Regulation of a Novel Splice Variant of Early Growth Response 4 (EGR4-S) by HER+ Signalling and HSF1 in Breast Cancer.

The zinc finger transcription factor EGR4 has previously been identified as having a critical role in the proliferation of small cell lung cancer. Here, we have identified a novel, shortened splice variant of this transcription factor (EGR4-S) that is regulated by Heat Shock Factor-1 (HSF1). Our findings demonstrate that the shortened variant (EGR4-S) is upregulated with high EGFR, HER2, and H-Rasv12-expressing breast cell lines, and its expression is inhibited in response to HER pathway inhibitors. Protein and mRNA analyses of HER2+ human breast tumours indicated the novel EGR4-S splice variant to be preferentially expressed in tumour tissue and not detectable in patient-matched normal tissue. Knockdown of EGR4-S in the HER2-amplified breast cancer cell line SKBR3 reduced cell growth, suggesting that EGR4-S supports the growth of HER2+ tumour cells. In addition to chemical inhibitors of the HER2 pathway, EGR4-S expression was also found to be suppressed by chemical stressors and the overexpression of HSF1. Under these conditions, reduced EGR4-S levels were associated with the observed lower cell growth rate, but the augmentation of properties associated with higher metastatic potential. Taken together, these findings identify EGR4-S as a potential biomarker for HER2 pathway activation in human tumours that is regulated by HSF1.

Primary non-metastatic extra-nodal diffuse large B-cell lymphoma of the prostate and seminal vesicle.

Extra-nodal lymphoma accounts for 30-50% of non-Hodgkin lymphoma, and most of the cases are of the diffuse large B-cell lymphoma (DLBCL) type. Primary malignant lymphomas of the prostate are extremely rare, representing 0.09% of prostate neoplasms. Prostatic cancers can be classified into various subtypes, which have distinct molecular pathologies and clinical features. Lymphoma is seldom considered as a differential diagnosis of prostatic enlargement considering the low incidence. We present a case of an 85-year-old gentleman diagnosed with Primary Extra-nodal DLBCL of the Seminal Vesicle and Prostate.

Incorporating Resource Protection Constraints in an Analysis of Landscape Fuel-Treatment Effectiveness in the Northern Sierra Nevada, CA, USA.

Finding novel ways to plan and implement landscape-level forest treatments that protect sensitive wildlife and other key ecosystem components, while also reducing the risk of large-scale, high-severity fires, can prove to be difficult. We examined alternative approaches to landscape-scale fuel-treatment design for the same landscape. These approaches included two different treatment scenarios generated from an optimization algorithm that reduces modeled fire spread across the landscape, one with resource-protection constrains and one without the same. We also included a treatment scenario that was the actual fuel-treatment network implemented, as well as a no-treatment scenario. For all the four scenarios, we modeled hazardous fire potential based on conditional burn probabilities, and projected fire emissions. Results demonstrate that in all the three active treatment scenarios, hazardous fire potential, fire area, and emissions were reduced by approximately 50 % relative to the untreated condition. Results depict that incorporation of constraints is more effective at reducing modeled fire outputs, possibly due to the greater aggregation of treatments, creating greater continuity of fuel-treatment blocks across the landscape. The implementation of fuel-treatment networks using different planning techniques that incorporate real-world constraints can reduce the risk of large problematic fires, allow for landscape-level heterogeneity that can provide necessary ecosystem services, create mixed forest stand structures on a landscape, and promote resilience in the uncertain future of climate change.

Management of duodenal adenomatosis in FAP: single centre experience.

Duodenal and ampullary carcinoma in familial adenomatosis (FAP) is the third leading cause of FAP related deaths. Management of this condition is a challenging. The aim of this study was to evaluate the role of multiple targeted endoscopic biopsies and macroscopic appearance as the major determinants for surgical intervention. A secondary aim was to assess histological heterogeneity through comparing endoscopic biopsies and describe the clinical outcomes of our cohort after intervention. We reviewed our FAP surveillance database of 67 patients, between January 1999--June 2011 undergoing upper GI surveillance and where indicated, subsequent surgical intervention. Among 67 patients, 11 underwent surgical resection. Pancreas-preserving duodenectomy was performed in four patients (five procedures), and Whipple's operation in seven patients. The average size of polyps was 43 mm (range 17-65 mm), and the average number of targeted endoscopic biopsies per lesion was 7.5 (range 5-10). Two cases of high-grade (severe) dysplasia were diagnosed on endoscopic biopsies each understaged compared with the subsequent surgical specimen. All carcinomas identified have been resectable with no evidence of local spread or distant metastasis. There was one postoperative death, but no cancer related deaths. We identified both cancers at an early stage and there were no missed or late diagnoses. There have been no recurrences of carcinoma in a more than 7 years follow-up. Due to the heterogeneous nature of these lesions, comprehensive macroscopic assessment should be complemented with multiple targeted biopsies to improve the chance of early detection of advanced lesions.

Pretreatment transcriptional profiling for predicting response to neoadjuvant chemoradiotherapy in rectal adenocarcinoma.

PURPOSE: Patients presenting with locally advanced rectal cancer currently receive preoperative radiotherapy with or without chemotherapy. Although pathologic complete response is achieved for approximately 10% to 30% of patients, a proportion of patients derive no benefit from this therapy while being exposed to toxic side effects of treatment. Therefore, there is a strong need to identify patients who are unlikely to benefit from neoadjuvant therapy to help direct them toward alternate and ultimately more successful treatment options. EXPERIMENTAL DESIGN: In this study, we obtained expression profiles from pretreatment biopsies for 51 rectal cancer patients. All patients underwent preoperative chemoradiotherapy, followed by resection of the tumor 6 to 8 weeks posttreatment. Gene expression and response to treatment were correlated, and a supervised learning algorithm was used to generate an original predictive classifier and validate previously published classifiers. RESULTS: Novel predictive classifiers based on Mandard's tumor regression grade, metabolic response, TNM (tumor node metastasis) downstaging, and normal tissue expression profiles were generated. Because there were only 7 patients who had minimal treatment response (>80% residual tumor), expression profiles were used to predict good tumor response and outcome. These classifiers peaked at 82% sensitivity and 89% specificity; however, classifiers with the highest sensitivity had poor specificity, and vice versa. Validation of predictive classifiers from previously published reports was attempted using this cohort; however, sensitivity and specificity ranged from 21% to 70%. CONCLUSIONS: These results show that the clinical utility of microarrays in predictive medicine is not yet within reach for rectal cancer and alternatives to microarrays should be considered for predictive studies in rectal adenocarcinoma.

Biallelic PMS2 mutations and a distinctive childhood cancer syndrome.

Biallelic mutations in PMS2, a gene usually associated in heterozygous form with hereditary nonpolyposis colorectal cancer (HNPCC), results in a recently described childhood cancer syndrome. The tumor spectrum encompasses atypical brain cancers, hematologic malignancies, and colonic polyposis and cancer. Cutaneous stigmata resembling café-au-lait macules with more diffuse margins are frequently seen. Onset is as young as 2 years. The risk of second malignancy is high. Evidence exists for surveillance for bowel cancer, but surveillance for the wider tumor spectrum is of uncertain benefit. We report a consanguineous Australian-Lebanese family with multiple affected individuals shown to be homozygous for a PMS2 exon 7 deletion. We also review published cases of biallelic mutations in HNPCC-related genes. Early recognition of this familial cancer syndrome is critical, and should prompt investigation for familial HNPCC mutations.