. Males have a high representation of missense mutations among the patient cohort, while females are much more likely to have DNA rearrangements, particularly toward the 3' end of the coding sequence of the gene. Missplicing mutations involving exon 6 deletion have been reported, as has a missense mutation conferring true thiamin-responsiveness of the enzyme and the patient's clinical symptoms. Pyruvate carboxylase deficiency, on the other hand, is a true autosomal recessive disease, though it has high occurrences in particular ethnic groups, especially in Algonkian-speaking Amerindians and in Arabs. In the former group the defect is a simple type in which material cross-reactive to pyruvate carboxylase antibody is present in cultured cells (CRM+ve). In the latter group, cross-reacting material is rarely present (CRM-ve). The CRM+ve patients can survive into teenage years with careful supervision, while the CRM-ve patients have complications due to hyperammonaemia and dysfunction of the urea cycle and rarely survive beyond 3 months of life.

Amino Acid Sequence↗
PubMed1996

Fibro-osseous pseudotumor of the digit: a comparison to myositis ossificans by light microscopy and immunohistochemical methods.

Fibro-osseous pseudotumor of the digit is an unusual cutaneous process characterized histologically by a fibroblastic proliferation admixed with reactive/metaplastic osteoid formation. The osteoid formation can be florid and immature, mimicking the appearance of malignant osteoid-forming neoplasms. Fibro-osseous pseudotumor of the digit has histologic and clinical features in common with myositis ossificans. This has led many to consider the two to be synonymous. We studied three cases of fibro-osseous pseudotumor, compared to five cases of myositis ossificans, using routine light microscopy and a battery of immunohistochemical stains. Both entities displayed a "zoning" pattern of immature spindled areas admixed with more mature areas having osteoid metaplasia. This was more pronounced in myositis ossificans. In each lesion, the spindle cells stained positively for vimentin and actin. CD34 and Factor VIII highlighted the vasculature. No stromal staining for MAK-6 (cytokeratin) or S-100 was identified. Ki-67, a proliferation marker, showed positive staining of the stromal cells in both lesions, which was strongest in the immature spindled areas. The immunohistochemical and histologic similarities of the lesions support fibro-osseous pseudotumor of the digit being a cutaneous variant of myositis ossificans.

Adolescent↗