Discrepancy in the assessment of tumor response in patients with pancreatic cancer: WHO versus RECIST criteria.

PURPOSE: The Response Evaluation Criteria in Solid Tumors (RECIST) have largely replaced the World Health Organization (WHO) criteria as a preferred method for assessing tumor response in clinical trials. We hypothesized that due to frequent asymmetric growth pattern, as well as somewhat diffuse margins of pancreatic cancer, the use of WHO vs. RECIST criteria may result in significantly different tumor response assessments. The purpose of this retrospective study was to compare the WHO (bidimensional) to RECIST (unidimensional) in assessing treatment response in pancreatic cancer patients enrolled in clinical trials. MATERIALS AND METHODS: We have evaluated the contrast- enhanced computed tomography (CT) images from 12 pancreatic cancer patients with measurable disease enrolled in two phase I/II clinical trials at the Arizona Cancer Center, between July 2000 and July 2003. The tumor measurements were re-calculated by RECIST and WHO criteria and were compared. RESULTS: In 3 out of the 12 patients (25%) there was discordant response categorization when WHO criteria were used instead of RECIST. Clinical presentations in all 3 patients were more consistent with WHO categorization. CONCLUSION: Our retrospective data analysis suggests that use of different tumor response criteria (RECIST vs. WHO) may result in different assessments of treatment efficacy in patients with pancreatic cancer on clinical trials. This finding warrants further confirmation in a larger prospectively designed trial.

A novel tyrosine kinase switch is a mechanism of imatinib resistance in gastrointestinal stromal tumors.

KIT or alpha-platelet-derived growth factor receptor (alpha-PDGFR) activating mutations are the pathogenic mechanisms that characterize gastrointestinal stromal tumors (GIST). Despite excellent responses to imatinib mesylate (IM), patients are relapsing. We developed an IM-resistant GIST cell line (GIST-R) from the IM-sensitive GIST882 cell line (GIST-S) by growing these cells in IM. Gene expression profiling (GEP) of GIST-S, GIST-R cells and two IM resistant GIST patients demonstrated that KIT is downregulated implying a major role in IM resistance. Instead, GIST-R cells have acquired IM resistance by overexpressing the oncogenic receptor tyrosine kinase - AXL - in a 'kinase switch'. Further, the two IM resistant GIST patients express AXL and not c-Kit, seen by immunohistochemistry (IHC). Real time reverse transcriptase-polymerase chain reaction and Western blotting of the GIST-S and GIST-R cells confirmed the switch from Kit to AXL. In GIST-R, AXL is tyrosine phosphorylated and its ligand growth-arrest-specific gene 6 is overexpressed implying autocrine activation. The kinase switch is associated with a morphological change from spindle to epithelioid. Molecular modeling of the kinase domain of mutant c-Kit (V654A) and AXL showed no binding to IM but efficient binding to MP470, a novel c-Kit/AXL kinase inhibitor. MP470 synergizes with docetaxel (taxotere) and is cytotoxic to GIST cells.

Deoxycholate induces mitochondrial oxidative stress and activates NF-kappaB through multiple mechanisms in HCT-116 colon epithelial cells.

Nuclear factor kappa B (NF-kappaB) is a redox-associated transcription factor that is involved in the activation of survival pathways. We have previously shown that deoxycholate (DOC) activates NF-kappaB in hepatocytes and colon epithelial cells and that persistent exposure of HCT-116 cells to increasing concentrations of DOC results in the constitutive activation of NF-kappaB, which is associated with the development of apoptosis resistance. The mechanisms by which DOC activates NF-kappaB in colon epithelial cells, and whether natural antioxidants can reduce DOC-induced NF-kappaB activation, however, are not known. Also, it is not known if DOC can generate reactive oxygen species within mitochondria as a possible pathway of stress-related NF-kappaB activation. Since we have previously shown that DOC activates the NF-kappaB stress-response pathway in HCT-116 cells, we used this cell line to further explore the mechanisms of NF-kappaB activation. We found that DOC induces mitochondrial oxidative stress and activates NF-kappaB in HCT-116 cells through multiple mechanisms involving NAD(P)H oxidase, Na+/K+-ATPase, cytochrome P450, Ca++ and the terminal mitochondrial respiratory complex IV. DOC-induced NF-kappaB activation was significantly (P < 0.05) inhibited by pre-treatment of cells with CAPE, EGCG, TMS, DPI, NaN3, EGTA, Ouabain and RuR. The NF-kappaB-activating pathways, induced by the dietary-related endogenous detergent DOC, provide mechanisms for promotion of colon cancer and identify possible new targets for chemoprevention.

Correlation of gastroesophageal reflux disease symptoms characteristics with long-segment Barrett's esophagus.

Thus far, there has been a paucity of studies that have assessed the value of the different gastroesophageal reflux disease (GERD) symptom characteristics in identifying patients with long-segment Barrett's esophagus versus those with short-segment Barrett's esophagus. To determine if any of the symptom characteristics of GERD correlates with long-segment Barrett's esophagus versus short-segment Barrett's esophagus. Patients seen in our Barrett's clinic were prospectively approached and recruited into the study. All patients underwent an endoscopy, validated GERD symptoms questionnaire and a personal interview. Of the 88 Barrett's esophagus patients enrolled into the study, 47 had short-segment Barrett's esophagus and 41 long-segment Barrett's esophagus. Patients with short-segment Barrett's esophagus reported significantly more daily heartburn symptoms (84.1%) than patients with long-segment Barrett's esophagus (63.2%, P = 0.02). There was a significant difference in reports of severe to very severe dysphagia in patients with long-segment Barrett's esophagus versus those with short-segment Barrett's esophagus (76.9%vs. 38.1%, P = 0.02). Longer duration in years of chest pain was the only symptom characteristic of gastroesophageal reflux disease associated with longer lengths of Barrett's mucosa. Reports of severe or very severe dysphagia were more common in long-segment Barrett's esophagus patients. Only longer duration of chest pain was correlated with longer lengths of Barrett's esophagus.

Esophageal acid exposure at pH < or = 2 is more common in Barrett's esophagus patients and is associated with oxidative stress.

Barrett's esophagus (BE) patients demonstrate a higher distal esophageal acid exposure profile than other gastroesophageal reflux disease patients. Cellular oxidative stress has been proposed to contribute to the development of BE and esophageal adenocarcinoma. However, a relationship between low esophageal pH and oxidative stress has yet to be elucidated. The aim of this study was to determine the duration of low pH exposure in the esophagus of BE patients compared to those with erosive esophagitis (EE) and to test if brief exposure to low pH leads to the induction of reactive oxygen species (ROS). Seventy-three patients with BE or EE were evaluated by 24-hour esophageal pH monitoring and the percentage of time during which there was exposure to pH < or = 4 and pH < or = 2 was recorded. In vitro, Seg-1 and Het-1A cells were evaluated after brief exposure to pH4 or pH2 by flow cytometry and fluorescent microscopy for the production of ROS. BE patients demonstrated a significantly higher exposure to low pH values (pH < or = 2) than EE patients. The mean percent total time, duration and mean number of reflux episodes at pH < or = 2 were 2.8 +/- 0.53%, 28.8 +/- 3.6 seconds and 79 +/- 11.4 episodes in BE patients, whereas in EE patients they were significantly less, 1.16 +/- 0.3%, 15.6 +/- 1.2 seconds and 48.3 +/- 8.8 episodes, respectively (P < 0.05). In vitro experiments indicate that esophageal cells, when exposed to pH 2, produce ROS. In vitro studies using brief pH 2 exposure are biologically relevant to the clinical situation. Our studies indicate that such exposure induces oxidative stress. This stress may cause DNA damage, mutations and progression to cancer.

Mitochondrial perturbation attenuates bile acid-induced cytotoxicity.

Hydrophobic bile acids such as deoxycholate (DOC) are known to damage liver cells during cholestasis and promote colon cancer. Cellular stresses induced by bile acids, which include mitochondrial and endoplasmic reticulum (ER) stresses, can result in apoptosis. We found that inhibition of mitochondrial complexes I-V with rotenone, thenoyltrifluoroacetone (TTFA), antimycin A, myxothiazol or oligomycin strongly protected against DOC-induced apoptosis of HCT-116 cells. To understand the mechanism of this protection, we explored the ability of these specific inhibitors to reduce DOC-induced mitochondrial and ER stresses. Different inhibitors markedly reduced DOC-induction of mitochondrial condensation, the DOC-induced decrease in mitochondrial membrane potential and the DOC-induced dilatation of the ER (evidence of ER stress). A dramatic induction of nucleolar segregation by antimycin A and myxothiazol, two distinct complex III inhibitors, was also observed. These findings strongly implicate mitochondrial crosstalk with apoptotic signaling pathways and mitochondrial-nucleolar crosstalk in the development of apoptosis resistance in the colon.

Bile acids as carcinogens in human gastrointestinal cancers.

Bile acids were first proposed to be carcinogens in 1939 and 1940. On the basis of later work with rodent models, bile acids came to be regarded as cancer promoters rather than carcinogens. However, considerable indirect evidence, obtained more recently, supports the view that bile acids are carcinogens in humans. At least 15 reports, from 1980 through 2003, indicate that bile acids cause DNA damage. The mechanism is probably indirect, involving induction of oxidative stress and production of reactive oxygen species that then damage DNA. Repeated DNA damage likely increases the mutation rate, including the mutation rate of tumor suppressor genes and oncogenes. Additional reports, from 1994 through 2002, indicate that bile acids, at the increased concentrations accompanying a high fat diet, induce frequent apoptosis. Those cells within the exposed population with reduced apoptosis capability tend to survive and selectively proliferate. That bile acids cause DNA damage and may select for apoptosis-resistant cells (both leading to increased mutation), indicates that bile acids are likely carcinogens. In humans, an increased incidence of cancer of the laryngopharyngeal tract, esophagus, stomach, pancreas, the small intestine (near the Ampulla of Vater) and the colon are associated with high levels of bile acids. The much larger number of cell generations in the colonic (and, likely, other gastrointestinal) epithelia of humans compared to rodents may allow time for induction and selection of mutations leading to cancer in humans, although not in rodents.

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. AIM: To determine the acid reflux and symptom patterns of patients with NERD in comparison with those with erosive oesophagitis and Barrett's oesophagus, and to identify different NERD subgroups. METHODS: One hundred and forty-nine consecutive patients seen for classic heartburn symptoms were evaluated for the study. Oesophageal mucosal injury was assessed by upper endoscopy and classified by Hetzel-Dent criteria. Patients with Hetzel-Dent grades 0-1 were considered to have NERD. The extent of oesophageal acid exposure was determined by ambulatory 24-h oesophageal pH monitoring. RESULTS: Seventy-one patients were found to have NERD, 36 erosive oesophagitis and 42 Barrett's oesophagus. Compared with patients with erosive oesophagitis (75%) and Barrett's oesophagus (93%), those with NERD (45%) were significantly less likely to have an abnormal pH test (P = 0.0001). Patients with Barrett's oesophagus had the highest mean number of acid reflux events (210 +/- 17.7), compared with those with erosive oesophagitis (139.7 +/- 15.2) and NERD (95.3 +/- 9.4) (P = 0.0001); however, the rate of perceived acid reflux events was similar and very low in all groups (NERD, 3.6%; erosive oesophagitis, 2.9%; Barrett's oesophagus, 2.17%). NERD-positive patients (abnormal pH test) had a similar extent of oesophageal acid exposure to those with erosive oesophagitis. NERD-positive patients were more likely to demonstrate a symptom index greater than 75% than NERD-negative patients (normal pH test) (61.9% vs. 10.5%; P = 0.0001). In the NERD-negative group, those with a negative symptom index reported having heartburn at pH < 4 only 12.7% of the time, compared with 70.7% of the time in those with a positive symptom index, despite a similar mean number of heartburn episodes. CONCLUSIONS: Patients with NERD commonly demonstrate a negative pH test. Acid reflux characteristics and symptom patterns suggest a heterogeneous group of patients.

Caspase-6 mediated cleavage of guanylate cyclase alpha 1 during deoxycholate-induced apoptosis: protective role of the nitric oxide signaling module.

Hydrophobic bile acids such as deoxycholate are known tumor promoters in the gastrointestinal tract. We have previously shown that deoxycholate induces apoptosis in colon epithelial cells and that these cells can be made resistant to deoxycholate-induced apoptosis. We now show that the nitric oxide synthase/nitric oxide/guanylate cyclase/cyclic guanosine monophosphate/cGMP-activated protein kinase (NOS/NO/GC/cGMP/PKG) signaling module contributes, in part, to the observed resistance of the cultured DOC-resistant colon epithelial cells (HCT-116R) using pharmacological inhibitors/antagonists (NS2028, Rp-8pCPT-cGMP, KT5823) of members of this signaling module. A novel finding from this study is the caspase-6 mediated cleavage of guanylate cyclase alpha 1 during deoxycholate-induced apoptosis of deoxycholate-sensitive HCT-116SA cells and the absence of guanylate cyclase alpha 1 cleavage in deoxycholate-treated HCT-116R resistant cells using Western blot analyses. This cleavage was specific to caspases as lysosomal, proteasomal, serine protease, cathepsin and calpain inhibitors failed to prevent the cleavage, whereas a general caspase inhibitor and a specific caspase-6 inhibitor did prevent guanylate cyclase alpha 1 cleavage.

Activation of the metallothionein IIA promoter and other key stress response elements by ursodeoxycholate in HepG2 cells: relevance to the cytoprotective function of ursodeoxycholate.

Ursodeoxycholate, used to treat a variety of pathologies, has the ability to reverse cytotoxic and hepatotoxic conditions. We examined HepG2, a hepatic cell line, treated with increasing levels of ursodeoxycholate, for responses of a range of promoters/response elements responsive to DNA damage, heavy metal ions, protein denaturants, aromatic hydrocarbons, retinoids, changes in intracellular AMP levels, end endoplasmic reticulum stress. The metallothionein IIA promoter was the most highly activated by ursodeoxycholate. Since ursodeoxycholate protects against the cytotoxic effects of deoxycholate, our data, combined with observations made by others, implicate metallothionein IIA as being important in this protective pathway.

Short segment Barrett's esophagus: relationship of age with extent of intestinal metaplasia.

OBJECTIVE: Short segment Barrett's esophagus (SSBE) is defined by the presence of intestinal metaplasia in biopsies obtained from mucosa with an appearance suggestive of Barrett's that extends <3 cm into the esophagus. It has been suggested that this lesion may represent a stage in an ongoing process of Barrett's esophagus progression. If so, then the prevalence of SSBE would be expected to decrease with advancing age, and patients followed over time should exhibit an increase in the extent of columnar-lined esophagus. The aim of this study was to determine whether SSBE length progresses or regresses over time by following a prospective cohort and by assessing the relationship between age and the length, as well as prevalence of SSBE. METHODS: The study included consecutive patients who were evaluated prospectively by an upper endoscopy and were found to have SSBE between October, 1983, and December, 1999, at the Southern Arizona VA Health Care System. All patients underwent a systematic biopsy protocol, and a designated pathologist who reviewed all specimens confirmed the diagnosis of Barrett's esophagus. Patients were subsequently interviewed for demographic information. In those patients who were enrolled into our surveillance program, SSBE length was remeasured and intestinal metaplasia reconfirmed on follow-up endoscopies. RESULTS: Of 343 patients with endoscopically proven Barrett's esophagus, 116 (33.8%) were found to have SSBE. Almost all were male (97.4%) and white (85.3%), with a mean age of 60.1+/-1.0 yr. The prevalence of SSBE increased with age and reached a plateau during the seventh decade of life. One-way analysis of variance showed that there was no significant difference in the mean length of SSBE among the various age groups (p = 0.84). This trend was maintained when only the white group was assessed. Follow-up endoscopies were performed in 57 patients, revealing a mean interval of 64 months to the latest endoscopy, with no significant difference in SSBE length between the first and last endoscopy (p = 0.16). CONCLUSIONS: The prevalence of SSBE increases with age until the seventh decade of life. Finding that SSBE length does not change across the various age groups and during a 64-month mean follow-up, suggests that SSBE does not progress over time.

Preferential repair by squamous epithelium of thermal induced injury to the proximal stomach in patients undergoing ablation of Barrett's esophagus.

BACKGROUND: The presence of extensions of squamous epithelium into the proximal stomach in patients undergoing routine upper endoscopy has recently been described. The factors that may favor development of squamous epithelium within the proximal stomach remain unknown. METHODS: Patients with Barrett's esophagus who agreed to undergo ablation of Barrett's epithelium by using multipolar electrocoagulation were included. Patients were treated with a high dose of a proton pump inhibitor. The columnar-appearing mucosa was systematically treated. Occasionally, thermal injury was inadvertently induced in the proximal stomach. On endoscopy performed 4 to 6 weeks after treatment, the presence of squamous epithelium extending into the proximal stomach was documented. The use of Lugol's stain assisted in confirming the squamous nature of the abnormal tissue, which was confirmed histologically by cytokeratin immunohistochemistry. RESULTS: The 12 patients included in the study had a mean length of Barrett's epithelium of 3.8 +/- 0.7 cm. Patients were treated with omeprazole, mean dose 66 +/- 6.0 mg, and had a mean percent total time that the pH was less than 4 of 1.9 +/- 0.8. The mean length and width of gastric squamous extensions were 1.7 +/- 0.2 cm and 0.8 +/- 0.1 cm, respectively. None of the squamous extensions into the stomach were documented before mucosal ablation. The extensions stained positively for cytokeratin 13 and negatively for cytokeratin 8, thereby confirming their squamous nature. CONCLUSIONS: Thermal injury to the proximal stomach in patients undergoing ablation of Barrett's epithelium and profound acid suppression results in repair by squamous epithelium. Recognition of this lesion is essential because it may lead to confusion as to the location of the esophagogastric junction in subsequent endoscopic evaluations.

Inability to noninvasively diagnose gastric intestinal metaplasia in Hispanics or reverse the lesion with Helicobacter pylori eradication.

BACKGROUND: Helicobacter pylori infection has been linked with the development of gastric adenocarcinoma and its precursor lesion, intestinal metaplasia (IM). The presence of gastric IM is not associated with symptoms, which makes identification of individuals with this lesion difficult. It is not clear whether eradication of H. pylori infection leads to reversal of gastric IM or the potential decrease in the risk of cancer in these patients. GOALS: The purpose of this pilot study was to define the prevalence of gastric IM in a population at high risk for gastric cancer (Southwestern Hispanics), examine the ability of noninvasive testing to identify individuals with the lesion, and determine whether eradication of H. pylori infection reverses gastric IM in this population. STUDY: Subjects from the Tucson metropolitan area were recruited, and baseline data, including the presence of upper gastrointestinal (UGI) symptoms, urinary sodium, and serum pepsinogen levels, were obtained. Upper endoscopy was performed and six gastric biopsies from specific anatomic sites were obtained, followed by methylene blue staining with targeted biopsies from blue-stained mucosa. Biopsies were evaluated for the presence of H. pylori infection and gastric IM. A subset of patients with gastric IM were treated to eradicate H. pylori infection. Follow-up exams with methylene blue staining, including biopsies for histology and rapid urease testing, were performed for up to 48 months. RESULTS: There were 84 subjects with a mean age of 53.0 years; 24 (29%) had gastric IM and 65 (77%) had H. pylori. There was no significant association between gastric IM and age, gender, UGI symptoms, H. pylori, or urine sodium. There was an association identified between gastric IM and a decreased pepsinogen I:II ratio (p = 0.03). Of the 11 individuals with gastric IM treated for H. pylori infection, 9 had successful therapy and underwent at least 2 follow-up examinations. The mean length of follow-up was 3.3 years. Eight of the nine (89%) had gastric IM identified histologically at the final endoscopic exam. CONCLUSIONS: H. pylori infection and gastric IM are frequent findings in Southwestern Hispanics, a high-risk population for gastric cancer. Noninvasive testing is not clinically useful in distinguishing individuals within this group who harbor gastric IM. Although eradication of H. pylori infection may lead to a decrease in the amount of gastric IM in some individuals, the lesion may be detected in the majority of individuals after more than 3 years of follow-up. These data suggest that therapy for H. pylori may not eliminate the risk of gastric cancer once IM has developed.

Correlation of oesophageal acid exposure with Barrett's oesophagus length.

BACKGROUND: Gastro-oesophageal reflux disease (GORD) plays a major role in the development of Barrett's oesophagus. However, it has yet to be elucidated what factors determine the length of Barrett's mucosa in each individual patient. AIMS: To determine if there is a correlation between oesophageal acid exposure and the length of Barrett's mucosa. We also compared the extent of oesophageal acid exposure between patients with short segment (SSBE) and long segment (LSBE) Barrett's oesophagus. METHODS: Twenty seven patients with Barrett's oesophagus were recruited prospectively into the study from the outpatient gastroenterology clinic at the Southern Arizona VA Health Care System. Diagnosis of Barrett's 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 Barrett's 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 Barrett's mucosa (r=0.5847, p=0.0014 and r=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 Barrett's 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 Barrett's mucosa.

The specific NOS2 inhibitor, 1400W, sensitizes HepG2 cells to genotoxic, oxidative, xenobiotic, and endoplasmic reticulum stresses.

We tested the hypothesis that the constitutive activity of the inducible form of nitric oxide synthase (NOS2) serves to protect cells against numerous endogenous stresses. To accomplish this, we treated HepG2 cell lines that were individually transfected with 13 different promoter/response element (RE) chloramphenicol acetyl transferase (CAT) reporter constructs, with a highly selective NOS2 inhibitor, 1400W [N-(3-(aminomethyl)benzyl) acetamidine)]. HepG2 cells were incubated for 6 h with 0, 1, 10, 50, 100, and 200 microM 1400W, and the activation of the promoter/RE CAT reporter constructs was simultaneously determined. The highest fold inductions occurred at 200 microM 1400W, a concentration that had no effect on overall cell viability, as determined by the MTT assay. Twelve of the 13 promoter/RE CAT reporter constructs were significantly activated by 200 microM 1400W. These results indicate the extensive protective role of constitutive NOS2 against genotoxic, oxidative, and endoplasmic reticulum stresses. The mechanism of this protection may involve the complexing of iron by nitric oxide (NO) to reduce hydroxyl radical formation, NO inhibition of electron transport and the generation of reactive oxygen species within mitochondria, NO inhibition of cyclooxygenase, lipoxygenase, and cytochrome P450 enzyme activity, and the scavenging of superoxide anions by NO to form peroxynitrite.

Recent developments in Barrett's esophagus.

Barrett's esophagus is a precancerous condition in which the squamous esophageal epithelium is replaced by a columnar epithelium. Although different types of columnar epithelium have been described, the most frequently encountered is specialized columnar epithelium or intestinal metaplasia. Most investigators believe that increased cancer risk is only associated with this type. Esophageal adenocarcinoma is increasing in frequency in the United States and in Western Europe. Recent studies highlight the importance of gastroesophageal reflux disease in esophageal adenocarcinoma. Bile-acid reflux may also play a role. Increasing interest has been expressed in short-segment (2-3 cm) Barrett's esophagus. The contribution of short-segment Barrett's esophagus to cancer at the gastroesophageal junction is currently being studied. Although regular surveillance is often recommended, the commonness of Barrett's esophagus makes such a practice impractical for every patient. Biomarker development is needed to identify patients at greatest risk, with p53 a promising candidate based on recent studies. Initial data suggest that redox mechanisms may be involved in Barrett's esophagus. Several methods have recently been described for reversing Barrett's esophagus to squamous epithelium, but the significance of this practice in terms of reducing cancer risk remains to be demonstrated.

Use of colonoscopy to screen asymptomatic adults for colorectal cancer. Veterans Affairs Cooperative Study Group 380.

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.

Symptom severity and oesophageal chemosensitivity to acid in older and young patients with gastro-oesophageal reflux.

INTRODUCTION: elderly patients appear to have a more aggressive form of gastro-oesophageal reflux disease than younger patients. Reduced pain perception with age is a possible underlying mechanism. AIMS: to compare the extent of oesophageal mucosal injury, acid exposure, symptom severity and perception thresholds for acid infusion in older (aged 60 or older) and younger patients with gastro-oesophageal reflux. METHODS: twenty-five younger and 23 older patients completed the study. We determined acid exposure and oesophageal mucosal injury by ambulatory 24-h oesophageal pH monitoring and upper endoscopy, respectively. We determined chemosensitivity by infusing 0.1 N hydrochloric acid into the mid-oesophagus for 10 min at 10 ml/min after a 2-min infusion of normal saline at a similar rate. We quantified acid perception thresholds by the lag time to initial typical symptom perception, intensity rating at the end of acid infusion and an acid perfusion sensitivity score, calculated from the fractional duration of symptom perception and intensity rating. RESULTS: mean percentage of total time with pH <4 was higher in the older (15.8+/-2.4) than in the younger patients (11.9+/-1.8; P = 0.18). Of the older group, 74% had erosive oesophagitis versus 64% in the younger group. Frequency of symptoms (heartburn, acid regurgitation and dysphagia) was lower in the elderly group. Older patients perceived heartburn and acid regurgitation as much less severe than younger patients (P < 0.05).Younger patients had a significantly shorter lag time to initial symptom perception (P < 0.05) and a higher sensory intensity rating (P < 0.08). The acid perfusion sensitivity score was significantly lower in the older group (P < 0.05). CONCLUSIONS: older patients with gastro-oesophageal reflux disease have reduced symptom severity for heartburn despite a tendency towards increased severity of oesophageal mucosal injury and acid exposure. Age-related reduction in chemosensitivity to acid is a possible underlying mechanism.

Failure of oesophageal acid control in candidates for Barrett's oesophagus reversal on a very high dose of proton pump inhibitor.

BACKGROUND: Normalization of oesophageal acid exposure using high dose proton pump inhibitors in patients who are candidates for ablation therapy has been suggested to be essential for successful Barrett's reversal. However, the success rate for achieving pH normalization has not been determined. METHODS: Patients with Barrett's oesophagus (2-6 cm in length) who were found to be eligible for ablation therapy using multipolar electrocoagulation were included in this prospective study. Patients underwent an upper endoscopy to determine Barrett's length and other anatomic characteristics. Biopsies were obtained to rule out dysplasia. Subsequently, patients were treated with omeprazole 40 mg b.d. Twenty-four hour oesophageal pH monitoring was performed after a mean period of 8.4 +/- 0.6 days of therapy. RESULTS: Twenty-five patients were enrolled into the study. The pH test was abnormal in four (16%) of the study subjects. An additional two (8%) patients had abnormal supine percentage time with pH less than 4. There was no significant difference in oesophageal acid control between patients with long vs. short segment Barrett's oesophagus. Elderly (> 60 years) patients tended to have less acid control than younger (

A collaborative end-of-life care curriculum.

Death and dying in America has received limited attention in medical education. The Southern Arizona VA Health Care System and the University of Arizona have collaborated with three nonprofit community hospice programs to develop an end-of-life care curriculum. This formal and comprehensive program is offered as a one-month elective to senior medical students, residents and fellows. The goal of the program is to improve clinical skills in caring for the dying patient and foster research in palliative and supportive care.