EP3 (prostaglandin E2 receptor 3) expression is a prognostic factor for progression-free and overall survival in sporadic breast cancer

Background: In various cancers, overexpression of cyclooxygenase (COX)-2 and elevated prostaglandin (PG) E2 synthesis have been associated with tumor development and progression. The potential of COX-2 inhibitors in cancer prevention and treatment has been shown repeatedly;however, their clinical use is limited due to toxicity. PGE2 signals via EP receptors 1-4, whose functions are analyzed in current research in search for targeted anti-PG therapies. EP2 and EP4 rather promote tumorigenesis, while the role of EP3, especially in breast cancer, is not yet clear and both pro-and anti-tumorigenic effects have been described. Our study evaluates EP3 receptor expression in sporadic breast cancer and its association with clinicopathological parameters, progression-free and overall survival. Methods: Two hundred eighty-nine sporadic breast cancer samples without primary distant metastasis were immunohistochemically analyzed for EP3 receptor expression. Tissue was stained with primary anti-EP3-antibodies. Immunoreactivity was quantified by the immunoreactivity-score (IRS);samples with an IRS >= 2 scored as EP3 positive. Chi-squared and Mann-Whitney-U test were used for comparison of data;Kaplan-Meier estimates and Cox-regression were used for survival analyses. Results: EP3 receptor was expressed in 205 of 289 samples analyzed (70.9%). EP3 receptor expression was not associated with clinicopathological parameters (e. g. tumor size, hormone receptors, lymph node status). Kaplan-Meier estimates showed a significant association of EP3 positivity with improved progression-free survival (p = 0.002) and improved overall survival (p = 0.001) after up to 10 years. Cox regression analysis confirmed EP3 positivity as a significant prognostic factor even when other known prognosticators were accounted for. Conclusions: In sporadic breast cancer, EP3 receptor expression is not significantly associated with clinicopathological parameters but is a significant prognostic factor for improved progression-free and overall survival. However, the functional aspects of EP3 receptor in breast cancer and the way how EP3 may oppose the pro-tumorigenic effects of PGE2 elevation and COX-2 overexpression are not fully understood so far. Further studies aiming at identification of the factors regulated by EP3 are necessary to evaluate the possibility of targeting EP3 in future anti-tumor therapy in breast cancer

Additional file 1: of EP3 (prostaglandin E2 receptor 3) expression is a prognostic factor for progression-free and overall survival in sporadic breast cancer

Figure S1. Metastasis and local recurrence in sporadic breast cancer. 10-years Kaplan-Meier-estimates of cumulative metastasis (A) and cumulative local recurrence (B) of EP3 positive and negative patient groups are displayed. Estimated metastasis and local recurrence rates are displayed at the end of each graph, p-values in the upper left corner. EP3 positivity was significantly associated with reduced metastasis (A) and local recurrence (B). Note that in the rates of metastasis and local recurrence named there, all cases of metastasis/local recurrence are considered, regardless if they were the primary cause of progression or happened later in the course of disease; therefore, the sum of both rates here is higher than the progression rate named in Fig. 2. yrs. = years. (PDF 437 kb

Additional file 2: of EP3 (prostaglandin E2 receptor 3) expression is a prognostic factor for progression-free and overall survival in sporadic breast cancer

Figure S2. Schoenfeld residuals for EP3. To test for PH assumption, Schoenfeld residual test was performed for EP3 for OS and PFS. Schoenfeld residuals for EP3 are displayed (left: OS, right: PFS). There is no violation of PH assumption, as the ratio of both curves is stable over the time. (PDF 20 kb

The role of semantic processing in reading Japanese orthographies : an investigation using a script-switch paradigm

Research on Japanese reading has generally indicated that processing of the logographic script Kanji primarily involves whole-word lexical processing and follows a semantics-to-phonology route, while the two phonological scripts Hiragana and Katakana (collectively called Kana) are processed via a sub-lexical route, and more in a phonology-to-semantics manner. Therefore, switching between the two scripts often involves switching between two reading processes, which results in a delayed response for the second script (a script switch cost). In the present study, participants responded to pairs of words that were written either in the same orthography (within-script), or in two different Japanese orthographies (cross-script), switching either between Kanji and Hiragana, or between Katakana and Hiragana. They were asked to read the words aloud (Experiments 1 and 3) and to make a semantic decision about them (Experiments 2 and 4). In contrast to initial predictions, a clear switch cost was observed when participants switched between the two Kana scripts, while script switch costs were less consistent when participants switched between Kanji and Hiragana. This indicates that there are distinct processes involved in reading of the two types of Kana, where Hiragana reading appears to bear some similarities to Kanji processing. This suggests that the role of semantic processing in Hiragana (but not Katakana) reading is more prominent than previously thought and thus, Hiragana is not likely to be processed strictly phonologically. First Online: 08 November 2017</p

L1CAM in Early-Stage Type I Endometrial Cancer: Results of a Large Multicenter Evaluation

Contains fulltext : 124525.pdf (publisher's version ) (Closed access)BACKGROUND: Despite the excellent prognosis of Federation Internationale de Gynecologie et d'Obstetrique (FIGO) stage I, type I endometrial cancers, a substantial number of patients experience recurrence and die from this disease. We analyzed the value of immunohistochemical L1CAM determination to predict clinical outcome. METHODS: We conducted a retrospective multicenter cohort study to determine expression of L1CAM by immunohistochemistry in 1021 endometrial cancer specimens. The Kaplan-Meier method and Cox proportional hazard model were applied for survival and multivariable analyses. A machine-learning approach was used to validate variables for predicting recurrence and death. RESULTS: Of 1021 included cancers, 17.7% were rated L1CAM-positive. Of these L1CAM-positive cancers, 51.4% recurred during follow-up compared with 2.9% L1CAM-negative cancers. Patients bearing L1CAM-positive cancers had poorer disease-free and overall survival (two-sided Log-rank P < .001). Multivariable analyses revealed an increase in the likelihood of recurrence (hazard ratio [HR] = 16.33; 95% confidence interval [CI] = 10.55 to 25.28) and death (HR = 15.01; 95% CI = 9.28 to 24.26). In the L1CAM-negative cancers FIGO stage I subdivision, grading and risk assessment were irrelevant for predicting disease-free and overall survival. The prognostic relevance of these parameters was related strictly to L1CAM positivity. A classification and regression decision tree (CRT)identified L1CAM as the best variable for predicting recurrence (sensitivity = 0.74; specificity = 0.91) and death (sensitivity = 0.77; specificity = 0.89). CONCLUSIONS: To our knowledge, L1CAM has been shown to be the best-ever published prognostic factor in FIGO stage I, type I endometrial cancers and shows clear superiority over the standardly used multifactor risk score. L1CAM expression in type I cancers indicates the need for adjuvant treatment. This adhesion molecule might serve as a treatment target for the fully humanized anti-L1CAM antibody currently under development for clinical use