Clinical impact of HLA class I expression in rectal cancer

Contains fulltext : 69499.pdf (publisher's version ) (Open Access)PURPOSE: To determine the clinical impact of human leukocyte antigen (HLA) class I expression in irradiated and non-irradiated rectal carcinomas. EXPERIMENTAL DESIGN: Tumor samples in tissue micro array format were collected from 1,135 patients. HLA class I expression was assessed after immunohistochemical staining with two antibodies (HCA2 and HC10). RESULTS: Tumors were split into two groups: (1) tumors with >50% of tumor cells expressing HLA class I (high) and (2) tumors with < or =50% of tumor cells expressing HLA class I (low). No difference in distribution or prognosis of HLA class I expression was found between irradiated and non-irradiated patients. Patients with low expression of HLA class I (15% of all patients) showed an independent significantly worse prognosis with regard to overall survival and disease-free survival. HLA class I expression had no effect on cancer-specific survival or recurrence-free survival. CONCLUSIONS: Down-regulation of HLA class I in rectal cancer is associated with poor prognosis. In contrast to our results, previous reports on HLA class I expression in colorectal cancer described a large population of patients with HLA class I negative tumors, having a good prognosis. This difference might be explained by the fact that a large proportion of HLA negative colon tumors are microsatellite instable (MSI). MSI tumors are associated with a better prognosis than microsatellite stable (MSS). As rectal tumors are mainly MSS, our results suggest that it is both, oncogenic pathway and HLA class I expression, that dictates patient's prognosis in colorectal cancer. Therefore, to prevent confounding in future prognostic analysis on the impact of HLA expression in colorectal tumors, separate analysis of MSI and MSS tumors should be performed

Sex differences in frontal lobe connectivity in adults with autism spectrum conditions

Autism spectrum conditions (ASC) are more prevalent in males than females. The biological basis of this difference remains unclear. It has been postulated that one of the primary causes of ASC is a partial disconnection of the frontal lobe from higher-order association areas during development (that is, a frontal ‘disconnection syndrome’). Therefore, in the current study we investigated whether frontal connectivity differs between males and females with ASC. We recruited 98 adults with a confirmed highfunctioning ASC diagnosis (61 males: aged 18–41 years; 37 females: aged 18–37 years) and 115 neurotypical controls (61 males: aged 18–45 years; 54 females: aged 18–52 years). Current ASC symptoms were evaluated using the Autism Diagnostic Observation Schedule (ADOS). Diffusion tensor imaging was performed and fractional anisotropy (FA) maps were created. Mean FA values were determined for five frontal fiber bundles and two non-frontal fiber tracts. Between-group differences in mean tract FA, as well as sex-by-diagnosis interactions were assessed. Additional analyses including ADOS scores informed us on the influence of current ASC symptom severity on frontal connectivity. We found that males with ASC had higher scores of current symptom severity than females, and had significantly lower mean FA values for all but one tract compared to controls. No differences were found between females with or without ASC. Significant sex-by-diagnosis effects were limited to the frontal tracts. Taking current ASC symptom severity scores into account did not alter the findings, although the observed power for these analyses varied. We suggest these findings of frontal connectivity abnormalities in males with ASC, but not in females with ASC, have the potential to inform us on some of the sex differences reported in the behavioral phenotype of ASC.This work was supported by grant GO 400061 (to DGMM) from the UK Medical Research Council (http://www.mrc.ac.uk/index.htm). The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115300, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007–2013) and EFPIA companies’ in kind contribution. The National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care—East of England (CLAHRC-EoE) also supported the project. This paper represents independent research (part) funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. During the period of the study M-CL and AR were supported by the William Binks Autism Neuroscience Fellowship and Autism Research Trust, and M-CL was also supported by the O’Brien Scholars Program within the Child and Youth Mental Health Collaborative at the Centre for Addiction and Mental Health and The Hospital for Sick Children, Toronto. The Autism Research Trust supported SB-C, BC and ML

Copy number alterations and allelic ratio in relation to recurrence of rectal cancer

BACKGROUND: In rectal cancer, total mesorectal excision surgery combined with preoperative (chemo)radiotherapy reduces local recurrence rates but does not improve overall patient survival, a result that may be due to the harmful side effects and/or co-morbidity of preoperative treatment. New biomarkers are needed to facilitate identification of rectal cancer patients at high risk for local recurrent disease. This would allow for preoperative (chemo)radiotherapy to be restricted to high-risk patients, thereby reducing overtreatment and allowing personalized treatment protocols. We analyzed genome-wide DNA copy number (CN) and allelic alterations in 112 tumors from preoperatively untreated rectal cancer patients. Sixty-six patients with local and/or distant recurrent disease were compared to matched controls without recurrence. Results were validated in a second cohort of tumors from 95 matched rectal cancer patients. Additionally, we performed a meta-analysis that included 42 studies reporting on CN alterations in colorectal cancer and compared results to our own data. RESULTS: The genomic profiles in our study were comparable to other rectal cancer studies. Results of the meta-analysis supported the hypothesis that colon cancer and rectal cancer may be distinct disease entities. In our discovery patient study cohort, allelic retention of chromosome 7 was significantly associated with local recurrent disease. Data from the validation cohort were supportive, albeit not statistically significant, of this finding. CONCLUSIONS: We showed that retention of heterozygosity on chromosome 7 may be associated with local recurrence in rectal cancer. Further research is warranted to elucidate the mechanisms and effect of retention of chromosome 7 on the development of local recurrent disease in rectal cancer. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12864-015-1550-0) contains supplementary material, which is available to authorized users

Systematic evaluation of immune regulation and modulation

Cancer immunotherapies are showing promising clinical results in a variety of malignancies. Monitoring the immune as well as the tumor response following these therapies has led to significant advancements in the field. Moreover, the identification and assessment of both predictive and prognostic biomarkers has become a key component to advancing these therapies. Thus, it is critical to develop systematic approaches to monitor the immune response and to interpret the data obtained from these assays. In order to address these issues and make recommendations to the field, the Society for Immunotherapy of Cancer reconvened the Immune Biomarkers Task Force. As a part of this Task Force, Working Group 3 (WG3) consisting of multidisciplinary experts from industry, academia, and government focused on the systematic assessment of immune regulation and modulation. In this review, the tumor microenvironment, microbiome, bone marrow, and adoptively transferred T cells will be used as examples to discuss the type and timing of sample collection. In addition, potential types of measurements, assays, and analyses will be discussed for each sample. Specifically, these recommendations will focus on the unique collection and assay requirements for the analysis of various samples as well as the high-throughput assays to evaluate potential biomarkers

Texture Analysis of T1 weighted and fluid attenuated inversion recovery images detects abnormalities which correlate with disease progression in small vessel disease

Background and Purpose MRI techniques may be useful to assess disease severity in cerebral small vessel disease (SVD), identify those individuals who are most likely to progress to dementia, monitor disease progression and act as surrogate markers to test new therapies. Texture analysis extracts information on the relationship between signal intensities of neighbouring voxels. A potential advantage over some techniques used to characterise SVD, such as diffusion tensor imaging, is that it can be used on routine clinically obtained MR sequences. We determined whether texture parameters (TP) were abnormal in SVD, correlated with cognitive impairment, or predict cognitive decline. Methods In the prospective SCANS study we assessed TP in 121 individuals with symptomatic SVD at baseline, 99 of whom attended for repeat MRI and cognitive testing performed yearly for 3 years after which cognitive testing alone was performed for a further 2 years. Conversion to dementia was recorded for all subjects over the 5 years period. Texture analysis was performed on FLAIR and T1-weighted images. The SVD cohort was compared with 54 age matched controls scanned on the same system. Results There were highly significant differences in a number of TP between SVD cases and controls. Within the SVD population TP were highly correlated to other MRI parameters (brain volume, white matter lesion volume, lacune count). TP predicted executive function and global function at baseline and predicted conversion to dementia, after controlling for age, gender, pre-morbid IQ and other MR parameters. Conclusions TP, which can be obtained from sequences used in routine clinical imaging, are abnormal in SVD and the degree of abnormality correlates with executive dysfunction and global cognition at baseline and decline over five years. TP may be useful to assess disease severity in clinically collected data. This needs testing in data clinically acquired across multiple sites

Texture Analysis of T1 weighted and fluid attenuated inversion recovery images detects abnormalities which correlate with disease progression in small vessel disease

Background and Purpose MRI techniques may be useful to assess disease severity in cerebral small vessel disease (SVD), identify those individuals who are most likely to progress to dementia, monitor disease progression and act as surrogate markers to test new therapies. Texture analysis extracts information on the relationship between signal intensities of neighbouring voxels. A potential advantage over some techniques used to characterise SVD, such as diffusion tensor imaging, is that it can be used on routine clinically obtained MR sequences. We determined whether texture parameters (TP) were abnormal in SVD, correlated with cognitive impairment, or predict cognitive decline. Methods In the prospective SCANS study we assessed TP in 121 individuals with symptomatic SVD at baseline, 99 of whom attended for repeat MRI and cognitive testing performed yearly for 3 years after which cognitive testing alone was performed for a further 2 years. Conversion to dementia was recorded for all subjects over the 5 years period. Texture analysis was performed on FLAIR and T1-weighted images. The SVD cohort was compared with 54 age matched controls scanned on the same system. Results There were highly significant differences in a number of TP between SVD cases and controls. Within the SVD population TP were highly correlated to other MRI parameters (brain volume, white matter lesion volume, lacune count). TP predicted executive function and global function at baseline and predicted conversion to dementia, after controlling for age, gender, pre-morbid IQ and other MR parameters. Conclusions TP, which can be obtained from sequences used in routine clinical imaging, are abnormal in SVD and the degree of abnormality correlates with executive dysfunction and global cognition at baseline and decline over five years. TP may be useful to assess disease severity in clinically collected data. This needs testing in data clinically acquired across multiple sites

Prognostic and Predictive Relevance of Immunological Biomarkers in Colorectal Cancer

Surgical oncolog