Stromal micropapillary pattern predominant lung adenocarcinoma - a report of two cases

Generally, adenocarcinomas with micropapillary pattern, featuring small papillary tufts lacking a central fibrovascular core, are thought to have poor prognosis. This pattern has been described in various organs. However, tumor cells with micropapillary pattern of lung adenocarcinoma are more often seen to float within alveolar spaces (aerogenous micropapillary pattern, AMP) than in fibrotic stroma like other organs (stromal micropapillary pattern, SMP) and SMP predominant lung adenocarcinoma (SMPPLA) has not been well described yet. We presented two cases of SMPPLA which were found in the last four years. Both the cases showed more than 50% of SMP in the tumor area. The majority of the stromal micropapillary clusters expressed MUC1 and epithelial membrane antigen along the outer surface of cell membrane. On the other hand, connective tissues surrounding stromal micropapillary clusters showed no reactivity for epithelial markers (thyroid transcription factor-1 and cytokeratin) or endothelial marker (D2-40 and CD34). It means clusters of SMP do not exist within air space or lymphatic or vessel lumens. The tumors with SMP often presented lymphatic permeation and vessel invasion, and intriguingly, one of the two cases showed metastasis to the mediastinal lymph node. Additionally, both the cases showed EGFR point mutations of exon 21. These results suggest that SMPPLA might be associated with poor prognosis and effective for EGFR tyrosine kinase inhibitors

Multicentre randomised phase II study of the perioperative administration of flurbiprofen axetil in patients with non-small cell lung cancer: study protocol of the FLAX Study

Introduction In patients with non-small cell lung cancer, surgical treatment with postoperative adjuvant chemotherapy is performed. However, the improvement of overall survival achieved by postoperative adjuvant chemotherapy may be insufficient in consideration of the deterioration of quality of life (QOL). Considering the relationships among surgical treatments, inflammation and carcinogenesis, non-steroidal anti-inflammatory drugs (NSAIDs) are a candidate postoperative treatment for preventing recurrence and maintaining QOL. In this study, we investigate the effects of the perioperative administration of flurbiprofen axetil on postoperative recurrence in patients with non-small cell lung cancer.Methods and analysis This study is a multicentre, parallel group, open label, randomised controlled trial. Patients clinically suspected of non-small cell lung cancer are randomly assigned to the flurbiprofen axetil group or the no-NSAIDs group. A total of 420 patients (210 per group) will be registered. The primary analysis will evaluate the treatment effect of flurbiprofen axetil on postoperative recurrence.Ethics and dissemination The study protocol was approved by the Clinical Research Review Board of Saitama Medical University in September 2019 (No. 192002) and will be approved by each institutional review board of all participating institutions before patient enrolment. This study complies with the latest version of the Declaration of Helsinki, Clinical Trial Act and related notifications. Results will be published in a peer-reviewed journal.Trial registration number Japan Registry of Clinical Trials (jRCTs031190167; Pre-results) (https://jrct.niph.go.jp/)

Up-Regulation of S100A11 in Lung Adenocarcinoma - Its Potential Relationship with Cancer Progression.

We previously reported that patients with lung adenocarcinomas with KRAS gene mutations and strong proliferating activity had poorer outcomes, even in the early stage of the disease. The aim of the present study was to elucidate the potential molecular basis of these highly malignant lung tumors by focusing on S100 proteins (S100A2, S100A7, and S100A11), which are downstream targets of oncogenic KRAS and promoters of tumor progression. The immunohistochemical expression of S100 proteins was examined in 179 primary lung adenocarcinomas, and the potential relationships between their levels and clinicopathologic factors were analyzed. Among the three subtypes, S100A11 levels were significantly higher in adenocarcinomas with KRAS mutations and strong proliferating activity. They were also higher in adenocarcinomas with poorly differentiated tumors. Furthermore, higher levels of S100A11 were associated with shorter disease-free survival. These results suggest that the up-regulation of S100A11 plays a role in tumor progression, particularly in KRAS-mutated lung adenocarcinomas

S100A11 expression levels in adenocarcinomas with KRAS mutations and proliferating activity.

<p>The thickened lines indicate the median score of S100 A11 expression, which was 1.00 in KRAS Wild-type/Ki-67 Low cases (n = 94), 1.50 in KRAS Wild-type/Ki-67 High cases (n = 62), 1.20 in KRAS Mutated-type/Ki-67 Low cases (n = 11) and 1.80 in KRAS Mutated-type/Ki-67 High cases (n = 11). S100A11 expression levels were significantly higher in adenocarcinomas with KRAS mutations and strong proliferating activity (P = 0.038 in the Kruskal-Wallis test). Wt, Wild-type; Mt, Mutated-type.</p

Relationship between S100A11 expression and clinicopathologic characteristics of stage I lung adenocarcinomas.

<p>No., number of cases; WEL, well differentiated; MOD, moderately differentiated; POR, poorly differentiated carcinomas; AIS, adenocarcinoma in situ; MIA, minimally invasive adenocarcinoma; LEP, lepidic predominant; ACN, acinar predominant; PAP, papillary predominant, SOL, solid predominant; MUC, invasive mucinous adenocarcinoma.</p><p>Histologic subtypes were classified according to the 2011 IASLC/ ATS/ETS classification of lung adenocarcinoma.</p><p>P, significant level for Mann-Whitney or Kruskal-Wallis test.</p><p>Relationship between S100A11 expression and clinicopathologic characteristics of stage I lung adenocarcinomas.</p

Downstream targets up-regulated by oncogenic KRAS with proteomic analysis.

<p>Accession, gene bank accession number; Map, chromosome locus; MOCK, mock-transduced NHBE-T; G12, wild-type KRAS-transduced NHEB-T; V12, oncogenic mutant KRAS-transduced NHBE-T.</p><p>Proteins whose signal intensities were more than 2-fold higher in KRAS/V12 cells than in mock- and/or KRAS/G12 cells are extracted from our date of a comprehensive proteomic analysis previously described [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0142642#pone.0142642.ref008" target="_blank">8</a>]. The proteins sorted are listed in this table.</p><p>Downstream targets up-regulated by oncogenic KRAS with proteomic analysis.</p

Immunohistochemical examination of S100A11 and S100A2 protein expression levels in tumors and non-tumorous epithelia from lung adenocarcinoma (ADC) patients undergoing surgical resection.

<p>Representative photographs from normal bronchioles (A, E) and tumors, in which the expression of S100A11 and S100A2 was negative (B, F), weak (C, G) and strong (D, H), are shown.</p