Automatic segmentation of atrial fibrillation and flutter in single-lead electrocardiograms by self-supervised learning and Transformer architecture.

OBJECTIVES: Automatic detection of atrial fibrillation and flutter (AF/AFL) is a significant concern in preventing stroke and mitigating hemodynamic instability. Herein, we developed a Transformer-based deep learning model for AF/AFL segmentation in single-lead electrocardiograms (ECGs) by self-supervised learning with masked signal modeling (MSM). MATERIALS AND METHODS: We retrieved data from 11 open-source databases on PhysioNet; 7 of these databases included labeled ECGs, while the other 4 were without labels. Each database contained ECG recordings with durations of ≥30 s. A total of 24 intradialytic ECGs with paroxysmal AF/AFL during 4 h of hemodialysis sessions at Seoul National University Hospital were used for external validation. The model was pretrained by predicting masked areas of ECG signals and fine-tuned by predicting AF/AFL areas. Cross-database validation was used for evaluation, and the intersection over union (IOU) was used as a main performance metric in external database validation. RESULTS: In the 7 labeled databases, the areas marked as AF/AFL constituted 41.1% of the total ECG signals, ranging from 0.19% to 51.31%. In the evaluation per ECG segment, the model achieved IOU values of 0.9254 and 0.9477 for AF/AFL segmentation and other segmentation tasks, respectively. When applied to intradialytic ECGs with paroxysmal AF/AFL, the IOUs for the segmentation of AF/AFL and non-AF/AFL were 0.9896 and 0.9650, respectively. Model performance by different training procedure indicated that pretraining with MSM and the application of an appropriate masking ratio both contributed to the model performance. It also showed higher IOUs of AF/AFL labels than in previous studies when training and test databases were matched. CONCLUSION: The present model with self-supervised learning by MSM performs robustly in segmenting AF/AFL.

Interdiffusion and Intermetallic Compounds at Al/Cu Interfaces in Al-50vol.%Cu Composite Prepared by Solid-State Sintering.

Al-Cu composites have attracted significant interest recently owing to their lightweight nature and remarkable thermal properties. Understanding the interdiffusion mechanism at the numerous Al/Cu interfaces is crucial to obtain Al-Cu composites with high thermal conductivities. The present study systematically investigates the interdiffusion mechanism at Al/Cu interfaces in relation to the process temperature. Al-50vol.%Cu composite powder, where Cu particles were encapsulated in a matrix of irregular Al particles, was prepared and then sintered at various temperatures from 340 to 500 °C. Intermetallic compounds (ICs) such as CuAl2 and Cu9Al4 were formed at the Al/Cu interfaces during sintering. Microstructural analysis showed that the thickness of the interdiffusion layer, which comprised the CuAl2 and Cu9Al4 ICs, drastically increased above 400 °C. The Vickers hardness of the Al-50vol.%Cu composite sintered at 380 °C was 79 HV, which was 1.5 times that of the value estimated by the rule of mixtures. A high thermal conductivity of 150 W∙m-1∙K-1 was simultaneously obtained. This result suggests that the Al-50vol.%Cu composite material with large number of Al/Cu interfaces, as well as good mechanical strength and heat conductance, can be prepared by solid-state sintering at a low temperature.

Investigation of Formation Behaviour of Al-Cu Intermetallic Compounds in Al-50vol%Cu Composites Prepared by Spark Plasma Sintering under High Pressure.

Al-Cu matrix composites with excellent mechanical and thermal properties are among the most promising materials for realising high performance in thermal management systems. However, intermetallic compounds (ICs) formed at the Al/Cu interfaces prevent direct contact between the metals and severely deteriorate the thermal conductivity of the composite. In this study, we systemically investigated the formation behaviour of Al-Cu ICs as a function of compaction pressure at a low temperature of 380 °C. The phases of the Al-Cu ICs formed during sintering were detected via X-ray diffraction, and the layer thickness and average area fraction of each IC at different compaction pressures were analysed via micro-scale observations of the cross-sections of the Al-Cu composites. The ICs were partially formed along the Al/Cu interfaces at high pressures, and the formation region was related to the direction of applied pressure. The Vickers hardness of the Al-Cu composites with ICs was nearly double those calculated using the rule of mixtures. On the other hand, the thermal conductivity of the composites increased with compaction pressure and reached 201 W·m-1·K-1. This study suggests the possibility of employing Al-Cu matrix composites with controlled IC formation in thermal management applications.

Aluminum/Stainless Steel Clad Materials Fabricated via Spark Plasma Sintering.

Aluminum (Al)/stainless steel (SUS) clad materials were fabricated via the process of spark plasma sintering (SPS) using Al powder/bulk and an SUS sheet. Three Al/SUS clad types were fabricated: powder/bulk (P/B), bulk/bulk (B/B), and bulk/powder/bulk (B/P/B). During the SPS, Al and SUS reacted with each other, and intermetallic compounds were created in the clads. The thermal conductivity and thermal-expansion coefficient were measured using a laser flash analyzer and dynamic mechanical analyzer, respectively. The Al/SUS (P/B) clad had a thermal conductivity of 159.5 W/mK and coefficient of thermal expansion of 15.3 × 10-6/°C. To analyze the mechanical properties, Vickers hardness and three-point bending tests were conducted. The Al/SUS (P/B) clad had a flexural strength of about 204 MPa. The Al/SUS clads fabricated via SPS in this study are suitable for use in applications in various engineering fields requiring materials with high heat dissipation and high heat resistance.

Effect of Intermetallic Compounds on the Thermal and Mechanical Properties of Al⁻Cu Composite Materials Fabricated by Spark Plasma Sintering.

Aluminium-copper composite materials were successfully fabricated using spark plasma sintering with Al and Cu powders as the raw materials. Al-Cu composite powders were fabricated through a ball milling process, and the effect of the Cu content was investigated. Composite materials composed of Al-20Cu, Al-50Cu, and Al-80Cu (vol.%) were sintered by a spark plasma sintering process, which was carried out at 520 °C and 50 MPa for 5 min. The phase analysis of the composite materials by X-ray diffraction (XRD) and energy-dispersive spectroscopy (EDS) indicated that intermetallic compounds (IC) such as CuAl2 and Cu9Al4 were formed through reactions between Cu and Al during the spark plasma sintering process. The mechanical properties of the composites were analysed using a Vickers hardness tester. The Al-50Cu composite had a hardness of approximately 151 HV, which is higher than that of the other composites. The thermal conductivity of the composite materials was measured by laser flash analysis, and the highest value was obtained for the Al-80Cu composite material. This suggests that the Cu content affects physical properties of the Al-Cu composite material as well as the amount of intermetallic compounds formed in the composite material.

Semisolid State Sintering Behavior of Aluminum⁻Stainless Steel 316L Composite Materials by Powder Metallurgy.

Aluminum (Al)-stainless steel 316L (SUS316L) composites were successfully fabricated by the spark plasma sintering process (SPS) using pure Al and SUS316L powders as raw materials. The Al-SUS316L composite powder comprising Al with 50 vol.% of SUS316L was prepared by a ball milling process. Subsequently, it was sintered at 630 °C at a pressure of 200 MPa and held for 5 min in a semisolid state. The X-ray diffraction (XRD) patterns show that intermetallic compounds such as Al13Fe4 and AlFe3 were created in the Al-SUS316L composite because the Al and SUS316L particles reacted together during the SPS process. The presence of these intermetallic compounds was also confirmed by using XRD, scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDS), and EDS mapping. The mechanical hardness of the Al-SUS316L composites was analyzed by a Vickers hardness tester. Surprisingly, the Al-SU316L composite exhibited a Vickers hardness of about 620 HV. It can be concluded that the Al-SUS316L composites fabricated by the SPS process are lightweight and high-hardness materials that could be applied in the engineering industry such as in automobiles, aerospace, and shipbuilding.

Behavior of Intermetallic Compounds of Al-Ti Composite Manufactured by Spark Plasma Sintering.

In this research, we successfully fabricate high-hardness and lightweight Al-Ti composites. Al-Ti composites powders with three compositions (Al-20, 50, and 80 vol.% Ti) are mixed using ball milling and subsequently subjected to spark plasma sintering (SPS). The microstructures and phases of the Al-Ti composites are characterized using scanning electron microscopy (SEM), X-ray diffraction (XRD) spectroscopy, and field emission-electron probe microanalysis (FE-EPMA). These tests confirm the presence of several intermetallic compounds (ICs) (Al3Ti, Al5Ti2, Al11Ti5) in the composites, and we are able to confirm that these ICs are produced by the reaction of Al and Ti during the SPS process. Furthermore, thermogravimetric-differential thermal analysis (TG-DTA) is used to analyze the formation behavior of the ICs. In addition, the mechanical properties of the composites are measured using their Vickers hardness and it is observed that the Al-80 vol.% Ti composite exhibits the highest hardness. Consequently, it is assumed that SPS is suitable for fabricating Al-Ti composites which represent the next-generation materials to be used in various industrial fields as high-hardness and lightweight materials.

Sodium Nitrite Attenuates Hepatic Ischemia-Reperfusion Injury in Rats.

OBJECTIVES: Nitrite as an alternative source of nitric oxide has been proposed, as it can mediate the protective response in the presence of ischemia or hypoxic conditions and inorganic nitrite can be reduced to nitric oxide by xanthine oxidoreductase. Here, we investigated whether pretreatment with sodium nitrite can attenuate liver damage in hepatic ischemia-reperfusion injury and identified the possible mechanism of nitrite reduction using 2-(4-carboxyphenyl)-4,5dihydro-4,4,5,5-tetramethyl-1H-imidazolyl-1-oxy-3oxide (C-PTIO), a nitric oxide scavenger, and allopurinol, a xanthine oxidoreductase inhibitor. MATERIALS AND METHODS: In experiment 1, 30 male Sprague-Dawley rats were divided into 5 groups: (1) sham-operated; (2) hepatic ischemia-reperfusion injury; and (3-5) sodium nitrite administered intra-peritoneally 30 minutes before ischemia at 2.5, 25, and 250 µmol/kg, respectively. In experiment 2, 24 male Sprague-Dawley rats were divided into 4 groups: (1) hepatic ischemia-reperfusion injury; (2) sodium nitrite + hepatic ischemia-reperfusion injury; (3) C-PTIO + sodium nitrite + hepatic ischemia-reperfusion injury; and (4) allopurinol + sodium nitrite + hepatic ischemia-reperfusion injury. Sodium nitrite (25 µmol/kg) was then administered 30 minutes before hepatic ischemia, and C-PTIO or allopurinol was administered 5 minutes before sodium nitrite administration. Blood aspartate aminotransferase, alanine aminotransferase, hepatic tissue malondialdehyde, histologic changes, and expression of mitogen-activated protein kinase family members were evaluated. RESULTS: Sodium nitrite limited serum elevation of alanine aminotransferase and aspartate aminotransferase induced by hepatic ischemia-reperfusion with a peak effect occurring at 25 µmol/kg sodium nitrite. Pre-treatment with allopurinol abolished the protective effect of sodium nitrite, and C-PTIO treatment attenuated the hepatoprotection of sodium nitrite in rats with hepatic ischemia-reperfusion injury. Liver malondialdehyde activity after ischemia-reperfusion decreased in sodium nitrite-treated rats. Sodium nitrite also prevented hepatic ischemia-reperfusion-induced c-Jun N-terminal kinase and extracellular signal-regulated kinase phosphorylation. CONCLUSIONS: Exogenous sodium nitrite had protective effects against hepatic ischemia-reperfusion injury. Catalytic reduction to nitric oxide and attenuation of hepatic ischemia-reperfusion is dependent on xanthine oxidoreductase.

A case report of intrahepatic bile duct confluence anomalies in VACTERL syndrome.

RATIONALE: The clinical manifestations of VACTERL association include vertebral anomalies, anal atresia, congenital heart diseases, tracheoesophageal fistula, renal dysplasia, and limb abnormalities. The association of intrahepatic anomalies and VACTERL syndrome is a rare coincidence. VACTER syndrome and intrahepatic bile drainage anomalies might be genetically related. PATIENT CONCERNS: A 12-year-old girl presented with episodic colicky abdominal pain, nausea, and vomiting for several years. The individual episodes resolved spontaneously within a few days. She had a history of VACTERL syndrome, including a butterfly shape of the L3 vertebra, anal atresia, and an atrial septal defect. DIAGNOSES: On laboratory findings, abnormal liver function tests included elevated total bilirubin, alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyltransferase. There was no significant abnormal finding in hepatobiliary system sonography except mild gallbladder wall thickening. We performed magnetic resonance cholangiopancreatography and demonstrated an abnormal intrahepatic bile duct confluence, which showed 3 bile ducts draining directly into the neck of the gallbladder. INTERVENTION: Her symptoms related to bile reflux during gallbladder contraction. Cholecystectomy with choledochojejunostomy was undertaken because segments of the bile drainage were intertwined. OUTCOMES: After surgery, her symptoms decreased, but abdominal discomfort remained due to uncorrected left intrahepatic anomalies. LESSONS: Although hepatobiliary anomalies are not included in VACTERL association diagnostic criteria, detailed hepatobiliary work up is needed when gastrointestinal symptoms are present in VACTERL association patients.

Thyroid Fine-Needle Aspiration Cytology Practice in Korea.

We reviewed the current status of thyroid fine-needle aspiration cytology (FNAC) in Korea. Thyroid aspiration biopsy was first introduced in Korea in 1977. Currently, radiologists aspirate the thyroid nodule under the guidance of ultrasonography, and cytologic interpretation is only legally approved when a cytopathologist makes the diagnosis. In 2008, eight thyroid-related societies came together to form the Korean Thyroid Association. The Korean Society for Cytopathology and the endocrine pathology study group of the Korean Society for Pathologists have been updating the cytologic diagnostic guidelines. The Bethesda System for Reporting Thyroid Cytopathology was first introduced in 2009, and has been used by up to 94% of institutions by 2016. The average diagnosis rates are as follows for each category: I (12.4%), II (57.9%), III (10.4%), IV (2.9%), V (3.7%), and VI (12.7%). The malignancy rates in surgical cases are as follows for each category: I (28.7%), II (27.8%), III (50.6%), IV (52.3%), V (90.7%), and VI (100.0%). Liquid-based cytology has been used since 2010, and it was utilized by 68% of institutions in 2016. The categorization of thyroid lesions into "atypia of undetermined significance" or "follicular lesion of undetermined significance" is necessary to draw consensus in our society. Immunocytochemistry for galectin-3 and BRAF is used. Additionally, a molecular test for BRAF in thyroid FNACs is actively used. Core biopsies were performed in only 44% of institutions. Even the institutions that perform core biopsies only perform them for less than 3% of all FNACs. However, only 5% of institutions performed core biopsies up to three times more than FNAC.

Combined prognostic effect of PD-L1 expression and immunoscore in microsatellite-unstable advanced gastric cancers.

BACKGROUND: The aim of this study was to evaluate how programmed death-ligand-1 (PD-L1) expression is linked to the immunoscore in the context of the tumor microenvironment and to assess the differential prognostic value of PD-L1 expression according to the immunoscore in 153 patients with microsatellite instability-high (MSI-H) advanced gastric cancer (GC). RESULTS: We found that T-PD-L1 (+) and I-PD-L1 (+) were significantly associated with a high immunoscore. The integrated PD-L1 expression of tumor and immune cells was not significantly correlated with the overall survival (OS) of patients. However, a combined survival analysis of PD-L1 expression and immunoscore revealed four distinct subgroups with a statistically significant difference in OS. That is, the PD-L1 (+)/immunoscoreLow group showed the worst and the PD-L1 (+)/immunoscoreHigh group showed the best prognosis. Furthermore, a multivariate analysis revealed that the combined status of PD-L1 expression and immunoscore was an independent and significant prognostic factor for OS in patients with MSI-H GC. MATERIALS AND METHODS: The immunoscore was quantified by the number of high-density areas of CD3+ and CD8+ tumor infiltrating lymphocytes both in the tumor regions and compartments (i.e., epithelial and stromal compartments of the tumor center and the invasive front), the scores of which range from I0 to I8. By using immunohistochemistry, the expression of PD-L1 was also analyzed in tumor cells (T-PD-L1) and immune cells (I-PD-L1) using four different cut-off values (1%, 5%, 10% and 50%). CONCLUSIONS: Our study revealed that PD-L1 expression is associated with the corresponding immunoscore and that the immunoscore can be a relevant marker for the determination of the prognostic role of PD-L1 expression in MSI-H GCs.

Human cholestatic hepatitis owing to polyoxyethylene nonylphenol ingestion: A case report.

RATIONALE: The purpose of this study was to identify the chemical responsible for cholestatic hepatitis in a 55-year-old woman who ingested 1,1'-iminodi (octamethylene) diguanidinium triacetate (iminoctadine triacetate), a fungicide. The fungicide formulation was also composed of polyoxyethylene nonylphenol (NP-40) and methanol. PATIENT CONCERNS: Severe cholestatic hepatitis developed, which led to the patient's death on day 88 of hospitalization. Post-mortem necropsy of the liver showed focal hepatocyte necrosis involving mostly the mid-zone, along with intracytoplasmic and intracanalicular cholestasis. DIAGNOSES: To identify the chemical responsible for hepatic injury, the cellular toxicity of all chemicals in the fungicide formulation was assessed in HepG2 cells using the 3-(4,5-dimethylthiaxol-2yl)-2, 5-diphenyl tetrazolium bromide test. OUTCOMES: Viability of cells treated with the surfactant NP-40 was significantly lower (P < .001), but that of cells treated with other components of the fungicide, including the active ingredient, iminoctadine triacetate, was unaffected. Fluorescence-activated cell sorting analysis confirmed that necrosis was induced in HepG2 cells treated with 25-80 µM of NP-40, while significant numbers of apoptotic cells were not detected. LESSONS: NP-40 appears to be the chemical responsible for the patient's irreversible hepatic injury, accompanied by intracytoplasmic and intracanalicular cholestasis.

Deletion in HSP110 T17: correlation with wild-type HSP110 expression and prognostic significance in microsatellite-unstable advanced gastric cancers.

Deletion of the HSP110 T17 mononucleotide repeat has recently been identified as a prognostic marker that is correlated with wild-type HSP110 (HSP110wt) expression in microsatellite instability-high (MSI-H) colorectal cancers. The aim of this study was to assess the correlation between deletion of the HSP110 T17 repeat and expression of HSP110wt using DNA testing and immunohistochemistry and to determine the prognostic implications of HSP110 T17 deletion in MSI-H advanced gastric cancers (GCs). The status of HSP110wt expression was evaluated by immunohistochemistry using an HSP110wt-specific antibody in 142 MSI-H advanced GCs. The size of the HSP110 T17 repeat deletion was analyzed in 96 MSI-H advanced GCs; deletions were divided into small (0-2base pairs) and large deletions (3-5base pairs). Low and high expressions of HSP110wt were detected in 38 (26.8%) and 104 (73.2%) of the 142 cases, respectively. The HSP110 T17 deletion was observed in 45 (46.9%) of the 96 MSI-H GC samples. Tumors with high expression of HSP110wt showed a tendency to have small or no deletion of HSP110 T17. In Kaplan-Meier survival analysis, tumors with a large HSP110 T17 deletion were associated with favorable overall survival and disease-free survival compared with those with small/no deletion of HSP110 T17. However, HSP110 T17 deletion size was not an independent prognostic factor in multivariate analysis. In summary, deletion of the HSP110 T17 repeat was frequently observed in MSI-H GCs, and HSP110 T17 deletion size was inversely correlated with HSP110wt expression status. Large HSP110 T17 was not a prognostic indicator in MSI-H GCs.

Loss of CADM4 expression is associated with poor prognosis in small intestinal adenocarcinomas.

We evaluated the association of cell adhesion molecule 4 (CADM4) expression with clinicopathologic parameters and overall survival (OS) in patients with small intestinal adenocarcinomas (SIAs) and determined its prognostic significance. CADM4 immunohistochemical staining was performed for 170 SIA samples. Loss of or low CADM4 expression was observed in 26 (15.3%) and 50 (29.4%) cases, respectively, and it was significantly associated with undifferentiated histology (p < 0.044), high-grade tumor (p < 0.001), high pT3 or pT4 stage (p < 0.038), pancreatic invasion (p < 0.018), and lymphatic invasion (p < 0.020). Patients with CADM4 expression loss had significantly poorer OS (p < 0.042). On multivariate analysis, SIA in the jejunum and ileum, (hazard ratio [HR], 2.465; 95% confidence interval [CI], 1.288-4.720; p = 0.006 and HR, 3.407; 95% CI, 1.515-7.662; p = 0.003, respectively), signet ring cell carcinoma (HR, 92.388; 95% CI, 14.813-576.230; p = 0.000), SIA with lymph node metastasis (HR, 3.223; 95% CI, 1.697-6.124; p = 0.000), retroperitoneal seeding (HR, 3.696; 95% CI, 1.303-10.479; p = 0.014), and CADM4 expression loss (HR, 2.348; 95% CI, 1.130-4.882; p = 0.022) were associated with poor OS. CADM4 expression loss is an important prognostic marker for SIA.

CpG Island Methylator Phenotype-High Colorectal Cancers and Their Prognostic Implications and Relationships with the Serrated Neoplasia Pathway.

The concept of a CpG island methylator phenotype (CIMP) was first introduced by Toyota and Issa to describe a subset of colorectal cancers (CRCs) with concurrent hypermethylation of multiple CpG island loci. The concept of CIMP as a molecular carcinogenesis mechanism was consolidated by the identification of the serrated neoplasia pathway, in which CIMP participates in the initiation and progression of serrated adenomas. Distinct clinicopathological and molecular features of CIMP-high (CIMP-H) CRCs have been characterized, including proximal colon location, older age of onset, female preponderance, and frequent associations of high-level microsatellite instability and BRAF mutations. CIMP-H CRCs arise in sessile or traditional serrated adenomas and thus tend to display the morphological characteristics of serrated adenomas, including epithelial serration, vesicular nuclei, and abundant cytoplasm. Both the frequent association of CIMP and poor prognosis and different responses of CRCs to adjuvant therapy depending on CIMP status indicate clinical implications. In this review, we present an overview of the literature documenting the relevant findings of CIMP-H CRCs and their relationships with the serrated neoplasia pathway.

CD9 Expression in Colorectal Carcinomas and Its Prognostic Significance.

BACKGROUND: CD9, a member of the tetraspanin superfamily, is a tumor suppressor in many malignancies. The aim of this study was to evaluate the immunohistochemical expression of CD9 in colorectal carcinomas (CRCs) and determine clinicopathological and prognostic significance of its expression. METHODS: The CD9 expression status of 305 CRCs was evaluated using a semi-quantitative scoring system in tumor cells (T-CD9) and immune cells (I-CD9) by classifying the results as high and low expression. RESULTS: High T-CD9 (T-CD9 [+]) expression was detected in 175 samples (57.6%) and high I-CD9 (I-CD9 [+]) expression was detected in 265 samples (86.9%). Using Kaplan- Meier survival analysis, the T-CD9 (+) group showed a tendency for better disease-free survival (DFS) (p = .057). In left-sided tumors, DFS was significantly longer in the T-CD9 (+) group (p = .021) but no statistical significance was observed with right-sided tumors (p = .453). I-CD9 (+) CRCs significantly correlated with well/moderately differentiation (p = .014). In Kaplan-Meier analysis, the I-CD9 (+) group had a tendency towards worse DFS compared to the I-CD9 (-) group (p = .156). In combined survival analysis of T-CD9 and I-CD9, we found that the longest DFS was among patients in the T-CD9 (+)/I-CD9 (-) group, whereas the T-CD9 (-)/I-CD9 (+) group showed the shortest DFS (p = .054). CONCLUSIONS: High expression of T-CD9 was associated with a favorable DFS, especially in left-sided CRCs. Combined evaluation of T-CD9 and I-CD9 is required to determine the comprehensive prognostic effect of CD9 in CRCs.

Clinicopathological Significance of Elevated PIK3CA Expression in Gastric Cancer.

PURPOSE: PIK3CA is often mutated in a variety of malignancies, including colon, gastric, ovary, breast, and brain tumors. We investigated PIK3CA expression in gastric cancer and explored the relationships between the PIK3CA expression level and clinicopathological features as well as survival of the patients. MATERIALS AND METHODS: We examined PIK3CA expression in a tissue microarray of 178 gastric adenocarcinomas by immunohisto-chemistry and reviewed patients' medical records. RESULTS: In our study, 112 of the 178 gastric cancer patients displayed positive PIK3CA expression. Overexpression of PIK3CA was correlated with low grade differentiation (P=0.001), frequent lymphatic invasion (P=0.032), and high T stage (P=0.040). Patients with positive PIK3CA staining were more likely to display worse overall survival rate than those with negative PIK3CA staining, as determined by Kaplan-Meier survival analysis with log-rank test (P=0.047) and a univariate analysis using the Cox proportional hazard model (hazard ratio=1.832, P=0.051). CONCLUSIONS: Elevated PIK3CA expression was significantly correlated with tumor invasiveness, tumor phenotypes, and poor patient survival.

Adverse prognostic impact of the CpG island methylator phenotype in metastatic colorectal cancer.

BACKGROUND: The association between the CpG island methylator phenotype (CIMP) and clinical outcomes in metastatic colorectal cancer remains unclear. We investigated the prognostic impact of CIMP in patients with metastatic colorectal cancer treated with systemic chemotherapy. METHODS: Eight CIMP-specific promoters (CACNA1G, IGF2, NEUROG1, RUNX3, SOCS1, CDKN2A, CRABP1, and MLH1) were examined. The CIMP status was determined by the number of methylated promoters as high (⩾5), low (1-4), and negative (0). RESULTS: A total of 153 patients were included (men/women, 103/50; median age, 61 years; range, 22-80 years). The CIMP status was negative/low/high in 77/ 69/7 patients, respectively. Overall survival (OS) was significantly different among the three CIMP groups, with median values of 35.7, 22.2, and 9.77 months for the negative, low, and high groups, respectively (P<0.001). For patients treated with fluoropyrimidine and oxaliplatin first-line chemotherapy (N=128), OS and progression-free survival (PFS) were significantly different among the three CIMP groups; the median OS was 37.9, 23.8, and 6.77 months for the negative, low, and high groups, respectively (P<0.001), while the median PFS was 9.97, 7.87, and 1.83 months, respectively (P=0.002). Response rates were marginally different among the three CIMP groups (53.4% vs 45.1% vs 16.7%, respectively; P=0.107). For patients treated with fluoropyrimidine and irinotecan second-line chemotherapy (N=86), only OS showed a difference according to the CIMP status, with median values of 20.4, 13.4, and 2.90 months for the negative, low, and high groups, respectively (P<0.001). CONCLUSIONS: The CIMP status is a negative prognostic factor for patients with metastatic colorectal cancer treated with chemotherapy.

High EZH2 Protein Expression Is Associated with Poor Overall Survival in Patients with Luminal A Breast Cancer.

PURPOSE: The enhancer of zeste homologue 2 (EZH2) is a catalytic subunit of the polycomb repressive complex 2, a highly conserved histone methyltransferase. EZH2 overexpression has been implicated in various malignancies, including breast cancer, where is associated with poor outcomes. This study aims to clarify nuclear EZH2 expression levels in breast cancers using immunohistochemistry (IHC) and correlate these findings with clinicopathologic variables, including prognostic significance. METHODS: IHC was performed on tissue microarrays of 432 invasive ductal carcinoma (IDC) tumors. Associations between EZH2 expression, clinicopathologic characteristics, and molecular subtype were retrospectively analyzed. The relationship between EZH2 protein expression in normal breast tissue and ductal carcinoma in situ (DCIS) was also assessed. RESULTS: High EZH2 expression was demonstrated in 215 of 432 tumors (49.8%). EZH2 was more frequently expressed in DCIS and IDC than in normal breast tissue (p=0.001). High EZH2 expression significantly correlated with high histologic grade (p<0.001), large tumor size (p=0.014), advanced pathologic stage (p=0.006), negative estrogen receptor status (p<0.001), positive human epidermal growth factor receptor 2 (HER2) status (p<0.001), high Ki-67 staining index (p<0.001), positive cytokeratin 5/6 status (p=0.003), positive epidermal growth factor receptor status (p<0.001), and positive p53 status (p<0.001). Based on molecular subtypes, high EZH2 expression was significantly associated with HER2-negative luminal B, HER2-positive luminal B, and HER2 type and triple-negative basal cancers (p<0.001). In patients with luminal A, there was a significant trend toward shorter overall survival for those with tumors having high EZH2 expression compared to those with tumors having low EZH2 expression (p=0.045). CONCLUSION: EZH2 is frequently upregulated in breast malignancies, and it may play an important role in cancer development and progression. Furthermore, EZH2 may be a prognostic marker, especially in patients with luminal A cancer.