Expression of the global regulator SATB1 is an independent factor of poor prognosis in high grade epithelial ovarian cancer

Background: The global gene regulator Special AT-rich sequence-binding protein1 (SATB1) has been reported to reprogramme tumour cells into a more malignant phenotype and associate with poor clinical outcome in several cancer forms. In this study, we investigated the molecular correlates and prognostic impact of SATB1 expression in human epithelial ovarian cancer (EOC). Findings: Immunohistochemical expression of SATB1 was examined in tissue microarrays with tumours from 151 incident EOC cases from two prospective, population-based cohorts. Benign-appearing fallopian tube epithelium from 32 cases was also analyzed. A multiplier of nuclear fraction and staining intensity of SATB1 was calculated. While barely expressed in tubal epithelium, nuclear SATB1 expression was denoted in 35/151 (23.2%) EOC cases. Spearman's Rho test revealed an inverse correlation between SATB1 expression and histological grade (R = -0.22, p = 0.006) and a positive correlation with expression of dachshund 2 protein (R = 0.28, p = 0.001), phosphorylated Chek1 (R = 0.26, p = 0.002) and minichromosome maintenance protein 3 (R = 0.17, p = 0.042). Univariable Cox regression analysis revealed that SATB1 expression, while not prognostic in the full cohort, was associated with a reduced ovarian cancer-specific survival and 5-year overall survival in high grade tumours (n = 105) (HR = 2.14 and HR = 1.96, respectively). This association remained significant in multivariable analysis, adjusted for age and clinical stage (HR = 2.20 and HR = 2.06, respectively). Conclusions: These results demonstrate that SATB1 expression is an independent factor of poor prognosis in high grade EOC and correlates in vivo with cellular processes involved in the maintenance of DNA integrity. The functional basis for these observations merits further investigation

Prognostic biomarkers in upper gastrointestinal adenocarcinoma

Estimates indicate that the global cancer burden may be ever-increasing. Gastric cancer is one of the major cancer forms. Despite its declining incidence, the high mortality of gastric cancer makes it the third most common cause of cancer-related death. Esophageal cancer is less common, but the incidence is increasing in parts of the world. Although some progress has been made in the treatment of these cancer forms, survival rates between 10 and 27 percent confer a dismal prognosis for the afflicted patients.The main aim of this thesis is to study the prognostic and predictive value of selected biomarkers in upper gastrointestinal cancer in order to identify novel, clinically relevant subgroups of the disease.Tissue microarrays were created with primary tumours from two consecutive cohorts, one consisting of patients surgically treated for adenocarcinoma in the esophagus or stomach without prior neoadjuvant treatment and the other consisting of patients surgically treated for adenocarcinoma in the esophagus or stomach after neoadjuvant therapy, both in the University hospitals of Lund and Malmö. In addition, a subset of paired normal tissue, pre-treatment biopsies, intestinal metaplasia and lymph node, as well as distant metastases, was sampled. Further, by means of Western blot analysis, siRNA-mediated knockdown, qPCR and immunocyto- and immunohistochemistry, the specificities of the Special AT-rich Sequence-binding Protein (SATB) 1, SATB2 and Human Epidermal Growth Factor Receptor (HER) 3 antibodies used were confirmed.Immunohistochemichal expression of SATB1, a global genome organiser that has been demonstrated to promote aggressive tumour behaviour in several types of cancer, was shown to be an independent adverse prognostic biomarker in patients with radically resected adenocarcinomas of the esophagus and stomach. The distribution, interrelationship and prognostic significance of protein expression and gene amplification of the treatment target HER2 was examined in the tumours from the first cohort. Expression of HER2 in primary tumours had no prognostic impact, whereas conversion of expression between primary tumour and lymph node metastasis was an independent adverse prognostic factor. The expression of EGFR (Epidermal Growth Factor Receptor 1) and HER3 in tissue from the first cohort was also examined. EGFR was independently associated with a shorter overall survival. High HER3 expression was associated with a longer overall survival, although not independently. The expression, interrelationship and prognostic significance of EGFR, HER2 and HER3 was also examined in the tumours from the second cohort. No associations between EGFR or HER2 expression and survival were seen. A non-independent association between post-treatment HER3 expression and longer overall survival was seen. A change in expression of the examined proteins between pre-treatment biopsies and post-treatment resection specimens was seen in 5, 6 and 20% of the cases, respectively.In conclusion, our results provide further evidence that SATB1 expression is associated with poor prognosis. Our studies also shed light on new aspects of HER expression, associations with prognosis and changes in expression during the growth, spread and treatment of tumours, which could affect diagnostic and treatment strategies

Associations between Presence of Relevant Information in Referrals to Radiology and Prevalence Rates in Patients with Suspected Pulmonary Embolism.

The purpose of this study was to assess if the presence of information including the pretest probability (Wells score), other known risk factors, and symptoms given on referrals for computed tomography (CT) pulmonary angiography correlated with prevalence rates for pulmonary embolism (PE). Also, to evaluate for differences between a university and a regional hospital setting regarding patient characteristics, amount of relevant information provided on referrals, and prevalence rates for pulmonary embolism

Expression and Prognostic Significance of Human Epidermal Growth Factor Receptors 1 and 3 in Gastric and Esophageal Adenocarcinoma.

Gastric and esophageal adenocarcinomas are major global cancer burdens. These cancer forms are characterized by a poor prognosis and a modest response to chemo- radio- and targeted treatment. Hence there is an obvious need for further enhanced diagnostic and treatment strategies. The aim of this study was to examine the expression and prognostic impact of human epidermal growth factor receptor 1 (HER1/EGFR) and 3 (HER3), as well as the occurrence of EGFR and KRAS mutations in gastric and esophageal adenocarcinoma

Expression and prognostic significance of human epidermal growth factor receptors 1, 2 and 3 in oesophageal and gastric adenocarcinomas preneoadjuvant and postneoadjuvant treatment

AIMS: Neoadjuvant treatment has now become the standard of care for oesophageal and gastric cancer. The aim of this study was to investigate the influence of neoadjuvant therapy on the expression of human epidermal growth factor receptor 1 (HER1/EGFR), HER2 and HER3, in oesophageal and gastric adenocarcinoma.METHODS: Immunohistochemical expression of EGFR, HER2 and HER3 was examined and compared in pretreatment biopsies, post-treatment surgical resection specimens and metastases in a retrospective cohort of 166 patients with adenocarcinoma of the oesophagus or stomach. The relationship between expression of the investigative markers and histopathological response to neoadjuvant treatment, overall survival (OS) and recurrence free survival (RFS) was analysed.RESULTS: Conversion of protein expression between pretreatment biopsy and post-treatment surgical resection was seen in 4.6% of the cases for EGFR, 5.9% for HER2% and 19.4% for HER3. Histopathological response to neoadjuvant treatment was significantly and stepwise associated with OS and RFS . High HER3 protein expression in post-treatment surgical resection specimens was significantly associated with a prolonged OS in univariable analysis (HR=0.39; 95% CI 0.17 to 0.93), but did not remain significant in multivariable analysis. Expression of EGFR and HER2 in post-treatment surgical resection specimens was not prognostic. No correlation between pretreatment HER-protein expression and histopathological response was seen.CONCLUSIONS: The results from this study underscore the need for further studies on the influence of neoadjuvant treatment on biomarker expression, as this may influence treatment strategy as well as prognosis. Histopathological response is validated as a useful prognostic factor

Discordant HER2 overexpression in primary and metastatic upper gastrointestinal adenocarcinoma signifies poor prognosis.

Targeted therapy with trastuzumab has proven to be effective for patients with gastric cancer overexpressing the human epidermal growth factor receptor 2 (HER2). Further studies are needed to determine the best method for assessment of HER2 overexpression. Moreover, the prognostic value of HER2 overexpression, including the significance of tumour heterogeneity, remains unclear

Podocalyxin-like protein as a predictive biomarker for benefit of neoadjuvant chemotherapy in resectable gastric and esophageal adenocarcinoma

Abstract Background We have previously shown that podocalyxin-like protein (PODXL) is a prognostic biomarker for poor survival in gastric and esophageal adenocarcinoma treated with surgery up-front. The aim of the present study was to assess PODXL expression in tumors from patients treated with neoadjuvant ± adjuvant (i.e. preoperative with or without postoperative) chemotherapy, with regard to histopathologic response, time to recurrence (TTR) and overall survival (OS). Methods The neoadjuvant cohort encompasses 148 consecutive patients who received neoadjuvant ± adjuvant chemotherapy for resectable gastric or esophageal adenocarcinoma between 2008 and 2014. Immunohistochemical expression of PODXL was assessed in pre-neoadjuvant biopsies, resected primary tumors and lymph node metastases. Histopathologic response was evaluated using the Chirieac grading. TTR and OS were estimated using Kaplan–Meier and Cox regression analyses. To investigate a potential predictive role for PODXL, the neoadjuvant cohort was pooled with the previously reported surgery up-front cohort. Results The majority (> 95%) of the patients were treated with fluoropyrimidine- and oxaliplatin-based chemotherapy. Patients with high PODXL expression in their pre-neoadjuvant biopsies had a superior histopathologic response (notably 36% with no residual cancer cells) compared to those with negative or low PODXL expression, and were all recurrence-free at last follow-up. In the pooled cohort, no benefit of chemotherapy could be shown for PODXL negative cases, whereas PODXL positive (low or high) cases had a prolonged TTR and OS when treated with neoadjuvant ± adjuvant chemotherapy compared to surgery alone. The potential predictive role of PODXL was further strengthened for TTR in Cox regression analyses, especially for patients treated with neoadjuvant fluoropyrimidine and oxaliplatin for a minimum of 8 weeks, with a significant interaction term in both unadjusted (p = 0.006) and adjusted (p = 0.024) analyses. The interaction term was not statistically significant for overall survival. Conclusions Patients with resectable gastric or esophageal adenocarcinoma with high PODXL expression in their diagnostic biopsies have an excellent prognosis when treated with neoadjuvant ± adjuvant fluoropyrimidine- and oxaliplatin-based chemotherapy. If the suggested predictive role of PODXL for benefit of chemotherapy can be confirmed, patients with PODXL negative tumors could be spared chemotherapy and treated with surgery alone

Expression and prognostic significance of the polymeric immunoglobulin receptor in esophageal and gastric adenocarcinoma.

The polymeric immunoglobulin receptor (PIGR) has been proposed to be a candidate prognostic biomarker in a few cancer forms, and one previous study reported that reduced PIGR expression signifies more aggressive tumours of the distal esophagus and gastroesophageal junction (GEJ). In the present study, we examined the expression, clinicopathological correlates and prognostic significance of PIGR expression in an extended cohort of adenocarcinoma of the upper gastrointestinal tract

Expression of podocalyxin-like protein is an independent prognostic biomarker in resected esophageal and gastric adenocarcinoma

Background: Podocalyxin-like protein (PODXL) is a cell surface transmembrane glycoprotein, the expression of which has been associated with poor prognosis in a range of malignancies. The aim of this study was to investigate the impact of PODXL expression on survival in esophageal and gastric adenocarcinoma. Methods: The study cohort consists of a consecutive series of 174 patients with esophageal (including the gastroesophageal junction) or gastric adenocarcinoma, surgically treated between 2006 and 2010 and not subjected to neoadjuvant treatment. Immunohistochemical expression of PODXL was assessed in tissue microarrays with cores from primary tumors, lymph node metastases, intestinal metaplasia and adjacent normal epithelium. Survival analyses were performed on patients with no distant metastases and no macroscopic residual tumor. Results: In the majority of cases, expression of PODXL was significantly higher in cancer cells compared to normal epithelial cells and was significantly associated with lymph node metastases and high grade tumors. In esophageal adenocarcinoma, Kaplan-Meier analyses revealed that patients with PODXL negative tumors had a superior time to recurrence (TTR) and overall survival (OS) compared to patients with PODXL positive tumors. In gastric adenocarcinoma, patients with PODXL negative tumors had a superior TTR and a trend towards an improved OS. In esophageal and gastric adenocarcinoma combined, the prognostic significance of PODXL expression on TTR was confirmed in unadjusted Cox regression analysis (HR = 5.36, 95 % CI 1.68-17.06, p = 0.005) and remained significant in the adjusted model (HR = 3.39, 95 % CI 1.01-11.35, p = 0.048). Moreover, the impact of PODXL expression on OS was also confirmed in unadjusted analysis (HR = 2.52, 95 % CI 1.31-4.85, p = 0.006) and remained significant in the adjusted model (HR = 2.03, 95 % CI 1.04-3.98, p = 0.039). Conclusions: In esophageal and gastric adenocarcinoma, PODXL expression is an independent prognostic biomarker for reduced time to recurrence and poor overall survival. This is the first report on the prognostic role of PODXL in esophageal adenocarcinoma and validates recent findings in gastric cancer