The purpose of this retrospective study was to examine the prognostic value of expression of luminal epithelial antigen (LEA.135) for recurrence and overall survival of patients with primary invasive breast carcinoma by both univariate and multivariate analyses. The possible prognostic value of LEA.135 was also compared with some widely utilized prognostic biomarkers such as c-erbB 2, topoisomerase II.alpha (TPII.alpha), MIB 1, estrogen receptor (ER) and progesterone receptor (PR), as well as age of the patients and clinicopathologic parameters. The study was carried out by immunohistochemical methods on formalin-fixed/paraffin-embedded tissue sections in a series of 225 patients with median follow-up of 8.5 years. Prognostic significance of the biomarkers was determined by two-sided p value. In this series of patients, among the age and clinicopathologic parameters, only age, was significantly associated with a decreased overall survival (logrank p = 0.027). Among the prognostic biomarkers, TPII a expression at high (> 50% positive cells) or moderate (6-50% positive cells) level was associated with an increased rate of recurrence (logrank p < 0.001). However, the association of TPII.alpha expression with a decreased overall survival failed to reach a statistically significance. Expression of c-erbB 2 showed a trend of being associated with an increased probability of recurrence, but the association did not reach statistical significance. The remaining biomarkers were not associated with either the probability of recurrence or overall survival. LEA.135 expression was observed in 163 (72.4%) of the 225 patients. The patients with high (> 50% positive cells) or moderate (6-50% positive cells) level of LEA.135-positive cancer cells showed a significantly decreased probability of recurrence (logrank p < 0.001) and an increased overall survival (logrank p < 0.001) compared with those with LEA.135-negative cancer cells. The association remained significant by multivariate analysis for recurrence (likelihood ratio test p < 0.001) and overall survival (likelihood ratio test p < 0.001) when assessed with other prognostic parameters. Furthermore, the combination of LEA.135 with other prognostic biomarkers stratified four subgroups of patients with distinct clinical outcome. The subgroup of patients who were LEA.135+/TPII.alpha- showed the lowest probability of recurrence and the longest overall survival compared with those who were LEA.135-/TPII.alpha+ (logrank p < 0.001). Interestingly, the patients whose cancer cells were LEA.135+/TPII.alpha+, LEA.135+ MIB.1+ or LEA.135+/c-erbB 2+ experienced a decreased probability of recurrence and an increased overall survival compared with those with LEA.135-/TPII.alpha+, LEA.135- MIB.1+ or LEA.135-/c-erbB 2+ (logrank p < 0.001). The results demonstrated that LEA.135 is an independent and favorable prognostic biomarker for patients with primary invasive breast carcinoma, that the loss of LEA.135 expression is associated with aggressive phenotype of cancer cells during the breast cancer progression, and that its continued expression seems to override the adverse effects of expression of an oncogene or cell proliferation-associated molecules.

Background

Glucose-regulated protein 78 (GRP78) plays an essential role in protein folding, transportation, and degradation, thus regulates ER homeostasis and promotes cell survival, proliferation and invasion. GRP78 expression in PDAC patients who received neoadjuvant therapy has not been reported.

Methods

This retrospective study of resected PDAC patients included 125 patients treated with neoadjuvant therapy (NAT) and 140 patients treated with surgery first (SF). The expression of GRP78 was evaluated by immunohistochemistry on tissue microarrays and the results were correlated with clinicopathologic parameters and survival.

Results

GRP78 expression was higher in SF patients compared to NAT patients (P < 0.001). In SF cohort, the median disease-free survival (DFS) and overall survival (OS) for patients with GRP78-positive tumors were 11.2 months and 25.0 months, respectively, compared to DFS of 52.1 months (P = 0.008) and OS of 69.5 months (P = 0.02) for those with GRP78-negative tumors. GRP78 expression correlated with higher frequency of recurrent/metastasis (P = 0.045). In NAT cohort, GRP78 expression correlated with shorter OS (P = 0.03), but not DFS (P = 0.08). GRP78 expression was an independent prognosticator for both DFS (P = 0.02) and OS (P = 0.049) in SF cohort and was an independent prognosticator for OS (P = 0.03), but not for DFS (P = 0.06) in NAT cohort by multivariate analysis.

Conclusions

Our study showed that GRP78 expression in NAT cohort is lower than that in SF cohort. GRP78 expression correlated with shorter survival in both SF and NAT patients. Our findings suggest that targeting GRP78 may help to improve the prognosis in PDAC patients.

Objectives

Tumor size measurement is critical for accurate tumor staging in patients with pancreatic ductal adenocarcinoma (PDAC). However, accurate tumor size measurement is challenging in patients who received neoadjuvant therapy before resection, due to treatment-induced fibrosis and tumor invasion beyond the grossly identified tumor area. In this study, we evaluated the correlation between the tumor size and tumor volume measured on post-therapy computed tomography (CT) scans and the pathological measurement. Also, we investigated the correlation between these measurements and clinicopathological parameters and survival.

Materials and methods

Retrospectively, we evaluated 343 patients with PDAC who received neoadjuvant therapy, followed by pancreaticoduodenectomy and had pre-operative pancreatic protocol CT imaging. We measured the longest tumor diameter (RadL) and the radiological tumor volume (RadV) on the post-therapy CT scan, then we categorized RadL into four radiologic tumor stages (RTS) based on the current AJCC staging (8th edition) protocol and RadV based on the median. Pearson correlation or Spearman's coefficient (δ), T-test and ANOVA was used to test the correlation between the radiological and pathological measurement. Chi-square analysis was used to test the correlation with the tumor pathological response, lymph-node metastasis and margin status and Kaplan-Meier and Cox-proportional hazard for survival analysis. P-value < 0.05 was considered significant.

Results

As a continuous variable, RadL showed a positive linear correlation with the post-therapy pathologic tumor size in the overall patient population (Pearson correlation coefficient: 0.72, P < 0.001) and RadV (δ: 0.63, p < 0.0001). However, there was no correlation between RadL and pathologic tumor size in patients with ypT0 and those with pathologic tumor size of ≤1.0 cm. Post-therapy RTS and RadV group correlated with ypT stage, tumor response grades using either CAP or MDA grading system, distance of superior mesenteric artery margin and tumor recurrence/metastasis.

Conclusion

Although RadL tends to understage ypT in PDAC patients who had no radiologically detectable tumor or small tumors (RTS0 or RTS1), radiologic measurement of post-therapy tumor size may be used as a marker for the pathologic tumor staging and tumor response to neoadjuvant therapy.

The regional distribution of white matter (WM) abnormalities in schizophrenia remains poorly understood, and reported disease effects on the brain vary widely between studies. In an effort to identify commonalities across studies, we perform what we believe is the first ever large-scale coordinated study of WM microstructural differences in schizophrenia. Our analysis consisted of 2359 healthy controls and 1963 schizophrenia patients from 29 independent international studies; we harmonized the processing and statistical analyses of diffusion tensor imaging (DTI) data across sites and meta-analyzed effects across studies. Significant reductions in fractional anisotropy (FA) in schizophrenia patients were widespread, and detected in 20 of 25 regions of interest within a WM skeleton representing all major WM fasciculi. Effect sizes varied by region, peaking at (d=0.42) for the entire WM skeleton, driven more by peripheral areas as opposed to the core WM where regions of interest were defined. The anterior corona radiata (d=0.40) and corpus callosum (d=0.39), specifically its body (d=0.39) and genu (d=0.37), showed greatest effects. Significant decreases, to lesser degrees, were observed in almost all regions analyzed. Larger effect sizes were observed for FA than diffusivity measures; significantly higher mean and radial diffusivity was observed for schizophrenia patients compared with controls. No significant effects of age at onset of schizophrenia or medication dosage were detected. As the largest coordinated analysis of WM differences in a psychiatric disorder to date, the present study provides a robust profile of widespread WM abnormalities in schizophrenia patients worldwide. Interactive three-dimensional visualization of the results is available at www.enigma-viewer.org.