Durable Response of Pembrolizmab for EGFR Mutation-positive Lung Adenocarcinoma with Early Progression to Osimertinib in First-line Treatment.

Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), is the standard first-line treatment for EGFR mutation-positive non-small-cell lung cancer (NSCLC) and demonstrates favorable disease control. Conversely, immune checkpoint inhibitors (ICIs) that target programmed cell death-1/programmed cell death ligands demonstrate a restrictive tumor response. We herein report a patient who achieved a durable response to pembrolizumab following early progression within two months of osimertinib administration for EGFR mutation-positive lung adenocarcinoma. Our findings suggest that treatment with ICIs for patients with EGFR mutation-positive NSCLC experiencing early progression to osimertinib as first-line treatment might represent a viable approach.

Hierarchical approach to evaluating storage requirements for renewable-energy-driven grids.

Energy storage can accelerate the decarbonization of the electrical grid. As useful energy storage technologies are developed, investors and manufacturers want to determine the needs for storage in a wide range of scenarios. In this study, we introduce a strategy for identifying the types of storage that will be most valuable to the grid given specific generation and load profiles. This method estimates the annual minimum number of cycles for each storage, how long each holds the charge, and charging and discharging rates for an idealized system, giving insight into tomorrow's complex systems. We demonstrate the proposed hierarchical approach and quantify how many fewer times wind-driven grids cycle the storage at night compared with solar-driven grids, as well as how winter-dominant wind generation and latitude-tilt solar may reduce the need for seasonal storage. Also, we quantify how higher discharging rates are required for energy storage products that cycle most frequently.

Pan-cancer methylome analysis for cancer diagnosis and classification of cancer cell of origin.

The accurate and early diagnosis and classification of cancer origin from either tissue or liquid biopsy is crucial for selecting the appropriate treatment and reducing cancer-related mortality. Here, we established the CAncer Cell-of-Origin (CACO) methylation panel using the methylation data of the 28 types of cancer in The Cancer Genome Atlas (7950 patients and 707 normal controls) as well as healthy whole blood samples (95 subjects). We showed that the CACO methylation panel had high diagnostic potential with high sensitivity and specificity in the discovery (maximum AUC = 0.998) and validation (maximum AUC = 1.000) cohorts. Moreover, we confirmed that the CACO methylation panel could identify the cancer cell type of origin using the methylation profile from liquid as well as tissue biopsy, including primary, metastatic, and multiregional cancer samples and cancer of unknown primary, independent of the methylation analysis platform and specimen preparation method. Together, the CACO methylation panel can be a powerful tool for the classification and diagnosis of cancer.

Accurate expression of PD-L1/L2 in lung adenocarcinoma cells: A retrospective study by double immunohistochemistry.

The percentage of programmed death ligand 1 (PD-L1) positivity in cancer cells, named as the tumor proportion score, is considered to be a predictive biomarker for anti-PD-1/PD-L1 therapy in lung cancer. PD-L1 is expressed on not only cancer cells but also on immune cells, including macrophages. Although previous studies related to PD-L1/2 expression in cancer tissues have been generally based on single immunohistochemistry (IHC), in the present study, we attempted to evaluate accurate PD-L1/2 expression in cancer cells in lung adenocarcinoma cells using double IHC to also evaluate macrophages. Of the 231 patients, PD-L1 expression was negative in 169 patients (73.2%), 1%-49% positive in 47 patients (20.3%), and ≥50% positive in 15 patients (6.5%). Interestingly, PD-L1 positivity was decreased when using double IHC compared with the estimation by single IHC. High PD-L1 expression was associated with high-grade cancer cells and in higher stage cancer. PD-L2 was negative in 109 patients (47.2%), 1%-49% positive in 50 patients (21.6%), and ≥50% positive in 72 patients (31.2%). The number of PD-L2-positive patients was increased in cases that had an epidermal growth factor receptor (EGFR) mutation and in lower stage cancer. Thirty-five patients (15.2%) were positive for both PD-L1 and PD-L2, whereas 81 patients (35.1%) were negative for both PD-L1 and PD-L2. Log-rank analysis showed that progression-free survival and overall survival were significantly the longest in the PD-L1-negative and PD-L2-positive groups (P < .0001 and P = .0120). We observed lower PD-L1 or PD-L2 expression in lung adenocarcinoma than previously reported. Double IHC for macrophages may help clinicians to evaluate PD-L1 or PD-L2 expression specifically in cancer cells.

Influence of edge magnetization and electric fields on zigzag silicene, germanene and stanene nanoribbons.

Using a multi-orbital tight-binding model, we have studied the edge states of zigzag silicene, germanene, and stanene nanoribbons (ZSiNRs, ZGeNRs and ZSnNRs, respectively) in the presence of the Coulomb interaction and a vertical electric field. The resulting edge states have non-linear energy dispersions due to multi-orbital effects, and the nanoribbons show induced magnetization at the edges. Owing to this non-linear dispersion, ZSiNRs, ZGeNRs and ZSnNRs may not provide superior performance in field effect transistors, as has been proposed from single-orbital tight-binding model calculations. We propose an effective low-energy model that describes the edge states of ZSiNRs, ZGeNRs, and ZSnNRs. We demonstrate that the edge states of ZGeNR and ZSnNR show anti-crossing of bands with opposite spins, even if only out-of-plane edge magnetization is present. The ability to tune the spin polarizations of the edge states by applying an electric field points to future opportunities to fabricate silicene, germanene and stanene nanoribbons as spintronics devices.

Interstitial fluid pressure of thymic epithelial tumours.

Tumours show an increased interstitial fluid pressure, which correlates with various pathophysiological features. Moreover, interstitial fluid pressure is a prognostic factor for cervical and lung cancer. However, there have been no reports on the usefulness of measuring interstitial fluid pressure in thymic epithelial tumours. Therefore, this study aimed to examine the relationship between interstitial fluid pressure and the clinicopathological characteristics of thymic epithelial tumours. Interstitial fluid pressure was prospectively measured at the centre of the tumour using a 1-Fr Mikro-Tip sensor catheter in 44 patients with thymic epithelial tumours, 40 with thymomas and 4 with thymic carcinomas. Data from these 44 patients were analysed for correlations between interstitial fluid pressure and clinicopathological and demographic factors including sex, age, tumour size, World Health Organization histological subtypes, myasthenia gravis, capsular invasion, mediastinal pleura invasion, lung invasion, pericardium invasion, dissemination, Masaoka-Koga stage, maximal standardized uptake value and recurrence-free survival (RFS). The mean interstitial fluid pressure was 11.3 mmHg; interstitial fluid pressure was significantly correlated with maximal standardized uptake value, lung invasion, dissemination and Masaoka-Koga stage. Low interstitial fluid pressure (≤14 mmHg) showed a tendency for better RFS compared with high interstitial pressure (P = 0.053). Lung invasion, dissemination and Masaoka-Koga stage were correlated with RFS in univariable analysis; lung invasion was selected as an independent prognostic factor in multivariable analysis. On the basis of these results, interstitial fluid pressure of thymic epithelial tumours has been shown to correlate with their clinicopathological features.

Edge states of hydrogen terminated monolayer materials: silicene, germanene and stanene ribbons.

We investigate the energy dispersion of the edge states in zigzag silicene, germanene and stanene nanoribbons with and without hydrogen termination based on a multi-orbital tight-binding model. Since the low buckled structures are crucial for these materials, both the π and σ orbitals have a strong influence on the edge states, different from the case for graphene nanoribbons. The obtained dispersion of helical edge states is nonlinear, similar to that obtained by first-principles calculations. On the other hand, the dispersion derived from the single-orbital tight-binding model is always linear. Therefore, we find that the non-linearity comes from the multi-orbital effects, and accurate results cannot be obtained by the single-orbital model but can be obtained by the multi-orbital tight-binding model. We show that the multi-orbital model is essential for correctly understanding the dispersion of the edge states in tetragen nanoribbons with a low buckled geometry.

[Chronic Progressive Pulmonary Aspergillosis after Surgery for Lung Cancer].

Case 1:A 62-year-old man underwent right S9+10 segmentectomy for non-small cell lung cancer. Three years later, pleural thickening appeared in the apex, and gradually developed cystic change. Case 2:A 64-year-old man underwent left upper lobectomy for non-small cell lung cancer. One year after surgery, chest computed tomography (CT) showed cysts in the apex of the lower lobe. The cysts expanded slowly with consolidation. Both cases were diagnosed as chronic progressive pulmonary aspergillosis. Although anti-fungal drugs were administered in both cases, case 1 died of the disease. Chronic progressive pulmonary aspergillosis is a rare late postoperative complication;when CT shows progressive cysts with consolidation in the apex area of the residual lung, frequent check-ups are needed.

Synchronous Multiple Lung Adenocarcinomas: Estrogen Concentration in Peripheral Lung.

BACKGROUND: The detection rate of synchronous multiple lung adenocarcinomas (SMLA), which display multiple ground glass opacity nodules in the peripheral lung, is increasing due to advances in high resolution computed tomography. The backgrounds of multicentric development of adenocarcinoma are unknown. In this study, we quantitated estrogen concentration in the peripheral lungs of postmenopausal female patients with SMLA. METHODS: The tissue concentration of estrogens (estrone [E1] and estdadiol [E2]) in the noncancerous peripheral lung were measured with liquid chromatography/electrospray tandem mass spectrometry in postmenopausal female patients with lung adenocarcinoma. The expression levels of CYP19A1 in the normal lung were also quantitated with real-time PCR. Thirty patients with SMLA and 79 cases of control patients with single lung adenocarcinoma were analyzed. RESULTS: The concentrations of E1 and E2 in the noncancerous tissue were significantly higher in SMLA cases than control cases (P = 0.004 and P = 0.02, respectively). The minor allele (A) of single nucleotide polymorphism rs3764221 were significantly associated with higher concentration of E1 and E2 (P = 0.002 and P = 0.01, respectively) and higher CYP19A1 mRNA expression (P = 0.03). CONCLUSION: The tissue estrogen concentration of peripheral lung was significantly higher in SMLA than control cases. The high concentration of estrogen may be one of the causes of multicentric development of peripheral lung adenocarcinomas.

Novel approach to pleurodesis with 50 % glucose for air leakage after lung resection or pneumothorax.

PURPOSE: Pleurodesis is performed in patients demonstrating air leakage after lung resection and in those with pneumothorax who must avoid surgery. However, there have so far been very few reports of pleurodesis with 50 % glucose. We herein examined the feasibility and effectiveness of this novel pleurodesis technique. METHODS: Thirty-five patients after lung resection and 11 pneumothorax patients without surgery were treated with pleurodesis using 50 % glucose. Approximately, 200 mL of 50 % glucose solution was injected into the pleural space and repeated until the air leakage stopped. Cases in which the air leakage did not stop after three injections were considered to be unsuccessful and subsequently treated with conventional pleurodesis using OK-432. RESULTS: Thirty-nine patients were successfully treated with 50 % glucose, although 7 patients required further treatment with OK-432. The unsuccessful group had some pulmonary comorbidities (P < 0.001), and the pleural effusion volume after pleurodesis was less than that in the successful group (P < 0.001). Although the air leakage did not stop in unsuccessful patients, the amount of air leakage markedly decreased. A temporary elevation of the blood sugar level was observed in 20 patients, but no other side effects had appeared. CONCLUSIONS: Pleurodesis with 50 % glucose is an easy, safe, and effective treatment modality. It is therefore considered to be a useful alternative method for pleurodesis.

Prognostic Significance of Aberrant Methylation of Solute Carrier Gene Family 5A8 in Lung Adenocarcinoma.

BACKGROUND: Solute carrier family 5 member A8 (SLC5A8) is a sodium-coupled transporter for several chemicals. The SLC5A8 gene has been reported to function as a tumor suppressor gene that contributes to carcinogenesis and tumor progression. The expression of SLC5A8 is silenced in colon neoplasia by hypermethylation of CpG-rich islands located in exon 1. In this study, we assessed the significance of aberrant methylation of the SLC5A8 gene as a prognostic factor for lung adenocarcinoma (AD). METHODS: We analyzed the methylation levels of a consecutive series of 143 node-negative stage I and II lung AD samples using pyrosequencing. RESULTS: The methylation level of exon 1 in the SLC5A8 gene was significantly associated with poor prognosis in cases of node-negative stage I and II lung AD. CONCLUSIONS: Gene silencing of SLC5A8 by hypermethylation was associated with poor prognosis in cases of node-negative stage I and II lung AD.

Interstitial Fluid Pressure Correlates Clinicopathological Factors of Lung Cancer.

PURPOSE: Solid tumors show increased interstitial fluid pressure (IFP), which correlates to a number of pathophysiological features of tumors. There have been no reports on the usefulness of measuring IFP in lung cancer. The aim of this study was to examine the relationship between IFP and the clinicopathological characteristics of lung cancer. METHODS: IFP was measured prospectively in 215 patients with 219 lesions showing solid or part-solid appearance. Four patients with double lung cancer were excluded from the analysis, resulting in 211 patients with lung cancer being analyzed for the correlation between IFP and computed tomography (CT) appearance, size, Tumor-node-metastasis (TNM) classification, maximal standardized uptake value (SUVmax), histological type, tumor grade, pleural and vessel invasion, Ki-67 index, and recurrence-free survival (RFS). RESULTS: The mean IFP was 8.5 mmHg; IFP was significantly correlated with the tumor size, SUVmax, TNM, vessel and pleural invasion, and Ki-67 index. Low IFP was associated with a better RFS compared to high IFP. Multivariate analysis did not select IFP as independent prognostic factor. In subgroup analysis of patients with adenocarcinoma, IFP was selected as independent one. CONCLUSIONS: IFP correlates clinicopathological factors of lung cancer. IFP might be used as a prognostic factor for lung cancer.

Multiple lung adenocarcinomas associated with von hippel-lindau disease.

Lung adenocarcinoma has never before been reported to be associated with von Hippel-Lindau (VHL) disease. Here, we report a case of VHL disease in a patient who had metachronous multiple lung adenocarcinomas. The patient is a 64-year-old-woman with VHL disease. She underwent surgical resection of one adenocarcinoma and one atypical adenomatous hyperplasia. A second lung adenocarcinoma developed metachronously. A point mutation in the VHL gene was confirmed in DNA from a blood sample, and loss of heterozygosity at the VHL locus was detected in the lung adenocarcinoma. The VHL dysfunction may have a role in the development of multiple lung adenocarcinomas.

Aberrant methylation and silencing of IRF8 expression in non-small cell lung cancer.

The aim of the present study was to investigate the aberrant methylation and altered expression of the interferon regulatory factor 8 (IRF8) gene in non-small cell lung cancer (NSCLC). Pyrosequencing assays were performed on 191 tumor specimens from NSCLC patients. The changes in IRF8 mRNA expression, prior to and following treatment with a demethylating agent and methylation itself, were examined in 13 lung cancer cell lines by quantitative polymerase chain reaction (qPCR) and pyrosequencing. IRF8 protein expression was examined in 94 of the 191 NSCLC specimens by immunohistochemical analysis. The IRF8 methylation level was significantly higher in the tumor tissues than in matched non-malignant lung tissues (P<0.0001). IRF8 was more frequently methylated in tumor tissues compared with matched non-malignant lung tissues, as defined by a predetermined cut-off value (P<0.0001). The IRF8 methylation level was strongly correlated with the change in mRNA expression in lung cancer cell lines and with the protein expression level in primary tumors. The IRF8 gene was more frequently methylated in patients without an epidermal growth factor receptor (EGFR) mutation than in patients with an EGFR mutation (P=0.015). IRF8 methylation correlated with recurrent prognosis in adenocarcinomas (log-rank test, P=0.048). IRF8 protein expression was frequently silenced in males, smokers, patients with non-adenocarcinoma or with wild-type EGFR, or in an advanced stage. IRF8 is often silenced by its methylation, which is a frequent event in NSCLC and, therefore, methylation of IRF8 may act as a prognostic marker for recurrence. Analysis of IRF8 methylation status may provide novel opportunities for improved prognosis and therapy of resected NSCLC.

Photoluminescence characterization in silicon nanowire fabricated by thermal oxidation of nano-scale Si fin structure.

Low-temperature photoluminescence (PL) spectra of electron-hole systems in Si nanowires (NWs) prepared by thermal oxidization of Si fin structures were studied. Mapping of PL reveals that NWs with uniform width are formed over a large area. Annealing temperature dependence of PL peak intensities was maximized at 400 °C for each NW type, which are consistent with previous reports. Our results confirmed that the micro-PL demonstrated here is one of the important methods for characterizations of the interface defects in Si NWs.

A QM/MM study of the L-threonine formation reaction of threonine synthase: implications into the mechanism of the reaction specificity.

Threonine synthase catalyzes the most complex reaction among the pyridoxal-5'-phosphate (PLP)-dependent enzymes. The important step is the addition of a water molecule to the Cß-Cα double bond of the PLP-α-aminocrotonate aldimine intermediate. Transaldimination of this intermediate with Lys61 as a side reaction to form α-ketobutyrate competes with the normal addition reaction. We previously found that the phosphate ion released from the O-phospho-l-homoserine substrate plays a critical role in specifically promoting the normal reaction. In order to elucidate the detailed mechanism of this "product-assisted catalysis", we performed comparative QM/MM calculations with an exhaustive search for the lowest-energy-barrier reaction pathways starting from PLP-α-aminocrotonate aldimine intermediate. Satisfactory agreements with the experiment were obtained for the free energy profile and the UV/vis spectra when the PLP pyridine N1 was unprotonated and the phosphate ion was monoprotonated. Contrary to an earlier proposal, the base that abstracts a proton from the attacking water was the ε-amino group of Lys61 rather than the phosphate ion. Nevertheless, the phosphate ion is important for stabilizing the transition state of the normal transaldimination to form l-threonine by making a hydrogen bond with the hydroxy group of the l-threonine moiety. The absence of this interaction may account for the higher energy barrier of the side reaction, and explains the mechanism of the reaction specificity afforded by the phosphate ion product. Additionally, a new mechanism, in which a proton temporarily resides at the phenolate O3' of PLP, was proposed for the transaldimination process, a prerequisite step for the catalysis of all the PLP enzymes.

A case of desmoid-type fibromatosis arising after thoracotomy for lung cancer with a review of the english and Japanese literature.

Chest wall desmoid-type fibromatoses are rare, locally aggressive tumors that occasionally arise from previous thoracotomy sites. Tumors arising from previous sites of thoracotomy to treat malignant disease should be discriminated from the pleural dissemination of the previous malignancy. In this study, we report a case of desmoid-type fibromatosis arising from a site for thoracotomy to treat lung cancer. Additionally we reviewed 15 reported cases of desmoid-type fibromatosis following thoracotomy and summarized their features. A 62-year-old woman was found to have a tumor on computed tomography (CT) at a 1-year routine checkup for lung cancer. The tumor (diameter, 3.4 cm) was located at the previous thoracotomy site. Positron emission tomography (PET) revealed mild (18)F-fluorodeoxyglucose (FDG) accumulation in the tumor, with a maximal standardized uptake value (SUVmax) of 1.9. CT-guided biopsy revealed only fibrous tissue. Eighteen months after the biopsy, CT revealed apparent tumor growth, and a biopsy revealed the same histology observed previously. The tumor was removed and diagnosed as desmoid-type fibromatosis. Currently, the patient is alive without recurrence 4 years after desmoid surgery.

Association of a genetic variant of CYP19A1 with multicentric development of lung adenocarcinomas.

BACKGROUND: The detection rate of multiple lung adenocarcinomas, which display multiple ground glass opacity nodules in the peripheral lung, is increasing because of advances in high resolution computed tomography. The genetic backgrounds of multiple nodules and the mechanisms that underlie their multicentric development are unknown. In this study, we examined single nucleotide polymorphisms (SNPs) of the cytochrome P450 19A1 gene to determine if they are associated with multiple adenocarcinomas risk. METHODS: Fifty-one cases of multiple adenocarcinomas with lepidic growth, 62 cases of a single adenocarcinoma with lepidic growth, and 126 control cases were analyzed. Three SNPs were analyzed by using a 5' nuclease assay with TaqMan minor-groove-binder probe. The expression level of CYP19A1 in the noncancerous lung was quantified by real-time reverse transcription polymerase chain reaction (RT-PCR). RESULTS: A minor allele of SNP rs3764221, which is located in the CYP19A1 gene, was significantly associated with multiple adenocarcinomas risk (adjusted odds ratio = 3.06; P = 0.006). Other polymorphisms of CYP19A1 were not significantly associated with the risk of multiple adenocarcinomas. A minor allele of SNP rs3764221 was also associated with a higher level of CYP19A1 messenger RNA expression (P = 0.03). CONCLUSIONS: SNP rs3764221 contributes to the development of multicentric adenocarcinomas in the peripheral lung by causing higher levels of CYP19A1 expression.

Substrate-mediated proton relay mechanism for the religation reaction in topoisomerase II.

The DNA religation reaction of yeast type II topoisomerase (topo II) was investigated to elucidate its metal-dependent general acid/base catalysis. Quantum mechanical/molecular mechanical calculations were performed for the topo II religation reaction, and the proton transfer pathway was examined. We found a substrate-mediated proton transfer of the topo II religation reaction, which involves the 3' OH nucleophile, the reactive phosphate, water, Arg781, and Tyr782. Metal A stabilizes the transition states, which is consistent with a two-metal mechanism in topo II. This pathway may be required for the cleavage/religation reaction of topo IA and II and will provide a general explanation for the catalytic mechanism in the topo IA and II.