Citations

Liposarcoma is one of the most common sarcomas in adults, but only rarely presents as an esophageal primary. There have been several reports of well-differentiated liposarcoma (WDL) arising in the esophagus, but we present a case of dedifferentiated liposarcoma (DL) presenting as a large esophageal polyp. We believe this is the first reported case of DL of the esophagus with morphologic evidence of both well-differentiated and dedifferentiated components. The diagnosis was confirmed by demonstration of CPM gene amplification by fluorescence in situ hybridization (FISH).

Abstract Background. Autophagy maintains energy metabolism and enables tumor cell survival during cellular stress. Beclin 1 is involved in autophagosome formation during which membrane-bound LC3 binds to p62/sequestosome 1. We reported that ectopic p62 can promote 5-fluorouracil-induced cell death (JBC 286:40002-12, 2011). It is unknown whether these autophagy markers can predict clinical outcome. Materials & Methods. Beclin 1, LC3B, and p62 proteins were analyzed by immunohistochemistry in tissue microarrays containing stage II and III colon carcinomas (N=151) from patients receiving 5-FU or surgery alone. The mean weighted score (intensity x extent) was dichotomized for survival analysis using Cox models. Results. Increased levels of cytoplasmic LC3, Beclin 1, and p62 expression were detected in 21%, 14%, and 68% of cancers, respectively, and were not associated with tumor site, stage or grade. By multivariable analysis, increased LC3 was significantly associated with worse disease-free survival (DFS) (p=0.022), but not overall survival (OS) [p=0.069](Table). Beclin 1 was not prognostic, but increased p62 was significantly associated with improved DFS (p=0.038), but not OS (p= 0.176)[Table]. When restricted to 5-FU-treated patients, increased LC3 was associated with worse DFS [HR= 2.38 (1.19, 4.75, p=0.020), elevated Beclin 1 predicted worse OS [HR=2.83 (1.27, 6.34), p = 0.019], and p62 was not prognostic. Conclusion. LC3 and Beclin 1 overexpression were independently associated with adverse outcome. Increased p62 was associated with better outcome consistent with its ability to promote cell death. These data support strategies to inhibit autophagy for therapeutic advantage. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4112. doi:1538-7445.AM2012-4112

Abstract Purpose: We examined the frequency, tumor characteristics, and prognostic impact of HER2 protein expression and gene amplification in patients with curatively resected esophageal adenocarcinoma (EAC). Experimental Design: HER2 expression was analyzed by immunohistochemistry (IHC) in surgical EAC specimens (n = 713). Gene amplification was examined by FISH in a large subset (n = 344). Most tumors were T3–4 (66%) or node positive (72%); 95% were located in the esophagus or gastroesophageal junction. No patient received neoadjuvant therapy. Cox models were used. Results: Overall, 17% of EACs were HER2 positive (i.e., IHC3+ or IHC2+ with amplification), with strong agreement between HER2 amplification (HER2/CEP17 ratio ≥2) and expression (κ = 0.83). HER2 positivity was significantly associated with lower tumor grade, less invasiveness, fewer malignant nodes, and the presence of adjacent Barrett's esophagus (BE). EACs with BE had higher odds of HER2 positivity than EACs without BE, independent of pathologic features [OR = 1.8 (95% CI: 1.1–2.8), P = 0.014]. Among all cases, HER2 positivity was significantly associated with disease-specific survival (DSS) in a manner that differed by the presence or absence of BE (Pinteraction = 0.0047). In EACs with BE, HER2 positivity was significantly associated with improved DSS [HR = 0.54 (95% CI: 0.35–0.84), P = 0.0065] and overall survival (P = 0.0022) independent of pathologic features, but was not prognostic among EACs without BE. Conclusions: HER2 positivity was shown in 17% of resected EACs and associated with reduced tumor aggressiveness. EACs with BE had nearly twice the odds of being HER2 positive and, within this subgroup, HER2 positivity was independently associated with improved survival. Clin Cancer Res; 18(2); 546–54. ©2012 AACR.

Abstract Barrett's esophagus, a columnar metaplasia of the lower esophagus epithelium related to gastroesophageal reflux disease, is the strongest known risk factor for the development of esophageal adenocarcinoma (EAC). Understanding the signal transduction events involved in esophageal epithelium carcinogenesis may provide insights into the origins of EAC and may suggest new therapies. To elucidate the molecular pathways of bile acid–induced tumorigenesis, the newly identified inflammation-associated signaling pathway involving IκB kinases β (IKKβ), tuberous sclerosis complex 1 (TSC1), and mammalian target of rapamycin (mTOR) downstream effector S6 kinase (S6K1) was confirmed to be activated in immortalized Barrett's CPC-A and CPC-C cells and esophageal cancer SEG-1 and BE3 cells. Phosphorylation of TSC1 and S6K1 was induced in response to bile acid stimulation. Treatment of these cells with the mTOR inhibitor rapamycin or the IKKβ inhibitor Bay 11-7082 suppressed bile acid–induced cell proliferation and anchorage-independent growth. We next used an orthotopic rat model to evaluate the role of bile acid in the progression of Barrett's esophagus to EAC. Of interest, we found high expression of phosphorylated IKKβ (pIKKβ) and phosphorylated S6K1 (pS6K1) in tumor tissues and the Barrett's epithelium compared with normal epithelium. Furthermore, immunostaining of clinical EAC tissue specimens revealed that pIKKβ expression was strongly correlated with pS6K1 level. Together, these results show that bile acid can deregulate TSC1/mTOR through IKKβ signaling, which may play a critical role in EAC progression. In addition, Bay 11-7082 and rapamycin may potentially be chemopreventive drugs against Barrett's esophagus–associated EAC. [Cancer Res 2008;68(8):2632–40]