[Show abstract][Hide abstract] ABSTRACT: Background/objectives
Recent studies have shown that the KIT mutational type appears to be a predictive marker for the efficacy of imatinib in treating melanoma. However, a wide range of KIT mutation rates was reported in different types of melanoma, suggesting that the mutation frequency of KIT may be associated with clinicopathological subsets of melanoma.
To characterize their relationship, we sequenced exons 11, 13, 17, and 18 of KIT in 80 of 85 melanomas collected from two hospitals and categorized KIT mutation by tumor type, age and gender of patients, and mutation hot spots of KIT.
Our results showed that KIT mutation rates were 25%, 22%, and 8% in acral, mucosal, and cutaneous melanomas, respectively. Approximately 38% (5/13) of male patients with acral melanoma and 45% (5/11) of female patients with mucosal melanomas of the anorectal and genitourinary regions had a KIT mutation. Approximately 81% of KIT mutations occurred in L576P, K642E, V559A, and D820Y.
This result shows that KIT mutation is enriched in a certain subset of melanoma patients and mutation hot spots do exist.
Full-text · Article · Jan 2013 · Dermatologica Sinica
[Show abstract][Hide abstract] ABSTRACT: A 4-year-old boy presented with enteroviral infection complicated with atypical hemolytic uremic syndrome (aHUS). Enterovirus RNA was detected by reverse transcription polymerase chain reaction (RT-PCR) of both blood and kidney biopsy specimens. A survey of the complement system did not reveal a specific complement defect. Supportive therapy with blood components transfusion, plasma therapy, and immunosuppressants was administered, however, renal function did not recover. The results of this report demonstrate that the enterovirus is the cause of aHUS.
No preview · Article · Dec 2012 · Pediatrics & Neonatology
[Show abstract][Hide abstract] ABSTRACT: Here we presented a 60-year-old Taiwanese man with advanced gastrointestinal stromal tumor. Disease progression was noted during imatinib treatment. Surgical resection was done and mutation analysis of KIT gene in all the resected tumors revealed deletion mutations of codons 558-565 in exon 11, whereas a missense mutation was also identified at codon 822 in exon 17 in one resected tumor. Patient's disease was refractory to escalating dose of imatinib and dasatinb. Surprisingly, combination of imatinib with pegylated liposomal doxorubicin produced a substantial response and resulted in a 5-month progression free period for this imatinib-resistant gastrointestinal stromal tumor.
Full-text · Article · Jun 2011 · Journal of the Chinese Medical Association
[Show abstract][Hide abstract] ABSTRACT: Indoxyl sulphate (IS) and p-cresyl sulphate (PCS) are uraemic toxins that have similar protein binding, dialytic clearance and proinflammatory features. However, only a few prospective studies have evaluated possible associations between these two retained solutes and renal disease progression in chronic kidney disease (CKD) patients.
This prospective observational study evaluated independent associations between serum total IS and PCS with renal progression in a selected cohort of patients having different stages of CKD. Baseline PCS and IS were correlated with renal progression [defined as decrements in estimated glomerular filtration rate (eGFR) > 50% from baseline or progression to end-stage renal disease (ESRD)] and death during a follow-up period of 24 months.
Of 268 patients, 35 (13.1%) had renal progression and 14 (5.2%) died after a mean follow-up of 21 ± 3 months. Univariate Cox regression analysis followed by multivariate analysis showed that high-serum PCS levels were associated with renal progression and all-cause mortality independent of age, gender, diabetes status, albumin levels, serum IS, serum creatinine, Ca × P product, intact parathyroid hormone, haemoglobin or high-sensitivity C-reactive protein level. Serum IS was only associated with renal progression; however, the predictive power of serum IS was weakened when serum PCS was also present in the analytical model.
In addition to traditional and uraemia-related risk factors such as renal function, serum IS and PCS levels may help in predicting the risk of renal progression in patients having different stages of CKD.
[Show abstract][Hide abstract] ABSTRACT: Human KIT protooncogene is the cellular homolog of v-kit from the Hardy-Zuckerman 4 feline sarcoma virus, and encodes a 145-kDa type III tyrosine kinase growth factor receptor that is often mutated in gastrointestinal stromal tumors (GIST). Standardized mutation analysis is not available in many countries; therefore, we aimed to determine if the presence of KIT mutation in GIST can be predicted by the immunoprofile of the tumor cells.
One hundred and forty-nine GIST were subjected to mutation analysis for KIT and immunohistochemical analysis for the expression of CD117, CD34, alpha-smooth muscle actin (SMA), and S100 protein. Mutation and immunohistochemistry data were correlated.
KIT mutation rates were higher in certain immunoprofile subsets of GIST than in GIST in general. Compared with the overall mutation rate of KIT (70%), all GIST with CD117+ and S100+ had > 80% probability of harboring mutated KIT, and the subset with additional CD34+ and SMA- had a mutation rate of 88%. The overall KIT mutation rate in CD117- GIST was 31%. However, the probability of KIT mutation in CD117- GIST with CD34+SMA+S100-, CD34-SMA-S100+, and CD34+SMA-S100+ was 100%, 100%, and 67%, respectively. Compared with the overall mutation rate (8.7%) of exon 9, GISTs with CD34+SMA+ had > or = 20% probability of harboring an exon 9 mutation, and all GISTs in the small intestine had a probability of 19%.
When mutation analysis is not available, immunoprofiles based on CD117, CD34, SMA, and S100 can be used to predict the presence of KIT mutation, but it is less useful for the prediction of exon 9 mutation in GISTs.
No preview · Article · Jan 2010 · Journal of the Formosan Medical Association
[Show abstract][Hide abstract] ABSTRACT: We report an 18-gestational-week fetus with oligohydramnios, orofacial clefting, bilateral multicystic kidneys and the Dandy–Walker malformation. Characteristic craniofacial features include a turricephalic prominent forehead, hypertelorism, low-set ears, a flat nasal bridge, mid-face hypoplasia, bilateral cleft lip and palate, and a thick nuchal fold. Array-comparative genomic hybridization (CGH) analysis demonstrated a 12 Mb deletion of 6p24.1 → pter.
No preview · Article · Feb 2009 · European journal of medical genetics
[Show abstract][Hide abstract] ABSTRACT: This study was aimed to test whether PIK3CA, BRAF and RAS are mutated in nasopharyngeal carcinomas (NPCs) and, if so, to further determine whether such mutations affect patients' survival. For this purpose, a total of 73 NPCs were subjected to mutational analyses for PIK3CA (exons 4, 7, 9, and 20), BRAF (codon 600), and RAS (codons 12, 13 and 61). Clinicopathological characteristics were correlated to the mutation data. Survival rates were compared with the log-rank test. The result showed that the mutation rate of PIK3CA in NPC (n = 73) was 9.6%, whereas both BRAF (n = 65) and RAS (n = 45) were wild type in every specimen with adequate DNA for analysis. PIK3CA mutation was slightly influenced by sex (P = 0.0418, Fisher's exact test), but had no significant relationship to other clinicopathological characteristics. Disease-specific survival was not significantly affected by PIK3CA mutations (P = 0.8825, log-rank test), albeit it was slightly better in younger patients (< or = 35 vs. >35 years of age) (P = 0.0477). These findings show that mutated PI3K may be involved in the NPC tumorigenesis but does not affect patient's prognosis, suggesting that PI3K is a potential target in NPC for targeted therapeutics using specific kinase inhibitors.
No preview · Article · Nov 2008 · Medical Oncology
[Show abstract][Hide abstract] ABSTRACT: Prognostic factors that could select breast cancer patients with poor survival, and influence clinical trials of targeted therapy, are needed. However, the reported observations regarding the impact of PI3KCA mutation on breast cancers are controversial.
We analyzed exons 4, 7, 9, and 20 of PI3KCA on a series of 158 patients. Clinicopathological characteristics were correlated with the mutation data.
Among 152 patients who were available for follow-up (median follow-up time, 6.57 years), 26% had PIK3CA mutations, more than half of which occurred in exon 20. The five-year survival rate of patients with exon 20 mutations (46%) was significantly lower than that of patients without (75%) (p = 0.0054). Multivariate analysis showed that PIK3CA exon 20 mutations and nodal involvement were independent risk factors for overall survival. The relative risk of death in patients with PIK3CA exon 20 mutations was 2.881 (95% CI, 1.406-5.900; p = 0.0038).
PIK3CA mutations are common in invasive ductal carcinomas of the breast. Our result suggests that PIK3CA exon 20 mutation is an independent risk factor for poor prognosis in breast cancer patients, indicating that differences in patient numbers with PIK3CA exon 20 mutations in study and control arms should be avoided in clinical trials of PI3K inhibitors.
No preview · Article · May 2008 · Annals of Surgical Oncology
[Show abstract][Hide abstract] ABSTRACT: Most gastrointestinal stromal tumors (GISTs) are associated with activating kinase mutation in KIT or platelet-derived growth factor receptor alpha (PDGFRA) gene, and imatinib has revolutionized the care of advanced GISTs. However, most patients gradually developed resistance to imatinib. We intend to identify the secondary kinase mutations in imatinib-resistant GISTs and to study the relationship between secondary kinase mutations and the clinical response to imatinib. Twelve advanced GIST patients, who have developed resistance to imatinib were included in this study. Paraffin-embedded pretreatment GIST specimens and progression lesions of the tumors after resistance to imatinib were analyzed for kinase mutations in exons 9, 11, 13, and 17 of KIT gene and exons of 10, 12, 14, and 18 of PDGFRA gene. Primary KIT mutations have been found in all but one of the primary tumors including one case harboring de novo double KIT exon 11 mutations. Secondary kinase mutations in KIT and PDGFRA were found in seven and 1 of 12 patients, respectively. Two patients harbored more than one secondary KIT mutations in different progression sites, and there are four types of clonal or polyclonal evolution being observed. The secondary PDGFRA exon 14 mutation H687Y is a novel mutation that has never been reported before. Acquired secondary kinase mutations are the most important cause of secondary imatinib resistance in advanced GISTs. The identification of secondary kinase mutations is important in the development of new therapeutic strategies.
No preview · Article · Feb 2008 · Medical Oncology
[Show abstract][Hide abstract] ABSTRACT: Anaplastic thyroid carcinoma (ATC), a rare and highly malignant tumor, has long been thought to arise from well-differentiated carcinoma (WDC) such as follicular thyroid carcinoma (FTC) and papillary thyroid carcinoma (PTC). The purpose of this study was to test this notion by examining whether and, if so, how often ATC harbors the oncogenes that are commonly associated with WDC, such as RAS in FTC and BRAF in PTC.
We analyzed the mutation hotspots of BRAF (codon 600) and N-, K-, and H-RAS (codons 12, 13, and 61) in 16 ATCs. We also examined two genes, PIK3CA (exons 9 and 20) and TP53 (exons 5-9), both of which have been reported in ATCs.
The results showed that approximately 31% (5 of 16) of ATCs harbored N-RAS mutation, 6% (1 of 16) had mutated BRAF, and approximately 56% (9 of 16) had mutated TP53. As to the three ATCs that had coexisted PTCs, mutated BRAF was detected in all PTC components but only in one ATC, while mutated PIK3CA was found in only one PTC component but not in the ATC.
A number of ATCs arise from WDCs, more often from RAS-mutant tumors than from BRAF-mutant tumors, implying that particular attention should be paid to the WDC harboring RAS mutation.
Full-text · Article · Nov 2007 · Annals of Surgical Oncology
[Show abstract][Hide abstract] ABSTRACT: To investigate how mitochondrial mutation occurs in cancers, we analyzed ND4 mutation in 53 transitional cell carcinomas (TCCs) of the upper urinary tract and the normal counterpart (perirenal soft tissue). Three methods, i.e., DNA sequencing, restriction fragment length polymorphism (RFLP), and denaturing high-performance liquid chromatography (DHPLC), were employed because of their different sensitive of detecting mutation. The results of sequencing and RFLP showed that ND4 mutations were only found in 24.5% (13/53) of tumor. However, 11 of these mutations could also be identified in the normal tissue by DHPLC, indicating that most mitochondrial mutations identified in tumors preexist as minor components, which are too low in quantity to be detected by less sensitive methods such as DNA sequencing. The result suggests that mtDNA mutation occurs before tumorigenesis and become apparent in cancer cells.
[Show abstract][Hide abstract] ABSTRACT: The mechanism governing cell quiescence remains to be elucidated, albeit some tumor suppressor genes are known to be involved in this process. If more genes belonging to this regulatory circuit are identified, we will have a better understanding on cell quiescence. For this purpose, the present study was designed to clone genes preferentially expressed in cell quiescence. Using the method of differential display, we cloned ras-recision gene (rrg), also known as lysyl oxidase gene (lox), from BALB/c 3T3T cells, which were rendered quiescent by serum deprivation. Northern blot analysis showed that the induction of rrg/lox gene could be detected as early as 12 h following serum deprivation and it was dramatically elevated from 24 hours on after serum starvation. Induction of rrg/lox was also observed in cells rendered quiescent by contact inhibition, indicating that rrg/lox is induced by cell quiescence in general rather than specific to serum deprivation. Because rrg/lox gene products are known to be involved in extracellular matrix maturation, and function as tumor suppressors against ras oncogene, our finding suggests that quiescence-associated cell physiology is partly mediated by induction of rrg/lox.
Preview · Article · May 2007 · The Chinese journal of physiology
[Show abstract][Hide abstract] ABSTRACT: The objective of this study is to investigate the potential protective effects of intravesical instillation of epinephrine in cyclophosphamide-induced hemorrhagic cystitis. In an earlier study, we have shown that epinephrine promotes hemostasis on established hemorrhagic cystitis induced by cyclophosphamide. Female Sprague-Dawley rats were divided into seven groups as follows: group 1: positive control (150 mg/kg, cyclophosphamide, i.p.), group 2: negative control (10 microg/ml, epinephrine, intravesical), co-administration of cyclophosphamide (150 mg/kg, i.p.), group 3: saline (intravesical), groups 4-6: epinephrine (2.5, 5, and 10 mu g/ml, intravesical), and group 7: mesna (50 mg/kg, i.p.). Rats were sacrificed on 3 consecutive days and the urinary bladders were removed, weighed, and evaluated. The vesical vascular permeability was determined by wet bladder weight and Evan's blue dye absorbance. After 24 hours of cyclophosphamide administration, severe hemorrhagic cystitis was induced with marked edema, hemorrhage, and inflammation. In the epinephrine-treated groups, symptoms of hemorrhagic cystitis (such as edema, inflammation, and hemorrhage) were reduced significantly. Intravesical instillation of epinephrine prevents edema, hemorrhage, and inflammation in rats with cyclophosphamide-induced hemorrhagic cystitis.
Preview · Article · Apr 2007 · Experimental Biology and Medicine
[Show abstract][Hide abstract] ABSTRACT: The aim of this study is to estimate the incidence of the gastrointestinal stromal tumor after the previous diagnoses were confirmed and/or revised by both immunohistochemical and mutational analyses. We reviewed 17,858 surgically excised gastrointestinal lesions in our hospital from 1998 to 2004. All mesenchymal tumors were examined for CD117 expression by immunohistochemistry, and every CD117-negative mesenchymal tumors were further subjected to mutational analysis for KIT and PDGFRA exons. The results showed that approximately 35% of gastrointestinal stromal tumors were misdiagnosed if immunohistochemical analysis of CD117 expression was not performed; and approximately 15% misdiagnosed if mutation analysis was not available. Because approximately 4.72% of patients with gastrointestinal malignancies in Taiwan were treated in our hospital and the average of newly diagnosed gastrointestinal stromal tumors in our hospital was 14.33 cases per year, the estimated annual incidents of gastrointestinal stromal tumor in Taiwan were 303.60. Therefore, the annual incidence of gastrointestinal stromal tumor is 13.74 per million Taiwanese.
No preview · Article · Apr 2007 · Digestive Diseases and Sciences