8-hydroxy-2--deoxyguanosine and Gastroesophageal-Reflux

The initial results from ablation therapy for metaplastic/dysplastic Barrett's esophagus (BE) are promising, but the results of extended follow-up evaluation are seldom reported.. Neodymium:yttrium-aluminum-garnet laser ablation and successful antireflux surgery for 18 patients with metaplastic BE primarily resulted in the total histologic eradication of BE in 15 patients (83%). After antireflux surgery, the healing of gastroesophageal reflux disease (GERD) was objectively verified in all the patients. At late follow-up evaluation, endoscopy, conventional histology, molecular oxidative stress analyses in comparison with normal control conditions (8-hydroxydeoxyguanosine [8-OHdG], superoxide dismutase [SOD], glutathione [GSH], myeloperoxydase [MP]), and immunohistochemistry (p53, and Cdx2, caudal-related homeobox gene 2, marking intestinal differentiation) of the neosquamous epithelium were performed.. At the end of the follow-up period (range, 3-15 years; mean, 8 years), intestinal metaplasia without dysplasia was detected histologically in eight patients (44%). Six patients had macroscopic BE (mean length, 3.5 cm; range 1-10 cm). The neosquamous epithelium was histologically normal, with no underlying columnar tissue. The fundoplication was endoscopically normal in 14 patients (82%). The 8-OHdG level was higher in the neosquamous epithelium than in the control conditions in the distal esophagus (4.3 vs. 0.52; P = 0.0002) and the proximal esophagus (1.8 vs. 0.95; P = 0.006). Likewise, SOD activity was higher in the neosquamous epithelium (0.38 vs. 0.12; P = 0.0005), whereas MP activity and GSH levels remained normal. Three patients showed slight nuclear p53 expression (typical in normal inflammatory reactions), whereas Cdx2 positivity was confined to one case with recurrent intestinal metaplasia.. The neosquamous mucosa, generated by the ablation of BE and the treatment of GERD with fundoplication, was stable during long-term follow-up evaluation in two-thirds of the patients with initial eradication. It had normal p53 expression and no Cdx2 protein expression. The oxidative stress of the neosquamous esophagus remained high, although the clinical significance of this is unclear.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aluminum; Barrett Esophagus; CDX2 Transcription Factor; Combined Modality Therapy; Deoxyguanosine; Esophagus; Female; Fundoplication; Gastroesophageal Reflux; Glutathione; Homeodomain Proteins; Humans; Intestinal Mucosa; Laser Therapy; Male; Metaplasia; Oxidative Stress; Peroxidase; Postoperative Complications; Recurrence; Superoxide Dismutase; Treatment Outcome; Tumor Suppressor Protein p53; Yttrium

Increased fruit and vegetable consumption is associated with decreased risk of a number of cancers of epithelial origin, including esophageal cancer. Dietary administration of lyophilized black raspberries (LBRs) has significantly inhibited chemically induced oral, esophageal, and colon carcinogenesis in animal models. Likewise, berry extracts added to cell cultures significantly inhibited cancer-associated processes. Positive results in preclinical studies have supported further investigation of berries and berry extracts in high-risk human cohorts, including patients with existing premalignancy or patients at risk for cancer recurrence. We are currently conducting a 6-mo chemopreventive pilot study administering 32 or 45 g (female and male, respectively) of LBRs to patients with Barrett's esophagus (BE), a premalignant esophageal condition in which the normal stratified squamous epithelium changes to a metaplastic columnar-lined epithelium. BE's importance lies in the fact that it confers a 30- to 40-fold increased risk for the development of esophageal adenocarcinoma, a rapidly increasing and extremely deadly malignancy. This is a report on interim findings from 10 patients. To date, the results support that daily consumption of LBRs promotes reductions in the urinary excretion of two markers of oxidative stress, 8-epi-prostaglandin F2alpha (8-Iso-PGF2) and, to a lesser more-variable extent, 8-hydroxy-2'-deoxyguanosine (8-OHdG), among patients with BE.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Anticarcinogenic Agents; Barrett Esophagus; Biomarkers; Deoxyguanosine; Dinoprost; Esophageal Neoplasms; Female; Food Preservation; Freeze Drying; Fruit; Gastroesophageal Reflux; Humans; Male; Middle Aged; Oxidative Stress; Phytotherapy; Pilot Projects; Precancerous Conditions; Rosaceae

Gastro-oesophageal reflux has been shown to induce oxidative DNA damage.. To determine whether oxidative DNA damage, detected in oesophageal biopsies by simple immunohistochemical staining, correlates with gastro-oesophageal reflux disease as determined by pH monitoring.. The study included 47 patients with reflux symptoms who had oesophageal biopsy and 24-h pH monitoring studies performed within 3 months of each other with no variation in treatment in the time between the two procedures. Sections of formalin-fixed and paraffin-embedded oesophageal biopsies were stained for 8-hydroxy-2'-deoxyguanosine using the standard immunoperoxidase method. Positive nuclear immunoreactivity was considered to indicate oxidative DNA damage.. Seven (33%) of the 21 cases with normal 24-h pH monitoring results were negative for oxidative DNA damage, compared with only two (8%) of the 26 cases with abnormal 24-h pH results (P=0.058, two-sided Fisher's exact test). Five of the patients with normal 24-h pH results had oesophageal biopsies performed within 24 h of the monitoring procedure and, of these, four (80%) were positive for oxidative DNA damage, including a case in which both biopsy and 24-h pH monitoring were performed on the same day whilst the patient was on proton pump inhibitor therapy. All cases with normal 24-h pH results and positive oxidative DNA damage showed features of reflux on routine morphological evaluation.. Oxidative DNA damage can occur in the absence of acid reflux and despite adequate antisecretory therapy. This may indicate that other agents, such as bile, can induce oxidative DNA damage in an acid-suppressed environment. The significant discordance between oxidative DNA damage and 24-h pH results makes the determination of oxidative DNA damage a poor surrogate marker for 24-h pH monitoring.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Biopsy; Deoxyguanosine; DNA Damage; Female; Gastroesophageal Reflux; Humans; Hydrogen-Ion Concentration; Immunohistochemistry; Male; Middle Aged; Oxidative Stress

Oxidative damage has long been related to carcinogenesis in human cancers and animal cancer models. Recently a rat esophageal adenocarcinoma (EAC) model was established in our laboratory by using esophagoduodenal anastomosis (EDA) plus iron supplementation. Our previous study suggested that iron supplementation enhanced inflammation and the production of reactive nitrogen species in the esophageal epithelium, which could contribute to esophageal adenocarcinogenesis. Here we further characterized oxidative damage in this model. We were particularly interested in how excess iron was deposited in the esophagus, and which cells were targeted by oxidative damage. Male Sprague-Dawley rats received iron supplementation (50 mg Fe/kg/month, i.p.) starting 4 weeks after EDA. The animals were killed at 11, 30 or 35 weeks after surgery. EAC appeared as early as week 11 after surgery, and increased over time, up to 60% at 35 weeks after surgery. All EACs were well-differentiated mucinous adenocarcinoma at the squamocolumnar junction. Iron deposition was found at the squamocolumnar junction and in the area with esophagitis. Esophageal iron overload could result from transient increase of blood iron after i.p. injection, and the overexpression of transferrin receptor in the premalignant columnar-lined esophagus (CLE) cells. Oxidative damage to DNA (8-hydroxy-2'-deoxyguanosine), protein (carbonyl content) and lipid (thiobarbituric acid reactive substance) in the esophagus was significantly higher than that of the non-operated control. CLE cells were believed to be the target cells of oxidative damage because they overexpressed heme oxygenase 1 and metallothionein, both known to be responsive to oxidative damage. We propose that oxidative damage plays an important role in the formation of EAC in the EDA model, and a similar situation may occur in humans with gastroesophageal reflux and iron over-nutrition.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adenocarcinoma, Mucinous; Anastomosis, Surgical; Animals; Barrett Esophagus; Cocarcinogenesis; Deoxyguanosine; Disease Models, Animal; DNA Adducts; Duodenum; Epithelial Cells; Esophageal Neoplasms; Esophagitis; Esophagus; Gastroesophageal Reflux; Heme Oxygenase (Decyclizing); Humans; Iron; Isoenzymes; Male; Metallothionein; Oxidative Stress; Postoperative Complications; Precancerous Conditions; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Receptors, Transferrin; Thiobarbituric Acid Reactive Substances