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Background: Sex-determining region Y-box 2 (SOX2) is a transcriptional factor that drives embryonic stem cells to neuroendocrine cells in lung development and is highly expressed in small-cell lung cancer (SCLC). However, the prognostic role of SOX2 and its relationship with tumor-infiltrating lymphocytes (TILs) has not been determined in SCLC. Herein, we assessed the expression of SOX2 and CD8+ TILs to obtain insights into the prognostic role of SOX2 and CD8+ TILs in limited-stage (LS)-SCLC. Methods: A total of 75 patients with LS-SCLC was enrolled. The SOX2 expression and CD8+ TILs were evaluated by immunohistochemistry. Results: High SOX2 and CD8+ TIL levels were identified in 52 (69.3%) and 40 (53.3%) patients, respectively. High SOX2 expression was correlated with increased density of CD8+ TILs ( p = 0.041). Unlike SOX2, high CD8+ TIL numbers were associated with significantly longer progression-free survival (PFS; 13.9 vs. 8.0 months, p = 0.014). Patients with both high SOX2 expression and CD8+ TIL numbers ( n = 29, 38.7%) had significantly longer PFS and overall survival (OS) compared to those from the other groups (median PFS 19.3 vs. 8.4 months; p = 0.002 and median OS 35.7 vs. 17.4 months; p = 0.004, respectively). Multivariate Cox regression analysis showed that the combination of high SOX2 expression and CD8+ TIL levels was an independent good prognostic factor for OS (HR = 0.471, 95% CI, 0.250–0.887, p = 0.02) and PFS (HR = 0.447, 95% CI, 0.250–0.801, p = 0.007) in SCLC. Conclusions: Evaluation of the combination of SOX2 and CD8+ TIL levels may be of a prognostic value in LS-SCLC.

Background Pulmonary sarcomatoid carcinoma (PSC) is rare with a poor outcome and is resistant to conventional cytotoxic chemotherapy. The efficacy and safety of durvalumab and tremelimumab for treating recurrent or metastatic PSCs were assessed by a nonrandomized, open‐label, phase II study. Methods A total of 18 patients with recurrent or metastatic PSC received 1500 mg of durvalumab and 75 mg of tremelimumab every four weeks, followed by 750 mg of durvalumab every two weeks until the disease progressed, or an unacceptable toxicity level was reached. The primary endpoint was the objective response rate (ORR). The secondary endpoints were progression‐free survival (PFS), overall survival (OS), and toxicity. Genomic profiling of PSC by next‐generation sequencing (NGS) and determination of peripheral blood lymphocyte subsets using flow cytometry were performed for exploratory analysis. Results A total of 15 out of 18 patients were evaluated for the analysis of the primary endpoint. At the data cutoff point, the ORR of 26.7% (95% confidence interval [CI]: 7.8–55.1) was achieved with the median follow‐up duration of 12.0 months (range, 8.4–16.1). Median PFS and OS were 5.9 months (95% CI: 1.1–11.9) and 15.4 months (95% CI: 11.1‐not reached), respectively. Treatment‐related adverse events (AEs) of any grade were reported in 16 patients; the most common AEs were pruritus (n = 5), pneumonitis (n = 4), and rash (n = 4). Treatment was discontinued in two patients due to AEs of grade ≥ 3. Conclusions Durvalumab and tremelimumab demonstrated clinical benefit with a prolonged survival and manageable toxicity profile in patients with recurrent or metastatic PSC., This first prospective phase II trial for recurrent or metastatic pulmonary sarcomatoid carcinomas demonstrated that durvalumab and tremelimumab was effective with a confirmed ORR of 26.7%. The combination of durvalumab and tremelimumab was well‐tolerated with favorable toxicity profiles.

Histology-based tumour microenvironment (TME) scores are useful in predicting the prognosis of gastrointestinal cancer. However, their prognostic roles in distal bile duct cancer (DBDC) have not been previously studied. This study aimed to evaluate the prognostic significance of the TME scores using the Klintrup-Mäkinen (KM) grade, tumour stroma percentage (TSP) and the Glasgow microenvironment score (GMS) in resected DBDC.Eighty-one patients with DBDC who underwent curative resection were enrolled. DBDC was graded according to KM grade, TSP and GMS. A high KM grade was found in 19 patients (24%) and a high TSP was found in 47 patients (58%). A high TSP was significantly correlated with a low KM grade (P 0.001). The distribution of the GMS, which was developed by combining the KM grade and TSP, was as follows: 0 (n = 19, 24%), 1 (n = 19, 24%) and 2 (n = 43, 52%). A low KM grade, high TSP and high GMS were significantly associated with short overall survival (OS) (P 0.001) and relapse-free survival (RFS) (P 0.001). Furthermore, multivariate analysis showed that a low KM grade [hazard ratio (HR) = 3.826; confidence interval (CI) = 1.650-8.869; P = 0.014], high TSP (HR = 2.193; CI = 1.173-4.100, P = 0.002) and high GMS (HR = 7.148; CI = 2.811-18.173) were independent prognostic factors for short RFS; a low KM grade (HR = 4.324; CI = 1.594-11.733) and high GMS (HR = 6.332; CI = 2.743-14.594) were independent prognostic factors for short OS.Histology-based TME scores, including the KM grade, TSP and GMS, are useful for predicting the survival of patients with resected DBDC.

The role of radiosurgery has become further accentuated in the era of targeted agents (TA). Thus, the neurologic outcome of radiosurgery in brain metastasis (BM) of non-small cell lung cancer (NSCLC) was reviewed. We analyzed 135 patients with BM of NSCLC who were administered Cyberknife radiosurgery (CKRS) as either initial or salvage therapy. We evaluated local failure (LF), intracranial failure (IF), and neurological death (ND) due to BM. Primary outcome was neurological death-free survival (NDFS). Median follow-up was 16.2 months. Median CKRS dose of 22 Gy was administered to median 2 targets per patient. Among 99 deaths, 14 (14%) were ND. Upfront treatment for BM included CKRS alone in 85 patients (63%), CKRS + TA in 26 patients (19%), and WBRT in 24 patients (18%). No patients or tumor related factors were associated with ND. However, the type of upfront treatment for BM was significantly associated with ND [HR 0.07 (95% CI 0.01–0.57) for CKRS + TA, HR 0.56 (95% CI 0.19–1.68) for CKRS alone] compared with the WBRT group (P = 0.01). The 2-year NDFS rates for the CKRS + TA, CRKS alone, and WBRT groups were 94%, 87%, and 78%, respectively (P = 0.03). Upfront CKRS showed significantly higher 2-year LF-free survival rate (P

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.

Background Immune checkpoint blockades (ICBs) are characterized by a durable clinical response and better tolerability in patients with a variety of advanced solid tumors. However, we not infrequently encounter patients with hyperprogressive disease (HPD) exhibiting paradoxically accelerated tumor growth with poor clinical outcomes. This study aimed to investigate implications of clinical factors and immune cell composition on different tumor responses to immunotherapy in patients with non-small cell lung cancer (NSCLC). Methods This study evaluated 231 NSCLC patients receiving ICBs between January 2014 and May 2018. HPD was defined as a > 2-fold tumor growth kinetics ratio during ICB therapy and time-to-treatment failure of ≤2 months. We analyzed clinical data, imaging studies, periodic serologic indexes, and immune cell compositions in tumors and stromata using multiplex immunohistochemistry. Results Of 231 NSCLC patients, PR/CR and SD were observed in 50 (21.6%) and 79 (34.2%) patients, respectively and 26 (11.3%) patients met the criteria for HPD. Median overall survival in poor response groups (HPD and non-HPD PD) was extremely shorter than disease-controlled group (SD and PR/CR) (5.5 and 6.1 months vs. 16.2 and 18.3 months, respectively, P = 0.000). In multivariate analysis, HPD were significantly associated with heavy smoker (p = 0.0072), PD-L1 expression ≤1% (p = 0.0355), and number of metastatic site ≥3 (p = 0.0297). Among the serologic indexes including NLR, PLR, CAR, and LDH, only CAR had constantly significant correlations with HPD at the beginning of prior treatment and immunotherapy, and at the 1st tumor assessment. The number of CD4+ effector T cells and CD8+ cytotoxic T cells, and CD8+/PD-1+ tumor-infiltrating lymphocytes (TIL) tended to be smaller, especially in stromata of HPD group. More M2-type macrophages expressing CD14, CD68 and CD163 in the stromal area and markedly fewer CD56+ NK cells in the intratumoral area were observed in HPD group. Conclusions Our study suggests that not only clinical factors including heavy smoker, very low PD-L1 expression, multiple metastasis, and CAR index, but also fewer CD8+/PD-1+ TIL and more M2 macrophages in the tumor microenvironment are significantly associated with the occurrence of HPD in the patients with advanced/metastatic NSCLC receiving immunotherapy.

Background Immune checkpoint blockers (ICBs) are characterized by a durable clinical response and better tolerability in patients with a variety of advanced solid tumors. However, we not infrequently encounter patients with hyperprogressive disease (HPD) exhibiting paradoxically accelerated tumor growth with poor outcomes. This study aimed to determine differences in factors among patients with non-small cell lung cancer (NSCLC) displaying different tumor responses to immunotherapy. Methods This study evaluated 231 NSCLC patients receiving ICBs between January 2014 and May 2018. HPD was defined as a > 2-fold tumor growth kinetics ratio during ICB therapy and time-to-treatment failure of ≤ 2 months. We analyzed clinical data, imaging studies, periodic serologic indexes, and immune cell compositions in tumors and stromata using multiplex immunohistochemistry. Results Twenty-six patients (11.3%) met the HPD criteria. HPD was more frequent in patients with oncogenic driver mutations, ≥ 3 metastatic sites, ≥ 4 prior systemic treatments, and low PD-L1 expression (

EGFR tyrosine kinase inhibitor (EGFR TKI) is approved as first-line treatment for advanced-stage EGFR mutant lung adenocarcinoma (LADC). Yes-associated protein 1 (YAP1), a main effector of the Hippo pathway, is associated with adverse prognosis and disruption of EGFR TKI modulation of non-small cell lung cancer. In this study, we demonstrated a prognostic role of YAP1 in EGFR mutant LADC and efficacy of EGFR TKI therapy. A total of 63 patients, including 41 with paired lung cancer specimens before and after EGFR TKI therapy and 22 with non-paired lung cancer specimens prior to EGFR TKI, were enrolled for examination. Expression of YAP1 protein was evaluated using immunohistochemistry. Fifteen paired cases (36.6%) with high nuclear YAP1 expression were detected in the pre-EGFR TKI LADC group and 21 paired cases (52.5%) after treatment with EGFR TKI. Nuclear YAP1 expression was significantly upregulated after EGFR TKI therapy (P = .002). Fifteen paired cases with high nuclear YAP1 expression before EGFR TKI LADCs showed poorer overall survival (OS) (P = .023) and progression-free survival (PFS) (P = .041). Among the 63 patients under study, those with high nuclear YAP1 expression before EGFR TKI showed shorter OS (P = .038) and PFS (P .001). High nuclear YAP1 expression in cases with acquired EGFR exon 20 T790 M mutant LADCs showed poorer OS (P .001). We demonstrated that YAP1 burden before clinical application of EGFR TKI plays a crucial role in prognosis of EGFR mutant LADC treated using EGFR TKI.

// Tae-Jung Kim 1 , Soon Auck Hong 2 , Okran Kim 3 , Seung Joon Kim 4 , Ji-Hyun Yang 5 , Eun Kyo Joung 5 , Jin-Hyoung Kang 5 and Sook-Hee Hong 3, 5 1 Department of Hospital Pathology, College of Medicine, The Catholic University of Korea, Seoul, Korea 2 Department of Pathology, Soonchunhyang University Cheonan Hospital, College of Medicine, Soonchunhyang University, Cheonan, Republic of Korea 3 Cancer Research Institute, The Catholic University of Korea, Seoul, Korea 4 Division of Respiratory and Critical Care Medicine, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea 5 Division of Medical Oncology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea Correspondence to: Sook-Hee Hong, email: ssuki76@catholic.ac.kr Keywords: epidermal growth factor receptor; programmed death receptor ligand 1; CD8 + tumor infiltrating lymphocyte; non-small cell lung cancer Received: August 14, 2017 Accepted: October 31, 2017 Published: November 21, 2017 ABSTRACT Backgrounds: EGFR-mutant non-small cell lung cancer (NSCLC) that developed acquired resistance to EGFR-tyrosine kinase (TKI) are potential candidates for programmed death 1 (PD1) inhibitor. Results: TPS≥1% for PD-L1 and low CD8 + TIL in post-TKI tumor showed a trend for a lower PFS of EGFR-TKIs (14.2 vs 9.9 months; P = 0.060) (cohort A). Only 2 of 22 specimens (9.1%) with an acquired EGFR exon 20 T790M mutation exhibited in post-TKI TPS≥50% for PD-L1. The degree in post-TKI tumor of PD-L1 expression was varied in 19 patients (40.5%), with 10 (21.2%) showing higher levels in the resistant biopsy (cohort B). Among the post-TKI high TPS groups, median PFS with low post- TKI CD8 + TIL scores treated with EGFR-TKIs (6.6 months) was significantly lower than that for the other patients (14.2 months; P = 0.015). Conclusions: The change of PD-L1 expression was accompanied by dynamic change in CD8 + TILs and might reflect diverse mechanism of resistance to EGFR-TKI therapy. Material and Methods: We identified 69 patients (cohort A) with sufficient post-TKI tumor tissues and 47 patients (cohort B) with paired tumor tissues available. TPS for PD-L1 expression of tumor cells and CD8 + TILs score in tumor specimens were determined by immunohistochemistry.

Background The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) has standardized the reporting of thyroid cytology specimens. The objective of the current study was to evaluate the nationwide usage of TBSRTC and assess the malignancy rates in each category of TBSRTC in Korea. Methods Questionnaire surveys were used for data collection on the fine needle aspiration (FNA) of thyroid nodules at 74 institutes in 2012. The incidences and follow-up malignancy rates of each category diagnosed from January to December, 2011, in each institute were also collected and analyzed. Results Sixty out of 74 institutes answering the surveys reported the results of thyroid FNA in accordance with TBSRTC. The average malignancy rates for resected cases in 15 institutes were as follows: nondiagnostic, 45.6%; benign, 16.5%; atypical of undetermined significance, 68.8%; suspicious for follicular neoplasm (SFN), 30.2%; suspicious for malignancy, 97.5%; malignancy, 99.7%. Conclusions More than 80% of Korean institutes were using TBSRTC as of 2012. All malignancy rates other than the SFN and malignancy categories were higher than those reported by other countries. Therefore, the guidelines for treating patients with thyroid nodules in Korea should be revisited based on the malignancy rates reported in this study.

Epidermal growth factor receptor (EGFR) mutation testing is essential for individualized treatment using tyrosine kinase inhibitors. We evaluated two EGFR mutation tests, cobas v2 and PANAMutyper, for detection of EGFR activating mutations Ex19del, L858R, and T790M in tumor tissue and plasma from 244 non-small cell lung cancer (NSCLC) patients. The Kappa coefficient (95% CI) between the tests was 0.82 (0.74−0.92) in tumor samples (suggesting almost perfect agreement) and 0.69 (0.54−0.84) in plasma (suggesting substantial agreement). In plasma samples, both tests showed low to moderate sensitivity depending on disease stage but high diagnostic precision (86%−100%) in all disease stages (sensitivity: percentage of mutations in tumors that are also detected in plasma; precision: percentage of mutations in plasma which are also detected in tumors). Among the 244 patients, those previously diagnosed as T790M carriers who received osimertinib treatment showed dramatically better clinical outcomes than T790M carriers without osimertinib treatment. Taken together, our study supports interchangeable use of cobas v2 and PANAMutyper in tumor and plasma EGFR testing. Both tests have high diagnostic precision in plasma but are particularly valuable in late-stage disease. Our clinical data in T790M carriers strongly support the clinical benefits of osimertinib treatment guided by both EGFR mutation tests.

Background This study aimed to assess the effect of antibiotics on the clinical outcomes of patients with solid cancers undergoing treatment with immune checkpoint inhibitors (ICIs). Methods The medical records of 234 patients treated with ICIs for any type of solid cancer between February 2012 and May 2018 at the Seoul St. Mary’s Hospital were retrospectively reviewed. The data of patients who received antibiotics within 60 days before the initiation of ICI treatment were analyzed. The patients’ responses to ICI treatment and their survival were evaluated. Results Non-small-cell lung carcinoma was the most common type of cancer. About half of the patients were treated with nivolumab (51.9%), and cephalosporin (35.2%) was the most commonly used class of antibiotics. The total objective response rate was 21%. Antibiotics use was associated with a decreased objective response (odds ratio 0.466, 95% confidence interval [CI] 0.225–0.968, p = 0.040). The antibiotics group exhibited shorter progression-free survival (PFS) and overall survival (OS) than the no antibiotics group (median PFS: 2 months vs. 4 months, p p p = 0.001; OS: HR 1.785, 95% CI 1.265–2.519, p = 0.001). Conclusions The use of antibiotics may affect the clinical outcomes of patients with solid cancers treated with ICIs. Careful prescription of antibiotics is warranted in candidates who are scheduled for ICI treatment. Trial registration Not applicable (retrospective study).

Purpose This study aimed to investigate neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) as prognostic factors in patients with locally advanced non-small cell lung cancer (NSCLC) who received concurrent chemoradiotherapy (CCRT). Materials and Methods We retrospectively analyzed 66 patients with locally advanced NSCLC treated with definitive CCRT. Among these patients, 95% received paclitaxel/carboplatin or docetaxel/cisplatin. The median radiation dose was 66 Gy in 33 fractions. The NLR and PLR before/after CCRT were evaluated. The maximally selected log-rank test was used to obtain the cutoff values related to the overall survival (OS). Results Patients with high post-CCRT NLR (>3.12) showed worse OS, locoregional progression-free survival (LRPFS), and distant metastasis-free survival (DMFS) than those with low NLR (2-year OS: 25.8% vs. 68.2%, p < 0.001; 2-year LRPFS: 12.9% vs. 33.8%, p = 0.010; 2-year DMFS: 22.6% vs. 38.2%, p = 0.030). Patients with high post-CCRT PLR (>141) showed worse OS and LRPFS than those with low PLR (2-year OS: 37.5% vs. 71.1%, p = 0.004; 2-year LRPFS: 16.5% vs. 40.3%, p = 0.040). Patients with high NLR change (>1.61) showed worse OS and LRPFS than those with low NLR change (2-year OS: 26.0% vs. 59.0%, p < 0.001; 2-year LRPFS: 6.8% vs. 31.8%, p = 0.004). The planning target volume (hazard ration [HR] = 2.05, p = 0.028) and NLR change (HR = 3.17, p = 0.025) were the significant factors for OS in the multivariate analysis. Conclusion NLR change after CCRT was associated with poor prognosis of survival in patients with locally advanced NSCLC. An elevated NLR after CCRT might be an indicator of an increased treatment failure risk.

Background Several studies have suggested risk factors for poor survival in stage IB non–small-cell lung cancer (NSCLC) patients. However, these factors are not definite indicators of adjuvant chemotherapy for stage IB cancer, and most of them can be used to consider adjuvant chemotherapy. We aimed to determine the clinicopathologic factors and assess whether c-MET is a prognostic factor in stage IB NSCLC patients who have undergone surgery. Additionally, we determined the relevance of the factors and the recurrence pattern in these patients. Patients and Methods This study included 115 patients who underwent resection of pathologic stage IB NSCLC between January 2005 and December 2013. We retrospectively reviewed the clinicopathologic data and performed immunohistochemical analysis for c-MET. Recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS) were evaluated according to clinicopathologic factors and c-MET expression. Results Lymphovascular invasion (LVI) and c-MET overexpression were significantly associated with poor RFS. A large tumor with visceral pleural invasion (VPI) or LVI, moderate/poor differentiation with LVI, and VPI with LVI were negative prognostic factors for RFS and CSS. c-MET overexpression with a large tumor, VPI, or LVI was an independent prognostic factor for poor RFS and CSS, and LVI was a significant factor for distant recurrence. Conclusion LVI and c-MET overexpression might be associated with poor prognosis in stage IB NSCLC patients. Additionally, survival might be poor in stage IB patients with multiple pathologic risk factors. Moreover, there is a high possibility of distant recurrence in patients with LVI.

The programmed cell death protein (PD)-1 and programed death ligand 1 (PD-L1) based immunotherapeutic agent is a cornerstone for the treatment of cancer. The expression of PD-L1 was developed as a biomarker to predict the efficacy of anti-PD1/PD-L1 pathway based immune check point inhibitor. In addition, increased PD-L1 in tumor and tumor microenvironment could be considered as representative biomarkers for immune suppressive microenvironment.

e21108 Background: SOX2 is a transcriptional factor that drives embryonic stem cell to neuroendocrine cells in lung development and is highly expressed in SCLC. The serum SOX2 antibody in SCLC has been known to mediate neurologic paraneoplastic syndrome. In this study, we evaluated the expression of SOX2 and CD8+ tumor infiltrating lymphocyte (TIL) in LS-SCLC from clinical tumor tissue and their impact on PFS and OS. Methods: Among the total 245 patients with SCLC treated between 2010 and 2018, 75 patients with LS-SCLC with available tumor tissue were enrolled. SOX2 and CD8+ TIL were evaluated by immunohistochemistry. High SOX2 expression was defined as above 100 of H score that was derived from multiplying intensity by the proportion of stained tumor cells. The number of CD8+TILs was counted under high magnification (x400) with four fields in intratumoral area. The cut value for high CD8+TIL was the above the median of total case. Results: 64 patients (85.4%) received etoposide/platinum and definite local therapy (radiation therapy or surgery) and 18 patients (24.0%) received surgical resection. High expression of CD8+ TIL was related to significantly longer PFS (13.9 vs. 8.0 months, P = 0.014) and tended to related to longer OS (32.1 vs. 17.4 months, P = 0.056) than low expression. High expression of SOX2 was tended to related with longer OS and PFS compared to low expression of SOX2 (median, 21.7 vs. 17.1 months, P = 0.118; 12.7 vs. 9.0 months, P = 0.110, respectively) without statistical significance. 29 patients with high CD8+TIL among 52 patients with high SOX2 had significantly longer PFS and OS compared to the other groups (median PFS 19.3 vs. 8.4 months, P = 0.002 and median OS 35.7 vs. 17.4 months, P = 0.004, respectively). Multivariate Cox regression analysis showed that combined high expression SOX2 and CD8+ TIL was an independent good prognostic factor for OS (HR = 0.449, P = 0.018) and PFS of SCLC (HR = 0.481, P = 0.021). Conclusions: In our study, high expression level of combined SOX2 and CD8+ TIL were related to longer OS and PFS, and it could be used as a prognostic biomarker for LS-SCLC. [Table: see text]

Development of molecular technology has led to the expansion of next generation sequencing (NGS) in area of diagnostic pathology. Here we present a case in which a lung tumor, which resembled an atypical carcinoid tumor, was revealed as metastatic breast cancer by next generation sequencing. A 50-year-old female, who had received modified radical mastectomy for breast cancer, presented with a 2.1 cm sized lung mass. The mass was well-defined, well-enhanced, and showed endobronchial component by computed tomography. Under the impression of carcinoid tumor, right upper lobectomy was performed. Tumor cells were immunohistochemically positive for chromogranin and CD56, but negative for cytokeratin 7 and GCDFP-15. Initially, the patient was diagnosed with atypical carcinoid tumor. However, subsequent NGS test revealed GATA3 mutation (p.Ala333fs) of the lung tumor. After a thorough review of literature and public cancer genome data about GATA3 mutation, the diagnosis was revised to metastatic invasive carcinoma from breast.

The Asian Society of Gynecologic Oncology International Workshop 2018 on gynecologic oncology was held in the Ajou University Hospital, Suwon, Korea on the 24th to 25th August 2018. The workshop was an opportunity for Asian doctors to discuss the latest findings of gynecologic cancer, including cervical, ovarian, and endometrial cancers, as well as the future of fertility-sparing treatments, minimally invasive/radical/debulking surgery, radiotherapy, chemotherapy, targeted therapy, and immunotherapy. Clinical guidelines and position statement of Asian countries were presented by experts. Asian clinical trials for gynecologic cancers were reviewed and experts emphasized the point that original Asian study is beneficial for Asian patients. In Junior session, young gynecologic oncologists presented their latest research on gynecologic cancers.

Objectives: Anti-angiogenic agents are reported to exert clinical activity on epidermal growth factor receptor (EGFR) mutant non-small-cell lung cancers. We evaluated the clinical outcomes of nintedanib and docetaxel in refractory NSCLC according to EGFR mutation status during the Korean nintedanib named patient program. Methods: Docetaxel was administered either 75 or 37.5 mg/m2 on D1, D8 q every 3 weeks for 4–6 cycles plus nintedanib 200 mg orally twice daily until disease progression or unacceptable toxicity. Results: Sixty-two patients were enrolled for study. Twenty-eight patients with activating EGFR mutations progressed after EGFR-tyrosine kinase inhibitors (TKI) therapy and 25 out of 28 patients showing progression after platinum doublet chemotherapy were enrolled. The objective response rate was 29% and median PFS and OS were 3.9 months and 11.7 months. Based on the EGFR mutation status, the objective response rate was 39.3 vs. 21.9% (EGFR mut(+) vs. EGFR mut(–), p = 0.142) and median PFS was 6.5 vs. 3.3 months (EGFR mut(+) vs. EGFR mut(–), p = 0.009). No treatment-related deaths were reported. The most frequent drug-related adverse events (AE) were neutropenia (53.2%) and diarrhea (37.1%). Treatment in 12 patients (19.3%) was permanently discontinued due to AEs without disease progression. Conclusions: Our data indicated that nintedanib-docetaxel combination could be considered to be effective treatment in EGFR TKI-resistant EGFR mutant NSCLC.

Background Olaparib (Lynparza®) is a poly(ADP-ribose) polymerase (PARP) inhibitor approved as maintenance treatment of PSR OC. MEDIOLA assessed olaparib in combination with the anti-programmed cell death ligand1 antibody, durvalumab, in germline BRCA1 and/or BRCA2 mutated (gBRCAm) PSR OC (NCT02734004). The 12-week (wk) disease control rate (DCR) = complete response [CR] + partial response + stable disease) was presented at SGO 2018 (late-breaker abst. 4). Methods Pts had PSR OC, gBRCA1 or gBRCA2 mutation, and had received at least one prior line of platinum. Pts received olaparib 300mg PO BID for a 4-wk runin, then olaparib 300mg PO BID and durvalumab 1.5g IV q 4 wks until progressive disease. Tumours were assessed by RECIST 1.1 at baseline, 4 wks, then every 8 wks. Primary endpoints were 12wk DCR and safety. Secondary endpoints were 28-wk DCR, objective response rate (ORR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and biomarker analyses. Results Thirty-two/thirty-four pts treated were eligible. With the data cut-off on 1 Nov 2018, 28% pts were still on treatment. Most common ≥Grade 3 AEs were anaemia (17.6%), elevated lipase (11.8%), neutropenia (8.8%), and lymphopenia (8.8%). Five pts discontinued olaparib and three discontinued durvalumab due to an adverse event. The 28-wk DCR was 65.6% (90% CI: 49.6%, 79.4%). ORR was 71.9% (95% CI: 53.25%, 86.25%) with a total of seven CRs. Median PFS was 11.1 months (95% CI: 8.2, 15.9) with a median DoR of 10.2 months (25/75th percentile: 5.6, NC). Second-line pts (N=13, 40.6%) had not yet reached the medians for PFS or DoR. Median OS for all pts was not yet reached, with 87.0% of pts alive at 24 months (median follow up=20.4 months). Updated results will be presented. Conclusions The combination of olaparib and durvalumab was well tolerated and showed promising median PFS and DoR. Median PFS and DoR for pts with fewer prior lines of chemotherapy was not yet reached, suggesting that these pts may derive a greater benefit from the combination. The CR rate was higher than anticipated. This cohort has been expanded to further explore the durability of this chemotherapy-sparing combination. Clinical trial identification NCT02734004. Editorial acknowledgement Emma Robinson, Mudskipper Business, Ltd, funded by AstraZeneca. Legal entity responsible for the study AstraZeneca. Funding AstraZeneca. Disclosure Y. Drew: Advisory / Consultancy, Research grant / Funding (institution): Clovis Oncology; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: Merck; Advisory / Consultancy, Research grant / Funding (institution): Tesaro ; Advisory / Consultancy: Genmab; Research grant / Funding (institution): Oncology; Research grant / Funding (institution): Veratsem. B. Kaufman: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: Medison. S. Banerjee: Honoraria (self), Research grant / Funding (self): AstraZeneca; Honoraria (self): Tesaro; Honoraria (self): Clovis Oncology; Honoraria (self): Merck; Honoraria (self): PharmaMar; Honoraria (self): Roche; Honoraria (self): Seattle Genetics; Honoraria (self): Nucana. A. Lortholary: Honoraria (self): AstraZeneca; Honoraria (self): Tesaro. P. Roxburgh: Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Research grant / Funding (institution), Travel / Accommodation / Expenses: Tesaro. R.H. Alvarez: Honoraria (self): Eisai; Honoraria (self): Puma; Leadership role: Cancer Treatment Center of America. S. Domchek: Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self), Research grant / Funding (institution): Clovis Oncology; Honoraria (self): Bristol-Myers Squibb; Research grant / Funding (institution): PharmaMar. C. Gresty: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. H.K. Angell: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. V. Rocher Ros: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. K. Meyer: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. M. Lanasa: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. P. Herbolsheimer: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. All other authors have declared no conflicts of interest.

Background Recent studies demonstrated that miR-137 is downregulated in various tumors, and that it functions as a tumor suppressor. miR-137 could be silenced by its aberrant promoter hypermethylation. The purpose of this study was to investigate the significance of MIR137 promoter methylation on its expression in lung cancer. Methods Lung cancer cell lines were treated with either a DNA methyltransferase inhibitor (5-azacytidine, AZA) and/or an HDAC inhibitor (trichostatin A, TSA) to determine whether miR-137 expression was reactivated. Paired lung tumor and adjacent non-tumor lung tissues were obtained ( n =50). Quantitative methylation-specific PCR and bisulfite sequencing were used to analyze the methylation status of MIR137 , and real-time RT-PCR was performed to analyze miR-137 expression. Results miR-137 was reactivated by treatment with either AZA and/or TSA in lung cancer cell lines. Methylation-specific PCR showed increased MIR137 promoter methylation in lung tumors compared with adjacent non-tumor tissues, which was further validated by bisulfite sequencing. The expression of miR-137 was downregulated significantly in lung tumors, which was correlated with level of MIR137 promoter methylation inversely. Conclusions miR-137 downregulation was related to its promoter hypermethylation in lung cancer. Further studies are needed to assess its value as a prognostic factor and potential therapeutic applications in lung cancer.

The efficacy of tyrosine kinase inhibitors (TKIs) with and without radiotherapy (RT) has not been determined in patients with brain metastases from epidermal growth factor receptor-mutant TKI naive non-small cell lung cancer (NSCLC). Between 2008 and 2016, 586 patients were diagnosed with NSCLC and treated with TKIs at a hospital in Seoul, South Korea; 81 of these patients met the eligibility criteria for our study. Outcomes analyzed included intracranial progression (ICP), neurological death, and overall survival (OS). The 2-year cumulative incidence of ICP was 36.5% in the TKI plus RT group and 62.2% in the TKI alone group (P = 0.006). The chronological pattern analysis indicated that 64.3% of ICP developed within 12 months of the start of TKI treatment in the TKI alone group. The multivariate analysis revealed that treatment group (P = 0.003) and duration of TKI treatment ≤ 12 months (P

Objective The main aim of this study was to evaluate the antitumor activity and safety of vinorelbine and gemcitabine combination chemotherapy in patients with primary refractory or recurrent platinum-resistant epithelial ovarian and primary peritoneal cancers. Methods Patients with platinum-resistant or primary refractory disease were eligible. Patients were allowed one prior chemotherapy for the treatment of platinum-resistant or refractory disease. Vinorelbine 25mg/m 2 , followed by gemcitabine 1000mg/m 2 , was administered intravenously on days 1 and 8 every 3weeks. Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 and cancer antigen 125 test (CA-125 criteria) were adopted to classify responses. Results 44 patients received the median of 4 (range, 1–24) treatments with fifteen (34.1%) receiving six or more cycles. The overall objective response rate was 22.7%. One patient (2.3%) had complete while 9 patients (20.4%) had partial responses with median duration of response of 5.9months. 17 patients (38.6%) had stable disease for a median of 3.3months. Median progression-free survival (PFS) was 3.4months and overall survival (OS) was 14.5months. Four (9.1%) patients were not assessable. Neutropenia was the most frequently encountered toxicity, with grade 3 or 4 observed in 22 patients (50.0%). Fifteen patients (34.1%) needed immediate dose reduction. No treatment related death was reported. Conclusions The combination chemotherapy with gemcitabine and vinorelbine achieved the primary end point of our clinical trial in management of platinum resistant recurrent ovarian cancer. However, further sophisticated dosing and scheduling of combination chemotherapy are needed because of a significant proportion of dose reduction.

Background Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a standard procedure to evaluate suspicious lymph node involvement of lung cancer because computed tomography (CT) and 18F-fluorodeoxyglucose positron emission tomography-CT (PET-CT) have limitations in their sensitivity and specificity. There are a number of benign causes of false positive lymph node such as anthracosis or anthracofibrosis, pneumoconiosis, old or active tuberculosis, interstitial lung disease, and other infectious conditions including pneumonia. The purpose of this study was to evaluate possible causes of false positive lymph node detected in chest CT or PET-CT. Methods Two hundred forty-seven patients who were initially diagnosed with lung cancer between May 2009 and December 2012, and underwent EBUS-TBNA to confirm suspicious lymph node involvement by chest CT or PET-CT were analyzed for the study. Results Of 247 cases, EBUS-TBNA confirmed malignancy in at least one lymph node in 189. The remaining 58 patients whose EBUS-TBNA results were negative were analyzed. Age ≥65, squamous cell carcinoma as the histologic type, and pneumoconiosis were related with false-positive lymph node involvement on imaging studies such as chest CT and PET-CT. Conclusion These findings suggest that lung cancer staging should be done more carefully when a patient has clinically benign lymph node characteristics including older age, squamous cell carcinoma, and benign lung conditions.

Acquired drug resistance is a major factor limiting the effectiveness of targeted cancer therapies. Targeting tumors with kinase inhibitors induces complex adaptive programs that promote the persistence of a fraction of the original cell population, facilitating the eventual outgrowth of inhibitor-resistant tumor clones. We show that the addition of a newly identified CDK7/12 inhibitor, THZ1, to targeted therapy enhances cell killing and impedes the emergence of drug-resistant cell populations in diverse cellular and in vivo cancer models. We propose that targeted therapy induces a state of transcriptional dependency in a subpopulation of cells poised to become drug tolerant, which THZ1 can exploit by blocking dynamic transcriptional responses, promoting remodeling of enhancers and key signaling outputs required for tumor cell survival in the setting of targeted therapy. These findings suggest that the addition of THZ1 to targeted therapies is a promising broad-based strategy to hinder the emergence of drug-resistant cancer cell populations. Significance: CDK7/12 inhibition prevents active enhancer formation at genes, promoting resistance emergence in response to targeted therapy, and impedes the engagement of transcriptional programs required for tumor cell survival. CDK7/12 inhibition in combination with targeted cancer therapies may serve as a therapeutic paradigm for enhancing the effectiveness of targeted therapies. Cancer Discov; 8(1); 59–73. ©2017 AACR. See related commentary by Carugo and Draetta, p. 17. This article is highlighted in the In This Issue feature, p. 1

Purpose To date, the risk factors for central venous port-related bloodstream infection (CVPBSI) in solid cancer patients have not been fully elucidated. We conducted this study in order to determine the risk factors for CVP-BSI in patients with solid cancer. Materials and Methods A total of 1,642 patients with solid cancer received an implantable central venous port for delivery of chemotherapy between October 2008 and December 2011 in a single center. CVP-BSI was diagnosed in 66 patients (4%). We selected a control group of 130 patients, who were individually matched with respect to age, sex, and catheter insertion time. Results CVP-BSI occurred most frequently between September and November (37.9%). The most common pathogen was gram-positive cocci (n=35, 53.0%), followed by fungus (n=14, 21.2%). Multivariate analysis identified monthly catheter-stay as a risk factor for CVP-BSI (p=0.000), however, its risk was lower in primary gastrointestinal cancer than in other cancer (p=0.002). Initial metastatic disease and long catheter-stay were statistically significant factors affecting catheter life span (p=0.005 and p=0.000). Results of multivariate analysis showed that recent transfusion was a risk factor for mortality in patients with CVP-BSI (p=0.047). Conclusion In analysis of the results with respect to risk factors, prolonged catheter-stay should be avoided as much as possible. It is necessary to be cautious of CVP-BSI in metastatic solid cancer, especially non-gastrointestinal cancer. In addition, avoidance of unnecessary transfusion is essential in order to reduce the mortality of CVP-BSI. Finally, considering the fact that confounding factors may have affected the results, conduct of a well-designed prospective controlled study is warranted.

Purpose Collecting duct carcinoma (CDC) of the kidney is an aggressive disease with a poor prognosis, accountings for less than 1% of all renal cancers. To date, no standard therapy for CDC has been established. The aim of this study is an investigation of clinicopathologic findings of CDC and correlation of the disease status with a prognosis. Materials and methods From 1996 to 2009, 35 patients with CDC were treated at eight medical centers. The diagnosis of CDC was made based on nephrectomy in 27 cases and renal biopsy in eight cases. Results Median PFS and OS for all patients were 5.8 months (95% CI 3.5 to 9.2) and 54.4 months (95% CI 0 to 109.2), respectively. The OS of patients with Stages I-III was 69.9 months (95% CI 54.0 to 85.8), while that of patients with Stage IV was 8.6 months (95% CI 0 to 23.3), which showed a statistically significant difference (p=0.01). In addition, among patients with Stage IV, the OS of patients who received a palliative treatment (immunotherapy, chemotherapy, or targeted therapy) was 18.4 months, which was higher than the OS of patients without treatment of 4.5 months. Conclusion CDC is a highly aggressive form of renal cell carcinoma. Despite most of the treatments, PFS and OS were short, however, there were some long-term survivors, therefore, conduct of additional research on the predictive markers of the several clinical, pathological differences and their treatments will be necessary.

Background Limited stage small cell lung cancer (LS-SCLC) could be potentially curable with chemotherapy and radiation therapy. Notch pathway could be critically implicated with SCLC development, but there are few studies about its expression and clinical implications in SCLC. In this study, we evaluated the expression of Notch1, Notch2, and HES1 in LS-SCLC from clinical tumor tissue and their impact on PFS and OS. Methods A total of 75 patients with LS-SCLC, treated between 2010 and 2018, were enrolled, and their retrospective data were analyzed. Notch1, Notch2 and HES1 protein as Notch transcription factor were evaluated by immunohistochemistry. Staining was considered as low expression when 50% or less of the tumor cells expressed Notch1, Notch2, and HES1 with weak intensity. Results Among 75 patients, 42 patients (62.7%) received concurrent chemoradiotherapy, and 13 (17.3%) were diagnosed SCLC combined with NSCLC. Notch1, Notch2, and HES1 were identified in 50 (66.7%), 54 (72.0%), 24 (32.0%). There was no correlation of expression between Notch1 and HES1 (P = 0.115). Low expression of Notch1 or Notch2 was not associated with shorter PFS compared to high expression of them (median, 10.0 vs. 14.23, P = 0.172; 9.93 vs. 12.43, P = 0.759). Low expression of HES1 was tended to shorter PFS than high expression (8.40 vs. 13.57, P = 0.068). Low Notch1 expression was significantly associated with poor OS (median, 17.37 vs. 49.83, P = 0.022), but Notch2 and HES1 were not with OS (median; 21.73 vs. 18.40, P = 0.930; 15.37 vs. 27.90, P = 0.076). Of note, combined low expression of Notch1 and HES1 was significantly related with poor OS (median 15.37 vs. 28.63, P = 0.012). Multivariate Cox regression analysis showed that combined low expression Notch1 and HES1 was an independent poor prognostic factor for SCLC (HR = 1.23, P = 0.423). Conclusions Despite dramatic response rate of current standard treatment for LS-SCLC, more than half of patients experience failure within 2 years. It is clinically important to previse who the poor responder to the treatment is. In our study, low expression level of Notch1 and combined low expression of Notch1 and HES1 were related to poor overall survival, and these could be used as a prognostic biomarker for LS-SCLC. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Background: This study aimed to clarify the clinical associations between serum carcinoembryonic antigen (CEA) levels and whole-body metastatic distribution in stage IV NSCLC patients. Methods: This study analyzed 377 eligible patients between June 2007 and December 2012. All patients enrolled in the study were newly diagnosed with stage IV NSCLC and had records of pre-treatment serum CEA levels. The serum CEA levels were categorized as normal (< 5 ng/ml) or abnormal (≥ 5 ng/ml) to reveal clinically correlated factors with abnormal serum CEA levels. Results: The median age of the study cohort was 65 years old (range, 30-94), and 236 (62.6%) patients were male. Two hundred seventy-seven (73.5%) patients had tumors with a histology that is consistent with adenocarcinoma. The median serum CEA value was 8.2 ng/ml (range, 0.1-2872.7), and 218 (57.8%) patients had abnormal serum CEA levels. In multivariate analysis, abnormal serum CEA levels had statistically strong associations with non-squamous cell histology (P=0.002), bone (P=0.001), and brain metastases (P=0.005); and were also closely correlated with positive metastatic LN status (P=0.083) and pulmonary metastasis (P=0.065). Very high serum CEA levels (≥ 100 ng/ml) were additionally correlated with abdominal/pelvic metastasis (P < 0.001). Conclusions: Our findings suggested that abnormal serum CEA levels were strongly correlated with increased whole-body metastatic potential in advanced NSCLC. The results provided evidence for future exploratory anti-CEA targeting and intensive systemic assessment in advanced NSCLC patients with abnormal serum CEA levels.

Background We investigated the safety and effectiveness of routine harvest of the left kidney for renal transplantation regardless of the presence of multiple renal arteries to obtain the longer renal vein. Patients and Methods Between February 2000 and July 2008, 325 patients underwent left hand-assisted laparoscopic living donor nephrectomy. The true renal arterial anatomy as evaluated intraoperatively was compared with the renal arterial anatomy by computed tomography (CT). We compared the results for the patients with a single renal artery (group I) with the patients with multiple renal arteries (group II) in terms of the donor and recipient outcomes. Results Multiple renal arteries in left kidney were identified in 86 patients (26.5%). Thirty-seven CTs (11.4%) were in discord with the renal arterial anatomy evaluated intraoperatively. There was no difference in age, gender, body mass index, estimated blood loss, complication rate, or length of hospital stay between the 2 groups in the donor. Although the warm ischemic time and the operation time were significantly longer in group II (P = .008 and .001), overall graft survival was similar between the groups. Conclusion Routine harvest of the left kidney can be performed safely and effectively for the donor and recipient, even in the presence of multiple renal arteries.

Few studies of systemic chemotherapy have focused on gastric cancer with peritoneal carcinomatosis (PC) without measurable lesions. In the present study, we characterized the outcomes of systemic chemotherapy and prognostic factors for gastric cancer with PC, particularly in patients without measurable disease.Clinical data from 211 gastric cancer patients with PC (137 without and 74 with measurable disease) who had received systemic chemotherapy between January 2003 and December 2010 at a single center were reviewed.The median overall survival (OS) rate of gastric cancer patients with PC with no measurable disease was significantly longer than that of patients with measurable disease (18.0 vs. 11.6 months, p = 0.010). On multivariate analysis, poor performance status [hazard ratio (HR) = 2.15, p 0.001], the presence of metastatic lymphadenopathy (HR = 2.17, p 0.001), and high-grade PC (HR = 1.83, p = 0.001) were associated with significantly decreased OS. When patients with low-grade PC were stratified by clinical PC grade, the median OS of those without measurable disease was 19.6 months. The median OS of patients with low-grade PC with no measurable disease was longer than those of patients with high-grade PC without measurable disease, patients with low-grade PC with measurable disease, and patients with high-grade PC with measurable disease (p = 0.001, p = 0.029, and p 0.001, respectively). Among the patients with low-grade PC, patients who received a gastrectomy had longer survival than patients who did not receive a gastrectomy (p 0.001).In our study, clinically low-grade PC without measurable disease was associated with better outcomes of systemic chemotherapy than the outcomes in the other groups examined. Clinical trials in patients with gastric cancer with PC should be stratified according to PC grade.

A 31-yr-old man with abdominal pain was diagnosed with a pancreatic endocrine tumor and multiple hepatic metastases. Despite optimal treatment with interferon alpha, a somatostatin analog, local therapy with high-intensity focused ultrasound ablation for multiple hepatic metastases, and multiple lines of chemotherapy with etoposide/cisplatin combination chemotherapy and gemcitabine monotherapy, the tumor progressed. As few chemotherapeutic options were available for him, sorafenib (800 mg/day, daily) was administered as a salvage regimen. Sorafenib was continued despite two episodes of grade 3 skin toxicity; it delayed tumor progression compared to the previous immunotherapy and chemotherapy. Serial computed tomography scans showed that the primary and metastatic tumors were stable. Thirteen months after beginning targeted therapy, and up to the time of this report, the patient is well without disease progression. We suggest that sorafenib is effective against pancreatic endocrine tumors.

Laboratory-based biochemical acute pancreatitis (BAP) is considered to be a benign but common complication after liver transplantation (LT), which to compensate for transfusion-related hypocalcemia, usually demands a large quantity of exogenous calcium which may be associated with pancreatic injury. We sought to investigate the relationship between intraoperative calcium–related factors and BAP occurrence after living-donor LT. Perioperative data, including intraoperative calcium chloride administration and serum calcium levels, were reviewed from 217 patients who underwent living-donor LT. Hyperamylasemia (≥458 U/L) was used to define posttransplantation BAP according to previous reports. Posttransplantation BAP was identified among 37 patients (17.3%), who showed a greater death rate than those in the non-BAP group (21.6% vs 8.6%; P = .013). Compared to with calcium-related parameters, the 2 groups showed differences in the amount of calcium chloride administered during the preanhepatic phase, the serum calcium surge during the initial 2 h after the liver graft reperfusion, the last serum calcium level, and the amount of transfused pack red blood cells (P < .05). However, after multivariate adjustment, only the amount of administered calcium chloride during the preanhepatic phase (odds ratios, 2.11–5.87, depending an amount) and the serum calcium surge during the initial 2 hours after liver graft reperfusion (odds ratio, 2.34) were selected as risk factors for posttransplantation BAP. The risk ratio of posttransplantation BAP increased in proportion to the administered amount of calcium chloride. In conclusion, limiting excessive calcium administration during the preanhepatic phase and close monitoring of the serum calcium surge after reperfusion may be required to prevent posttransplantation BAP in living-donor LT.

140 Background: Olaparib is a PARP inhibitor that has shown activity in relapsed gastric cancer (GC) when combined with chemotherapy. MEDIOLA assesses the efficacy and safety of a chemo-free combination of olaparib and durvalumab, an anti-programmed cell death ligand-1 (PD-L1) agent in patients (pts) with solid tumors, including relapsed GC (NCT02734004). Methods: Eligible pts had GC that relapsed following platinum-containing therapy. Pts received olaparib 300 mg PO BID for a 4-wk run-in to allow for serial biopsies, followed by combination olaparib and durvalumab (1.5 g IV q 4 wks) until progressive disease (PD) as measured by RECIST 1.1. Tumor measurements were taken at baseline, 4 wks and q 8 wks thereafter. Primary endpoints were disease control rate (DCR) at 12 wks, safety, and tolerability. The secondary endpoints included DCR at 28 wks, objective response rate (ORR), duration of response (DoR), progression-free survival, and OS. Biomarker endpoints included PD-L1 expression and evaluation of tumor infiltrating lymphocytes. Bayesian predictive probability design was used for statistical analysis. Results: Forty pts were included in the safety and 39 in the efficacy analysis. Among 39 pts, median age was 57 yrs (range 28–77). Nineteen pts (48%) had a grade 3 AE; three pts (8%) a grade 4 AE. Most common AEs were anemia, lipase increase, fatigue, dysphagia, hyponatremia, and alkaline phosphatase increase. Ten pts (25%) had immune-mediated AEs, most commonly rash. The ORR was 10%; two pts had complete response; two had partial response. Median DoR was 11.1 months. DCR at 12 wks was 26%. Further efficacy and biomarker data will be presented. Conclusions: The combination of olaparib and durvalumab was tolerable, with no unexpected AEs. All responses occurred after the addition of durvalumab and were durable, suggesting synergistic treatment effect of the combination in some pts. Furthermore, several pts with early PD showed unexpectedly long survival. DCR at 12 wks was below the target (70%) due to a high rate of early PDs following the olaparib run-in. To address the early treatment failures, an upfront addition of more aggressive therapies to the combination should be explored. Clinical trial information: NCT02734004.

Objective Platinum-based neoadjuvant chemotherapy for locally advanced cervical cancer has some benefits for patients responding to chemotherapy. However, no validated clinical or biologic predictor of response to this chemotherapy has been identified to date. Methods We employ immunohistochemical analysis to determine the expression patterns of the excision repair cross-complementation group1 (ERCC1) protein in pre-treatment cervical biopsy tissue. In total, 43 stage IIB patients had been enrolled in a previous etoposide and cisplatin neoadjuvant phase II clinical trial, allowing comparison of the effects of cisplatin-based neoadjuvant chemotherapy on response in relation to ERCC1 expression. Results Among the 43 patients studied, 34 (79.1%) were positive and 9 (20.9%) were negative for ERCC1. Response to chemotherapy (according to RECIST criteria) was observed in all patients with negative ERCC1 expression. In logistic regression analysis, ERCC1 negativity continued to be an independent predictor for responsiveness to neoadjuvant chemotherapy (p = 0.021). Among the pretreatment factors, low ERCC1 expression was a significant prognostic factor of disease-free survival in multivariate analysis (p = 0.046). Conclusions The ERCC1 expression patterns in pretreatment specimens may thus facilitate the prediction of responses to cisplatin-based NAC. We propose that patients expressing low levels of ERCC1 derive the most benefit from cisplatin-based NAC.

In Korea, many health care professionals have shown increased concern about the management of cancer pain. Five years after a pain management guideline was distributed to Korean physicians, the Korean Society of Hospice and Palliative Care evaluated the change in cancer pain management. The period evaluated was between 2001 and 2006.We did a prospective, cross-sectional cancer pain survey on the change of the pain prevalence and pain intensity, its impact on daily activities and the adequacy of pain management between 2001 and 2006.Overall, 7565 patients were enrolled from 72 cancer hospitals in the 2001 cancer pain survey and 7245 patients were enrolled from 63 cancer hospitals in the 2006 cancer pain survey. The overall prevalence of cancer pain and the percentage of patients reporting a negative pain management index were significantly decreased in the 2006 cancer pain survey compared with the 2001 cancer pain survey (44.9% vs. 52.1%, P0.0001 and 41.6% vs. 45.0%, respectively, P=0.0005). However, in 2006, physicians did not prescribe analgesics to 25.8% of the patients with severe pain and they did not adjust the prescribed analgesics properly in 47.4% of the patients with severe pain.Some improvement in cancer pain management was noted during the five years between 2001 and 2006. However, all of the physicians who care for cancer patients should pay more attention to cancer pain management, and an educational program for cancer pain management should be distributed to all of the physicians who care for cancer patients.

Anticancer agents can induce sarcoidosis. Interferon-alpha, which is used for the treatment of malignant melanoma and renal cell cancer, is one causative agent of sarcoidosis. However, there are few reports of interferon-alpha-induced sarcoidosis in patients with malignant melanoma. Clinically, it is important to consider the possibility of sarcoidosis in such patients because it could be easily regarded as a metastatic lesion due to underlying malignancy and given unnecessary treatment. Here, we report on the first case of interferon-alpha-induced sarcoidosis in an Asian melanoma patient.

The aim of the present study was to examine the anti-inflammatory activities of extracts from Tetraselmis suecica with respect to nitric oxide (NO) production, tumor necrosis factor (TNF)-α and interlukin (IL)-6 release in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. We prepared methanolic extracts and water extract using protease. Of all the prepared extracts, 80% methanol extract exhibited the strongest anti-inflammatory effect. Thus, we further characterized the hexane fraction (He-TS) and ethyl acetate fraction (EA-TS) that contained potential bioactive compounds from the 80M-TS fraction of T. suecica. Both He-TS and EA-TS fractions resulted in a significant and dose-dependent inhibition of LPS-induced NO production, TNF-α, and IL-6 release (p

Cardiac mesotheliomas are rare. It is difficult to diagnose them at an early stage because the symptoms are nonspecific. Here we report two cases that had been initially diagnosed as constrictive pericarditis but later were definitively diagnosed, after pericardiectomy, as mesothelioma. The two patients complained of dyspnea that lasted 4 months and 10 years. Chest CT showed mild pericardial effusion and thickened pericardium, which was found enveloping the heart without any lumps. Median sternotomy showed that the overall pericardium was thickened by more than 10 ㎜. Pericardiectomy (phrenic nerve to phrenic nerve) was performed and post-operative histology confirmed malignant mesothelioma. In one patient the disease recurred near the pericardium post-operatively at 7 months and the patient died at 11 months. The other patient received chemotherapy and was still alive at post-operative month 16. Pericardial mesothelioma is an extremely rare disease exhibiting clinical signs similar to those of constrictive pericarditis, and should be diagnosed at an early stage of onset.

Purpose: EGFR tyrosine kinase inhibitor (EGFR TKI) was approved as a first line treatment for EGFR mutant lung adenocarcinoma (LADC) with advanced stage. YAP1 (Yes-associated protein 1) is a main effector of hippo pathway, related with adverse prognosis and EGFR TKI modulation of non-small cell lung cancer. This study aimed to clarify a prognostic role of YAP1 in EGFR mutant LADC and efficacy for EGFR TKI through the course of EGFR TKI. Materials and Methods: 41 patients with paired lung cancer specimen before and after EGFR TKI were enrolled in this study. The expression of YAP1 protein was evaluated by immunohistochemistry. Results: 15 cases (36.6%) with high YAP1 expression was found in pre-EGFR TKI LADC, while high YAP1 expression in 21 cases (52.5%) was detected after EGFR-TKI. The transitional level of YAP1 between pre- and post-EGFR TKI was significantly upregulated (P=0.002). High YAP1 before EGFR TKI was related with shorter OS (P=0.023) and PFS (P=0.041). In addition, high YAP1 before EGFR TKI in T790M mutant LADC was related with poor OS (P Conclusion: YAP1 burden before EGFR TKI was crucial role in prognosis of EGFR mutant LADC treated by EGFR TKI. Citation Format: Soon Auck Hong, Jin-Hyoung Kang, Sook Hee Hong. Overexpression of YAP1 of EGFR-mutant lung adenocarcinoma before tyrosine kinase inhibitor is associated with poor survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2609.

8574Background: Even with standard platinum doublet therapy, most patients with small-cell lung cancer (SCLC) survive < 1 year. For those with refractory or relapsed disease, second-line, single-ag...

Uncoupling protein 3 (UCP3) is a mitochondrial protein that is expressed predominantly in skeletal muscle. It may play a role in altering metabolic function. However, its major physiological roles are not fully understood. Recently de novo expression of UCP3 in rat liver by fenofibrate was reported. We also reported previously that fenofibrate-induced de novo expression of UCP3 contributes to reduction of adipose tissue in obese rats. In the present study, we investigated that fenofibrate-induced expression of UCP3 in rat liver is related with metabolic function such as body weight and hepatic lipid content by time-dependent manner in high-fat diet rats. Eight-week-old male Sprague-Dawley rats were randomly divided into two groups; the high fat diet group (HF, n=16) and fenofibrate-treated high fat diet group (HFF, n=16). The mRNA expression of hepatic UCP3 was detected as early as 1 week of fenofibrate treatment by quantitative real-time PCR and the amount of mRNA was increased time-dependently. The mean body weight of the HFF group was significantly less compared with the HF group after 6 weeks of fenofibrate treatment, even though there was no difference of food intake between the two groups. Rectal temperature was increased during 4 to 6 weeks of fenofibrate treatment and body weight was decreased after 6 weeks of treatment. These results were corresponded with the increased amount of the expression of UCP3 mRNA and protein. We suggest that de novo expression of hepatic UCP3 is increased time-dependently with fenofibrate treatment and that the amount of expression is correlated with metabolic function.