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Lung adenocarcinoma (LAC) is the most prevalent form of lung cancer. Epithelial cell transforming sequence 2 (ECT2) is a guanine nucleotide exchange factor that has been implicated in oncogenic and malignant phenotypes of LAC. Here, we identified an oncogenic role of ECT2 in the extracellular matrix (ECM) dynamics of LAC cells. We showed that suppression of ECT2 decreased adhesion and spreading of LAC cells on ECM components. Morphologically, ECT2‐depleted cells exhibited a rounded shape and cytoskeletal changes. Examination of transcriptional changes by RNA sequencing revealed a total of 1569 and 828 genes whose expressions were altered (absolute fold change and a difference of >2 fold) in response to suppression of ECT2 in two LAC cells (Calu‐3 and NCI‐H2342), respectively, along with 298 genes that were common to both cell lines. Functional enrichment analysis of common genes demonstrated a significant enrichment of focal adhesions. In accord with this observation, we found that ECT2 suppression decreased the expression level of proteins involved in focal adhesion signaling including focal adhesion kinase (FAK), Crk, integrin β1, paxillin, and p130Cas. FAK knockdown leads to impaired cell proliferation, adhesion, and spreading of LAC cells. Moreover, in LAC cells, ECT2 binds to and stabilizes FAK and is associated with the formation of the focal adhesions. Our findings provide new insights into the underlying role of ECT2 in cell‐ECM dynamics during LAC progression and suggest that ECT2 could be a promising therapeutic avenue for lung cancer. In this study, we demonstrated that epithelial cell transforming sequence 2 (ECT2) is an essential mediator of cell‐extracellular matrix (ECM) dynamics in the malignant progression of lung adenocarcinoma. We found that suppression of ECT2 decreased adhesion and spreading of lung adenocarcinoma cells on the ECM and demonstrated that ECT2 has a regulatory role in focal adhesion signaling, being associated with the focal adhesion formation that contains both focal adhesion kinase (FAK) and ECT2.

Dietary factors may affect the prognosis of digestive tract cancer, but evidence has been sparse. We investigated the association between pretreatment intake of 6 Japanese foods (including soy food, miso [soybean paste] soup and seaweed) and the risk of death among patients with histologically confirmed major digestive tract cancers (stomach, 1931; colon, 793; rectum, 510) diagnosed during 1997‐2013 at a single institution in Japan. Pretreatment dietary intake was assessed using a food frequency questionnaire, and the patients were followed until December 2016. The Cox proportional hazards model was used to estimate hazard ratios (HR) and 95% confidence intervals (CI). Among the patients with stomach cancer, frequent intake of soy food was inversely associated with the risk of all‐cause (Ptrend for four frequency groups = 0.01; HR = 0.72, 95% CI: 0.50‐1.04 for highest vs lowest group) and stomach cancer (Ptrend = 0.03; HR = 0.63, 95% CI: 0.40‐0.99) death. A similar inverse association was also found for intake of miso soup. In contrast, frequent seaweed intake was inversely associated with the risk of all‐cause death among the patients with colon cancer (Ptrend = 0.03). Rectal cancer patients who had frequently consumed seaweed tended to have a lower risk of rectal cancer death (Ptrend = 0.02). These findings indicate that pretreatment intake of Japanese foods such as soybean products and seaweed may have favorable effects on patient survival of stomach and colorectal cancer, although this needs to be confirmed by further research. The aim of this patient cohort study is to clarify the relationship between intake of selected traditional Japanese foods and survival after diagnosis of stomach and colorectal cancer. The results indicate that intake of Japanese foods such as soybean products and seaweed may have a favorable effect on patient survival of stomach and colorectal cancer.

It has been postulated that being breastfed in infancy affects not only health status in childhood but also disease risk in adulthood. To investigate the association of being breastfed with the risks of adult colorectal cancer and benign tumor, we conducted a case–control study including 1190 colorectal cancer and 1585 benign tumor cases and 5301 controls, admitted to a single hospital in Miyagi Prefecture, Japan, between 1997 and 2013. History of having been breastfed was assessed using a self-administered questionnaire, and odds ratios (ORs) were estimated using unconditional logistic regression. There was no association between being breastfed and colorectal cancer risk (breastfed versus formula-only fed, OR = 1.21; 95% CI 0.87–1.67). There was also no association with the risk of benign tumor (OR = 1.04). On the other hand, analyses stratified by sex and birth year found heterogeneous associations. Women born after 1950 who had been breastfed tended to have increased risks of colorectal cancer (OR = 1.58) and benign tumor (OR = 1.51) relative to those who had been formula-only fed, although not statistically significant. In men born after 1950, being breastfed was associated with a significantly decreased risk of benign tumor (OR = 0.57; 95% CI 0.33–0.98).

Histological subtyping of pulmonary adenocarcinoma has recently been updated based on predominant pattern, but data on reproducibility are required for validation. This study first assesses reproducibility in subtyping adenocarcinomas and then assesses further the distinction between invasive and non-invasive (wholly lepidic) pattern of adenocarcinoma, among an international group of pulmonary pathologists. Two ring studies were performed using a micro-photographic image-based method, evaluating selected images of lung adenocarcinoma histologic patterns. In the first study, 26 pathologists reviewed representative images of typical and ‘difficult’ histologic patterns. A total number of scores for the typical patterns combined (n=94) and the difficult cases (n=21) were 2444 and 546, respectively. The mean kappa score (±s.d.) for the five typical patterns combined and for difficult cases were 0.77±0.07 and 0.38±0.14, respectively. Although 70% of the observers identified 12–65% of typical images as single pattern, highest for solid and least for micropapillary, recognizing the predominant pattern was achieved in 92–100%, of the images except for micropapillary pattern (62%). For the second study on invasion, identified as a key problem area from the first study, 28 pathologists submitted and reviewed 64 images representing typical as well as ‘difficult’ examples. The kappa for typical and difficult cases was 0.55±0.06 and 0.08±0.02, respectively, with consistent subdivision by the same pathologists into invasive and non-invasive categories, due to differing interpretation of terminology defining invasion. In pulmonary adenocarcinomas with classic morphology, which comprise the majority of cases, there is good reproducibility in identifying a predominant pattern and fair reproducibility distinguishing invasive from in-situ (wholly lepidic) patterns. However, more precise definitions and better education on interpretation of existing terminology are required to improve recognition of purely in-situ disease, this being an area of increasing importance.

It is unclear whether alcohol consumption may impact survival after breast cancer diagnosis. To clarify the association between pretreatment alcohol consumption and survival in breast cancer patients, a prospective patient cohort study was conducted. The cohort comprised 1,420 breast cancer patients diagnosed during 1997-2013 at a single institute in Japan. Alcohol drinking and other lifestyle factors were assessed by questionnaire survey at the initial admission. The patients were followed until December 31, 2016. The crude associations of pretreatment alcohol intake with survival were evaluated by Kaplan-Meier analysis. The Cox proportional hazards model was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) controlled by confounders. During a median follow-up period of 8.6 years, 261 all-cause and 193 breast cancer-specific deaths were documented. Survival curves showed that ever-drinkers tended to have better survival than never-drinkers (breast cancer-specific survival, log-rank p = 0.0381). Better survival was also observed for light drinkers with an intake of <5.0 g per day. In the Cox model, ever-drinking was associated with a decreased risk of all-cause (HR: 0.75; 95% CI: 0.54-1.05) and breast cancer-specific death (HR: 0.68; 95% CI: 0.46-0.99). Light drinkers had a lower risk of breast cancer-specific death (frequency of drinking, HR = 0.57 for occasional or 1-2 times per week and 0.72 for 3-7 times per week; amount of alcohol consumed per day, HR = 0.57 for <5.0 g and 0.68 for ≥5.0 g compared with never-drinking). In terms of hormone receptor status, a significantly decreased risk of death associated with ever-drinking was observed among women with receptor-negative cancer (ER-/PR-, HR = 0.41; 95% CI: 0.20-0.84 for breast cancer-specific death). Pretreatment, i.e., pre-diagnosis alcohol consumption is unlikely to have an adverse effect on survival after breast cancer diagnosis. Light alcohol consumption may have a beneficial effect on patient survival.

Genetic abnormality in early‐stage lung adenocarcinoma was examined to search for new prognostic biomarkers. Six in situ lung adenocarcinomas and nine small but invasive adenocarcinomas were examined by array‐comparative genomic hybridization, and candidate genes of interest were screened. To examine gene abnormalities, 83 cases of various types of lung carcinoma were examined by quantitative real‐time genomic PCR and immunohistochemistry. The results were then verified using another set of early‐stage adenocarcinomas. Array‐comparative genomic hybridization indicated frequent amplification at chromosome 3q26. Of the seven genes located in this region, we focused on the epithelial cell transforming sequence 2 (ECT2) oncogene, as ECT2 amplification was detected only in invasive adenocarcinoma, and not in in situ carcinoma. Quantitative PCR and immunohistochemistry analyses also detected overexpression of ECT2 in invasive adenocarcinoma, and this was correlated with both the Ki‐67 labeling index and mitotic index. In addition, it was associated with disease‐free survival and overall survival of patients with lung adenocarcinoma. These results were verified using another set of early‐stage adenocarcinomas resected at another hospital. Abnormality of the ECT2 gene occurs at a relatively early stage of lung adenocarcinogenesis and would be applicable as a new biomarker for prognostication of patients with lung adenocarcinoma. Abnormality of the ECT2 gene occurs at a relatively early stage of lung adenocarcinogenesis and would be applicable as a new biomarker for prognostication of patients with lung adenocarcinoma.

Epithelial cell transforming sequence 2 (ECT2), a guanine nucleotide exchange factor, is predominantly localized in the nucleus of non-transformed cells and functions to regulate cytokinesis. ECT2 is also localized in the cytoplasm of cancer cells. Aberrant cytoplasmic expression of ECT2 is thought to drive tumor growth and invasion. In this study, we investigated the cytoplasmic expression of ECT2 and its prognostic and biological significance in lung adenocarcinoma. Western blotting of cellular fractions from the nucleus and cytoplasm was performed to determine the subcellular localization of ECT2 in lung adenocarcinoma cell lines. The cytoplasmic expression of ECT2 in 167 lung adenocarcinomas was evaluated by immunohistochemistry and its clinical significance was examined using Kaplan–Meier curves and Cox regression analysis. Scraping cytology specimens of 13 fresh lung adenocarcinomas were used to assess the subcellular localization of ECT2 and its phosphorylation at Thr790 (P-ECT2(T790)). We found that ECT2 was localized in both the nucleus and cytoplasm of lung adenocarcinoma cell lines and tumor tissues. Cytoplasmic expression of ECT2 was detected by immunohistochemistry in 83 (50%) of the lung adenocarcinomas, and was found to increase during cancer progression. It was expressed in 30 (29%) small adenocarcinomas ( ≤ 2 cm in diameter) and 53 (82%) advanced adenocarcinomas ( > 2 cm in diameter). Cytoplasmic positivity for ECT2 was associated with a poor outcome in terms of both disease-free and overall survival (both P < 0.001), and was an independent prognostic factor for overall survival (P = 0.025). Immunocytochemical staining for P-ECT2(T790) demonstrated cytoplasmic and membrane positivity in Calu-3 cells and scraping cytology specimens. Positive P-ECT2(T790) staining was correlated with cytoplasmic ECT2 expression in 6 of 13 scraped cytology specimens tested. In conclusion, our findings indicate that cytoplasmic ECT2 expression could promote the malignant progression of lung adenocarcinoma and may represent a potent therapeutic target for patients with lung adenocarcinoma.

Background Body mass index (BMI) may be an important factor affecting breast cancer outcome. Studies conducted mainly in Western countries have reported a relationship between higher BMI and a higher risk of all-cause death or breast cancer-specific death among women with breast cancer, but only a few studies have been reported in Japan so far. In the present prospective study, we investigated the associations between BMI and the risk of all-cause and breast cancer-specific death among breast cancer patients overall and by menopausal status and hormone receptor status. Methods The study included 653 breast cancer patients admitted to a single hospital in Japan, between 1997 and 2005. BMI was assessed using a self-administered questionnaire. The patients were completely followed up until December, 2008. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated according to quartile points of BMI categories, respectively: <21.2, ≥21.2 to <23.3 (reference), ≥23.3 to <25.8 and ≥25.8 kg/m 2 . Results During the follow-up period, 136 all-cause and 108 breast cancer-specific deaths were observed. After adjustment for clinical and confounding factors, higher BMI was associated with an increased risk of all-cause death (HR = 2.61; 95% CI: 1.01–6.78 for BMI ≥25.8 vs. ≥21.2 to <23.3 kg/m 2 ) among premenopausal patients. According to hormonal receptor status, BMI ≥25.8 kg/m 2 was associated with breast cancer-specific death (HR = 4.95; 95% CI: 1.05–23.35) and BMI <21.2 kg/m 2 was associated with all-cause (HR = 2.91; 95% CI: 1.09–7.77) and breast cancer-specific death (HR = 7.23; 95% CI: 1.57–33.34) among patients with ER + or PgR + tumors. Analysis by hormonal receptor status also showed a positive association between BMI and mortality risk among patients with ER + or PgR + tumors and with BMI ≥21.2 kg/m 2 (p for trend: 0.020 and 0.031 for all-cause and breast cancer-specific death, respectively). Conclusions Our results suggest that both higher BMI and lower BMI are associated with an increased risk of mortality, especially among premenopausal patients or among patients with hormonal receptor positive tumors. Breast cancer patients should be informed of the potential importance of maintaining an appropriate body weight after they have been diagnosed.

Although cigarette smoking is a well‐known risk factor for lung cancer, histology‐specific risk has not been fully clarified in Japan. This case‐control study evaluated the associations between smoking and lung cancer risk according to sex and histologic type. From among patients aged 30 years and over admitted to a single hospital in Japan between 1997 and 2009, 1670 lung cancer cases and 5855 controls were selected. History of smoking, quantity and duration of smoking, and passive smoking from spouses were assessed using a self‐administered questionnaire. Odds ratios (ORs) and 95% confidence intervals (CIs) for each exposure were estimated by unconditional logistic regression. Ever‐smoking was significantly associated with a higher risk of squamous cell and small cell carcinoma. The OR for these two histologic types combined was larger in women (OR = 24.98, 95% CI: 13.50–46.23) than in men (OR = 9.43, 95% CI: 5.73–15.51). Analysis of the quantity and duration of smoking showed that the OR for each exposure level tended to be larger in women than in men. For adenocarcinoma, clear positive associations with quantity and duration‐related factors were observed among men, and a significant positive association with passive smoking from spouses was found among non‐smoking women (OR = 1.44, 95% CI: 1.06–1.95). These results suggest sex‐ and histologic type‐ differences in the association of smoking with lung cancer risk. Although smoking control should be continued to prevent lung cancers, further studies are required to better clarify differences in smoking‐related lung cancer risk between the sexes and histologic types.

The results of previous studies investigating whether there is an association between active smoking and risk of death among breast cancer patients have been inconsistent. We investigated the association between active and passive smoking and risk of all‐cause and breast cancer‐specific death among female breast cancer patients in relation to menopausal and tumor estrogen/progesterone receptor (ER/PR) status. The present study included 848 patients admitted to a single hospital in Japan from 1997 to 2007. Active or passive smoking status was assessed using a self‐administered questionnaire. The patients were followed until 31 December 2010. We used a Cox proportional‐hazard model to estimate hazard ratios (HR). During a median follow‐up period of 6.7 years, 170 all‐cause and 132 breast cancer‐specific deaths were observed. Among premenopausal patients, current smokers showed a non‐significant higher risk of all‐cause and breast cancer‐specific death. A duration of smoking >21.5 years was positively associated with all‐cause (HR = 3.09, 95% confidence interval [CI], 1.17–8.20) and breast cancer‐specific death (HR = 3.35, 95% CI: 1.22–9.23, Ptrend = 0.035) among premenopausal patients. In premenopausal patients with ER+ or PR+ tumors, there was some suggestion that a longer duration of smoking was associated with higher risk of all‐cause and breast cancer‐specific death. Passive smoking demonstrated no significant risk. Our results suggest that a longer duration of active smoking is associated with an increased risk of all‐cause and breast cancer‐specific death among premenopausal patients, possibly with hormonal receptor‐positive tumors. Breast cancer patients should be informed about the importance of smoking cessation. Our results suggest that a longer duration of active smoking is associated with an increased risk of all‐cause and breast cancer‐specific death among premenopausal patients, possibly with hormonal receptor‐positive tumors. Breast cancer patients should be informed about the importance of smoking cessation.