Publications

Coinfection with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) challenges the immune system with two viruses that elicit distinct immune responses. Chronic immune activation is a hallmark of HIV infection and an accurate indicator of disease progression. Suppressing HIV viremia by antiretroviral therapy (ART) effectively prolongs life and significantly improves immune function. HIV/HCV coinfected individuals have peripheral immune activation despite effective ART control of HIV viral load. Here we examined freshly isolated CD14 monocytes for gene expression using high-density cDNA microarrays and analyzed T cell subsets, CD4 and CD8, by flow cytometry to characterize immune activation in monoinfected HCV and HIV, and HIV-suppressed coinfected subjects. To determine the impact of coinfection on cognition, subjects were evaluated in 7 domains for neuropsychological performance, which were summarized as a global deficit score (GDS). Monocyte gene expression analysis in HIV-suppressed coinfected subjects identified 43 genes that were elevated greater than 2.5 fold. Correlative analysis of subjects' GDS and gene expression found eight genes with significance after adjusting for multiple comparisons. Correlative expression of six genes was confirmed by qPCR, five of which were categorized as type 1 IFN response genes. Global deficit scores were not related to plasma lipopolysaccharide levels. In the T cell compartment, coinfection significantly increased expression of activation markers CD38 and HLADR on both CD4 and CD8 T cells but did not correlate with GDS. These findings indicate that coinfection is associated with a type 1 IFN monocyte activation profile which was further found to correlate with cognitive impairment, even in subjects with controlled HIV infection. HIV-suppressed coinfected subjects with controlled HIV viral load experiencing immune activation could benefit significantly from successful anti-HCV therapy and may be considered as preferential candidates.

BACKGROUND

Colorectal adenocarcinoma with depth of invasion ≤1,000 μm from the muscularis mucosa and favorable histology is now considered for local resection. We aimed to examine the strength of evidence for this emerging practice.

METHODS

We searched Medline, Scopus, and Cochrane (1950-2011), then performed a meta-analysis on the risk of lymph node metastasis in nonpedunculated (sessile and nonpolypoid) T1 colorectal cancers. We included studies with nonpedunculated lesions, actual invasion depth, and pathologic factors of interest. Synchronous, polyposis or secondary cancers, and chemoradiation studies were excluded. Our primary outcome was the risk of LNM. We analyzed using Review Manager; we estimated heterogeneity using Cochran Q χ(2) test and I (2). We generated summary risk ratios using a random effects model, performed sensitivity analyses, and evaluated the quality of evidence using GRADEPro.

RESULTS

We identified 209 articles; 5 studies (n = 1213 patients) met the inclusion criteria. The risk of LNM in nonpedunculated ≤1,000 μm is 1.9 % (95 % confidence interval 0.5-4.8 %). The risk for all T1 is 13 % (95 % confidence interval 11.5-15.4 %). Characteristics protective against LNM were ≤1,000 μm invasion, well differentiation, absence of lymphatic and vascular invasion, and absence of tumor budding. We did not detect significant study heterogeneity. The quality of evidence was poor.

CONCLUSIONS

Well-differentiated nonpedunculated T1 colorectal cancer invasive into the submucosa ≤1,000 μm, without lymphovascular involvement or tumor budding, has the lowest risk of nodal metastasis. Importantly, the risk was not zero (1.9 %), and the qualitative formal analysis of data was not strong. As such, endoscopic resection alone may be adequate in select patients with submucosal invasive colorectal cancers, but more studies are needed. Overall, the quality of evidence was poor; data were from small retrospective studies from limited geographic regions.