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Introduction We investigated the timing and patterns of recurrence after the treatment of stage IIIA (N2) non-small cell lung cancer via neoadjuvant concurrent chemoradiotherapy followed by surgery. Materials and methods An institutional database was reviewed retrospectively between 1997 and 2013 (N = 570). Eligible patients had pathologically proven N2 disease, and they completed the planned trimodality therapy with curative intent. The hazard rate function and competing risk analysis were used to evaluate the recurrence dynamics. Results Among the included patients, 76% had single station N2 involvement and 95% had complete resection. The 5-year overall and recurrence-free survival rates were 47% and 29%, respectively. Of the 290 patients who experienced recurrence, 25 (8.4%) experienced loco-regional recurrence, whereas 238 (80.4%) had distant metastases. The hazard rate function for overall recurrence revealed a peak at approximately 8 months after surgery and a marked decline after 2 years. The peak recurrence frequency of distant metastasis differed at each site, with isolated brain metastases exhibiting the earliest peak (6 months) and a narrow recurrence interval (15 months). A histological comparison revealed a higher recurrence hazard rate for adenocarcinoma than for squamous cell carcinoma but similar pattern of recurrences. Patients with complete responses had a lower cumulative incidence rate of recurrence but a slightly earlier peak of recurrence. Nodal responses to induction therapy demonstrated that patents with ypN0 had the lowest recurrence risk, whereas patients with ypN1 and ypN2 had similar hazard rates and cumulative incidence rates of recurrence. Conclusions The dynamics of recurrence after trimodality therapy is organ-specific and varies according to pathologic factors. Our finding provides information on selection patients with risk of recurrence and timing of surveillance study.

BACKGROUND: Programmed death ligand 1 (PD-L1) expression may predict response to anti-programmed death 1 (anti-PD-1) or anti-PD-L1 treatment. There is limited information on changes in PD-L1 expression over time in patients with non-small cell lung cancer (NSCLC).PATIENTS AND METHODS: Eligible patients with NSCLC who received surgery or underwent biopsy at Samsung Medical Center, Seoul, Republic of Korea, and Aarhus University Hospital, Aarhus, Denmark, between February 2004 and April 2012 were included. PD-L1 expression in paired tumor tissue samples from the same patients at different dates and lesions was measured using a laboratory-developed prototype immunohistochemistry assay (22C3 antibody). PD-L1 positivity was defined as tumor cell membrane positivity in ≥ 1% of tumor cells (proportion score). Concordance of PD-L1 expression was analyzed by treating proportion score as categoric or continuous variables.RESULTS: Ninety-one patients were included in the analysis. The median interval between the 2 tumor collection dates was 20 months, with 91% of paired samples collected > 3 months apart. The concordance rate for PD-L1 classification between paired samples was 67% (95% confidence interval, 57%-77%). When treating the immunohistochemistry proportional score as a continuous variable, a significant correlation of PD-L1 expression was observed between the paired samples (Pearson correlation coefficient, 0.61; P < .001).CONCLUSION: There are good correlations of PD-L1 expression from paired NSCLC samples. For patients whose PD-L1 status is negative, it may be valuable to obtain additional tissue samples for retesting PD-L1 expression when anti-PD-1 immunotherapy is considered.

Molecular profiling of actionable mutations in refractory cancer patients has the potential to enable "precision medicine," wherein individualized therapies are guided based on genomic profiling. The molecular-screening program was intended to route participants to different candidate drugs in trials based on clinical-sequencing reports. In this screening program, we used a custom target-enrichment panel consisting of cancer-related genes to interrogate single-nucleotide variants, insertions and deletions, copy number variants, and a subset of gene fusions. From August 2014 through April 2015, 654 patients consented to participate in the program at Samsung Medical Center. Of these patients, 588 passed the quality control process for the 381-gene cancer-panel test, and 418 patients were included in the final analysis as being eligible for any anticancer treatment (127 gastric cancer, 122 colorectal cancer, 62 pancreatic/biliary tract cancer, 67 sarcoma/other cancer, and 40 genitourinary cancer patients). Of the 418 patients, 55 (12%) harbored a biomarker that guided them to a biomarker-selected clinical trial, and 184 (44%) patients harbored at least one genomic alteration that was potentially targetable. This study demonstrated that the panel-based sequencing program resulted in an increased rate of trial enrollment of metastatic cancer patients into biomarker-selected clinical trials. Given the expanding list of biomarker-selected trials, the guidance percentage to matched trials is anticipated to increase. Implications for practice This study demonstrated that the panel-based sequencing program resulted in an increased rate of trial enrollment of metastatic cancer patients into biomarker-selected clinical trials. Given the expanding list of biomarker-selected trials, the guidance percentage to matched trials is anticipated to increase.

Programmed cell death 4 (PDCD4) is a bona fide tumor suppressor protein and plays a critical role in controlling the rate of protein synthesis. Here, we show that TPA selectively activated the S6K1 and ERK1/2 kinases, contributing to PDCD4 proteolysis and Pdcd4 mRNA degradation in HepG2 cells, respectively. In addition, we observed that sulforaphane suppression of TPA-induced S6K1 and ERK1/2 activation played a critical role in attenuating PDCD4 poly-ubiquitination and Pdcd4 mRNA downregulation. Moreover, we observed that silencing Pdcd4 led to not only an increased expression of c-Jun, but also a decreased expression of p21, the latter of which contributed to suppression of Keap1-dependent Nrf2 poly-ubiquitination. Finally, we demonstrate that the expression of PDCD4, p21 and Nrf2 is higher, but that of c-Jun is lower in normal human liver tissues, compared with hepatoma tissues. Collectively, our study illustrates that attenuating the rate of PDCD4 proteolysis and Pdcd4 mRNA degradation serves as a novel anti-inflammatory and cytoprotective mechanism of sulforaphane.

Background: The purpose of this study was to evaluate the outcome of reoperation with curative intent for the treatment of anastomotic recurrent gastric cancer. Methods: Ten patients with anastomotic recurrence of gastric cancer who underwent reoperation from November 1995 to February 2011 were analyzed retrospectively. The time interval between the first operation and reoperation, recurrence pattern, type of surgery, survival, and postoperative outcome were analyzed. Results: The average time to recurrence after initial surgery was 48.8 months (median, 23.5 months). Of the ten patients, eight (80.0%) had recurrence at the esophagojejunostomy, one (10.0 %) at the esophagogastrostomy, and two (20.0%) at the esophagus. Among these patients, five had combined metastasis or invasion to major organs in addition to anastomotic recurrence. Complete resection was achieved in five patients (50.0%), and incomplete resection or bypass surgery was performed in the remaining five patients (50.0%). The overall median survival time was 7.0 months (range, 2.2 to 105.5 months). The median survival time following complete resection and palliative surgery (incomplete resection or bypass surgery) was 28.1 months (range, 4.2 to 105.5 months) and 5.5 months (range, 2.2 to 7.5 months), respectively. Conclusion: Surgical resection of anastomotic recurrent gastric cancer should be implemented only in selected patients in whom complete resection is possible.

Purpose Data are limited on programmed death ligand 1 (PD-L1) expression in epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). Materials and Methods We retrospectively evaluated the relationship between PD-L1 expression and recurrence-free survival (RFS) and overall survival in 319 patients with EGFR-mutant NSCLC who were treated at Samsung Medical Center from 2006 to 2014. Membranous PD-L1 expression on tumor cells was measured using the PD-L1 IHC 22C3 pharmDx antibody and reported as tumor proportion score (TPS). Kaplan-Meier methods, log-rank test, and Cox proportional hazards models were used for survival analysis. Results All patients had ≥1 EGFR mutation—54% in exon 19 and 39% in exon 21. Overall, 51% of patients had PD-L1–positive tumors. The prevalence of PD-L1 positivity was higher among patients with stages II-IV versus stage I disease (64% vs. 44%) and among patients with other EGFR mutations (75%) than with L858R mutation (39%) or exon 19 deletion (52%). PD-L1 positivity was associated with shorter RFS, with an adjusted hazard ratio of 1.52 (95% confidence interval [CI], 0.81 to 2.84; median, 18 months) for the PD-L1 TPS ≥ 50% group, 1.51 (95% CI, 1.02 to 2.21; median, 31 months) for the PD-L1 TPS 1%-49% group, and 1.51 (95% CI, 1.05 to 2.18) for the combined PD-L1–positive groups (TPS ≥ 1%) compared with the PD-L1–negative group (median, 35 months). Conclusion PD-L1 expression is associated with disease stage and type of EGFR mutation. PD-L1 positivity might be associated with worse RFS among patients with surgically treated EGFR-mutant NSCLC.

Background Circulating tumor DNA (ctDNA) analysis has been successfully applied to therapy selection and treatment monitoring in advanced cancer patients. However, it is not yet established whether ctDNA can be used clinically for early cancer detection or recurrence prediction in early stage lung cancer patients. Methods We analyzed pre-operative plasma samples from 55 early stage NSCLC patients (stages I-IIIA) using next-generation sequencing assay incorporating somatic and epigenomic analysis, and a bioinformatic classifier to filter non-tumor derived variants. Table: 111P . Cell type Stage Somatic mutation Epigenetic pattern Total number Recurrence+, n (%) Site of recurrence Adenocarcinoma stage 1 ctDNA- methylation- 9 1 (11) Lung n = 17 methylation+ 6 2 (33.3) Stump, bone ctDNA+ 2 1 (50) lung stage 2 ctDNA- methylation- 0 0 (0) n = 2 methylation+ 0 0(0) ctDNA+ 1 1 (100) multiple stage 3 ctDNA- methylation- 0 0 (0) n = 4 methylation+ 2 0 (0) ctDNA+ 2 2 (100) brain, multiple Sqaumous cell carcinoma stage1 ctDNA- methylation- 0 0 (0) n = 7 methylation+ 3 0 (0) ctDNA+ 4 1 (25) multiple stage2 ctDNA- methylation- 0 0 (0) n = 9 methylation+ 0 0 (0) ctDNA+ 9 2 (22.2) multiple, lung stage3 ctDNA- methylation- 0 0 (0) n = 4 methylation+ 1 0 (0) ctDNA+ 3 1 (33.3) Mediastinal LNs Results Somatic mutation analysis alone detected ctDNA in 42% (23/55) of patients, whereas combined mutational and epigenomic analysis detected ctDNA in 67% (37/55). ctDNA detection rate varied by pathological subtypes; using combined approach, ctDNA was detected in all squamous cell carcinoma patients, while only 55% (12/22) in adenocarcinoma (ADC) (p=0.006). Within the ADC subgroup, ctDNA detection rates using the combined approach were dependent on disease stage: 47% (8/17) in stage I, 100% (2/2) in stage II, and 100% (2/2) in stage IIIA. Importantly, within 2 years of follow-up, pre-operative ctDNA status was correlated with tumor recurrence after resection; among 17 stage I ADC patients, three of eight (38%) ctDNA-positive cases showed recurrence, while only one of nine (11%) ctDNA-negative cased did (p=0.29). Interestingly, patients with somatic mutation in their ctDNA have shown higher recurrence rate. Conclusion Utilizing a plasma-only sequencing assay incorporating somatic genomic and epigenomic analysis, ctDNA detection rate in early stage lung cancer (stage I-III) can far outperform the detection rate of somatic sequence variant detection alone. And, the presence of pre-operative ctDNA in patients with early stage lung adenocarcinoma may identify those who are more likely to have disease recurrence. Legal entity responsible for the study: Guradant Health, Inc. Funding Guardant Health, Redwood City, CA, USA. Disclosure I. Kim: Full / Part-time employment, Officer / Board of Directors: Guardant Health. M. Shultz: Officer / Board of Directors: Guardant Health. A. Jaimovich: Officer / Board of Directors: Guardant Health. J. Odegaard: Officer / Board of Directors: Guardant health, Inc. S. Olsen: Officer / Board of Directors: Guardant Health, Inc. A. Talasaz: Officer / Board of Directors: Guardant health. J. Kim: Research grant / Funding (self): Guardant health, Inc. All other authors have declared no conflicts of interest.

8520 Background: The standard treatment option for stage IIIA-N2 subgroup is still under discussion with controversies. We hypothesize that immune checkpoint inhibitor consolidation therapy could have an additional role in prolongation of the disease-free survival (DFS) for stage IIIA-N2 NSCLC treated with tri-modalities therapy. Methods: This is a phase 2 study evaluating the clinical efficacy of pembrolizumab treatment after CCRT with curative resection in stage IIIA-N2 NSCLC pts. Pathologically confirmed pts were treated with five cycles of CCRT, weekly paclitaxel (50mg/m2) and cisplatin (25mg/m2) combined with radiotherapy (total of 44Gy over 22 fractions) followed by curative resection. Adjuvant Pembrolizumab (200mg fixed dose) is applied every three weeks up to 2 years or until disease recurrence. The primary objective is disease-free survival of more than 20 months. The first patient was recruited in October 2017, and the data for this abstract was locked at 20th of January, 2019. Results: Total of 40 pts were screened, and 37 pts received treatment. Median age was 64 years (range 39-74), and twenty-three pts were male (62.2%). As a curative surgery, pts received lobectomy (n=34), bi-lobectomy (n=2), or pneumonectomy (n=1). Adenocarcinoma was predominant (n=27, 73.0%). After the neoadjuvant CCRT, down-staging were observed in nine pts (24.3%). The median follow-up duration was 10.6 months (range 3.1-17.2), and pts received a median of 11 cycles (range 1-22) of adjuvant pembrolizumab. DFS is not reached. Fourteen patients discontinued treatment due to disease progression (n=9), adverse events (n=4) and withdraw consent (n=1). There was a case of grade 4 pneumonitis and a case of grade 3 autoimmune hepatitis which lead to discontinuation of the treatment. Otherwise, grade 1-2 hypothyroidism (n=6), pneumonitis (n=5), skin rash (n=3) were observed. Patients with sever immune-related adverse event showed a significantly high percentage of Ki-67 + cells among CD8 T-cells in peripheral blood. Conclusions: This study is the first study to demonstrate the feasibility of adjuvant pembrolizumab monotherapy in stage IIIA-N2 patients. Updated and detail clinical and exploratory biomarker outcome will be presented at the annual meeting. Clinical trial information: NCT03053856.

e14557 Background: Circulating tumor DNA (ctDNA) analysis has been successfully applied to therapy selection and treatment monitoring in advanced cancer patients. However, it is not yet established whether ctDNA can be used clinically for early cancer detection or predicting tumor recurrence in early stage lung cancer patients. Methods: We analyzed pre-operative plasma samples from 55 early stage NSCLC patients (stages I-IIIA) using next-generation sequencing to detect somatic mutations and differential epigenomics patterns, including methylation signatures. Results: Using somatic mutation analysis alone, ctDNA was detected in 42% (23/55) of patients, whereas combined mutational and epigenomic analysis detected ctDNA in 71%. ctDNA detection rate also varied markedly between lung squamous cell carcinoma (SCC) and adenocarcinoma (ADC);using combined analysis of somatic mutations and epigenomic patterns, ctDNA was detected in all SCC patients, while only 55% of ADC (12/22) were ctDNA-positive (p= 0.006). Within the ADC subgroup, ctDNA detection rates using the combined approach were dependent on disease stage: 47% (8/17) in stage I, 100% (2/2) in stage II, and 100% (2/2) in stage IIIA. Importantly, pre-operative ctDNA status was correlated with tumor recurrence post-resection; three of eight (38%) ctDNA-positive stage I ADC patients recurred within 2 years of resection, while only one of nine (11%) ctDNA-negative stage I ADC patients recurred (p= 0.29). Conclusions: Taken together, we show that the combination of somatic mutation detection and epigenomic analysis outperforms each individual biomarker in the detection of ctDNA in early stage lung cancer. Importantly, we also demonstrate that pre-operative ctDNA detection may identify a high-risk population of early stage lung cancer patients that may benefit from (neo)adjuvant therapy.

In chest wall reconstruction after wide chest wall resection, the use of a musculocutaneous flap or prosthetic materials is inevitable for maintaining thoracic movement and a closed pleural cavity. We report a case of a 63-year-old male with a large invasive thymic carcinoma in the anterior mediastinum. The mass measured 6.8 cm and involved the sternum, left side of the parasternal area, ribs, and intercostal muscles. The patient underwent subtotal sternectomy, radical thymectomy, and reconstruction with biological mesh (Permacol). Successful chest wall reconstruction without any other complications was achieved, demonstrating the effectiveness of Permacol.

TNF-α-blocking agents such as infliximab, adalimumab and etanercept are widely used for the treatment of severe inflammatory diseases including rheumatoid arthritis and psoriasis. The currently used TNF-α blockers have Fc regions of the human IgG1 subtype, which is advantageous in terms of in vivo half-life but also raise the potential for unwanted effector-mediated effects, such as antibody dependent cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC). To address this issue, we constructed a novel hybrid protein by fusing the TNF receptor (TNFR) with a hybrid Fc (hyFc) consisting of the CH2 and CH3 regions of IgG4 and the highly flexible hinge regions of IgD which would not have ADCC and CDC activity. The resulting fusion protein, TNFR-hyFc, was over-expressed in CHO and pharmacological characteristics were evaluated in comparison with the structurally similar etanercept. TNFR-hyFc effectively neutralized TNF-α in L929 bioassay and showed a 1.5-fold higher neutralizing activity compared to etanercept. In a pharmacokinetic study in cynomolgus monkeys, TNFR-hyFc showed plasma half-life and AUC comparable to etanercept. In a mouse collagen induced arthritis model, TNFR-hyFc showed significant amelioration of arthritis compared to etanercept or vehicle control. In an LPS-induced septic shock model, TNFR-hyFc showed a similar level of protection against mortality as etanercept. These results confirm the feasibility of the TNFR-hyFc as an effective TNF-α blocker for the treatment of inflammatory diseases.

Objectives For early-stage thymoma, complete thymectomy has classically been regarded as the standard treatment protocol. However, several studies have shown that limited thymectomy may be an alternative treatment option for thymoma. This study compared perioperative outcomes, survival, and recurrence rates between patients undergoing limited thymectomy and complete thymectomy. Materials and methods Between January 2000 and December 2013, a total of 762 patients underwent thymectomy for stage I or II thymomas at four institutions participating in the Korean Association for Research on the Thymus. Patients were divided into two groups: limited thymectomy group (n = 295) and complete thymectomy group (n = 467). Comparative clinicopathological, surgical, and oncological features were reviewed retrospectively. Results The median follow-up time was 49 months (range: 0.2–189 months). A propensity score-matching analysis, based on seven variables (age, sex, surgical approach, tumor size, WHO histological type, Masaoka-Koga stage, and adjuvant radiotherapy), was performed using 141 patients selected from each group. The 5- and 10-year freedom-from-recurrence rates in the limited thymectomy group were 96.3% and 89.7%, respectively, and those in the complete thymectomy group were 97.0% and 85.0%, respectively. No significant differences in these rates were observed between groups (p = 0.86). A multivariate Cox regression analysis showed that overall survival and freedom-from-recurrence rates did not significantly differ by surgery extent (p = 0.27, 0.66, respectively). Perioperative outcomes were better in the limited thymectomy group. Conclusion Limited thymectomy was not inferior to complete thymectomy with respect to recurrence, and had better perioperative outcomes. Limited thymectomy may be a viable treatment option for early-stage thymoma.

To find the faster and easier way than the existing intubating technique for double-lumen tube, we modified the angle of double-lumen tube according to an individual’s upper airway anatomy and compared the time needed and the number of attempts for successful intubation between individually angle-modified and non-modified double-lumen tubes. Adult patients undergoing elective thoracic surgery were randomly allocated in either non-angle-modified (Group N, n = 54) or angle-modified (Group M, n = 54) groups. During mask ventilation in the sniffing position, angle-modification was performed in Group M as follows: the distal tip of the tube was placed at the level of the cricoid cartilage and the shaft was bent at the intersection of the oral and pharyngeal axes estimated from the patient’s surface anatomy. The time needed and the number of attempts for successful intubation and Cormack and Lehane (C-L) grade were recorded. Overall median intubation time (sec) was significantly shorter in Group M than in Group N [10.2 vs. 15.1, P

Background: Cryosurgery was recently introduced as a treatment for varicose veins in the lower extremities. Cryosurgery with freezing probes can be used to remove the great saphenous vein (GSV) via an inguinal incision alone. The aim of this study was to assess early outcomes and the feasibility of cryosurgery for varicose veins. Materials and Methods: Forty patients were enrolled in the present study from March 2009 to July 2010. All patients underwent careful physical examinations, and their GSV reflux was demonstrated by duplex ultrasonography. Clinical severity was measured according to the clinical-etiology-anatomy-pathophysiology (CEAP) classification. The impaired GSVs were removed with rigid cryoprobes after freezing. Patients had follow-up appointments at 1 week, 1 month, 3 months, and 6 months after surgery. Sclerotherapy was performed during follow-up on an outpatient basis as needed. Results: A total of 19 men and 21 women were enrolled. The mean follow-up duration was 3.4 months (range, 1 to 12 months). The clinical severity ranged from CEAP 2 to CEAP 6a. Thirty-eight patients underwent concomitant phlebectomy during surgery. No recurrences were reported during follow-up. There were three cases of minor complications. Two patients had paresthesia, and one had thrombophlebitis. Conclusion: Using cryosurgery techniques to treat varicose veins, the complication rates were minimal and outcomes were comparable to those of previous reports. This procedure is a safe and feasible treatment modality for varicose veins.

Pb(Zr,Ti)O 3 (PZT) based ceramics with superior piezoelectric properties have been extensively used in various domestic and industrial appliances. However, PZT ceramics causing environmental contamination and health problems need to be eventually replaced by any of Pb-free materials. (Na 0.53 K 0.47 )(Nb 1?x Ta x )O 3 (NKNT), one of Pb-free piezoelectric ceramics, has long been known but its properties are not fully understood and developed. In this study, dielectric and piezoelectric properties of Pb-free NKNT ceramics were studied with Ta substitution for B-site at x=0~0.6. It was found that polymorphic phase transition (PPT) between orthorhombic and tetragonal phases was notably influenced by Ta substitution. The highest piezoelectric coefficient (d 33 ) of 284 pC/N was occurred at x = 0.45.

The structural, dielectric and piezoelectric characteristics of lead-free (1−x)BaTiO3-xBiScO3 (0 ≤ x ≤ 0.45) solid solution ceramics synthesized by using a solid state reaction have been investigated for use in high-temperature applications. Their polycrystalline structure change from a tetragonal ferroelectric phase to a pseudocubic phase at 0.04 < x < 0.08, and secondary impurity peaks appear at x = 0.45. The temperature-dependent dielectric constants indicate a phase transition that becomes more diffuse as x increases and a crossover from a diffuse phase transition (DPT) to a relaxor behavior that takes place at 0.04 < x < 0.08. The dielectric permittivity maximum temperature, Tm, increases with increasing BiScO3 content above x = 0.08. The values of the piezoelectric coefficient (d33) and the electromechanical coupling factor (kp) decrease rapidly with increasing x. Ceramics with x = 0.01 show a coercive field of about 6.6 kV/cm and a remanent polarization near 8.5 μC/cm, which are maximum values for (1− x)BaTiO3-xBiScO3 systems.

The structure, dielectric properties, and Curie temperatures of Pb(Zr 1− x Ti x )O 3 doped with 5 mol% Bi(Zn 0.5 Ti 0.5 )O 3 (PZT–5BZT), 5 mol% BiFeO 3 (PZT–5BF), and 5 mol% BiAlO 3 (PZT–5BA) ceramics prepared by the conventional solid state reaction are reported. The structural phase transition temperature are compared with undoped and Bi( B )O 3 doped Pb(Zr 1− x Ti x )O 3 ceramics for 0.48 x ≤ 1 where B = Zn, Fe, and Al. A turning point was found around x = 0.70 where the Curie temperature ( T C ) of Bi( B )O 3 –PZT solid solution increases beyond that of pure PZT. Unlike most PZT-based ceramics, these systems show enhanced tetragonality. This effect is most dramatic in the PZT–5BF system, in which an extremely large c/a ratio of 1.057 is achieved for x = 0.90 sample, leading to the T C as high as 768 K.

Purpose We explored the association between different molecular biomarkers and PD-L1 mRNA and protein expression in Asian patients with lung adenocarcinoma. Experimental design PD-L1 protein expression level was evaluated using a prototype immunohistochemistry (IHC) assay with the 22C3 antibody in tumor samples from 157 patients with lung adenocarcinoma from Samsung Medical Center. Other biomarkers, including PD-L1, PD-L2 and IFN-γ mRNA expression detected using the Affymetrix array, EGFR and KRAS mutation detected using the Sequenom platform, ALK fusion detected using the NanoString system and tumor mutation burden (TMB) calculated as total number of non-synonymous single nucleotide substitution from Illumina HiSeq 2000 sequencing platform were provided as part of the Asian Cancer Research Group collaboration. Spearman correlation test, t test, Fisher exact test, and multivariate regression models were utilized to test the association between different biomarkers and PD-L1 mRNA/protein expression. PD-L1 IHC tumor proportion score was analyzed as a continuous or categorical variable, where PD-L1 strong and weak positivity were defined to be traceable to the 1% and 50% cutoffs used in the clinical trial version of the assay. Results The median age was 61 years (range, 20-84), 50% were female, 40% were smokers, and 77% had stage I/II disease. There was strong correlation between PD-L1 mRNA and protein expression (N = 79, Spearman R = 0.762, P < 0.0001). Absence of EGFR mutation was associated with higher PD-L1 expression (for mRNA, N = 166, t test P = 0.023; for protein, N = 83, Fisher test P = 0.051), and presence of ALK fusion was associated with higher PD-L1 expression (for mRNA, N = 229, t test P = 0.001; for protein, N = 144, Fisher test P = 0.002). Similar associations between EGFR mutation, ALK fusion, and PD-L1 mRNA and protein expression were observed after adjusting for age, sex, smoking status, and disease stage. No association was found between PD-L1 expression and KRAS mutation (for mRNA, N = 140, t test P = 0.305; for protein, N = 78, Fisher test P = 0.243). mRNA expression of PD-L2, the other PD-1 ligand, was highly correlated with PD-L1 expression (for mRNA, N = 253, Spearman R = 0.650, P < 0.0001; for protein, N = 79, Spearman R = 0.444, P < 0.0001). As evidence for IFN-γ-inducible biology, IFN-γ mRNA expression was significantly correlated with PD-L1 expression (for mRNA, N = 253, Spearman R = 0.57, P < 0.0001; for protein, N = 79, Spearman R = 0.44, P < 0.0001). TMB was not significantly correlated with PD-L1 expression (for mRNA, N = 31, Spearman R = 0.092, P = 0.62; for protein, N = 8, Spearman R = 0.19, P = 0.65), which suggested independent predictive ability for anti-PD-1 therapy. Conclusion Our study provides evidence that DNA and RNA features, including PD-L1 mRNA, lack of EGFR mutation, and ALK fusion are associated with PD-L1 protein expression for Asian lung adenocarcinoma patients. Citation Format: Xiaoqiao Liu, Jinseon Lee, Soo Jung Lee, Jong Ho Cho, Jong-Mu Sun, Lu Zhang, Yunfei Pei, Lan Chen, Marisa Dolled-Filhart, Kenneth Emancipator, Jared Lunceford, Ronghua Chen, Wei Zhou, Jhingook Kim. Molecular biomarker study of programmed death receptor ligand 1 (PD-L1) in Korean patients with lung adenocarcinoma [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 4213.

A patient with a long-standing intradiploic epidermoid cyst with perforation of the dura and brain parenchymal involvement is reported. A 69-year-old man, who had previously presented with a subcutaneous mass on the left frontoparietal scalp, developed a sudden grand mal seizure. Magnetic resonance imaging showed a well-defined mass in the frontoparietal scalp with destruction of the skull. Penetration of the dura allowed for communication with the intracranial structures. Surgical resection and cranioplasty were performed. There were no well-defined margins in the deep portion and the mass was subtotally removed. Histological examination showed that the cystic structure was lined by squamous epithelium containing laminated keratin material. The pathologic findings were consistent with the diagnosis of an epidermoid cyst.

The detection of circulating tumor cells (CTCs) is limited by the rarity of these cells in the peripheral blood of patients with cancer. Understanding tumor biology may be useful in the development of novel therapeutic strategies for patients with lung cancer. The present study evaluated a novel size-based filtration platform for enriching CTCs from patients with lung cancer. Blood samples were obtained from 82 patients with lung cancer for CTC analysis. CTC enrichment by size-based filtration was performed on 5-ml blood samples. The collected cells were detected by immunofluorescence using monoclonal anti-human antibodies against protein tyrosine phosphatase, receptor type C (CD45) and epithelial cell adhesion molecule (EpCAM; an epithelial cell marker), as well as a DAPI nucleic acid stain. CTCs were detected in 57 patients (69.5%) using the size-based filtration platform. The mean CTC counts, defined as the number of cells with DAPI-positive, CD45-negative and EpCAM-positive staining, were 1.48±1.71 per 5 ml blood for the 66 stage I-III patients and 8.00±9.95 per 5 ml blood for the 16 stage IV patients. The presence of ≥1 CTCs per 5-ml blood sample was significantly associated with pathological stage (stage IV vs. stage I-III, P=0.009), but not with patient age or gender, tumor histology, tumor size or lymphovascular invasion. The mean CTC count of healthy donors was 0.25±0.55 per 5 ml blood. In summary, CTCs from the blood of patients with lung cancer were enriched using a size-based filtration platform and immunofluorescent staining with DAPI, CD45 and EpCAM. The CTC counts of patients with stage IV cancer were higher than those of patients with stages I-III cancer. These results suggest that this novel platform may be a useful tool for determining the prognosis of patients with lung cancer.

// Seung Tae Kim 1, * , Jeeyun Lee 1, * , Mineui Hong 2, 3, * , Kyunghee Park 4, 5, * , Joon Oh Park 1 , Tae Jin Ahn 3, 4 , Se Hoon Park 1 , Young Suk Park 1 , Ho Yeong Lim 1 , Jong-Mu Sun 1 , Jin Seok Ahn 1 , Myung-Ju Ahn 1 , Hee Cheol Kim 6 , Tae Sung Sohn 6 , Dong Il Choi 7 , Jong Ho Cho 8 , Jin Seok Heo 6 , Wooil Kwon 6 , Sang Won Uhm 9 , Hyuk Lee 10 , Byung-Hoon Min 10 , Sung No Hong 10 , Duk Hwan Kim 5, 11 , Sin Ho Jung 12 , Woongyang Park 4, 5 , Kyoung-Mee Kim 2, 3 , Won Ki Kang 1 , Keunchil Park 1, 2 1 Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 2 Innovative Cancer Medicine Institute, Samsung Cancer Center, Samsung Medical Center, Seoul, Korea 3 Department of Pathology & Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 4 Samsung Genome Institute, Seoul, Korea 5 Samsung Biological Research Institute, Seoul, Korea 6 Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 7 Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 8 Department of Thoracic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 9 Division of Pulmonology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 10 Division of Gastroenterology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 11 Medical Translational Research Center, Samsung Biological Research Institute, Seoul, Korea 12 Biostatistics and Clinical Epidemiology, Samsung Medical Center, Seoul, Korea * These authors have contributed equally to this work Correspondence to: Won Ki Kang, e-mail: wkkang@skku.edu Kyoung-Mee Kim, e-mail: kkmkys@skku.edu Keunchil Park, e-mail: kpark@skku.edu Keywords: molecular profiling, genome, ampliseq Received: July 01, 2015 Accepted: August 27, 2015 Published: September 09, 2015 ABSTRACT We conducted a prospective genomic screening trial with high throughput sequencing and copy number variation (CNV) assay, and immunohistochemistry array in metastatic solid cancer patients. We used Ion AmpliSeq Cancer Hotspot Panel v2 and nCounter Copy Number Variation Assay (21 genes) to identify molecular targets for potential matched therapy. Metastatic solid tumor patients were prospectively consented for molecular profiling tests. The primary outcome for this trial was the feasibility of molecular tests and response rate (matched vs non-matched treatment). Between November 2013 and August 2014, a total of 428 metastatic solid tumor patients were enrolled on to this study. The mutational profiles were obtained for 407 (95.1%) patients. CNV 21-gene assays were successfully performed in 281 (65.7%) of 428 patients. Of the 407 patients with molecular profiling results, 342 (84.0%) patients had one or more aberrations detected. Of the 342 patients, 103 patients were matched to molecularly targeted agents in the context of clinical trials or clinical practice. The response rate was significantly higher in the genome-matched treated group for gastrointestinal/hepatobiliary/rare tumors (matched vs non-matched treatment, 42.6% vs 24.3%, P = .009) and lung cancer cohort (matched vs non-matched treatment, 61.2% vs 28.6% < P = .001) when compared with the non-matched group. In this trial, we demonstrate that genome-matched treatment based on molecular profiling result in better treatment outcome in terms of response rate.

Background Post-pneumonectomy syndrome (PPS) is a rare syndrome characterized by trachea-bronchial stenosis and severe dyspnea. In this study, we retrospectively evaluated the clinical outcomes in patients who underwent placement of tissue expanders for PPS. Methods Data from patients who underwent placement of tissue expanders for PPS were analyzed for preoperative characteristics, surgical techniques, and postoperative outcomes. Between 1997 and 2014, a total of 10 patients were treated for PPS by tissue expanders. Results The median age of the 10 patients was 45 years (range, 16–70). Four patients had undergone right pneumonectomy, three patients had undergone left pneumonectomy, and three patients had post-pneumonectomy-like syndrome. Preoperatively, seven patients initially received high oxygen therapy for hypoxemia but progressed to respiratory failure, and three patients required mechanical ventilator support. Among these three patients, one required intraoperative extracorporeal membrane oxygenation support because of sudden cardiac arrest during preparation for surgery. The median follow-up was 59.5 months (range, 2–204). The median interval between pneumonectomy and repositioning was 13 months (range, 8–581). Two patients underwent placement of a single tissue expander, and two tissue expanders were placed in eight of the 10 patients. The median volume of tissue expanders inflated with saline was 450 cc (range, 60–850 cc) per tissue expander. There was no perioperative mortality in our study. Complications occurred in four patients (40%). Conclusions Repositioning of the mediastinum with placement of a saline filled tissue expander for PPS is very effective for the relief of symptoms, with low mortality.

Supplemental Digital Content is available in the text, Quantitative imaging using radiomics can capture distinct phenotypic differences between tumors and may have predictive power for certain phenotypes according to specific genetic mutations. We aimed to identify the clinicoradiologic predictors of tumors with ALK (anaplastic lymphoma kinase), ROS1 (c-ros oncogene 1), or RET (rearranged during transfection) fusions in patients with lung adenocarcinoma. A total of 539 pathologically confirmed lung adenocarcinomas were included in this retrospective study. The baseline clinicopathologic characteristics were retrieved from the patients’ medical records and the ALK/ROS1/RET fusion status was reviewed. Quantitative computed tomography (CT) and positron emission tomography imaging characteristics were evaluated using a radiomics approach. Significant features for the fusion-positive tumor prediction model were extracted from all of the clinicoradiologic features, and were used to calculate diagnostic performance for predicting 3 fusions’ positivity. The clinicoradiologic features were compared between ALK versus ROS1/RET fusion-positive tumors to identify the clinicoradiologic similarity between the 2 groups. The fusion-positive tumor prediction model was a combination of younger age, advanced tumor stage, solid tumor on CT, higher values for SUVmax and tumor mass, lower values for kurtosis and inverse variance on 3-voxel distance than those of fusion-negative tumors (sensitivity and specificity, 0.73 and 0.70, respectively). ALK fusion-positive tumors were significantly different in tumor stage, central location, SUVmax, homogeneity on 1-, 2-, and 3-voxel distances, and sum mean on 2-voxel distance compared with ROS1/RET fusion-positive tumors. ALK/ROS1/RET fusion-positive lung adenocarcinomas possess certain clinical and imaging features that enable good discrimination of fusion-positive from fusion-negative lung adenocarcinomas.

Early diagnosis and aggressive surgical drainage are very important for successful treatment of descending necrotizing mediastinitis (DNM). However, the surgical techniques used for DNM treatment remain controversial. The purpose of this study was to evaluate the effectiveness of video-assisted thoracoscopic surgery (VATS) and cervical drainage for the management of DNM. Nine patients diagnosed with DNM were treated from May 2001 to April 2004. The mean age of the patients was 51.1+/-15.0 years. VATS and cervical drainage, including debridement and drainage of the mediastinum and pleura, were performed simultaneously. The mean postoperative hospital stay was 20.6+/-6.6 days. One patient (11%) died of sepsis and renal failure on the 15th postoperative day. Minimal mastication difficulty developed in 2 patients (22%). The mean postoperative follow-up period was 28.7+/-14.7(5 to 52) months. All the survivors are in good health with no recurrences. VATS was safe, effective, and a less invasive surgical option for the management of DNM and should be considered as a good alternative therapeutic modality.

We previously reported that a methanolic extract of Coptis japonica, which is a well-known traditional oriental medicine, inhibits morphine-induced conditioned place preference (CPP) in mice. Berberine is a major component of Coptis japonica extract, and it has been established that the adverse effects of morphine on the brain involve dopamine (DA) receptors. However, to our knowledge, no study has investigated the inhibitory effects of berberine on morphine-induced locomotor sensitization and analgesic tolerance in mice. Here, we investigated the effects of berberine on morphine-induced locomotor sensitization and on the development of analgesic tolerance. Furthermore, we examined the effects of berberine treatment on N-methyl-D-aspartate (NMDA) receptor channel activity expressed in Xenopus laevis oocytes. Berberine was found to completely block both morphine-induced locomotor sensitization and analgesic tolerance, and reduce D(1) and NMDA receptor bindings in the cortex. Moreover, berberine markedly inhibited NMDA current in Xenopus laevis oocytes expressing NMDA receptor subunits. Our results suggest that the inhibitory effects of berberine on morphine-induced locomotor sensitization and analgesic tolerance are closely related to the modulation of D1 and NMDA receptors, and that berberine should be viewed as a potential novel means of attenuating morphine-induced sensitization and analgesic tolerance.

Recently perovskite niobates were paid much attention as lead-free piezoelectric materials to replace lead-based Pb(Zr,Ti)O3 or relaxor systems which cause much environmental problems. Piezoelectric and ferroelectric properties of electromechanical coupling coefficient and quality factor in (K0.5Na0.5)NbO3 ceramic were studied. Dielectric properties of niobates including Ag ion; AgNbO3 and (Ag0.5Na0.5)NbO3 were studied. Phase transitions and dielectric relaxations were studied from the frequency and temperature dependent dielectric constant measurements. The piezoelectric properties were hardly observed in silver niobate systems.

Ferroelectric SrBi 2 Ta 2 O 9 (SBT) with different Sr/Bi ratio were synthesized. Crystallized single-phases with Bi-layered perovskite structure was confirmed by X-ray diffraction (XRD). With increasing Bi/Sr ratio, the Curie temperature T c was increased and remanent polarization P r increased. The dielectric and ferroelectric properties were strongly influenced by the Bi/Sr ratio. The effect on dielectric properties and ac conductivity were investigated as functions of temperature and frequency.

Mossbauer spectra of Ti0.99 57Fe0.01O2 prepared with 57Fe enriched iron have been taken at various temperatures ranging from 80 to 300 K. The Mossbauer spectrum of Ti0.99 57Fe0.01O2 consists of a ferromagnetic (six-Lorentzian) and a paramagnetic phase (doublet) over all temperature ranges. Isomer shifts indicate Fe2+ for the ferromagnetic phase, but Fe3+ for the paramagnetic phase of Ti0.99 57Fe0.01O2 sample. It is noted that the magnetic hyperfine field of ferromagnetic phase had the value about 1.5 times as large as that of α-Fe. The XRD data for Ti0.99 57Fe0.01O2 showed a pure rutile phase with tetragonal structures without any segregation of Fe into particulates within the instrumental resolution limit. The magnetic hysteresis (M–H) curve at room temperature showed an obvious ferromagnetic behavior and the magnetic moment per Fe atom under the applied field of 1 T was estimated to be about 0.68 μB, suggesting a low spin configuration of Fe ions.

Nonstoichiometric SrBi2Ta2O9 (SBT) and SrBi2Nb2O9 (SBN) ceramics were prepared by a solid state reaction method. X-ray diffraction analysis showed that single-phase of Bi-layered perovskite was obtained. With different Sr/Bi content ratios of SBT and SBN, Curie temperature (T C ), electromechanical factor (K p ) and mechanical quality factor (Q m ) were measured. T C of SBN (SBT) rose from 414∘C (314∘C) to 494∘C (426∘C) when Sr/Bi content ratio was increased from 0.55/2.3 to 1.2/1.8. In the most Sr-deficient/Bi-excess ratio of 0.55/2.3, the maximum values of Q m were obtained approximately 1013 and 3325 for SBT and SBN, respectively.

Ionic doping effects of various ions in Bi-layered ferroelectric SrBi2Nb2O9 (SBN) ceramics were studied. Un-doped and doped SBN ceramics with Ba2+, Pb2+, Ca2+, Bi3+, La3+, Ti4+, Mo6+, and W6+ ions were made with solid state reactions. Temperature dependent dielectric constants were measured. Ferroelectric transition temperature (TC) decreased with Ba2+ and Pb2+ ions but increased with Ca2+ ion which substitutes the 12-coordinated Sr2+ site. TC increased with Ti4+, Mo6+, and W6+ ions which substitute the 6-coordinated Nb5+ sites. With trivalent Bi3+ and La3+ ions, TC increased with Bi3+ ion but much decreased with La3+ ion. These results showed that the ion size plays an important role in ferroelectricity of SBN ceramics.

Here, we describe an external tracheal stabilization technique used in a patient with tracheomalacia. A 56-year-old man presented with tracheomalacia due to prolonged mechanical ventilation. The malacic tracheal segment was approximately 2 cm in length. The malacic segment was covered with a silicone tube sutured in place using Prolene sutures (Ethicon, Somerville, NJ). Several anchoring sutures were placed between the tracheal mucosa and the silicone tube without violating the mucosal continuity. The patient was discharged on postoperative day 5 without complication. This method of external tracheal stabilization is a less invasive alternative for the management of this particular patient.