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The optimal treatment for patients with asymptomatic carotid artery stenosis is under debate. Since best medical treatment (BMT) has improved over time, the benefit of carotid endarterectomy (CEA) or carotid artery stenting (CAS) is unclear. Randomised data comparing the effect of CEA and CAS versus BMT alone are absent. We aimed to directly compare CEA plus BMT with CAS plus BMT and both with BMT only.SPACE-2 was a multicentre, randomised, controlled trial at 36 study centres in Austria, Germany, and Switzerland. We enrolled participants aged 50-85 years with asymptomatic carotid artery stenosis at the distal common carotid artery or the extracranial internal carotid artery of at least 70%, according to European Carotid Surgery Trial criteria. Initially designed as a three-arm trial including one group for BMT alone (with a randomised allocation ratio of 2·9:2·9:1), the SPACE-2 study design was amended (due to slow recruitment) to become two substudies with two arms each comparing CEA plus BMT with BMT alone (SPACE-2a) and CAS plus BMT with BMT alone (SPACE-2b); in each case in a 1:1 randomisation. Participants and clinicians were not masked to allocation. The primary efficacy endpoint was the cumulative incidence of any stroke or death from any cause within 30 days or any ipsilateral ischaemic stroke within 5 years. The primary safety endpoint was any stroke or death from any cause within 30 days after CEA or CAS. The primary analysis was by intention-to treat, which included all randomly assigned patients in SPACE-2, SPACE-2a, and SPACE-2b, analysed using meta-analysis of individual patient data. We did two-step hierarchical testing to first show superiority of CEA and CAS to BMT alone then to assess non-inferiority of CAS to CEA. Originally, we planned to recruit 3640 patients; however, the study had to be stopped prematurely due to insufficient recruitment. This report presents the primary analysis at 5-year follow-up. This trial is registered with ISRCTN, number ISRCTN78592017.513 patients across SPACE-2, SPACE-2a, and SPACE-2b were recruited and surveyed between July 9, 2009, and Dec 12, 2019, of whom 203 (40%) were allocated to CEA plus BMT, 197 (38%) to CAS plus BMT, and 113 (22%) to BMT alone. Median follow-up was 59·9 months (IQR 46·6-60·0). The cumulative incidence of any stroke or death from any cause within 30 days or any ipsilateral ischaemic stroke within 5 years (primary efficacy endpoint) was 2·5% (95% CI 1·0-5·8) with CEA plus BMT, 4·4% (2·2-8·6) with CAS plus BMT, and 3·1% (1·0-9·4) with BMT alone. Cox proportional-hazard testing showed no difference in risk for the primary efficacy endpoint for CEA plus BMT versus BMT alone (hazard ratio [HR] 0·93, 95% CI 0·22-3·91; p=0·93) or for CAS plus BMT versus BMT alone (1·55, 0·41-5·85; p=0·52). Superiority of CEA or CAS to BMT was not shown, therefore non-inferiority testing was not done. In both the CEA group and the CAS group, five strokes and no deaths occurred in the 30-day period after the procedure. During the 5-year follow-up period, three ipsilateral strokes occurred in both the CAS plus BMT and BMT alone group, with none in the CEA plus BMT group.CEA plus BMT or CAS plus BMT were not found to be superior to BMT alone regarding risk of any stroke or death within 30 days or ipsilateral stroke during the 5-year observation period. Because of the small sample size, results should be interpreted with caution.German Federal Ministry of Education and Research (BMBF) and German Research Foundation (DFG).

Background: Given that peak age of breast cancer (BC) is younger in Asians than in Western populations, relatively higher prevalence of pregnancy-associated breast cancer (PABC) has been reported. This study aimed to analyze the characteristics and clinical outcomes of PABC in Korea. Methods: We defined PABC as BC diagnosed during pregnancy or in the first postpartum year. We compared the clinicopathological characteristics and BC outcomes between patients with PABC and non-PABC patients in the prospective YBC cohort from Samsung Medical Center. Results: In total, 1492 patients were initially enrolled, and 1364 patients were included, of which 93 had PABC (6.8%). The median age of patients with PABC was 34 years. Hormone receptor expression was lower (64.6% vs 74.6%) and frequency of HER2 overexpression was higher (26.9% vs 17.6%) in patients with PABC than in non-PABC patients. The 5-year overall survival (OS) rates were 83.2% and 93.4% in patients with PABC and non-PABC patients, respectively (p < 0.001). The 5-year disease-free survival (DFS) rates were 72.2% and 83.8% in PABC and non-PABC patients. Conclusion: Compared to non-PABC patients, patients with PABC had poorer OS and DFS in this prospective cohort. Exploratory biomarker analysis for PABC is warranted.

Little has been determined regarding the association between patients’ and families’ illness understanding and preferences for medical care. We aimed to evaluate the association of illness understanding with advance care planning (ACP) and preferences for end-of-life care, such as aggressive care, early palliative care (EPC), and hospice care, among advanced cancer patients and their family caregivers. Patients were recruited for a prospective cohort study at outpatient and inpatient facilities in nine university hospitals in Korea (n = 150), and their primary family caregivers were also asked to participate (n = 101). Data on ACP and end-of-life care preferences were collected only at baseline in the cohort study with optional questions and were used to analyze these study results. Patients with illness understanding were more likely to have documented physician orders for life-sustaining treatment (POLSTs) (adjusted odds ratio [aOR] of 4.94) and to have discussed ACP with their families (aOR 2.15) than those who did not. Being expected to live for several months, they were unlikely to prefer active treatment. Caregivers understanding patients’ illness were more likely to write advance directives (ADs) and to discuss ACP; furthermore, they had already discussed ACP with family members. They did not prefer active treatment or life-sustaining treatments when their family members were expected to die within a few weeks. There was no significant association between illness understanding and preferences for EPC. Accurately recognizing an incurable disease is associated with preferences for more ACP and less aggressive care but not with preferences for EPC or hospice care among both advanced cancer patients and their family caregivers.

Background/Aims Colorectal cancer is associated with different anatomical, biological, and clinical characteristics. We determined the impact of the primary tumor location in patients with metastatic colorectal cancer (mCRC). Methods Demographic data and clinical information were collected from 1,115 patients from the Republic of Korea, who presented with mCRC between January 2009 and December 2011, using web-based electronic case report forms. Associations between the primary tumor location and the patient’s clinical characteristics were assessed, and factors inf luencing overall survival were analyzed using Cox proportional hazards regression models. Results Of the 1,115 patients recruited to the study, 244 (21.9%) had right colon cancer, 483 (43.3%) had left colon cancer, and 388 (34.8%) had rectal cancer. Liver and lung metastases occurred more frequently in patients with left colon and rectal cancer (p = 0.005 and p = 0.006, respectively), while peritoneal and ovarian metastases occurred more frequently in patients with right and left colon cancer (p < 0.001 and p = 0.031, respectively). The median overall survival of patients with tumors originating in the right colon was significantly shorter than that of patients whose tumors had originated in the left colon or rectum (13.7 months [95% confidence interval (CI), 12.0 to 15.5] vs. 18.0 months [95% CI, 16.3 to 19.7] or 19.9 months [95% CI, 18.5 to 21.3], respectively; p = 0.003). Tumor resection, the number of metastatic sites, and primary tumor location correlated with overall survival in the univariate and multivariate analyses. Conclusions Primary tumor location influences the metastatic sites and prognosis of patients with mCRC.

NB4 cell, the human acute promyelocytic leukemia (APL) cell line, was treated with various concentrations of arsenic trioxide (ATO) to induce apoptosis, measured by staining with 7-amino-actinomycin D (7-AAD) by flow cytometry. 2’, 7’-dichlorodihydro-fluorescein-diacetate (DCF-DA) and MitoSOXTM Red mitochondrial superoxide indicator were used to detect intracellular and mitochondrial reactive oxygen species (ROS). The steady-state level of SO2 (Cysteine sulfinic acid, Cys-SO2H) form for peroxiredoxin 3 (PRX3) was measured by a western blot. To evaluate the effect of sulfiredoxin 1 depletion, NB4 cells were transfected with small interfering RNA and analyzed for their influence on ROS, redox enzymes, and apoptosis. The mitochondrial ROS of NB4 cells significantly increased after ATO treatment. NB4 cell apoptosis after ATO treatment increased in a time- dependent manner. Increased SO2 form and dimeric PRX3 were observed as a hyperoxidation reaction in NB4 cells post- ATO treatment, in concordance with mitochondrial ROS accumulation. Sulfiredoxin 1 expression is downregulated by small interfering RNA transfection, which potentiated mitochondrial ROS generation and cell growth arrest in ATO- treated NB4 cells. Our results indicate that ATO-induced ROS generation in APL cell mitochondria is attributable to PRX3 hyperoxidation as well as dimerized PRX3 accumulation, subsequently triggering apoptosis. The downregulation of sulfiredoxin 1 could amplify apoptosis in ATO-treated APL cells.

Background: Positive attitudes for end-of-life (EOL) care along with adequate education are key factors for the provision of quality EOL care. This national study was conducted to identify the factors that influence attitudes toward EOL care on medical students. Method: An anonymous survey was designed and administered to fourth-year medical students at all 41 medical schools in Korea. Topics related to EOL care were assessed in classroom teaching, bedside teaching, and feedback experiences during clinical clerkships. Seven questions for self-rated attitudes and affecting factors were analyzed toward EOL care. Results: With a response rate of 49.2%, the median number of topics recognized by the students as having been delivered was 5 of 11 topics in classroom lectures and 1 of 8 topics in clinical experience. Although few (21.2%) participants indicated that they felt ready for EOL care practice, nevertheless, most felt that they should have adequate knowledge of and preparation for clinical competency in EOL care. Several parameters including respondent’s demographics and exposure to EOL care topics in classroom and in bedside teaching influenced the responses to all 7 attitude questions. However, having more than 1 bedside experience was the only factor positively affecting all attitudinal measures. Conclusions: Clinical experience related to EOL care seems to be the utmost priory in fostering positive attitudes and competency among medical students.

The most common sites for extragonadal germ cell tumors are the midline mediastinum, retroperitoneum and, much less frequently, the stomach. The stomach-originated primary germ cell tumor carries a poor prognosis, especially when metastasis occurs to the liver, with a mean survival time of 1 month. We describe the case of a 77-year-old male who presented with usual symptoms of gastric malignancy. Gastrectomy was performed. Histopathology of surgically resected tissue revealed a mixture of adenocarcinoma and endodermal sinus tumor components with α-fetoprotein production. After liver metastasis was identified, oxaliplatin and capecitabine were administered as palliative chemotherapy. The response was poor. For the second-line therapy, bleomycin, etoposide, and cisplatin (BEP) therapy was initiated. The overall response to these drugs was a partial response and the residual liver lesion was considered to be resectable. The patient died of pneumonia 11 months following the BEP session, representing an overall survival time of 22 months. Gastric adenocarcinoma with a germ cell tumor component is uncommon and an effective combination of chemotherapeutic agents is not yet clear. In this case, the patient received germ cell tumor-targeting chemotherapy and showed a durable response. Hence, germ cell-targeting cytotoxic agents have potential as the ‘front-line regimen'.

Aim To identify the candidate marker predicting treatment response and survival outcome in rectal cancer patients who received preoperative chemoradiotherapy (CRT). Patients and methods Between 2000 and 2015, 159 patients with histologically-confirmed rectal adenocarcinoma underwent preoperative CRT followed by surgery. Among them, 70 patients were enrolled and the expression of survivin, cancer stem cell markers (CD44 and CD133) and epithelial-mesenchymal transition markers (E-cadherin and TWIST1) in pretreatment biopsy specimens were evaluated by immunohistochemistry. Associations between the expression of markers and clinical outcomes were evaluated. Results The median follow-up period of all patients was 71 (range=15-203) months. Five-year overall (OS), disease-free (DFS), locoregional recurrence-free (LRRFS) and distant metastasis-free (DMFS) survival were 80.5%, 60.2% 90.1% and 76.5%, respectively. A significant association between survivin overexpression and worse treatment outcome was shown on univariate analyses for OS, DFS and DMFS (p=0.022, 0.002, and 0.005, respectively). On multivariate analysis, survivin overexpression was an adverse prognosticator for DFS and DMFS (p=0.007 and 0.015, respectively), with a borderline significant trend towards a shorter OS (p=0.069). Four other single biomarkers were not associated with survival outcomes. However, overexpression of both survivin and CD44 was significantly associated with worse OS on multivariate analysis (p=0.003). Conclusion Survivin combined with CD44 might be a candidate biomarker for the prediction of recurrence and survival in patients who received preoperative CRT for rectal cancer. Further research with a larger population is needed to validate these results.

Context To respect a patient's wish for end-of-life care, “the Act on Decisions on Life-Sustaining Treatment for Patients at the End-of-Life” was enacted in South Korea in 2016. Current understanding of people who would be involved in advance care planning (ACP) is crucial to disseminate it systematically. Objectives The objective of this study was to investigate awareness and attitudes toward ACP in South Korea. Methods A multicenter, nationwide cross-sectional study was conducted a survey regarding ACP among four groups that would have different positions and experiences: 1,001 cancer patients, 1,006 family caregivers, 928 physicians, and 1,005 members of the general public. Results A total of 16% of the general population, 33% of the patients and caregivers, and 61% of the physicians had knowledge of advance directives. More than 63% of the general population, above 72% of the patients and caregivers, and 97% of the physicians were willing to do so when the disease status was aggravated or terminal. The possibility for changing the plan, uncertainty as to whether directives would actually be followed, and psychological discomfort were common reasons for not wanting to engage in ACP. Routine recommendations for a specific medical condition, heightened accessibility, and health insurance support were common factors that could help facilitate ACP. Conclusion Our findings suggest that strategies for promoting ACP should reflect different perspectives among the general public, patients, family caregivers, and physicians. Public advocacy, resources for approaching and integrating ACP into routine health care, as well as systematic support provisions are needed.

Background It is difficult to decide whether to inform the child of the incurable illness. We investigated attitudes of the general population and physicians toward prognosis disclosure to children and associated factors in Korea. Methods Physicians working in one of 13 university hospitals or the National Cancer Center and members of the general public responded to the questionnaire. The questionnaire consisted of the age appropriate for informing children about the prognosis and the reason why children should not be informed. This survey was conducted as part of research to identify perceptions of physicians and general public on the end-of-life care in Korea. Results A total of 928 physicians and 1,241 members of the general public in Korea completed the questionnaire. Whereas 92.7% of physicians said that children should be informed of their incurable illness, only 50.7% of the general population agreed. Physicians were also more likely to think that younger children should know about their poor prognosis compared with the general population. Physicians who opposed incurable illness disclosure suggested that children might not understand the situation, whereas the general public was primarily concerned that disclosure would exacerbate the disease. Physicians who were women or religious were more likely to want to inform children of their poor prognosis. In the general population, gender, education, comorbidity, and caregiver experience were related to attitude toward poor prognosis disclosure to children. Conclusion Our findings indicate that physicians and the general public in Korea differ in their perceptions about informing children of poor prognosis., Graphical Abstract

We conducted a phase II trial of 5-fluorouracil and oxaliplatin combination chemotherapy as a second-line treatment in unresectable/metastatic biliary tract cancer patients who had failed gemcitabine-based chemotherapy. Patients treated with gemcitabine-based palliative treatment were enrolled in this study. Patients were received modified FOLFOX3 (mFOLFOX3) consists of oxaliplatin 85 mg/m2 (day 1) and leucovorin 30 mg (days 1, 2) followed by 5-fluorouracil 1,500 mg/m2 (days 1, 2) every 2 weeks. Between March 2010 and June 2012, a total of 30 patients were enrolled in this study. Twenty-eight patients were measurable for treatment response. One achieved complete response, and one a partial response was observed. Overall response rate was 7.1 % (95 % confidence interval 0.9–23.5 %). The median progression-free survival was 1.6 months, and the median overall survival was 4.4 months. Grade 3–4 hematologic toxicities included neutropenia (6.7 %) and thrombocytopenia (3.4 %). The most common non-hematologic toxicity was neuropathy (22.2 %). However, the most common grade 3–4 non-hematologic toxicity was hyperbilirubinemia (5.0 %). There was one treatment-related death due to neutropenic infection. mFOLFOX3 as a second-line regimen has modest effect and tolerable toxicity in unresectable/metastatic biliary tract cancer patients who have been treated previously via gemcitabine-based chemotherapy.

Background Combination therapy with oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX) chemotherapy drastically improves survival of advanced pancreatic cancer patients. However, the efficacy of FOLFIRINOX as a second-line treatment after gemcitabine failure has not been tested prospectively. We investigated the feasibility and safety of attenuated FOLFIRINOX in patients with gemcitabine-refractory advanced pancreatic cancer. Methods A multicenter phase II prospective open-label, single-arm study was conducted at 14 hospitals. Patients with histologically proven invasive ductal pancreatic adenocarcinoma, a measurable or evaluable lesion, Eastern Cooperative Oncology Group performance status 0 or 1, adequate organ function, and aged 19 years or older were eligible. Attenuated FOLFIRINOX consisted of oxaliplatin 65 mg/m2, irinotecan 135 mg/m2, and leucovorin 400 mg/m2 injected intravenously on day 1 and 5-fluorouracil 2000 mg/m2 continuously infused intravenously over 46 h on days 1–2, repeated every 2 weeks. The primary endpoint was progression-free survival from the initiation of FOLFIRINOX. Secondary endpoints were the objective response rate, disease control rate, overall survival, safety, and tolerability. We estimated overall survival and progression-free survival using the Kaplan–Meier methods. Results We enrolled 39 patients from 14 institutions. The objective response rate was 10.3%, while the disease control rate was 64.1%. The 6-month and 1-year overall survival rates were 59.0% and 15.4%, respectively. Median progression-free survival and overall survival were 3.8 months (95% confidence interval [CI] 1.5–6.0 months) and 8.5 months (95% CI 5.6–11.4 months), respectively. Grade 3 or 4 adverse events were neutropenia (41.0%), nausea (10.3%), anorexia (10.3%), anemia (7.7%), mucositis (7.7%), pneumonia/pleural effusion (5.1%), and fatigue (5.1%). One treatment-related death attributable to septic shock occurred. Conclusion Attenuated FOLFIRINOX may be promising as a second-line therapy for gemcitabine-refractory pancreatic cancer.

ABC-02 trial of gemcitabine plus cisplatin combination showed prolongation of overall survival in biliary tract cancer (BTC) patients. In this multicenter retrospective study, we evaluated the treatment outcome of gemcitabine combined with platinum (GP) compared to that of gemcitabine (G) alone in Korean BTC patients. One hundred and fifty-one patients with histologically confirmed biliary tract adenocarcinoma were enrolled at nine institutions between July 2003 and May 2011, including 100 treated with GP and 51 treated with G. With a median follow-up of 7.7 months (range 0.4–38.3 months), the median overall survival (OS) was 12.4 months [95 % confidence interval (CI) 9.4–15.6 months] of the G group, which was not significantly different for the median OS of 11.0 months (95 % CI 9.7–12.3 months) of the GP group (p = 0.599). The median progression-free survival (PFS) was 3.9 months (95 % CI 0.8–7.0 months) in the G group and 3.3 months (95 % CI 2.6–4.0 months) in the GP group (p = 0.504). Overall response rates (ORR) were 18.8 % in G group and 23.9 % in GP group (p = 0.485). There was no significant difference in ORR, PFS, or OS for patients between the G group and the GP group, which was different from the ABC-02 trial. Therefore, gemcitabine monotherapy and GP combination are both effective regimens for Korean BTC patients.

Background & Aims The CpG island methylator phenotype (CIMP), defined by a high frequency of aberrantly methylated genes, is a characteristic of a subclass of colon tumors with distinct clinical and molecular features. Cohort studies have produced conflicting results on responses of CIMP-positive tumors to chemotherapy. We assessed the association between tumor CIMP status and survival of patients receiving adjuvant fluorouracil and leucovorin alone or with irinotecan (IFL). Methods We analyzed data from patients with stage III colon adenocarcinoma randomly assigned to groups given fluorouracil and leucovorin or IFL after surgery, from April 1999 through April 2001. The primary end point of the trial was overall survival and the secondary end point was disease-free survival. DNA isolated from available tumor samples (n = 615) was used to determine CIMP status based on methylation patterns at the CACNA1G , IGF2 , NEUROG1 , RUNX3 , and SOCS1 loci. The effects of CIMP on survival were modeled using Kaplan-Meier and Cox proportional hazards; interactions with treatment and BRAF , KRAS , and mismatch repair (MMR) status were also investigated. Results Of the tumor samples characterized for CIMP status, 145 were CIMP positive (23%). Patients with CIMP-positive tumors had shorter overall survival times than patients with CIMP-negative tumors (hazard ratio = 1.36; 95% confidence interval: 1.01–1.84). Treatment with IFL showed a trend toward increased overall survival for patients with CIMP-positive tumors, compared with treatment with fluorouracil and leucovorin (hazard ratio = 0.62; 95% CI: 0.37–1.05; P = .07), but not for patients with CIMP-negative tumors (hazard ratio = 1.38; 95% CI: 1.00–1.89; P = .049). In a 3-way interaction analysis, patients with CIMP-positive, MMR-intact tumors benefited most from the addition of irinotecan to fluorouracil and leucovorin therapy (for the interaction, P = .01). CIMP was more strongly associated with response to IFL than MMR status. Results for disease-free survival times were comparable among all analyses. Conclusions Patients with stage III, CIMP-positive, MMR-intact colon tumors have longer survival times when irinotecan is added to combination therapy with fluorouracil and leucovorin.

The aims of this study were to investigate the correlation between topoisomerase II alpha (TOP2A), microtubule-associated protein-tau (MAP-tau) and other prognostic factors in breast cancer and to evaluate the predictive value of TOP2A and MAP-tau in breast cancer patients who received anthracycline and taxane-containing adjuvant chemotherapy.Seventy patients with axillary lymph node positive breast cancer who underwent curative surgery between January 2000 and December 2005 were evaluated retrospectively. The levels of protein expression of TOP2A and MAP-tau were assessed using immunohistochemistry.Among the 70 patients, 43 (61.4%) showed TOP2A overexpression and 30 (42.9%) showed MAP-tau positivity. TOP2A overexpression was associated with p53 positivity and high histological grade. MAP-tau positivity was associated with a lower positive lymph node ratio, lower proliferative activity, and hormone receptor positivity. Based on the TOP2A and MAP-tau expression, there was no significant difference in disease-free survival in the breast cancer patients who received anthracycline and taxane-containing adjuvant chemotherapy.We conclude that immunohistochemical analysis of TOP2A and MAP-tau protein expression may not predict the benefits of adjuvant anthracycline and taxane chemotherapy in axillary node positive breast cancer.

Objective: To generate a map of local recurrences after pancreaticoduodenectomy (PD) for patients with distal extrahepatic cholangiocarcinoma (DEHC) and to evaluate the adequate target volume coverage encompassing the majority of local recurrences when the clinical target volume (CTV) for pancreatic cancer was applied. Methods: We retrospectively reviewed the records of DEHC patients who underwent pancreaticoduodenectomy and had postoperative CT scans acquired between 1991 and 2015 available. The sites of local recurrence were delineated on individual CT scans, and then, mapping was manually performed onto template CT images. Coverage of each site of local recurrence was evaluated by applying the CTV defined according to Radiation Therapy Oncology Group (RTOG) consensus guidelines (CTVRTOG ) for target delineation in the postoperative treatment of pancreatic head cancer. Results: Of the 99 patients, 36 patients had a total of 62 local relapses identifiable by postoperative CT scans; the relapses were the most frequent in the choledochojejunostomy (CJ) site, 11 sites (17.7%); para-aortic area, 10 sites (16.1%), superior mesenteric artery area, 10 sites (16.1%); and portal vein area, 9 sites (14.5%). 21 sites (33.9%) were not covered by the CTVRTOG, and the most common site of local recurrence outside the CTVRTOG was the CJ site. Conclusion: When mapping of local relapses was evaluated according to the CTVRTOG, the choledochojejunostomy site was identified as a high-risk area of local recurrence but was insufficiently covered within the CTVRTOG. These findings may help construct a target volume for postoperative radiotherapy in DEHC. Advances in knowledge: Mapping local recurrences can aid in defining appropriate target volume for postoperative radiotherapy in DEHC.

55 Background: This study explored the current state of end-of-life (EoL) care education provided to Korean medical students and their self-rated attitudes toward EoL-related education. Methods: An anonymous survey was given to fourth year medical s tudents and the principle EoL care educators at all 41 Korean medical schools. The medical educators were asked to identify the EoL care-related topics that they usually teach students. Both students and medical educators completed seven items regarding self-perceived attitudes. Results: In total, 23 medical educators (56.1%) and 1,545 medical students (46.3%) responded. Of nine topics related to EoL care, the most frequently taught topics were delivering bad news (100%) and managing physical symptoms (74.1%), whereas setting treatment goals was taught the least frequently (37.0%). Approximately half of the educators taught the withdrawal of life-sustaining devices (59.3%), death and dying (55.6%), and advanced directives (55.6%). When the medical students were dichotomized into groups taught at least six topics (n = 815) versus five or fewer topics (n = 729), the group taught at least six topics expressed more satisfaction with EoL care education and they considered EoL care-related issues during their clerkship rotations. They also had fewer negative answers when they were asked about their readiness to practice EoL care. Conclusions: EoL education is inadequate for Korean medical students. However, medical students who were more fully instructed in this topic reported self-rated competency regarding EoL care-related issues. Further research should develop an education system that provides sufficient knowledge and training in EoL care for Korean medical students.

To investigate the significance of carbohydrate antigen 19-9 (CA19-9) levels for survival in locally advanced pancreatic cancer (LAPC) treated with concurrent chemoradiotherapy (CCRT).We retrospectively reviewed data from 97 LAPC patients treated with CCRT between 2000 and 2013. CA19-9 levels (initial and post-CCRT) and their changes [{(post-CCRT CA19-9 level - initial CA19-9 level)/(initial CA19-9 level)} × 100] were analyzed for overall survival. A cut-off point of 37 U/mL was used to analyze initial and post-CCRT CA19-9 levels. In order to define an optimal cut-off point for change in CA19-9 level, the maxstat package of R was applied.Median overall survival was 14.7 months (95% CI 13.4-16.0), and the 2-year survival rate was 16.5%. The estimated optimal cut-off point of CA19-9 level change was 94.4%. On univariate analyses, CA19-9 level change between initial and post-CCRT was significantly correlated with overall survival (median survival time 9.7 vs 16.3 months, p 0.001). Multivariate analyses confirmed that CA19-9 level change from initial to post-CCRT was the only prognostic factor (p 0.001).Change in CA19-9 level between initial and post-CCRT was a significant prognostic marker for overall survival in LAPC treated with CCRT. A CA19-9 level increase94.4% might serve as a surrogate marker for poor survival in patients with LAPC undergoing CCRT, and the prognostic power surpassed other CA19-9 variables including initial and post-CCRT values.

Background The β-catenin signaling is important in cell growth and differentiation and is frequently dysregulated in various cancers. The most well-known mechanism of endocrine resistance is cross-talk between the estrogen receptor (ER) and other growth factor signaling, such as phosphatidylinositol-3-kinase (PI3K)/Akt and the mammalian target of rapamycin (mTOR) signaling pathway. In the present study, we investigated whether β-catenin could be a potential target to overcome endocrine resistance in breast cancer. Methods We established tamoxifen-resistant (TamR) cell line via long-term exposure of MCF-7 breast cancer cells to gradually increasing concentrations of tamoxifen. The levels of protein expression and mRNA transcripts were determined using western blot analysis and real-time quantitative PCR. The transcriptional activity of β-catenin was measured using luciferase activity assay. Results TamR cells showed a mesenchymal phenotype, and exhibited a relatively decreased expression of ER and increased expression of human epidermal growth factor receptor 2 and the epidermal growth factor receptor. We confirmed that the expression and transcriptional activity of β-catenin were increased in TamR cells compared with control cells. The expression and transcriptional activity of β-catenin were inhibited by β-catenin small-molecule inhibitor, ICG-001 or β-catenin siRNA. The viability of TamR cells, which showed no change after treatment with tamoxifen, was reduced by ICG-001 or β-catenin siRNA. The combination of ICG-001 and mTOR inhibitor, rapamycin, yielded an additive effect on the inhibition of viability in TamR cells. Conclusion These results suggest that β-catenin plays a role in tamoxifen-resistant breast cancer, and the inhibition of β-catenin may be a potential target in tamoxifen-resistant breast cancer.

Purposes: Most medical schools in Korea do not provide adequate education in end-of-life care. This study was designed to illustrate the need to improve end-of-life care edu cation and to assess the effect of the education on fourth-year medical students’ awareness and attitude towards hospice and palliative care for terminally ill patients. Methods: One hundred sixty six fourth-year medical students were surveyed with questionnaires on end-of-life care before and after they received the education. Results: Before receiving the education, students most frequently answered “ at the end of life” (33.6%) was appropriate time to write an advance medical directive. After the education, the most frequent answer was “ in healthy status” (58.7%). More students agreed to withholding or withdrawing futile life-sustaining treatment increased after the education (48.1% vs. 92.5% (P＜0.001) for cardiopulmonary resuscitation, 38.3% vs. 92.5% (P＜0.001) for intubation and mechanical ventilation, 39.1% vs. 85.8% (P＜ 0.001) for inotropics, 60.9% vs. 94.8% (P＜ 0.001) for dialysis and 27.8% vs. 56.0% (P＜0.001) for total parenteral nutrition). Significantly more students opposed euthanasia after the education (46.6% vs. 82.1%, P＜0.001). All students agreed to the need for education in end-of-life care. Conclusion: After reflecting on the meaning of death through the end-of-life care education, most s tudents recognized the need for the education. The education brought remarkable changes in students’ awareness and attitude towards patients at the end of life. We suggest end-of-life care education should be included in the regular curriculum of all medical schools in Korea. (Korean J Hosp Palliat Care 2012;15:30-35)

Purpose The HER2 gene encodes a 185-kd transmembrane glycoprotein receptor (p185(HER2)) that has partial homology with the epidermal growth factor receptor (EGFR) and shares intrinsic tyrosine kinase activity. The HER2 gene has been found to be amplified in various human cancers and to be associated with poor prognosis. The authors investigated the correlation between clinicopathologic factors and the overexpression of the p185(HER2) in Korean gastric adenocarcinoma patients, and determined whether the antiproliferative effects of anti- p185(HER2) antibody can also be observed on gastric cancer cell lines that overexpress this growth factor receptor. Materials and methods We evaluated the relationship between p185(HER2) overexpression and clinicopathological features in 94 (M: F=52: 42) gastric adenocarcinoma patients (median age 59 years). Protein expression was analysed by immunohistochemical staining in paraffin embedded tissues with monoclonal antibody for p185(HER2). To explore the role of humanized anti-p185(HER2) monoclonal antibody trastuzumab (Herceptin ) in vitro, the growth curve of Korean gastric cancer cells that overexpress the p185(HER2) protein was studied and a cell cycle analysis was performed. Results p185(HER2) overexpression correlates positively with lymph node metastasis (p=0.002), distant metastasis (p=0.01), AJCC classification (p=0.01), higher relapse rate p=0.001), and a tendential association with the pT stage (p=0.054). p185(HER2) overexpression was found to be more frequent in advanced gastric cancer than early gastric cancer (54.1% vs 24.2%, p=0.008). Patients with overexpression of p185(HER2) were found to have significantly lower relapse-free (p=0.003) and overall survival (p= 0.0004) than patients without overexpression. Among several Korean gastric cancer cell lines, SNU-1, SNU-5, and SNU-620 overexpress p185(HER2). Trastuzumab inhibited the proliferation of p185(HER2) overexpressed Korean gastric cancer cell line by 21% with down-regulation of p185(HER2) protein expression. DNA fluorescence flow cytometry of propidium iodide-stained nuclei showed a reduction in the fraction of the S phase following treatment with trastuzumab. Conclusion S: Taken together, our observations suggest the potential prognostic significance of p185(HER2) overexpression in Korean gastric adenocarcinoma patients and point to the need for further research on this mechanism. This suggests the possible use of p185(HER2) as a therapeutic target in gastric cancer.

Backgrounds : Autophagy plays an important role in the pathogenesis of multiple myeloma. Autophagy usually acts on a pro-survival mechanism, and cooperates with the ubiquitin proteasome system in the homeostasis of myeloma cells by degrading excessive and misfolded proteins for energy recycling. Therefore, the inhibition of autophagy could effectively induce death and could synergize with proteasome inhibitors in myeloma cells. In this study, we investigated the synergistic mechanism of apoptosis with bortezomib (BTZ) and autophagy inhibitors in the MM cells. Methods : We evaluated the change of autophagy, apoptosis, mitochondrial ROS and cellular level of redox enzymes, including peroxiredoxin (Prx), thioredoxin (Trx), thioredoxin reductase (Trx-R) using human myeloma cell lines, MM.1S and MM.1R during BTZ treatment. To study the status of oxidation for redox enzyme, sulfinic acid (SO2) or multimeric form of Prx, Trx and Trx-R by western blot were measured using non-reducing or reducing gel. Results : Mitochondrial over cytosolic ROS of MM cells was increased significantly after 24 hour of BTZ (2.5 nM) treatment. Apoptosis of MM cell after BTZ treatment was increased in concordance with mitochondrial ROS increment of MM cells. N-acetylcystein (NAC) reversed BTZ-induced mitochondrial ROS elevation and apoptosis of MM cells as well. Increased expressions of cleaved caspase-9 and cleaved caspase-3 were also observed during BTZ-induced MM cell apoptosis. LC3-II expression was elevated along with increment of mitochondrial ROS and apoptosis of MM cells after BTZ treatment. Oxidation of PRX4 and TRX2 was observed during BTZ-induced apoptosis of MM cells. After treatment of NAC, LC3-II and PRX4/TRX2 expression was reversed. Inhibition of autophagy with 3-Methyladenine (3-MA) not only resulted in a further increase in BTZ-induced apoptosis but also induced mitochondrial ROS in MM cells. Conclusions : Autophagy is induced during BTZ treatment in MM cells. Our experiment showed crosstalk between autophagy and mitochondrial ROS and its redox enzymes during BTZ-induced MM cell apoptosis. Inhibition of autophagy with 3-MA potentiates BTZ-induced apoptosis of MM cells via up regulation of mitochondrial ROS. Our results provide new perspective on the cellular mechanism of action of BTZ and support the synergism of BTZ with autophagy inhibitor for an improved therapy of the multiple myeloma. Disclosures No relevant conflicts of interest to declare.

ObjectivesThis study determined attitudes of four groups—Korean patients with cancer, their family caregivers, physicians and the general Korean population—towards five critical end-of-life (EOL) interventions—active pain control, withdrawal of futile life-sustaining treatment (LST), passive euthanasia, active euthanasia and physician-assisted suicide.Design and settingWe enrolled 1001 patients with cancer and 1006 caregivers from 12 large hospitals in Korea, 1241 members of the general population and 928 physicians from each of the 12 hospitals and the Korean Medical Association. We analysed the associations of demographic factors, attitudes towards death and the important components of a ‘good death’ with critical interventions at EoL care.ResultsAll participant groups strongly favoured active pain control and withdrawal of futile LST but differed in attitudes towards the other four EoL interventions. Physicians (98.9%) favoured passive euthanasia more than the other three groups. Lower proportions of the four groups favoured active euthanasia or PAS. Multiple logistic regression showed that education (adjusted OR (aOR) 1.77, 95% CI 1.33 to 2.36), caregiver role (aOR 1.67, 95% CI 1.34 to 2.08) and considering death as the ending of life (aOR 1.66, 95% CI 1.05 to 1.61) were associated with preference for active pain control. Attitudes towards death, including belief in being remembered (aOR 2.03, 95% CI 1.48 to 2.79) and feeling ‘life was meaningful’ (aOR 2.56, 95% CI 1.58 to 4.15) were both strong correlates of withdrawal of LST with the level of monthly income (aOR 2.56, 95% CI 1.58 to 4.15). Believing ‘freedom from pain’ negatively predicted preference for passive euthanasia (aOR 0.69, 95% CI 0.55 to 0.85). In addition, ‘not being a burden to the family’ was positively related to preferences for active euthanasia (aOR 1.62, 95% CI 1.39 to 1.90) and PAS (aOR 1.61, 95% CI 1.37 to 1.89).ConclusionGroups differed in their attitudes towards the five EoL interventions, and those attitudes were significantly associated with various attitudes towards death.

This study evaluated the outcome of salvage radiotherapy for locoregionally recurrent extrahepatic bile duct cancer.We performed a retrospective review of 23 extrahepatic bile duct cancer patients who underwent radiotherapy with or without concomitant chemotherapy for isolated locoregional recurrence after radical surgery between August 2001 and September 2013. The median disease-free interval was 11.8 months. Salvage radiotherapy was delivered to the recurrent tumour with or without initial operation bed up to a median dose of 54 Gy (range, 45-60). 18 patients received concomitant chemotherapy.The median follow-up period was 14.2 months for all patients, and 48.8 months for survivors. The median overall survival and progression-free survival (PFS) were 18.4 (range, 4.4-114.6) and 15.5 months (range, 1.6-114.6), respectively. On multivariate analysis, the use of concomitant chemotherapy was a favourable prognostic factor for PFS (p = 0.027), and prolonged disease-free interval (≥1 year) was associated with a significantly poor overall survival (p = 0.047). Grade 3 or higher toxicities did not occur in follow-up period.Salvage radiotherapy showed promising survival outcomes in locoregional recurrence of extrahepatic bile duct cancer. Our results indicated that concomitant chemotherapy was associated with improved PFS. Concurrent chemoradiotherapy can be a viable salvage treatment option in selected patients. Advances in knowledge: Locoregional recurrence is the most common pattern of failure after radical resection in extrahepatic bile duct cancer. In this study, salvage radiotherapy showed favourable survival outcomes without severe complications in locoregionally recurrent extrahepatic bile duct cancer patients.

The aims of this study were to determine the number of Complementary and Alternative Medicine (CAM) web sites retrieved form Korean search engines, and to evaluate the quality of online CAM content. We evaluated results retrieved by the use of the key word 'anticancer treatment' on six common search engines in Korea. Among a total of 651 web sites, 226 web sites (35%) related to CAM were identified. The quality and risk of these sites were assessed for 97 web sites after removing duplicate and dysfunctional web sites. We evaluated the quality of the sites using Sandvik score. Scores in this study varied between 5 and 12 points, with a maximum of 14 points. We categorized the risk score for each web site based on the following criteria: (1) the site discourages the use of conventional medicine (23%: 22/97); (2) the site discourages adherence to the advice of a clinician (15%:15/97); (3) the site either provides opinions and experiences, or factual details (26%: 25/97); and (4) the site provides commercial details (46%: 45/97). The most popular web sites in Korea that relate to CAM for cancer offer information of extremely variable quality. Clinicians should be aware of the risks of inaccurate online information and attempt to protect their patients from those.

SummaryEvaluation of the Janus kinase 2 (JAK2) V617F mutation has been widely used for the diagnosis of myeloproliferative neoplasms (MPN). However, its prognostic relevance to clinical outcome is not completely understood. We investigated the association of JAK2 V617F with vascular events in Korean patients with myeloproliferative neoplasms (MPN). We studied 283 patients from 15 centers, who were diagnosed with MPN. The JAK2 V617F status was evaluated by allele-specific polymerase chain reaction (PCR) and sequencing. The patients’ diagnoses were essential thrombocythemia (ET n=146), polycythemia vera (PV n=120), primary myelofibrosis (n=12), and unclassifiable MPN (MPNu n=5). JAK2 V617F was detected in 89 (61%) patients with ET, 103 (86%) with PV, four (33%) with myelofibrosis, and four (80%) with MPNu. A higher number of leukocytes, haemoglobin levels and BM cellularity as well as an older age, lower platelet counts, and diagnosis of PV were significantly correlated with JAK2 V617F. Eighty-three and 43 episodes of thrombosis and bleeding occurred in 100 patients each before and after the diagnosis. Vascular events more frequently occurred in 37% of patients with JAK2 V617F than in 29% of those without the mutation (p=0.045). Among 175 patients whose samples were available for sequencing, 28 patients with homozygous JAK2 V617F had vascular events more frequently (57%) than those who were heterozygotes (39%) or had the wild type (27%) (p=0.03). The multivariate analysis showed that a JAK2 homozygous mutation, hypercholesterolemia and older age were independent risk factors for a vascular event. The results of this study showed that Korean patients with MPN had a similar JAK2 mutation rate and frequency of vascular events when compared to Western patients. The presence of V617F was significantly related to vascular events. Therefore, initial evaluation for the JAK2 mutation and careful monitoring for vascular events should be performed in MPN patients.

Type 2N von Willebrand disease (vWD) can be confused with hemophilia A due to decreased factor VIII levels and a bleeding tendency, and differential diagnosis is of importance for providing the optimal treatment and genetic counseling. For the accurate diagnosis of type 2N vWD, von Willebrand Factor (vWF) function tests, multimer assay and gene mutation analysis are needed. The patient was a 38-yr-old Nepalese woman with a history of bleeding manifestations from childhood, such as hemarthrosis, intramuscular hematoma, and menorrhagia. Family history revealed that her mother and elder brothers also had bleeding manifestations from childhood. When she had a laparotomy in 1991, she was diagnosed as hemophilia A with factor VIII level of 3.6% and was transfused with whole blood, factor VIII and cryoprecipitates. In June 2007, she was admitted to our hospital for further evaluation of bleeding tendency. Blood tests revealed normal CBC; bleeding time, 2 min; PT, 14.9 sec (11-14 sec); aPTT, 51.2 sec (24-38 sec); and factor VIII, 4.9% (50-150%). The prolonged aPTT was corrected by 1:1 mixing test to the levels of 106% and 84%, respectively, before and after 2 hr-incubation at 37°C. No abnormalities were found in the vWF antigen level (71.3%), ristocetin cofactor assay (130.4%), and multimer assay. Direct DNA sequencing of the VWF gene revealed homozygous missense mutation located in exon 19, c.2446C>T (p.Arg816Trp), confirming the diagnosis of type 2N vWD. (Korean J Lab Med 2008;28:258-61)

Objective. To evaluate the efficacy of intravenous lorazepam as premedication for bone marrow aspiration and biopsy (BMAB). Design. Randomized, double-blind, placebo-controlled. Patients. One hundred and thirty-eight consenting patients planned to receive BMAB. Intervention. Patients were randomly assigned to receive either intravenous lorazepam 1 mg or placebo just prior to BMAB. Setting. Tertiary referral center, inpatient setting. Outcome Measures. A questionnaire was used to determine the patient perception about the procedure and pain at baseline, which was completed just after the procedure, and the next day after the BMAB. Pain was rated using a 10-cm linear visual analog scale (VAS). Results. The mean VAS scores measured during the BMAB examination were 6.0 for lorazepam vs 6.2 for placebo. Few adverse events were noted during intravenous lorazepam administration. The patients in the lorazepam group were more likely to accept the next BMAB (P = 0.044). Conclusion. Intravenous lorazepam was safe in patients undergoing BMAB and was more effective than placebo in enhancing cooperation during BMAB and willingness to undergo another procedure. However, use of lorazepam 1 mg provided no reduction in the pain associated with BMAB. Further studies should focus on providing appropriate analgesia for this potentially painful procedure.

Objective: Nail toxicity is one of the most frequent non-hematologic toxicities of docetaxel and often deteriorates patients’ quality of life, leading to treatment discontinuation. To define the incidence of nail change as well as its association with specific risk factors, we prospectively investigated data of 84 consecutive patients with advanced non-small cell lung cancer who received first-line docetaxel/cisplatin combination chemotherapy. Methods: Chemotherapy-nao¨ve patients were treated with docetaxel, either 3-weekly or weekly, in combination with cisplatin. All patients received adequate premedications including corticosteroids, antiemetics and intravenous hydration. Toxicity was evaluated using National Cancer Institute (NCI) CTCAE version 3. Results: Twenty-two patients (26%) developed nail changes, including nine (11%) with grade 3. Nine patients who developed grade 3 nail changes (seven of whom received weekly docetaxel) were not able to complete planned chemotherapy despite topical and/or oral antibiotic treatment. Most occurrences of nail changes were diagnosed in patients who were treated with weekly schedule (P ¼ 0.02). The number of chemotherapy cycles and cumulative docetaxel doses were strongly associated with the development of nail changes. The cumulative hazard of developing nail changes increased above 10% after 2.8 months up to 40% at 6 months. A multivariate analysis of factors associated with the development of nail changes identified the following to have independent adverse significance: weekly docetaxel administration (odds ratio, 0.084; 95% CI, 0.014 –0.510; P ¼ 0.01) and the number of chemotherapy cycles given (odds ratio, 0.232; 95% CI, 0.067–0.805; P ¼ 0.02). Conclusion: Nail changes occur with more frequent and prolonged use of docetaxel.

Mapping of brain perfusion using bolus tracking methods is increasingly used to assess the amount and severity of cerebral ischemia in acute stroke. Using relative perfusion maps, however, it is difficult to identify the tissue at risk-maximum (TARM) of infarction with sufficient reliability and reproducibility.We analysed 76 perfusion computed tomography (PCT) derived maps of cerebral blood flow (CBF), cerebral blood volume (CBV) and time-to-peak (TTP) in 40 acute stroke patients using multidetector row technology and standard software (Somatom VolumeZoom, Siemens, Germany). 'Window narrowing' of the color maps was performed until color homogenisation of the contralateral unaffected hemisphere was reached. Tissue still depictable on the affected hemisphere after sufficient window narrowing was defined as the TARM. We analysed presence and size of the TARM on PCT maps, its relative perfusion values by comparison with contralateral, mirrored tissue, and its correlation with occurrence and final size of cerebral infarction on follow-up imaging.An ischemic area was visible in 64, 58.9 and 72.6% on the conventional CBF, CBV and TTP maps, respectively. After window narrowing, a TARM was present in 56.8, 54.1 and 63.0% of slices comprising 11.9, 11.6 and 21.1% of the ipsilateral hemisphere (CBF, CBV and TTP), respectively. The relative perfusion values were 38.7 (CBF) and 43.0% (CBV) for the entire ischemic area and 11.3 (CBF) and 13.3% (CBV) for the TARM. Definite cerebral infarction was visible on 68.1% of the target slices comprising 23.7 +/- 22.9% of the ipsilateral hemisphere. The size of the TARM correlated slightly better with the final infarction size (r=0.74-0.82) than the entire ischemic area (r=0.61-0.79). With respect to the occurrence of cerebral infarction, the presence of a TARM on CBF maps showed the best positive (97.9%) and negative (72.7%) predictability.On PCT maps, window narrowing provides a standardized display of the TARM in peracute stroke. The severely reduced values of relative CBF and CBV suggest the TARM to indicate tissue most prone to infarction.

Imatinib mesylate is the first molecule of targeted therapy in chronic myelogenous leukaemia inhibiting constitutively activated BCR-ABL kinase. There are no long-term follow-up studies of large sample sizes to assess the toxicity of the use of imatinib mesylate over 10 years. Several cases of hepatotoxicity, including fatal liver failure, have been associated with the long-term use of imatinib mesylate. We report here on a patient who experienced immediate dominant cholestatic damage of the liver and mild hepatocyte damage during imatinib mesylate therapy. This differs from most reports showing dominantly acute hepatitis with necrosis associated with the use of imatinib mesylate.

The objective of this retrospective study was to investigate clinical features and treatment outcomes in patients with angioimmunoblastic T-cell lymphoma (AITL), data of which were collected over a 15-year period. Sixty-five patients diagnosed with AITL were included in the study. About half of the patients (46.2%) presented with poor performance status (ECOGor = 2); 72.3% of patients belonged to high intermediate or high-risk of IPI and same proportion belonged to Class 2 of PIT (Prognostic index for PTCL-U), and most patients (95.4%) were diagnosed at an advanced stage. At diagnosis, 27 patients (41.5%) presented with malignant pleural effusion, and 22 patients (33.8%) had skin involvement. Most of the initial chemotherapy regimens were anthracycline-based (88.2%). Overall response rate to initial chemotherapy was 86.2% (64.7% of complete response, 21.5% of partial response). The median progression-free survival and overall survival of all patients was 7.1 months (95% CI, 2.8 - 11.4) and 15.1 months (95% CI, 6.7 - 23.5), respectively. Age, performance status, and PIT scores were predictive prognostic factors for survival. In conclusion, although AITLs showed a good response to the initial chemotherapy, their response durations were short; therefore, chemotherapy for AITL should be modified or intensified as in high-dose chemotherapy.

Nodal marginal zone B-cell lymphoma (NMZL) is a relatively uncommon type of lymphoma. Because of the rarity, the natural history and the optimal treatment modality have not been well defined. Therefore, we performed a retrospective analysis of the clinical features and treatment outcomes of NMZL. Thirty-six patients who were histologically diagnosed as NMZL were included in the analysis. Fifty-three percent of the patients had localized disease (stages I and II), and 21.2% (7/33) had bone marrow involvement at presentation. B symptom was present in only three patients (8.3%). Most patients were categorized as low or low-intermediate risk group by international prognostic index (IPI) (77.1%). Majority (94.4%) of the patients with localized disease achieved complete remission (CR) after the initial treatment. Of the seven patients with disseminated disease, who were treated with anthracycline-based chemotherapy, four patients achieved CR. Of the seven patients who received nonanthracycline-based chemotherapy, no patient achieved CR. After the median follow-up duration of 36 months, the median progression-free survival (PFS) was 3.9 (95% CI; 2.9-5.6) years, and the estimated 5-year PFS and overall survival rates were 47.2 and 82.7%, respectively. The significant predictive factors for PFS were performance status, advanced stage, and follicular lymphoma IPI (FLIPI) in this study. This clinical feature is similar to FL rather than to MZL-MALT type.

The selection of chemotherapeutic regimens is challenging for metastatic breast cancer (MBC) patients whose diseases have failed to respond to anthracyline and taxane. Capecitabine has advantages of oral administration and favorable toxicity profiles. This study was conducted to evaluate the efficacy of capecitabine and to identify the subgroup of patients who would potentially have benefit from capecitabine monotherapy in patients with anthracycline- and taxane-pretreated MBC. Female patients with MBC who had been previously treated with anthracycline and taxane received oral capecitabine 2500 mg/m(2) divided in two doses daily for 2 wk with 1-wk rest period. Between September, 1999, and December, 2002, a total of 38 patients were enrolled. Among the 36 evaluable patients, one patient achieved a complete response (CR), 9 patients had partial responses (PRs), and 13 patients had stable diseases (SDs). Response rate was 26% [95% confidence interval (CI), 12-40%] and the tumor control rate (TCR, CR+PR+SD) was 61% (95% CI, 45-77%). The median follow-up duration was 27.8 mo. The median duration of response was 8.9 mo, the median time to progression was 4.6 mo, and the median overall survival was 18.1 mo. The major toxicities were hand-foot syndrome, diarrhea, and emesis. There was no treatment-related death. The predictors of better overall survival were positivity of hormone receptor, disease-free survival longer than 1 yr, non-refractoriness to anthracycline, and fewer number (

Combined chemoradiotherapy (CRT) is the standard treatment modality for limited-stage small-cell lung cancer (LSCLC), but the optimal timing of radiation is controversial. Prolonged oral etoposide has the advantage of prolonged exposure, which possibly leads to improved clinical outcome. We conducted a phase II trial of early concurrent CRT, starting from the very beginning of the first cycle of chemotherapy for previously untreated LSCLC.Chemotherapy was given for six cycles, each consisting of oral etoposide (50 mg/m(2) daily from day 1 to 14) and intravenous cisplatin (75 mg/m(2) on day 1), every 3 weeks. Thoracic radiation therapy was given from day 1 of the first cycle of chemotherapy, administered at 2.0 Gy in 22 daily fractions to a total dose of 44 Gy.Forty-four patients were enrolled. The median age was 60 years (range, 42-77 years), including 15 patients (34%) over 65 years-of-age. We observed a complete response rate of 52% (95% CI, 37-67%), and an overall response rate of 88% in an intent-to-treat (ITT) analysis. Median overall survival was 14.9 months (95% CI, 11.4-18.3 months) and the median time to progression was 10.8 months (95% CI, 9.3-12.4 months) for the ITT population. In 220 cycles, grade 3-4 neutropenia was observed in 48% of cycles and grade 3-4 thrombocytopenia in 30% of cycles. Neutropenic fever was observed in 18 patients (41%).Early concurrent CRT, starting from the very beginning of the first cycle of chemotherapy with prolonged oral etoposide and cisplatin failed to show any improvement in survival compared with other CRT regimens.

Clinically silent circulating microembolic signals (MES) can be identified by transcranial Doppler ultrasound (TCD). It is not yet clear whether their occurrence is always linked to the presence of embolic sources. 24 terminally ill patients (7 women, 17 men; mean age 68 years) were investigated by TCD of the middle cerebral arteries. These findings were correlated with a complete post-mortem examination of potential embolic pathways. Four patients out of the 24 under investigation showed MES, 2 of them bilaterally. All these 4 MES-positive patients had a definite embolic source, i. e. bilateral carotid artery occlusive disease, endocarditis with thrombotic valvular adhesions and severe plaques in the aortic arch, dilated left atrium and a patent foramen ovale, or severe plaques in the aortic arch and a dilated left atrium, respectively. In the investigated patient group, we could demonstrate that MES can only be found when an embolic source is present. The finding of MES justifies an extensive clinical and laboratory search for potential embolic sources including extracranial and intracranial colour-coded duplex ultrasound, ECG, Holter-ECG, and TEE.

Carotid bruits are supposed to indicate the presence of high-grade common carotid or extracranial internal carotid artery stenosis in a large proportion of patients. Using a stethoscope, we prospectively auscultated 273 carotid arteries of 145 patients blinded to the results of a complete extracranial and intracranial Doppler investigation including extracranial color-coded duplex ultrasound. Fifty-four arteries showed stenosis of > or = 50%-99%, or occlusion of the extracranial internal or the common carotid artery. In 25 of these arteries, a bruit was present. In 9 out of 16 patients with extracranial stenosis from 70%-99%, a bruit was detected. In one additional patient with a middle-grade external carotid artery stenosis, a bruit was also present. In seven additional patients, a bruit was present in the absence of any carotid artery stenosis, cardiac vitium or goiter. The sensitivity of carotid auscultation for the detection of a 70%-99% stenosis of the common or extracranial internal carotid artery was 56% and specificity was 91%. The positive predictive value of a bruit found during carotid auscultation was 27%, and the negative predictive value of a normal auscultation was 97%. Carotid auscultation is a useful screening procedure in the detection of carotid stenosis or occlusion, but requires confirmation by carotid ultrasound.

Background and Purpose: Cardiac right-to-left shunts (RLS) can be identified by transesophageal echocardiography (TEE) as well as by transcranial Doppler ultrasound (TCD) using contrast agents, such as Echovist®-200 or Echovist®-300 in conjunction with a Valsalva maneuver (VM) as provocation procedure. Both Echovist preparations are in use. Currently, the appropriate timing of the VM is still under debate. Methods: Sixty-four patients were investigated by both TEE and bilateral TCD of the middle cerebral arteries. The following protocol was applied in a randomized way: (1) no VM, (2) VM for 5 s starting with the beginning of Echovist-300 injection, (3) VM for 5 s starting 5 s after the beginning of Echovist-300 injection, (4) VM for 5 s starting 10 s after the beginning of Echovist-300 injection, and (5) VM for 5 s starting 5 s after the beginning of Echovist-200 injection. Results: In 27 patients, an RLS was demonstrated by both TEE and contrast TCD (shunt-positive). Twenty-two patients were negative in both investigations, no patient was positive on TEE but negative on TCD, 15 patients were only positive on at least one TCD investigation but negative on TEE. Tests 3 and 5 were the most appropriate ones; test 3 was slightly superior to test 5. Conclusions: TCD using Echovist-300 or Echovist-200 is a sensitive method to identify TEE-proven cardiac RLS. To achieve the best diagnostic accuracy, the VM should be performed for a duration of 5 s starting at 5 s following the beginning of contrast injection.

To evaluate the benefit of adjuvant radiotherapy (RT) after surgical resection for extrahepatic bile duct (EHBD) cancer.From 1997 to 2015, 59 patients with EHBD cancer were the subject of this study; 36 patients not undergoing adjuvant treatment after surgery (observation group) and 23 patients receiving adjuvant RT (RT group) were compared. Microscopic residual disease (R1) was in 9 (25%) patients and 5 (22%) patients, and macroscopic residual disease (R2) was in 2 (6%) patients and 6 (26%) patients in the observation and RT groups, respectively. Adjuvant RT was delivered to the tumour bed and regional lymph nodes up to 50.4 Gy (range, 45-61 Gy).With a median follow-up of 19 months, local recurrence was observed in 10 (28%) patients and 2 (9%) patients in the observation and RT groups, respectively. On univariate analysis, the 5-year local recurrence-free survival (LRFS) rates were 50% in the observation group and 54% in the RT group (p = 0.401). The 5-year overall survival (OS) rates were 29.3% in the observation group and 26.3% in the RT group (p = 0.602). On multivariable analysis, however, adjuvant RT significantly improved LRFS [hazard ratio (HR), 0.310; 95% confidence interval (CI), 0.100-0.963; p = 0.043] and had a trend towards increased OS (HR, 0.491; 95% CI, 0.219-1.102; p = 0.085). Resection margin (RM) status was also correlated with LRFS (HR for R1 6.134, 95% CI 2.051-18.344; and HR for R2 18.551, 95% CI 3.680-93.520; p 0.001) and OS (HR for R1 1.816, 95% CI 0.853-3.867; and HR for R2 3.564, 95% CI 1.175-10.809; p = 0.054).RM status was a significant prognosticator of EHBD cancer, and adjuvant RT improved local control rate; thereby, survival rate might be increased. Advances in knowledge: The benefit of adjuvant RT in EHBD cancer was demonstrated via comparison with observation group.

PURPOSE Brain metastasis is estimated to occur in 20~40% of solid tumor patients and the most common primary tumor is lung cancer. Even though the prognosis of brain metastasis is grave and the 1-year survival rate is only 15%, symptom palliations are made with whole brain radiation therapy. We retrospectively evaluated the clinical features and prognostic factors of lung cancer with brain metastasis. MATERIALS AND METHODS From January 1987 to October 1999, 50 lung cancer patients with brain metastasis underwent whole brain radiation therapy. We reviewed the improvement in neurologic symptoms and survival according to the following parameters; performance status, histological type, presence of brain metastasis at the initial diagnosis of lung cancer, presence of extracranial metastasis, multiplicity of brain lesion, presence of primary lung symptom and treatment modalities. RESULTS The most frequent symptom with brain metastasis was a headache (50%). Palliation of the headache and other symptoms was achieved in 81% of the patients. Median overall survival after brain metastasis was 21 weeks and the 1 year survival rate was 15%. Patients without extracranial metastasis had a longer median survival than those with, 38 weeks versus 15 weeks, respectively (p=0.01). CONCLUSION In lung cancer with brain metastasis, neurologic symptoms can be palliated with whole brain radiation therapy, and in this study among such patients, absence of extracranial metastasis can be a good prognostic factor.

Backgrounds : Bortezomib (BTZ) is the first generation proteosome inhibitor providing excellent response in newly diagnosed multiple myeloma. BTZ treatment increases oxidative stress in myeloma cells. However the roles of antioxidant enzymes during upregulation of ROS and the mechanisms of resistance from BTZ treatment are unclear. The aims of current study are to elucidate that the changes of redox enzyme could have a important roles of anti-myeloma effect during BTZ treatment. Methods : MM.1S, MM.1R, and RPMI8226, the human myeloma cell lines, were treated with BTZ to induce apoptosis. 2, 7-dichlrodihydro-fluorescein-diacetate (H2DCF-DA) and MitoSOX Red were used to detect cellular and mitochondrial reactive oxygen species (ROS) respectively. Sulfinic acid, (SO2) form of preoxiredoxin (Prx) was studied by western blot assay using Prx SO2 form-specific antibody. Monomer/dimer assay for subtypes of Prx and thioredoxin (Trx) was performed by western blot using non-reducing gel. To evaluate the effect of down regulation on sulfiredoxin (Srx), myeloma cells were transfected with small interfering RNA (siRNA) followed by Western blot analysis. Results : Mitochondrial over cytosolic ROS of MM cells was increased significantly after 19 hour of BTZ (2.5 nM). Apoptosis of MM cell after BTZ treatment was increased in concordance with mitochondrial ROS increment of MM cells. N-acetylcystein (NAC) reversed BTZ-induced mitochondrial ROS elevation and apoptosis of MM cells as well. Increased expressions of cleaved caspase-9 and cleaved caspase-3 were also observed during BTZ-induced MM cell apoptosis. Monomer, indicated active and reduced form, of Prx III was decreased and dimer, indicated inactive and oxidized form, of Prx III was increased in MM cells after treatment of BTZ among Prxs. Similarly, monomer of Trx 2, mitochondrial Trx was decreased in MM cells after BTZ treatment. However, increment of cysteine SO2 Prx III was not observed. Meanwhile, Srx, reducing enzyme of SO2 Prx, was induced in MM cells after BTZ treatment. Down regulation of Srx by siRNA did not promote ROS generation or apoptosis in BTZ-treated MM cells, otherwise. Conclusions : Our results showed inactivation of Prx III by multimer formation as hyperoxidation is found during BTZ-induced mitochondrial ROS generation and apoptosis in MM cells. This Prx III oxidation was due to down regulation of reduced Trx 2 in BTZ-treated MM cells. To design of raising ROS stress and down regulation of anti-oxidants(ie, Trx), as a treatment-strategies may be worthwhile to potentiate BTZ-induced apoptosis in MM cells. Disclosures No relevant conflicts of interest to declare.

The aim of the present study is to evaluate the kinetics of CD34(+) cells and investigate the potential modulation of CD44 and CD31 expression on CD34(+) cells during continuous i.v. administration of G-CSF, thus to elucidate the possible mechanism of peripheral blood progenitor cell (PBPC) mobilization. Fifteen healthy donors were enrolled in this study. G-CSF (10 microg/kg/day) was administered for four consecutive days through continuous 24-h i.v. infusion. For measurement of complete blood counts, CD34(+) cell levels and their expression of CD44 and CD31, PB sampling was performed immediately before the administration of G-CSF (steady-state) and after 4, 8, 24, 48, 72, 96, and 120 h of G-CSF administration. The percentage and absolute number of CD34(+) cells significantly increased at day 3 (0. 55 +/- 0.09%, 51.12 +/- 24.83 x 10(3)/ml) and day 4 (0.47 +/- 0.09%, 46.66 +/- 24.93 x 10(3)/ml), compared to the steady-state level (0. 06 +/- 0.09%, 2.03 +/- 5.69 x 10(3)/ml). At day 3 to day 5 following the onset of G-CSF administration, a strong decrease of CD44 and CD31 expression was observed on mobilized CD34(+) cells compared to controls: the relative fluorescence intensity of CD44 and CD31 was, respectively, 50%-70% and 40%-90% lower than that of controls. We conclude that continuous i.v. administration of G-CSF apparently results in more rapid mobilization of CD34(+) cells, and downregulation of CD44 and CD31 on CD34(+) cells is likely to be involved in the mobilization of PBPC after treatment with G-CSF.

Statins have potential antineoplastic properties via arrest of cell-cycle progression and induction of apoptosis. A previous study demonstrated in vitro and in vivo antineoplastic synergism between statins and gemcitabine. The present randomized, double-blinded, phase II trial compared the efficacy and safety of gemcitabine plus simvastatin (GS) with those of gemcitabine plus placebo (GP) in patients with locally advanced and metastatic pancreatic cancer.Patients were randomly assigned to receive a 3-week regimen with GS (gemcitabine 1,000 mg/m(2) on days 1, 8, and 15 plus simvastatin 40 mg once daily) or GP (gemcitabine 1,000 mg/m(2) on days 1, 8, and 15 plus placebo). The primary end point was time to progression (TTP).Between December 2008 and April 2012, 114 patients were enrolled. The median TTP was not significantly different between the two arms, being 2.4 months (95 % CI 0.7-4.1 months) and 3.6 months (95 % CI 3.1-4.1 months) in the GS and GP arms, respectively (P = 0.903). The overall disease control rate was 39.7 % (95 % CI 12.2-33.8 %) and 57.1 % (95 % CI 19.8-44.2 %) in the GS and GP arms, respectively (P = 0.09). The 1-year expected survival rates were similar (27.7 and 31.7 % in the GS and GP arms, respectively; P = 0.654). Occurrence of grade 3 or 4 adverse events was similar in both arms, and no patients had rhabdomyolysis.Adding low-dose simvastatin to gemcitabine in advanced pancreatic cancer does not provide clinical benefit, although it also does not result in increased toxicity. Given the emerging role of statins in overcoming resistance to anti-EGFR treatment, further studies are justified to evaluate the efficacy and safety of combined simvastatin and anti-EGFR agents, such as erlotinib or cetuximab, plus gemcitabine for treating advanced pancreatic cancer.