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1.  A case of disseminated coccidioidomycosis--autopsy report. 
Journal of Korean Medical Science  1996;11(3):258-264.
Disseminated coccidioidomycosis is a systemic fungal infection that is occurring more commonly and causes high mortality in patients with compromised host defense or debilitated. It is endemic in certain areas of North, Central, and South America. Increasingly, cases are being recognized outside the endemic area, due to travelers who have visited an endemic area. We experienced a case of disseminated coccidioidomycosis, as a reactivation of infection acquired earlier in a patient, who was a former resident of an endemic area.
PMCID: PMC3054048  PMID: 8843009
2.  A Phase 2 Trial of Ponatinib in Philadelphia Chromosome–Positive Leukemias 
The New England journal of medicine  2013;369(19):10.1056/NEJMoa1306494.
BACKGROUND
Ponatinib is a potent oral tyrosine kinase inhibitor of unmutated and mutated BCR-ABL, including BCR-ABL with the tyrosine kinase inhibitor–refractory threonine-to-isoleucine mutation at position 315 (T315I). We conducted a phase 2 trial of ponatinib in patients with chronic myeloid leukemia (CML) or Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph-positive ALL).
METHODS
We enrolled 449 heavily pretreated patients who had CML or Ph-positive ALL with resistance to or unacceptable side effects from dasatinib or nilotinib or who had the BCR-ABL T315I mutation. Ponatinib was administered at an initial dose of 45 mg once daily. The median follow-up was 15 months.
RESULTS
Among 267 patients with chronic-phase CML, 56% had a major cytogenetic response (51% of patients with resistance to or unacceptable side effects from dasatinib or nilotinib and 70% of patients with the T315I mutation), 46% had a complete cytogenetic response (40% and 66% in the two subgroups, respectively), and 34% had a major molecular response (27% and 56% in the two subgroups, respectively). Responses were observed regardless of the baseline BCR-ABL kinase domain mutation status and were durable; the estimated rate of a sustained major cytogenetic response of at least 12 months was 91%. No single BCR-ABL mutation conferring resistance to ponatinib was detected. Among 83 patients with accelerated-phase CML, 55% had a major hematologic response and 39% had a major cytogenetic response. Among 62 patients with blast-phase CML, 31% had a major hematologic response and 23% had a major cytogenetic response. Among 32 patients with Ph-positive ALL, 41% had a major hematologic response and 47% had a major cytogenetic response. Common adverse events were thrombocytopenia (in 37% of patients), rash (in 34%), dry skin (in 32%), and abdominal pain (in 22%). Serious arterial thrombotic events were observed in 9% of patients; these events were considered to be treatment-related in 3%. A total of 12% of patients discontinued treatment because of an adverse event.
CONCLUSIONS
Ponatinib had significant antileukemic activity across categories of disease stage and mutation status. (Funded by Ariad Pharmaceuticals and others; PACE ClinicalTrials.gov number, NCT01207440.)
doi:10.1056/NEJMoa1306494
PMCID: PMC3886799  PMID: 24180494
3.  Evaluation of survival benefits by platinums and taxanes for an unfavourable subset of carcinoma of unknown primary: a systematic review and meta-analysis 
British Journal of Cancer  2012;108(1):39-48.
Background:
Although chemotherapeutic regimens containing a taxane or platinum agent have been widely recommended for unfavourable carcinoma of unknown primary (CUP), no evidence exists for the superiority of any administered regimens. To date, the efficacy has been mostly assessed in the limited setting of phase II trials, and few attempts have been made to synthesise all available data for survival outcomes.
Methods:
Electronic databases were searched from 1980 to 2011. Survival results were combined for each pre-specified category of regimens using a random-effects model, and meta-regression models were used to adjust for heterogeneity in some known prognostic factors.
Results:
A total of 32 studies were included for meta-analysis. Tendency towards better survival outcome by platinums or taxanes was indicated. After adjustment for important prognostic factors, however, the difference between the platinum-based and non-platinum regimens became no longer significant. Survival benefits by the taxane-based regimens remained significant, with a prolonged median survival time of 1.52 months (P=0.03) and a higher 1-year survival rate of 6.25% (P=0.05), but the benefit did not sustain for 2 years.
Conclusion:
Although no effective therapies have been established, this meta-analysis helps to fill an important gap of evidence. However, caution should still be taken because of the potential unmeasured confounding.
doi:10.1038/bjc.2012.516
PMCID: PMC3553519  PMID: 23175147
carcinoma of unknown primary; chemotherapy; meta-analysis; systematic review
4.  Ultrasonography-guided ethanol ablation of predominantly solid thyroid nodules: a preliminary study for factors that predict the outcome 
The British Journal of Radiology  2012;85(1015):930-936.
Objectives
The aim of this study was to evaluate the success rate in ultrasonography-guided ethanol ablation (EA) of benign, predominantly solid thyroid nodules and to assess the value of colour Doppler ultrasonography in prediction of its success.
Methods
From January 2008 to June 2009, 30 predominantly solid thyroid nodules in 27 patients were enrolled. Differences in the success rate of EA were assessed according to nodule vascularity, nodule size, ratio of cystic component, amount of injected ethanol, degree of intranodular echo-staining just after ethanol injection and the number of EA sessions.
Results
On follow-up ultrasonography after EA for treatment of thyroid nodules, 16 nodules showed an excellent response (90% or greater decrease in volume) and 2 nodules showed a good response (50–90% decrease in volume) on follow-up ultrasonography. However, 5 nodules showed an incomplete response (10–50% decrease in volume) and 7 nodules showed a poor response (10% or less decrease in volume). Statistical analysis revealed a significant association of nodule vascularity (p = 0.002) and degree of intranodular echo-staining just after ethanol injection (p = 0.003) with a successful outcome; however, no such association was observed with regard to nodule size, ratio of cystic component, amount of infused ethanol and the number of EA sessions. No serious complications were observed during or after EA.
Conclusion
The success rate of EA was 60%, and nodule vascularity and intranodular echo-staining on colour Doppler ultrasonography were useful in predicting the success rate of EA for benign, predominantly solid thyroid nodules.
doi:10.1259/bjr/81849588
PMCID: PMC3474049  PMID: 22167503
5.  Hounsfield units upon PET/CT are useful in evaluating metastatic regional lymph nodes in patients with oesophageal squamous cell carcinoma 
The British Journal of Radiology  2012;85(1013):606-612.
Objectives
This study evaluated the usefulness of measurements of X-ray attenuation (in Hounsfield units) obtained from unenhanced CT images for attenuation correction of the positron emission tomography (PET) data from PET/CT in the assessment of regional lymph node metastasis in oesophageal squamous cell carcinoma.
Methods
17 patients with oesophageal squamous cell carcinoma underwent surgery after evaluation with PET/CT. After the excised lymph nodes were reviewed, we compared the histopathology and PET/CT findings, and analysed the lymph node metastasis. When 18-F fludeoxyglucose (FDG) uptake in the lymph nodes was focally prominent in comparison with background mediastinal activity (regardless of lymph node size), the lymph nodes were considered to be positive for malignancy by PET/CT. The mean Hounsfield units of mediastinal lymph nodes showing abnormally increased FDG uptake in PET/CT was retrospectively evaluated using images from the unenhanced CT component of PET/CT. Receiver operating characteristic (ROC) curve analysis was applied to determine the optimal cut-off value of mean Hounsfield units for detecting individual lymph node metastases.
Results
For depiction of malignant nodal groups in each lymph node group, the sensitivity, specificity and accuracy of PET/CT based on increased FDG uptake were 58.8%, 74.5% and 70.8%, respectively. For patients with nodal groups that were positive for uptake by PET/CT, the mean attenuation in lymph nodes as measured by CT was 48±13 HU for malignant nodes and 75±18 HU for benign nodes. This difference was statistically significant (p<0.001). Using ROC curve analysis, we determined the cut-off as 71 HU. When we excluded lymph nodes with attenuation higher than 71 HU from the nodes determined as malignant by PET/CT, the specificity and accuracy for detecting metastatic lymph nodes improved to 90.9% and 83.3%, respectively.
Conclusions
When interpreting lymph node metastasis in oesophageal squamous cell carcinoma using PET/CT, the assumption that any lymph node with mean HU>71 is benign can improve diagnostic accuracy.
doi:10.1259/bjr/73516936
PMCID: PMC3479874  PMID: 21304006
6.  Acinar cell carcinoma with fatty change arising from the pancreas 
The British Journal of Radiology  2011;84(1008):e226-e228.
Acinar cell carcinoma of the pancreas is a rare malignant tumour developing from acinar cells, accounting for approximately 1% of pancreatic exocrine tumours. We experienced a case of an acinar cell carcinoma with fatty change. To the best of our knowledge, this is the first case report of an acinar cell carcinoma with fatty change in the clinical literature.
doi:10.1259/bjr/15914752
PMCID: PMC3473822  PMID: 22101587
7.  Gene expression signatures associated with the in vitro resistance to two tyrosine kinase inhibitors, nilotinib and imatinib 
Blood Cancer Journal  2011;1(8):e32-.
The use of selective inhibitors targeting Bcr-Abl kinase is now established as a standard protocol in the treatment of chronic myelogenous leukemia; however, the acquisition of drug resistance is a major obstacle limiting the treatment efficacy. To elucidate the molecular mechanism of drug resistance, we established K562 cell line models resistant to nilotinib and imatinib. Microarray-based transcriptome profiling of resistant cells revealed that nilotinib- and imatinib-resistant cells showed the upregulation of kinase-encoding genes (AURKC, FYN, SYK, BTK and YES1). Among them, the upregulation of AURKC and FYN was observed both in nilotinib- and imatinib-resistant cells irrespective of exposure doses, while SYK, BTK and YES1 showed dose-dependent upregulation of expression. Upregulation of EGF and JAG1 oncogenes as well as genes encoding ATP-dependent drug efflux pump proteins such as ABCB1 was also observed in the resistant cells, which may confer alternative survival benefits. Functional gene set analysis revealed that molecular categories of ‘ATPase activity', ‘cell adhesion' or ‘tyrosine kinase activity' were commonly activated in the resistant clones. Taken together, the transcriptome analysis of tyrosine kinase inhibitors (TKI)-resistant clones provides the insights into the mechanism of drug resistance, which can facilitate the development of an effective screening method as well as therapeutic intervention to deal with TKI resistance.
doi:10.1038/bcj.2011.32
PMCID: PMC3255246  PMID: 22829191
tyrosine kinase inhibitor; chronic myelogenous leukemia; drug resistance; microarray; pathway analysis
8.  Biomarker analysis in stage III–IV (M0) gastric cancer patients who received curative surgery followed by adjuvant 5-fluorouracil and cisplatin chemotherapy: epidermal growth factor receptor (EGFR) associated with favourable survival 
British Journal of Cancer  2009;100(5):732-738.
The aim of this study was to analyse the impact of epidermal growth factor receptor (EGFR), thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), thymidine phosphorylase (TP), aurora kinase (ARK) A/B, and excision repair cross-complementing gene 1 (ERCC1) on the efficacy of adjuvant chemotherapy with 5-fluorouracil and cisplatin (FP) after curative gastric resection. Normal and cancer tissue were separately obtained from gastrectomy samples of 153 patients with AJCC stage III–IV (M0) who subsequently treated with adjuvant FP chemotherapy. TS, DPD, TP, ERCC1, and ARK proteins were measured by immunohistochemistry (IHC). EGFR expression was investigated using a standardized IHC with the EGFR PharmDx assay. Amplification of EGFR gene was analysed using fluorescent in situ hybridisation (FISH). In multivariate analysis, stage, ratio of positive to removed lymph nodes, and EGFR expression were significant prognostic factors for overall survival. Patients with higher EGFR expression had better overall survival than those with lower expression (relative risk: 0.475 (95% confidence interval, 0.282–0.791, P=0.005). Low EGFR expression might be a predictive marker for relapse in curative resected stage III–IV (M0) gastric cancer patients who received adjuvant FP chemotherapy.
doi:10.1038/sj.bjc.6604936
PMCID: PMC2653762  PMID: 19259093
gastric cancer; adjuvant chemotherapy; pharmacogenetics; epidermal growth factor receptor; thymidine phosphorylase; excision repair cross-complementing gene 1
9.  Cancer patients' awareness of clinical trials, perceptions on the benefit and willingness to participate: Korean perspectives 
British Journal of Cancer  2008;99(10):1593-1599.
To understand patients' perceptions of clinical trials (CTs) is the principal step in the enrolment of patients to CTs. However, these perceptions in eastern countries are very rare. From 12 February 2007 to 13 April 2007, we consecutively distributed the questionnaire to 842 cancer patients who initiated a first cycle of chemotherapy regardless of each treatment step in the Seoul National University Hospital. Younger age, higher educational degree, higher economic status, and possession of private cancer insurance were related with significantly higher awareness of CTs (P=0.001, P=0.006, P=0.002, and P=0.009, respectively). However, unlike awareness, perceptions on benefits of CTs were not changed according to age, educational degree, and economic status (P=0.709, P=0.920, and P=0.847, respectively). Willingness was also not changed according to age, educational degree, economic status, and private cancer insurance (P=0.381, P=0.775, P=0.887, and P=0.392, respectively). Instead, males and heavily treated patients had more positive perceptions on benefits (P=0.002 and P=0.001, respectively) and more willingness to participate in CTs (OR=1.17, 1.14–2.75: OR=1.59, 1.01–2.51, respectively). In summary, cancer patients' awareness of CTs, perceptions on the benefit in CTs, and willingness to participate are differently influenced by diverse medical and social conditions. This information would be very helpful for investigators to properly conduct CTs in eastern cancer patients.
doi:10.1038/sj.bjc.6604750
PMCID: PMC2584950  PMID: 19002181
cancer patient; clinical trial; perception; awareness; willingness
10.  High tumour islet macrophage infiltration correlates with improved patient survival but not with EGFR mutations, gene copy number or protein expression in resected non-small cell lung cancer 
British Journal of Cancer  2008;98(6):1118-1124.
The purpose of this study was to investigate the prognostic value of tumour-associated macrophages with a focus on micro-anatomical localisation and determine whether molecular changes of the epidermal growth factor receptor (EGFR) are related to macrophage infiltration in resected non-small cell lung cancer (NSCLC). One hundred and forty-four patients were included in this study. Immunohistochemistry was used to identify CD68+ macrophages in the tumour islet and surrounding stroma. Epidermal growth factor receptor mutations were studied by direct sequencing. The EGFR gene copy number and protein expression were analysed by fluorescence in situ hybridisation and immunohistochemistry. Patients with a high tumour islet macrophage density survived longer than did the patient with a low tumour islet macrophage density (5-year overall survival rate was 63.9 vs 38.9%, P=0.0002). A multivariate Cox proportional hazard analysis revealed that the tumour islet macrophage count was an independent prognostic factor for survival (hazard ratio 0.471, 95% confidence interval 0.300–0.740). However, EGFR mutations, gene copy number, and protein expression were not related to the macrophage infiltration. In conclusion, tumour islet macrophage infiltration was identified as a strong favourable independent prognostic marker for survival but not correlated with the molecular changes of the EGFR in patients with resected NSCLC.
doi:10.1038/sj.bjc.6604256
PMCID: PMC2275476  PMID: 18283317
macrophage; non-small cell lung cancer; epidermal growth factor receptor; survival analysis
11.  Magnetic resonance imaging of the bone marrow after bone marrow transplantation or immunosuppressive therapy in aplastic anemia. 
Journal of Korean Medical Science  2001;16(6):725-730.
To compare magnetic resonance (MR) images of the bone marrow (BM) after bone marrow transplantation or immunosuppressive therapy in patients with aplastic anemia (AA), MR imaging of BM was reviewed retrospectively in 16 patients (13 males and 3 females, mean age 26 yr) with AA who completely responded clinically after transplantation or immunosuppressive therapy. The signal intensity (SI) of BM was classified into four patterns according to the increasing amount of cellular marrow, i.e., pattern I to IV. SI of MR imaging of BM exhibited an increase of cellular marrows following both transplantation and immunosuppressive therapy. Of the eight patients on transplantation, the SI of the lumbar spinal BM was pattern III in two patients and IV in six on T1-weighted and short tau inversion recovery (STIR) images. In the eight patients with immunosuppressive therapy, the SI of the lumbar spinal BM was pattern II in one, III in five, and IV in two on T1-weighted images and pattern II in one, III in four, and IV in three on STIR images. SI on MR imaging of the lumbar spinal BM showed a more cellular pattern in patients on transplantation than in those on immunosuppressive therapy.
PMCID: PMC3054786  PMID: 11748352
12.  Aberrant nuclear factor-kappaB/Rel expression and the pathogenesis of breast cancer. 
Journal of Clinical Investigation  1997;100(12):2952-2960.
Expression of nuclear factor-kappaB (NF-kappaB)/Rel transcription factors has recently been found to promote cell survival, inhibiting the induction of apoptosis. In most cells other than B lymphocytes, NF-kappaB/Rel is inactive, sequestered in the cytoplasm. For example, nuclear extracts from two human untransformed breast epithelial cell lines expressed only very low levels of NF-kappaB. Unexpectedly, nuclear extracts from two human breast tumor cell lines displayed significant levels of NF-kappaB/Rel. Direct inhibition of this NF-kappaB/ Rel activity in breast cancer cells induced apoptosis. High levels of NF-kappaB/Rel binding were also observed in carcinogen-induced primary rat mammary tumors, whereas only expectedly low levels were seen in normal rat mammary glands. Furthermore, multiple human breast cancer specimens contained significant levels of nuclear NF-kappaB/Rel subunits. Thus, aberrant nuclear expression of NF-kappaB/Rel is associated with breast cancer. Given the role of NF-kappaB/Rel factors in cell survival, this aberrant activity may play a role in tumor progression, and represents a possible therapeutic target in the treatment of these tumors.
PMCID: PMC508506  PMID: 9399940
13.  Mutational analysis of the hepatitis C virus RNA helicase. 
Journal of Virology  1997;71(12):9400-9409.
The carboxyl-terminal three-fourths of the hepatitis C virus (HCV) NS3 protein has been shown to possess an RNA helicase activity, typical of members of the DEAD box family of RNA helicases. In addition, the NS3 protein contains four amino acid motifs conserved in DEAD box proteins. In order to inspect the roles of individual amino acid residues in the four conserved motifs (AXXXXGKS, DECH, TAT, and QRRGRTGR) of the NS3 protein, mutational analysis was used in this study. Thirteen mutant proteins were constructed, and their biochemical activities were examined. Lys1235 in the AXXXXGKS motif was important for basal nucleoside triphosphatase (NTPase) activity in the absence of polynucleotide cofactor. A serine in the X position of the DEXH motif disrupted the NTPase and RNA helicase activities. Alanine substitution at His1318 of the DEXH motif made the protein possess high NTPase activity. In addition, we now report inhibition of NTPase activity of NS3 by polynucleotide cofactor. Gln1486 was indispensable for the enzyme activity, and this residue represents a distinguishing feature between DEAD box and DEXH proteins. There are four Arg residues in the QRRGRTGR motif of the HCV NS3 protein, and the second, Arg1488, was important for RNA binding and enzyme activity, even though it is less well conserved than other Arg residues. Arg1490 and Arg1493 were essential for the enzymatic activity. As the various enzymatic activities were altered by mutation, the enzyme characteristics were also changed.
PMCID: PMC230244  PMID: 9371600
14.  A case-control study on the risk factors of hepatitis C virus infection among Koreans. 
In order to identify the risk factors for hepatitis C virus (HCV) infections, a case-control study was conducted from September 1993 to April 1994. HCV infection was confirmed by the second generation of recombinant immunoblot assay. Sixty-four cases and 128 controls matched for age and sex with a 1:2 ratio of cases to controls were enrolled. Exposure data were obtained from all participants by self-administered questionnaire and the odds ratios of possible risk factors of HCV infection analysed. Sixty-four cases consisted of forty-two patients with chronic hepatitis, nine with cirrhosis, one with hepatocellular carcinoma, and twelve with normal liver function. History of acute hepatitis (OR 3.9) and transfusion (OR 2.4) were associated with an increased risk of HCV infection. Operation, acupuncture, endoscopy, tooth extraction, tattooing, ear piercing, needle sharing and family history of hepatitis were not associated with an increased risk of HCV infection. In conclusion, transfusion remains the major route of transmission of HCV in Korea.
PMCID: PMC3053912  PMID: 8703369
15.  Familial clustering of hepatitis B and C viruses in Korea. 
In order to evaluate the familial clustering of hepatitis B virus(HBV) and hepatitis C virus(HCV) infections and to elucidate the possible routes of HCV transmission among Korean adults with chronic liver disease, 137 household contacts of 51 chronic carriers of HBsAg and 111 household contacts of 38 controls, and 181 household contacts of 96 anti-HCV positives and 102 household contacts of 76 anti-HCV negatives were tested from July 1990 to March 1994. Of 71 non-vaccinated household contacts of HBsAg carriers, 10 gave positive result for HBsAg(14.1%), but none of the household contacts of the controls were positive for HBsAg(p < 0.05). Familial clustering of HBV infection was found, when the offspring of carriers and controls were compared. A significantly higher percentage of the offspring of carriers were positive for HBV infection(54.6% vs 15.4%, p < 0.05) with OR of 6.6(95% Cl; 1.3-34.5). No evidence of familial clustering of HCV infection was found with 2.2%(4/181) anti-HCV positivity among the household contacts of index cases, similar to 1.0%(1/102) among those of controls. History of acute hepatitis(OR 3.2), transfusion(OR 3.2), and acupuncture(OR 2.5) were associated with an increased risk of HCV infection. In conclusion, HBV has strong familial clustering whereas HCV does not in Korea.
PMCID: PMC3054225  PMID: 7786439
16.  Hallervorden-Spatz syndrome in two siblings diagnosed by the clinical features and magnetic resonance imaging (MRI). 
Hallervorden-Spatz syndrome (HSS) is a heredodegenerative disorder characterized by both progressive pyramidal and extrapyramidal signs, dysarthric speech, and mental deterioration. No diagnostic biochemical test is yet available, and diagnosis of HSS can be confirmed only at autopsy by the characteristic neuropathology including abnormal iron storage, disordered myelination, and loss of brain substance. We present two siblings with clinical features consistent with HSS, in whom magnetic resonance imaging (MRI) demonstrated the deposition of iron in the globus pallidus and the substantia nigra thus allowing an antemortem diagnosis of HSS.
PMCID: PMC3053717  PMID: 8305140
17.  Prevalence of hepatitis C virus antibody among Korean adults. 
To estimate the prevalence of hepatitis C virus (HCV) infection among Korean adults and to present the putative route of HCV transmission among them, serum samples from 4917 adults older than 20 years of age were tested for antibody to HCV (anti-HCV), and histories of blood transfusion and other pertinent information were obtained by self-administered questionnaires. The overall prevalence of anti-HCV was 1.7%; prevalence was 1.4% in subjects with normal levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), 3.3% in those with slightly elevated and 5.9% in those with markedly elevated levels of the enzymes. The prevalence of anti-HCV increased with increasing age (P < 0.01), but was not associated with blood transfusion. The present study suggests that the prevalence of HCV infection was 1.4% and that the major routes of HCV transmission may be other than blood transfusion in healthy Korean adults.
PMCID: PMC3053841  PMID: 1284374

Results 1-17 (17)