A randomized phase III trial comparing adjuvant single-agent S1, S-1 with oxaliplatin, and postoperative chemoradiation with S-1 and oxaliplatin in patients with node-positive gastric cancer after D2 resection: the ARTIST 2 trial☆.

BACKGROUND: Adjuvant chemotherapy and chemoradiotherapy are some of the standards of care for gastric cancer (GC). The Adjuvant chemoRadioTherapy In Stomach Tumors (ARTIST) 2 trial compares two adjuvant chemotherapy regimens and chemoradiotherapy in patients with D2-resected, stage II or III, node-positive GC. PATIENTS AND METHODS: The ARTIST 2 compared, in a 1:1:1 ratio, three adjuvant regimens: oral S-1 (40-60 mg twice daily 4 weeks on/2 weeks off) for 1 year, S-1 (2 weeks on/1 week off) plus oxaliplatin 130 mg/m2 every 3 weeks (SOX) for 6 months, and SOX plus chemoradiotherapy 45 Gy (SOXRT). Randomization was stratified according to surgery type (total or subtotal gastrectomy), pathologic stage (II or III), and Lauren histologic classification (diffuse or intestinal/mixed). The primary endpoint was disease-free survival (DFS) at 3 years; a reduction of 33% in the hazard ratio (HR) for DFS with SOX or SOXRT, when compared with S-1, was considered clinically meaningful. The trial is registered at clinicaltrials.gov (NCT0176146). RESULTS: A total of 546 patients were recruited between February 2013 and January 2018 with 182, 181, and 183 patients in the S-1, SOX, and SOXRT arms, respectively. Median follow-up period was 47 months, with 178 DFS events observed. Estimated 3-year DFS rates were 64.8%, 74.3%, and 72.8% in the S-1, SOX, and SOXRT arms, respectively. HR for DFS in the control arm (S-1) was shorter than that in the SOX and SOXRT arms: S-1 versus SOX, 0.692 (P = 0.042) and S-1 versus SOXRT, 0.724 (P = 0.074). No difference in DFS was found between SOX and SOXRT (HR 0.971; P = 0.879). Adverse events were as anticipated in each arm, and were generally well-tolerated and manageable. CONCLUSIONS: In patients with curatively D2-resected, stage II/III, node-positive GC, adjuvant SOX or SOXRT was effective in prolonging DFS, when compared with S-1 monotherapy. The addition of radiotherapy to SOX did not significantly reduce the rate of recurrence after D2 gastrectomy.

Both cardiovascular and cerebrovascular events are decreased following long-term narrowband ultraviolet B phototherapy in patients with vitiligo: a propensity score matching analysis.

BACKGROUND: Systemic effects of long-term narrowband ultraviolet B (NB-UVB) phototherapy have not been well studied in vitiligo patients. An 11-year nationwide population-based retrospective cohort study was conducted using the Korean National Health Insurance claims database (2007-2017). OBJECTIVES: To investigate the effects of long-term NB-UVB phototherapy on the risk of cardiovascular and cerebrovascular events in vitiligo patients. METHODS: This study included vitiligo patients with ≥100 phototherapy sessions (phototherapy group, n = 3229) and <3 phototherapy sessions (no phototherapy group, n = 9687), in which covariables with age, sex, insurance type and comorbidities such as diabetes, hypertension and hyperlipidemia were matched by 1 : 3 propensity score matching. The outcomes of interest were cardiovascular (ischaemic heart disease and myocardial infarction) and cerebrovascular events (cerebrovascular infraction and haemorrhage). Cox proportional hazards models were used to assess the associations between NB-UVB phototherapy and each event. RESULTS: The risk of cardiovascular or cerebrovascular events was significantly decreased in the phototherapy group compared with the no phototherapy group [hazard ratio (HR) 0.637, 95% confidence interval (CI) 0.523-0.776]. Subgroup analysis revealed that the risk of cardiovascular (HR: 0.682, 95% CI: 0.495-0.940) and cerebrovascular events (HR: 0.601, 95% CI: 0.470-0.769) were significantly lower in the phototherapy group than the no phototherapy group, respectively. CONCLUSIONS: Our findings suggest that long-term NB-UVB phototherapy could decrease the risk of cardiovascular and cerebrovascular events in patients with vitiligo.

Non-melanoma skin cancer as a clinical marker for internal malignancies: a nationwide population-based cohort study.

INTRODUCTION: Non-melanoma skin cancers (NMSCs) are the most common cancers in the world, but the risk of internal malignancy in patients with NMSC has not been well investigated. OBJECTIVES: We aimed to assess the risk of internal malignancy in patients with NMSC compared with controls without NMSC in Korean population. METHODS: This nationwide cohort study, compared 27 259 NMSC patients with 54 518 matched controls without NMSC, 40 years or older using the data from Korea Health Insurance Review and Assessment Service from 2007 to 2016. The first 2 years were washout period, and we followed the patients for 8 years to observe the development of any internal malignancies after a diagnosis of NMSC. The Cox proportional hazard model was used to determine the hazard ratios (HRs) for developing internal malignancies. RESULTS: The overall risk of internal malignancies at all sites was 2727.7 and 1392.4 per 100 000 person-years for the patients with NMSC and controls, respectively. The risk was significantly higher in the patients with NMSC (HR 1.866, 95% confidence interval [CI] 1.768-1.970). Bone cancer showed the highest risk (HR 12.745, 95% CI 6.288-25.834), followed by nasal cavity and larynx (HR 10.279, 95% CI 6.178-7.103), oral cavity and pharynx (HR 10.211, 95% CI 7.375-14.137), anus and anal canal (HR 8.147, 95% CI 3.893-17.051) and cervical (HR 5.900, 95% CI 3.694-9.423) cancers with risks greater than fivefold higher in NMSC patients compared with the controls. The risks of cancers of the thorax, oesophagus, breast, lung, stomach, thyroid gland and non-Hodgkin's lymphoma were also statistically higher in the patients with NMSC. In contrast, the risks of cancers of the colon and rectum were found to be significantly decreased in the patients with NMSC (HR 0.765, 95% CI 0.657-0.890). CONCLUSION: Patients with NMSC require careful screening and follow-up for internal malignancy.

Incidence of psoriasiform diseases secondary to tumour necrosis factor antagonists in patients with inflammatory bowel disease: a nationwide population-based cohort study.

BACKGROUND: There are increasing reports of paradoxical psoriasiform diseases secondary to anti-tumour necrosis factor (TNF) agents. AIMS: To determine the risks of paradoxical psoriasiform diseases secondary to anti-TNF agents in patients with inflammatory bowel disease (IBD). METHODS: A nationwide population study was performed using the Korea National Health Insurance Claim Data. A total of 50 502 patients with IBD were identified between 2007 and 2016. We compared 5428 patients who were treated with any anti-TNF agent for more than 6 months (anti-TNF group) and 10 856 matched controls who had never taken anti-TNF agents (control group). RESULTS: Incidence of psoriasis was significantly higher in the anti-TNF group (36.8 per 10 000 person-years) compared to the control group (14.5 per 10 000 person-years) (hazard ratio [HR] 2.357, 95% confidence interval [CI] 1.668-3.331). Palmoplantar pustulosis (HR 9.355, 95% CI 2.754-31.780) and psoriatic arthritis (HR 2.926, 95% CI 1.640-5.218) also showed higher risks in the anti-TNF group. In subgroup analyses, HRs for psoriasis by IBD subtype were 2.549 (95% CI 1.658-3.920) in Crohn's disease and 2.105 (95% CI 1.155-3.836) in ulcerative colitis. Interestingly, men and younger (10-39 years) patients have significantly higher risks of palmoplantar pustulosis (HR 19.682 [95% CI 3.867-100.169] and HR 14.318 [95% CI 2.915-70.315], respectively), whereas women and older (≥40 years) patients showed similar rates between the two groups. CONCLUSIONS: The risks of psoriasiform diseases are increased by anti-TNF agents in patients with IBD. Among psoriasiform diseases, the risk of palmoplantar pustulosis shows the biggest increase particularly in male and younger patients.

Prevalence and comorbidities associated with hidradenitis suppurativa in Korea: a nationwide population-based study.

BACKGROUND: The prevalence of hidradenitis suppurativa (HS) in Asia is unknown. The associations between HS and other autoimmune disorders have rarely been reported. OBJECTIVE: We sought to determine the prevalence of and diseases associated with HS using the National Health Insurance (NHI) database. METHODS: We examined Korean NHI claim database data from 2007 to 2016. We enrolled all patients with HS and age- and sex-matched control subjects without HS. We estimated the period prevalence of HS and associated comorbidities in Korea. RESULTS: We identified 28 516 patients with HS (61.3% males and 38.7% females). The period prevalence rate was 0.06%, 55.8 patients (95% confidence interval 55.1-56.4) per 100 000 persons, and the female-to-male ratio was 1 : 1.6. HS patients were at significantly increased risk of rheumatoid arthritis, ankylosing spondylitis, type 1 diabetes, ulcerative colitis, type 2 diabetes, hypertension, hyperlipidaemia, acne conglobata, pilonidal cysts, psoriasis, pyoderma gangrenosum, alopecia areata and vitiligo. CONCLUSION: The overall prevalence of HS in Korea was lower than that in Western populations, and male patients predominated.

Impact of genomic alterations on lapatinib treatment outcome and cell-free genomic landscape during HER2 therapy in HER2+ gastric cancer patients.

Background: To identify predictive markers for responders in lapatinib-treated patients and to demonstrate molecular changes during lapatinib treatment via cell-free genomics. Patients and methods: We prospectively evaluated the efficacy of combining lapatinib with capecitabine and oxaliplatin as first line neoadjuvant therapy in patients with previously untreated, HER2-overexpressing advanced gastric cancer. A parallel biomarker study was conducted by simultaneously performing immunohistochemistry and next-generation sequencing (NGS) with tumor and blood samples. Results: Complete response was confirmed in 7/32 patients (21.8%), 2 of whom received radical surgery with pathologic-confirmed complete response. Fifteen partial responses (46.8%) were observed, resulting in a 68.6% overall response rate. NGS of the 16 tumor specimens demonstrated that the most common co-occurring copy number alteration was CCNE1 amplification, which was present in 40% of HER2+ tumors. The relationship between CCNE1 amplification and lack of response to HER2-targeted therapy trended toward statistical significance (66.7% of non-responders versus 22.2% of responders harbored CCNE1 amplification; P = 0.08). Patients with high level ERBB2 amplification by NGS were more likely to respond to therapy, compared with patients with low level ERBB2 amplification (P = 0.02). Analysis of cfDNA showed that detectable ERBB2 copy number amplification in plasma was predictive to the response (100%, response rate) and changes in plasma-detected genomic alterations were associated with lapatinib sensitivity and/or resistance. The follow-up cfDNA genomics at disease progression demonstrated that there are emergences of other genomic aberrations such as MYC, EGFR, FGFR2 and MET amplifications. Conclusions: The present study showed that HER2+ GC patients respond differently according to concomitant genomic aberrations beyond ERBB2, high ERBB2 amplification by NGS or cfDNA can be a positive predictor for patient selection, and tumor genomic alterations change significantly during targeted agent therapy.

Periorbital melasma: Hierarchical cluster analysis of clinical features in Asian patients.

BACKGROUND: Studies have shown melasma lesions to be distributed across the face in centrofacial, malar, and mandibular patterns. Meanwhile, however, melasma lesions of the periorbital area have yet to be thoroughly described. METHODS: We analyzed normal and ultraviolet light-exposed photographs of patients with melasma. The periorbital melasma lesions were measured according to anatomical reference points and a hierarchical cluster analysis was performed. RESULTS: The periorbital melasma lesions showed clinical features of fine and homogenous melasma pigmentation, involving both the upper and lower eyelids that extended to other anatomical sites with a darker and coarser appearance. The hierarchical cluster analysis indicated that patients with periorbital melasma can be categorized into two clusters according to the surface anatomy of the face. Significant differences between cluster 1 and cluster 2 were found in lateral distance and inferolateral distance, but not in medial distance and superior distance. Comparing the two clusters, patients in cluster 2 were found to be significantly older and more commonly accompanied by melasma lesions of the temple and medial cheek. CONCLUSION: Our hierarchical cluster analysis of periorbital melasma lesions demonstrated that Asian patients with periorbital melasma can be categorized into two clusters according to the surface anatomy of the face.

Clinical significance of skip lymph node metastasis in gastric cancer patients.

PURPOSE: Given the recent increase in the incidence of early gastric cancer, there is greater interest in identifying a minimally invasive therapy. The purpose of this study was to analyze the patterns of lymph node metastasis in patients with gastric cancer and to elucidate the clinical significance of skip metastasis. METHODS: We retrospectively analyzed patterns of lymph node metastasis (LNM) and clinicopathologic factors related to skip metastasis. RESULTS: Among 2963 patients with gastric cancer, 997 patients (33.6%) were detected as having LNM, and 27 patients (2.7%) with skip metastasis were detected among 997 patients with LNM. Skip metastasis were detected more frequently in the elderly. Compared with the N1 group, the skip metastasis group showed lower frequency of vascular invasion, and compared with the stepwise N2 group, the skip metastasis group showed smaller tumor size and a significantly higher incidence of negative lymphatic, vascular, and perineural invasion. CONCLUSIONS: Currently there is no way to predict N2 station LNM including skip metastasis, D2 LN dissection for gastric cancer is thought to be the appropriate treatment, even during early stage disease. Minimally invasive therapy should be performed cautiously in consideration of possible skip metastasis.

Role of bursectomy for advanced gastric cancer: result of a case-control study from a large volume hospital.

AIMS: According to the recent Japanese Gastric Cancer Association's gastric cancer treatment guidelines, bursectomy is recommended for tumors penetrating the serosa of the posterior gastric wall. However, there is still little data to show whether bursectomy improves patient survival. The aim of this study is to evaluate the efficacy of bursectomy for subserosa or serosa-positive gastric cancer in terms of overall survival. METHOD: From April 2001 to December 2006, 470 patients underwent curative resection for macroscopically subserosa or serosa-positive gastric cancer. These patients were grouped according to whether bursectomy was performed or not (bursectomy+/bursectomy-). Clinicopathological characteristics and incidence of complications were compared between the groups. The overall survival rates were analyzed using a Cox proportional hazards model. RESULTS: There was no significant difference in morbidity and mortality between the bursectomy+ and bursectomy- groups. In the multivariable analysis for overall survival, bursectomy was not a significant independent factor (p = 0.978). In the subgroup analysis for clinical and pathological stage III and IV, and tumors penetrating the serosa of the posterior gastric wall, bursectomy did not have significant effect on overall survival as well (p = 0.582, 0.453, and 0.532, respectively). In the propensity score-matched patients, bursectomy still showed no significant effect on overall survival (p = 0.804). CONCLUSIONS: Bursectomy is unlikely to improve overall survival in patients with macroscopically subserosa or serosa-positive gastric cancer.

Prognostic implication of the CpG island methylator phenotype in colorectal cancers depends on tumour location.

BACKGROUND: Colorectal cancer (CRC) is usually categorised as proximal or distal CRC. Recently, many researchers have tried to determine the molecular heterogeneity of CRCs along bowel subsites. However, the differential effects of the CpG island methylator phenotype (CIMP) and microsatellite instability (MSI) on the clinical outcome according to tumour location are not well-known. METHODS: We analysed clinicopathologic and molecular characteristics, including CIMP, MSI, KRAS and BRAF mutations, in 734 CRCs according to bowel subsites. And the prognostic value of CIMP and MSI was analysed according to tumour location. RESULTS: We found a linear increase of female predominance, T, N category, stage, differentiation, absence of luminal necrosis, tumour -infiltrating lymphocytes, Crohn's-like lymphoid reaction, serration and mucin production from the rectum to caecum. CpG island methylator phenotype -high and MSI-high gradually increased from the rectum to caecum. CpG island methylator phenotype is a poor prognostic factor of overall survival (hazard ratio (HR): 4.13, 95% confidence interval (CI): 1.27-13.46) and disease-free survival (HR: 2.90, 95% CI: 1.04-8.08) in rectal cancers. CONCLUSION: Clinicopathologic and molecular profiles of CRCs gradually change along bowel subsites, and the prognostic implication of CIMP is different according to tumour location.

Prognostic implication of mucinous histology in colorectal cancer patients treated with adjuvant FOLFOX chemotherapy.

BACKGROUND: There have been controversies in prognostic impact of mucinous histology on colorectal cancer, and its implication in patients treated with adjuvant 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) is unclear. METHODS: Stage II and III colorectal cancer patients who underwent curative resection followed by adjuvant FOLFOX were included. Patients were grouped according to the mucinous content: >50%, mucinous adenocarcinoma (MAC); <50%, adenocarcinoma with intermediated mucinous component (AIM); and without any mucinous component, non-MAC (NMA). Clinicopathological features and disease-free survival (DFS) were compared. RESULTS: Among a total of 521 patients, 27 patients (5.2%) had MAC, 41 patients (7.9%) had AIM, and 453 patients (86.9%) had NMA. Mucinous adenocarcinoma and AIM had higher frequency of proximal location and microsatellite instability, but lower frequency of angiolymphatic invasion. Disease-free survival was significantly worse in the MAC compared with NMA (3-year DFS 57% and 86%, respectively; P<0.001) and AIM (3-year DFS 87%, P=0.01 vs MAC). Multivariate analysis revealed MAC as an independent negative prognostic factor of DFS (adjusted hazard ratio 7.96, 95% confidence interval 3.76-16.8). CONCLUSION: Adenocarcinoma with intermediated mucinous component and MAC have distinct clinicopathological features compared with NMA. Mucinous adenocarcinoma has an adverse prognostic impact on stage II or III colorectal cancer treated with adjuvant FOLFOX.

Predictive factors for lymph node metastasis in patients with poorly differentiated early gastric cancer.

BACKGROUND: Endoscopic submucosal dissection is gaining popularity in the treatment of early gastric cancer. This study aimed to identify clinicopathological factors predictive of lymph node metastasis in patients with the poorly differentiated early gastric cancer to assess the feasibility of using endoscopic submucosal dissection for these cancers. METHODS: The records of patients with poorly differentiated early gastric cancer who had undergone gastric cancer surgery between January 2002 and December 2009 were reviewed. Associations between clinicopathological factors and the presence of lymph node metastasis were analysed by univariable and multivariable logistic regression analysis. RESULTS: Some 1005 patients were included in the analysis. Univariable analysis indicated that lymph node metastasis was associated with sex, ulceration, tumour size, depth of invasion, macroscopic type, lymphatic invasion and venous invasion. Logistic regression revealed that lymph node metastasis was significantly associated with sex, tumour size, depth of tumour invasion and lymphatic involvement. In the group with none of these risk factors (men with mucosal tumour no larger than 2 cm in size, with no lymphatic involvement), lymph node metastasis was present in four (3·2 per cent) of 124 patients. CONCLUSION: In the present study 3·2 per cent of patients who were negative for all identified risk factors had lymph node metastasis. The use of endoscopic submucosal dissection should be considered carefully in the treatment of poorly differentiated early gastric cancer.

Surgical outcome after incomplete endoscopic submucosal dissection of gastric cancer.

BACKGROUND: Endoscopic resection of early gastric cancer is a relatively new and attractive treatment, but occasionally fails to remove all cancer lesions completely. This study aimed to elucidate clinicopathological factors that could be helpful in predicting residual tumour in the surgical specimen after incomplete endoscopic submucosal dissection (ESD). METHODS: Patients who underwent gastrectomy because of incomplete ESD between August 2004 and August 2008 were analysed. Clinicopathological characteristics were reviewed retrospectively from prospectively collected medical records. Patients were classified into groups with and without residual tumour. Pathology results following gastrectomy were compared with those of incomplete ESD. RESULTS: A total of 118 patients were included. The incidence of residual tumour in the surgical specimen was 24·6 per cent after incomplete ESD. Elevated/flat-type cancers, large tumours (at least 2 cm) and those limited to the mucosa had significantly higher incomplete ESD rates. Cancer limited to the mucosa and the presence of tumour in the lateral margin were associated with residual tumour in the surgical specimen (both P = 0·001). CONCLUSION: Radical gastrectomy should be performed if pathological examination reveals a positive lateral resection margin after ESD.

Comparison of image quality and radiation dose between fixed tube current and combined automatic tube current modulation in craniocervical CT angiography.

BACKGROUND AND PURPOSE: The combined automatic tube current modulation (ATCM) technique adapts and modulates the x-ray tube current in the x-y-z axis according to the patient's individual anatomy. We compared image quality and radiation dose of the combined ATCM technique with those of a fixed tube current (FTC) technique in craniocervical CT angiography performed with a 64-section multidetector row CT (MDCT) system. MATERIALS AND METHODS: A retrospective review of craniocervical CT angiograms (CTAs) by using combined ATCM (n = 25) and FTC techniques (n = 25) was performed. Other CTA parameters, such as kilovolt (peak), matrix size, FOV, section thickness, pitch, contrast agent, and contrast injection techniques, were held constant. We recorded objective image noise in the muscles at 2 anatomic levels: radiation exposure doses (CT dose index volume and dose-length product); and subjective image quality parameters, such as vascular delineation of various arterial vessels, visibility of small arterial detail, image artifacts, and certainty of diagnosis. The Mann-Whitney U test was used for statistical analysis. RESULTS: No significant difference was detected in subjective image quality parameters between the FTC and combined ATCM techniques. Most subjects in both study groups (49/50, 98%) had acceptable subjective artifacts. The objective image noise values at shoulder level did not show a significant difference, but the noise value at the upper neck was higher with the combined ATCM (P < .05) technique. Significant reduction in radiation dose (18% reduction) was noted with the combined ATCM technique (P < .05). CONCLUSIONS: The combined ATCM technique for craniocervical CTA performed at 64-section MDCT substantially reduced radiation exposure dose but maintained diagnostic image quality.

Preoperative grading of presumptive low-grade astrocytomas on MR imaging: diagnostic value of minimum apparent diffusion coefficient.

BACKGROUND AND PURPOSE: Histopathologic grade of glial tumors is inversely correlated with the minimum apparent diffusion coefficient (ADC). We assessed the diagnostic values of minimum ADC for preoperative grading of supratentorial astrocytomas that were diagnosed as low-grade astrocytomas on conventional MR imaging. MATERIALS AND METHODS: Among 118 patients with astrocytomas (WHO grades II-IV), 16 who showed typical MR imaging findings of low-grade supratentorial astrocytomas on conventional MR imaging were included. All 16 patients underwent preoperative MR imaging and diffusion-weighted imaging. The minimum ADC value of each tumor was determined from several regions of interest in the tumor on ADC maps. To assess the relationship between the minimum ADC and tumor grade, we performed the Mann-Whitney U test. A receiver operating characteristic (ROC) analysis was used to determine the cutoff value of the minimum ADC that had the best combination of sensitivity and specificity for distinguishing low- and high-grade astrocytomas. RESULTS: Eight of the 16 patients (50%) were confirmed as having high-grade astrocytomas (WHO grades III and IV), and the other 8 patients were confirmed as having low-grade astrocytomas (WHO grade II). The median minimum ADC of the high-grade astrocytoma (1.035 x 10(-3) mm(2) . sec(-1)) group was significantly lower than that of the low-grade astrocytoma group (1.19 x 10(-3) mm(2) . sec(-1)) (P = .021). According to the ROC analysis, the cutoff value of 1.055 x 10(-3) mm(2) . sec(-1) for the minimum ADC generated the best combination of sensitivity (87.5%) and specificity (79%) (P = .021). CONCLUSION: Measuring minimum ADC can provide valuable diagnostic information for the preoperative grading of presumptive low-grade supratentorial astrocytomas.