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

Prognostic Impact of Number of Resected and Involved Lymph Nodes at Complete Resection on Survival in Non-small Cell Lung Cancer

BackgroundLymph node (LN) status is a major determinant of stage and survival in patients with lung cancer. In the 7th edition of the TNM Classification of Malignant Tumors, the number of involved LNs is included in the definition of pN factors in breast, stomach, esophageal, and colorectal cancer, and the pN status significantly correlates with prognosis.MethodsWe retrospectively investigated the prognostic impact of the number of resected LNs (RLNs) and involved LNs in the context of other established clinical prognostic factors, in a series of 928 consecutive patients with non-small cell lung cancer (NSCLC) who underwent complete resection at our institution between 2000 and 2007.ResultsThe mean number of RLNs was 15. There was a significant difference in the total number of RLNs categorized between less than 10 and ≥10 (p = 0.0129). Although the incidence of LN involvement was statistically associated with poor prognosis, the largest statistically significant increase in overall survival was observed between 0 to 3 and ≥4 involved LNs (hazard ratio = 7.680; 95% confidence interval = 5.051–11.655, p < 0.0001). On multivariate analysis, we used the ratio between the number of involved LNs and RLNs. The number of RLNs was found to be a strong independent prognostic factor for NSCLC (hazard ratio = 6.803; 95% confidence interval = 4.137–11.186, p < 0.0001).ConclusionComplete resection including 10 or more LNs influenced survival at complete NSCLC resection. Four involved LNs seemed to be a benchmark for NSCLC prognosis. The number of involved LNs is a strong independent prognostic factor in NSCLC, and the results of this study may provide new information for determining the N category in the next tumor, node, metastasis classification

Cancer cell immunity-related protein co-expression networks are associated with early-stage solid-predominant lung adenocarcinoma

BackgroundSolid-predominant lung adenocarcinoma (SPA), which is one of the high-risk subtypes with poor prognosis and unsatisfactory response to chemotherapy and targeted therapy in lung adenocarcinoma, remains molecular profile unclarified. Weighted correlation network analysis (WGCNA) was used for data mining, especially for studying biological networks based on pairwise correlations between variables. This study aimed to identify disease-related protein co-expression networks associated with early-stage SPA.MethodsWe assessed cancerous cells laser-microdissected from formalin-fixed paraffin-embedded (FFPE) tissues of a SPA group (n = 5), referencing a low-risk subtype, a lepidic predominant subtype group (LPA) (n = 4), and another high-risk subtype, micropapillary predominant subtype (MPA) group (n = 3) and performed mass spectrometry-based proteomic analysis. Disease-related co-expression networks associated with the SPA subtype were identified by WGCNA and their upstream regulators and causal networks were predicted by Ingenuity Pathway Analysis.ResultsAmong the forty WGCNA network modules identified, two network modules were found to be associated significantly with the SPA subtype. Canonical enriched pathways were highly associated with cellular growth, proliferation, and immune response. Upregulated HLA class I molecules HLA-G and HLA-B implicated high mutation burden and T cell activation in the SPA subtype. Upstream analysis implicated the involvement of highly activated oncogenic regulators, MYC, MLXIPL, MYCN, the redox master regulator NFE2L2, and the highly inhibited LARP1, leading to oncogenic IRES-dependent translation, and also regulators of the adaptive immune response, including highly activated IFNG, TCRD, CD3-TCR, CD8A, CD8B, CD3, CD80/CD86, and highly inhibited LILRB2. Interestingly, the immune checkpoint molecule HLA-G, which is the counterpart of LILRB2, was highly expressed characteristically in the SPA subtype and might be associated with antitumor immunity.ConclusionOur findings provide a disease molecular profile based on protein co-expression networks identified for the high-risk solid predominant adenocarcinoma, which will help develop future therapeutic strategies

Safety analysis of two different regimens of uracil–tegafur plus leucovorin as adjuvant chemotherapy for high-risk stage II and III colon cancer in a phase III trial comparing 6 with 18 months of treatment: JFMC33-0502 trial

PURPOSE: The JFMC33-0502 trial is a phase III clinical study designed to determine the most appropriate duration of postoperative adjuvant chemotherapy with uracil–tegafur (UFT) plus leucovorin in patients with stage IIB or III colon cancer. We report the interim results of preplanned safety analyses. METHODS: Patients with stage IIB or III colon cancer who had undergone curative resection were randomly assigned to receive UFT (300 mg/m(2)) plus leucovorin (75 mg/day) for 6 months (control group, 4 weeks of treatment followed by a 1-week rest, five courses) or for 18 months (study group, 5 days of treatment followed by a 2-day rest, 15 courses). Treatment status and safety were evaluated. RESULTS: A total of 1,071 patients were enrolled, and 1,063 were included in safety analyses. Treatment completion rate at 6 months was 74.0 % in the control group and 76.7 % in the study group. Treatment completion rate in the study group at 18 months was 56.0 %. The overall incidence of adverse events (AEs) was 75.3 % in the control group and 77.6 % in the study group. The incidences of grade 3 or higher AEs were low in both groups. During the first 6 months, the incidences of the subjective AEs were significantly lower in the study group. CONCLUSIONS: Oral UFT plus leucovorin given by either dosage schedule is a very safe regimen for adjuvant chemotherapy. In particular, 5 days of treatment followed by a 2-day rest was a useful treatment option from the viewpoint of toxicity even when given for longer than 6 months. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00280-014-2461-5) contains supplementary material, which is available to authorized users

ACPA-negative RA consists of two genetically distinct subsets based on RF positivity in Japanese.

HLA-DRB1, especially the shared epitope (SE), is strongly associated with rheumatoid arthritis (RA). However, recent studies have shown that SE is at most weakly associated with RA without anti-citrullinated peptide/protein antibody (ACPA). We have recently reported that ACPA-negative RA is associated with specific HLA-DRB1 alleles and diplotypes. Here, we attempted to detect genetically different subsets of ACPA-negative RA by classifying ACPA-negative RA patients into two groups based on their positivity for rheumatoid factor (RF). HLA-DRB1 genotyping data for totally 954 ACPA-negative RA patients and 2,008 healthy individuals in two independent sets were used. HLA-DRB1 allele and diplotype frequencies were compared among the ACPA-negative RF-positive RA patients, ACPA-negative RF-negative RA patients, and controls in each set. Combined results were also analyzed. A similar analysis was performed in 685 ACPA-positive RA patients classified according to their RF positivity. As a result, HLA-DRB1*04:05 and *09:01 showed strong associations with ACPA-negative RF-positive RA in the combined analysis (p = 8.8×10(-6) and 0.0011, OR: 1.57 (1.28-1.91) and 1.37 (1.13-1.65), respectively). We also found that HLA-DR14 and the HLA-DR8 homozygote were associated with ACPA-negative RF-negative RA (p = 0.00022 and 0.00013, OR: 1.52 (1.21-1.89) and 3.08 (1.68-5.64), respectively). These association tendencies were found in each set. On the contrary, we could not detect any significant differences between ACPA-positive RA subsets. As a conclusion, ACPA-negative RA includes two genetically distinct subsets according to RF positivity in Japan, which display different associations with HLA-DRB1. ACPA-negative RF-positive RA is strongly associated with HLA-DRB1*04:05 and *09:01. ACPA-negative RF-negative RA is associated with DR14 and the HLA-DR8 homozygote

Role of the Gulf Stream and Kuroshio–Oyashio systems in large-scale atmosphere–ocean interaction : a review

Author Posting. © American Meteorological Society, 2010. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Journal of Climate 23 (2010): 3249-3281, doi:10.1175/2010JCLI3343.1.Ocean–atmosphere interaction over the Northern Hemisphere western boundary current (WBC) regions (i.e., the Gulf Stream, Kuroshio, Oyashio, and their extensions) is reviewed with an emphasis on their role in basin-scale climate variability. SST anomalies exhibit considerable variance on interannual to decadal time scales in these regions. Low-frequency SST variability is primarily driven by basin-scale wind stress curl variability via the oceanic Rossby wave adjustment of the gyre-scale circulation that modulates the latitude and strength of the WBC-related oceanic fronts. Rectification of the variability by mesoscale eddies, reemergence of the anomalies from the preceding winter, and tropical remote forcing also play important roles in driving and maintaining the low-frequency variability in these regions. In the Gulf Stream region, interaction with the deep western boundary current also likely influences the low-frequency variability. Surface heat fluxes damp the low-frequency SST anomalies over the WBC regions; thus, heat fluxes originate with heat anomalies in the ocean and have the potential to drive the overlying atmospheric circulation. While recent observational studies demonstrate a local atmospheric boundary layer response to WBC changes, the latter’s influence on the large-scale atmospheric circulation is still unclear. Nevertheless, heat and moisture fluxes from the WBCs into the atmosphere influence the mean state of the atmospheric circulation, including anchoring the latitude of the storm tracks to the WBCs. Furthermore, many climate models suggest that the large-scale atmospheric response to SST anomalies driven by ocean dynamics in WBC regions can be important in generating decadal climate variability. As a step toward bridging climate model results and observations, the degree of realism of the WBC in current climate model simulations is assessed. Finally, outstanding issues concerning ocean–atmosphere interaction in WBC regions and its impact on climate variability are discussed.Funding for LT was provided by the NASA-sponsored Ocean Surface Topography Science Team, under Contract 1267196 with the University of Washington, administered by the Jet Propulsion Laboratory. HN was supported in part by the Grant-in-Aid 18204044 by the Japan Society for Promotion for Science (JSPS) and the Global Environment Research Fund (S-5) of the Japanese Ministry of Environment. YK was supported by the Kerr Endowed Fund and Penzance Endowed Fund

Factors affecting insulation failure in reusable surgical devices

Abstract The purpose of this study was to investigate the associated factors of insulation failure (IF) in reusable endoscopic instruments. The insulation coating of reusable endoscopic instruments underwent routine visual checks, hand washing to remove visible stains, and mechanized sterilization. We recorded the cleaning number and usage period of all instruments. The instruments were tested for IF using a detector. IF was found in eight of 69 devices (11.6%). Examining by clinical specialty, we found IF in 4 of 28 gastrointestinal (14.3%), 3 of 20 gynecological (15.0%), 1 of 12 urological (8.3%), and none of the nine thoracic devices. The median distance from the tip to the damaged part was 5 cm (3–5 cm). In the IF and the intact groups, the period of use [7 years (6–8) versus 7 years (4–8), P = 0.90] and the number of cleanings [281 (261–323) versus 261 (179–320), P = 0.27] were not significantly different. The IF group included products of three different companies; however, six of the eight (75.0%) were from the same company. Cleaning methods and usage period have a lower impact on IF. The use of reusable forceps as a monopolar device was found to pose a higher risk, requiring regular assessments

Current status of clinical proteogenomics in lung cancer

Introduction: Lung cancer is the leading cause of cancer death worldwide. Proteogenomics, a way to integrate genomics, transcriptomics, and proteomics, have emerged as a way to understand molecular causes in cancer tumorigenesis. This understanding will help identify therapeutic targets that are urgently needed to improve individual patient outcomes. Areas covered: To explore underlying molecular mechanisms of lung cancer subtypes, several efforts have used proteogenomic approaches that integrate next generation sequencing (NGS) and mass spectrometry (MS)-based technologies. Expert opinion: A large-scale, MS-based, proteomic analysis, together with both NGS-based genomic data and clinicopathological information, will facilitate establishing extensive databases for lung cancer subtypes that can be used for further proteogenomic analyzes. Proteogenomic strategies will further be understanding of how major driver mutations affect downstream molecular networks, resulting in lung cancer progression and malignancy, and how therapy-resistant cancers resistant are molecularly structured. These strategies require advanced bioinformatics based on a dynamic theory of network systems, rather than statistics, to accurately identify mutant proteins and their affected key networks

Randomized phase II trial of first-line treatment with tailored irinotecan and S-1 therapy versus S-1 monotherapy for advanced or recurrent gastric carcinoma (JFMC31-0301)

Objective: The pharmacokinetics of irinotecan vary markedly between individuals. This study sought to compare tailored irinotecan and S-1 therapy with S-1 monotherapy for the treatment of patients with advanced/recurrent gastric cancer. Methods: Patients with advanced/recurrent gastric cancer were randomized to receive tailored irinotecan and S-1 (arm A) or S-1 alone (arm B). Arm A received S-1 (80-120 mg/m2/day) for 14 days, with irinotecan on days 1 and 15. The initial irinotecan dose of 75 mg/m2 (level 0) was adjusted for toxicity during the previous course. In arm B, S-1 (80-120 mg/day) was administered alone for 28 days, followed by 14 days without therapy. Results: Ninety-five patients were randomized (48 to arm A and 47 to arm B). The response rate of the primary tumor (Japanese criteria) was 25.0% in arm A (12/48) and 14.9% in arm B (7/47), whereas the response rates according to Response Evaluation Criteria In Solid Tumors (RECIST) were 27.8% (10/36) versus 21.9% (7/32). Hematological toxicity, anorexia, and diarrhea were significantly more common in arm A, but both arms had similar grade 3-4 toxicities. Conclusion: These findings suggest the usefulness of tailored irinotecan plus S-1 therapy for gastric cancer