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1.  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
2.  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
3.  Chemotherapy in Advanced Gastric Cancer Patients Associated with Disseminated Intravascular Coagulation 
Purpose
Little is known about the clinical features of advanced gastric cancer (AGC) combined with disseminated intravascular coagulation (DIC). The main objective of this study was to determine the clinical outcome of patients with AGC complicated by DIC.
Materials and Methods
We conducted a retrospective review of 68 AGC patients diagnosed with DIC at four tertiary medical centers between January 1995 and June 2010.
Results
Sixty eight patients were included. The median age was 55 years (range, 25 to 78 years). Nineteen patients received chemotherapy, whereas 49 patients received only best supportive care (BSC). The median overall survival (OS) of the 68 patients was 16 days (95% confidence interval [CI], 11 to 21 days). Significantly prolonged OS was observed in the chemotherapy group, with a median survival of 61 days compared to 9 days in the BSC group (p<0.001, log-rank test). Age and previous chemotherapy were another significant factors that were associated with OS in univariate analysis. In multivariate analysis, age (≥65 vs. <65; hazard ratio [HR], 0.38; 95% CI, 0.18 to 0.78; p<0.001), chemotherapy (BSC vs. chemotherapy; HR 0.31; 95% CI, 0.15 to 0.63; p<0.001), and previous chemotherapy (yes or no; HR, 0.49; 95% CI, 0.25 to 0.98; p<0.045) were consistently independent prognostic factors that impacted OS.
Conclusion
Our study showed that patients with AGC complicated by DIC had very poor OS, and suggested that chemotherapy might improve OS of these patients.
doi:10.4143/crt.2014.46.1.27
PMCID: PMC3918524  PMID: 24520220
Stomach neoplasms; Disseminated intravascular coagulation; Drug therapy
4.  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
5.  'Is tinnitus accompanied by hemifacial spasm in normal-hearing patients also a type of hyperactive neurovascular compression syndrome? : A magnetoencephalography study 
BMC Neurology  2013;13:42.
Background
Traditionally, tinnitus accompanied by hemifacial spasm has been considered a type of hyperactive neurovascular compression syndrome that is similar to hemifacial spasm alone because of the anatomically close relationship between the facial nerve and cochlear nerve as well as the hyperactive clinical nature.
Methods
Participants were 29 subjects who presented with hemifacial spasm and neuroradiological evidence of vascular compression of the cranial (facial/cochlear) nerve. We used magnetoencephalography (MEG) to estimate the activity of the cochlear nerve in patients with and without tinnitus on the ipsilateral side. We compared the difference in the latency and the ratio of the equivalent current dipole (ECD) strength between the ipsilateral and contralateral sides of the spasm and tinnitus.
Results
Cochlear nerve activity in patients with tinnitus was increased with a shorter latency (p = 0.016) and stronger ECD strength (p = 0.028) compared with patients without tinnitus.
Conclusion
The MEG results from normal-hearing patients who had tinnitus accompanied by hemifacial spasm suggest that the hyperactivity of the auditory central nervous system may be a crucial pathophysiological factor in the generation of tinnitus in these patients. The neurovascular compression that causes sensory input from the pathologic facial nerve activity may contribute to this hyperactivity of the central auditory nervous system.
doi:10.1186/1471-2377-13-42
PMCID: PMC3655871  PMID: 23651913
Hemifacial spasm; Magnetoencephalography; Pathophysiology; Tinnitus
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.  Long term survival results for gastric GIST: is laparoscopic surgery for large gastric GIST feasible? 
Background
Recently, laparoscopic resection for relatively small sized gastric gastrointestinal stromal tumors (GISTs) has been widely accepted as minimally invasive surgery. However, no report on the long-term safety and efficacy of this surgery for large sized gastric GISTs has been published to date.
Methods
Between July 1998 and January 2011, 104 consecutive patients who underwent resection for gastric GISTs were enrolled in this retrospective study. We assessed the clinicopathological characteristics, postoperative outcomes, patient survival, and tumor recurrence.
Results
Of the 104 patients with gastric GISTs who were included in the study, there were 47 males and 57 females whose mean age was 59.8 years. Sixty-four patients (61.5%) had symptoms associated with tumor. Ten patients included in the group 1, 49 in the group 2, 15 in the group 3a, 9 in the group 5, 14 in the group 6a, and 7 in the group 6b. There was one minor complication and no mortalities. Recurrence was noted in 5 patients, with a median follow-up period of 49.3 months (range, 8.4 to 164.4). The 5-year overall and disease free survival rates of 104 patients were 98.6% and 94.8%, respectively. When comparing large tumor (5–10 cm) between laparoscopic and open surgery, there were statistically differences in age, tumor size, tumor location, and length of hospitalization. There were no statistical differences in the 5-year survival rate between laparoscopic and open surgery for large tumor (5-10cm).
Conclusion
Laparoscopic surgery is feasible and effective as an oncologic treatment of gastric GISTs. Moreover, laparoscopic surgery can be an acceptable alternative to open methods for gastric GISTs of size bigger than 5 cm.
doi:10.1186/1477-7819-10-230
PMCID: PMC3517899  PMID: 23114111
Stomach; GIST; Laparoscopy; Survival
8.  Patient Perception of Natural Orifice Transluminal Endoscopic Surgery in an Endoscopy Screening Program in Korea 
Yonsei Medical Journal  2012;53(5):960-967.
Purpose
Natural orifice transluminal endoscopic surgery (NOTES) is a new method of accessing intracavitary organs in order to minimize pain by avoiding incisions in the body wall. The aim of this study is to determine patients' acceptance of NOTES in Korea and to compare their views about laparoscopic surgery and NOTES for benign and malignant diseases.
Materials and Methods
The target number of total subjects was calculated to be 540. The subjects were classified into 18 sub-groups based on age groups, gender, and history of prior surgery. The questionnaire elicited information about demographic characteristics, medical check-ups, diseases, endoscopic and surgical histories, marital status and childbirth, the acceptance of NOTES, and the preferred routes for NOTES. In addition, the subjects chose laparoscopic surgery or NOTES for a hypothetical cholecystectomy and rectal cancer surgery, and responded to questions regarding the acceptable complication rate of NOTES, the appropriate cost of NOTES, and the reason(s) why they did not select NOTES.
Results
486 of 540 patients (90.0%) who agreed to participate in this study completed the questionnaire. NOTES was preferred by the following patients: elderly; a history of treatment due to a disease; having regular check-ups; and a history of an endoscopic procedure (p<0.05). The most preferred route for NOTES was the stomach (67.1%). Eighty-four percent of the patients choosing NOTES responded that the complication rate of the new surgical method should be the same or lower than laparoscopic surgery. Vague anxiety over a new surgical method was the most common reason why NOTES was not selected in benign and malignant diseases (64% and 73%), respectively.
Conclusion
Patients appear to be interested in the potential benefits of NOTES and would embrace it if their concerns about safety are met. We believe that qualified surgical endoscopists can meet these safety concerns, and that NOTES development has the potential to flourish.
doi:10.3349/ymj.2012.53.5.960
PMCID: PMC3423838  PMID: 22869479
NOTES; endoscopy; surgery; patient perception; survey
9.  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
10.  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
11.  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
12.  Bevacizumab as a second- or later-line of treatment for metastatic colorectal cancer 
AIM: To determine the efficacy of bevacizumab in patients with metastatic colorectal cancer (MCRC) who have failed prior chemotherapy without bevacizumab.
METHODS: Between March 2002 and June 2010, 40 patients in South Korea with MCRC who were treated with bevacizumab plus chemotherapy as a second or later-line treatment were analyzed retrospectively for their overall response rate (ORR), overall survival (OS), and progression-free survival (PFS). The tumor responses were assessed using the Response Evaluation Criteria in Solid Tumors guidelines.
RESULTS: All of the patients had progressed under prior chemotherapy without bevacizumab. Three patients (7.5%) exhibited an ORR, twenty one patients (52.5%) exhibited stable disease (SD), and fifteen patients (37.5%) exhibited disease progression. The median duration of the OS and PFS were 14.0 mo and 6.13 mo respectively. The median OSs were 16.60, 14.07 and 13.00 mo for second-line, third-line and fourth- or later-line treatments, respectively. The median PFSs were 7.23, 7.30 and 3.87 mo for the second-line, third-line and fourth- or later-line treatments, respectively.
CONCLUSION: In patients with MCRC, bevacizumab combined chemotherapy may be beneficial during second- or later-line treatment.
doi:10.3748/wjg.v18.i10.1104
PMCID: PMC3296985  PMID: 22416186
Colorectal cancer; Metastasis; Bevacizumab; Efficacy; Second- or later-line
13.  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
14.  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
15.  Prognostic implication of metastatic lymph node ratio in node-positive rectal cancer 
Purpose
The aim of this study was to evaluate the prognostic significance of the ratio between metastatic and examined lymph nodes (LNs) in patients with stage III rectal cancer.
Methods
A review was made of 175 (male, 98) patients with stage III rectal cancer of R0 resection. LN disease was stratified both by the American Joint Committee on Cancer/International Union Against Cancer nodal classification (pN) and by quartiles of the lymph node ratio (LNR). Disease-free survivals (DFS) were made using Kaplan-Meier curves and assessed by the log rank test and multivariate analysis was performed using the Cox proportional hazards model.
Results
Patients ranged in age from 29 to 83 (median, 60) years with median follow-up of 47 months (range, 13 to 181 months). months. There was a significant correlation between the number of metastatic LNs and the LNR (r = 0.8681, P < 0.0001). Cut-off points of LNR quartiles best to separate patients with regard to 5-year DFS were between quartile 2 and 3, and between 3 and 4 (LNR1, 2, and 3); the 5-year DFS according to such stratification was 89.6%, 55.8%, and 18.2% in LNR1, 2, and 3, respectively (P < 0.0001). Cox model identified the LNR as the most significant independent prognostic covariate; LNR2 showed 3.6 times (95% confidence interval [CI], 1.682 to 7.584; P = 0.0009) and LNR3, 18.7 times (95% CI, 6.872 to 50.664; P < 0.0001) more risky than LNR1.
Conclusion
This study suggests that ratio-based LN staging, which reflects the number of LNs examined and the quality of LN dissection, is a simple and reliable system for prognostic LN stratification in patients with stage III rectal cancer.
doi:10.4174/jkss.2011.80.4.260
PMCID: PMC3204678  PMID: 22066045
Rectal cancer; Metastatic lymph node ratio; Prognostic factor
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.  A Case of Pathologic Splenic Rupture as the Initial Manifestation of Acute Myeloid Leukemia M2 
Yonsei Medical Journal  2009;51(1):138-140.
A pathologic splenic rupture refers to a rupture without trauma. A splenic rupture as the initial manifestation of acute myeloid leukemia is extremely rare. In this study, we described a rare case of acute myeloid leukemia presenting principally as an acute abdomen due to a pathologic splenic rupture in a 35-year old male patient. We can assert that a pathologic splenic rupture in hematologic diseases is a potentially life-threatening complication, which necessitates immediate operative intervention. Any such patient complaining about left upper abdominal tenderness should be closely observed, and further diagnostic investigations (ultrasonograph of the abdomen, abdominal CT scan) should be initiated in order to rule out a splenic rupture. The oncologist should be aware of this rare initial presentation of acute myeloid leukemia (AML) M2, as the condition generally necessitates a prompt splenectomy.
doi:10.3349/ymj.2010.51.1.138
PMCID: PMC2799964  PMID: 20046528
Acute myeloid leukemia M2; pathologic; splenic rupture
20.  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
21.  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
22.  Clinicopathologic significance of HIF-1α, p53, and VEGF expression and preoperative serum VEGF level in gastric cancer 
BMC Cancer  2008;8:123.
Background
Hypoxia influences tumor growth by inducing angiogenesis and genetic alterations. Hypoxia-inducible factor 1α (HIF-1α), p53, and vascular endothelial growth factor (VEGF) are all important factors in the mechanisms inherent to tumor progression. In this work, we have investigated the clinicopathologic significance of HIF-1α, p53, and VEGF expression and preoperative serum VEGF (sVEGF) level in gastric cancer.
We immunohistochemically assessed the HIF-1α, p53, and VEGF expression patterns in 114 specimens of gastric cancer. Additionally, we determined the levels of preoperative serum VEGF (sVEGF).
Results
The positive rates of p53 and HIF-1α (diffuse, deep, intravascular pattern) were 38.6% and 15.8%, respectively. The VEGF overexpression rate was 57.9%. p53 and HIF-1α were correlated positively with the depth of invasion (P = 0.015, P = 0.001, respectively). Preoperative sVEGF and p53 levels were correlated significantly with lymph node involvement (P = 0.010, P = 0.040, respectively). VEGF overexpression was more frequently observed in the old age group (≥ 60 years old) and the intestinal type (P = 0.013, P = 0.014, respectively). However, correlations between preoperative sVEGF level and tissue HIF-1α, VEGF, and p53 were not observed. The median follow-up duration after operation was 24.5 months. HIF-1α was observed to be a poor prognostic factor of disease recurrence or progression (P = 0.002).
Conclusion
p53, HIF-1α and preoperative sVEGF might be markers of depth of invasion or lymph node involvement. HIF-1α expression was a poor prognostic factor of disease recurrence or progression in patients with gastric cancers.
doi:10.1186/1471-2407-8-123
PMCID: PMC2397429  PMID: 18452596
23.  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
24.  Unusual Presentation of Large B Cell Lymphoma- Bone and Stomach- Treated with Autologous Transplantation 
Extranodal presentation of diffuse large B cell lymphoma (DLBL) is frequently observed in the gastrointestinal tract, CNS, bone, testes and liver. However, the simultaneous detection of multiple extranodal involvement at presentation is quite an uncommon occurrence. In this study, we report on a patient with an uncommon presentation of DLBL, and he had symptoms of left knee joint pain and hematemesis, characterized by bone and stomach involvement. Computed tomography and fluorodeoxyglucose-positron emission tomography (FDG-PET) scanning revealed a rapid, extensive spread to the bones and soft tissues. Subsequent histopathological examination verified the bony and gastric CD20-positive DLBL localization. We diagnosed this case as DLBL of stage IV with an international prognostic index of 3, and classified him into the high intermediate risk group. This patient was treated via chemotherapy with an R-CHOP regimen. After achieving a partial response, the patient received autologous peripheral blood stem cell transplantation. The patient attained partial remission, as shown on the FDG-PET scan, and he displayed improvement of his left femur pain.
doi:10.4143/crt.2007.39.4.181
PMCID: PMC2739372  PMID: 19746186
Extranodal; Diffuse large B-cell lymphoma; Stomach; Bone
25.  Extraskeletal Mesenchymal Chondrosarcoma of the Heart Responded to Systemic Chemotherapy: A Case Report 
Mesenchymal chondrosarcoma is a rare cartilaginous ne - oplasm of an extraskeletal origin, and this predominately occurs in the head and neck, and also in the lower extremities. Fewer than twenty cases of cardiac mesenchymal chondrosarcoma have so far been reported on. For the most part, the results of treatment for patients with this condition have been dismal. In this study, we describe a case of cardiac mesenchymal chondrosarcoma that responded to chemotherapy following surgical biopsy. A 46-year-old man was referred for evaluation of his pleural effusions in both lungs. Chest computed tomography revealed an ovoid-shaped mass in the posterior wall of the patient's left atrium. The echocardiogram revealed a large ovoid-shaped immobile mass (11×6 cm2) in the pericardiac space, which was attached to the posterior wall of the left atrium. Emergency pericardiostomy with closure thoracostomy was performed. Seven days later, a thoracotomy was performed for reduction and diagnosis of the cardiac mass. The pathological diagnosis was extraskeletal mesenchymal chondrosarcoma of the heart.. Postoperative chemotherapy was performed for the huge remaining mass with a combined regimen of etoposide, ifosfamide and cisplatin. After 6 cycles, the patient showed a partial response without symptoms. Although cardiac mesenchymal chondrosarcoma has been reported to be chemotherapy-resistant with a short survival duration, chemotherapy may prove to be an effective treatment modality.
doi:10.4143/crt.2007.39.3.131
PMCID: PMC2739328  PMID: 19746223
Mesenchymal chondrosarcoma; Extraskeletal; Heart

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