Large nonlinear optical magnetoelectric response in a noncentrosymmetric magnetic Weyl semimetal.

Weyl semimetals resulting from either inversion (P) or time-reversal (T) symmetry breaking have been revealed to show the record-breaking large optical response due to intense Berry curvature of Weyl-node pairs. Different classes of Weyl semimetals with both P and T symmetry breaking potentially exhibit optical magnetoelectric (ME) responses, which are essentially distinct from the previously observed optical responses in conventional Weyl semimetals, leading to the versatile functions such as directional dependence for light propagation and gyrotropic effects. However, such optical ME phenomena of (semi)metallic systems have remained elusive so far. Here, we show the large nonlinear optical ME response in noncentrosymmetric magnetic Weyl semimetal PrAlGe, in which the polar structural asymmetry and ferromagnetic ordering break P and T symmetry. We observe the giant second harmonic generation (SHG) arising from the P symmetry breaking in the paramagnetic phase, being comparable to the largest SHG response reported in Weyl semimetal TaAs. In the ferromagnetically ordered phase, it is found that interference between this nonmagnetic SHG and the magnetically induced SHG emerging due to both P and T symmetry breaking results in the magnetic field switching of SHG intensity. Furthermore, such an interference effect critically depends on the light-propagating direction. The corresponding magnetically induced nonlinear susceptibility is significantly larger than the prototypical ME material, manifesting the existence of the strong nonlinear dynamical ME coupling. The present findings establish the unique optical functionality of P- and T-symmetry broken ME topological semimetals.

Circulating microRNA Panel for Prediction of Recurrence and Survival in Early-Stage Lung Adenocarcinoma.

Early-stage lung adenocarcinoma (LUAD) patients remain at substantial risk for recurrence and disease-related death, highlighting the unmet need of biomarkers for the assessment and identification of those in an early stage who would likely benefit from adjuvant chemotherapy. To identify circulating miRNAs useful for predicting recurrence in early-stage LUAD, we performed miRNA microarray analysis with pools of pretreatment plasma samples from patients with stage I LUAD who developed recurrence or remained recurrence-free during the follow-up period. Subsequent validation in 85 patients with stage I LUAD resulted in the development of a circulating miRNA panel comprising miR-23a-3p, miR-320c, and miR-125b-5p and yielding an area under the curve (AUC) of 0.776 in predicting recurrence. Furthermore, the three-miRNA panel yielded an AUC of 0.804, with a sensitivity of 45.8% at 95% specificity in the independent test set of 57 stage I and II LUAD patients. The miRNA panel score was a significant and independent factor for predicting disease-free survival (p < 0.001, hazard ratio [HR] = 1.64, 95% confidence interval [CI] = 1.51-4.22) and overall survival (p = 0.001, HR = 1.51, 95% CI = 1.17-1.94). This circulating miRNA panel is a useful noninvasive tool to stratify early-stage LUAD patients and determine an appropriate treatment plan with maximal efficacy.

Five-Year Overall Survival Analysis of the JIPANG Study: Pemetrexed or Vinorelbine Plus Cisplatin for Resected Stage II-IIIA Nonsquamous Non-Small-Cell Lung Cancer.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The JIPANG study is an open-label phase III trial evaluating the efficacy of pemetrexed plus cisplatin (PemP) versus vinorelbine plus cisplatin (NP) as adjuvant chemotherapy in patients with stage II-IIIA nonsquamous non-small-cell lung cancer (NSCLC). Here, we report the long follow-up overall survival (OS) data. Eligible patients were randomly assigned to receive either PemP or NP. The primary end point was recurrence-free survival (RFS), and the secondary end point included OS. This analysis was performed using data collected 5 years after the last patient enrollment. Among 804 patients enrolled, 783 patients were eligible (384 for NP and 389 for PemP). The updated median RFS was 37.5 months in the NP arm and 43.4 months in the PemP arm with a hazard ratio of 0.95 (95% CI, 0.79 to 1.14). At a median follow-up of 77.3 months, the OS rates at 3 and 5 years were 84.1% and 75.6% versus 87.0% and 75.0% with a hazard ratio of 1.04 (95% CI, 0.81 to 1.34). This long-term follow-up analysis showed that PemP had similar efficacy to NP in both RFS and OS for this population, with one of the longest OS data compared with the historical data.

Neoadjuvant pemetrexed plus cisplatin followed by pleurectomy for malignant pleural mesothelioma.

PURPOSE: Despite becoming the preferred surgical technique for malignant pleural mesothelioma, pleurectomy/decortication has received few prospective clinical trials. Therefore, the Japan Mesothelioma Interest Group conducted a prospective multi-institutional study to evaluate the feasibility of neoadjuvant chemotherapy followed by pleurectomy/decortication. METHODS: Patients with histologically confirmed, resectable malignant pleural mesothelioma underwent neoadjuvant chemotherapy comprising pemetrexed 500 mg/m2 plus cisplatin 75 mg/m2 for 3 cycles, followed by pleurectomy/decortication. The primary end point was macroscopic complete resection rate regardless of the surgical technique used. RESULTS: Among the 24 patients enrolled, 20 received neoadjuvant chemotherapy and 18 proceeded to surgery, all of whom achieved macroscopic complete resection. Pleurectomy/decortication was performed in 15 patients. The trial satisfied the primary end point, with a macroscopic complete resection rate of 90% (18/20, 95% confidence interval, 68.3-98.8). No treatment-related 30- and 90-day mortality occurred. The overall survival after 1 and 2 years and median overall survival after registration were 95.0% (95% confidence interval, 69.5-99.3), 70.0% (95% confidence interval, 45.1-85.3), and 3.45 years (95% confidence interval, 1.64 to not available), respectively. The cumulative incidence of progression after 1 and 2 years and median time to progression were 33.3% (95% confidence interval, 17.3-64.1), 61.1% (95% confidence interval, 42.3-88.3), and 1.71 years (95% confidence interval, 1.00-2.99), respectively. The best postoperative value for forced expiratory volume was 78.0% of preoperative values. CONCLUSIONS: Neoadjuvant chemotherapy followed by pleurectomy/decortication was feasible with acceptable survival and mortality/morbidity. Postoperative pulmonary function was approximately 80% of the preoperative pulmonary function.

Pleural Invasion Depth of Disseminated Nodules in Patients with Stage IVa or Recurrent Thymoma: Assessment, Curative Impact, and Surgical Outcomes.

BACKGROUND: Thymoma patients with pleural dissemination are difficult to manage, and their treatment strategy remains undefined. This study aimed to investigate the clinicopathologic features of these patients, focusing on the association between the depth of pleural invasion and prognosis. METHODS: Between 2003 and 2019, the study identified 120 disseminated lesions in 20 thymoma patients. Seven patients had de novo stage IVa thymoma and 13 were recurrent cases. Extrapleural pneumonectomy was performed for 8 patients and debulking surgery for 12 patients. Invasion depth of pleural tumors was classified into two groups: when the disseminated tumors invaded the pleura beneath the elastic layer, the tumor was diagnosed as Da, and when the disseminated tumors invaded the pleura beyond the elastic layer, the tumor was diagnosed as Db. RESULTS: Of 120 nodules, 31 (26%), found in eight patients with recurrent malignancies, were classified as Db. The pathologic status of the surgical margin (PSM) was positive in eight patients, seven of whom had Db nodules. The 5-year overall survival (OS) rate was 100% in the Da group and 75% in the Db group (P = 0.02). The 5-year progression-free survival (PFS) rate was 66.7% in the Da group and 25% in the Db group (P = 0.02). Cox univariate analysis showed that PFS was significantly influenced by the depth of invasion (P = 0.04) and PSM (P = 0.03). CONCLUSION: Depth of pleural invasion may influence survival outcomes for thymoma patients with pleural dissemination. The patients in this study with Da-disseminated nodules had an increased probability of a longer OS and PFS and tended to achieve negative PSM compared with the patients with Db.

SRGN-Triggered Aggressive and Immunosuppressive Phenotype in a Subset of TTF-1-Negative Lung Adenocarcinomas.

BACKGROUND: Approximately 20% of lung adenocarcinoma (LUAD) is negative for the lineage-specific oncogene Thyroid transcription factor 1 (TTF-1) and exhibits worse clinical outcome with a low frequency of actionable genomic alterations. To identify molecular features associated with TTF-1-negative LUAD, we compared the transcriptomic and proteomic profiles of LUAD cell lines. SRGN , a chondroitin sulfate proteoglycan Serglycin, was identified as a markedly overexpressed gene in TTF-1-negative LUAD. We therefore investigated the roles and regulation of SRGN in TTF-1-negative LUAD. METHODS: Proteomic and metabolomic analyses of 41 LUAD cell lines were done using mass spectrometry. The function of SRGN was investigated in 3 TTF-1-negative and 4 TTF-1-positive LUAD cell lines and in a syngeneic mouse model (n = 5 to 8 mice per group). Expression of SRGN was evaluated in 94 and 105 surgically resected LUAD tumor specimens using immunohistochemistry. All statistical tests were 2-sided. RESULTS: SRGN was markedly overexpressed at mRNA and protein levels in TTF-1-negative LUAD cell lines (P < .001 for both mRNA and protein levels). Expression of SRGN in LUAD tumor tissue was associated with poor outcome (hazard ratio = 4.22, 95% confidence interval = 1.12 to 15.86, likelihood ratio test, P = .03), and with higher expression of Programmed cell death 1 ligand 1 (PD-L1) in tumor cells and higher infiltration of Programmed cell death protein 1-positive lymphocytes. SRGN regulated expression of PD-L1 as well as proinflammatory cytokines, including Interleukin-6, Interleukin-8, and C-X-C motif chemokine 1 in LUAD cell lines; increased migratory and invasive properties of LUAD cells and fibroblasts; and enhanced angiogenesis. SRGN was induced by DNA demethylation resulting from Nicotinamide N-methyltransferase-mediated impairment of methionine metabolism. CONCLUSIONS: Our findings suggest that SRGN plays a pivotal role in tumor-stromal interaction and reprogramming into an aggressive and immunosuppressive tumor microenvironment in TTF-1-negative LUAD.

Budd-Chiari syndrome caused by latent hepatic metastasis from a thymoma.

A 34-year-old woman visited our hospital because she had had abdominal bloating for 2 months. She had been diagnosed with invasive thymoma (WHO pathological type B2), for which she had undergone chemotherapy and total thymectomy 10 years previously. Six years previously, pleural dissemination was diagnosed and she had undergone right extra-pleural pneumonectomy. On presentation to our hospital, abdominal computed tomography and ultrasound scans revealed abundant ascites and a huge liver lesion, likely a metastasis from her thymoma, obstructing the inferior vena cava. The serum-ascites albumin gradient was high at 1.4 g/dL, which indicated portal hypertension. We diagnosed Budd-Chiari syndrome caused by liver metastasis from a previous thymoma. Steroid therapy resulted in shrinkage of her liver tumor and a marked decrease in her ascites. Although rare, Budd-Chiari syndrome caused by liver metastasis from a thymoma is a possible serious complication of advanced invasive thymoma.

Phase III study of adjuvant gemcitabine compared with adjuvant uracil-tegafur in patients with completely resected pathological stage IB-IIIA non-small cell lung cancer (WJTOG0101).

BACKGROUND: Adjuvant oral uracil-tegafur (UFT) has led to significantly longer postoperative survival among patients with non-small-cell lung cancer (NSCLC). Gemcitabine (GEM) monotherapy is also reportedly effective for NSCLC and has minor adverse events (AEs). This study compared the efficacy of GEM- versus UFT-based adjuvant regimens in patients with completely resected pathological stage (p-stage) IB-IIIA NSCLC. PATIENTS AND METHODS: Patients with completely resected p-stage IB-IIIA NSCLC were randomly assigned to GEM or UFT. The primary endpoint was overall survival (OS); secondary endpoints were disease-free survival (DFS), and AEs. RESULTS: We assigned 305 patients to the GEM group and 303 to the UFT group. Baseline factors were balanced between the arms. Of the 608 patients, 293 (48.1%) had p-stage IB disease, 195 (32.0%) had p-stage II disease and 121 (19.9%) had p-stage IIIA disease. AEs were generally mild in both groups, and only one death occurred, in the GEM group. After a median follow-up of 6.8 years, the two groups did not significantly differ in survival: 5 year OS rates were GEM: 70.0%, UFT: 68.8% (hazard ratio 0.948; 95% confidence interval 0.73-1.23; P = 0.69). CONCLUSION: Although GEM-based adjuvant therapy for patients with completely resected stage IB-IIIA NSCLC was associated with acceptable toxicity, it did not provide longer OS than did UFT.

Survival benefits of salvage surgery for primary lung cancer based on routine clinical practice.

BACKGROUND: Premeditated induction chemotherapy followed by surgical resection is accepted as safe and effective. Studies on salvage surgery in patients with incompletely cured lung cancer are lacking. This study aimed to demonstrate the safety and efficacy of salvage surgery. METHODS: We conducted a retrospective multi-institutional cohort study on patients who underwent salvage surgery for advanced (stage III and IV) non-small cell lung cancer (NSCLC) between January 2005 and December 2016 at the 14 hospitals of the Chubu Lung Cancer Surgery Study Group. A total of 37 patients were assigned to the salvage surgery group; a lobectomy with mediastinal lymph node dissection was performed. The survival benefit was assessed using the Kaplan-Meier method and the Cox proportional hazard model. RESULTS: Although postoperative complications were observed in 11 patients (29.7%), surgery-related death occurred in only one patient (mortality rate: 2.7%) resulting from respiratory failure caused by interstitial pneumonia exacerbation. Postoperative recurrence was observed in 22 patients (61.1%), the incidence of brain metastasis being high (nine patients: 40.9%). The five-year survival rate from the first day of treatment was 60%. The survival of the postoperative pathological stage (s'-stage) I group was significantly better (five-year survival rate: 80.9%) than that of the other groups (p < 0.05). S'-stage was the most significant factor (p < 0.01) associated with long-term survival. CONCLUSIONS: Salvage surgery is a feasible therapeutic modality for advanced lung cancer. Downstaging to s'-stage I with previous treatment was most important for survival. Complete resection (R0) should be the goal because surgical procedures were tolerated despite intense treatment.

Clinical features and prognostic impact of coexisting autoimmune disease other than myasthenia gravis in resected thymomas: analysis of a Japanese multi-institutional retrospective database.

OBJECTIVES: The purpose of this study was to clarify the prevalence, clinical features and survival of patients with thymoma and non-myasthenia gravis autoimmune disease (NMAD) using a nationwide cohort. METHODS: The Japanese Association for Research on the Thymus nationwide database, which includes data from 32 institutions, was examined to clarify the prevalence and characteristics of NMAD associated with thymomas and elucidate the prognostic impact of NMAD for thymoma patients. RESULTS: Among the 2423 patients with thymomas who were surgically treated between 1991 and 2010, 114 (4.7%) were identified with NMAD. The most frequently observed NMAD was pure red cell aplasia (PRCA) in 44 (1.8%), followed by hypogammaglobulinaemia (0.5%) and rheumatic arthritis (0.5%). Twenty-eight percent of patients with NMAD had concomitant myasthenia gravis. The presence of NMAD was not an independent prognostic factor for overall survival (OS) irrespective of the type of NMAD [PRCA+: hazard ratio (HR) 1.99, 95% confidence interval 0.74-4.47; PRCA- NMAD: HR 1.28, 0.30-3.56]; however, there were more cases with advanced age and disease of the thymoma amongst PRCA+ patients and these showed a worse OS than patients with PRCA- NMAD (P < 0.001), who had an OS similar to those without NMAD (P = 0.489). The 10-year OS rates in PRCA+, PRCA- NMAD and NMAD- groups were 45.5%, 97.4% and 89.5%, respectively. The main causes of death in PRCA+ patients were the progression of thymoma and other diseases including pneumonia. CONCLUSIONS: Although the presence of NMAD itself did not significantly affect survival after surgery for thymoma, the type of NMAD was associated with different clinical features and prognosis. The NMAD+ thymomas should be separately categorized according to the presence or absence of PRCA.

CD109 regulates in vivo tumor invasion in lung adenocarcinoma through TGF-ß signaling.

Stromal invasion is considered an important prognostic factor in patients with lung adenocarcinoma. The mechanisms underlying the formation of tumor stroma and stromal invasion have been studied in the lung; however, they are still unclear. CD109 is a glycosylphosphatidylinositol-anchored glycoprotein highly expressed in several types of human malignant tumors including lung cancers. In this study, we investigated the in vivo functions of CD109 protein in malignant lung tumors. Initially, we identified an association between higher expression of CD109 protein in human lung adenocarcinoma and a significantly worse prognosis, according to immunohistochemical analysis. We also showed that CD109 deficiency significantly reduced the area of stromal invasive lesions in a genetically engineered CD109-deficient lung adenocarcinoma mouse model, which correlated with the results observed in human lung adenocarcinoma. Furthermore, we identified latent TGF-ß binding protein-1 (LTBP1) as a CD109-interacting protein using mass spectrometry and confirmed their interaction by co-immunoprecipitation. Importantly, increased CD109 expression enhanced stromal TGF-ß activation in the presence of LTBP1. Therefore, these data suggest the significance of the regulation of TGF-ß signaling through CD109 and LTBP1 interaction in tumor stroma and also reveal the importance of CD109 expression levels in promoting lung cancer cell proliferation, migration, and invasion, and thus predicting the outcome of patients suffering from lung adenocarcinoma. Therefore, CD109 protein could be a potential therapeutic target for this disease.

CERS6 required for cell migration and metastasis in lung cancer.

Sphingolipids constitute a class of bio-reactive molecules that transmit signals and exhibit a variety of physical properties in various cell types, though their functions in cancer pathogenesis have yet to be elucidated. Analyses of gene expression profiles of clinical specimens and a panel of cell lines revealed that the ceramide synthase gene CERS6 was overexpressed in non-small-cell lung cancer (NSCLC) tissues, while elevated expression was shown to be associated with poor prognosis and lymph node metastasis. NSCLC profile and in vitro luciferase analysis results suggested that CERS6 overexpression is promoted, at least in part, by reduced miR-101 expression. Under a reduced CERS6 expression condition, the ceramide profile became altered, which was determined to be associated with decreased cell migration and invasion activities in vitro. Furthermore, CERS6 knockdown suppressed RAC1-positive lamellipodia/ruffling formation and attenuated lung metastasis efficiency in mice, while forced expression of CERS6 resulted in an opposite phenotype in examined cell lines. Based on these findings, we consider that ceramide synthesis by CERS6 has important roles in lung cancer migration and metastasis.

Connective tissue growth factor produced by cancer­associated fibroblasts correlates with poor prognosis in epithelioid malignant pleural mesothelioma.

Malignant mesothelioma is an aggressive neoplasm for which effective treatments are lacking. We often encounter mesothelioma cases with a profound desmoplastic reaction, suggesting the involvement of cancer­associated fibroblasts (CAFs) in mesothelioma progression. While the roles of CAFs have been extensively studied in other tumors and have led to the view that the cancer stroma contains heterogeneous populations of CAFs, their roles in mesothelioma remain unknown. We previously showed that connective tissue growth factor (CTGF), a secreted protein, is produced by both mesothelioma cells and fibroblasts and promotes the invasion of mesothelioma cells in vitro. In this study, we examined the clinical relevance of CAFs in mesothelioma. Using surgical specimens of epithelioid malignant pleural mesothelioma, we evaluated the clinicopathological significance of the expression of α­smooth muscle actin (αSMA), the most widely used marker of CAFs, the expression of CTGF, and the extent of fibrosis by immunohistochemistry and Elastica­Masson staining. We also analyzed the expression of mesenchymal stromal cell­ and fibroblast­expressing Linx paralogue (Meflin; ISLR), a recently reported CAF marker that labels cancer­restraining CAFs and differ from αSMA­positive CAFs, by in situ hybridization. The extent of fibrosis and CTGF expression in mesothelioma cells did not correlate with patient prognosis. However, the expression of αSMA and CTGF, but not Meflin, in CAFs correlated with poor prognosis. The data suggest that CTGF+ CAFs are involved in mesothelioma progression and represent a potential molecular target for mesothelioma therapy.

Current status of surgery for clinical stage IA lung cancer in Japan: analysis of the national clinical database.

PURPOSE: As the number of cases of early lung cancer in Japan grows, an analysis of the present status of surgical treatments for clinical stage IA lung cancer using a nationwide database with web-based data entry is warranted. METHODS: The operative and perioperative data from 47,921 patients who underwent surgery for clinical stage IA lung cancer in 2014 and 2015 were obtained from the National Clinical Database (NCD) of Japan. Clinicopathological characteristics, surgical procedure, mortality, and morbidity were analyzed, and thoracotomy and video-assisted thoracic surgery (VATS) were compared. RESULTS: The patients comprised 27,208 men (56.8%) and 20,713 women (43.2%); mean age, 69.3 years. Lobectomy was performed in 64.8%, segmentectomy in 15.2%, and wedge resection in 19.8%. The surgical procedures were thoracotomy in 12,194 patients (25.4%) and a minimally invasive approach (MIA) in 35,727 patients (74.6%). MIA was divided into VATS + mini-thoracotomy (n = 13,422, 28.0%) and complete VATS (n = 22,305, 46.5%). The overall postoperative mortality rate was 0.4%, being significantly lower in the MIA group than in the thoracotomy group (0.3% vs 0.8%, P < 0.001). CONCLUSIONS: Our analysis of data from the NCD indicates that MIA has become the new standard treatment for clinical stage IA lung cancer.

Randomized Phase III Study of Pemetrexed Plus Cisplatin Versus Vinorelbine Plus Cisplatin for Completely Resected Stage II to IIIA Nonsquamous Non-Small-Cell Lung Cancer.

PURPOSE: To evaluate the efficacy of pemetrexed plus cisplatin versus vinorelbine plus cisplatin as postoperative adjuvant chemotherapy in patients with pathologic stage II-IIIA nonsquamous non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: We performed a randomized, open-label, phase III study at 50 institutions within 7 clinical study groups in Japan. Patients with completely resected pathologic stage II-IIIA (TNM 7th edition) nonsquamous NSCLC were randomly assigned to receive either pemetrexed (500 mg/m2, day 1) plus cisplatin (75 mg/m2, day 1) or vinorelbine (25 mg/m2, days 1 and 8) plus cisplatin (80 mg/m2, day 1) with stratification by sex, age, pathologic stage, EGFR mutation, and institution. These treatments were planned to be given every 3 weeks for 4 cycles. The primary end point was recurrence-free survival in the modified intent-to-treat population, excluding ineligible patients. RESULT: Between March 2012 and August 2016, 804 patients were enrolled (402 assigned to vinorelbine plus cisplatin and 402 assigned to pemetrexed plus cisplatin). Of 784 eligible patients, 410 (52%) had stage IIIA disease and 192 (24%) had EGFR-sensitive mutations. At a median follow-up of 45.2 months, median recurrence-free survival was 37.3 months for vinorelbine plus cisplatin and 38.9 months for pemetrexed plus cisplatin, with a hazard ratio of 0.98 (95% CI, 0.81 to 1.20; 1-sided P = .474). Grade 3-4 toxicities reported more frequently for vinorelbine plus cisplatin than for pemetrexed plus cisplatin were febrile neutropenia (11.6% v 0.3%, respectively), neutropenia (81.1% v 22.7%, respectively), and anemia (9.3% v 2.8%, respectively). One treatment-related death occurred in each arm. CONCLUSION: Although this study failed to show the superiority of pemetrexed plus cisplatin for patients with resected nonsquamous NSCLC, this regimen showed a better tolerability as adjuvant chemotherapy.

Involvement of heme oxygenase-1 in suppression of T cell activation by quercetin.

AIM: Acute rejection is still a major problem in transplantation and one of the most important causes of late graft loss. Cyclosporine and tacrolimus are widely used for suppression of T cell function to avoid graft rejection, but long-term use of these compounds is associated with serious toxicities. Quercetin, a flavonoid found in fruits and vegetables, has been demonstrated to exhibit cytoprotective effects through the induction of heme oxygenase (HO) -1, an enzyme involved in heme catabolism. We hypothesized that quercetin induces HO-1 in T cells and suppresses T cell function via HO-1. In the present study, we showed that quercetin suppressed the A23187-mediated expression of interleukin (IL) -2 in T cells. METHODS: Mouse splenocytes, enriched T cells, and EL4 cells, a mouse T cell line, were treated with quercetin, and then stimulated with A23187, a calcium ionophore, concanavalin A, or anti-CD3ε and anti-CD28 antibodies. Cell proliferation, expression of IL-2, calcium mobilization, apoptosis, cell cycle, and phosphorylation of extracellular signal-regulated kinase (ERK) were investigated. RESULTS: Quercetin induced HO-1, and this induction of HO-1 was implicated in the suppression of IL-2 production. Furthermore, the induction of HO-1 by quercetin suppressed the influx of calcium ions, a known trigger of IL-2 production. Additionally, quercetin suppressed T cell proliferation through promotion of cell cycle arrest via HO-1 induction, but quercetin did not induce apoptosis. To investigate the role of the signal transduction pathway in quercetin's effect on cell proliferation, we evaluated the phosphorylation of ERK in T cells. Quercetin suppressed the A23187-mediated stimulation of ERK, an effect that was mediated through HO-1. These results suggested that HO-1 is involved in the suppressive effects of quercetin on T cell activation and proliferation. CONCLUSION: Our findings indicate that the quercetin may be a promising candidate for inducing HO-1 in T cells, thereby facilitating immunosuppressive effects.

Micro-computed tomography images of lung adenocarcinoma: detection of lepidic growth patterns.

Micro-computed tomography (µCT) provides extremely high-resolution images of samples and can be employed as a non-destructive inspection tool. Using µCT, we can obtain images comparable with microscopic images. In this work, we have attempted to take high-resolution images of the human lung using µCT. Compared to clinical high-resolution computed tomography (HRCT) images of living body (in-vivo imaging), we can obtain extremely high-resolution images by µCT of ex-vivo tissues (resected lungs) as three-dimensional data. The purpose of this study was to distinguish between areas of normal lung and lung cancer by µCT images in order to study the feasibility of cancer diagnosis using this novel radiological image modality. Ten resected human lungs containing primary cancer were fixed by Heitzman's methods to obtain high-resolution µCT images. After fixation of the lung, images of the specimens were taken by µCT between January 2016 and November 2017. The imaging conditions were tube voltage: 90 kV and tube current: 110 µA. To compare details of images gained by conventional HRCT and µCT, we measured the thickness of the alveolar walls of the normal lung area and the cancer area of which alveoli might be replaced by tumor cells, and compared their appearance by means of histopathological images. All the nodules were diagnosed as adenocarcinoma. The median whole tumor size was 18 mm (9 mm-24 mm). Each specimen was clearly divided into areas of normal alveolar wall and of thickened alveolar wall on µCT 'visually'. Median thickness of alveolar walls of the normal lung was 0.037 mm (0.034 mm-0.048 mm), and that of the cancer area was 0.084 mm (0.074 mm-0.094 mm); there was a statistically significant difference between both thicknesses by Student's t-test (P < 0.01). The area of thickened alveolar walls on µCT corresponded well with the area of microscopically lepidic growth patterns of adenocarcinoma. We found that µCT images could be correctly divided by alveolar walls into normal lung area and lung cancer area. Further detailed investigations with regard to µCT are needed to make comparable histological diagnoses using µCT images with conventional microscopic methods of pathological diagnoses.

Clinical application of a surgical navigation system based on virtual thoracoscopy for lung cancer patients: real time visualization of area of lung cancer before induction therapy and optimal resection line for obtaining a safe surgical margin during surgery.

BACKGROUND: We have developed a surgical navigation system that presents virtual thoracoscopic images using computed tomography (CT) image data, as if you are observing intra-thoracic cavity in synchronization with the real thoracoscopic view. Using this system, we made it possible to simultaneously visualize the 'area of lung cancer before induction therapy' and the 'optimal resection line for obtaining a safe surgical margin' as a virtual thoracoscopic view. We applied this navigation system in the clinical setting in operations for lung cancer patients with chest wall invasion after induction chemoradiotherapy. METHODS: The proposed surgical navigation system consisted of a three-dimensional (3D) positional tracker and a virtual thoracoscopy system. The 3D positional tracker was used to recognize the positional information of the real thoracoscope. The virtual thoracoscopy system generated virtual thoracoscopic views based on CT image data. Combined with these two technologies, patient-to-image registration was performed in two patients, and the results generated a virtual thoracoscopic view that was synchronized with the real thoracoscopic view. RESULTS: The operations were started with video-assisted thoracic surgery (VATS), and the navigation system was activated at the same time. The virtual thoracoscopic view was synchronized with the real thoracoscopic view, which also simultaneously indicated the 'area of lung cancer before induction therapy' and the 'optimal resection lines for obtaining a safe surgical margin'. We marked the optimal lines using an electric scalpel, and then performed lobectomy and chest wall resection with a sufficient surgical margin using these landmarks. Pathological examinations confirmed that the surgical margin was negative. No complications related to the navigation system were encountered during or after the procedures. CONCLUSIONS: Using this proposed navigation system, we could obtain a 'CT-derived virtual intra-thoracic 3D view of the patient' that was aligned with the thoracoscopic view during surgery. The accurate identification of areas of cancer invasion before induction therapy using this system might be a useful for determining optimal surgical resection lines.