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Purpose The aim of this study is to evaluate the safety and efficacy of ex vivo activated and expanded natural killer (NK) cell therapy (SNK01) plus pembrolizumab in a randomized phase I/IIa clinical trial.Materials and Methods Overall, 18 patients with advanced non–small cell lung cancer (NSCLC) and a programmed death ligand 1 tumor proportion score of 1% or greater who had a history of failed frontline platinum-based therapy were randomized (2:1) to receive pembrolizumab every 3 weeks +/– 6 weekly infusions of SNK01 at either 2×109 or 4×109 cells per infusion (pembrolizumab monotherapy vs. SNK01 combination). The primary endpoint was safety, whereas the secondary endpoints were the objective response rate (ORR), progression-free survival (PFS), overall survival, and quality of life.Results Since no dose-limiting toxicity was observed, the maximum tolerated dose was determined as SNK01 4×109 cells/dose. The safety data did not show any new safety signals when SNK01 was combined with pembrolizumab. The ORR and the 1-year survival rate in the NK combination group were higher than those in patients who underwent pembrolizumab monotherapy (ORR, 41.7% vs. 0%; 1-year survival rate, 66.7% vs. 50.0%). Furthermore, the median PFS was higher in the SNK01 combination group (6.2 months vs. 1.6 months, p=0.001).Conclusion Based on the findings of this study, the NK cell combination therapy may consider as a safe treatment method for stage IV NSCLC patients who had a history of failed platinum-based therapy without an increase in adverse events.

Anaplastic lymphoma kinase positive large B-cell lymphoma (ALK+LBCL) is a rare subtype of B-cell lymphoma with aggressive features and a poor prognosis. The rarity of this disease and similarity of microscopic features with undifferentiated epithelial neoplasm disturb the provision of proper treatment. A 57-year-old male presented with a rapidly growing and painless mass on the left side of the neck. Metastatic carcinoma of an unknown primary (CUP) lesion was initially suspected based on the pathologic results obtained from a core needle biopsy, but it was finally diagnosed as ALK+LBCL after a modified radical neck dissection. We herein report a case of ALK+LBCL mimicking CUP with a literature review.

Background: To identify work–family balance and level of happiness among married women dental hygienists in Seoul and Gyeonggi Province. The goal of this study is to use the outcome as basic data to determine the compatibility of dental hygienists with work and family, systems, and improvement of happiness levels.Methods: From July 3 to August 10, 2020, 250 dental hygienists in Seoul and Gyeonggi Province were targeted. The questionnaire comprised 65 questions, including general characteristics (perception of work–family balance, perception of work–family balance system, job satisfaction, parenting type, happiness level) whether or not they were implemented. The results were obtained through a self-control questionnaire.Results: The perception of work–family balance was significantly different in job rank and average income, while that of the work–family balance system had significant differences in workplace type, total work experience, current job work experience, childcare system status, and parental leave period. Happiness level and job satisfaction were significantly different in job rank, average income, and childcare system status. Additionally, the perception of work–family balance and that of the work–family balance system showed a positive correlation with job satisfaction and happiness level. Finally, the perception of married women dental hygienists toward work–family compatibility was determined, where the higher the satisfaction with the job, the higher the level of happiness.Conclusion: To improve the work–family balance and job satisfaction of dental hygienists and their levels of happiness, changes in social perception and improvement of the working environment such as proper staffing, flexible work systems, and incentive systems should be considered.

As a disease with high mortality and prevalence rates worldwide, colorectal cancer (CRC) has been thoroughly investigated. Mucins are involved in the induction of CRC and regulation of intestinal homeostasis. However, the role of MUC4, which is a member of the mucin gene family, is controversial because it shows an association with either decreased susceptibility to or a worse prognosis of CRC. In our study, the multifunctional aspects of MUC4 were elucidated by genetic polymorphism analysis in a case-control study of 420 controls and 464 CRC patients. The MUC4 rs1104760 A>G polymorphism had a protective effect on CRC risk (AG, AOR = 0.537; GG, AOR = 0.297; dominant model, AOR = 0.493; recessive model, AOR = 0.382). In addition, the MUC4 rs2688513 was associated with an increased mortality rate of CRC (5 years, GG, adjusted HR = 6.496; recessive model, adjusted HR = 5.848). Furthermore, a significant synergistic effect was observed between MUC4 rs1104760 A>G and low-density lipoprotein cholesterol (LDL-C) indicating a high potential as a biomarker for CRC susceptibility. This is the first study to indicate a significant association between MUC4 genetic polymorphisms and CRC prevalence, suggesting a functional genetic variant with the LDL-C level, for CRC prevention.

Purpose This study aimed to evaluate the survivals of patients with metastatic or recurrent gastric cancer (MRGC) over a period of 16 years and to investigate the recent changes in chemotherapy patterns. Materials and Methods A total of 5,384 patients who received chemotherapy for MRGC between 2000 and 2015 were analyzed. The analysis focused on a comparison of the first-line chemotherapy between four periods: 2000–2003 (period 1), 2004–2007 (period 2), 2008–2011 (period 3), and 2012–2015 (period 4). Results There were 880 patients (16%) in period 1, 1,573 (29%) in period 2, 1,435 (27%) in period 3, and 1,496 (28%) in period 4. Cytotoxic doublet-based therapy was the most commonly used (78%) first-line chemotherapy, and the combination of trastuzumab and doublet chemotherapy was provided to 288 patients. The overall survival (OS) rates at 12 and 24 months were steadily improved as follows: 39.2% and 14.6% in period 1, 43.5% and 17.6% in period 2, 50.3% and 20.6% in period 3, and 51.7% and 24.1% in period 4, respectively (p < 0.001). Among the patients who received the doublet-based chemotherapy, the median OS of those who received trastuzumab was 18.0 months (95% confidence interval [CI], 15.5 to 20.6), while that of those who received other doublet therapies was 11.2 months (95% CI, 10.8 to 11.6). Conclusion The OS was improved over time with advancements in chemotherapy, particularly the introduction of the anti-HER2–targeted agent, which contributed to the increase in the number of long-term survivors and established the superiority of OS for the treatment of MRGC.

BACKGROUND & AIMS The optimal systemic chemotherapy for combined hepatocellular-cholangiocarcinoma (cHCC-CCA) has not yet been defined. The definition and classification of cHCC-CCA has changed recently in the 5th edition of WHO classification. We reviewed the pathological findings with the new classification and analysed the efficacy of systemic chemotherapy in patients with unresectable/metastatic cHCC-CCA. METHODS Among 254 patients with histologically confirmed cHCC-CCA from 1999 to 2015 in Asan Medical Center, Seoul, Korea, 99 patients who received systemic chemotherapy for unresectable/metastatic disease were included. Overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) were retrospectively evaluated. RESULTS Sorafenib (n = 62) and cytotoxic chemotherapy (n = 37) were administered as first-line chemotherapies; the ORR was 14.1%, and the median PFS and OS were 3.8 and 10.6 months, respectively, with a median follow-up duration of 39.6 months. The efficacy outcomes were not significantly different between patients who received sorafenib and those who received cytotoxic chemotherapy (ORR, 9.7% vs 21.6%, P = .14; median PFS, 4.2 vs 2.9 months, P = .52; median OS, 10.7 vs 10.6 months, P = .34). In multivariate analysis, large intrahepatic tumour burden (≥30% of liver volume), elevated serum bilirubin and non-platinum containing first-line chemotherapy remained as significant prognostic factors for poorer OS. CONCLUSIONS The efficacy outcomes according to first-line treatment were not significantly different between sorafenib and cytotoxic chemotherapy, and pathological findings were not found to help for determining appropriate therapeutic agent or assessing the prognosis. To overcome the poor treatment outcomes, further studies are needed to find proper treatment targets, biomarkers and the best treatment strategies.

Background/aim Oxaliplatin-based chemotherapy is associated with hepatic sinusoidal obstruction syndrome (SOS). Patients and methods We analyzed patients from two prospective trials, in which capecitabine/oxaliplatin (XELOX, 8 cycles; n=51) and S-1/oxaliplatin [SOX, continuous (SOX-C, n=50), or intermittent (discontinuation after cycle 6 and restart on progression, SOX-I, n=50)] were administered. We compared severity (splenomegaly, thrombocytopenia, liver enzyme levels, and hepatic parenchymal heterogeneity), clinical significance (delay or dose-reduction of chemotherapy), and reversibility of SOS (splenomegaly and thrombocytopenia after stopping chemotherapy) between SOX and XELOX in gastric cancer patients. Results SOX was more likely to be associated with splenomegaly, thrombocytopenia, hyperbilirubinemia, and hepatic parenchymal heterogeneity than XELOX. Splenomegaly was partially reversible after stopping chemotherapy in both regimens, but recovery rate was lower in SOX. Proportion of delayed or dose-reduced chemotherapy cycles due to thrombocytopenia was significantly higher in SOX-C than in XELOX. Conclusion S-1 combination is more likely to worsen oxaliplatin-induced hepatic sinusoidal injuries than capecitabine in gastric cancer patients.

Because non–anthracycline-based chemotherapy with l-asparaginase has improved survival outcomes in patients with extranodal natural killer/T-cell lymphoma (ENKTL), the incidence of central nerve system (CNS) relapse can be different when compared with that in previous reports. In this research, we sought to identify the incidence of and predictors for CNS relapse and to evaluate the necessity of CNS prophylaxis with intermediate-dose methotrexate (ID-MTX). The records of 399 patients in the training cohort and 253 patients in the validation cohort with ENKTL who received non-anthracycline–based chemotherapy were reviewed. Patients were divided into 2 groups according to whether the chemotherapy regimen included ID-MTX above 2 g/m2. A new central nervous system-prognostic index of natural killer (CNS-PINK) model was developed using 1-point powerful predictors of CNS relapse (PINK; hazard ratio [HR], 2.908; P = .030 and extranodal involvement [≥2]; HR, 4.161; P = .001) and was calculated as a sum of scores. The high-risk group of CNS-PINK was defined as 2 points. The cumulative incidence of CNS relapse was different between the CNS-PINK risk groups in the training (P < .001) and validation (P = .038) cohorts. Patients in the high-risk CNS-PINK group who were treated with SMILE or SMILE-like regimens with ID-MTX (S-ID-MTX) displayed a lower incidence rate of CNS relapse than did those who received other regimens without ID-MTX in the training cohort (P = .029). The CNS-PINK was demonstrated its strong predictability of CNS relapse in ENKTL patients. The effectiveness of S-ID-MTX in preventing CNS events in high-risk CNS-PINK patients should be verified in future studies.

Background and aims Exercise training (ET) helps treat atherosclerosis. However, many patients stop regular ET for various reasons. The effect of detraining on atherosclerosis is not well studied. We examined the effects of ET vs. short-term detraining on atheromatous matrix-metalloproteinase (MMP) activity in preexisting plaque and circulating cytokines/lipids. Methods and results Eighteen-week-old apolipoprotein-E−/− mice (n = 56) on a Western diet underwent: 1) ET for 6-weeks (ET5+1), 2) ET for 5-weeks and detraining for 1-week (ET5+0), 3) ET for the last 1-week (ET0+1), or 4) no treadmill ET at all for 6-weeks (ET0+0). Atheromatous MMP-activity was visualized using molecular imaging with an MMP-2/9-activatable near-infrared-fluorescent probe. Compared with no ET (ET0+0), regular ET (ET5+1) decreased carotid atheromatous MMP activity, but this protective effect was significantly blunted by short-term detraining (ET5+0). Short-term detraining after longer-term ET showed a reduction in MMP-activity similar to short-term ET (ET0+1). Blood levels of lipids and cytokines paralleled the molecular imaging results: exercise caused higher levels of high-density lipoprotein, adiponectin, and interleukin-10 and lower levels of vascular cell adhesion molecule, monocyte chemoattractant protein-1, interleukin-1β, and low-density lipoprotein. However, this beneficial effect was short-lived, with the ET5+0 group being similar to the ET0+0 group, and the ET0+1 group being similar to the ET5+1 group. The effect of exercise can be modeled with an exponential-decay of the protective factor of about 15%/day. Conclusions Even short-term detraining reduces atheroprotective effects, and tips the balance towards atherosclerosis. This suggests that ET, to be effective, needs to be prolonged and regular, and that detraining should be avoided.

461 Background: In localized gastric cancer (GC), deficient mismatch repair (dMMR) tumors reportedly have a favorable prognosis. However, a potentially detrimental effect of the dMMR status was suggested in patients treated with adjuvant chemotherapy. It remains unclear whether the mismatch repair (MMR) status can impact clinical outcomes in patients with metastatic GC (mGC) receiving palliative chemotherapy. We examined the impact of the MMR status on survival outcomes of patients with HER2-negative mGC receiving first-line fluoropyrimidine plus platinum (FP) chemotherapy. Methods: We reviewed patients with histologically confirmed metastatic, recurrent, or locally advanced unresectable adenocarcinoma of the stomach or gastroesophageal junction receiving first-line FP chemotherapy between January 2015 and August 2018 at Asan Medical Center, Korea. MMR status was correlated with clinical characteristics and survival outcomes for patients with available MMR immunohistochemistry results. Results: Of 895 patients, we analyzed 543 with available MMR protein expression results, and dMMR was detected in 4.4% (n=24). Patients with dMMR exhibited a significantly higher median age than those with proficient MMR (pMMR) (64 vs. 58 years, p=0.044). No signet ring cell carcinoma (SRCC) was detected among dMMR tumors, whereas SRCC was found in 17.5% of pMMR tumors. Based on our prognostic model (Koo DH et al, 2011), only 4.2% of patients with dMMR were classified as the poor-risk group (vs. 16.8% of patients with pMMR, p=0.097). No significant difference in progression-free survival (PFS) was noted between patients with dMMR and pMMR tumors (median, 5.6 vs. 5.8 months, p=0.266). Patients with dMMR tumors tended to have better overall survival than those with pMMR tumors; this difference was not statistically significant (median, 17.9 vs. 12.2 months, p=0.183). In the good-risk subgroup, patients with dMMR tumors had a significantly worse PFS than those with pMMR tumors (median, 5.6 vs. 9.2 months, p=0.009); multivariate analysis revealed that MMR status was an independent factor for poor PFS in this subgroup. Conclusions: Survival outcomes of dMMR mGC did not differ from pMMR in patients who received first-line FP chemotherapy. However, in the good-risk subgroup, patients with dMMR tumors had a significantly shorter PFS than those with pMMR, suggesting a potentially reduced efficacy of cytotoxic chemotherapy in these patients.

KRAS mutation is a major regulator in the tumor progression of pancreatic cancer. Here, we compared the frequency and mutation burden of KRAS mutation subtypes with paired tumor tissue and blood in patients and examined their clinical significance. DNA from tumor tissues and cell-free DNA (cfDNA) from preoperative blood were obtained from 70 patients with pancreatic cancer. Subtypes and mutation burdens of KRAS G12D and G12V mutations were evaluated using droplet digital PCR. Comparing the presence of mutations in tissue, accumulative and simultaneous mutations of G12D or G12V were identified of 67 (95.7%), and 48 patients (68.6%). Conversely, in blood, they were only identified in 18 (25.7%) and four (5.7%) patients, respectively. Next, comparing the mutation burden in tissue, the mutation burden varied from less than 0.1 to more than five, whereas that of cfDNA in blood was mostly between one and five, as cases with a mutation burden lower than 0.1 and higher than five were rare. Finally, the presence of the G12V mutation alone in cfDNA and the combination of the G12V mutation with elevated CA 19-9 levels were associated with poor recurrence-free survival. These fundamental data on the KRAS mutation subtypes and their clinical significance could support their potential as predictive markers for postoperative recurrence.

Adult pancreatic hemangioma is an extremely rare disease, with only 22 cases reported since 1939. Pancreatic hemangioma has no specific symptoms, diagnostic imaging, or laboratory findings, making it difficult to be clinically suspected and diagnosed. The majority are confirmed after surgery. In this report, a 61-year-old woman presented with melena and showed multiple small hyper-vascular lesions in the pancreas. A pancreatic neuroendocrine tumor was suspected, and the patient underwent a distal pancreatectomy. The pathology examination and immunohistochemical study revealed a pancreatic hemangioma.

Although many radiographic measurements of the foot and ankle have been used, reference values for normal functional groups are rarely reported. These can change according to sex and age; therefore, this study aimed to: (1) determine reference values for radiographic foot and ankle angles in an asymptomatic healthy Korean population, and (2) compare differences in the measurements according to sex and age. A total of 200 healthy volunteers were recruited, including 100 young adults (50 males, 50 females) aged 20 to 35 years, and 100 older adults (50 males, 50 females) aged 60 to 69 years. Weightbearing ankle anteroposterior views, talar tilt, and tibiotalar angles were measured. On the weightbearing foot anteroposterior views, the hallux valgus, hallux interphalangeal, and talo-first metatarsal angles were measured. On the weightbearing lateral foot views, the calcaneal pitch, lateral talo-calcaneal, lateral talo-first metatarsal, and lateral calcaneo-first metatarsal angles were measured. Values were stratified by sex and age, and statistically compared. The hallux valgus, calcaneal pitch, and lateral calcaneo-first metatarsal angles were affected by both sex and age; the hallux interphalangeal angle was affected by age and the lateral talo-first metatarsal angle by sex. We presented reference values for foot and ankle radiographic measurements in a healthy Korean population; several radiographic indices varied significantly by sex or age, which were grossly similar to previous studies based on white race. The study data can serve as a basis for evaluation of foot and ankle disorders.

Colorectal cancer (CRC) is the third most common type of cancer and the second leading cause of cancer-related mortality in Western countries. Polymorphisms in one-carbon metabolism and angiogenesis-related genes have been shown to play important roles in tumor development, progression, and metastasis for many cancers, including CRC. Moreover, recent studies have reported that polymorphisms in specific microRNA (miRNA)-binding regions, which are located in the 3′-untranslated region (UTR) of miRNA-regulated genes, are present in a variety of cancers. Here, we investigated the association between two thymidylate synthase (TYMS or TS) 3′-UTR polymorphisms, 1100T&gt, C [rs699517] and 1170A&gt, G [rs2790], and CRC susceptibility and progression in Korean patients. A total of 450 CRC patients and 400 healthy controls were enrolled in this study, and genotyping at the TS locus was performed by polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) or TaqMan allelic discrimination assays. We found that TS 1170A&gt, G genotypes, as well as the TS 1100T-1170G and 1100C-1170A haplotypes, are strongly associated with CRC. The TS 1100TC+CC type was associated with a poor survival (OS and RFS) rate. In addition, levels of the TS 1100C and TS 1170G allele were found to be significantly increased in CRC tissue. Our study provides the first evidence for 3′-UTR variants in TS genes as potential biomarkers of CRC prognosis and prevention.

For locally advanced esophageal cancer, concurrent chemoradiotherapy (CRT) followed by surgery has been a standard treatment, while clinical studies showed comparable survival outcomes between definitive CRT and neoadjuvant CRT followed by surgery in patients responding to CRT. Thus, biomarkers are required to predict treatment outcomes and benefit of adding surgery after CRT. This prospective biomarker study examined the role of cell-free DNA (cfDNA) fragmentation profiles and genomic copy number variations (CNVs) in predicting treatment outcomes in esophageal squamous cell carcinoma patients treated with neoadjuvant or definitive CRT. The clinical response was evaluated after induction chemotherapy and after CRT. Fragment Ratio (FR)-score and I-score were calculated from plasma cfDNA reflecting fragment lengths and CNV of cfDNA, respectively. The association between indices of cfDNA (cfDNA concentration, FR-score, and I-score) and treatment outcomes (clinical response, time to progression [TTP], and overall survival [OS]) were evaluated. Sixty-one patients were included. Thirty patients received neoadjuvant CRT followed by surgery, whereas 31 received definitive CRT. Low baseline, post-induction chemotherapy, and post-CRT FR-scores and low post-induction I-score were significantly associated with improved treatment response (P0.05). Additionally, patients with surgery after CRT showed significantly longer survival than patients without surgery in the FR-score-high group (median TTP, 12.7 vs 3.4 months; P = 0.011; OS, not reached vs 12.9 months; P = 0.02), while there was no survival benefit with surgery in the FR-score-low group. FR-score may be a new biomarker to predict treatment response, residual tumor burden after CRT, and consequently, survival benefit of adding morbid surgery after CRT. FR-score has strength in a relatively simple and inexpensive methodology compared to deep sequencing, resulting in high availability and accessibility, despite limited sensitivity.

Oxaliplatin-based chemotherapy is associated with hepatic sinusoidal obstruction syndrome (SOS).We analyzed patients from two prospective trials, in which capecitabine/oxaliplatin (XELOX, 8 cycles; n=51) and S-1/oxaliplatin [SOX, continuous (SOX-C, n=50), or intermittent (discontinuation after cycle 6 and restart on progression, SOX-I, n=50)] were administered. We compared severity (splenomegaly, thrombocytopenia, liver enzyme levels, and hepatic parenchymal heterogeneity), clinical significance (delay or dose-reduction of chemotherapy), and reversibility of SOS (splenomegaly and thrombocytopenia after stopping chemotherapy) between SOX and XELOX in gastric cancer patients.SOX was more likely to be associated with splenomegaly, thrombocytopenia, hyperbilirubinemia, and hepatic parenchymal heterogeneity than XELOX. Splenomegaly was partially reversible after stopping chemotherapy in both regimens, but recovery rate was lower in SOX. Proportion of delayed or dose-reduced chemotherapy cycles due to thrombocytopenia was significantly higher in SOX-C than in XELOX.S-1 combination is more likely to worsen oxaliplatin-induced hepatic sinusoidal injuries than capecitabine in gastric cancer patients.

Cell-free nucleic acids (cfNAs) in liquid biopsy samples are emerging as important biomarkers for cancer diagnosis and monitoring, and for predicting treatment outcomes. Many cfNA isolation methods have been developed recently. However, most of these techniques are time-consuming, complex, require large equipment, and yield low-purity cfNAs because the genetic background of normal cells is amplified during cell lysis, which limits their clinical application. Here, we report a rapid and simple cfNA sampling platform that can overcome the limitations of conventional methods. We synthesised a biocomposite by combining amine-modified diatomaceous earth (DE) and cucurbituril (CB). The biocomposite platform showed high capture efficiency (86.78–90.26%) with genomic DNA and amplified DNA products (777, 525 and 150 bp). The biocomposite platform allowed the isolation of high purity and quantity cfDNAs from the plasma of 13 cancer patients (three colorectal cancer and ten pancreatic cancer samples) without requiring a lysis step or special equipment. The biocomposite platform may be useful to isolate cfNAs for the diagnosis and treatment of cancers in clinical applications.

This study was conducted to identify the composition and diversity of the microbiome in tissues of pancreatic cancer and to determine its role. First, extracellular vesicles (EVs) were obtained from the paired tumor and normal tissues, and 16s rRNA gene sequencing was performed. We identified the microbiomes, compared the diversity between groups, and found that Tepidimonas was more abundant in tumors. Second, larger tumors resulted in lower levels of Leuconostoc and Sutterella, and increased lymph node metastasis resulted in higher levels of Comamonas and Turicibacter in tumor tissues. Moreover, in the case of tumor recurrence, the levels of Streptococcus and Akkermansia were decreased in tumor tissues. Finally, with the supernatant of Tepidimonasfonticaldi, proliferation and migration of cells increased, and epithelial-mesenchymal transition and the Tricarboxylic Acid (TCA) cycle-related metabolites were enhanced. The composition and diversity of EV-derived microbiomes are important for providing novel insights into theragnostic approaches in pancreatic cancer.

Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is a potentially life-threatening but reversible autoimmune disorder characterized by psychiatric symptoms, cognitive dysfunction, speech dysfunction, seizures, movement disorder, decreased level of consciousness, and autonomic dysfunction or central hypoventilation. It occurs predominantly in young women and approximately half of them have underlying tumors, mainly ovarian teratoma. A 24-year old woman was admitted because of fever, headache, abnormal movement and decreased mental status. Five cycles of plasmapheresis improved her neurological and mental status. Anti-NMDAR antibodies in her CSF and serum were positive, and computed tomography revealed a 1-cm sized mass suggestive of mature cystic teratoma arising from the right ovary. We promptly performed laparoscopic right ovarian cystectomy. She was discharged after 2 weeks with mild memory deficit. Prompt removal of ovarian teratoma and multidisciplinary care are particularly important for good outcome., Graphical Abstract

Background The use of three-dimensional multi-segment foot models (3D MFMs) is increasing since they have superior ability to illustrate the effect of foot and ankle pathologies on intersegmental motion of the foot compared to single-segment foot model gait analysis. However, validation of the repeatability of the 3D MFMs is important for their clinical use. Although many MFMs have been validated in normal adults, research on MFM repeatability in children is lacking. The purpose of this study is to validate the intrasession, intersession, and interrater repeatability of an MFM with a 15-marker set (DuPont foot model) in healthy children. Methods The study included 20 feet of 20 healthy children (10 boys and 10 girls). We divided the participants into two groups of 10 each. One group was tested by the same operator in each test (intersession analysis), while the other group was tested by a different operator in each test (interrater analysis). The multiple correlation coefficient (CMC) and intraclass correlation coefficient (ICC) were calculated to assess repeatability. The difference between the two sessions of each group was assessed at each time point of gait cycle. Results The intrasession CMC and ICC values of all parameters showed excellent or very good repeatability. The intersession CMC of many parameters showed good or better repeatability. Interrater CMC and ICC values were generally lower for all parameters than intrasession and intersession. The mean gaps of all parameters were generally similar to those of the previous study. Conclusions We demonstrated that 3D MFM using a 15-marker set had high intrasession, intersession, and interrater repeatability in the assessment of foot motion in healthy children but recommend some caution in interpreting the hindfoot parameters.

Background and Purpose— Quantitative imaging for the noninvasive assessment of thrombolysis is needed to advance basic and clinical thrombosis-related research and tailor tissue-type plasminogen activator (tPA) treatment for stroke patients. We quantified the evolution of cerebral thromboemboli using fibrin-targeted glycol chitosan–coated gold nanoparticles and microcomputed tomography, with/without tPA therapy. Methods— We injected thrombi into the distal internal carotid artery in mice (n=50). Fifty-five minutes later, we injected fibrin-targeted glycol chitosan–coated gold nanoparticles, and 5 minutes after that, we treated animals with tPA or not (25 mg/kg). We acquired serial microcomputed tomography images for 24 hours posttreatment. Results— Thrombus burden at baseline was 784×10 3 ±59×10 3 μm 2 for the tPA group (n=42) and 655×10 3 ±103×10 3 μm 2 for the saline group (n=8; P =0.37). Thrombus shrinkage began at 0.5 to 1 hour after tPA therapy, with a maximum initial rate of change at 4603±957 μm 2 /min. The rate of change lowered to ≈61% level of the initial in hours 1 to 2, followed by ≈29% and ≈1% in hours 2 to 3 and 3 to 24, respectively. Thus, 85% of total thrombolysis over 24 hours (≈500 μm 2 , equivalent to 64% of the baseline thrombus burden) occurred within the first 3 hours of treatment. Thrombus burden at 24 hours could be predicted at around 1.5 to 2 hours. Saline treatment was not associated with significant changes in the thrombus burden. Infarct size was smaller in the tPA group versus saline group (18.1±2.3 versus 45.8±3.3 mm 2 ; P r =0.71; P Conclusions— Thromboembolic burden and the efficacy of tPA therapy can be assessed serially, noninvasively, and quantitatively using high-resolution microcomputed tomography and a fibrin-binding nanoparticle imaging agent.

Background We have found that infarcted brain regions exhibit green channel autofluorescence (GCAF). Here, we compare ex vivo GCAF-imaging with 2,3,5-triphenylteterazolium chloride (TTC)-staining. New method C57BL/6 mice (n = 120) underwent GCAF-imaging after transient or permanent middle cerebral artery occlusion (tMCAO or pMCAO). Comparison with existing methods TTC-staining may not reflect subtle ischemic injury. TTC-stained tissues, when reused, are prone to processing artifacts related to prior TTC-staining. GCAF imaging requires little experimental manipulation of animals and brain tissues, and allows for more consistent measurements of infarct volume and reliable reuse of the fresh unstained tissues. Results Lesion volumes measured at 24-h after 1-h tMCAO by using GCAF-images were similar to those using TTC-staining: 87.6 ± 13.6 mm 3 vs. 83.8 ± 12.8 mm 3 in 1 mm-thick sections (n = 9 mice, 10 slices/mouse, p = 0.88; Pearson’s r = 0.91, p 0.001) and 75.1 ± 7.6 mm 3 vs. 73.6 ± 6.7 mm 3 in 2 mm-thick sections (n = 9 mice, 5 slices/mouse, p = 0.99; Pearson’s r = 0.87, p 0.001), respectively. In serial ex vivo imaging performed at 1, 2, 3, 6, 12, and 24-h after tMCAO, GCAF-imaging correlated well with TTC-staining at all time-points. In the pMCAO model however, the correlation was strong at later time-points (6–24-h); but at time points up to 3-h, GCAF-imaging was more sensitive than TTC-staining to detect ischemic areas, as verified by histology, where ischemic damage was observed in the GCAF-positive areas of the cerebral cortex and striatum, even in the face of normal TTC-staining. Conclusion GCAF-imaging is a reliable alternative to TTC-staining in the qualitative and quantitative assessments of focal brain ischemia, and more sensitive for detecting early ischemic damage in pMCAO.

Background To achieve optimal clinical outcomes in patients with gastrointestinal stromal tumor (GIST), it is crucial to maintain sufficient dosing of imatinib. Skin rash is a common imatinib-associated adverse event and may affect compliance. This phase II study was conducted to evaluate whether imatinib-associated severe skin rash can be managed with systemic steroids without dose reduction or interruption of imatinib. This study is registered at ClinicalTrials.gov, number NCT03440515. Patients and Methods Between 2014 and 2016, 29 patients with imatinib-associated severe skin rash were enrolled. Skin rash of grade 2 with grade ≥2 pruritus or of grade 3 was considered severe. Oral prednisolone was administered 30 mg/day for 3 weeks, then tapered off over 12 weeks. The primary endpoint was treatment success rate (TSR). Treatment success was defined as maintaining imatinib for more than 15 weeks after completion of the steroid administration schedule without skin rash that led to additional steroid treatment or dose reduction or interruption of imatinib. Results Of the 29 patients enrolled, 22 patients with skin rash were treated successfully (TSR, 75.8%), 2 (6.9%) were evaluated as treatment failures, and 5 (17.2%) were not evaluable. The 2-year rash-free and imatinib reduction-free interval rate was 67.2% with median follow-up of 22.0 months (range, 0.4–30.3). Recurrence of severe skin rash occurred in seven patients (24.1%). Systemic steroids were well tolerated except in one patient who experienced pneumocystis pneumonia. Conclusion This study demonstrated that imatinib-associated severe skin rash can be effectively controlled by systemic steroid treatment without interruption or dose reduction of imatinib in patients with GIST. Implications for Practice Imatinib has been the standard treatment of gastrointestinal stromal tumor in both adjuvant and palliative settings. It is crucial to maintain sufficient dosing of imatinib to achieve optimal clinical outcomes. Imatinib commonly causes imatinib-associated skin rash, which may worsen drug compliance. This phase II study demonstrated that systemic steroids could help maintaining the efficacy of imatinib by preventing interruption or dose reduction of imatinib. The present study provides a new administration strategy of systemic steroids and its efficacy and safety data. Thus, this study can be a cornerstone to establish treatment guidelines for imatinib-associated skin rash.

In colorectal carcinogenesis, the unique molecular and genetic changes that occur within cells result in specific CRC phenotypes. The involvement of the long non-coding RNA, HOTAIR, in cancer development, progression, and metastasis is well-established. Various studies have reported on the contribution of HOTAIR to cancer pathogenesis. Therefore, we selected four HOTAIR polymorphisms (rs7958904G>C, rs1899663G>T, rs4759314A>G, and rs920778T>C) to evaluate the association of each variant with CRC prevalence and prognosis. We conducted a case–control study of 850 individuals to identify the genotype frequencies of each polymorphism. The study population included 450 CRC patients and 400 control individuals that were randomly selected following a health screening. Notably, rs7958904 and rs1899663, their hetero genotype, and the dominant model were significantly different when compared to the healthy control group (rs7958904; AOR = 1.392, 95% CI = 1.052–1.843, P = 0.021). To evaluate the effect of HOTAIR polymorphisms on the survival rate, we analyzed patient mortality and relapse occurrence within 3 and 5 years with Cox-regression analysis. The rs7958904 CC polymorphism mortality rate was significantly higher than the GG polymorphism mortality rate (adjusted HR = 2.995, 95% CI = 1.189–7.542, P = 0.021). In addition, the rs920778 CC genotype was significantly different than the TT genotype (adjusted HR = 3.639, 95% CI = 1.435–9.230, P = 0.007). In addition, this study confirmed that genetic variants of HOTAIR alter the mRNA expression level (P < 0.01). We suggest that HOTAIR rs7958904G>C which is associated with CRC prevalence and mortality is a potential biomarker for CRC. The association between HOTAIR gene polymorphisms and CRC prevalence were reported for the first time.

Venous thromboembolism (VTE) involves the formation of a blood clot, typically in the deep veins of the leg or arm (deep vein thrombosis), which then travels via the circulatory system and ultimately lodges in the lungs, resulting in pulmonary embolism. A number of microRNAs (miRNAs) are well-known regulators of thrombosis and thrombolysis, and mutations in miRNA biogenesis genes, such as DICER1, DROSHA have been implicated in miRNA synthesis and function. We investigated the genetic association between polymorphisms in four miRNA biogenesis genes, DICER1 rs3742330A &gt, G, DROSHA rs10719T &gt, C, RAN rs14035C &gt, T and XPO5 rs11077A &gt, C, and VTE in 503 Koreans: 300 controls and 203 patients. Genotyping was assessed with polymerase chain reaction-restriction fragment length polymorphism assays. We detected associations between polymorphisms in RAN and XPO5 and VTE prevalence (RAN rs14035CC + CT versus TT: p = 0.018, XPO5 rs11077AA + AC versus CC: p &lt, 0.001). Analysis of allele combinations of all four polymorphisms (DICER1, DROSHA, RAN, XPO5) revealed that A-T-T-A was associated with decreased VTE prevalence (p = 0.0002), and A-T-C-C was associated with increased VTE prevalence (p = 0.027). Moreover, in subjects with provoked VTE, the DROSHA rs10719T &gt, C, polymorphism was associated with increased disease prevalence (TT versus TC + CC: p &lt, 0.039). Our study demonstrates that RAN and XPO5 polymorphisms are associated with risk for VTE in Korean subjects.

The objective of this study was to find the effect of hallux valgus (HV) deformity on the inter-segmental motion of the foot using an MFM with a 15-marker set (DuPont Foot Model, DuFM) in comparison with age and sex controlled healthy adults. Fifty-eight female symptomatic HV patients and 50 female asymptomatic older female volunteers were included in this study. According to the radiographic hallux valgus angle (HVA), the study population was divided into severe HV (SHV, HVA ≥ 40°, n = 25), moderate HV (MHV, 20° ≤ HVA < 40°, n = 47), and control (CON, n = 36). MHV group was divided into symptomatic MHV group (S-MHV, n = 33) and asymptomatic MHV group (A-MHV, n = 14) according to the symptoms associated with HV. For temporal parameters, gait speed and stride length were diminished according to the severity of HV deformity. Sagittal range of motion of hallux and hindfoot decreased significantly in SHV group. Loss of push-off during the preswing phase was observed and forefoot adduction motion during terminal stance was decreased in SHV group. In a subgroup analysis of MHV, asymptomatic HV minimally affects gait and inter-segmental motion during gait. HV deformity affects gait parameters and inter-segmental motion of the foot during gait in proportion to the severity of the deformity. However, the effect of MHV itself on foot kinematics might be limited while pain or arthritic change of the joint might cause changes in gait in patients with symptomatic HV.

Background and Objective Lasers have been successfully used for decades to remove dark hair. However, laser removal of nonpigmented hair is challenging due to the lack of chromophores. The aim of this study was to use photodynamic therapy (PDT) to remove nonpigmented hair. Study Design/Material and Methods We compared the efficacy of permanent hair reduction in white BALB/c and black C57BL/6 mice treated with PDT or an 800-nm diode laser. We collected skin biopsy specimens and investigated post-PDT histologic changes and molecular changes. Results We observed keratin 15 staining in the bulge area and alkaline phosphatase staining in the dermal papilla following PDT. We observed a temporary, catagen-like transformation in nonpigmented hair follicles after PDT. We observed apoptotic cells in the hair matrix after PDT. Irradiation with an 800-nm diode laser did not achieve nonpigmented hair removal. Multiple PDT sessions achieved permanent reduction of nonpigmented hair. Interestingly, removal of black hair using PDT was less efficient. Conclusion Our results suggest that PDT can damage the nonpigmented hair matrix, but not stem cells or dermal papillae. Repeated PDT may impair the hair-regeneration capacity via a bystander effect on bulge stem cells or dermal papillae. In this study, we found it was possible to remove nonpigmented hair using PDT. Lasers Surg. Med. 48:748–762, 2016. © 2016 Wiley Periodicals, Inc.

// Joo Hoon Kim 1, * , Jae Seok Lee 2, * , Eo Jin Kim 2 , Kyu Hyun Park 3 , Ki Hyang Kim 4 , Seong Yoon Yi 5 , Han Seong Kim 6 , Yong Jin Cho 7 , Kyoo-Ho Shin 7 , Joong Bae Ahn 1 , Hyuk Hu 8 , Kyung Sik Kim 8 , Young Deuk Choi 9 , Sunghoon Kim 10 , Young Han Lee 11 , Jin-Suck Suh 11 , Sung Hoon Noh 8 , Sun Young Rha 1 , Hyo Song Kim 1 1 Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea 2 Department of Pathology, Dongguk University College of Medicine, Dongguk University Ilsan Hospital, Goyang, Korea 3 Cancer Metastasis Research Center, Song Dang Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Korea 4 Department of Internal Medicine, Busan Paik Hospital, Inje University College of Medicine, Busan, Korea 5 Department of Internal Medicine, Ilsan Paik Hospital, Inje University College of Medicine, Ilsan, Korea 6 Department of Pathology, Ilsan Paik Hospital, Inje University College of Medicine, Ilsan, Korea 7 Department of Orthopedic Surgery, Yonsei University College of Medicine, Seoul, Korea 8 Department of Surgery, Yonsei University College of Medicine, Seoul, Korea 9 Department of Urology, Yonsei University College of Medicine, Seoul, Korea 10 Department of Obstetrics and Gynecology, Yonsei University College of Medicine, Seoul, Korea 11 Department of Radiology, Yonsei University College of Medicine, Seoul, Korea * These authors have contributed equally to this work Correspondence to: Sun Young Rha, e-mail: rha7655@yuhs.ac Hyo Song Kim, e-mail: hyosong77@yuhs.ac Keywords: liposarcoma, PIK3CA, amplification, mutation Received: January 05, 2016 Accepted: March 02, 2016 Published: March 21, 2016 ABSTRACT Background: We investigated the epidemiologic characteristics and prognostic significance of PIK3CA mutations/amplifications in curative resected liposarcoma. Patients and methods: A total of 125 liposarcoma tissue samples were collected over a 12-year period. PIK3CA mutations and gene copy number amplifications were analyzed by pyrosequencing and fluorescence in situ hybridization (FISH). Results: Nine of the 105 liposarcomas (8.6%) had activating PIK3CA mutation. PIK3CA mutations were more frequent in myxoid/round cell and pleomorphic tumors compared with well-differentiated/dedifferentiated tumors (13.3% vs. 2.2%, P=0.043). In FISH PIK3CA analysis, copy number gain was detected in 14 of the 101 tumors (13.9%): 11 (10.9%) tumors had increased gene copy number (polysomy) and 3 (3.0%) exhibited gene amplification. In survival analysis, patients with PIK3CA copy number gain had a worse prognosis compared to patients without PIK3CA amplification (median disease-free survival [DFS] 22.2 vs. 107.6 months p=0.005). By multivariate analysis, PIK3CA copy number gain was an independent prognostic factor for worse DFS (P=0.027; hazard ratio, 2.400; 95% confidence interval 1.105 to 5.213). PIK3CA mutation was not associated with DFS and overall survival. Conclusions: We demonstrated PIK3CA mutation and amplification in liposarcoma. PIK3CA copy number gain was an independent poor prognostic factor for DFS. Further studies are needed to evaluate the potential diagnostic and therapeutic role of PIK3CA mutations and amplifications in liposarcoma.

339 Background: Immunotherapy, including anti-PD-1 inhibitor, represents a promising breakthrough treatment in poor prognostic cancers such as biliary tract cancer (BTC). However, subset of pts suffer from unexpected acceleration of tumor growth following the initiation of immunotherapy, termed hyperprogressive disease (HPD). We assessed HPD in BTC pts treated with anti-PD-1 inhibitor in association with clinicopathologic features. Methods: This retrospective study included pts with BTC who were treated with pembrolizumab 200mg IV as palliative second or third line treatment in 4 tertiary hospitals in South Korea. Previous proposed tumor dynamic parameters including time to treatment failure (TTF), tumor growth kinetics (TGK) and tumor growth rate (TGR) were calculated per RECIST v1.1. Neural network modeling technique was adopted to find clinicopathologic features that can predict HPD. Results: Total of 223 pts with BTC were treated with palliative second or third line pembrolizumab between December 2015 to August 2020. ORR was 11.2% (n=1 for CR, n=24 for PR, n=70 for SD, n=118 for PD, and 10 pts not evaluable). Among patients with best response as PD (n=118), 41 patients (18.4% from total pts) met the criteria for HPD definition (>2-fold increase in both TGK and TGR in the experimental period compared to the reference period). HPD pts had worse prognosis compared to non-HPD pts in terms of TTF (median 1.4 vs 2.7 months, P =