Citations

Gut dysbiosis, host genetics, and environmental triggers are implicated as causative factors in inflammatory bowel disease (IBD), yet mechanistic insights are lacking. Longitudinal analysis of ulcerative colitis (UC) patients following total colectomy with ileal anal anastomosis (IPAA) where >50% develop pouchitis offers a unique setting to examine cause vs. effect. To recapitulate human IPAA, we employed a mouse model of surgically created blind self-filling (SFL) and self-emptying (SEL) ileal loops using wild-type (WT), IL-10 knockout (KO) (IL-10), TLR4 KO (T4), and IL-10/T4 double KO mice. After 5 wk, loop histology, host gene/protein expression, and bacterial 16s rRNA profiles were examined. SFL exhibit fecal stasis due to directional motility oriented toward the loop end, whereas SEL remain empty. In WT mice, SFL, but not SEL, develop pouchlike microbial communities without accompanying active inflammation. However, in genetically susceptible IL-10-deficient mice, SFL, but not SEL, exhibit severe inflammation and mucosal transcriptomes resembling human pouchitis. The inflammation associated with IL-10 required TLR4, as animals lacking both pathways displayed little disease. Furthermore, germ-free IL-10 mice conventionalized with SFL, but not SEL, microbiota populations develop severe colitis. These data support essential roles of stasis-induced, colon-like microbiota, TLR4-mediated colonic metaplasia, and genetic susceptibility in the development of pouchitis and possibly UC. However, these factors by themselves are not sufficient. Similarities between this model and human UC/pouchitis provide opportunities for gaining insights into the mechanistic basis of IBD and for identification of targets for novel preventative and therapeutic interventions.

Purpose We evaluated atypical response patterns and the relationship between overall survival and best overall response measured per immune-related response criteria (irRC) and Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) in patients with advanced melanoma treated with pembrolizumab in the phase Ib KEYNOTE-001 study (clinical trial information: NCT01295827). Patients and Methods Patients received pembrolizumab 2 or 10 mg/kg every 2 weeks or every 3 weeks. Atypical responses were identified by using centrally assessed irRC data in patients with ≥ 28 weeks of imaging. Pseudoprogression was defined as ≥ 25% increase in tumor burden at week 12 (early) or any assessment after week 12 (delayed) that was not confirmed as progressive disease at next assessment. Response was assessed centrally per irRC and RECIST v1.1. Results Of the 655 patients with melanoma enrolled, 327 had ≥ 28 weeks of imaging follow-up. Twenty-four (7%) of these 327 patients had atypical responses (15 [5%] with early pseudoprogression and nine [3%] with delayed pseudoprogression). Of the 592 patients who survived ≥ 12 weeks, 84 (14%) experienced progressive disease per RECIST v1.1 but nonprogressive disease per irRC. Two-year overall survival rates were 77.6% in patients with nonprogressive disease per both criteria (n = 331), 37.5% in patients with progressive disease per RECIST v1.1 but nonprogressive disease per irRC (n = 84), and 17.3% in patients with progressive disease per both criteria (n = 177). Conclusion Atypical responses were observed in patients with melanoma treated with pembrolizumab. Based on survival analysis, conventional RECIST might underestimate the benefit of pembrolizumab in approximately 15% of patients; modified criteria that permit treatment beyond initial progression per RECIST v1.1 might prevent premature cessation of treatment.

Study Design Review of the literature. Objective Surgery and cement augmentation procedures are effective palliative treatment of symptomatic spinal metastases. Our objective is to systematically review the literature to describe the survival, prognostic factors, and clinical outcomes of surgery and cement augmentation procedures for breast cancer metastases to the spine. Methods We performed a literature review using PubMed to identify articles that reported outcomes and/or prognostic factors of the breast cancer patient population with spinal metastases treated with any surgical technique since 1990. Results The median postoperative survival for metastatic breast cancer was 21.7 months (8.2 to 36 months), the mean rate of any pain improvement was 92.9% (76 to 100%), the mean rate of neurologic improvement was 63.8% (53 to 100%), the mean rate of neurologic decline was 4.1% (0 to 8%), and the local tumor control rate was 92.6% (89 to 100%). Kyphoplasty studies reported a high rate of pain control in selected patients. Negative prognostic variables included hormonal (estrogen and progesterone) and human epidermal growth factor receptor 2 (HER2) receptor refractory tumor status, high degree of axillary lymph node involvement, and short disease-free interval (DFI). All other clinical or prognostic parameters were of low or insufficient strength. Conclusion With respect to clinical outcomes, surgery consistently yielded neurologic improvements in patients presenting with a deficit with a minimal risk of worsening; however, negative prognostic factors associated with shorter survival following surgery include estrogen receptor/progesterone receptor negativity, HER2 negativity, and a short DFI.

ABSTRACTEpithelial‐mesenchymal transition (EMT) is a process whereby epithelial cells assume mesenchymal characteristics to facilitate cancer metastasis. However, EMT also contributes to the initiation and development of primary tumors. Prior studies that explored the hypothesis that EMT gene variants contribute to epithelial ovarian carcinoma (EOC) risk have been based on small sample sizes and none have sought replication in an independent population. We screened 15,816 single‐nucleotide polymorphisms (SNPs) in 296 genes in a discovery phase using data from a genome‐wide association study of EOC among women of European ancestry (1,947 cases and 2,009 controls) and identified 793 variants in 278 EMT‐related genes that were nominally (P < 0.05) associated with invasive EOC. These SNPs were then genotyped in a larger study of 14,525 invasive‐cancer patients and 23,447 controls. A P‐value <0.05 and a false discovery rate (FDR) <0.2 were considered statistically significant. In the larger dataset, GPC6/GPC5 rs17702471 was associated with the endometrioid subtype among Caucasians (odds ratio (OR) = 1.16, 95% CI = 1.07–1.25, P = 0.0003, FDR = 0.19), whereas F8 rs7053448 (OR = 1.69, 95% CI = 1.27–2.24, P = 0.0003, FDR = 0.12), F8 rs7058826 (OR = 1.69, 95% CI = 1.27–2.24, P = 0.0003, FDR = 0.12), and CAPN13 rs1983383 (OR = 0.79, 95% CI = 0.69–0.90, P = 0.0005, FDR = 0.12) were associated with combined invasive EOC among Asians. In silico functional analyses revealed that GPC6/GPC5 rs17702471 coincided with DNA regulatory elements. These results suggest that EMT gene variants do not appear to play a significant role in the susceptibility to EOC.

Abstract Background: Genome-wide association studies (GWAS) have so far reported 12 loci associated with serous epithelial ovarian cancer (EOC) risk. We hypothesized that some of these loci function through nearby transcription factor (TF) genes and that putative target genes of these TFs as identified by coexpression may also be enriched for additional EOC risk associations. Methods: We selected TF genes within 1 Mb of the top signal at the 12 genome-wide significant risk loci. Mutual information, a form of correlation, was used to build networks of genes strongly coexpressed with each selected TF gene in the unified microarray dataset of 489 serous EOC tumors from The Cancer Genome Atlas. Genes represented in this dataset were subsequently ranked using a gene-level test based on results for germline SNPs from a serous EOC GWAS meta-analysis (2,196 cases/4,396 controls). Results: Gene set enrichment analysis identified six networks centered on TF genes (HOXB2, HOXB5, HOXB6, HOXB7 at 17q21.32 and HOXD1, HOXD3 at 2q31) that were significantly enriched for genes from the risk-associated end of the ranked list (P &lt; 0.05 and FDR &lt; 0.05). These results were replicated (P &lt; 0.05) using an independent association study (7,035 cases/21,693 controls). Genes underlying enrichment in the six networks were pooled into a combined network. Conclusion: We identified a HOX-centric network associated with serous EOC risk containing several genes with known or emerging roles in serous EOC development. Impact: Network analysis integrating large, context-specific datasets has the potential to offer mechanistic insights into cancer susceptibility and prioritize genes for experimental characterization. Cancer Epidemiol Biomarkers Prev; 24(10); 1574–84. ©2015 AACR.