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Background/objective Open thyroidectomy has been the standard approach for patients undergoing thyroidectomy. However, this approach leads to prominent scars, hypesthesia, paresthesia, and uncomfortable sensations. We aimed to describe our modified technique of minimally invasive open thyroidectomy (MIT) and to compare the results with those of conventional thyroidectomy. Methods This study included 880 patients who underwent surgery between January 2016 and December 2016. Modified MIT was performed in 249 patients (28.3%), and conventional thyroidectomy was performed in the remaining 631 patients. Results Lobectomy was performed in the majority of cases (MIT 204 [81.9%] vs. conventional 429 [67.9%]). There were no significant differences in complications between the two approaches (6 [2.4%] vs. 8 [1.3%]). Patients who underwent surgery using the minimally invasive approach had a shorter operative time (77.99 ± 34.5 vs. 91.23 ± 36.58 min) and were discharged earlier (2.4 ± 0.8 vs. 3.2 ± 0.8) than those who underwent conventional thyroidectomy. Conclusion Modified MIT is a safe alternative to standard open thyroidectomy and allows the performance of bilateral total thyroidectomy with proper central compartment neck dissection. Level of evidence 2b.

Hee Jun Kim,1 Sunjoo Boo,1 Timothy J Meeker2 1Research Institute of Nursing Science, College of Nursing, Ajou University, Suwon, 16499, Gyeonggi, Republic of Korea; 2Department of Neurosurgery, Johns Hopkins Medical Institute, Baltimore, MD, 21287, USACorrespondence: Sunjoo BooResearch Institute of Nursing Science, College of Nursing, Ajou University, 164, World Cup-ro, Yeongtong-gu, Suwon, Gyeonggi, 16499, Republic of KoreaTel +82-31-219-7032Fax +82 31 219 7020Email sjboo@ajou.ac.krBackground: Pain is a global health issue with a significant impact on young adults. Adverse effects caused by inappropriate pain management among university students are related to poor mental/physical health. This study aimed to explore pain prevalence, management, and interference among university students in South Korea.Methods: Pain intensity, painful body areas, pain management, and pain interference were measured in a convenience sample of 404 students. Descriptive statistics are reported, and a multivariable binomial logistic regression was conducted to reveal factors associated with pain interference.Results: The prevalence of acute and chronic pain was 73.5%, while 7.8% reported chronic pain (≥ 3 months). Half of university students who experienced pain reported at least four painful body areas. The average pain intensity during the past 6 months was 4.8/10. About 56% of university students who experienced pain used over-the-counter pain pills for pain management. Rest and massage were the most used non-pharmacological pain management strategies. Mood was the most reported pain interference complaint amongst university students. Greater pain interference was associated with longer pain duration, more painful body areas, and greater pain intensity.Discussion: Pain is highly prevalent among South Korean university students. Pain management programs, including education about appropriate methods of pain relief, should be developed for university students. Attention should be given to university students with widespread acute and chronic pain of high intensity to mitigate the negative impacts caused by pain interference.Keywords: pain, pain management, prevalence, young adults

In 2017, Korean Society of Medical Oncology (KSMO) published the Korean man agement guideline of metastatic prostate cancer. This paper is the 2nd edition of the Korean management guideline of metastatic prostate cancer. We updated recent many changes of management in metastatic prostate cancer in this 2nd edition guideline. The present guideline consists of the three categories: man agement of metastatic hormone sensitive prostate cancer; management of meta static castration resistant prostate cancer; and clinical consideration for treating patients with metastatic prostate cancer. In category 1 and 2, levels of evidence (LEs) have been mentioned according to the general principles of evidence-based medicine. And grades of recommendation (GR) was taken into account the qual ity of evidence, the balance between desirable and undesirable effects, the values and preferences, and the use of resources and GR were divided into strong rec ommendations (SR) and weak recommendations (WR). A total of 16 key questions are selected. And we proposed recommendations and described key evidence for each recommendation. The treatment landscape of metastatic prostate cancer is changing very rapid and many trials are ongoing. To verify the results of the fu ture trials is necessary and should be applied to the treatment for metastatic prostate cancer patients in the clini cal practice. Especially, many prostate cancer patients are old age, have multiple underlying medical comorbidities, clinicians should be aware of the significance of medical management as well as clinical efficacy of systemic treat ment.

BackgroundAt least 80% of ordered enteral nutrition should be delivered to improve outcomes in critical care patients. However, these patients typically receive 60% to 70% of ordered enteral nutrition volume. In a practice review within a 28-bed medical-surgical adult intensive care unit, patients received a median of 67.5% of ordered enteral nutrition with standard rate-based feeding. Volume-based feeding is recommended to deliver adequate enteral nutrition to critically ill patients.ObjectiveTo use a quality improvement project to increase the volume of enteral nutrition delivered in the medical-surgical intensive care unit.MethodsPercentages of target volume achieved were monitored in 73 patients. Comparisons between the rate-based and volume-based feeding groups used nonparametric quality of medians test or the χ2 test. A customized volume-based feeding protocol and order set were created according to published protocols and then implemented. Standardized education included lecture, demonstration, written material, and active personal involvement, followed by a scenario-based test to apply learning.ResultsImmediately after implementation of this practice change, delivered enteral nutrition volume increased, resulting in a median delivery of 99.8% of ordered volume (P = .003). Delivery of a mean of 98% ordered volume was sustained over the 15 months following implementation.ConclusionsImplementation of volume-based feeding optimized enteral nutrition delivery to critically ill patients in this medical-surgical intensive care unit. This success can be attributed to a comprehensive, individualized, and proactive process design and educational approach. The process can be adapted to quality improvement initiatives with other patient populations and units.

Hee Jun Kim,1 Hyunjeong Park,2 Hee-Soon Juon3 1Research Institute of Nursing Science, College of Nursing, Ajou University, Suwon, 16499, Republic of Korea; 2Department of Nursing, Towson University, Towson, MD, 21252, USA; 3Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA, 19107, USACorrespondence: Hee Jun KimResearch Institute of Nursing Science, College of Nursing, Ajou University, 206 World cup-ro, Yeongtong-gu, Suwon-si, Gyeonggi-do, Republic of KoreaTel +82 31-219-7024Fax +82 31-219-7020Email hkim20@ajou.ac.krPurpose: The association between depression and chronic pain is well established. However, few studies have examined the pathways from depression to chronic pain. The present cross-cultural study aimed to test the mediating effects of pain catastrophizing on associations between depression and chronic pain (eg, pain severity, pain intensity) among Korean American elderly.Patients and Methods: A total of 132 elderly Korean Americans with chronic pain were recruited from elderly daycare centers and Korean ethnic churches in the community. For mediation analyses, structural equation modeling with full information maximum likelihood estimation method was used. The bias-corrected bootstrap confidence interval (CI) method for inferential tests of the indirect effects was also conducted in mediation analysis.Results: The results indicated that the proportion of comorbid depression and chronic pain was 45.7%. Elderly Korean Americans with depression scored higher in pain severity, pain interference, and pain catastrophizing than those without depression. Pain catastrophizing was found to have a significant mediating effect on the relationship between depression and pain severity (indirect effect = 0.147, Bootstrap 95% CI = [0.079, 0.226]), controlling for demographic covariates, comorbidities and pain area. Pain catastrophizing also mediated the relationship between depression and pain interference (indirect effect =0.164, Bootstrap 95% CI = [0.097, 0.244]), controlling for the covariates.Conclusion: These findings add to the literature by providing evidence that pain catastrophizing plays a role in high levels of pain severity and pain interference comorbid chronic pain and depression in Asian elderly immigrants. Appropriate culturally tailored programs to redirect pain catastrophizing cognitive process should be developed and provided for elderly Asian Americans to reduce chronic pain disparity.Keywords: Korean immigrants, cross-cultural, comorbid, mediation

To identify the risk factors leading to new brain metastases (BM) following brain-directed treatment for initial BM resulting from breast cancer (BC). In this multi-institutional study, 538 BC patients with available follow-up imaging after brain-directed treatment for initial BM were analyzed. Tumor molecular subtypes were classified as follows: hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−, n = 136), HER2-positive (HER2+, n = 253), or triple-negative BC (TNBC, n = 149). In 37.4% of patients, new BM emerged at a median of 10.5 months after brain-directed treatment for initial BM. The 1-year actuarial rate of new BM for HR+/HER2−, HER2+, and TNBC were 51.9%, 44.0%, and 69.6%, respectively (p = 0.008). Initial whole-brain radiotherapy (WBRT) reduced new BM rates (22.5% reduction at 1 year, p 4) (p

Both retrobulbar hemorrhage and plate extrusion are uncommon complications after implantation of a glaucoma drainage device (GDD). There are no published reports on extrusion of an Ahmed glaucoma valve after delayed-onset retrobulbar hemorrhage in Korea. Herein, we report a case of spontaneous extrusion of a GDD after delayed-onset retrobulbar hemorrhage in a patient on anticoagulation. The case was a 72-year-old man with open-angle glaucoma and proliferative diabetic retinopathy, as well as systemic hypertension, atrial fibrillation, congestive heart failure due to coronary heart disease, and chronic kidney disease, who underwent combined Ahmed glaucoma valve implantation and cataract extraction surgery in his right eye. The body remained in position with control of intraocular pressure for 2 months. On day 67 (5 days post-coronary artery bypass surgery), he complained of decreased visual acuity, periorbital swelling, bloody discharge, and limited extraocular movement. One month later, the body was extruded with a scleral flap tear. Therefore, delayed-onset retrobulbar hemorrhage should be kept in mind in patients on anticoagulants after insertion of a GDD.

Due to its regulation of CDK1/2 phosphorylation, WEE1 plays essentially roles in the regulations of G2/M checkpoint and DNA damage response (DDR). WEE1 inhibition can increase genomic instability by inducing replication stress and G2/M checkpoint inactivation, which result in increased cellular sensitivity to DNA damaging agents. We considered an increase in genomic instability induced by WEE1 inhibition might be used to augment the effects of drugs targeting DNA repair protein. Typically, PARP inhibitors are effective in germline BRCA 1/2 mutated breast and ovarian cancer, but their applicabilities in triple-negative breast cancer (TNBC) are limited. This study was conducted to investigate the anti-tumor effects of the WEE1 inhibitor, AZD1775, and the mechanism responsible for its potentiation of sensitivity to olaparib (a PARP inhibitor) via the modulation of DDR in TNBC cells. Our results suggest that AZD1775 could be used to broaden the application range of olaparib in TNBC and provide a rationale for a clinical trial of combined olaparib and AZD1775 therapy.

Purpose To describe and compare the levels of pain severity and pain interference, pain catastrophizing, and associated factors between elderly Koreans living in South Korea and Korean Americans living in the United States with chronic pain. Methods An exploratory, comparative design was used for this study. A total of 270 individuals (138 Koreans living in South Korea and 132 Korean Americans living in the United States), aged more than 65 years, with self-reported chronic pain, and defined as at least 3 months of persistent musculoskeletal pain, is included. Outcome variables were pain severity, pain interference, and pain catastrophizing. Multivariate linear regression was conducted to examine factors associated with the outcome variables. Results In multivariate analysis, Korean Americans had higher levels of pain severity and pain catastrophizing than Koreans. Depressive symptoms, sleep quality, and health-related quality of life were significant factors for pain severity, pain interference, and pain catastrophizing for both groups. Among those factors, health-related quality of life was the most significant factor for predicting pain severity and pain interference, whereas depressive symptoms were the most significant factor for predicting pain catastrophizing for both groups. Conclusions Intra-ethnic differences in pain severity and pain catastrophizing were found between elderly Koreans living in South Korea and Korean Americans living in the United States. Clinical relevance Because unfamiliar sociocultural and environmental factors may influence the pain responses, cultural differences and language barriers should be taken into account in pain research and management strategies for Asian immigrants in the United States. Psychological factors, including depressive symptoms, sleep quality, and health-related quality of life, should also be considered in chronic pain management for both elderly Koreans and Korean Americans.

Background Chronic pain is one of the most common health problems for older adults worldwide and is likely to result in lower quality of life. Living in a different culture may also influence chronic pain and quality of life in older adults. The purpose of this study was to explore how multifaceted elements affect chronic pain and quality of life in older Koreans living in Korea and in older Korean–Americans (KAs) living in the USA. Methods We conducted a secondary data analysis of data from 270 adults aged 65 years or over (138 Koreans and 132 KAs). We compared the effects of multifaceted elements on pain and quality of life by testing structural equation models (SEMs) for each group, using a maximum likelihood estimation and bootstrapping. Results SEMs for both Korean and KAs showed that age and depressive symptoms directly affected quality of life. The number of comorbidities and depressive symptoms had mediating effects on quality of life through chronic pain in both groups. In older Koreans only, perceived financial status directly affected quality of life. In older KAs only, sleep quality indirectly affected quality of life through chronic pain. Conclusion The data showed that multimorbidity and depressive symptoms play critical roles for explaining chronic pain in older Koreans and KAs and ultimately negatively influence quality of life. Future intervention program to improve quality of life in older adults with chronic pain should consider the different cultural aspects affecting quality of life for Koreans and KAs.

Background The continuum of anti-HER2 agents is a standard treatment of HER2 + metastatic breast cancer (MBC). This study evaluated the efficacy of lapatinib plus vinorelbine in patients progressed on both trastuzumab and lapatinib treatments. Methods A total of 149 patients were randomly assigned to lapatinib with vinorelbine (LV) (n = 75; lapatinib, 1000 mg daily; vinorelbine 20 mg/m2 D1, D8 q3w) or vinorelbine (V) (n = 74; 30 mg/m2 D1, D8 q3w). The primary endpoint was progression-free survival (PFS) rate at 18 weeks. Results The median number of previous anti-HER2 therapies was 2 (range 2–5). There was no significant difference in PFS rate at 18 weeks between LV and V arms (45.9% vs 38.9%, p = 0.40). ORR was 19.7% in LV arm, and 16.9% in V arm (p = 0.88). PFS and OS did not differ between two arms (LV vs V; median PFS, 16 vs 12 weeks, HR = 0.86, 95% CI 0.61–1.22; median OS, 15.0 vs 18.9 months, HR = 1.07, 95% CI 0.72–1.58). Toxicity profiles were similar in both arms and all were manageable. Conclusions Lapatinib plus vinorelbine treatment was tolerable; however, it failed to demonstrate the clinical benefits over vinorelbine alone in patients with HER2 + MBC after progression on both trastuzumab and lapatinib. Clinical trial registration ClinicalTrials.gov number NCT01730677.

The regional lymph node‐positive bladder cancer was classified as stage IV in the AJCC 7th edition but was changed to stage IIIB in the 8th edition, revised in 2018. Among the various studies involving immune checkpoint inhibitors, groups that had only lymph node metastasis showed better outcomes than those with distant metastasis. Therefore, it is necessary to rethink the treatment strategy for lymph node‐positive bladder cancer. The aim of this study was to compare the treatment outcomes of chemotherapy, surgery, and combination therapy in patients with lymph node‐positive bladder cancer. From 1 January 2010 to 31 December 2015, patients with bladder cancer presenting local lymph node metastasis at the time of diagnosis were treated with a single treatment strategy, with either radical cystectomy or chemotherapy or with a combined strategy using both. Treatment outcomes were retrospectively analyzed on the basis of clinical indices and survival time. Out of 230 patients with bladder cancer, 44 (19.1%) were treated with palliative chemotherapy, 30 (13.0%) with neoadjuvant chemotherapy followed by cystectomy, 129 (56.1%) with cystectomy followed by adjuvant chemotherapy, and 27 (11.7%) with cystectomy alone. Median survival among all groups was 30.4 months. For each group, median overall survival was 19.3, 49.1, 42.6, and 11.2 months, respectively. This study represents an advancement in understanding the impact of clinical treatment patterns of lymph node‐positive bladder cancer through comparison of survival data of patients treated with different therapeutic strategies. Combined treatment resulted in better outcomes than did single treatments., This multi‐center retrospective study compared the outcome of different treatment modalities in node positive urothelial bladder cancer. The best survival rates were achieved in group treatment by neoadjuvant chemotherapy followed by radical cystectomy and radical cystectomy followed by adjuvant chemotherapy. This disease entity had not been studied homogenously until now. This study was the first to directly compare the results of various treatments in node‐ positive bladder cancer.

Purpose The purpose of this study was to evaluate clinical characteristics and treatment pattern of ovarian clear cell carcinoma (OCCC) in Korea and the role of adjuvant chemotherapy in early-stage. Materials and Methods Medical records of 308 cases of from 21 institutions were reviewed and data including age, performance status, endometriosis, thromboembolism, stage, cancer antigen 125, treatment, recurrence, and death were collected. Results Regarding stage of OCCC, it was stage I in 194 (63.6%), stage II in 34 (11.1%), stage III in 66 (21.6%), and stage IV in 11 (3.6%) patients. All patients underwent surgery. Optimal surgery (residual disease ≤ 1 cm) was achieved in 89.3%. Majority of patients (80.5%) received postoperative chemotherapy. The most common regimen was taxane-platinum combination (96%). Median relapse-free survival (RFS) was 138.5 months for stage I, 33.4 for stage II, 19.3 for stage III, and 9.7 for stage IV. Median overall survival (OS) were not reached, 112.4, 48.7, and 18.3 months for stage I, II, III, and IV, respectively. Early-stage (stage I), endometriosis, and optimal debulking were identified as favorable prognostic factors for RFS. Early-stage and optimal debulking were also favorable prognostic factors for OS. Majority of patients with early-stage received adjuvant chemotherapy. However, additional survival benefit was not found in terms of recurrence. Conclusion Majority of patients had early-stage and received postoperative chemotherapy regardless of stage. Early-stage and optimal debulking were identified as favorable prognostic factors. In stage IA or IB, adding adjuvant chemotherapy did not show difference in survival. Further study focusing on OCCC is required.

In recent research involving assisted-living residents with mild to moderate cognitive impairment, a structured 12-week Pet Assisted Living (PAL) intervention led to improved physical activity (PA)...

Purpose: Acute kidney injury (AKI) affects cancer therapy outcome and increases morbidity and mortality in cancer patients. We investigated the incidence, risk factors, and clinical outcomes of AKI caused by palliative chemotherapy in lung cancer patients. Materials and Methods: Between January 2005 and November 2014, 207 lung cancer patients who had been treated with first-line palliative chemotherapy were enrolled. Renal function was assessed during every cycle of chemotherapy. AKI was defined based on changes in serum creatinine levels as described in the Kidney Disease: Improving Global Outcomes guidelines. Clinical outcomes were evaluated depending on AKI occurrence during the first-line chemotherapy. Results: Of the 207 patients, 36 (17.4%) experienced AKI. Among the 36 patients who developed AKI during chemotherapy, 33 (91.8%) had AKI stage I. Although 19 patients (52.7%) with AKI during chemotherapy progressed to chronic kidney disease (CKD), no patients were reported to progress to end-stage renal disease (ESRD). The number of chemotherapy cycles was independently associated with chemotherapy-induced AKI in multivariate analysis (OR = 1.71, 95% CI 1.29-2.26, p < 0.001). The median follow-up duration was 83 months. Patients with AKI during chemotherapy (AKI group) showed significantly longer time to treatment failure than patients without AKI (non-AKI group) (4.2 vs. 2.5 months, p < 0.001). However, the median overall survival (11.7 vs. 8.8 months, p = 0.147) and progression-free survival (5.5 vs. 5.2 months, p = 0.347) were not different between the groups. Conclusions: AKI that developed during chemotherapy was mostly of mild degree and its prognosis was favorable. The occurrence of AKI was associated with the number of chemotherapy cycles administered. AKI did not adversely affect survival of lung cancer patients during chemotherapy.

BackgroundIBM’s Watson for Oncology (WFO) is an artificial intelligence tool that trains by acquiring data from the Memorial Sloan Kettering Cancer Center and learns from test cases and experts. This study aimed to analyze the adequacy and effectiveness of WFO in determining the treatment method for patients with thyroid carcinoma.Materials and MethodsWe retrospectively enrolled 50 patients with thyroid cancer who underwent surgery in 2018 and entered their clinical data into WFO. The WFO treatment recommendations were compared with the surgical procedures and recommended treatments performed according to the Korean Thyroid Endocrine Surgery Association guidelines.ResultsThe overall concordance rate between WFO-recommended treatments and actual surgical treatments was 48%, and for patients with stage I, II, and III disease, these rates were 52.4, 50, and 16.7%, respectively. A lower concordance rate was observed with respect to treatment for advanced thyroid cancer.ConclusionWFO is a useful clinical aid but must be used with caution. A surgeon’s decision takes precedence over WFO recommendations in the treatment of advanced thyroid cancer.

Background Liver fibrosis is defined as the accumulation of the extracellular matrix and scar formation. The receptor for advanced glycation end products (RAGE) has been demonstrated to participate in fibrogenesis. S100B is a ligand of RAGE and exerts extracellular functions by inducing a series of signal transduction cascades. However, the involvement of S100B and RAGE in cholestasis-induced liver fibrosis remains unclear. In this study, we investigated S100B and RAGE expression during liver fibrosis in mice that underwent common bile duct ligation (BDL). Methods BDL was performed in 10-week-old male C57BL/6J mice with sham control (n = 26) and BDL (n = 26) groups. Expression levels of S100B, RAGE and fibrotic markers in the livers from both groups at week 1 and 3 after BDL were examined by western blot and quantitative real-time reverse transcription polymerase chain reaction analysis. Liver fibrotic changes were examined by histological and ultrastructural analysis. Results Histological staining with Sirius Red and the evaluation of the messenger RNA expression of fibrotic markers showed noticeable periportal fibrosis and bile duct proliferation. S100B was mainly present in bile duct epithelial cells, and its expression was upregulated in proportion to the ductular reaction during fibrogenesis by BDL. RAGE expression was also increased, and interestingly, triple immunofluorescence staining and transmission electron microscopy showed that both S100B and RAGE were expressed in proliferating bile duct epithelial cells and activated hepatic stellate cells (HSCs) of the BDL livers. In addition, in rat HSCs (HSC-T6), treatment with recombinant S100B protein significantly increased fibrotic markers in a dose-dependent manner, and RAGE small interfering RNA (siRNA) suppressed S100B-stimulated upregulation of fibrotic markers compared with cells treated with scramble siRNA and S100B. Conclusion These findings suggest that the increased expression of S100B and RAGE and the interaction between S100B and RAGE may play an important role in ductular reaction and liver fibrosis induced by BDL., Graphical Abstract

This study sought to adapt the existing value framework (VF) to produce a reliable and valid Korean oncology VF. Two VFs developed by The American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO) were selected for examination in the present study. Forward and backward translations were conducted for six high-priced drugs indicated for non-small-cell lung cancer and multiple myeloma. Inter-rater reliability was measured based on the intraclass correlation coefficient (ICC) and variation was described using the coefficient of variation. The relative weights of factors critically considered by Korean oncologists were derived following the analytic hierarchy process (AHP), and focus group interviews (FGIs) were used to obtain qualitative data regarding the applications of these two VFs in the Korean setting. The ICCs of the Korean VFs were 0.895 (0.654–0.983) for ASCO and 0.726 (0–0.982) for ESMO translations, suggesting excellent reliability for ASCO and good reliability for ESMO. AHP demonstrated that clinical benefit has the highest priority, which is consistent with the ASCO VF. The FGIs suggested that the result for AHP is acceptable and that both ESMO and ASCO VFs should be used complementarily. Although further evaluation with a larger sample size is needed, the Korean versions of ESMO/ASCO VFs are valid and reliable tools and are acceptable to Korean stakeholders, yet they should be applied with caution.

Anaplastic thyroid cancer (ATC) is an undifferentiated and advanced form of thyroid cancer, accompanied with a high ratio of epigenetic adjustment, which occurs more than genetic mutations. In this study, we aimed to evaluate the synergistic anticancer effect (in vitro and in vivo) of the new combination of N-hydroxy-7-(2-naphthylthio) heptanomide (HNHA) and sorafenib with radiation therapy in pre-clinical models of ATC. The ATC cell lines, YUMC-A1 and YUMC-A2, were isolated from the current patients who were treated with HNHA and sorafenib, either as monotherapy or combination therapy. Synergistic anticancer effect of the combination therapy on the intracellular signaling pathways and cell cycle was assessed via flow cytometry and immunoblot analysis. To examine tumor shrinkage activity in vivo, an ATC cell line-derived mouse xenograft model was used. Results showed that the combination therapy of HNHA and sorafenib with radiation promoted tumor suppression via caspase cleavage and cell cycle arrest in patient-derived ATC. In addition, the combination therapy of HNHA and sorafenib with radiation was more effective against ATC than therapy with HNHA or sorafenib with radiation. Thus, the combination of HNHA and sorafenib with radiation may be used as a novel curative approach for the treatment of ATC.

Advanced breast cancer frequently metastasizes to the skeleton causing major mobility issues and hazards to quality of life. To manage osteolytic bone metastasis, bone-modifying agents and chemotherapy are recommended as the standard of care. Here, we investigated serologic biomarkers that might be associated with prognosis in breast cancer patients treated with zoledronic acid (ZA) and taxane-based chemotherapy. We collected serum samples from breast cancer patients with bone metastasis who received taxane plus ZA as palliative treatment. Fourteen biomarkers of angiogenesis, immunogenicity, and apoptosis were assessed, and the correlation between serum cytokine levels and patient's prognosis was statistically analyzed. Sixty-six patients were enrolled, and samples from 40 patients were analyzed after laboratory quality control. Patients with low baseline PDGF-AA, high IFN-γ, low MCP-2, low TGF-β1, and low TNF-α were significantly associated with longer progression-free survival (PFS). Decreasing VEGF and TNF-α and increasing FGF-2 and PDGF-AA in the early treatment phase indicated longer PFS. In univariate and multivariate analyses, low TGF-β1 and TNF-α and high IFN-γ at baseline were associated with a significantly low hazard ratio for disease progression. Further, we designed a risk score with TGF-β1, TNF-α, and IFN-γ levels, which could prognosticate patients for PFS. In conclusion, serum cytokine level, such as TGF-β1, TNF-α, and IFN-γ, could be a potential prognostic biomarker for breast cancer patients with bone metastasis treated with ZA and taxane-based chemotherapy.

Background: Lobectomy with preservation of the contralateral lobe has already become the most preferred surgical method for patients with low-risk thyroid cancer. The incidence of and risk factors for the development of hypothyroidism after lobectomy for thyroid cancer remains unclear. The previous practice of levothyroxine supplementation post-thyroidectomy, to bring about thyroid stimulating hormone (TSH) suppression, had some serious side effects. This study aimed to evaluate the incidence of hypothyroidism and to identify the factors associated with hypothyroidism requiring thyroid hormone replacement. Methods: We retrospectively reviewed the charts of 256 consecutive patients with differentiated thyroid cancer treated with lobectomy at the Gangnam Severance Hospital between April and December 2014 who were followed-up for more than 5 years. Patients were evaluated using a thyroid function test at the time of outpatient visit every 6 months for the 1st year, with an annual follow-up thereafter. Results: After 5 years, 66.0% (169) of the patients needed levothyroxine supplementation to maintain euthyroid status. The incidence of hypothyroidism requiring levothyroxine supplementation increased until 3 years but showed no significant change in the 4 and 5th year. Recurrence showed no difference between the group with and without levothyroxine supplementation. The presence of thyroiditis and preoperative TSH levels were correlated with postoperative levothyroxine supplementation to maintain euthyroid status, in univariate and multivariate analyses. Conclusion: High preoperative TSH levels and/or thyroiditis indicate a significantly increased likelihood of developing hypothyroidism requiring thyroid hormone supplementation after a thyroid lobectomy. Patients with an increased risk of postoperative hypothyroidism must be aware of their risk factors and should undergo more intensive follow-ups.

Occult breast cancer (OBC) is an asymptomatic condition. We report a case of OBC in a 72-year-old male patient who presented with severe dyspnea and upper extremity swelling. Computed tomography scan showed multiple lymph node enlargements in the supraclavicular and infraclavicular areas, and ultrasound scan showed multiple axillary lymph node enlargements. Based on the radiological findings, clinicians suspected lymphoma or disseminated metastasis from unknown primary malignancies. However, the axillary biopsy specimen revealed invasive breast cancer with hormonal receptor positivity.

In this study, we report all-sputtered In–Ga–Zn–O (IGZO) thin-film transistors (TFTs) through the fabrication of a sputtered gate insulator. Furthermore, using simultaneous UV and thermal (SUT) treatment, we fabricate sputter-processed gate insulators at a low temperature of 150 °C with a higher amount of coordinated oxygen species and a higher surface energy than thermal-only (300 °C) treated gate insulators. Additionally, by activating the IGZO channel layer using SUT treatments, we fabricate all-sputter processed IGZO TFTs at 150 °C and they exhibit improved device performances compared to thermal-only treated ones; the field-effect mobility is increased from 7.32 ± 3.8 to 29.59 ± 2.5 cm2 V−1 s−1, the on/off ratio is increased from (1.1 ± 1.8) × 105 to (2.9 ± 1.7) × 108, and the subthreshold swing is decreased from 1.0 ± 0.07 to 0.4 ± 0.05 V dec−1.

Although papillary thyroid cancers are known to have a relatively low risk of recurrence, several factors are associated with a higher risk of recurrence, such as extrathyroidal extension, nodal metastasis, and BRAF gene mutation. However, predicting disease recurrence and prognosis in patients undergoing thyroidectomy is clinically difficult. To detect new algorithms that predict recurrence, inductive logic programming was used in this study. A total of 785 thyroid cancer patients who underwent bilateral total thyroidectomy and were treated with radioiodine were selected for our study. Of those, 624 (79.5%) cases were used to create algorithms that would detect recurrence. Furthermore, 161 (20.5%) cases were analyzed to validate the created rules. DELMIA Process Rules Discovery was used to conduct the analysis. Of the 624 cases, 43 (6.9%) cases experienced recurrence. Three rules that could predict recurrence were identified, with postoperative thyroglobulin level being the most powerful variable that correlated with recurrence. The rules identified in our study, when applied to the 161 cases for validation, were able to predict 71.4% (10 of 14) of the recurrences. Our study highlights that inductive logic programming could have a useful application in predicting recurrence among thyroid patients.

Secondhand smoke exposure (SHSE) in nonsmokers has been associated with premature cardiovascular mortality and ischemic heart disease. We conducted a cross-sectional, population-based study evaluating the relationship between SHSE, measured by subjective and objective methods, and conventional cardiovascular risks such as blood pressure, lipid profiles, and fasting glucose.We extracted information on 7376 healthy adults who had never smoked, for whom there were available urine cotinine levels, from the Korea National Health and Nutrition Examination Survey 2008-2011. SHSE was defined using self-report questionnaires and urine cotinine levels. The main outcomes included SBP and DBP, serum lipid profiles, and fasting glucose.The mean age of the study population was 45.4 ± 0.4 years and 75.2% were women. Self-reported SHSE had no significant association with study outcomes except for DBP, which had marginally positive relationships (P = 0.060). Unadjusted analysis showed higher cotinine levels were associated with lower SBP, total cholesterol, LDL cholesterol, and triglyceride. All associations lost statistical significance after multivariable adjustment. Fasting glucose had a positive relationship with urine cotinine in quartiles but not with logarithm-transformed cotinine.Although SHSE is associated with increased risk of cardiovascular mortality and morbidity, we did not find any consistent relationship among SHSE and blood pressure, lipid, or fasting glucose levels in this cross-sectional study. Using objective measurements of urine cotinine did not alter this relationship. Further long-term prospective studies are needed to evaluate the effect of SHSE as a cardiovascular risk factor.

Ataxia telangiectasia and Rad3-related (ATR) can be considered an attractive target for cancer treatment due to its deleterious effect on cancer cells harboring a homologous recombination defect. The aim of this study was to investigate the potential use of the ATR inhibitor, AZD6738, to treat gastric cancer. In SNU-601 cells with dysfunctional ATM, AZD6738 treatment led to an accumulation of DNA damage due to dysfunctional RAD51 foci formation, S phase arrest, and caspase 3–dependent apoptosis. In contrast, SNU-484 cells with functional ATM were not sensitive to AZD6738. Inhibition of ATM in SNU-484 cells enhanced AZD6738 sensitivity to a level comparable with that observed in SNU-601 cells, showing that activation of the ATM-Chk2 signaling pathway attenuates AZD6738 sensitivity. In addition, decreased HDAC1 expression was found to be associated with ATM inactivation in SNU-601 cells, demonstrating the interaction between HDAC1 and ATM can affect sensitivity to AZD6738. Furthermore, in an in vivo tumor xenograft mouse model, AZD6738 significantly suppressed tumor growth and increased apoptosis. These findings suggest synthetic lethality between ATR inhibition and ATM deficiency in gastric cancer cells. Further clinical studies on the interaction between AZD 6738 and ATM deficiency are warranted to develop novel treatment strategies for gastric cancer. Mol Cancer Ther; 16(4); 566–77. ©2017 AACR.

Summary Background Endocrine treatment is recommended by clinical guidelines as the preferred treatment option for premenopausal as well as postmenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer. In real-world clinical practice, however, a substantial number of patients are treated with chemotherapy. We aimed to compare the clinical antitumour activity and safety of palbociclib plus endocrine therapy with that of capecitabine chemotherapy in premenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer. Methods This multicentre, open-label, randomised, phase 2 study was done in 14 academic institutions in South Korea. Premenopausal women aged 19 years or older with hormone receptor-positive, HER2-negative breast cancer that had relapsed or progressed during previous tamoxifen therapy and with an Eastern Cooperative Oncology Group performance status of 0–2 were included. One line of previous chemotherapy for metastatic breast cancer was allowed. Patients were randomly assigned, using a random permuted block design (with a block size of two), to receive palbociclib plus combination endocrine therapy (oral exemestane 25 mg per day for 28 days and oral palbociclib 125 mg per day for 21 days every 4 weeks plus leuprolide 3·75 mg subcutaneously every 4 weeks) or chemotherapy (oral capecitabine 1250 mg/m2 twice daily for 2 weeks every 3 weeks). Randomisation was stratified by previous chemotherapy for metastatic breast cancer and visceral metastasis. The primary endpoint was progression-free survival. All analyses were done in a modified intention-to-treat population that excluded patients who did not receive study medication. This study is registered with ClinicalTrials.gov , NCT02592746 , and is ongoing for follow-up of overall survival. Findings Between June 15, 2016, and Dec 10, 2018, 189 patients were enrolled, of whom 184 were randomly assigned to the palbociclib plus endocrine therapy group (n=92) or the capecitabine group (n=92). Six patients in the capecitabine group withdrew from the study before drug administration; therefore, 92 patients in the palbociclib plus endocrine therapy group and 86 patients in the capecitabine group were included in the modified intention-to-treat analyses. 46 (50%) of 92 patients in the palbociclib plus endocrine therapy group and 45 (51%) of 92 in the capecitabine group were treatment naive for metastatic breast cancer. During a median follow-up of 17 months (IQR 9–22), median progression-free survival was 20·1 months (95% CI 14·2–21·8) in the palbociclib plus endocrine therapy group versus 14·4 months (12·1–17·0) in the capecitabine group (hazard ratio 0·659 [95% CI 0·437–0·994], one-sided log-rank p=0·0235). Treatment-related grade 3 or worse neutropenia was more common in the palbociclib plus endocrine therapy group than in the capecitabine group (69 [75%] of 92 vs 14 [16%] of 86 patients). 2 (2%) patients in the palbociclib plus endocrine therapy group and 15 (17%) patients in the capecitabine group had treatment-related serious adverse events. No treatment-related deaths occurred. Interpretation Exemestane plus palbociclib with ovarian function suppression showed clinical benefit compared with capecitabine in terms of improved progression-free survival in premenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer. Palbociclib plus exemestane with ovarian suppression is an active treatment option in premenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer who have been pretreated with tamoxifen. Funding Pfizer, Shinpoong, and Daewoong Korea and Takeda.

Although the migration of hepatic stellate cells (HSCs) is important for hepatic fibrosis, the regulation of this migration is poorly understood. Notably, transforming growth factor (TGF)-β1 induces monocyte migration to sites of injury or inflammation during the early phase, but inhibits cell migration during the late phase. In the present study, the role of transforming protein RhoA signaling in TGF-β1-induced HSC migration was investigated. TGF-β1 was found to increase the protein and mRNA levels of smooth muscle actin and collagen type I in HSC-T6 cells. The level of RhoA-GTP in TGF-β1-stimulated cells was significantly higher than that in control cells. Furthermore, the phosphorylation of cofilin and formation of filamentous actin (F-actin) were more marked in TGF-β1-stimulated cells than in control cells. Additionally, TGF-β1 induced the activation of nuclear factor-κB, and the expression of extracellular matrix proteins and several cytokines in HSC-T6 cells. The active form of Rap1 (Rap1 V12) suppressed RhoA-GTP levels, whereas the dominant-negative form of Rap1 (Rap1 N17) augmented RhoA-GTP levels. Therefore, the data confirmed that Rap1 regulated the activation of RhoA in TGF-β1-stimulated HSC-T6 cells. These findings suggest that TGF-β1 regulates Rap1, resulting in the suppression of RhoA, activation of and formation of F-actin during the migration of HSCs.

Purpose Gemcitabine–oxaliplatin (GEMOX) demonstrated mild toxicity and promising effectiveness in patients with advanced urothelial cell cancer (UCC). We investigated the activity and safety of first-line GEMOX compared with gemcitabine–carboplatin (GCb) in cisplatin-ineligible patients with advanced UCC. Methods Treatment-naive, cisplatin-ineligible patients with advanced UCC were randomly assigned to GEMOX (gemcitabine 1000 mg/m2, oxaliplatin 100 mg/m2 on day 1 [D1] every 2 weeks) or GCb (1000 mg/m2 of gemcitabine on D1 and D8 and carboplatin area under the curve of 4.5 mg/mL/min on D1 every 3 weeks). We evaluated the objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). Results Between January 2011 and March 2017, 80 patients were enrolled; 39 and 40 patients were allocated to GCb and GEMOX arms, respectively. The ORR was 48.7% in the GCb arm and 55.0% in the GEMOX arm. The median follow-up duration was 37.8 months; the median PFS and OS in the GCb and GEMOX arms were 5.5 months (95% confidence interval [CI], 4.8–6.2) vs. 4.4 months (95% CI, 2.7–6.1) and 9.1 months (95% CI, 5.2–13.0) vs. 11.0 months (95% CI, 6.9–15.0), respectively. ≥ Leucopenia, neutropenia and fatigue of ≥ grade III were significantly more common in the GCb arm (26% vs. 3%, P = 0.003; 33% vs. 10%, P = 0.014; 15% vs. 3%, P = 0.012), whereas any-grade neuropathy was more common in the GEMOX arm (8% vs. 60%). Conclusions GEMOX showed similar efficacy with GCb and a favourable haematologic toxicity profile. GEMOX may be an additional chemotherapy option for patients with UCC ineligible for cisplatin-containing chemotherapy (NCT01487915).

Aims Physical activity has been shown to reduce mortality in a dose-response fashion. Current guidelines recommend 500–1000 metabolic equivalent task (MET)-min per week of regular physical activity. This study aimed to compare the impact of leisure-time physical activity on mortality in primary versus secondary cardiovascular prevention. Methods and results This study included a total of 131 558 and 310 240 subjects with and without cardiovascular disease (CVD), respectively, from a population-based cohort. Leisure-time physical activity was measured by self-report questionnaires. The study subjects were followed-up for a median of 5.9 years, and the main study outcome was all-cause mortality. There was an inverse relationship between the physical activity level and the mortality risk in both groups. The benefit in the secondary prevention group was shown to be greater than that in the primary prevention group: every 500 MET-min/week increase in physical activity resulted in a 14% and 7% risk reduction in mortality in the secondary and primary prevention groups, respectively (interaction P < 0.001). In addition, while individuals without CVD benefited the most between 1 and 500 MET-min/week of physical activity, the benefit in those with CVD continued above 500 − 1000 MET-min/week. The adjusted mortality risk of individuals with CVD who performed a high level of physical activity (≥1000 MET-min/week) was shown to be comparable to or lower than that of their counterparts without CVD. Conclusion Individuals with CVD may benefit from physical activity to a greater extent than do healthy subjects without CVD.

Background: Endocrine treatment is preferred recommendation by clinical guidelines in premenopausal as well as postmenopausal women with hormone receptor (HR)-positive, HER2-negative metastatic breast cancer (MBC). In real-world clinical practice, however, substantial numbers of patients are treated with chemotherapy in earlier lines The purpose of this phase II study was to compare the clinical antitumor activity and safety of combined therapy with exemestane plus gonadotropin-releasing hormone (GnRH) agonist plus palbociclib with that of capecitabine in premenopausal women with HR-positive, HER2-negative MBC. Methods: This was a prospective, two-arm, randomized, multicenter open-label phase II study. Participants were premenopausal women with breast cancer that had relapsed or progressed during prior tamoxifen. One line of previous chemotherapy for metastatic setting was allowed. Patients were randomized to chemotherapy (capecitabine 1250 mg/m2 twice daily for 2 weeks every 3 weeks) or combination endocrine therapy (exemestane 25 mg/day for 28 days and palbociclib 125 mg/day for 21 days every 4 weeks plus leuprolide). Primary end point was progression-free survival (PFS). Findings: Of 189 patients enrolled between 2015 and 2018 from 14 centers, 184 were randomly assigned to chemotherapy (n=92) or endocrine therapy with palbociclib (n=92). Median age was 44 years (range 28–58). Approximately half the patients (51%) were treatment naive for MBC. During a median 17 months of followup, median PFS was superior for endocrine therapy plus palbociclib than for capecitabine [20·1 vs. 14·4 months, p=0·0469 by log-rank test; hazard ratio 0·659 (95 CI 0·437–0·994)]. Hematological toxicities of ≥ grade 3 were significantly more common with palbociclib than with capecitabine (75·0% vs. 16·3%). Diarrhea (12·0% vs. 38·4%) and hand–foot syndrome (1% vs. 77%) were more common with capecitabine. Interpretation: Exemestane plus palbociclib with ovarian suppression showed clinical benefit in terms of PFS compared with capecitabine in premenopausal patients with HR-positive, HER2-negative MBC. Trial Registration: The ClinicalTrials.gov identifier number was NCT02592746. Funding Statement: This study was supported by Pfizer (exemestane, palbociclib), Shinpoong (capecitabine), Daewoong Korea and Takeda (leuprolide) for study drugs. This work was partly funded by a grant from the Ministry of Health and Welfare, Republic of Korea (HA17C0055) and by the National R&D Program for Cancer Control, Ministry of Health and Welfare, Republic of Korea (1720150). Declaration of Interests: Dr. PARK reports grants and non-financial support from Pfizer, grants and non-financial support from AstraZeneca, grants and non-financial support from Novartis, grants and non-financial support from Merck, grants from Eisai, grants and non-financial support from Roche, outside the submitted work. Dr. Im reports grants from Pfizer, drug supply from Pfizer, Shinpoong, Daewoong, and Dakeda, during the conduct of the study; grants from AstraZeneca and Pfizer, travel expenses for advisory board participation and advisory role for Novartis, advisory role for Hanmi, Pfizer, Eisai, Amgen, Lilly, MediPacto, Roche, outside the submitted work. Dr. Jung reports personal fees from AstraZeneca Korea, personal fees from Roche Korea, outside the submitted work. Dr. Kim reports grants from Ono Pharma Korea Co., Ltd., outside the submitted work. Dr. Ahn reports personal fees and non-financial support from Astrazeneca, Roche, Beringer Ingelheim, Menarini, Pfizer, BMS, ONO, Boryung, grants from Samyang, outside the submitted work. Dr. Lee reports personal fees from AstraZeneca, personal fees from Bayer, personal fees from Eisai, personal fees from Novartis, personal fees from Ono, personal fees from Roche, personal fees from Samsung Bioepis, outside the submitted work. Dr. Kim reports grants from Novarts, grants from Sanofi Genzyme, non-financial support from Dongkook Pharma Co Ltd., outside the submitted work. Dr. Ahn reports personal fees from Amgen, personal fees from Pfizer, personal fees from AstraZeneca, personal fees from Menarini, personal fees from Roche, personal fees from Eisai, personal fees from Boehringer-Ingelheim, personal fees from BMS-Ono, personal fees from MSD, personal fees from Janssen, personal fees from Samsung Bioepis, personal fees from Takeda, outside the submitted work. All other authors declare they have no conflicts of interest. Ethics Approval Statement: The study was conducted in full accordance with the guidelines for Good Clinical Practice and the Declaration of Helsinki, and was approved by the institutional ethics committees of each hospital and the KCSG institutional review board. Written informed consent was obtained from each participant.

e14008 Background: We analyzed the treatment outcome of breast cancer patients with brain metastases (BM) in Korea to identify the prognostic factors and the role of whole brain radiation therapy (WBRT). Methods: Seven hundred thirty patients of breast cancer with BM treated at 17 institutions in Korea from 2000 to 2014 were analyzed. The median follow-up duration was 12 months. The analysis consisted of three cohorts: in cohort A, a total of 730 patients were included; in cohort B, 538 patients with available follow-up imaging after initial brain-directed treatment; and in cohort C, 54 patients receiving salvage WBRT due to recurrent BM after initial Stereotactic radiosurgery or WBRT. Overall survival (OS) was calculated from BM diagnosis in cohort A or from the last day of salvage WBRT in cohort C. Results: Median OS of cohort A was 15 months. In multivariate analysis, histologic grade 3, extracranial metastasis, number of BM > 4, hormone receptor (HR) or HER2 negativity, and shorter time interval to diagnosis of BM were associated with inferior OS. Among 538 patients in cohort B, 201 showed subsequent development of new BM at a median of 11 months after stereotactic radiosurgery or WBRT for the management of initial BM (at 1 year, HR+/HER2- 51.9%, HER2+ 44.0%, and TNBC 69.6%, respectively; p = 0.008). Upfront WBRT reduced subsequent development of new BM, which showed the significant difference among molecular subtypes (HR+/HER2-, 42% reduction at 1 year, p < 0.001; HER2+, 18.5%, p = 0.004; TNBC, 16.9%, p = 0.071). Multivariate analysis showed that shorter time interval to BM, TNBC subtype, extracranial systemic disease, number of BM > 4, and involvement of both tentoria increased subsequent development of new BM. Anti-HER2 therapy for HER2+ patients and upfront WBRT significantly reduced risk of new BM. In cohort C, upfront WBRT prolonged the salvage WBRT-free duration (median 6.9 vs. 8.7 months, p = 0.058). Median OS was 6.8 months after salvage WBRT. Longer interval to salvage WBRT, controlled primary tumor, high dose of salvage WBRT (BED10 > 37.5 Gy), and systemic treatment after salvage WBRT showed better OS. Uncontrolled extracranial systemic disease and salvage WBRT due to local progression without distant intracranial failure showed worse OS. Conclusions: The rates of new BM showed the significant differences among molecular subtypes. Upfront WBRT decreased subsequent development of new BM and this effect was dependent on the molecular subtype as well. Anti-HER2 therapy for HER2+ patients significantly decreased the subsequent development of new BM. On salvage WBRT setting, the patients having high dose of salvage WBRT, stable extracranial systemic disease and subsequent systemic therapy showed better OS.

The cellular prion protein (PrPC) is a cell surface glycoprotein expressed in many cell types that plays an important role in normal cellular processes. However, an increase in PrPC expression has been associated with a variety of human cancers, where it may be involved in resistance to the proliferation and metastasis of cancer cells. PrP-deficient (Prnp0/0) and PrP-overexpressing (Tga20) mice were studied to evaluate the role of PrPC in the invasion and metastasis of cancer. Tga20 mice, with increased PrPC, died more quickly from lung cancer than did the Prnp0/0 mice, and this effect was associated with increased transforming growth factor-beta (TGF-β) and programmed death ligand-1 (PD-L1), which are important for the development and function of regulatory T (Treg) cells. The number of FoxP3+CD25+ Treg cells was increased in Tga20 mice compared to Prnp0/0 mice, but there was no significant difference in either natural killer or cytotoxic T cell numbers. In addition, mice infected with the ME7 scrapie strain had decreased numbers of Treg cells and decreased expression of TGF-β and PD-L1. These results suggest that PrPC plays an important role in invasion and metastasis of cancer cells by inducing Treg cells through upregulation of TGF-β and PD-L1 expression.

Ataxia telangiectasia and Rad3-related (ATR) proteins are sensors of DNA damage, which induces homologous recombination (HR)-dependent repair. ATR is a master regulator of DNA damage repair (DDR), signaling to control DNA replication, DNA repair and apoptosis. Therefore, the ATR pathway might be an attractive target for developing new drugs. This study was designed to investigate the antitumor effects of the ATR inhibitor, AZD6738 and its underlying mechanism in human breast cancer cells. Growth inhibitory effects of AZD6738 against human breast cancer cell lines were studied using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (methyl thiazolyl tetrazolium, MTT) assay. Cell cycle analysis, Western blotting, immunofluorescence and comet assays were also performed to elucidate underlying mechanisms of AZD6738 action. Anti-proliferative and DDR inhibitory effects of AZD6738 were demonstrated in human breast cancer cell lines. Among 13 cell lines, the IC50 values of nine cell lines were less than 1 μmol/L using MTT assay. Two cell lines, SK-BR-3 and BT-474, were chosen for further evaluation focused on human epidermal growth factor receptor 2 (HER2)-positive breast cancer cells. Sensitive SK-BR-3 but not the less sensitive BT-474 breast cancer cells showed increased level of apoptosis and S phase arrest and reduced expression levels of phosphorylated check-point kinase 1 (CHK1) and other repair markers. Decreased functional CHK1 expression induced DNA damage accumulation due to HR inactivation. AZD6738 showed synergistic activity with cisplatin. Understanding the antitumor activity and mechanisms of AZD6738 in HER2-positive breast cancer cells creates the possibility for future clinical trials targeting DDR in HER2-positive breast cancer treatment.

Neurofibromas can occur anywhere in the body, but they usually involve the head, neck, pelvis, and extremities. Abdominal visceral involvement is rare, and intrahepatic involvement is even less common. We describe a patient who suffered from plexiform neurofibromatosis with liver involvement. A 49-year-old man, who had previously been diagnosed with neurofibromatosis, underwent esophagogastroduodenoscopy and abdominal ultrasonography for screening purposes. Esophagogastroduodenoscopy showed grade 2 esophageal varices and abdominal ultrasonography showed conglomerated nodules with echogenic appearances in the perihepatic space. Magnetic resonance imaging showed presumed plexiform neurofibroma involving the lesser sac and hepatic hilum and encasing the common hepatic artery celiac trunk and superior mesenteric artery left portal triad. We report an unusual case of portal hypertension attributed to the compressive narrowing of the portal vein by presumed as plexiform neurofibroma at the lesser sac and hepatic hilum.

Purpose We investigated the relationships between metastasis-free interval (MFI) and tumor characteristics, and assessed the prognostic value of MFI for survival after metastasis in patients with metastatic breast cancer. Furthermore, we compared MFI among the subtypes. Methods We identified 335 patients with postoperative tumor recurrence at distant site(s). All patients underwent curative resection and had a MFI of at least 6 months. MFI was categorized as short (

In the era of CDK4/6 inhibitors in hormone receptor (HR)-positive, HER2-negative metastatic breast cancer, few trials have been specifically studied to compare quality of life between palbociclib plus endocrine therapy (ET) and cytotoxic chemotherapy exclusively in premenopausal women. We aimed to evaluate differences of patient report outcomes (PROs) between palbociclib plus ET and capecitabine. PROs were assessed using EORTC QLQ-C30 at baseline, every 6 weeks, and the end of treatment. All EORTC QLQ-30 scores were maintained from baseline to the end of treatment. Patients treated palbociclib plus ET arm experienced delay in time-to-deterioration of physical functioning (HR = 0.58, 95% CI, 0.36 to 0.84, p = 0.0058), nausea and vomiting (HR = 0.48, 95% CI, 0.32 to 0.73, p = 0.0005), and diarrhea (HR = 0.42, 95% CI, 0.27 to 0.65, p = 0.001). There was a numeric trend for worsening of insomnia (HR = 1.43, 95% CI, 0.96 to 2.16, p = 0.079) and favoring of appetite loss (HR = 0.69, 95% CI, 0.44 to 1.07, p = 0.09) in the palbociclib plus ET arm. Premenopausal patients with palbociclib plus ET maintained QoL without compromising treatment efficacy.

To evaluate the safety and efficacy [intraocular pressure (IOP)-lowering effect and medication use] of a single trabecular microbypass stent (iStent; Glaukos Corp, San Clemente, CA) for medically controlled open-angle glaucoma. This retrospective case series included 42 eyes of 34 patients with medically controlled open-angle glaucoma with IOP less than 21 mm Hg. Clinical outcomes analyzed were IOP, medication use, corrected distance visual acuity (CDVA), and surgical complications. Surgical success was defined according to 4 criteria: IOP

e19391 Background: Emerging oncology drugs such as targeted agents and immune checkpoint inhibitors (ICIs) have brought dramatic advances in cancer treatment, while rapid rise in the drug cost. In Korea, the policy of expansion of health insurance coverage has improved accessibility to high-priced oncology drugs through their registrations in reimbursement list. However, this made a considerable impact on the financial burden of national health insurance. The objective of this study was to assess the awareness and perceptions of medical oncologists about the value frameworks of cancer drugs in Korea. Methods: We collected the data from survey for 102 medical oncologists at cancer conference. They were asked about prioritization among multiple considerations when they prescribe cancer drugs, The second question was awareness of value frameworks such as American Society of Clinical Oncology (ASCO) value framework and European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS). Additionally, potential application of value framework to the decision on reimbursement coverage was included. Results: The majority of respondents (90%) chose clinical efficacy as the most important factor when they selected oncology drug for cancer patients. Safety/tolerability and drug cost were followed as 5.9% and 1%, respectively. Meanwhile, the order of priority of considerations for ICIs treatment was as follows: clinical efficacy (74.5%), drug costs (13.7%), and safety/tolerability (9%). More than half of those questioned (53.9%) were already aware of ASCO value framework and ESMO-MCBS, while 26.5% did not recognize them at all. Over 90% of respondents agreed with the need for development of new value framework tool which can be complementary to current valuation system for oncology drugs. Oncologists responded positively to the necessity of the assessment tool as a criterion for reimbursement registration (84.3%) as well as post-reimbursement re-evaluation (89.2%). Conclusions: Our results suggest that value assessment tool of oncology drug be necessary for providing medical evidences for clinical decision and for determination to health insurance reimbursement in Korea.

Objective: Depression is common in cancer patients. We investigated the effects of playing a serious game in breast cancer patients with mild to moderate depression using functional neuroi...

Background Oxaliplatin is a platinum derivative that has shown efficacy in advanced hepatocellular carcinoma. S-1 is an oral fluoropyrimidine that has substituted for 5-fluorouracil in many cancers. This was a multicenter, open-label, single-arm phase II trial that evaluated the efficacy of S-1 and oxaliplatin (SOX) in advanced hepatocellular carcinoma. All patients included in the present study were systemic treatment-naïve. Prior treatment with sorafenib was allowed, but other treatments were not. Methods Patients received S-1 (40 mg/m2 twice daily from day 1–14) and oxaliplatin (130 mg/m2 on day 1) every 3 weeks. The primary end point was time to progression (TTP). Secondary end points included progression-free survival, overall survival (OS), response rate, and safety profile. Results Thirty six patients with advanced hepatocellular carcinoma were included in this study. The median TTP was 3.0 months (95% confidence interval (CI), 0.75–5.25), and the median OS was 10.3 months (95% CI, 6.4–14.3). Bone metastasis was associated with poorer TTP and OS. The efficacy of SOX was unaffected by prior sorafenib or locoregional therapy. The objective response rate was 13.9%. No grade 4 toxicity or death from adverse events occurred. The most common grade 3 toxicities were neutropenia (13.9%), thrombocytopenia (13.9%), and diarrhea (8.3%). Conclusions Although this trial did not meet its primary end point, the SOX regimen showed comparable efficacy and safety to the 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) regimen. As the SOX regimen is easier for patients, SOX may be a reasonable substitute for FOLFOX in hepatocellular carcinoma. Trial registration Clinicaltrials.gov NCT01429961. Registered 7 September 2011.

Hepatic stellate cells (HSCs) play pivotal roles in hepatic fibrosis as they synthesize glial fibrillary acidic protein (GFAP), which is increased in activated HSCs. GFAP-expressing HSCs and myofibroblasts accumulate in and around hepatic fibrosis lesions. Peptidylarginine deiminase 2 (PAD2) is responsible for the citrullination of GFAP (cit-GFAP). However, the involvement of PAD2 and cit-GFAP in hepatic fibrosis remains unclear. To determine the expression of PAD2 and cit-GFAP in hepatic fibrosis, C57BL/6 mice underwent bile duct ligation (BDL) or a sham operation. In BDL livers, the expression of PAD2 and its enzyme activity were significantly increased compared with controls. In addition, PAD2-postitive cells were rarely observed in only the portal vein and the small bile duct in sham-operated livers, whereas an increased number of PAD2-positive cells were detected in the bile duct and Glisson's sheath in BDL livers. Interestingly, PAD2 was colocalized with α-SMA-positive cells and CK19-positive cells in BDL livers, indicating upregulated PAD2 in activated HSCs and portal fibroblasts of the livers of BDL mice. We also found that citrullinated proteins were highly accumulated in the livers of BDL mice compared with controls. Moreover, the expression level of GFAP and the amount of cit-GFAP were higher in BDL livers than in control livers. In correlation with PAD2 localization, cit-GFAP was observed in α-SMA-positive and CK19-positive cells in the livers of BDL mice. These results suggest that the increased expression and activation of PAD2 along with increased citrullinated proteins, specifically cit-GFAP, may play important roles in the pathogenesis of hepatic fibrosis.