Association between Timing and Duration of Adjuvant Chemotherapy and Colorectal Cancer Survival in Korea, 2011-2014: A Nationwide Study based on the Health Insurance Review and Assessment Service Database.

Background: Population-based analyses of the treatment outcomes of colorectal cancer (CRC) in Asian countries are limited. Therefore, we conducted a nationwide study to assess the relationship between the timing and duration of adjuvant chemotherapy (AC) and survival in patients with CRC in South Korea. Methods: Data on AC from the Health Insurance Review and Assessment Service Database (HIRA) were analyzed, and the survival of patients who underwent curative-intent surgical resection for CRC between 2011 and 2014 was investigated. Results: From the HIRA data, 45,992 patients with stage II-III CRC were identified. Chemotherapy regimens were administered as follows: 10,640 (23.3%) received 5-fluorouracil and leucovorin/capecitabine (FL/CAP), 13,083 (28.7%) received FL/CAP plus oxaliplatin (FOLFOX/CAPOX), 299 (0.7%) received uracil and tegafur/doxifluridine (UFT/D), and 21,570 (47.3%) underwent surgery alone. Patients who did not receive AC had worse survival than those who received AC in both the colon and rectum groups (HR, 1.96, 95% CI, 1.85-2.07 and HR, 2.18, 95% CI, 2.01-2.37, respectively). Regarding patients with stage II-III CRC, AC initiation ≥ 2 months after surgery was associated with a significant decrease in overall survival (OS) (FL/CAP: HR, 1.82; 95% CI, 1.53-2.17 and FOLFOX/CAPOX: HR, 2.92; 95% CI, 2.47-3.45); however, the effects of UFT/D regimens were not statistically significant. For patients with stage II-III colon cancer, AC <3 months had lower OS (FL/CAP: HR, 3.72, 95% CI, 2.80-4.94; FOLFOX/CAPOX: HR, 2.15, 95% CI, 1.87-2.47; and UFT/D: HR, 1.74, 95% CI, 0.56-5.41). In terms of patients with stage II-III rectal cancer, AC <3 months, regardless of chemotherapy regimens, had a significant lower survival (FL/CAP: HR, 1.91, 95% CI, 1.66-2.20; FOLFOX/CAPOX: HR, 2.20, 95% CI, 1.75-2.77; and UFT/D: HR, 3.71, 95% CI, 1.45-9.44). Conclusions: Postoperative time to initiation and duration of AC were associated with survival. Based on our results, initiating AC within 2 months after surgery and administering AC for >3 months can potentially have an OS benefit in patients with stage II-III CRC.

Clinical characteristics and survival of colorectal cancer patients in Korea stratified by age.

BACKGROUND/AIMS: This nationwide study was undertaken to determine differences in clinicopathologic characteristics and survival of patients with colorectal cancer (CRC) according to age using big data from the Korean National Health Insurance Service (NHIS). METHODS: The NHIS data including quality assessment of CRC by the Health Insurance Review & Assessment Service in Korea between 2011 and 2014 were analyzed. Based on age, patients were divided into three groups: not-old patients (< 65), young-old patients (65 to 74 years old) and old-old patients (≥ 75 years old). RESULTS: We included 71,513 CRC patients. The median follow-up duration was 3.2 years (range, 0.003 to 5.5). Male patients constituted 60%. The median age of patients was 65 years (range, 18 to 102). Colon was the cancer site in 59.8% of not-old patients, 62.9% of young-old patients, and 66.1% of old-old patients. Compared to not-old patients, young-old and old-old patients were more likely to be diagnosed with colon adenocarcinoma and well/moderate differentiation or adequate differentiation (all p < 0.001). Old patients underwent more emergency operation (p < 0.001) and received less adjuvant therapy in stage I-III (p < 0.001). The probability of 3-year survival of young-old or old-old patients was worse than that for not-old patients (hazard ratio [HR], 1.55; 95% confidence interval [CI], 1.46 to 1.64) (HR, 3.19; 95% CI, 3.03 to 3.37). CONCLUSION: Old patients with CRC show different histology from younger patients. They are more frequently to have colon as primary lesion. They undergo less adjuvant therapy. Further studies and evidence-based guidelines for older patients with CRC are warranted to improve their outcome.

Coronary Event Analysis in Breast Cancer Patients Who Received Breast-Conserving Surgery and Post-Operative Radiotherapy: a Korean Nationwide Cohort Study.

PURPOSE: Adjuvant breast radiotherapy (RT) following breast-conserving surgery (BCS) has been reported to induce cardiac toxicity in breast cancer patients. We investigated the incidence and risk factors of major coronary events after breast RT using Korean nationwide Health Insurance Review and Assessment data. METHODS: Using data from a nationwide quality assessment of breast cancer treatment, we identified 3,251 patients who received breast RT after BCS in 2013. Data about major coronary events were additionally collected from national claims data. We defined major coronary events according to the International Classification of Diseases, 10th revision (ICD-10) codes I20-25. RESULTS: A total of 172 major coronary events (5.3%) occurred among 3,251 breast cancer patients. The 1-year, 2-year, and 3-year coronary event-free survival rates were 98.1%, 96.4% and 95.2%, respectively. Patients with underlying diabetes mellitus (88.6% vs. 95.7%, p < 0.001), high blood pressure (HBP) (89.4% vs. 96.3%, p < 0.001), and cerebrovascular accident (CVA) (84.0% vs. 95.4%, p < 0.001) showed significantly worse 3-year coronary event-free survival rates than those without comorbidities. Multivariate analysis revealed that patient age (p < 0.001), HBP (p < 0.001), CVA (p = 0.025), adjuvant hormonal therapy (p = 0.034), and Herceptin therapy (p < 0.001) were significantly associated with major coronary events in breast cancer patients. CONCLUSION: The incidence of major coronary events after breast RT may be higher in breast-cancer patients with risk factors such as underlying HBP or CVA, or who were in receipt of adjuvant Herceptin therapy. Heart-sparing RT techniques or intensity-modulated RT should be considered for breast-cancer patients with risk factors for heart toxicity.

Acute Stroke Care in Korea in 2013-2014: National Averages and Disparities.

BACKGROUND: This study aimed to describe the current status of acute stroke care in Korea and explore disparities among hospitals and regions. METHODS: The 2013 and 2014 national stroke audit data and the national health insurance claims data were linked and used for this study. Stroke patients hospitalized via emergency rooms within 7 days of stroke onset were selected. RESULTS: A total of 19,608 patients treated in 216 hospitals were analyzed. Among them 76% had ischemic stroke; 15%, intracerebral hemorrhage (ICH); and 9%, subarachnoid hemorrhage (SAH). Of the hospitals, 31% provided inpatient stroke unit care. Ambulances were used in 56% of cases, and the median interval from onset to arrival was 4.5 hours. One-quarter of patients were referred from other hospitals. Intravenous thrombolysis (IVT) and endovascular treatment (EVT) rates were 11% and 4%, respectively. Three-quarters of the analyzed hospitals provided IVT and/or EVT, whereas 47% of hospitals providing IVT and 67% of hospitals providing EVT had less than one case per month. Decompressive surgery was performed on 28% of ICH patients, and clipping and coiling were performed in 17.2% and 14.3% of SAH patients, respectively. There were noticeable regional disparities between the various interventions, ambulance use, arrival time, and stroke unit availability. CONCLUSION: This study describes the current status of acute stroke care in Korea. Despite quite acceptable quality of stroke care, it suggests regional and hospital disparities. Expansion of stroke units, stroke center certification or accreditation, and connections between stroke centers and emergency medical services are highly recommended.

Effect of Adjuvant Chemotherapy on Stage II Colon Cancer: Analysis of Korean National Data.

PURPOSE: Debates exist regarding the effectiveness of adjuvant chemotherapy for stage II colon cancer. This study aimed to investigate the current status of adjuvant chemotherapy and its impact on survival for Korean stage II colon cancer patients by analyzing the National Quality Assessment data. MATERIALS AND METHODS: A total of 7,880 patientswho underwent curative resection for stage II colon adenocarcinoma between January 2011 andDecember 2014 in Koreawere selected randomly as evaluation subjects for the quality assessment. The factors that influenced overall survival were identified. The high-risk group was defined as having at least one of the following: perforation/ obstruction, lymph node harvest less than 12, lymphovascular/perineural invasion, positive resection margin, poor differentiation, or pathologic T4 stage. RESULTS: The median follow-up period was 38 months (range, 1 to 63 months). Chemotherapy was a favorable prognostic factor for either the high- (hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.38 to 0.59; p < 0.001) or low-risk group (HR, 0.74; 95% CI, 0.61 to 0.89; p=0.002) in multivariate analysis. This was also the case in patients over 70 years of age. The hazard ratio was significantly increased as the number of involved risk factors was increased in patients who didn't receive chemotherapy. Adding oxaliplatin showed no difference in survival (HR, 1.36; 95% CI, 0.91 to 2.03; p=0.132). CONCLUSION: Adjuvant chemotherapy can be recommended for stage II colon cancer patients, but the addition of oxaliplatin to the regimen must be selective.

A functional single nucleotide polymorphism at the promoter region of cyclin A2 is associated with increased risk of colon, liver, and lung cancers.

BACKGROUND: The objective of this was to identify functional single nucleotide polymorphisms (SNPs) in cyclin-dependent kinases (CDKs) and cyclins that are associated with risk of human cancer. METHODS: First, 45 SNPs in CDKs and cyclins were analyzed in 106 lung cancers and 108 controls for a pilot study. One SNP (reference SNP [rs] 769236, +1 guanine to adenine [G→A]) at the promoter region of cyclin A2 (CCNA2) also was analyzed in 1989 cancers (300 breast cancers, 450 colorectal cancers, 450 gastric cancers, 367 hepatocellular carcinomas, and 422 lung cancers) and in 1096 controls. Genotyping was performed using matrix-assisted laser desorption-ionization/time-of-flight mass spectrometry. Transcriptional activity of the SNP according to the cell cycle was analyzed by using a luciferase reporter assay and fluorescence-activated cell sorting analysis in NIH3T3 cells. RESULTS: In the pilot study, the SNP (rs769236) was associated significantly with the risk of lung cancer. In the expanded study, multivariate logistic regression indicated that the AA homozygous variant of the SNP was associated significantly with the development of lung cancer (P < .0001; codominant model), colorectal cancer (P < .0001), and hepatocellular carcinoma (P = .02) but not with breast cancer or gastric cancer. The luciferase activity of a 300-base pair construct that contained the A allele was 1.5-fold greater than the activity of a construct with the G allele in NIH3T3 cells. The high luciferase activity of constructs that contained the A allele did not change with cell cycle progression. CONCLUSIONS: The current results suggested that an SNP (rs769236) at the promoter of CCNA2 may be associated significantly with increased risk of colon, liver, and lung cancers.

Candidate gene polymorphisms for diabetes mellitus, cardiovascular disease and cancer are associated with longevity in Koreans.

Long-lived people may have a unique genetic makeup that makes them more resistant than the general population to prevalent age-related diseases; however, not much is known about genes involved in the longevity. To identify susceptibility variants controlling longevity, we performed a high-throughput candidate gene study using 137 Koreans over 90 yr old and 213 young healthy Koreans. We evaluated 463 informative markers located in 176 candidate genes mostly for diabetes mellitus, cardiovascular disease and cancer under five genetic models. We estimated the odds ratios for each allele, genotype, haplotype, and gene-gene interaction using logistic regression analysis. Associations between 13 genes and longevity were detected at a P-value less than 0.01. Particularly, the rs671 (A) allele of the aldehyde dehydrogenase 2 family (mitochondrial) (ALDH2) gene was associated with longevity only in men (OR 2.11, P =0.008). Four genes, proprotein convertase subtilisin/kexin type 1 (PCSK1, P=0.008), epidermal growth factor receptor (EGFR, P=0.003), paired box 4 (PAX4, P=0.008), and V-yes-1 Yamaguchi sarcoma viral related oncogene homolog (LYN, P=0.002) consistently yielded statistical evidence for association with longevity. The findings of the current study may provide a starting point for future studies to unravel genetic factors controlling longevity in Koreans.

Association of interindividual differences in p14ARF promoter methylation with single nucleotide polymorphism in primary colorectal cancer.

BACKGROUND: CpG island hypermethylation has been reported at the promoter region of many tumor suppressor genes in colorectal cancers. However, there are significant interindividual differences in the degree of DNA methylation in colorectal cancers. The objective of the current study was to understand whether single nucleotide polymorphisms (SNPs) around the promoter of a gene are implicated in the interindividual differences of CpG island hypermethylation. METHODS: Promoter methylation of the p14(ARF) gene and messenger RNA (mRNA) expression levels of p14(ARF), DNA methyltransferase 1 (DNMT1), and DNMT3b were investigated by using methylation-specific polymerase chain reaction (PCR) analysis (MSP) and quantitative real-time PCR analysis in fresh tissues from 188 patients with colorectal cancer. SNPs around the p14(ARF) promoter were genotyped in DNA from peripheral blood lymphocytes in 300 healthy individuals and in 188 patients with colorectal cancer by using matrix-assisted laser desorption/ionization mass spectrometry. RESULTS: p14(ARF) methylation was present in 61 of 188 colorectal cancers (32%). Fourteen SNPs among the 20 candidate SNPs were identified as monomorphic in the Korean population studied. Two individual SNPs (-4256 thymine to cytosine [T-->C] and -1477 guanine to adenine [G-->A]), which were in strong linkage disequilibrium (|D'|=0.99; correlation coefficient [r(2)]=0.95), were associated significantly with p14(ARF) methylation. Patients who had the CC variant at the-4256 locus or the AA variant at the -1477 locus had 2.42 times (95% confidence interval [95% CI], 1.07-5.46; P = .03) and 2.47 times (95% CI, 1.09-5.56; P= .03) greater risk of p14(ARF) methylation than patients who had the TT or GG homozygote, respectively, after adjusting for mRNA levels of DNMTs. Four major haplotypes were identified within a block (-4256 T-->C, -3631 T-->C, -1477 G-->A, and +20,188 T-->C). p14(ARF) promoter methylation also was associated significantly with the CCAT haplotype (odds ratio [OR], 8.31; 95% CI, 2.43-28.41; P= .0007) and the CTAC haplotype (OR, 9.71; 95% CI, 1.09-86.24; P= .04). CONCLUSIONS: The current results suggested that SNPs around the p14(ARF) promoter region may be responsible for the interindividual susceptibility to p14(ARF) promoter methylation among individuals with colorectal cancer.

A case of Cushing's syndrome presenting as endometrial hyperplasia.

We describe here the case of a 39-year-old woman with a cortisol-producing adrenal adenoma and she presented with endometrial hyperplasia and hypertension without the specific characteristics of Cushing's syndrome. The patient had consulted a gynecologist for menometrorrhagia 2 years prior to her referral and she was diagnosed with endometrial hyperplasia and hypertension. Her blood pressure and the endometrial lesion were refractory despite taking multiple antihypertensives and repetitive dilation and curettage and progestin treatment. On admission, the clinical examination revealed mild central obesity (a body mass index of 22.9 kg/m2, a waist circumference of 85 cm and a hip circumference of 94cm), but there was no hirsutism and myopathy. She showed impaired glucose tolerance on an oral glucose tolerance test. The biochemical hypercortisolemia together with the prolactin and androgen levels were evaluated to explore the cause of her anovulation. Adrenal Cushing's syndrome was confirmed on the basis of the elevated urinary free cortisol (454 microg/24h, normal range: 20-70) with a suppressed ACTH level (2.0 pg/mL, normal range: 6.0-76.0) and the loss of circadian cortisol secretion. A CT scan revealed a 3.1 cm, hyperechoic, well-marginated mass in the left adrenal gland. Ten months post-adrenalectomy, the patient had unintentionally lost 9 kg of body weight, had regained a regular menstrual cycle and had normal thickness of her endometrium.

Association of the SUV39H1 histone methyltransferase with the DNA methyltransferase 1 at mRNA expression level in primary colorectal cancer.

This study was aimed at investigating the involvement of the SUV39H1 histone methyltransferase on the epigenetic change of euchromatic promoter in colorectal cancer. We retrospectively analyzed the mRNA levels of SUV39H1 and the promoter methylation of the p14(ARF), p16(INK4a) and HLTF genes as well as the mRNA levels of DNA methyltransferase 1 (DNMT1) in fresh frozen tissues from 219 colorectal cancer patients. The mRNA levels of the SUV39H1 and DNMT1 were assessed via quantitative real-time PCR and the methylation profiles of the CpG islands were determined using methylation-specific PCR. The mRNA levels of SUV39H1 and DNMT1 were elevated in 25% and 42% of 219 colorectal cancers, respectively. The hypermethylation of the p14(ARF), p16(INK4a) and HLTF genes occurred in 36%, 51% and 34% of the patients. The elevated mRNA levels of SUV39H1 were not associated with the hypermethylation of the 3 genes. However, the mRNA levels of DNMT1 were significantly different between patients with elevated mRNA levels of SUV39H1 and those without (1.62 +/- 0.84, 0.91 +/- 0.81, respectively; p = 0.007). Patients with elevated mRNA levels of SUV39H1 showed a higher prevalence of DNMT1 elevation than those without (61 vs. 35%, p = 0.0008). Patients with an elevated mRNA level of SUV39H1 had a 2.71 (95% CI = 1.09-4.48, p = 0.002) times greater risk of an elevated mRNA level of DNMT1, after controlling for age and gender. In conclusion, the present study suggests that SUV39H1 is significantly associated with DNMT1, but not with euchromatic promoter methylation in colorectal cancer.