Cytotoxicity, cellular localization and photophysical properties of Re(I) tricarbonyl complexes bound to cysteine and its derivatives.

The potential chemotherapeutic properties coupled to photochemical transitions make the family of fac-[Re(CO)3(N,N)X]0/+ (N,N = a bidentate diimine such as 2,2'-bipyridine (bpy); X = halide, H2O, pyridine derivatives, PR3, etc.) complexes of special interest. We have investigated reactions of the aqua complex fac-[Re(CO)3(bpy)(H2O)](CF3SO3) (1) with potential anticancer activity with the amino acid L-cysteine (H2Cys), and its derivative N-acetyl-L-cysteine (H2NAC), as well as the tripeptide glutathione (H3A), under physiological conditions (pH 7.4, 37 °C), to model the interaction of 1 with thiol-containing proteins and enzymes, and the impact of such coordination on its photophysical properties and cytotoxicity. We report the syntheses and characterization of fac-[Re(CO)3(bpy)(HCys)]·0.5H2O (2), Na(fac-[Re(CO)3(bpy)(NAC)]) (3), and Na(fac-[Re(CO)3(bpy)(HA)])·H2O (4) using extended X-ray absorption spectroscopy, IR and NMR spectroscopy, electrospray ionization spectrometry, as well as the crystal structure of {fac-[Re(CO)3(bpy)(HCys)]}4·9H2O (2 + 1.75 H2O). The emission spectrum of 1 displays a variance in Stokes shift upon coordination of L-cysteine and N-acetyl-L-cysteine. Laser excitation at λ = 355 nm of methanol solutions of 1-3 was followed by measuring their ability to produce singlet oxygen (1O2) using direct detection methods. The cytotoxicity of 1 and its cysteine-bound complex 2 was assessed using the MDA-MB-231 breast cancer cell line, showing that the replacement of the aqua ligand on 1 with L-cysteine significantly reduced the cytotoxicity of the Re(I) tricarbonyl complex. Probing the cellular localization of 1 and 2 using X-ray fluorescence microscopy revealed an accumulation of 1 in the nuclear and/or perinuclear region, whereas the accumulation of 2 was considerably reduced, potentially explaining its reduced cytotoxicity. Replacing the aqua ligand with cysteine in the antitumor active fac-[Re(CO)3(bpy)(H2O)](CF3SO3) complex significantly reduced its cellular accumulation and cytotoxicity against the MDA-MB-213 breast cancer cell line, shifted its maximum emission to considerably higher energies, and decreased its fluorescence quantum yield.

Glycobiomarker, Fucosylated Short-Form Secretogranin III Levels Are Increased in Serum of Patients with Small Cell Lung Carcinoma.

Secretogranin III (SgIII) is a member of the chromogranin/secretogranin family of neuroendocrine secretory proteins. Granins are expressed in endocrine and neuroendocrine cells and subsequently processed into bioactive hormones. Although granin-derived peptide expression is correlated with neuroendocrine carcinomas, little is known about SgIII. We previously identified SgIII by a comparative glycoproteomics approach for elucidation of glycobiomarker candidates in lung carcinoma. Here, we examined the expression, secretion, and glycosylation of SgIII to identify novel biomarkers of small cell lung carcinoma (SCLC). In comparative immunohistochemical analysis and secretion profiling, SgIII was observed in all types of lung cancer. However, low-molecular-weight SgIII (short-form SgIII) was specifically found in SCLC culture medium. Glycoproteomics analysis showed that a fucosylated glycan was attached to the first of three potential N-glycosylation sites and an unfucosylated glycan was detected on the second site; however, the third site was not glycosylated. Next, we performed lectin capture with a fucose-binding lectin and detected short-form SgIII specifically in the sera of patients with SCLC. The results suggested an association between the fucosylated glycoform of short-form SgIII and SCLC. Thus, fucosylated short-form SgIII may be a valuable biomarker for SCLC and could be used to monitor development of the disease. All MS data are available via ProteomeXchange and jPOST with identifiers PXD007626 and JPST000313, respectively.

A selected reaction monitoring mass spectrometric assessment of biomarker candidates diagnosing large-cell neuroendocrine lung carcinoma by the scaling method using endogenous references.

Selected reaction monitoring mass spectrometry (SRM-MS) -based semi-quantitation was performed to assess the validity of 46 selected candidate proteins for specifically diagnosing large-cell neuroendocrine lung carcinoma (LCNEC) and differentiating it from other lung cancer subtypes. The scaling method was applied in this study using specific SRM peak areas (AUCs) derived from the endogenous reference protein that normalizes all SRM AUCs obtained for the candidate proteins. In a screening verification study, we found that seven out of the 46 candidate proteins were statistically significant for the LCNEC phenotype, including 4F2hc cell surface antigen heavy chain (4F2hc/CD98) (p-ANOVA ≤ 0.0012), retinal dehydrogenase 1 (p-ANOVA ≤ 0.0029), apolipoprotein A-I (p-ANOVA ≤ 0.0004), ß-enolase (p-ANOVA ≤ 0.0043), creatine kinase B-type (p-ANOVA ≤ 0.0070), and galectin-3-binding protein (p-ANOVA = 0.0080), and phosphatidylethanolamine-binding protein 1 (p-ANOVA ≤ 0.0012). In addition, we also identified candidate proteins specific to the small-cell lung carcinoma (SCLC) subtype. These candidates include brain acid soluble protein 1 (p-ANOVA < 0.0001) and γ-enolase (p-ANOVA ≤ 0.0013). This new relative quantitation-based approach utilizing the scaling method can be applied to assess hundreds of protein candidates obtained from discovery proteomic studies as a first step of the verification phase in biomarker development processes.

Elevated ß-catenin pathway as a novel target for patients with resistance to EGF receptor targeting drugs.

There is a high death rate of lung cancer patients. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are effective in some lung adenocarcinoma patients with EGFR mutations. However, a significant number of patients show primary and acquire resistance to EGFR-TKIs. Although the Akt kinase is commonly activated due to various resistance mechanisms, the key targets of Akt remain unclear. Here, we show that the Akt-ß-catenin pathway may be a common resistance mechanism. We analyzed gene expression profiles of gefitinib-resistant PC9M2 cells that were derived from gefitinib-sensitive lung cancer PC9 cells and do not have known resistance mechanisms including EGFR mutation T790M. We found increased expression of Axin, a ß-catenin target gene, increased phosphorylation of Akt and GSK3, accumulation of ß-catenin in the cytoplasm/nucleus in PC9M2 cells. Both knockdown of ß-catenin and treatment with a ß-catenin inhibitor at least partially restored gefitinib sensitivity to PC9M2 cells. Lung adenocarcinoma tissues derived from gefitinib-resistant patients displayed a tendency to accumulate ß-catenin in the cytoplasm. We provide a rationale for combination therapy that includes targeting of the Akt-ß-catenin pathway to improve the efficacy of EGFR-TKIs.

A proteomic profiling of laser-microdissected lung adenocarcinoma cells of early lepidic-types.

BACKGROUND: In the new pathologic classification of lung adenocarcinoma proposed by IASLC/ATS/ERS in 2011, lepidic type adenocarcinomas are constituted by three subtypes; adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and lepidic predominant invasive adenocarcinoma (LPIA). Although these subtypes are speculated to show sequential progression from preinvasive lesion to invasive lung cancer, changes of protein expressions during these processes have not been fully studied yet. This study aims to glimpse a proteomic view of the early lepidic type lung adenocarcinomas. METHODS: A total of nine formalin-fixed and paraffin-embedded (FFPE) lepidic type lung adenocarcinoma tissues were selected from our archives, three tissues each in AIS, MIA and LPIA. The tumor and peripheral non-tumor cells in these FFPE tissues were collected with laser microdissection (LMD). Using liquid chromatography-tandem mass spectrometry (MS/MS), protein compositions were compared with respect to the peptide separation profiles among tumors collected from three types of tissues, AIS, MIA and LPIA. Proteins identified were semi-quantified by spectral counting-based or identification-based protein-based approach, and statistical evaluation was performed by pairwise G-tests. RESULTS: A total of 840 proteins were identified. Spectral counting-based semi-quantitative comparisons of all identified proteins through AIS to LPIA have revealed that the protein expression profile of LPIA was significantly differentiated from other subtypes. 70 proteins including HPX, CTTN, CDH1, EGFR, MUC1 were found as LPIA-type marker candidates, 15 protein candidates for MIA-type marker included CRABP2, LMO7, and NPEP, and 26 protein candidates for AIS-type marker included LTA4H and SOD2. The STRING gene set enrichment resulted from the protein-protein interaction (PPI) network analysis suggested that AIS was rather associated with pathways of focal adhesion, adherens junction, tight junction, that MIA had a strong association predominantly with pathways of proteoglycans in cancer and with PI3K-Akt. In contrast, LPIA was associated broadly with numerous tumor-progression pathways including ErbB, Ras, Rap1 and HIF-1 signalings. CONCLUSIONS: The proteomic profiles obtained in this study demonstrated the technical feasibility to elucidate protein candidates differentially expressed in FFPE tissues of LPIA. Our results may provide candidates of disease-oriented proteins which may be related to mechanisms of the early-stage progression of lung adenocarcinoma.

Establishment of successively transplantable rabbit VX2 cancer cells that express enhanced green fluorescent protein.

Morphological detection of cancer cells in the rabbit VX2 allograft transplantation model is often difficult in a certain region such as serosal cavity where reactive mesothelial cells mimic cancer cells and both cells share common markers such as cytokeratins. Therefore, tagging VX2 cells with a specific and sensitive marker that easily distinguishes them from other cells would be advantageous. Thus, we tried to establish a successively transplantable, enhanced green fluorescent protein (EGFP)-expressing VX2 model. Cancer cells obtained from a conventional VX2-bearing rabbit were cultured in vitro and transfected with an EGFP-encoding vector, and then successively transplanted in Healthy Japanese White rabbits (HJWRs) (n = 8). Besides, conventional VX2 cells were transplanted in other HJWRs (n = 8). Clinicopathological comparison analyses were performed between the two groups. The success rate of transplantation was 100% for both groups. The sensitivity and specificity of EGFP for immunohistochemical detection of VX2 cells were 84.3 and 100%, respectively. No significant differences in cancer cell morphology, tumor size (P = 0.742), Ki-67 labeling index (P = 0.878), or survival rate (P = 0.592) were observed between the two. VX2 cells can be genetically altered, visualized by EGFP, and successively transplanted without significant alteration of morphological and biological properties compared to those of the conventional model.

Glycoproteomics approach for identifying Glycobiomarker candidate molecules for tissue type classification of non-small cell lung carcinoma.

Histopathological classification of lung cancer has important implications in the application of clinical practice guidelines and the prediction of patient prognosis. Thus, we focused on discovering glycobiomarker candidates to classify the types of lung cancer tissue. First, we performed lectin microarray analysis of lung cancer tissue specimens and cell lines and identified Aleuria aurantia lectin (AAL), Hippeastrum hybrid lectin (HHL), and Concanavalia ensiformis agglutinin (ConA) as lectin probes specific to non-small cell lung carcinoma (NSCLC). LC-MS-based analysis was performed for the comprehensive identification of glycoproteins and N-linked glycosylation sites using lectin affinity capture of NSCLC-specific glycoforms of glycoproteins. This analysis identified 1092 AAL-bound glycoproteins (316 gene symbols) and 948 HHL/ConA-bound glycoproteins (279 gene symbols). The lectin microarray-assisted verification using 15 lung cancer cell lines revealed the NSCLC-specific expression of fibronectin. The glycosylation profiling of fibronectin indicated that the peanut agglutinin (PNA) signal appeared to differentiate two NSCLC types, adenocarcinoma and large cell carcinoma, whereas the protein expression level was similar between these types. Our glycoproteomics approach together with the concurrent use of an antibody and lectin is applicable to the quantitative and qualitative monitoring of variations in glycosylation of fibronectin specific to certain types of lung cancer tissue.

In situ back-side illumination fluorescence XAFS (BI-FXAFS) studies on platinum nanoparticles deposited on a HOPG surface as a model fuel cell: a new approach to the Pt-HOPG electrode/electrolyte interface.

We measured the in situ polarization-dependent X-ray absorption fine structure of platinum nanoparticles (PtNPs) deposited on a flat highly oriented pyrolytic graphite (HOPG) substrate under electrochemical conditions using a back-side illumination method. In this method, the thin HOPG substrate with PtNPs deposited on one side was used as a window for incident and fluorescent X-rays, as well as an electrode. A bent crystal Laue analyzer (BCLA) was applied to the extraction of the Pt Lα fluorescent X-ray signals from strong scattered X-rays. Pt L3 edge XAFS spectra were observed for various electrode potentials and polarization directions.

Clinical initiatives linking Japanese and Swedish healthcare resources on cancer studies utilizing Biobank Repositories.

The Tokyo Medical University Hospital in Japan and the Lund University hospital in Sweden have recently initiated a research program with the objective to impact on patient treatment by clinical disease stage characterization (phenotyping), utilizing proteomics sequencing platforms. By sharing clinical experiences, patient treatment principles, and biobank strategies, our respective clinical teams in Japan and Sweden will aid in the development of predictive and drug related protein biomarkers. Data from joint lung cancer studies are presented where protein expression from Neuro- Endocrine lung cancer (LCNEC) phenotype patients can be separated from Small cell- (SCLC) and Large Cell lung cancer (LCC) patients by deep sequencing and spectral counting analysis. LCNEC, a subtype of large cell carcinoma (LCC), is characterized by neuroendocrine differentiation that small cell lung carcinoma (SCLC) shares. Pre-therapeutic histological distinction between LCNEC and SCLC has so far been problematic, leading to adverse clinical outcome. An establishment of protein targets characteristic of LCNEC is quite helpful for decision of optimal therapeutic strategy by diagnosing individual patients. Proteoform annotation and clinical biobanking is part of the HUPO initiative (http://www.hupo.org) within chromosome 10 and chromosome 19 consortia.

Cancer stem cell-related marker expression in lung adenocarcinoma and relevance of histologic subtypes based on IASLC/ATS/ERS classification.

BACKGROUND: The cancer stem cell (CSC) theory has been proposed to explain tumor heterogeneity and the carcinogenesis of solid tumors. The aim of this study was to clarify the clinical role of CSC-related markers in patients with lung adenocarcinoma and to determine whether each CSC-related marker expression correlates with the histologic subtyping proposed by the International Association for the Study of Lung Cancer (IASLC), the American Thoracic Society (ATS), and the European Respiratory Society (ERS) classifications. METHODS: We reviewed data for all 103 patients in whom complete resection of adenocarcinoma had been performed. Expression of CSC-related markers, ie, aldehyde dehydrogenase 1A1 (ALDH1A1), aldo-keto reductase 1C family member 1 (AK1C1), and 1C family member 3 (AK1C3), was examined using immunostaining on whole-mount tissue slides, and the tumors were reclassified according to the IASLC/ATS/ERS classification. RESULTS: ALDH1A1 expression was observed in 66.0% of tumors, AK1C1 in 62.7%, and AK1C3 in 86.1%. Immunoreactivities with the frequency of mean expression of ALDH1A1 in papillary predominant adenocarcinoma were significantly higher than those of solid predominant adenocarcinoma (P<0.05). Papillary predominant adenocarcinoma had significantly lower expression of AK1C1 when compared with noninvasive or solid predominant adenocarcinomas (P<0.05). On multivariate analysis, larger tumor size (hazards ratio 1.899, P=0.044), lymph node metastasis (hazards ratio 2.702, P=0.005), and low expression of ALDH1A1 (hazards ratio 3.218, P<0.001) were shown to be independently associated with an unfavorable prognosis. CONCLUSION: Immunohistochemistry of ALDH1A1 expression is strongly associated with prognosis. Expression of each CSC-related marker varies according to subtype, suggesting that a comprehensive histologic subtyping approach in the IASLC/ATS/ERS classification provides new molecular biology insights into the genesis of lung adenocarcinoma according to CSC theory.

A proposal for combination of total number and anatomical location of involved lymph nodes for nodal classification in non-small cell lung cancer.

BACKGROUND: We previously reported the prognostic impact of the number of involved lymph nodes (LNs) on survival in non-small cell lung cancer (NSCLC). However, it remains unknown whether the total number or anatomic location of involved LNs is a superior prognostic factor. METHODS: A total of 689 patients with NSCLC who underwent complete resection involving dissection of the hilar and mediastinal LNs with curative intent of ≥ 10 LNs were enrolled. The association between the total number of LNs (nN) involved and survival was assessed by comparison with the anatomic location of LN involvement (pathologic lymph node [pN]), the present nodal category. RESULTS: We classified the patients into five categories according to the combined pN and nN status as follows: pN0-nN0, pN1-nN1-3, pN1-nN4-, pN2-nN1-3, and pN2-nN4. Although there was no statistically significant difference between the pN1-nN4- and pN2-nN1-3 categories, pN2-nN1-3 had better prognoses than pN1-nN4-. On multivariate analysis, the nN category was an independent prognostic factor for overall survival and disease-free survival (vs nN4-; the hazard ratios of nN0 and nN1-3 for overall survival were 0.223 and 0.369, respectively, P < .0001 for all), similar to the pN category. We propose a new classification based on a combination of the pN and nN categories: namely, N0 becomes pN0-nN0, the N1 category becomes pN1-nN1-3, the N2a category becomes pN2-nN1-3 + pN1-nN4-, and the N2b category becomes pN2-nN4. Each survival curve was proportional and was well distributed among the curves. CONCLUSIONS: A combined anatomically based pN stage classification and numerically based nN stage classification is a more accurate prognostic determinant in patients with NSCLC, especially in the prognostically heterogeneous pN1 and pN2 cases. Further large-scale international cohort validation analyses are warranted.

Prognostic factors and the significance of treatment after recurrence in completely resected stage I non-small cell lung cancer.

OBJECTIVE: The objective of this study was to identify the clinicopathologic factors influencing postrecurrence survival (PRS) in and the effect of postrecurrence therapy (PRT) on patients with completely resected stage I non-small cell lung cancer (NSCLC). METHODS: We reviewed the data of 919 patients in whom complete resection of stage I NSCLC had been performed. RESULTS: Of the 919 patients, 170 (18.5%) had recurrent disease. Initial PRT was performed in 118 patients (69.1%) (surgery in eight, chemotherapy in 79, radiotherapy in 10, and chemoradiotherapy in 21). On multivariate analyses, PRT (hazard ratio [HR], 0.542; 95% CI, 0.344-0.853; P = .008), female sex (HR, 0.487; 95% CI, 0.297-0.801; P = .005), and differentiation (HR, 1.810; 95% CI, 1.194-2.743; P = .005) demonstrated a statistically significant association with favorable PRS. Bone metastasis (HR, 3.288; 95% CI, 1.783-6.062; P < .001), liver metastasis (HR, 4.518; 95% CI, 1.793-11.379; P = .001), chemotherapy (HR, 0.478; 95% CI, 0.236-0.975; P = .040), epidermal growth factor receptor-tyrosine kinase inhibitors treatment (EGFR-TKIs) (HR, 0.460; 95% CI, 0.245-0.862; P = .015), and nonadenocarcinoma (HR, 2.136; 95% CI, 1.273-3.585; P = .004) were independently and significantly associated with PRS in the 118 patients who underwent any PRT. Subgroup analysis with a combination of these five PRS factors in the patients who underwent any PRT revealed median PRS times of 42.4 months for 20 patients lacking all five risk factors and 18.8 months for 98 patients with at least one of these risk factors (P = .001). CONCLUSIONS: PRT, sex, and differentiation were independently associated with PRS. In the patients who underwent any PRT, PRS was related to EGFR-TKIs, chemotherapy, histology, and initial recurrence sites. One challenge for the future will be to create systematic treatment strategies for recurrent NSCLC according to the risk factor status of individual patients.

Epidermal growth factor receptor tyrosine kinase defines critical prognostic genes of stage I lung adenocarcinoma.

PURPOSE: To identify stage I lung adenocarcinoma patients with a poor prognosis who will benefit from adjuvant therapy. PATIENTS AND METHODS: Whole gene expression profiles were obtained at 19 time points over a 48-hour time course from human primary lung epithelial cells that were stimulated with epidermal growth factor (EGF) in the presence or absence of a clinically used EGF receptor tyrosine kinase (RTK)-specific inhibitor, gefitinib. The data were subjected to a mathematical simulation using the State Space Model (SSM). "Gefitinib-sensitive" genes, the expressional dynamics of which were altered by addition of gefitinib, were identified. A risk scoring model was constructed to classify high- or low-risk patients based on expression signatures of 139 gefitinib-sensitive genes in lung cancer using a training data set of 253 lung adenocarcinomas of North American cohort. The predictive ability of the risk scoring model was examined in independent cohorts of surgical specimens of lung cancer. RESULTS: The risk scoring model enabled the identification of high-risk stage IA and IB cases in another North American cohort for overall survival (OS) with a hazard ratio (HR) of 7.16 (P = 0.029) and 3.26 (P = 0.0072), respectively. It also enabled the identification of high-risk stage I cases without bronchioalveolar carcinoma (BAC) histology in a Japanese cohort for OS and recurrence-free survival (RFS) with HRs of 8.79 (P = 0.001) and 3.72 (P = 0.0049), respectively. CONCLUSION: The set of 139 gefitinib-sensitive genes includes many genes known to be involved in biological aspects of cancer phenotypes, but not known to be involved in EGF signaling. The present result strongly re-emphasizes that EGF signaling status in cancer cells underlies an aggressive phenotype of cancer cells, which is useful for the selection of early-stage lung adenocarcinoma patients with a poor prognosis. TRIAL REGISTRATION: The Gene Expression Omnibus (GEO) GSE31210.

Impact of visceral pleural invasion on the survival of patients with non-small cell lung cancer.

BACKGROUND: In this study, we investigated visceral pleural invasion (VPI) as a poor prognostic factor in patients with non-small cell lung cancer (NSCLC) according to the 7th edition of the TNM classification. METHODS: Between January 2000 and December 2007, 886 consecutive patients with pathological T1a-T2b NSCLC underwent complete resection with systematic lymph node dissection in Tokyo Medical University. We statistically analyzed the association between VPI and clinicopathologic factors, or clinical outcomes. RESULTS: The 5-year overall survival (OS) rates of the pl0, pl1, and pl2 patients were 80.8%, 63.7%, and 49.6%, respectively, with significant differences between pl0 and pl1 (p=0.002), pl1 and pl2 (p=0.03). Thus, the pl1 and pl2 patient groups were defined as patients with VPI. VPI was found to be a significant independent prognostic factor by multivariate survival analysis (p=0.0002). In patients with tumors ≤3 cm, especially with tumors ≤2 cm, VPI was significantly associated with an increased rate of lymph node metastasis, compared with non-VPI (p=0.0003 and p=0.015, respectively). Analysis of the OS of patients stratified by tumor size (≤3 cm, 3.1-5 cm, 5.1-7 cm) and VPI status showed that in any nodal status, patients with 3.1-5 cm/VPI tumors had significantly worse survival than patients with ≤3 cm/VPI tumors (p=0.019) and patients with 3.1-5 cm/non-VPI tumors (p=0.001). On the other hand, there was no significant difference in the OS between patients with 3.1-5 cm/VPI tumors and patients with 5.1-7 cm tumors regardless of lymph node metastasis (T2b tumors). Similar relationships were observed among these groups with N0 disease. CONCLUSION: We identified the presence of VPI as an independent poor prognostic factor in patients with NSCLC of ≤7 cm. Tumors 3.1-5cm with VPI should be upstaged to T2b tumors in the future in the TNM classification of the Union of International Cancer Control staging system. In addition, the surgical strategy involving more extensive lymph node dissection for patients with ≤3 cm/VPI tumors, especially ≤2 cm/VPI, is warranted owing to more frequent lymph node metastasis.

A case of paravertebral mediastinal chordoma without bone destruction.

We report a unique case of mediastinal paravertebral chordoma without bone destruction in a 47-year-old Japanese woman. She was admitted to hospital after a tumor was incidentally detected on a chest radiograph. The tumor was located in the paravertebral region of the mediastinum and did not show any destruction of the thoracic vertebra radiologically. The tumor was clinically diagnosed as a benign neurogenic tumor and the tumor was easily removed surgically. Microscopically, the tumor mainly consisted of tumor cells with extensively vacuolated cytoplasm, arranged in cord- and nest-like fashion against a myxoid matrix background. Immunohistochemically, the tumor cells showed diffuse positivity for pancytokeratin (AE1/AE3) and vimentin. The tumor cell nuclei were positive for brachyury, which is a key transcription factor of notochordal development. These results confirmed the tumor to be an extraosseous chordoma in the paravertebral mediastinal region, which is an extremely rare location for a chordoma.

Pathological vascular invasion and tumor differentiation predict cancer recurrence in stage IA non-small-cell lung cancer after complete surgical resection.

INTRODUCTION: The appropriate therapeutic strategy and postoperative management for patients with stage IA non-small-cell lung cancer (NSCLC) still remain a matter of debate because of the prognostic heterogeneity of this population, including the risk of cancer recurrence. The objective of the current study was to identify the clinicopathological factors that affect overall prognosis and cancer recurrence of stage IA NSCLC. METHODS: We reviewed the data of 532 patients in whom complete resection of stage IA NSCLC had been performed. Overall survival and recurrence-free proportion (RFP) were estimated using the Kaplan-Meier method. RFP was estimated from the date of the primary tumor resection to the date of the first recurrence or last follow-up. We performed univariate and multivariate analyses to determine the independent prognostic factors. RESULTS: On multivariate analyses, three variables were shown to be independently significant recurrence risk factors: histological differentiation (hazard ratio [HR] = 1.925), blood-vessel invasion (HR = 1.712), and lymph-vessel invasion (HR = 1.751). On subgroup analyses combining these risk factors, the 5-year RFP was 91.3% for patients with no risk factors, 79.5% for those with either poorly differentiated carcinoma or vascular invasion, (p < 0.001 for both), and 62.9% for those with both poorly differentiated carcinoma and vascular invasion (p = 0.068). CONCLUSION: These results indicated that vascular invasion and tumor differentiation have a significant impact on the prediction of cancer recurrence in patients with stage IA NSCLC. Patients with these predictive factors of recurrence may be good candidates for adjuvant chemotherapy.

Cancer Phenotype Diagnosis and Drug Efficacy within Japanese Health Care.

An overview on targeted personalized medicine is given describing the developments in Japan of lung cancer patients. These new targeted therapies with novel personalized medicine drugs require new implementations, in order to follow and monitor drug efficacy and outcome. Examples from IRESSA (Gefitinib) and TARCEVA (Erlotinib) treatments used in medication of lung cancer patients are presented. Lung cancer is one of the most common causes of cancer mortality in the world. The importance of both the quantification of disease progression, where diagnostic-related biomarkers are being implemented, in addition to the actual measurement of disease-specific mechanisms relating to pathway signalling activation of disease-progressive protein targets is summarised. An outline is also presented, describing changes and adaptations in Japan, meeting the rising costs and challenges. Today, urgent implementation of programs to address these needs has led to a rebuilding of the entire approach of medical evaluation and clinical care.

Local structural studies of the cubic Cd1-xCaxO system through Cd K-edge extended X-ray absorption spectroscopic studies.

Cd K-edge extended X-ray absorption fine-structure spectroscopic studies were carried out on Cd(1-x)Ca(x)O (0 ≤ x ≤0.9) solid solutions and the first and second nearest neighbour (NN) distances and their mean square relative displacement σ(2) were estimated. The first NN distance, d(Cd-O)(x), was found to be smaller than its expected value, a(x)/2, obtained from the X-ray diffraction measurements. It increases monotonically and non-linearly with a negative curvature, comparable with that of the a(x) value variation. The variation σ(2) of the 1NN with x is consistent with a disordered solid solution model. The 2NN distances d(Cd-Cd)(x) and d(Cd-Ca)(x) are found to follow the average values obtained by X-ray diffraction with d(Cd-Ca)(x) > d(Cd-Cd)(x). From detailed analysis it is argued that the solid solution exhibits a bimodal distribution of the 1NN distances, d(Cd-O)(x) and d(Ca-O)(x), and that the system belongs to a persistent type.

[A case of plasmacytoid urothelial carcinoma of the bladder: rapid progression after transurethral resection].

An 85-year-old man complained of macroscopic hematuria and painful urination. Cytoscopy revealed a non-papillary tumor at the bladder neck extending to the trigone. Abdominal computed tomography revealed thickening of the bladder wall in the same area but did not reveal lymph node swelling. Urinary cytology was class IIIb. We conducted a transurethral resection of the bladder tumor (TURBT) after which a histopathological examination showed urothelial carcinoma, G3, INFγ, pT2. From 6 days after TURBT, severe fever persisted despite the administration of various antibiotics and his general condition deteriorated. He died of acute myocardial infarction at 37 days after TURBT. Histopathological examination at autopsy revealed extensive urothelial carcinoma, a plasmacytoid variant, of the bladder which had invaded into the entire body including the lungs, liver, kidneys, adrenal glands, and veins, although tumor cells were not identified in lymph nodes. We review the literature and report this rare case of urothelial carcinoma, a plasmacytoid variant, of the bladder.

Do tumours located in the left lower lobe have worse outcomes in lymph node-positive non-small cell lung cancer than tumours in other lobes?

OBJECTIVES: Although an association between prognosis and lobar location of lung cancer, particularly the left lower lobe (LLL), has been suggested, the certainty of such association remains controversial. The purpose of this study was to evaluate the impact of tumour lobar location on surgical outcomes as an independent prognostic factor for survival in our non-small cell lung cancer (NSCLC) patient series. METHODS: We retrospectively reviewed 978 NSCLC patients who underwent complete resection in our hospital between 2000 and 2007. We statistically analysed the association between clinicopathological factors and clinical outcomes. RESULTS: Among the 978 patients reviewed, the NSCLC was located in the LLL in 143 (14.6%) patients, and lymph node involvement was identified in 210 patients (21.5%). The 5-year overall survival rates of patients whose NSCLC was located in the LLL and in other lobes (non-LLL) were 73.1 and 74.3%, respectively, and showed no significant association (P = 0.86). On the other hand, the 5-year survival rates of patients whose NSCLC occurred in the LLL (n = 33) and non-LLL (n = 177) and with lymph node metastasis were 32.7 and 57.7%, respectively, and showed a significant association (P = 0.01). Therefore, we performed a more detailed analysis on the 210 NSCLC patients with lymph node metastasis. On multivariate analysis, we found that LLL tumour (P = 0.02), tumour size >3 cm (P = 0.02) and N status (P < 0.001) were significant independent predictors for survival. CONCLUSIONS: LLL tumours with lymph node metastasis are strongly associated with mortality in NSCLC patients. The location of the primary tumour may contribute in determining the optimal management strategy and accurate prediction of prognosis.