Treatment Of Esophageal Adenocarcinoma Research Articles

S2002 Impact of Vitamin C Supplementation On Regulators of Esophageal Inflammation and Carcinogenesis

Introduction Antioxidants such as vitamin C may have a role in chemoprevention and in modulating cancer treatment responses. The transcription factor NFkappaB is central in the regulation of genes encoding for mediators of inflammation, and Vitamin C modulates its responses In Vitro. The aim of this study was twofold: first, to assess the effect of vitamin C on the NFkappaB and associated cytokines in patients with Barrett's esophagus; and second, in a randomised study, to assess the effect of Vitamin C on the response of esophageal adenocarcinoma to neoadjuvant chemoradiation.. Methods In study 1, 25 patients with long segment Barretts received Vitamin C (1000mg/day) orally for four weeks, and had pre and post-VitaminC endoscopic biopsies. In study 2, 20 patients undergoingmultimodal treatment for esophageal adenocarcinoma were randomized to receive Vitamin C or no supplementation and standard chemoradiation. NFkappaB activity (activated p50 and p65 subunits) of nuclear extracts was assessed using the Active Motif NFkappaB TransAm assay. Cytokine analysis was performed using the Evidence Investigator biochip array. IkB expression was examined by Western blotting. Results NFkappaB (p50 & p65), along with proinflammatory (IL-8, VEGF, IL-1a, IL-1b) and anti-inflammatory cytokines (IL-4) were activated in the Barrett's tissue of all patients pre-treatment. Downregulation in activated NFkappaB (p50 subunit) and related cytokines was observed in 8/25 patients (32%). In study 2, NFkappaB (p50 & p65), along with proinflammatory (IL-8, VEGF, IL-1a, IL-1b) and anti-inflammatory cytokines (IL-4) were activated in the cancer tissue of all patients pre-treatment. Downregulation in NFkappaB and downstream cytokines was observed in five patients (25%), 2 from the Vitamin C arm. Conclusion Constitutive activation of NFkappaB and target cytokines was observed in all Barrett's esophagus and adenocarcinoma patients. Vitamin C supplementation however, in contrast to In Vitro studies, had little effect in modulating these responses, and the studies failed to support its value in chemoprevention or modulation of chemoradiation responses.

Molecular biological challenges in he treatment of esophageal adenocarcinoma

Despite improvements in detection and treatment, patients diagnosed with esophageal cancer continue to have a poor prognosis, with an increase in 5-year survival rates from 6 to 16% over the past 25 years. In the last decade there has been growing support for neoadjuvant therapy in patients with esophageal cancer. However, in approximately 30–60% of the patients no objective response is achieved after neoadjuvant chemotherapy and/or radiotherapy. These patients do not benefit from neoadjuvant therapy but do suffer from toxic side effects, and appropriate surgical treatment is delayed. Advances in molecular biology and new molecular technologies could possibly contribute to improvement of response to neoadjuvant therapy. This review categorizes the genetic and molecular alterations related to esophageal adenocarcinoma and links these changes to targeting therapy and prediction of tumor response to neoadjuvant chemotherapy and/or radiotherapy.

Barrett’s esophagus and esophageal adenocarcinoma in adults: Long-term GERD or something else?

Esophageal adenocarcinoma (EAC) is a highly lethal tumor and is currently the most rapidly rising incidence cancer in the Western world. Numerous risk factors in the development of Barrett's esophagus (BE) (a precursor of EAC) and EAC itself have been identified and are likely multifactorial. Gastroesophageal reflux disease (GERD) is a significant risk factor for BE and EAC; however, only a minority of patients with chronic GERD actually develop BE. Thus, other risk factors that modulate reflux-related inflammatory and neoplastic effects on esophageal epithelium must exist. Epidemiologic data have prompted initiation of chemopreventive trials using aspirin and proton pump inhibitors in the treatment of BE and EAC. Further research should also clarify the role of risk factors such as ethnicity and obesity in BE and EAC development and progression. Identification of prognostic factors would allow better risk stratification of patients and ultimately impact the rising incidence of EAC.

Activation of the serine/threonine protein kinase Akt during the progression of Barrett neoplasia

Esophageal adenocarcinoma has demonstrated a rapid increase in incidence over the last 10 years. This increase mirrors a dramatic rise in that of Barrett esophagus, which is associated with esophageal adenocarcinoma in at least 95% of cases. In an attempt to understand the pathogenesis of esophageal adenocarcinoma, attention has turned to the antiapoptotic and oncogenic pathways. Here we demonstrated that Akt was frequently activated in Barrett esophagus-related adenocarcinoma. Remarkably, the levels of Akt activation were associated with tumor progression. After institutional review board ethics approval, 60 archival tissue specimens of esophageal adenocarcinoma arising on a background of Barrett esophagus were selected for immunohistochemical staining with phosphorylated Akt (p-Akt) antibody. The slides were scored by 2 independent observers. Approximately 80% of high-grade dysplasia and esophageal adenocarcinoma cases demonstrated strong to moderate Akt activity. Sixty-two percent of Barrett mucosa revealed low Akt activity, the remaining cases being p-Akt negative. None of the low-grade dysplasia cases exhibited strong p-Akt staining, whereas only weak p-Akt activity is seen in a portion of metaplastic Barrett mucosa, Akt is highly activated in high-grade dysplasia and esophageal adenocarcinoma arising from Barrett esophagus. These findings suggest a role of p-Akt in the progression of Barrett esophagus to esophageal adenocarcinoma and provide the rationale for using p-Akt inhibitor API-2/triciribine, which is currently in clinical trial, in the treatment of esophageal adenocarcinoma.

Systematic review: the application of molecular pathogenesis to prevention and treatment of oesophageal adenocarcinoma

Oesophageal adenocarcinoma is an increasingly common cancer with a poor prognosis. It develops in a stepwise progression from Barrett's metaplasia to dysplasia, and then adenocarcinoma followed by metastasis. To outline the key molecular changes in oesophageal adenocarcinoma and to summarize the chemopreventative and therapeutic strategies proposed. A literature search was performed to identify appropriate research papers in the field. Search terms included: Barrett's (o)esophagus, intestinal metaplasia, (o)esophageal adenocarcinoma, molecular changes, genetic changes, pathogenesis, chemoprevention, therapeutic strategies and treatment. The search was restricted to English language articles. A large number of molecular changes have been identified in the progression from Barrett's oesophagus to oesophageal adenocarcinoma although there does not appear to be an obligate order of events. Potential chemoprevention strategies include acid suppression, anti-inflammatory agents and antioxidants. In established adenocarcinoma, targeted treatments under evaluation include receptor tyrosine kinase inhibitors of EGFR and cyclin-dependent kinase inhibitors, which may benefit a subgroup of patients. Advances in molecular methodology have led to a greater understanding of the oesophageal adenocarcinoma pathways, which provides opportunities for chemoprevention and therapeutic strategies with a mechanistic basis. More work is required to assess both the safety and efficacy of these new treatments.

Effects of selective PGE 2 receptor antagonists in esophageal adenocarcinoma cells derived from Barrett's esophagus

Accumulating evidence suggests that COX-2-derived prostaglandin E 2 (PGE 2) plays an important role in esophageal adenocarcinogenesis. Recently, PGE 2 receptors (EP) have been shown to be involved in colon cancer development. Since it is not known which receptors regulate PGE 2 signals in esophageal adenocarcinoma, we investigated the role of EP receptors using a human Barrett's-derived esophageal adenocarcinoma cell line (OE33). OE33 cells expressed COX-1, COX-2, EP 1, EP 2 and EP 4 but not EP 3 receptors as determined by real time RT-PCR and Western-blot. Treatment with 5-aza-dC restored expression, suggesting that hypermethylation is involved in EP 3 downregulation. Endogenous PGE 2 production was mainly due to COX-2, since this was significantly suppressed with COX-2 inhibitors (NS-398 and SC-58125), but not COX-1 inhibitors (SC-560). Cell proliferation ( 3H-thymidine uptake) was significantly inhibited by NS-398 and SC-58125, the EP 1 antagonist SC-51322, AH6809 (EP 1/EP 2 antagonist), and the EP 4 antagonist AH23848B, but was not affected by exogenous PGE 2. However, treatment with the selective EP 2 agonist Butaprost or 16,16-dimethylPGE 2 significantly inhibited butyrate-induced apoptosis and stimulated OE33 cell migration. The effect of exogenous PGE 2 on migration was attenuated when cells were first treated with EP 1 and EP 4 antagonists. These findings suggest a potential role for EP selective antagonists in the treatment of esophageal adenocarcinoma.

Infectivity-enhanced cyclooxygenase-2-based conditionally replicative adenoviruses for esophageal adenocarcinoma treatment.

The employment of conditionally replicative adenoviruses (CRAd) constitutes a promising alternative for cancer treatment; however, in the case of esophageal adenocarcinoma (EAC) the lack of an appropriate tumor-specific promoter and relative resistance to adenovirus infection have hampered the construction of CRAds with clinically applicable specificity and efficacy. By combining transcriptional targeting with infectivity enhancement for CRAds, we generated novel cyclooxygenase-2 (Cox-2) promoter-controlled replicative viral agents for the treatment of EAC. We used infectivity enhancement based on incorporation of an RGD-4C motif into the HI loop of the adenoviral (Ad) fiber knob domain as well as replacement of the Ad5 knob with the Ad3 knob. The Cox-2 promoter was highly active in EAC, whereas showing no significant activity in Cox-2-negative cell lines and primary cells isolated from normal mouse esophagus and stomach. Evaluation of infectivity-enhanced vectors revealed that the transduction and virus-cell binding ability of Ad5/Ad3-chimera were significantly more efficient than that of unmodified and Arg-Gly-Asp (RGD)-modified vectors. All of the Cox-2 CRAds demonstrated replication and subsequent oncolysis in EAC cells but not in Cox-2-negative cells in vitro, thus confirming the dependence of their replication on the Cox-2 promoter activity. Ad5/Ad3 CRAds exhibited significantly improved oncolysis and progeny production compared with unmodified and RGD-modified vectors without sacrificing tumor selectivity. Whereas unmodified and RGD-modified CRAds showed insignificant therapeutic effect in vivo, Ad5/Ad3 CRAds remarkably suppressed tumor growth of established xenografts in mice. Thus, our studies have demonstrated that Ad5/Ad3-chimeric Cox-2 promoter-driven CRAds are selective and potent agents for the treatment of EAC.

Role of cyclooxygenase-2 in the development and treatment of oesophageal adenocarcinoma.

Various studies suggest that aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) are promising anticancer agents. Epidemiological studies have found that long-term use of NSAIDs is associated with a reduced incidence of colorectal, gastric and oesophageal cancers, while experimental and clinical studies have demonstrated that treatment with NSAIDs causes a statistically significant reduction in both the number and the size of polyps in familial adenomatous polyposis (FAP) patients. In this review, the mechanisms by which NSAIDs exert their chemopreventive and antineoplastic effects are described. Although the precise anticancer actions of NSAIDs are not fully explained, they probably involve inhibition of cyclooxygenase (COX), which is the rate-limiting enzyme in the conversion of arachidonic acid to prostaglandins. Two isoforms of this enzyme (COX-1 and COX-2) have been identified. COX-1 is constitutively expressed and considered to be a housekeeping gene, while COX-2 is not usually detectable in normal tissues, but can be readily induced in processes like inflammation, reproduction and carcinogenesis. The mechanisms by which COX-2 is thought to be involved in the carcinogenesis include resisting apoptosis, increasing cell proliferation, stimulating angiogenesis and modulating the invasive properties of cancer cells. This report reviews the mechanisms by which COX-2 can contribute to carcinogenesis, its role in prognosis, and the possible place of selective COX-2 inhibitors in the prevention and treatment of gastrointestinal malignancies, focusing particularly on oesophageal cancer.

Potential role for selective PGE2 receptor antagonists in the treatment of esophageal adenocarcinoma derived from Barrett's esophagus

Potential role for selective PGE2 receptor antagonists in the treatment of esophageal adenocarcinoma derived from Barrett's esophagus

Spontaneous and inducible apoptosis in oesophageal adenocarcinoma

The use of neoadjuvant chemoradiotherapy prior to surgery in the treatment of oesophageal adenocarcinoma has increased in recent years, and up to 25% of patients will have a complete pathological response to the neoadjuvant therapy. Many patients will not respond, however, and the knowledge of molecular factors predicting response or resistance to chemoradiotherapy is required to enhance treatment results. An understanding of apoptosis and cell proliferation may be relevant and this study focused on apoptotic indices and cell-cycle related (Ki-67, p53 and bcl-2) protein expression in a cohort of 42 patients with primary oesophageal adenocarcinoma. We documented that apoptosis occurs among viable (proliferating) tumour cells in all adenocarcinoma cases examined in this study. Pre-operative chemoradiotherapy significantly increased apoptosis and significantly decreased cell proliferation (estimated by Ki-67 expression). Immunohistochemically detected p53 and bcl-2 gene products had no regulatory role in the apoptotic process. The cumulative expression of p53 protein is significantly associated with increasing proliferation activity. Evaluation of apoptosis in pre-treatment specimens may have potential utility in predicting the efficacy of treatment. Assessment of the tumours proliferation activity by Ki-67 expression might identify patients who are at risk of developing metastastic disease. © 2001 Cancer Research Campaign http://www.bjcancer.com

Role of laparoscopy and thoracoscopy in the treatment of esophageal adenocarcinoma.

Role of laparoscopy and thoracoscopy in the treatment of esophageal adenocarcinoma.

Determinants of survival following the diagnosis of esophageal adenocarcinoma (United States).

The rapidly rising incidence of esophageal adenocarcinomas in the United States and western Europe remains unexplained. Most persons who develop the disease have had long-standing gastroesophageal reflux symptoms with concomitant Barrett's metaplasia. They are, therefore, potentially identifiable for endoscopic screening and cancer surveillance, which should facilitate the early detection of these tumors. We undertook these analyses to determine the extent to which the opportunity for early diagnosis and treatment of esophageal adenocarcinomas has been realized in the US. Specifically, using data from the Surveillance, Epidemiology, and End Results (SEER) program of the US National Cancer Institute, we examined changes in stage of disease at diagnosis and in survival between 1973 and 1991 and investigated patient characteristics as predictors of survival. Improvements in stage at diagnosis and in survival between 1973 and 1991 were minor and clinically insignificant; overall five-year survival never exceeded 10 percent. Stage of disease at diagnosis was the strongest determinant of subsequent survival; five-year survival with patients with in situ tumors was 68.2 percent. This survival advantage persisted up to 15 years after diagnosis and was independent of other prognostic factors. We conclude that the opportunity for reduction in esophageal cancer mortality has been largely unrealized in the US. In light of the increasing incidence of esophageal adenocarcinoma, efforts should be devoted to identifying those at highest risk of developing Barrett's metaplasia and subsequent adenocarcinoma, and to developing cost-effective primary prevention and cancer surveillance methods targetting them.