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1.  Long-Term Survival Analysis and Clinical Follow-Up in Acral Lentiginous Malignant Melanoma Undergoing Sentinel Lymph Node Biopsy in Korean Patients 
Annals of Dermatology  2014;26(2):177-183.
Background
In cutaneous malignant melanoma (MM) with clinically uninvolved regional lymph nodes, sentinel lymph node (SLN) status is the most powerful indicator of both overall survival (OS) and disease-free survival (DFS). However, no studies on the long-term survival and clinical follow-up of Korean patients with acral lentiginous MM (ALM) undergoing SLN biopsy (SLNB) have been published.
Objective
The purpose of this study was to investigate the clinical prognosis and long-term survival of Korean patients with ALM according to SLN status.
Methods
Thirty-four ALM patients undergoing SLNB were included in this study. We evaluated clinical and histopathological follow-up data such as the stage of disease, treatment, recurrence, and metastasis, and analyzed OS and DFS according to SLN status.
Results
The median follow-up time was 60.5 months (range 3~127 months). Positive SLNs were noted in 14 patients (41.2%). Patients with negative SLNs had better OS and DFS than those with positive SLNs (p<0.05). Increased Breslow thickness was associated with short OS and DFS (p<0.05), and female patients showed better DFS than male patients (p<0.05).
Conclusion
To our knowledge, this is the first study on the long-term survival and clinical follow-up of patients undergoing SLNB for ALM in Korea. Our findings show that SLN status is an important prognostic factor for predicting OS and DFS.
doi:10.5021/ad.2014.26.2.177
PMCID: PMC4037669  PMID: 24882971
Acral lentiginous malignant melanoma; Prognosis; Sentinel lymph node biopsy; Survival
2.  Prognostic and Clinicopathologic Associations of BRAF Mutation in Primary Acral Lentiginous Melanoma in Korean Patients: A Preliminary Study 
Annals of Dermatology  2014;26(2):195-202.
Background
In the majority of melanomas, the RAS/RAF/MEK/ERK signaling pathway is constitutively activated, due to oncogenic mutations in the BRAF and NRAS genes. The BRAF mutation has been mainly described in Caucasian melanomas. However, there is a lack of study evaluating the status, and the clinical significance, of BRAF mutation in the Asian population.
Objective
This study was aimed to determine the frequency of BRAF mutation, and to evaluate the correlation of BRAF status with clinicopathologic features and outcomes, in Korean primary acral lentiginous melanoma (ALM) patients.
Methods
ALM samples (n=36) were analyzed for the BRAF V600E mutation, by dual-priming oligonucleotide (DPO) based real-time polymerase chain reaction. The clinicopathologic features and prognosis of the patients were analyzed with BRAF mutation status.
Results
The incidence of BRAF V600E mutation was 19.4% (7/36). The BRAF V600E mutations were not associated with clinicopathologic features, except for the age factor. All of the BRAF-mutant patients survived without recurrence or metastasis, and have a better clinical outcome than BRAF wild-type patients.
Conclusion
In Korean primary ALM, a low frequency of BRAF mutation was shown; and BRAF mutation presented with a favorable prognosis. These results indicate that other distinctive genetic mechanisms may have more important roles in the development and progression of disease. Further multicenter study with large sample size is firmly needed, to confirm the results of our preliminary study.
doi:10.5021/ad.2014.26.2.195
PMCID: PMC4037672  PMID: 24882974
Acral lentiginous melanoma; BRAF mutation; Korean; Prognosis
3.  Prognostic significance of thymidylate synthase, thymidine phosphorylase and dihydropyrimidine dehydrogenase expression in biliary tract cancer patients receiving adjuvant 5-fluorouracil-based chemotherapy 
Molecular and Clinical Oncology  2013;1(6):987-994.
Biliary tract cancer (BTC) is a relatively uncommon type of cancer, accounting for ∼4% of the malignant neoplasms of the gastrointestinal tract. The aim of this study was to determine whether the expression of thymidylate synthase (TS), thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) predict clinical outcome in BTC patients treated with adjuvant 5-fluorouracil (5-FU)-based chemotherapy. TS and TP expression were found to be significantly correlated with cancer location (P=0.044 and 0.031, respectively). The multivariate analysis revealed that age [hazard ratio (HR)=2.157, P=0.008], stage (HR=2.234, P<0.001), resection margin status (HR=2.748, P=0.004) and TP expression (HR=2.014, P=0.039) were independently associated with overall survival (OS).
doi:10.3892/mco.2013.166
PMCID: PMC3915652  PMID: 24649282
biliary tract cancer; 5-fluorouracil; thymidine phosphorylase
4.  Prognostic significance of neutrophil lymphocyte ratio and platelet lymphocyte ratio in advanced gastric cancer patients treated with FOLFOX chemotherapy 
BMC Cancer  2013;13:350.
Background
Several inflammatory response materials could be used for prediction of prognosis of cancer patients. The neutrophil lymphocyte ratio (NLR), and the platelet lymphocyte ratio (PLR) have been introduced for prognostic scoring system in various cancers. The objective of this study was to determine whether the NLR or the PLR would predict the clinical outcomes in advanced gastric cancer patients treated with oxaliplatin/ 5-fluorouracil (FOLFOX).
Methods
The study population consisted of 174 advanced gastric cancer patients. Patients were treated with 85 mg/m2 of oxaliplatin as a 2-h infusion at day 1 plus 20 mg/m2 of leucovorin over 10 min, followed by 5-FU bolus 400 mg/m2 and 22-h continuous infusion of 600 mg/m2 at days 1-2. Treatment was repeated in 2-week intervals. The NLR and PLR were calculated from complete blood counts in laboratory test before and after first cycle of chemotherapy.
Results
NLR was a useful prognostic biomarker for predicting inferior overall survival (OS) (p = 0.005), but was not associated with progression free survival (PFS) (p = 0.461). The normalization of NLR after one cycle of chemotherapy was found to be in association with significant improvement in PFS (5.3 months vs. 2.4 months, p < 0.001), and OS (11.9 months vs. 4.6 months, p < 0.001). The normalization of PLR was also associated with longer PFS (5.6 months vs. 3.4 months, p = 0.006), and OS (16.9 months vs. 10.9 months, p = 0.002). In multivariate analysis, changes in NLR were associated with PFS (Hazard ratio (HR): 2.297, 95% confidence interval (CI): 1.429-3.693, p = 0.001). The NLR, (HR: 0.245, 95% CI: 0.092-0.633, p = 0.004), PLR (HR: 0.347, 95% CI: 0.142-0.847, p = 0.020), changes in NLR (HR: 2.468, 95% CI: 1.567-3.886, p < 0.001), and changes in PLR (HR: 1.473, 95% CI: 1.038-2.090, p = 0.030) were independent prognostic markers for OS.
Conclusion
This study demonstrates that NLR, PLR, and changes in NLR or PLR are independent prognostic factor for OS in patients with advanced gastric cancer treated with chemotherapy. These specific factors may also help in identifying the patients, who are more sensitive to FOLFOX regimen.
doi:10.1186/1471-2407-13-350
PMCID: PMC3729814  PMID: 23876227
Neutrophil; Lymphocyte; Platelet; Gastric neoplasm
5.  Third-line docetaxel chemotherapy for recurrent and metastatic gastric cancer 
Background/Aims
To determine the efficacy and toxicity of docetaxel as a third-line therapy for patients with relapsed gastric cancer who have undergone modified oxaliplatin-fluorouracil (m-FOLFOX)-4 and modified irinotecan-fluorouracil (m-FOLFIRI) regimens.
Methods
We analyzed 33 patients who had been histologically diagnosed with adenocarcinoma of the stomach and who had progressed after m-FOLFOX-4 and m-FOLFIRI regimens. Patients were treated with cycles of 75 mg/m2 docetaxel on day 1 every 3 weeks.
Results
The median age of the patients was 56.0 years (range, 31.0 to 74.0), and 73% of the patients (24/33) had an Eastern Cooperative Oncology Group performance status of 0 or 1. All patients were evaluated in terms of tumor response: five (15%), nine (27%), and 19 (58%) patients experienced a partial response, stable disease, and progressive disease, respectively. The median time to progression was 2.1 months (95% confidence interval [CI], 1.63 to 2.58), and overall survival was 4.7 months (95% CI, 3.20 to 6.20), from the start of the docetaxel regimen. Assessing patients' toxicity profiles, the median number of cycles was 2.0 (range, 1.0 to 12.0). The major hematologic toxicities included grade 3 to 4 neutropenia (19/33, 58%), grade 3 to 4 thrombocytopenia (2/33, 6%), and grade 3 to 4 anemia (5/33, 15%). Neutropenic fever developed in three patients (3/33, 9%). The nonhematological toxicities were nausea and vomiting (10/33, 30%), abdominal pain (4/33, 12%), skin rash (1/33, 3%), and fluid retention (3/33, 9%).
Conclusions
Docetaxel is a feasible third-line therapy regimen for patients with advanced gastric cancer after m-FOLFIRI and m-FOLFOX-4 regimens.
doi:10.3904/kjim.2013.28.3.314
PMCID: PMC3654129  PMID: 23682225
Advanced gastric cancer; Docetaxel; Salvage therapy
6.  The relationship of Vascular endothelial growth factor gene polymorphisms and clinical outcome in advanced gastric cancer patients treated with FOLFOX: VEGF polymorphism in gastric cancer 
BMC Cancer  2013;13:43.
Background
The aim of this study is to evaluate the associations between vascular endothelial growth factor (VEGF) Single-nucleotide polymorphisms (SNPs) and clinical outcome in advanced gastric cancer patients treated with oxaliplatin, 5-fluorouracil, and leucovorin (FOLFOX).
Methods
Genomic DNA was isolated from whole blood, and six VEGF (−2578C/A, -2489C/T, -1498 T/C, -634 G/C, +936C/T, and +1612 G/A) gene polymorphisms were analyzed by PCR. Levels of serum VEGF were measured using enzyme-linked immunoassays.
Results
Patients with G/G genotype for VEGF -634 G/C gene polymorphism showed a lower response rate (22.2%) than those with G/C or C/C genotype (32.3%, 51.1%; P = 0.034). Patients with the VEGF -634 G/C polymorphism G/C + C/C genotype had a longer progression free survival (PFS) of 4.9 months, compared with the PFS of 3.5 months for those with the G/G (P = 0.043, log-rank test). By multivariate analysis, this G/G genotype of VEGF -634 G/C polymorphism was identified as an independent prognostic factor (Hazard ratio 1.497, P = 0.017).
Conclusion
Our data suggest that G/G genotype of VEGF -634 G/C polymorphism is related to the higher serum levels of VEGF, and poor clinical outcome in advanced gastric cancer patients.
doi:10.1186/1471-2407-13-43
PMCID: PMC3573956  PMID: 23374220
VEGF; Polymorphism; Gastric cancer
7.  Clinicopathologic significance of expression of nuclear factor-κB RelA and its target gene products in gastric cancer patients 
AIM: To assess the prognostic significance of nuclear factor-κB (NF-κB) and its target genes in gastric cancer.
METHODS: The tumor tissues of 115 patients with gastric cancer were immunohistochemically evaluated using monoclonal antibodies against NF-κB RelA. Preoperative serum levels of vascular endothelial growth factor (VEGF), interleukin-6 (IL-6) were assessed via enzyme-linked immuno-sorbent assay. C-reactive protein (CRP) and serum amyloid A (SAA) were measured via immunotrubidimetry.
RESULTS: Positive rate of NF-κB RelA was 42.6%. NF-κB RelA expression in tumor tissues was also related to serum levels of IL-6 (P = 0.044) and CRP (P = 0.010). IL-6, SAA, CRP were related to depth of invasion, VEGF and SAA were correlated with lymph node metastasis. IL-6, VEGF, SAA and CRP were related to the stage. Univariate analysis demonstrated that immunostaining of NF-κB RelA, levels of IL-6, VEGF, SAA were significantly related with both disease free survival and overall survival (OS). Multivariate analysis verified that NF-κB RelA [hazard ratio (HR): 3.40, P = 0.024] and SAA (HR: 3.39, P = 0.045) were independently associated with OS.
CONCLUSION: Increased expression of NF-κB RelA and high levels of serum SAA were associated with poor OS in gastric cancer patients.
doi:10.3748/wjg.v18.i34.4744
PMCID: PMC3442213  PMID: 23002344
Nuclear factor-κB; Vascular endothelial growth factor; Interleukin-6; C-reactive protein; Serum amyloid A; Stomach; Carcinoma
8.  Identification of genes underlying different methylation profiles in refractory anemia with excess blast and refractory cytopenia with multilineage dysplasia in myelodysplastic syndrome 
The Korean Journal of Hematology  2012;47(3):186-193.
Background
Myelodysplastic syndrome (MDS) is a preleukemic condition that transforms into acute myeloid leukemia. However, the genetic events underlying this transformation remain poorly understood. Aberrant DNA methylation may play a causative role in the disease and its prognosis. Thus, we compared the DNA methylation profiles in refractory anemia with excess blast (RAEB) to those in refractory cytopenia with multilineage dysplasia (RCMD).
Methods
Bone marrow samples were collected from 20 patients with primary MDS (9 with RAEB and 11 with RCMD), and peripheral blood samples were collected from 4 healthy controls. These samples were assessed using a commercial whole genome-wide methylation assay. Methylation-specific polymerase chain reaction (PCR) was used to detect the methylation of candidate gene promoters in RAEB and RCMD.
Results
Microarray data revealed significant hypermethylation in 69 genes within RAEB but not RCMD. Candidate genes were mapped to 5 different networks, and network 1 had the highest score due to its involvement in gene expression, cancer, and cell cycle. Five genes (GSTM5, BIK, CENPH, RERG, and ANGPTL2) were associated with malignant disease progression. Among them, the methylated promoter pairs of GSTM5 (55.5% and 20%), BIK (20% and 0%), and ANGPTL2 (44.4% and 10%) were observed more frequently in RAEB.
Conclusion
DNA methylation of GSTM5, BIK, and ANGPTL2 may induce epigenetic silencing and contribute to the increasing blasts and resulting MDS progression; however, the functions of these genes were not determined. Further study focusing on epigenetic silencing using various detection modalities is required.
doi:10.5045/kjh.2012.47.3.186
PMCID: PMC3464335  PMID: 23071473
Myelodysplastic syndrome; DNA methylation; GSTM5; ANGPTL2; BIK
9.  Prognostic factors in primary diffuse large B-cell lymphoma of adrenal gland treated with rituximab-CHOP chemotherapy from the Consortium for Improving Survival of Lymphoma (CISL) 
Background
The objective of this study was to identify prognostic factors for survival in patients with primary diffuse large B-cell lymphoma (DLBCL) of the adrenal gland.
Methods
Thirty one patients diagnosed with primary adrenal DLBCL from 14 Korean institutions and treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) were analyzed.
Results
Complete remission (CR) and overall response rate after R-CHOP chemotherapy were 54.8% and 87.0%. The 2-year estimates of overall survival (OS) and progression-free survival (PFS) were 68.3% and 51.1%. In patients achieving CR, significant prolongations of OS (P = 0.029) and PFS (P = 0.005) were observed. Ann Arbor stage had no influence on OS. There was no significant difference in OS between patients with unilateral involvement of adrenal gland and those with bilateral involvement. When staging was modified to include bilateral adrenal involvement as one extranodal site, early stage (I or II) significantly correlated with longer OS (P = 0.021) and PFS (P <0.001).
Conclusions
Contrary to prior reports, our data suggests that outcomes of primary adrenal DLBCL are encouraging using a regimen of R-CHOP, and that achieving CR after R-CHOP is predictive of survival. Likewise, our modified staging system may have prognostic value.
doi:10.1186/1756-8722-5-49
PMCID: PMC3445827  PMID: 22889180
Primary adrenal lymphoma; Diffuse large B-cell lymphoma; Prognostic factor; R-CHOP
10.  A Case of Near-triploidy in Myelodysplastic Syndrome with del(5q) Combined with del(1p) and del(13q) 
Annals of Laboratory Medicine  2012;32(4):294-297.
Numerical and structural chromosomal abnormalities are common in hematological malignancies. Near-triploidy (58-80 chromosomes) is a numerical abnormality observed in 3% of adult cases of acute lymphoblastic leukemia. Near-triploidy is rare in myeloid lineage hematologic malignancies and compared to near-triploidy in lymphoid malignancies, near-triploidy in myeloid malignancies is associated with poor outcomes. Few studies on near-triploidy in myelodysplastic syndrome (MDS) have been reported, and the clinicopathologic significance of this condition is still unclear. Here, we report a novel case of MDS with near-triploidy and multiple structural chromosomal abnormalities: del(5q) combined with del(1p) and del(13q). These abnormalities were detected by cytogenetic analysis with array comparative genomic hybridization (CGH). Our results suggest that array CGH can be a useful tool for detecting chromosomal abnormalities in patients with MDS.
doi:10.3343/alm.2012.32.4.294
PMCID: PMC3384812  PMID: 22779072
Near-triploidy; Myelodysplastic syndrome; Array CGH
11.  Should we still use Camitta's criteria for severe aplastic anemia? 
The Korean Journal of Hematology  2012;47(2):126-130.
Background
The criteria by Camitta for diagnosis in severe aplastic anemia (SAA) has been used since 1976. However, there has been no attempt to verify the Camitta's criteria, that the survival in patients with SAA may differ by absolute neutrophil count (ANC), platelet count (PLT), and corrected reticulocyte count (CRC), which are components of the Camitta's criteria.
Methods
117 SAA patients diagnosed by the Camitta's criteria were analyzed, retrospectively. Univariate and multivariate analyses were used to evaluate the factors affecting overall survival (OS).
Results
Response by immunosuppressive therapy (IST) or stem cell transplantation (SCT) significantly affected OS (P=0.001). Therefore, we excluded treatment responders for analysis. Finally, 92 SAA patients including treatment non-responders by IST or SCT and conservative care group were analyzed by using univariate and multivariate analyses. The median age of analyzed patients was 54.5 years. Male to female ratio was 1:1. The median follow-up duration was 74.23 months (range, 54.71-93.74 months). The median ANC, PLT, and CRC were 394/µL, 12,000/µL, and 0.39%, respectively. In multivariate analyses, ANC <500/µL or ≥500/µL (P=0.015, HR 2.694, 95% CI: 1.20-6.01) and age (P=0.015, HR 1.022, 95% CI: 1.00-1.04) were the significant factors for OS.
Conclusion
ANC could be an essential, not an optional criterion for diagnosing SAA. This study suggests the possibility that the Camitta's criteria be modified. Studies in large cohorts are needed to transform the Camitta's criteria.
doi:10.5045/kjh.2012.47.2.126
PMCID: PMC3389061  PMID: 22783359
Camitta's criteria; Severe aplastic anemia; Absolute neutrophil count
12.  Frequency of BRAF Mutation and Clinical Relevance for Primary Melanomas 
Korean Journal of Pathology  2012;46(3):246-252.
Background
This study was conducted to clarify the frequency of the BRAF mutation in primary melanomas and its correlation with clinicopathologic parameters.
Methods
We analyzed the frequency of BRAF mutation in patients with primary cutaneous melanoma (n=58) or non-cutaneous one (n=27) by performing dual priming oligonucleotide-based multiplex real-time polymerase chain reaction to isolate and to purify the DNA from the formalin-fixed and paraffin-embedded tumors.
Results
The BRAF mutation was found in 17.2% (10/58) of patients with primary cutaneous melanoma and 11.1% (3/27) of those with non-cutaneous melanoma. The frequency of BRAF mutation was not correlated with any clinicopathologic parameters with the exception of the patient age. The frequency of the BRAF mutation was significantly higher in patients younger than 60 years as compared with those older than 60 years (p=0.005).
Conclusions
Compared with previous reports, our results showed that the frequency of the BRAF mutation was relatively lower in patients with primary cutaneous melanoma. Besides, our results also showed that the frequency of the BRAF mutation had an inverse correlation with the age. Further studies are warranted to exclude methodological bias, to elucidate the difference in the frequency of the BRAF mutation from the previous reports from a Caucasian population and to provide an improved understanding of the molecular pathogenesis of malignant melanoma.
doi:10.4132/KoreanJPathol.2012.46.3.246
PMCID: PMC3479764  PMID: 23110010
Melanoma; BRAF; Mutation; Frequency
13.  A Phase II Study of Modified FOLFOX4 for Colorectal Cancer Patients with Peritoneal Carcinomatosis 
Purpose
Peritoneal carcinomatosis (PC) of colorectal cancer (CRC) is common and is the second most common cause of death. Clinical studies regarding chemotherapy for CRC with PC have been classically rather limited in scope. We evaluated the efficacy of modified oxaliplatin, leucovorin, and fluorouracil (m-FOLFOX4) regimen for PC of CRC origin.
Materials and Methods
CRC patients with PC were treated with cycles of oxaliplatin at 85 mg/m2 on day 1, leucovorin 20 mg/m2 followed by 5-fluorouracil (5-FU) via a 400 mg/m2 bolus and a 22 hours continuous infusion of 600 mg/m2 5-FU on days 1-2 at 2-week intervals.
Results
Forty patients participated in this study. Median age was 55 years. Thirty-two patients (80.0%) received previous operation, and 60.0% of PC occurred synchronously. Thirty-five patients (87.5%) were assessable and exhibited measurable lesions. Two patients (5.7%) demonstrated complete response and five patients (14.3%) showed partial response. The median time to progression was 4.4 months (95% confidence interval, 2.5 to 6.3 months), the median overall survival time was 21.5 months (95% confidence interval, 17.2 to 25.7 months). There was no treatment related death. Presence of liver metastasis (p=0.022), performance status (p=0.039), and carcinoembryonic antigen level (p=0.016) were related to the time to progression. Patients with low carcinoembryonic antigen level (37.2 months vs. 15.6 months, p=0.001) or good performance status (22.5 months vs. 6.8 months, p=0.040) showed better overall survival.
Conclusion
The m-FOLFOX4 regimen was determined to be effective for CRC patients with PC.
doi:10.4143/crt.2011.43.4.225
PMCID: PMC3253864  PMID: 22247707
Colorectal neoplasms; Peritoneum; Carcinoma; Drug therapy
14.  Predictive Value of In Vitro Adenosine Triphosphate-Based Chemotherapy Response Assay in Advanced Gastric Cancer Patients Who Received Oral 5-Fluorouracil after Curative Resection 
Purpose
To assess the usefulness of adenosine triphosphate-based chemotherapy response assay (ATP-CRA) results in advanced gastric cancer patients receiving adjuvant chemotherapy.
Materials and Methods
Sixty-two patients underwent curative surgical resection between January, 2006 and December, 2008. Their highly purified surgical specimens were evaluated by ATP-CRAs. Of the 62, 49 had successful assay results and they received either oral 5-fluorouracil or other chemotherapies. We retrospectively analyzed data for 24 patients who were treated with oral 5-fluorouracil and whose assays were successful.
Results
The median observation time was 24.6 months (range, 10.1 to 40.9 months). The median treatment time was 11.2 months (range, 1.2 to 17.7 months). The median age was 66 years (range, 30 to 81 years). Patients were grouped into sensitive- and resistant-groups according to adenosine triphosphate-based chemotherapy response results for fluorouracil. The sensitive-group showed a significantly longer time to relapse (not reached in the sensitive-group vs. 24.8 months in the resistant-group, p=0.043) and longer overall survival compared to the resistant-group (not reached in the sensitive-group vs. 35.7 months in the resistant-group, p=0.16, statistically insignificant).
Conclusion
Patients who receive curative surgical resection significantly benefit from sensitive adjuvant chemotherapy according to ATP-CRA results for time to relapse.
doi:10.4143/crt.2011.43.2.117
PMCID: PMC3138915  PMID: 21811428
Adenosine triphosphate; Chemotherapy response assay; Gastric cancer; Fluorouracil; Adjuvant chemotherapy
15.  Phase II Study of Vinorelbine Plus Trastuzumab in HER2 Overexpressing Metastatic Breast Cancer Pretreated with Anthracyclines and Taxanes 
Journal of Breast Cancer  2011;14(2):140-146.
Purpose
The role of first-line trastuzumab-based therapy has been firmly established in patients with human epidermal growth factor receptor-2 (HER2) positive metastatic breast cancer. In this trial, we evaluated the efficacy and safety of a vinorelbine and trastuzumab combination chemotherapy in patients who were pretreated with anthracyclines and taxanes.
Methods
Thirty-three patients with HER2 overexpressing metastatic breast cancer, all of whom had previously been treated with anthracyclines and taxanes, were included in this study. The patients were treated with 25 mg/m2 of vinorelbine (over a 15-minute infusion) on days 1 and 8 every 3 weeks. Additionally, trastuzumab was administered at an initial dose of 4 mg/kg over 90 minutes, and was subsequently administered at weekly doses of 2 mg/kg (over 30 minutes).
Results
The median age of the patients was 53 years (range, 39-72 years). The overall response rate was 30.3% (10 patients; 95% confidence interval [CI], 23-57%). The median time to progression was 6.8 months (95% CI, 5.3-8.2 months). The median overall survival was 12.4 months (95% CI, 10.3-14.6 months). In the 194 cycles of treatment, the incidence rates of grade ≥3 neutropenia and anemia were 7.2% and 1.0%, respectively. Neutropenic fever was detected in three cycles (1.5%). The non-hematological toxicities were not severe: grade 1 or 2 nausea or vomiting was detected in 15.2%, and grade 2 neuropathy was noted in 6.1% of patients. None of the patients experienced any serious cardiac toxicity, and no treatment-related deaths occurred.
Conclusion
These results show that a combination chemotherapy consisting of vinorelbine and trastuzumab is useful in patients with HER2-overexpressing metastatic breast cancer who were pretreated with anthracyclines and taxanes, with a favorable toxicity profile.
doi:10.4048/jbc.2011.14.2.140
PMCID: PMC3148545  PMID: 21847410
Breast neoplasms; Metastasis; Trastuzumab; Vinorelbine
16.  Incidence and clinical characteristics of clonal cytogenetic abnormalities of acquired aplastic anemia in adults 
The Korean Journal of Hematology  2010;45(4):242-246.
Background
Cytogenetic abnormalities (CAs) have been reported frequently in patients with otherwise typical aplastic anemia (AA), but their implications in the prognosis and in the evolution to hematologic malignancies are controversial.
Methods
We retrospectively analyzed 127 adult AA patients who had successful cytogenetic analysis at initial diagnosis.
Results
The patients were classified into 3 groups according to the initial and follow-up results of cytogenetic profiles. Group 1 included patients who had persistent AA with normal cytogenetic profiles (N=117); Group 2, those who had a normal cytogenetic profile at initial diagnosis but later acquired CA (N=4, 3.1%); and Group 3, those who had CA at the initial diagnosis, regardless of follow-up cytogenetic status (N=6,4.7%). In Group 2, 2 patients later developed CA without progression to acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS); the other 2 patients later progressed to AML. None of the patients in Group 3 progressed to AML or MDS. There was no significant difference in overall survival between Groups 1 and 3.
Conclusion
AA patients with CA at initial diagnosis or follow-up may not be at greater risk for evolution to AML or MDS, or show shorter survival periods. Prospective studies and a larger patient samples are needed to establish the clinical relevance of CA.
doi:10.5045/kjh.2010.45.4.242
PMCID: PMC3023049  PMID: 21253425
Aplastic anemia; Cytogenetic abnormality
17.  A Case of 5-Fluorouracil Induced Encephalopathy 
Patients with reduced dihydropyrimidine dehydrogenase (DPD) activity are at risk for experiencing serious adverse effects following 5-fluorouracil (5-FU) based chemotherapy. Neurotoxicity is considered an extremely rare side effect of 5-FU. We report here on an unusual case of 5-FU induced encephalopathy. A 38-year-old woman with advanced gastric carcinoma was treated with adjuvant chemotherapy that consisted of infused 5-FU (1,000 mg/m2) for 5 days and cisplatin (60 mg/m2) on day 1 following total gastrectomy. Nineteen days after starting chemotherapy, the patient displayed a sudden onset of slurred speech, confusion, cognitive disturbances and paranoia. A magnetic resonance image (MRI) of the brain showed no structural abnormalities, and the other laboratory tests provided no explanations for her symptoms, other than a slightly elevated ammonia level. The patient was treated with a lactulose retention enema and thiamine infusion, the 5-FU was halted and her symptoms then recovered after 7 days.
doi:10.4143/crt.2010.42.2.118
PMCID: PMC2901079  PMID: 20622967
5-FU; Neurotoxicity; Encephalopathy
18.  Fludarabine-based myeloablative regimen as pretransplant conditioning therapy in adult acute leukemia/myelodysplastic syndrome: comparison with oral or intravenous busulfan with cyclophosphamide 
The Korean Journal of Hematology  2010;45(2):102-108.
Background
A combination of busulfan (Bu) and cyclophosphamide (Cy) has been used as a standard myeloablative regimen for allogeneic hematopoietic stem cell transplantation (HSCT). Recent studies postulate that fludarabine (Flu) is a less toxic substitute for Cy.
Methods
Forty-two patients who were diagnosed with acute leukemia or myelodysplastic syndrome and received BuFlu (n=17) or BuCy (n=25) from August, 1999 to July, 2009 at Dong-A University Medical Center were retrospectively analyzed.
Results
The median follow-up duration was 39.75 months. The BuFlu group showed a lower incidence of mucositis (P=0.005), but there was no significant intergroup difference in the time of engraftment, nausea/vomiting, acute/chronic graft-versus-host disease, hepatic veno-occlusive disease, or hemorrhagic cystitis. Moreover, the 2 groups showed no significant difference in the cumulative risk of relapse, event-free survival, or overall survival.
Conclusion
BuFlu administration can be employed as a preparative regimen for allogeneic HSCT and shows efficacy and transplant-adverse effects comparable to those of BuCy. However, randomized prospective studies in more patients are warranted.
doi:10.5045/kjh.2010.45.2.102
PMCID: PMC2983027  PMID: 21120188
Myeloablative regimen; Allogeneic hematopoietic stem cell transplantation; Fludarabine; Busulfan
19.  Clinical significance of preoperative serum vascular endothelial growth factor, interleukin-6, and C-reactive protein level in colorectal cancer 
BMC Cancer  2010;10:203.
Background
Angiogenesis is a multistep process in which many growth factors and cytokines have an essential role. Vascular endothelial growth factor (VEGF) is a potent angiogenic agent that acts as a specific mitogen for vascular endothelial cells through specific cell surface receptors. The interleukin-6 (IL-6) pathway is another mechanism linking angiogenesis to malignancy. C-reactive protein (CRP), a representative marker for inflammation, is known for its association with disease progression in many cancer types. The aim of this study was to determine preoperative serum levels of VEGF, IL-6, and CRP in colorectal carcinoma, and to correlate them with disease status and prognosis.
Methods
A 132 of 143 patients who underwent curative resection for colorectal cancer were enrolled in this study. 11 patients with resection margin positive were excluded. Factors considered in analysis of the relationship between VEGF, IL-6, and CRP and histological findings. Patient prognosis was investigated. Serum levels of VEGF and IL-6 were assessed using Enzyme-Linked Immuno-Sorbent Assay (ELISA), and CRP was measured using immunoturbidimetry.
Results
Median follow-up duration was 18.53 months (range 0.73-43.17 months) and median age of the patients was 62 years (range, 26-83 years). Mean and median levels of VEGF and CRP in colorectal cancer were significantly higher than in the normal control group; 608 vs. 334 pg/mL and 528 (range 122-3242) vs. 312 (range 16-1121) (p < 0.001); 1.05 mg/dL vs. 0.43 mg/dL and 0.22 (range 0.00-18.40) vs. 0.07 (range 0.02-6.94) (p = 0.002), respectively. However mean and median level of IL-6 in patients were not significantly higher than in control; 14.33 pg/mL vs. 5.65 pg/mL and 6.00 (range 1.02-139.17) vs. 5.30 (4.50-13.78) (p = 0.327). Although IL-6 and CRP levels were not correlated with other pathological findings, VEGF level was significantly correlated with tumor size (p = 0.012) and CEA (p = 0.038). When we established the cutoff value for VEGF (825 pg/mL), IL-6 (8.09 pg/mL), and CRP (0.51 mg/dL) by Receiver Operating Characteristic (ROC) curve, we noted that high VEGF levels tended to reduce overall survival (p = 0.053), but not significantly. However, IL-6 and CRP demonstrated no significance with regard to disease free survival (p = 0.531, p = 0.701, respectively) and overall survival (p = 0.563, p = 0.572, respectively). Multivariate analysis showed that VEGF (p = 0.032), CEA (p = 0.012), lymph node metastasis (p = 0.002), and TNM stage (p = 0.025) were independently associated with overall survival.
Conclusions
Preoperative serum VEGF and CRP level increased in colorectal cancer patients. High VEGF level has been proposed as a poor prognostic factor for overall survival in patients with colorectal cancer.
doi:10.1186/1471-2407-10-203
PMCID: PMC2886042  PMID: 20465852
20.  A case of subdural hematoma in patient with chronic myeloid leukemia treated with high-dose imatinib mesylate 
Imatinib mesylate (IM) is used to treat a wide range of diseases, including Philadelphia chromosome-positive chronic myeloid leukemia (CML), on account of its high tolerability and low incidence of minor adverse events. Hemorrhage is thought to be a rare complication of IM. Recently, IM has been associated with reduced α2-plasmin inhibitor and platelet dysfunction. We report here the case of a 33-year-old female patient with CML who experienced subdural hematoma after an incremental increase in IM dosage due to a loss of complete molecular response. This case indicates that physicians should be alert to this atypical cause of headache in patients taking high-dose IM.
doi:10.5045/kjh.2010.45.1.73
PMCID: PMC2983009  PMID: 21120168
Chronic myeloid leukemia; Imatinib mesylate; Subdural hematoma
21.  Gastric leptomeningeal carcinomatosis: Multi-center retrospective analysis of 54 cases 
AIM: To identify the clinical features and outcomes of infrequently reported leptomeningeal carcinomatosis (LMC) of gastric cancer.
METHODS: We analyzed 54 cases of cytologically confirmed gastric LMC at four institutions from 1994 to 2007.
RESULTS: The male-to-female ratio was 32:22, and the patients ranged in age from 28 to 78 years (median, 48.5 years). The majority of patients had advanced disease at initial diagnosis of gastric cancer. The clinical or pathologic tumor, node and metastasis stage of the primary gastric cancer was IV in 38 patients (70%). The median interval from diagnosis of the primary malignancy to the diagnosis of LMC was 6.3 mo, ranging between 0 and 73.1 mo. Of the initial endoscopic findings for the 45 available patients, 23 (51%) of the patients were Bormann type III and 15 (33%) patients were Bormann type IV. Pathologically, 94% of cases proved to be poorly differentiated adenocarcinomas. Signet ring cell component was also observed in 40% of patients. Headache (85%) and nausea/vomiting (58%) were the most common presenting symptoms of LMC. A gadolinium-enhanced magnetic resonance imaging was conducted in 51 patients. Leptomeningeal enhancement was noted in 45 cases (82%). Intrathecal (IT) chemotherapy was administered to 36 patients-primarily methotrexate alone (61%), but also in combination with hydrocortisone/± Ara-C (39%). The median number of IT treatments was 7 (range, 1-18). Concomitant radiotherapy was administered to 18 patients, and concomitant chemotherapy to seven patients. Seventeen patients (46%) achieved cytological negative conversion. Median overall survival duration from the diagnosis of LMC was 6.7 wk (95% CI: 4.3-9.1 wk). In the univariate analysis of survival duration, hemoglobin, IT chemotherapy, and cytological negative conversion showed superior survival duration (P = 0.038, P = 0.010, and P = 0.002, respectively). However, in our multivariate analysis, only cytological negative conversion was predictive of relatively longer survival duration (3.6, 6.7 and 14.6 wk, P = 0.030, RR: 0.415, 95% CI: 0.188-0.918).
CONCLUSION: Although these patients had a fatal clinical course, cytologic negative conversion by IT chemotherapy may improve survival.
doi:10.3748/wjg.15.5086
PMCID: PMC2768889  PMID: 19860003
Carcinomatosis; Gastric cancer; Intrathecal chemotherapy; Leptomeningeal
22.  Clinical significances of preoperative serum interleukin-6 and C-reactive protein level in operable gastric cancer 
BMC Cancer  2009;9:155.
Background
The interleukin-6 (IL-6) pathway is one of the mechanisms that link inflammation and angiogenesis to malignancy. Because the C-reactive protein (CRP) is a representative marker for inflammation, CRP has recently been associated with the progression of disease in many cancer types. The principal objective of this study was to determine the preoperative serum levels of IL-6 and CRP in gastric carcinoma, and to correlate them with disease status and prognosis.
Methods
A total of 115 patients who underwent gastrectomy were enrolled in this study. Serum levels of IL-6 were assessed via Enzyme-Linked Immuno-Sorbent Assay (ELISA), and CRP was measured via immunoturbidimetry. Histological findings included tumor size, depth of tumor invasion, lymph node (LN) metastasis, and TNM stage (6th AJCC Stage Groupings: The staging systems; Primary tumor, regional LN, metastasis).
Results
Increases in cancer invasion and staging are generally associated with increases in preoperative serum IL-6 levels. IL-6 and CRP levels were correlated with invasion depth (P < 0.001, P = 0.001), LN metastasis (P < 0.001, P = 0.024) and TNM stage (P < 0.001, P < 0.001). The presence of peritoneal seeding metastasis is associated with IL-6 levels (P = 0.012). When we established the cutoff value for IL-6 level (6.77 pg/dL) by ROC curve, we noted significant differences in time to progression (TTP; P < 0.001) and overall survival (OS; P = 0.010). However, CRP evidenced no significance with regard to patients' TTP and OS levels. Serum IL-6 levels were correlated positively with CRP levels (r2 = 0.049, P = 0.018).
Conclusion
Preoperative serum IL-6 and CRP levels might be markers of tumor invasion, LN metastasis, and TNM stage. Preoperative high IL-6 levels were proposed as a poor prognostic factor for disease recurrence and overall survival in patients with gastric cancers.
doi:10.1186/1471-2407-9-155
PMCID: PMC2694817  PMID: 19457231
23.  Phase II Study of Gemcitabine plus Cisplatin in Patients with Anthracycline- and Taxane- Pretreated Metastatic Breast Cancer 
Purpose
Metastatic breast cancer patients are usually exposed to taxane and anthracycline as neoadjuvant, adjuvant and palliative chemotherapeutic agents. This study was designed to determine the efficacy and safety of the use of a gemcitabine and cisplatin (GP) combination treatment in patients with metastatic breast cancer that were pretreated with anthracycline and taxane.
Materials and Methods
We evaluated the use of a GP regimen (1,000 mg/m2 gemcitabine administered on days 1 and 8 plus 60 mg/m2 cisplatin administered on day 1 every 3 weeks) in 38 breast cancer patients who had received prior chemotherapy with anthracycline and taxane as an adjuvant or neoadjuvant therapy, or as a palliative therapy.
Results
The median patient age was 49 years (age range, 35~69 years). The overall response rate was 28.9% in 11 patients (95% confidence interval [CI], 14~44%). The median time to progression was 5.2 months (95% CI, 3.6~6.8 months). Median survival was 19.5 months (95% CI, 11.2~27.8 months). Major grade 3/4 hematological toxicity was due to leukopenia (36 of 157 cycles, 23.1%). Non-hematological toxicity was rarely severe; grade1/2 nausea and vomiting were observed in 37.8% of the patients. There were no treatment related deaths.
Conclusions
Our results suggest that the use of gemcitabine plus cisplatin appears to be effective and has an acceptable toxicity profile in patients with advanced breast cancer that have been pretreated with anthracycline and taxane.
doi:10.4143/crt.2008.40.3.101
PMCID: PMC2697461  PMID: 19688114
Breast neoplasms; Anthracycline; Taxane; Gemcitabine; Cisplatin
24.  Gemcitabine versus Gemcitabine Combined with Cisplatin Treatment Locally Advanced or Metastatic Pancreatic Cancer: A Retrospective Analysis 
Purpose
Gemcitabine is the most active agent to treat unresectable pancreatic cancer. The superiority of combining other drugs with cisplatin is still controversial; therefore, we performed a retrospective analysis of gemcitabine versus gemcitabine combined with cisplatin to determine the treatment outcomes for patients with locally advanced or metastatic pancreatic cancer.
Materials and Methods
From 2001 to 2007, we enrolled 60 patients who were treated with gemcitabine or gemcitabine combined with cisplatin for locally advanced or metastatic pancreatic cancer. Gemcitabine 1, 000 mg/m2 (G) was administrated at day 1 and day 8 every 3 weeks. Cisplatin 60 mg/m2 was added at day 1 every 3 weeks to the gemcitabine schedule (GP).
Results
Number of G: GP was 34: 26, locally advanced to metastatic ratio was 35% to 65% in group G and 46% to 54% in group GP. Median follow up duration was 29 months. The median number of chemotherapy cycles was 4 (range: 2~11) for the G group, and 4 (range: 1~11) for the GP group. The response rate of the G and GP groups was 17% and 11%, respectively. The progression free survival (PFS) was 4.5 months and 2.8 months, respectively, for the G and GP groups. The overall survival (OS) was 10.7 and 8.7 months respectively, for the G and GP groups, but there is no statistically significant difference of the PFS (p=0.2396) and OS (p=0.4643) between the 2 groups. The hematological toxicity profile was similar (the grade III neutropenia and thrombocytopenia was 4.4% and 3.1%, respectively, in G group, and 7.5% and 2.8%, respectively, in the GP group). But non-hematological toxicities such as skin rash, abnormal liver function and nausea/vomiting were observed in 3 patients of the GP group. On the prognostic factor analysis, no factors predicted a longer PFS and OS for both the G and GP groups.
Conclusions
Gemcitabine single treatment might be more tolerable and it had the same efficacy compared to cisplatin combination treatment in this retrospective study.
doi:10.4143/crt.2008.40.1.22
PMCID: PMC2699081  PMID: 19688061
Gemcitabine; Cisplatin; Pancreatic neoplasm
25.  Bevacizumab plus infusional 5-fluorouracil, leucovorin and irinotecan for advanced colorectal cancer that progressed after oxaliplatin and irinotecan chemotherapy: A pilot study 
AIM: To evaluate the combination of bevacizumab with infusional 5-fluorouracil (5-FU), leucovorin (LV) and irinotecan (FOLFIRI) in patients with advanced colorectal cancer (CRC) pretreated with combination regimens including irinotecan and oxaliplatin.
METHODS: Fourteen patients (median age 56 years) with advanced CRC, all having progressed after oxaliplatin- and irinotecan-based combination chemotherapy, were enrolled in this study. Patients were treated with 2 h infusion of irinotecan 150 mg/m2 on d 1, plus bevacizumab 5 mg/kg iv infusion for 90 min on d 2, and iv injection of LV 20 mg/m2 followed by a bolus of 5-FU 400 mg/m2 and then 22 h continuous infusion of 600 mg/m2 given on two consecutive days every 14 d.
RESULTS: The median number of cycles of chemotherapy was six (range 3-12). The response rate was 28.5%, one patient had a complete response, and three patients had a partial response. Eight patients had stable disease. The median time to progression was 3.9 mo (95% CI 2.0-8.7), and the median overall survival was 10.9 mo (95% CI 9.6-12.1). Grade 3/4 neutropenia occurred in five patients, and two of these developed neutropenic fever. Grade 3 hematuria and hematochezia occurred in one. Grade 2 proteinuria occurred in two patients. However, hypertension, bowel perforation or thromboembolic events did not occur in a total of 90 cycles.
CONCLUSION: Bevacizumab with FOLFIRI is well tolerated and a feasible treatment in patients with heavily treated advanced CRC.
doi:10.3748/wjg.v13.i46.6231
PMCID: PMC4171235  PMID: 18069765
Bevacizumab; Irinotecan; Leucovorin; 5-fluorouracil; Colorectal cancer

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