John C. Fang

Septin 9 methylated DNA is a sensitive and specific blood test for colorectal cancer

BackgroundAbout half of Americans 50 to 75 years old do not follow recommended colorectal cancer (CRC) screening guidelines, leaving 40 million individuals unscreened. A simple blood test would increase screening compliance, promoting early detection and better patient outcomes. The objective of this study is to demonstrate the performance of an improved sensitivity blood-based Septin 9 (SEPT9) methylated DNA test for colorectal cancer. Study variables include clinical stage, tumor location and histologic grade.MethodsPlasma samples were collected from 50 untreated CRC patients at 3 institutions; 94 control samples were collected at 4 US institutions; samples were collected from 300 colonoscopy patients at 1 US clinic prior to endoscopy. SEPT9 methylated DNA concentration was tested in analytical specimens, plasma of known CRC cases, healthy control subjects, and plasma collected from colonoscopy patients.ResultsThe improved SEPT9 methylated DNA test was more sensitive than previously described methods; the test had an overall sensitivity for CRC of 90% (95% CI, 77.4% to 96.3%) and specificity of 88% (95% CI, 79.6% to 93.7%), detecting CRC in patients of all stages. For early stage cancer (I and II) the test was 87% (95% CI, 71.1% to 95.1%) sensitive. The test identified CRC from all regions, including proximal colon (for example, the cecum) and had a 12% false-positive rate. In a small prospective study, the SEPT9 test detected 12% of adenomas with a false-positive rate of 3%.ConclusionsA sensitive blood-based CRC screening test using the SEPT9 biomarker specifically detects a majority of CRCs of all stages and colorectal locations. The test could be offered to individuals of average risk for CRC who are unwilling or unable to undergo colonscopy.

Eosinophilic oesophagitis in patients presenting with dysphagia – a prospective analysis

Background  Eosinophilic oesophagitis (EoO) may be a common finding in adults presenting with dysphagia.

Elemental diet induces histologic response in adult eosinophilic esophagitis.

OBJECTIVES:Elemental diets have not been studied in adults with eosinophilic esophagitis (EoE). The goal of this trial was to assess the efficacy of an elemental diet in adults with EoE.METHODS:A total of 18 adults with EoE were given an elemental diet for 4 weeks, or just 2 weeks if their response was complete. Symptoms and histologic findings, based on biweekly biopsies, were monitored. Six subjects were rebiopsied 2–7 days after resuming a normal diet.RESULTS:After therapy, esophageal tissue eosinophil content decreased from 54 to 10 per maximal high power field (P=0.0006). There was complete or nearly complete response (≤10 eosinophils) in 72% of subjects. Mast cell content, parabasal layer thickness, and endoscopic furrows and exudates also significantly decreased. Of the 29 qualified subjects, 11 (38%) failed to adhere to the diet. Several subjects had significant weight loss. Symptoms and endoscopic fixed strictures did not improve. After the subjects resumed a normal diet, the eosinophil content increased substantially in 3–7 days.CONCLUSIONS:While symptoms did not improve and dietary compliance was problematic, there was substantial histologic improvement after 4 weeks on the elemental diet. EoE in adults is substantially triggered by foods.

A critical approach to noncardiac chest pain: pathophysiology, diagnosis, and treatment

Approximately 30% of coronary angiograms performed in this country are negative for significant coronary artery disease. These patients are classified as having noncardiac or unexplained chest pain (UCP). Despite the good overall prognosis, this condition has significant morbidity and costs. The pathophysiology of this condition is likely caused by overlapping cardiac, esophageal, and psychiatric abnormalities with visceral hyperalgesia playing a central role. Gastroenterologists are often consulted in the evaluation of these patients because esophageal disorders are among the most common conditions associated with UCP. However, clinical symptoms are unreliable in differentiating between esophageal and cardiac causes of UCP. Gastroesophageal reflux disease, not esophageal motility disorders, is the most common esophageal disorder present in patients with UCP. The most useful diagnostic test in the evaluation of UCP is 24-h pH monitoring. An initial empiric trial of high-dose acid suppression is the most cost-effective intervention in the management of these patients. A clinical algorithm is suggested for the evaluation and treatment of UCP.

Teduglutide, a novel mucosally active analog of glucagon-like peptide-2 (GLP-2) for the treatment of moderate to severe Crohn's disease

Background: Teduglutide, an analog of glucagon‐like peptide‐2 (GLP‐2), is associated with trophic effects on gut mucosa. Its role in the treatment of active Crohns disease (CD) was assessed in a pilot, randomized, placebo‐controlled, double‐blinded, dose‐ranging study. Methods: Subjects with moderate‐to‐severe CD were randomized 1:1:1:1 to placebo or 1 of 3 doses of teduglutide (0.05, 0.10, or 0.20 mg/kg daily) delivered as a daily subcutaneous injection for 8 weeks. The primary outcome measure was the percentage of subjects in each group that responded to treatment, defined as a decrease in Crohns Disease Activity Index (CDAI) score to <150 or a decrease of > 100 points. At week 8 there was an optional 12‐week open‐label period of treatment with teduglutide 0.10 mg/kg/d. Results: One hundred subjects were enrolled and 71 completed the study. The mean baseline CDAI score was 290.8 ± 57.6 and was similar across groups. There were numerically higher response and remission rates in all teduglutide‐treated groups as compared with placebo, although the percentage of subjects who achieved a clinical response or remission was more substantial, and seen as early as week 2 of treatment in the highest dose (0.2 mg/kg/d) group (44% response and 32% remission versus 32% response and 20% remission in the placebo group). Of subjects who had not achieved remission during the 8‐week placebo‐controlled phase in the higher‐dose group, 50% achieved remission during the more prolonged, open‐label treatment phase. Plasma citrulline was similar across groups at baseline, but increased substantially over time in all teduglutide groups when compared with placebo at week 8. Adverse events were not different between placebo and active treatment groups. Conclusions: Teduglutide is a novel and potentially effective therapy for inducing remission and mucosal healing in patients with active moderate‐to‐severe CD. Further clinical investigation of this growth factor is warranted. Inflamm Bowel Dis 2009

Placement of Polyflex stents in patients with locally advanced esophageal cancer is safe and improves dysphagia during neoadjuvant therapy

BACKGROUND Patients with locally advanced esophageal cancer who require neoadjuvant therapy have significant dysphagia. OBJECTIVES To prospectively evaluate Polyflex stents to treat malignant dysphagia and to ameliorate weight loss in patients with locally advanced esophageal cancer who will undergo neoadjuvant therapy. DESIGN A prospective nonrandomized study. SETTING Tertiary-referral cancer center. PATIENTS Thirteen patients with esophageal cancer (11 adenocarcinoma, 2 squamous-cell carcinoma). All patients were men, with a mean age of 63 years. INTERVENTIONS EUS followed by stent placement. MAIN OUTCOME MEASUREMENTS Dysphagia scores and patient weights. RESULTS There were no perforations and no episodes of bleeding. Immediate complications included chest discomfort in 12 of 13 patients. The mean dysphagia score at the time of stent placement was 3. Mean dysphagia scores obtained at 1, 2, 3, and 4 weeks after stent placement were 1.1 (P = .005), 0.8 (P = .01), 0.9 (P = .02), and 1.0 (P = .008), respectively. Stent migration occurred at some point in 6 of 13 patients (46%). LIMITATIONS A single center and small size of study. CONCLUSIONS Simultaneous EUS staging and Polyflex stent placement is safe and allows oral feeding during neoadjuvant therapy. Dysphagia scores improved in a statistically significant manner. Stent migration was a common event, although not all patients with a migrated stent will require stent replacement, because migration may be a sign of tumor response to neoadjuvant therapy.

Placement of fully covered self-expandable metal stents in patients with locally advanced esophageal cancer before neoadjuvant therapy

BACKGROUND Most patients with locally advanced esophageal cancer requiring neoadjuvant therapy have significant dysphagia. OBJECTIVE To report our experience in using a fully covered self-expandable metal stent (FCSEMS) to treat malignant dysphagia and for maintenance of nutritional support during neoadjuvant therapy. DESIGN Retrospective study. SETTING Two tertiary-care referral centers. PATIENTS This study involved 55 patients with locally advanced esophageal cancer (50 adenocarcinoma, 5 squamous cell carcinoma). Forty-three patients were men, and the mean age was 65.8 years. INTERVENTION EUS followed by FCSEMS placement. MAIN OUTCOME MEASUREMENTS Procedural success, dysphagia scores, patient weights, stent migration, and stent-related complications. RESULTS All stents were successfully placed. Tumors were located in the middle esophagus (n = 10) and distal esophagus (n = 45). The mean dysphagia score obtained at 1 week after stent placement had improved significantly from baseline (2.4 and 1, respectively; P < .001). Patients maintained their weights at 1 month follow-up when compared with baseline (153 and 149 pounds, respectively; P = .58). Immediate complications included chest discomfort in 13 patients; 2 patients required stent removal because of intractable pain. One patient had stent removal because of significant acid reflux. Stent migration occurred at some point in 17 of 55 patients (31%). There was a delayed perforation in 1 patient. Because of disease progression or the discovery of metastasis after neoadjuvant therapy, only 8 of 55 patients underwent curative surgery. LIMITATIONS Retrospective study. CONCLUSION Placement of FCSEMSs in patients with locally advanced esophageal cancer significantly improves dysphagia and allows for oral nutrition during neoadjuvant therapy. FCSEMSs appear to be effective for palliating dysphagia. Migration was not associated with injury or harm to the patient and usually represented a positive response to neoadjuvant therapy. Few patients undergoing stenting in this situation ultimately undergo surgery because of disease progression or poor operative candidacy.

Retrospective Analysis of Esophageal Food Impaction: Differences in Etiology By Age and Gender

Eosinophilic Esophagitis (EE) is an emerging cause of esophageal food impaction (EFI) not accounted for in previous studies. We sought to determine the causes of EFI in a recent cohort with recognition of EE. A retrospective chart review of all patients with EFI during the past 5 years was performed. Etiology was determined by endoscopy report, pathology results, and follow-up studies. A total of 85 EFIs occurred, in 79 patients (55 men, 30 women, age 18–100). The most common etiologies of EFI were Schatzkis ring (n=18), peptic stricture (n=18), EE (n=9), esophagitis (n=9), and no underlying diagnosis (n=20). EE was significantly more frequent in men (P < .025) and those <50 years old (P < .025). There was a significant difference in the age at which men (median age=44) and women (median age=71) present with EFI (P < .001). The etiology of EFI differs significantly by age and gender. This information may be useful in evaluation and management of EFI.

How Drugs are Developed and Approved by the FDA: Current Process and Future Directions

OBJECTIVES:This article provides an overview of FDAs regulatory processes for drug development and approval, and the estimated costs associated with the development of a drug, and also examines the issues and challenges facing the FDA in the near future.METHODS:A literature search was performed using MEDLINE to summarize the current FDA drug approval processes and future directions. MEDLINE was further utilized to search for all cost analysis studies performed to evaluate the pharmaceutical industry R&D productivity and drug development cost estimates.RESULTS:While the drug approval process remains at high risk and spans over multiple years, the FDA drug review and approval process has improved, with the median approval time for new molecular drugs been reduced from 19 months to 10 months. The overall cost to development of a drug remains quite high and has been estimated to range from

Incision of recurrent distal esophageal (Schatzki) ring after dilation

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