Harinder S. Garewal

Use of colonoscopy to screen asymptomatic adults for colorectal cancer

BACKGROUND AND METHODS The role of colonoscopy in screening for colorectal cancer is uncertain. At 13 Veterans Affairs Medical Centers, we performed colonoscopy to determine the prevalence and location of advanced colonic neoplasms and the risk of advanced proximal neoplasia in asymptomatic patients (age range, 50 to 75 years) with or without distal neoplasia. Advanced colonic neoplasia was defined as an adenoma that was 10 mm or more in diameter, a villous adenoma, an adenoma with high-grade dysplasia, or invasive cancer. In patients with more than one neoplastic lesion, classification was based on the most advanced lesion. RESULTS Of 17,732 patients screened for enrollment, 3196 were enrolled; 3121 of the enrolled patients (97.7 percent) underwent complete examination of the colon. The mean age of the patients was 62.9 years, and 96.8 percent were men. Colonoscopic examination showed one or more neoplastic lesions in 37.5 percent of the patients, an adenoma with a diameter of at least 10 mm or a villous adenoma in 7.9 percent, an adenoma with high-grade dysplasia in 1.6 percent, and invasive cancer in 1.0 percent. Of the 1765 patients with no polyps in the portion of the colon that was distal to the splenic flexure, 48 (2.7 percent) had advanced proximal neoplasms. Patients with large adenomas (> or = 10 mm) or small adenomas (< 10 mm) in the distal colon were more likely to have advanced proximal neoplasia than were patients with no distal adenomas (odds ratios, 3.4 [95 percent confidence interval, 1.8 to 6.5] and 2.6 (95 percent confidence interval, 1.7 to 4.1], respectively). However, 52 percent of the 128 patients with advanced proximal neoplasia had no distal adenomas. CONCLUSIONS Colonoscopic screening can detect advanced colonic neoplasms in asymptomatic adults. Many of these neoplasms would not be detected with sigmoidoscopy.

DNA repair/pro-apoptotic dual-role proteins in five major DNA repair pathways: fail-safe protection against carcinogenesis

Two systems are essential in humans for genome integrity, DNA repair and apoptosis. Cells that are defective in DNA repair tend to accumulate excess DNA damage. Cells defective in apoptosis tend to survive with excess DNA damage and thus allow DNA replication past DNA damages, causing mutations leading to carcinogenesis. It has recently become apparent that key proteins which contribute to cellular survival by acting in DNA repair become executioners in the face of excess DNA damage. Five major DNA repair pathways are homologous recombinational repair (HRR), non-homologous end joining (NHEJ), nucleotide excision repair (NER), base excision repair (BER) and mismatch repair (MMR). In each of these DNA repair pathways, key proteins occur with dual functions in DNA damage sensing/repair and apoptosis. Proteins with these dual roles occur in: (1) HRR (BRCA1, ATM, ATR, WRN, BLM, Tip60 and p53); (2) NHEJ (the catalytic subunit of DNA-PK); (3) NER (XPB, XPD, p53 and p33(ING1b)); (4) BER (Ref-1/Ape, poly(ADP-ribose) polymerase-1 (PARP-1) and p53); (5) MMR (MSH2, MSH6, MLH1 and PMS2). For a number of these dual-role proteins, germ line mutations causing them to be defective also predispose individuals to cancer. Such proteins include BRCA1, ATM, WRN, BLM, p53, XPB, XPD, MSH2, MSH6, MLH1 and PMS2.

Non‐erosive reflux disease (NERD) — acid reflux and symptom patterns

Background: Recent reports suggest that patients with non‐erosive reflux disease (NERD) treated with anti‐reflux medications show lower symptom improvement rates than patients with erosive oesophagitis treated with the same medications.

Reversal of Barrett's esophagus with acid suppression and multipolar electrocoagulation: preliminary results

BACKGROUND Barretts esophagus is a premalignant lesion for esophageal adenocarcinoma. This study tests the hypothesis that re-injury of the metaplastic the epithelium in an acid-controlled environment will result in reversal of Barretts to squamous epithelium. METHODS Patients with at least 2 cm of Barretts esophagus were treated with omeprazole, and half the circumference of the Barretts was treated with multipolar electrocoagulation (MPEC); the other half served as an internal control. After 6 months, the remaining Barretts esophagus was treated with MPEC. RESULTS Twenty-four hour esophageal pH of less than 4 averaged 1.8% on a mean dose of 56 mg/day of omeprazole. Ten patients had visual and biopsy elimination of the targeted section of Barretts esophagus after an average of 2.5 MPEC sessions. The remainder of the Barretts esophagus is being treated in 9 patients; currently 5 have no evidence of Barretts. CONCLUSIONS The combination of control of esophageal acid exposure and reinjury of the metaplastic epithelium reverses Barretts esophagus to squamous epithelium as determined by endoscopy and biopsy.

Lack of impact of therapy on extent of Barrett's esophagus in 67 patients

Sixty-seven patients with Barretts esophagus have been prospectively followed over an average of 36 months (range 6 to 76 months) with standardized endoscopic observation and biopsies of the length of columnar epithelium. The initial length of Barretts epithelium ranged from 1 to 16 cm, mean 5.5 cm. Specialized columnar epithelium was present in 64 of the 67 patients. Patients were treated predominantly with H2-receptor blocker therapy to relieve symptoms. Eighty-two percent of patients had less than a 1-cm change in length per year. The mean rate of change of length was −0.093 cm per year. These results confirm in a relatively large, prospective study that standard antireflux therapy for Barretts esophagus does not result in consistent reduction in the extent of Barretts epithelium over a three-year interval.

Nicotine increases oxidative stress, activates NF-κB and GRP78, induces apoptosis and sensitizes cells to genotoxic/xenobiotic stresses by a multiple stress inducer, deoxycholate: relevance to colon carcinogenesis

Epidemiologic studies indicate that environmental (smoking) and dietary factors (high fat) contribute to carcinogenesis in many organ systems. The aim of our study was to test the hypothesis that nicotine, a component of cigarette smoke, and sodium deoxycholate (NaDOC), a cytotoxic bile salt that increases in concentration in the gastrointestinal tract after a high fat meal, induce similar cellular stresses and that nicotine may enhance some of the NaDOC-induced stresses. We found that nicotine, at 0.8 microM, the very low sub-micromolar level occurring in the tissues of smokers: (1). increases oxidative stress; (2). activates NF-kappaB, a redox-sensitive transcription factor; (3). activates the 78 kD glucose regulated protein promoter, an indication of endoplasmic reticulum stress; (4). induces apoptosis; (5). enhances the ability of NaDOC to activate the 153 kD growth arrest and DNA damage promoter, an indication of increased genotoxic stress; and (6). enhances the ability of NaDOC to activate the xenobiotic response element. Our findings have applicability to G.I. cancer, in general, since smoking is a risk factor in the development of esophageal, pancreatic, gastric and colon cancer, and these cancers are also promoted by bile acids.

Regression of Barrett's esophagus by laser ablation in an anacid environment

SummaryConsistent regression of intestinal metaplasia in Barretts esophagus has not been achieved with medical or surgical interventions. In this case report, a patient with Barretts esophagus of stable length had half the circumference of the Barretts epithelium ablated with laser therapy while on a high-dose proton-pump inhibitor. In the absence of esophageal acid exposure and after laser ablation, the intestinal metaplasia was documented to reepithelialize with normal squamous mucosa, which has oersisted.

Correlation of oesophageal acid exposure with Barrett's oesophagus length

BACKGROUND Gastro-oesophageal reflux disease (GORD) plays a major role in the development of Barretts oesophagus. However, it has yet to be elucidated what factors determine the length of Barretts mucosa in each individual patient. AIMS To determine if there is a correlation between oesophageal acid exposure and the length of Barretts mucosa. We also compared the extent of oesophageal acid exposure between patients with short segment (SSBE) and long segment (LSBE) Barretts oesophagus. METHODS Twenty seven patients with Barretts oesophagus were recruited prospectively into the study from the outpatient gastroenterology clinic at the Southern Arizona VA Health Care System. Diagnosis of Barretts oesophagus and its anatomical characteristics were determined during upper endoscopy. Ambulatory 24 hour oesophageal pH monitoring assessed the extent of oesophageal acid exposure. RESULTS There was a significant correlation between per cent total time pH less than 4 and length of Barretts mucosa (r=0.6234, p=0.0005). In addition, there was a significant correlation between per cent upright and supine time pH less than 4 and length of Barretts mucosa (r=0.5847, p=0.0014 andr=0.6265 p=0.0006, respectively). Patients with SSBE had significantly less oesophageal acid exposure than patients with LSBE, in terms of both per cent total time and per cent supine time pH less than 4 (p<0.05). CONCLUSIONS The length of Barretts mucosa correlated with the duration of oesophageal acid exposure. Patients with LSBE experienced significantly more oesophageal acid exposure than patients with SSBE. Duration of oesophageal acid exposure appears to be an important contributing factor in determining the length of Barretts mucosa.

The effects of 13‐cis‐retinoic acid and beta‐carotene on cellular immunity in humans

Deficiency of vitamin A and/or its precursors has been associated with increased cancer risk in animals and humans. Therapeutic trials of vitamin A and related compounds have demonstrated activity in several cancerous and precancerous conditions. The authors measured the effects of a retinoid, 13‐cis‐retinoic acid, and a carotenoid, beta‐carotene, on the human immune system in vivo in conjunction with their use in ongoing clinical trials. Immune cell subpopulations were analyzed by quantifying the expression of markers using flow cytometric study. Both compounds produced significant effects on immune cell populations. 13‐cis‐Retinoic acid resulted in an increase in the percentage of peripheral blood lymphoid cells expressing surface markers for T‐helper cells with only minimal effect on natural killer cell marker expression. In contrast, beta‐carotene produced an increase in the percentage of cells expressing natural killer cell markers with smaller effect on T‐helper markers. Modest increases in the percentage of cells expressing Ia antigen, transferrin, and interleukin‐2 receptors were produced by both drugs. These results suggest that retinoids and carotenoids can produce major changes in immune cellular marker expression in vivo in humans at doses relevant to their potential clinical use.

Expression of the multidrug resistance gene product (P‐glycoprotein) in myelodysplasia is associated with a stem cell phenotype

Summary Previous studies have indicated relative resistance to chemotherapy in the myelodysplastic syndromes (MDS) and associated acute leukaemia. To determine if multidrug resistance may contribute to chemoresistance in these disorders, we studied bone marrow specimens for P‐glycoprotein expression (P‐GP) by immunocytochemical staining with monoclonal antibodies reactive with cytoplasmic (C219) or surface epitopes (MRK16) of P‐GP. Forty‐five case specimens from 43 patients were studied, including 32 cases of primary MDS, seven cases of acute myeloid leukaemia (AML) following MDS, and six therapy‐related haematological disorders. Cytogenetic analysis was available on 36 specimens. Two staining patterns were detected: (1) cytoplasm and plasma membrane, and (2) staining restricted primarily to the nuclear‐cytoplasmic junction. P‐GP was detected in seven (22%) cases of primary MDS, four (57%) cases of AML evolving from MDS, and five (83%) cases of therapy‐related haematological disorders. Expression of P‐GP was restricted to blasts and leukaemic monocytes, and was otherwise absent from terminally differentiated blood cells. Analysis of the relation between P‐GP expression and reactivity with the human progenitor cell antigen CD34, revealed a highly significant association (P= 0·001). P‐GP reactivity was distributed equally among normal and abnormal karyotypes and did not correlate with specific cytogenetic abnormalities. These findings indicate that multidrug resistance in MDS and karyotypically‐related haematological disorders is closely linked to a stem cell phenotype and may contribute to chemoresistance in these disorders.