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Purpose The programmed death ligand 1 (PD-L1) SP142 assay with a 1% immune cell (IC) cutoff is approved for the selection of advanced triple-negative breast cancer (TNBC) patients for atezolizumab treatment. We aimed to evaluate the interobserver concordance of PD-L1 scoring and inter-assay variability of various PD-L1 assays in TNBC. Methods Thirty patients with primary TNBC were selected, and SP142, SP263, 22C3, and E1L3N assays were performed. PD-L1 staining in ICs and tumor cells (TCs) was scored by 10 pathologists who were blinded to the assay. The interobserver concordance among pathologists and the inter-assay variability of the four PD-L1 assays were analyzed. For SP142, the intraobserver concordance among the six pathologists was analyzed after training. Results The adjusted means of PD-L1 IC scoring ranged from 6.2% to 12.9% for the four assays; the intraclass correlations showed moderate (0.584-0.649) reader concordance. The PD-L1 IC scoring with a 1% cutoff resulted in identical scoring in 40.0%-66.7% of cases and a poor to moderate agreement (Fleiss κ statistic [FKS] = 0.345-0.534) for the four assays. The SP142 assay had the widest range of positive rate (56.5%-100.0%), lowest number of cases with identical scoring, and lowest FKS at 1% cutoff. Pairwise comparison of adjusted means showed significantly decreased PD-L1 staining in SP142 compared with the other assays in both ICs and TCs. As for the intraobserver concordance in the SP142 assay, the overall percent agreement was 87.8% with a 1% IC cutoff. After training, the proportion of cases with identical scoring at a 1% IC cutoff increased to 70.0%; the FKS also increased to 0.610. Conclusion The concordance of PD-L1 IC scoring among pathologists was low, at the 1% cutoff for the SP142 assay without training. SP142 showed the lowest PD-L1 expression in both IC and TC.

The prevalence of multiple lung cancers has been increasing recently. Molecular analysis of epidermal growth factor receptor (EGFR) mutations in individual tumors of multiple lung cancers is essential for devising an optimal therapeutic strategy. The EGFR mutation status in multiple lung cancers was evaluated to determine its therapeutic implications. In total, 208 tumors from 101 patients who underwent surgery for multiple lung cancers were analyzed. Individual tumors were subjected to histological evaluation and EGFR analysis using a real-time polymerase chain reaction. Additionally, EGFR-wildtype tumors were subjected to next-generation sequencing (NGS). EGFR mutations were detected in 113 tumors from 72 patients, predominantly in females (p < 0.001) and non-smokers (p < 0.001). Among patients with at least one EGFR-mutant tumor, approximately 72% of patients (52/72) had different EGFR mutations in individual tumors. NGS analysis of EGFR-wildtype tumors from 12 patients revealed four and eight cases with concordant and discordant molecular alterations, respectively. These findings revealed a high proportion of discordant EGFR mutations among multiple lung tumors. Hence, EGFR analysis of individual tumors of multiple lung tumors is essential for the evaluation of clonality and the development of an optimal treatment strategy.

To overcome the limitations of the tissue biopsy and plasma cfDNA liquid biopsy, we performed the EV-based BALF liquid biopsy of 224 newly diagnosed stage III-IV NSCLC patients and compared it with tissue genotyping and 110 plasma liquid biopsies. Isolation of EVs from BALF was performed by ultracentrifugation. EGFR genotyping was performed through peptide nucleic acid clamping-assisted fluorescence melting curve analysis. Compared with tissue-based genotyping, BALF liquid biopsy demonstrated a sensitivity, specificity, and concordance rates of 97.8%, 96.9%, and 97.7%, respectively. The performance of BALF liquid biopsy was almost identical to that of standard tissue-based genotyping. In contrast, plasma cfDNA-based liquid biopsy (n = 110) demonstrated sensitivity, specificity, and concordance rates of 48.5%, 86.3%, and 63.6%, respectively. The mean turn-around time of BALF liquid biopsy was significantly shorter (2.6 days) than that of tissue-based genotyping (13.9 days; p < 0.001). Therefore, the use of EV-based BALF shortens the time for confirmation of EGFR mutation status for starting EGFR-TKI treatment and can hence potentially improve clinical outcomes. As a result, we suggest that EV-based BALF EGFR testing in advanced lung NSCLC is a highly accurate rapid method and can be used as an alternative method for lung tissue biopsy.

Background Despite surgical resection, early lung adenocarcinoma has a recurrence rate of 20–50%. No clear predictive markers for recurrence of early lung adenocarcinoma are available. Targeted next-generation sequencing (NGS) is rarely used to identify recurrence-related genes. We aimed to identify genetic alterations that can predict recurrence, by comparing the molecular profiles of patient groups with and without recurrence. Methods Tissues from 230 patients with resected stage I–II lung adenocarcinoma (median follow-up: 49 months) were analyzed via targeted NGS for 207 cancer-related genes. The recurrence-free survival according to the number and type of mutation was estimated using the Kaplan–Meier method. Independent predictive biomarkers related to recurrence were identified using the Cox proportional hazards model. Results Recurrence was observed in 64 patients (27.8%). In multivariate analysis adjusted for age, sex, smoking history, stage, surgical mode, and visceral pleural invasion, the CTNNB1 mutation and fusion genes (ALK, ROS1, RET) were negative prognostic factors for recurrence in early-stage lung adenocarcinoma (HR 4.47, p = 0.001; HR 2.73, p = 0.009). EGFR mutation was a favorable factor (HR 0.51, p = 0.016), but the CTNNB1/EGFR co-mutations were negative predictors (HR 19.2, p p = 0.02). Conclusions: Targeted NGS can provide valuable information to predict recurrence and identify patients at high recurrence risk, facilitating selection of the treatment strategy among close monitoring and adjuvant-targeted therapy. Larger datasets are required to validate these findings.

Purpose Triple-negative breast cancer (TNBC) represents a major clinical challenge due to its aggressive and metastatic behavior and the lack of available targeted therapies. Therefore, therapeutic strategies are needed to improve TNBC patient management. Recently, atezolizumab and nab-paclitaxel chemotherapy has been approved by the Food and Drug Administration for the first-line treatment of patients with locally advanced and metastatic TNBC. The programmed death-ligand 1 (PD-L1) immunohistochemical SP142 assay was also approved as a companion diagnostic device for selecting TNBC patients for atezolizumab treatment. This study aimed to evaluate and compare the analytical performance of the PD-L1 22C3/SP263 assays in comparison with the SP142 assay for ≥ 1% immune cells (ICs). Methods Immunohistochemical expression for the PD-L1 22C3/SP263 assays, in comparison with the SP142 assay, was analyzed for the ≥ 1% ICs in 95 TNBCs. Results At the 1% cut-off value, the proportions of positive cases were 52.6% for the SP142 assay in infiltrating ICs and 50.5% and 52.6% for the 22C3 and SP263 assays in tumor cells, respectively. The PD-L1 SP263 assay had the highest while the PD-L1 22C3 assay had the lowest total positive expression rate at all cut-off values. The concordance rate between the assays was highest at a 1% cut-off value and decreased when the cut-off value increased. The concordance rate between the SP142 and SP263 assays at 1% cut-off was high, while in comparison, the concordance rate between the SP142 and 22C3 assays at 1% cut-off was relatively lower. Conclusion This study demonstrates that although the 22C3 assay at a 1% cut-off value compared with the PD-L1 SP142 assay at the clinically relevant cut-off shows comparable but not interchangeable analytical performance, the analytical performance of the SP263 assay at a 1% cut-off value shows interchangeable performance with the PD-L1 SP142 assay at the clinically relevant cut-off.

With advances in target therapy, molecular analysis of tumors is routinely required for treatment decisions in patients with advanced non-small cell lung cancer (NSCLC). Liquid biopsy refers to the sampling and analysis of circulating cell-free tumor DNA (ctDNA) in various body fluids, primarily blood. Because the technique is minimally invasive, liquid biopsies are the future in cancer management. Epidermal growth factor receptor (EGFR) ctDNA tests have been performed in routine clinical practice in advanced NSCLC patients to guide tyrosine kinase inhibitor treatment. In the near future, liquid biopsy will be a crucial prognostic, predictive, and diagnostic method in NSCLC. Here we present the current status and future perspectives of liquid biopsy in NSCLC.

Background/Aims We performed a large-scale, retrospective, nationwide, cohort study to investigate the risk factors for lung cancer among never-smoking Korean females. Methods The study data were collected from a general health examination and questionnaire survey of eligible populations conducted between January 1, 2003 and December 31, 2004; the data were acquired from the tailored big data distribution service of the National Health Insurance Service. After a 1-year clearance period, 5,860,922 of 6,318,878 never-smoking female participants with no previous history of lung cancer were investigated. After a median follow-up of 11.4 years, 43,473 (0.74%) participants were defined as “newly diagnosed lung cancer”. Results After adjusting for all variables at baseline, the variables older age, lower body mass index (BMI), less exercise, frequent alcohol drinking, meat-based diet, rural residence, and previous history of cancer were associated with a higher incidence of lung cancer. Low BMI (< 18.5 kg/m2: hazard ratio [HR], 1.33; 95% confidence interval [CI], 1.27 to 1.40) was a significant independent risk factor; as BMI decreased, HR increased. Negative associations between BMI and lung-cancer development were also observed after controlling for age (p for trend < 0.001). Drinking alcohol one to two times a week (HR, 1.25; 95% CI, 1.21 to 1.28) and eating a meat-based diet (HR, 1.08; 95% CI, 1.01 to 1.15) were associated with lung-cancer incidence. Conclusions Modifiable baseline characteristics, such as BMI, exercise, alcohol consumption, and diet, are risk factors for lung-cancer development among never- smoking females. Thus, lifestyle modifications may help prevent lung cancer.

Targeted NGS, widely applied to identify driver oncogenes in advanced lung adenocarcinoma, may also be applied to resected early stage cancers. We investigated resected EGFR-mutated lung adenocarcinoma mutation profiles to evaluate prognostic impacts. Tissues from 131 patients who had complete resection of stage I–IIIA EGFR-mutated lung adenocarcinoma were analyzed by targeted NGS for 207 cancer-related genes. Recurrence free survival (RFS) was estimated according to genetic alterations using the Kaplan–Meier method and Cox proportional regression analysis. The relapse rate was 25.2% (33/131). Five-year RFS of stages IA, IB, II, and IIIA were 82%, 75%, 35%, and 0%, respectively (p &lt, 0.001). RFS decreased with the number of co-mutations (p = 0.025). Among co-mutations, the CTNNB1 mutation was associated with short RFS in a multivariate analysis (hazard ratio: 5.4, 95% confidence interval: 2.1–14.4, p = 0.001). TP53 mutations were associated with short RFS in stage IB–IIIA (p = 0.01). RFS was shorter with EGFR exon 19 deletion (19-del) than with mutation 21-L858R in stage IB–IIIA tumors (p = 0.008). Among 19-del subtypes, pL747_P753delinS (6/56, 8.9%) had shorter RFS than pE746_A750del (39/56, 69.6%), the most frequent subtype (p = 0.004).

Porcine heart xenotransplantation is a potential treatment for patients with end-stage heart failure. To understand molecular mechanisms of graft rejection after heart transplantation, we transplanted a 31-day-old alpha-1,3-galactosyltransferase knockout (GTKO) porcine heart to a five-year-old cynomolgus monkey. Histological and transcriptome analyses were conducted on xenografted cardiac tissue at rejection (nine days after transplantation). The recipient monkey&rsquo, s blood parameters were analyzed on days &minus, 7, &minus, 3, 1, 4, and 7. Validation was conducted by quantitative real-time PCR (qPCR) with selected genes. A non-transplanted GTKO porcine heart from an age-matched litter was used as a control. The recipient monkey showed systemic inflammatory responses, and the rejected cardiac graft indicated myocardial infarction and cardiac fibrosis. The transplanted heart exhibited a total of 3748 differentially expressed genes compared to the non-transplanted heart transcriptome, with 2443 upregulated and 1305 downregulated genes. Key biological pathways involved at the terminal stage of graft rejection were cardiomyopathies, extracellular interactions, and ion channel activities. The results of qPCR evaluation were in agreement with the transcriptome data. Transcriptome analysis of porcine cardiac tissue at graft rejection reveals dysregulation of the key molecules and signaling pathways, which play relevant roles on structural and functional integrities of the heart.

The performance of our newly constructed cold-finger cryostat is investigated for quantum Hall resistance (QHR) and single-electron pump (SEP) devices. The cryostat features a vacuum-sealed sample chamber (SC) attached to a 0.3 K plate inside the inner vacuum can. The SC is designed to accommodate both the SEP and the QHR devices with a shielding partition between them. The measured QHR in the chamber approaches the nominal value for filling factor 2 within 20 parts in 109. The white-noise level of the SEP module, as obtained from the Allan deviation data, is 4.5 fA/ $\sqrt {\mathrm{ Hz}}$ . We also investigated the thermometry of the SC either under vacuum or filled with 3He gas. We calculated the thermal conductivity of the different heat conduction channels in the sample holder and found the dominant channel to be through the chip carriers not signal lines.

DNA replicase polymerase ε (POLE) is critical in proofreading and correcting errors of DNA replication. Low POLE expression plays a pivotal role in accumulation of mutations and onset of cancer, contributing to development and growth of tumor cells. The aim of this study is to reveal the survival, alternative genes and antitumoral immune activities in non-small cell lung cancer (NSCLC) patients with low POLE expression and provide treatment strategies that can increase their survival rates. This study investigated the clinicopathologic parameters, various tumor-infiltrating lymphocytes (TILs), endogenous retrovirus, molecular interactions and in vitro drug screen according to POLE mutation/expression in 168 and 1,019 NSCLC patients from the Konkuk University Medical Center (KUMC) and the Cancer Genome Atlas, respectively. We identified mutations of 75 genes in the sequencing panels, with POLE frame shift p.V1446fs being the most frequent (56.8%) in KUMC based on 170 targeted sequencing panels. Mutant and high expression of POLE correlated with favorable prognosis with increased TILs and tumor mutation burden, compared with wild type and low expression of POLE. We found specific molecular interactions associated with cell cycle and antigen presentation. An in vitro drug screen identified dasatinib that inhibited growth of the NSCLC cell line with low POLE expression. POLE could contribute to the future development of anticancer drugs for patients with NSCLC.

Background Although lung adenocarcinoma with activating epidermal growth factor receptor (EGFR) mutations is common in never smokers, one-third of the patients are ever-smokers. We aimed to investigate the effect of cumulative smoking dose(CSD) on clinical outcomes, including progression-free survival (PFS) and overall survival (OS), in patients with EGFR-mutated lung adenocarcinoma receiving EGFR-tyrosine kinase inhibitors (TKIs). Methods We retrospectively analyzed 142 patients with EGFR-mutation positive advanced or recurrent lung adenocarcinoma who were administered gefitinib, erlotinib, afatinib, and osimertinib. These patients were classified based on their CSD as never smokers, light smokers (≤10 pack-years [PYs]), moderate smokers (11–30 PYs), and heavy smokers (> 30 PYs). PFS and OS were analyzed according to smoking subgroups via Kaplan-Meier curves. Results Among the 142 patients, 91 (64.1%), 12 (8.5%), 22 (15.5%), and 17 (12%) were never, light, moderate, and heavy smokers, respectively. CSD was inversely associated with median PFS in a statistically significant dose-dependent manner (11.8 months (mo), 11.0 mo, 7.4 mo, and 3.9 mo; p

Targeted therapies guided by molecular diagnostics have become a standard treatment of lung cancer. Epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements are currently used as the best predictive biomarkers for EGFR tyrosine kinase inhibitors and ALK inhibitors, respectively. Besides EGFR and ALK, the list of druggable genetic alterations has been growing, including ROS1 rearrangements, RET rearrangements, and MET alterations. In this situation, pathologists should carefully manage clinical samples for molecular testing and should do their best to quickly and accurately identify patients who will benefit from precision therapeutics. Here, we grouped molecular biomarkers of lung cancers into three categories-mutations, gene rearrangements, and amplifications-and propose expanded guidelines on molecular testing of lung cancers.

ObjectiveThe current paradigm in the treatment of patients with non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is a diagnostic lobectomy rather than complete thyroidectomy and postoperative radioiodine treatment. Consequently, preoperative diagnosis of NIFTP is considered to be important.MethodsWe performed the comprehensive analysis for diagnosis of preoperative 20 NIFTPs in comparison with 41 invasive encapsulated follicular papillary thyroid carcinomas (I-EFVPTCs) using the Korean Thyroid Imaging Reporting and Data System (K-TIRADS), Bethesda System for Reporting Thyroid Cytopathology (TBSRTC), and molecular analysis for BRAF and RAS mutations.ResultsK-TIRADS 3 was identified as the most common sonographic diagnosis in both NIFTP and I-EFVPTC. Unlike I-EFVPTC, K-TIRADS 5 was not identified in NIFTP. AUS/FLUS was the most common cytopathological diagnosis and none of the cases were classified as malignant category in both groups, although the difference in distribution was not significant between the groups. BRAF mutation was not found in NIFTP but was present in 9.8% of cases in I-EFVPTC. The frequency of RAS mutation in I-EFVPTCs was twice as high as that of NIFTP. Wild-type BRAF and RAS in NIFTP was significantly higher than I-EFVPTC.ConclusionThe existence of overlapping features between the groups was evident, hence conclusive distinction between radiology, cytology and molecular analysis could not be achieved. Apparently, the diagnosis of NIFTP based on comprehensive analysis was not confirmable but could perceive or at least favor the diagnosis of NIFTP.

Thrombosis at the left ventricular outflow tract occurs without any detectable heart disease or predisposing factors only extremely rarely. A 48-year-old male visited Konkuk University Medical Center with loss of consciousness one month prior to presentation. Before he visited our hospital, he had been diagnosed with a cardiac tumor, which was located between the left atrium and posterior aortic root, and which was adjacent to both the aortic and mitral valves. Cardiac transplantation was recommended at the other hospital because of the high risk of cardiac dysfunction induced by both aortic and mitral valvular dysfunction after surgical resection. Based on preoperative transthoracic echocardiography, cardiac computed tomography, cardiac magnetic resonance imaging, and intra-operative transesophageal echocardiography, we considered it to be a benign tumor. Complete resection was achieved and the pathology confirmed organizing thrombus. We report a case of organizing thrombus mimicking a cardiac tumor, which was located at the mitral-aortic intervalvular fibrosa of the left ventricular outflow tract without any heart disease.

Advisory services are widely used in the field of medicine in many countries. Doctors commonly use consultations, especially in surgical pathology practice. In the United States, the Association of Directors of Anatomic and Surgical Pathology has defined various kinds of pathology consultations and devised regulations to control the quality of each type [1-3]. In Korea, pathologic consultations by doctors have also been performed in daily practice. However, most of these consultations have been conducted informally, without regulations or proper fees. Therefore, Korean pathologists agreed with the necessity for an official pathology advisory service system and organized the Medical Advisory Committee (MAC) as a subdivision of the Korean Society of Pathologists (KSP) in 2003. The MAC has been officially providing various kinds of advisory services, focusing on diagnostic pathology, since 2003. They have restrained the extent of users and contexts of pathologic consultations and have established detailed regulations. According to these regulations, certain individuals or institutions can use the consultation services: health and medical institutions run by government agencies such as the Ministry of Health and Welfare or community health centers; investigative authorities such as departments of prosecution or police departments; judicial offices; the Korean Medical Association; private insurance companies; specific institutions or individuals who are allowed to use the services of the KSP; and the members of the KSP. The contents of consultations are defined by the third provision of the regulations of the medical advisory services (MAS): classification and evaluation of the grade of malignant or premalignant lesion; confirmation of a pathologic diagnosis, including review of slides or pathologic reports; pathologic review of controversial cases among pathologists or clinicians; consultation about rare diseases; and other medical questions allowed by the MAC. The consultation process is quite simple (Fig. 1). After a client requests a pathologic consultation with the KSP, the advisory manager who is appointed by the MAC reviews the contents of the consultation. Then, he or she designates a specific pathologist as a consultant, considering his or her experience and subspecialty in pathologic fields. The appointed pathologist must have more than 10 years of experience as a surgical pathologist of the specific subspecialty. There must be no conflicts of interest between the consultant and client. After reviewing the consulted case, the assigned pathologist should report the result to the advisory manager within 2 weeks. Then, the advisory manager informs the clients of the result. Fig. 1. Schematic flow chart of the medical advisory service system of the Korean Society of Pathology (KSP). In this review, we discuss the medical advisory service system of Korea provided by the KSP and comprehensively review the consultation cases from 2003 to 2014.

Lung cancer is the leading cause of cancer-related death in Korea, accounting for approximately 20% of all cancer deaths [1]. Non-small cell lung cancer (NSCLC) accounts for more than 85% of all lung cancers, and the majority of patients with NSCLC present at an advanced cancer stage (stage III or IV) [2]. In the last decade, several studies have been performed on the molecular stratification of NSCLC in order to provide targeted treatment based on activating or driver mutations in these tumors. Activating mutations in the epidermal growth factor receptor gene (EGFR) can be used as therapeutic targets for treatment of NSCLC. In the Iressa Pan-Asia Study, tumors with EGFR mutations showed a 71.2% clinical response to first-line treatment with gefitinib, while tumors with wild-type EGFR showed only a 1.1% response [3]. Since then, several randomized control studies have shown an association between activating EGFR mutation and response to EGFR tyrosine kinase inhibitors (TKIs) [4-9]. Patient selection is important for using EGFR TKIs as the first-line treatment. At present, analysis of EGFR mutations is the accepted method for identifying patient response to EGFR TKIs. Direct DNA sequencing is a standard method for identifying mutations and is commonly used in the Asia-Pacific region [10]. Any routinely available pathological specimen can be used for analyzing EGFR mutations, including formalin-fixed, paraffin-embedded tissues from surgical resections; small tissue biopsies; or cell block preparations. Several publications have reported the prevalence of EGFR mutations in patients with NSCLC [10-14]. The rates of EGFR mutations are higher in Asian countries than in Western countries. Further, rates of EGFR mutations in Korean patients range from 17.4% to 51.3% [10,15-22]. Therefore, we performed a nationwide study of EGFR mutations in Korean patients with NSCLC in order to provide reliable information on the incidence and characteristics of EGFR mutations. This study was led by the Korean Cardiopulmonary Pathology Study Group.

Gigantomastia is a rare condition characterized by excessive breast growth. It has been reported that the majority of gigantomastia cases occur during either pregnancy or puberty. We were presented with a rare case of gigantomastia associated with neither pregnancy nor puberty, and successfully treated it with reduction mammaplasty and free nipple graft. This idiopathic gigantomastia is the very first case in Korea, and adds to the worldwide total of 9 reported cases.

We report on asymmetric electron-hole decoherence in epitaxial graphene gated by an ionic liquid. The observed negative magnetoresistance near zero magnetic field for different gate voltages, analyzed in the framework of weak localization, gives rise to distinct electron-hole decoherence. The hole decoherence rate increases prominently with decreasing negative gate voltage while the electron decoherence rate does not exhibit any substantial gate dependence. Quantitatively, the hole decoherence rate is as large as the electron decoherence rate by a factor of two. We discuss possible microscopic origins including spin-exchange scattering consistent with our experimental observations.

Tumor angiogenesis is one of the major hallmarks of tumor progression. Nobiletin is a natural flavonoid isolated from citrus peel that has anti-angiogenic activity. Steroid receptor coactivator (Src) is an intracellular tyrosine kinase so that focal adhesion kinase (FAK) binds to Src to play a role in tumor angiogenesis. Signal transducer and activator of transcription 3 (STAT3) is a marker for tumor angiogenesis which interacts with Src. Paxillin (PXN) acts as a downstream target for both FAK and STAT3. The main goal of this study was to assess inhibition of tumor angiogenesis by nobiletin in estrogen receptor positive (ER+) breast cancer cells via Src, FAK, and STAT3-mediated signaling through PXN. Treatment with nobiletin in MCF-7 and T47D breast cancer cells inhibited angiogenesis markers, based on western blotting and RT-PCR. Validation of in vitro angiogenesis in the human umbilical vein endothelial cells (HUVEC) endothelial cell line proved the anti-angiogenic activity of nobiletin. Electrophoretic mobility shift assay and the ChIP assay showed that nobiletin inhibits STAT3/DNA binding activity and STAT3 binding to a novel binding site of the PXN gene promoter. We also investigated the migration and invasive ability of nobiletin in ER+ cells. Nobiletin inhibited tumor angiogenesis by regulating Src, FAK, and STAT3 signaling through PXN in ER+ breast cancer cells.

Molecular markers are helpful diagnostic tools, particularly for cytologically indeterminate thyroid nodules. Preoperative RET/PTC1 rearrangement analysis in BRAF and RAS wild-type indeterminate thyroid nodules would permit the formulation of an unambiguous surgical plan. Cycle threshold values according to the cell count for detection of the RET/PTC1 rearrangement by real-time reverse transcription-polymerase chain reaction (RT-PCR) using fresh and routine air-dried TPC1 cells were evaluated. The correlation of RET/PTC1 rearrangement between fine-needle aspiration (FNA) and paired formalin-fixed paraffin-embedded (FFPE) specimens was analyzed. RET/PTC1 rearrangements of 76 resected BRAF and RAS wild-type classical PTCs were also analyzed. Results of RT-PCR and the Nanostring were compared. When 100 fresh and air-dried TPC1 cells were used, expression of RET/PTC1 rearrangement was detectable after 35 and 33 PCR cycles, respectively. The results of RET/PTC1 rearrangement in 10 FNA and paired FFPE papillary thyroid carcinoma (PTC) specimens showed complete correlation. Twenty-nine (38.2%) of 76 BRAF and RAS wild-type classical PTCs had RET/PTC1 rearrangement. Comparison of RET/PTC1 rearrangement analysis between RT-PCR and the Nanostring showed moderate agreement with a κ value of 0.56 (p = 0.002). The RET/PTC1 rearrangement analysis by RT-PCR using routine air-dried FNA specimen was confirmed to be technically applicable. A significant proportion (38.2%) of the BRAF and RAS wild-type PTCs harbored RET/PTC1 rearrangements.

We report on a case of malignant pleural effusion as initial metastatic presentation of occult gastric cardia cancer in a young woman. To the best of our knowledge, this is the first report of gastric adenocarcinoma metastasized to pleura as an initial presentation. Location of cardia and signet ring cell histology may contribute to the manifestation. Utilization of positron emission tomography-computed tomography was helpful for proper diagnosis. For patients with such distinct clinical presentations, it would be appropriate to consider gastric cancer as one of the possible primary sites.

Simian virus 40 (SV40) is a polyomavirus that originates from the rhesus macaque and was discovered in 1960 as a contaminant of human polio vaccines produced in monkey cells.1 Recently, there has been considerable interest in the identification of SV40 in human tumors, including malignant mesothelioma (MM) and other rare tumors such as osteosarcoma, ependymoma, and choroid plexus tumors.2-6 Subsequently, it has been found that SV40 may play an important role in the etiology of these tumors.2-6 However, SV40 was not detected in malignant lymphomas in Korean patients.7 Oncogenesis driven by SV40 is mediated by the large tumor antigen (T-Ag) oncoprotein, which is capable of transforming different types of cells in the absence of other viral genes.8,9 T-Ag induces DNA synthesis in host cells and prolongs the onset of the S-phase through the inhibition of tumor suppressor proteins p53 and Rb.8 MM is a rare and extremely aggressive neoplasm that arises from the serosal surfaces of pleural, peritoneal, and pericardial cavities and is very likely associated with amphibole asbestos exposure.10,11 In recent years, the incidence of MM has been gradually increasing in concert with industrial development and increased exposure to asbestos.12 However, only a small number of people who have been exposed to asbestos during their lifetime will develop MM.11 This suggests that SV40 may act as an independent carcinogenic agent or as a cofactor of asbestos to augment the risk of MM.13 Studies investigating the relation of SV40 to MM have been inconsistent and differ by geographical location.6 The incidence of MM varies according to geographic location, and the highest incidence rates are reported from Australia, Belgium, and Great Britain.14 In Korea, the incidence of MM is very low compared with other developed countries, with only about one case per million in the last decade.14,15 However, the incidence is recently increasing. Korea has a higher proportion of females (33.8%) among MM cases compared with other nations such as Canada (15.4%) or Italy (27.6%), and most of the patients are diagnosed when they are in their 50s, which is younger compared to cases in other countries.15 Although the majority of MM patients have had occupational (36.8%) and/or environmental (20.4%) asbestos exposure, the remaining patients (42.8%) had no known asbestos exposure.15 The role of SV40 in the oncogenesis of MM following asbestos exposure has not yet been studied in a Korean population. The purpose of this study is to identify SV40 DNA and protein in tissues extracted from MM from a Korean population using quantitative polymerase chain reaction (PCR) and immunohistochemical staining.

Mutations of the epidermal growth factor receptor (EGFR) are the strongest predictive factor for response to EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib. EGFR TKIs are approved in Korea as a first-line treatment for lung cancer patients with mutated EGFR. Rapid and accurate EGFR mutation testing is essential for patient selection and establishing targeted therapies with EGFR TKIs. Thus, a standard set of guideline recommendations for EGFR mutation testing suitable for the Korean medical community is necessary. In this article, we propose a set of guideline recommendations for EGFR mutation testing that was discussed and approved by the Cardiopulmonary Pathology Study Group of the Korean Society of Pathologists.

We report preliminary results of precision measurements of the graphene quantum Hall resistance plateau value with respect to magnetic field, temperature and applied current. Resistance value of SiC graphene Hall device was modulated by chemical doping, heating, and UV irradiation at the ambient condition. Precision measurements for Rh (filing factor v = 2) were then performed with a cryogenic current comparator resistance bridge. Relative deviation from RH (v = 2) less than 30 parts in 109 can be achieved down to 7 T of magnetic field and up to 6 K of temperature with driving current of 19. 37 μA.

Follicular variant of papillary thyroid carcinoma (FVPTC), particularly the encapsulated subtype, often causes a diagnostic dilemma. We reconfirmed the molecular profiles in a large number of FVPTCs and investigated the efficacy of the preoperative mutational analysis in indeterminate thyroid nodules. BRAF V600E/K601E and RAS mutational analysis was performed on 187 FVPTCs. Of these, 132 (70.6%) had a point mutation in one of the BRAF V600E (n=57), BRAF K601E (n=11), or RAS (n=64) genes. All mutations were mutually exclusive. The most common RAS mutations were at NRAS codon 61. FNA aspirates from 564 indeterminate nodules were prospectively tested for BRAF and RAS mutation and the surgical outcome was correlated with the mutational status. Fifty-seven and 47 cases were positive for BRAF and RAS mutation, respectively. Twenty-seven RAS-positive patients underwent surgery and all except one patient had FVPTC. The PPV and accuracy of RAS mutational analysis for predicting FVPTC were 96% and 84%, respectively. BRAF or RAS mutations were present in more than two-thirds of FVPTCs and these were mutually exclusive. BRAF mutational analysis followed by N, H, and KRAS codon 61 mutational analysis in indeterminate thyroid nodules would streamline the management of patients with malignancies, mostly FVPTC.

Background Combination therapy, which reduces the dosage intensity of the individual drugs while increasing their efficacy, is not a novel approach for the treatment of cancer. Methylsulfonylmethane (MSM) is an organic sulfur compound shown to act against tumor cells. Tamoxifen is a commercially available therapeutic agent for breast malignancies. Methods In the current study, we analyzed the combinatorial effect of MSM and tamoxifen on the suppression of ER-positive breast cancer xenograft growth and metastasis. Additionally, we also validated the molecular targets by which the drug combination regulated tumor growth and metastasis. Results We observed that the combination of MSM and tamoxifen regulated cell viability and migration in vitro. The intragastric administration of MSM and subcutaneous implantation of tamoxifen tablets led to tumor growth suppression and inhibition of the Janus kinase 2 (Jak2)/signal transducer and activator of transcription 5b (STAT5b) pathway. Our study also assessed the regulation of signaling molecules implicated in the growth, progression, differentiation, and migration of cancer cells, such as Jak2, STAT5b, insulin-like growth factor-1Rβ, and their phosphorylation status. Conclusions Study results indicated that this combination therapy inhibited tumor growth and metastasis. Therefore, this drug combination may have a synergistic and powerful anticancer effect against breast cancer. Electronic supplementary material The online version of this article (doi:10.1186/s12885-015-1445-0) contains supplementary material, which is available to authorized users.

Poorly differentiated ("insular") carcinoma of the thyroid shares insular, trabecular, and solid histological patterns that are different from those of papillary, follicular, medullary, and anaplastic varieties. This tumor is situated morphologically and biologically in the intermediate position between the well differentiated (papillary and follicular) and the totally undifferentiated (anaplastic) thyroid tumors. We report two cases of insular carcinoma of the thyroid, occurring in 39-year-old and 52-year-old women. Grossly, these cases showed a lobulated mass with fibrous septa. The histologic finding showed characteristic "insular" growth pattern with focal follicular or papillary areas. Thyroglobulin was demonstrated within cytoplasmic paranuclear vacuoles of the neoplastic cells. Calcitonin and amyloid were not demonstrated. The aspiration cytology showed high cellularity, low grade of atypia, presence of clusters, nests, and trabeculae of cells with poorly outlined cytoplasm. The ultrastructural finding showed primordial cells having cytoplasmic organelles such as rough endoplasmic reticulum, mitochondria, and free ribosomes. We believe that its separation from other types of thyroid carcinoma will lead to a more accurate estimate of its biologic behavior and a more appropriate therapeutic approach.

In a chemically defined medium, l -methionine decreased production of rapamycin and increased that of demethylrapamycin. Growth with l -methionine yielded cells with a lower ability to convert demethylrapamycin to rapamycin and decreased the level of S -adenosylmethionine synthetase and S -adenosylmethionine. Thus, methionine represses at least one methyltransferase of rapamycin biosynthesis and S -adenosylmethionine synthetase.