Pleiotropic genes for metabolic syndrome and inflammation.

Metabolic syndrome (MetS) has become a health and financial burden worldwide. The MetS definition captures clustering of risk factors that predict higher risk for diabetes mellitus and cardiovascular disease. Our study hypothesis is that additional to genes influencing individual MetS risk factors, genetic variants exist that influence MetS and inflammatory markers forming a predisposing MetS genetic network. To test this hypothesis a staged approach was undertaken. (a) We analyzed 17 metabolic and inflammatory traits in more than 85,500 participants from 14 large epidemiological studies within the Cross Consortia Pleiotropy Group. Individuals classified with MetS (NCEP definition), versus those without, showed on average significantly different levels for most inflammatory markers studied. (b) Paired average correlations between 8 metabolic traits and 9 inflammatory markers from the same studies as above, estimated with two methods, and factor analyses on large simulated data, helped in identifying 8 combinations of traits for follow-up in meta-analyses, out of 130,305 possible combinations between metabolic traits and inflammatory markers studied. (c) We performed correlated meta-analyses for 8 metabolic traits and 6 inflammatory markers by using existing GWAS published genetic summary results, with about 2.5 million SNPs from twelve predominantly largest GWAS consortia. These analyses yielded 130 unique SNPs/genes with pleiotropic associations (a SNP/gene associating at least one metabolic trait and one inflammatory marker). Of them twenty-five variants (seven loci newly reported) are proposed as MetS candidates. They map to genes MACF1, KIAA0754, GCKR, GRB14, COBLL1, LOC646736-IRS1, SLC39A8, NELFE, SKIV2L, STK19, TFAP2B, BAZ1B, BCL7B, TBL2, MLXIPL, LPL, TRIB1, ATXN2, HECTD4, PTPN11, ZNF664, PDXDC1, FTO, MC4R and TOMM40. Based on large data evidence, we conclude that inflammation is a feature of MetS and several gene variants show pleiotropic genetic associations across phenotypes and might explain a part of MetS correlated genetic architecture. These findings warrant further functional investigation.

Stereotactic body radiation therapy planning with duodenal sparing using volumetric-modulated arc therapy vs intensity-modulated radiation therapy in locally advanced pancreatic cancer: a dosimetric analysis.

Stereotactic body radiation therapy (SBRT) achieves excellent local control for locally advanced pancreatic cancer (LAPC), but may increase late duodenal toxicity. Volumetric-modulated arc therapy (VMAT) delivers intensity-modulated radiation therapy (IMRT) with a rotating gantry rather than multiple fixed beams. This study dosimetrically evaluates the feasibility of implementing duodenal constraints for SBRT using VMAT vs IMRT. Non-duodenal sparing (NS) and duodenal-sparing (DS) VMAT and IMRT plans delivering 25Gy in 1 fraction were generated for 15 patients with LAPC. DS plans were constrained to duodenal Dmax of<30Gy at any point. VMAT used 1 360° coplanar arc with 4° spacing between control points, whereas IMRT used 9 coplanar beams with fixed gantry positions at 40° angles. Dosimetric parameters for target volumes and organs at risk were compared for DS planning vs NS planning and VMAT vs IMRT using paired-sample Wilcoxon signed rank tests. Both DS VMAT and DS IMRT achieved significantly reduced duodenal Dmean, Dmax, D1cc, D4%, and V20Gy compared with NS plans (all p≤0.002). DS constraints compromised target coverage for IMRT as demonstrated by reduced V95% (p = 0.01) and Dmean (p = 0.02), but not for VMAT. DS constraints resulted in increased dose to right kidney, spinal cord, stomach, and liver for VMAT. Direct comparison of DS VMAT and DS IMRT revealed that VMAT was superior in sparing the left kidney (p<0.001) and the spinal cord (p<0.001), whereas IMRT was superior in sparing the stomach (p = 0.05) and the liver (p = 0.003). DS VMAT required 21% fewer monitor units (p<0.001) and delivered treatment 2.4 minutes faster (p<0.001) than DS IMRT. Implementing DS constraints during SBRT planning for LAPC can significantly reduce duodenal point or volumetric dose parameters for both VMAT and IMRT. The primary consequence of implementing DS constraints for VMAT is increased dose to other organs at risk, whereas for IMRT it is compromised target coverage. These findings suggest clinical situations where each technique may be most useful if DS constraints are to be employed.

Randomized phase III multi-institutional study of TNFerade biologic with fluorouracil and radiotherapy for locally advanced pancreatic cancer: final results.

PURPOSE: TNFerade biologic is a novel means of delivering tumor necrosis factor alpha to tumor cells by gene transfer. We herein report final results of the largest randomized phase III trial performed to date among patients with locally advanced pancreatic cancer (LAPC) and the first to test gene transfer against this malignancy. PATIENTS AND METHODS: In all, 304 patients were randomly assigned 2:1 to standard of care plus TNFerade (SOC + TNFerade) versus standard of care alone (SOC). SOC consisted of 50.4 Gy in 28 fractions with concurrent fluorouracil (200 mg/m(2) per day continuous infusion). TNFerade was injected intratumorally before the first fraction of radiotherapy each week at a dose of 4 × 10(11) particle units by using either a percutaneous transabdominal or an endoscopic ultrasound approach. Four weeks after chemoradiotherapy, patients began gemcitabine (1,000 mg/m(2) intravenously) with or without erlotinib (100 to 150 mg per day orally) until progression or toxicity. RESULTS: The analysis included 187 patients randomly assigned to SOC + TNFerade and 90 to SOC by using a modified intention-to-treat approach. Median follow-up was 9.1 months (range, 0.1 to 50.5 months). Median survival was 10.0 months for patients in both the SOC + TNFerade and SOC arms (hazard ratio [HR], 0.90; 95% CI, 0.66 to 1.22; P = .26). Median progression-free survival (PFS) was 6.8 months for SOC + TNFerade versus 7.0 months for SOC (HR, 0.96; 95% CI, 0.69 to 1.32; P = .51). Among patients treated on the SOC + TNFerade arm, multivariate analysis showed that TNFerade injection by an endoscopic ultrasound-guided transgastric/transduodenal approach rather than a percutaneous transabdominal approach was a risk factor for inferior PFS (HR, 2.08; 95% CI, 1.06 to 4.06; P = .032). The patients in the SOC + TNFerade arm experienced more grade 1 to 2 fever and chills than those in the SOC arm (P < .001) but both arms had similar rates of grade 3 to 4 toxicities (all P > .05). CONCLUSION: SOC + TNFerade is safe but not effective for prolonging survival in patients with LAPC.

Comparative analysis of traditional and coiled fiducials implanted during EUS for pancreatic cancer patients receiving stereotactic body radiation therapy.

BACKGROUND: EUS-guided fiducial placement facilitates image-guided radiation therapy (IGRT). OBJECTIVE: To compare 2 types of commercially available fiducials for technical success, complications, visibility, and migration. DESIGN: Retrospective, single-center, comparative study. SETTING: Tertiary-care medical center. INTERVENTIONS: Traditional fiducials (TFs) (5-mm length, 0.8-mm diameter) and Visicoil fiducials (VFs) (10-mm length, 0.35-mm diameter) were compared. Fiducials were placed using linear 19-gauge (for TFs) or 22-gauge (for VFs) needles. A subjective visualization scoring system (0-2; 0 = not visible, 1 = barely visible, 2 = clearly visible) was used to assess visibility on CT. Fiducial migration was calculated as a change in interfiducial distance. MAIN OUTCOME MEASUREMENTS: Technical success, complications, visibility, and migration of 2 types of fiducials. RESULTS: Thirty-nine patients with locally advanced pancreatic cancer underwent EUS-guided placement of 103 fiducials (77 TFs, 26 VFs). The mean number of fiducials placed per patient was 2.66 (standard deviation 0.67) for the 19-gauge needle and 2.60 (standard deviation 0.70) for the 22-gauge needle (P = .83). No intra- or postprocedural complications were encountered. The median visibility score for TFs was significantly better than that for VFs, both when scores of 0 were and were not included (2.00, interquartile range [IQR] 2.00-2.00 vs 1.75, IQR 1.50-2.00, P = .009 and 2.00, IQR 2.00-2.00 vs 2.00, IQR 1.50-2.00, P < .0001, respectively). The mean migration was not significantly different between the 2 types of fiducials (0.8 mm [IQR 0.4-1.6 mm] for TFs vs 1.3 mm [IQR 0.6-1.5 mm] for VFs; P = .72). LIMITATIONS: Retrospective, nonrandomized design. CONCLUSIONS: Visibility was significantly better for TFs compared with VFs. The degree of fiducial migration was not significantly different for TFs and VFs. There was no significant difference in the mean number of fiducials placed, indicating a similar degree of technical difficulty for TF and VF deployment.