Citations

Object Biomechanical studies have shown that anterior cervical fusion construct stiffness and arthrodesis rates vary with different reconstruction techniques; however, the behavior of the adjacent segments in the setting of different procedures is poorly understood. This study was designed to investigate the adjacent-segment biomechanics after 3 different anterior cervical decompression and fusion techniques, including 3-level discectomy and fusion, 2-level corpectomy and fusion, and a corpectomy-discectomy hybrid technique. The authors hypothesized that biomechanical changes at the segments immediately superior and inferior to the multilevel fusion would be inversely proportional to the number of fused bone grafts and that these changes would be related to the type of fusion technique. Methods A previously validated 3D finite element model of an intact C3–T1 segment was used. Three C4–7 fusion models were built from this intact model by varying the number of bone grafts used to span the decompression: a 1-graft model (2-level corpectomy), a 2-graft model (C-5 corpectomy and C6–7 discectomy), and a 3-graft model (3-level discectomy). The corpectomy and discectomy models were also previously validated and compared well with the literature findings. Range of motion, disc stresses, and posterior facet loads at the segments superior (C3–4) and inferior (C7–T1) to the fusion construct were assessed. Results Motion, disc stresses, and posterior facet loads generally increased at both of the adjacent segments in relation to the intact model. Greater biomechanical changes were noted in the superior C3–4 segment than in the inferior C7–T1 segment. Increasing the number of bone grafts from 1 to 2 and from 2 to 3 was associated with a lower magnitude of biomechanical changes at the adjacent segments. Conclusions At segments adjacent to the fusion level, biomechanical changes are not limited solely to the discs, but also propagate to the posterior facets. These changes in discs and posterior facets were found to be lower for discectomy than for corpectomy, thereby supporting the current study hypothesis of inverse relationship between the adjacent-segment variations and the number of fused bone grafts. Such changes may go on to influence the likelihood of adjacent-segment degeneration accordingly. Further studies are warranted to identify the causes and true impact of these observed changes.

Many neck pain complaints are associated with degenerated discs in cervical spine. Disc degeneration (DD) consists of cascading stages of events with complex changes in disc tissue properties. This results in deterioration of the ability of the disc to perform its function normally. Several biomechanical and biochemical changes occur in the disc with degeneration. Increase in motion segment stiffness and peak stresses in the posterior annulus are some of the gross changes that occur in the disc with degeneration.

Collagen fibers in the annulus fibrosus (AF) play a significant role in maintaining the disc mechanical behavior. In healthy discs, AF fibers are concentrically arranged in a zigzag fashion. Tensile loads are transmitted to these fibers when the disc is loaded in compression. As a result, disc bulging occurs. Initiation and progression of mild cervical disc degeneration (DD) has been the subject of clinical concern [1]. The mild DD is associated with structural interruption in laminar organization of fibers in partial AF regions and incomplete length of fibers is a major form of structural interruption in AF fibers [2]. Moreover, a loss of lamellar fiber structure contributes to the progression of spinal deformity [3]. Past research have documented the biomechanical role of complete length of fibers in governing a healthy disc behavior [4]; however, there is a lack of clear understanding as to how incomplete length of fibers in different AF regions affect overall disc biomechanics and how they may play a role in initiating the propagation of DD. The focus of the current study is to investigate the disc biomechanical response due to incomplete length of fibers in outer, middle, and inner AF regions.

SummaryBackgroundCurrent approaches to the detection of colorectal neoplasia associated with inflammatory bowel disease (IBD‐CRN) are suboptimal.AimTo test the feasibility of using stool assay of exfoliated DNA markers to detect IBD‐CRN.MethodsThis investigation comprised tissue and stool studies. In the tissue study, gene sequencing and methylation assays were performed on candidate genes using tissue DNA from 25 IBD‐CRNs and from 25 IBD mucosae without CRN. Mutations on p53, APC, KRAS, BRAF or PIK3CA genes were insufficiently informative, but several aberrantly methylated genes were highly discriminant. In the stool study, we evaluated candidate methylated genes (vimentin, EYA4, BMP3, NDRG4) in a prospective blinded study on buffered stools from 19 cases with known IBD‐CRN and 35 age‐ and sex‐matched IBD controls without CRN. From stool‐extracted DNA, target genes were assayed using quantitative allele‐specific real‐time target and signal amplification method.ResultsIBD‐CRN cases included 17 with ulcerative colitis (UC) and two with Crohn's disease (CD); nine had cancer and 10 had dysplasia. Controls included 25 with UC and 10 with CD. Individually, BMP3, vimentin, EYA4 and NDRG4 markers showed high discrimination in stools with respective areas under the ROC curve of 0.91, 0.91, 0.85 and 0.84 for total IBD‐CRN and of 0.97, 0.97, 0.95 and 0.85 for cancer. At 89% specificity, the combination of BMP3 and mNDRG4 detected 9/9 (100%) of CRC and 80% of dysplasia, 4/4 (100%) of high grade and 4/6 (67%) of low grade.ConclusionThese findings demonstrate the feasibility of stool DNA testing for non‐invasive detection of colorectal neoplasia associated with inflammatory bowel disease.

Tetralogy of Fallot (TOF) is a cyanotic congenital heart defect typically diagnosed in infancy and treated with early surgical correction. We report a patient with TOF diagnosed at age 78. Successful surgical repair was performed at age 83, the oldest reported age of surgical correction of this condition. Despite a complicated surgical and postoperative course, the patient is doing well almost four years later.

Abstract Pancreatic cancer is highly lethal with an estimated 5-year relative survival rate of less than 5%. A genome wide association study (GWAS) of pancreatic cancer (PanScan) conducted within the NCI Cohort Consortium and the Pancreatic Cancer Case-Control Consortium (PANC4) recently identified four common susceptibility loci for pancreatic cancer on chromosomes 1q32.1, 5p15.33, 9q34.2 and 13q22.1. To investigate how these germline variants influence pancreatic cancer risk, we are employing both genome wide and targeted approaches. For the former, we are characterizing the epigenome and transcriptome of pancreatic cell lines and tissue samples for genomic annotation and prioritization of methods to use in targeted approaches with the aim of directly linking pancreatic cancer risk variants to molecular phenotypes and mechanisms that underlie the association signals. As an example of our approach we will present results in a pancreatic cancer susceptibility locus on chromosome 1q32.2 marked by SNP (single nucleotide polymorphism) rs3790844. This SNP is located in the first intron of the NR5A2 gene that encodes a nuclear receptor of the Ftz-F1 family known to be involved in pancreatic development, cholesterol and bile acid homeostasis, steroidogenesis and cell proliferation. In ChIP-sequencing and MeDIP-chip experiments, we observed repressive histone modification marks (H3K27me3) and regions of DNA methylation in the NR5A2 gene locus in pancreatic cell lines whereas only a few weak positive histone modification marks were observed (H3K4me1 and H3K4me3). This pattern of epigenetic marks correlates well with low expression of NR5A2 in the same cell lines. Expression of the NR5A2 gene at the RNA level is high in normal pancreatic tissue samples as compared to stage I-III pancreatic adenocarcinoma, most islet cell and neuroendocrine tumors. Using immunohistochemistry, nuclear NR5A2 was detected in normal acinar cells and – at lower levels – in normal ductal cells. The protein was also expressed in low and high grade PanINs and in the majority of PDAC analyzed. Our analysis of the tissue specific expression of NR5A2 shows that it is mainly expressed in normal pancreas, colon, small intestine, liver and breast but detected at low levels or not at all in most other tissue types and cancer cell lines. Furthermore we have identified a novel NR5A2 transcript by rapid amplification of cDNA ends (RACE) and mapped a promoter in front of this transcript in the genomic region corresponding to first intron of the two annotated Refseq transcripts. Establishing a comprehensive catalog of epigenetic patterns coupled with targeted analysis to correlate risk variants to molecular phenotypes could provide functional plausibility for known pancreatic cancer association signals discovered by GWAS findings. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4965. doi:10.1158/1538-7445.AM2011-4965

AbstractVorinostat, an oral histone deacetylase inhibitor with antitumor activity, is in clinical trials for hematologic and solid tumors that metastasize and compromise bone structure. Consequently, there is a requirement to establish the effects of vorinostat on tumor growth within bone. Breast (MDA-231) and prostate (PC3) cancer cells were injected into tibias of SCID/NCr mice and the effects of vorinostat on tumor growth and osteolytic disease were assessed by radiography, micro-computed tomography, and histologic and molecular analyses. Vorinostat-treated and control mice without tumors were also examined. Tumor growth in bone was reduced ∼33% by vorinostat with inhibited osteolysis in the first few weeks of the experiment. However, osteolysis became more severe in both the vehicle and vorinostat-treated groups. Vorinostat increased the expression of tumor-derived factors promoting bone resorption, including PTHrP, IL-8, and osteopontin. After 4 weeks of vorinostat therapy, the non–tumor-bearing contralateral femurs and limbs from vorinostat-treated tumor-free SCID mice showed significant bone loss (50% volume density of controls). Thus, our studies indicate that vorinostat effectively inhibits tumor growth in bone, but has a negative systemic effect reducing normal trabecular bone mass. Vorinostat treatment reduces tumor growth in bone and accompanying osteolytic disease as a result of decreased tumor burden in bone. However, vorinostat can promote osteopenia throughout the skeleton independent of tumor cell activity. Mol Cancer Ther; 9(12); 3210–20. ©2010 AACR.