Phase 1/2a, dose-escalation, safety, pharmacokinetic and preliminary efficacy study of intratumoral administration of BC-819 in patients with unresectable pancreatic cancer.

BC-819 is a DNA plasmid that was developed to target the expression of diphtheria-toxin gene under the control of H19 regulatory sequences. BC-819 has the potential to treat pancreatic cancer that overexpresses the H19 gene. The objectives were to assess the safety, tolerability, pharmacokinetics and preliminary efficacy of BC-819 administered intratumorally in subjects with unresectable, locally advanced, non-metastatic pancreatic cancer. Nine patients with unresectable pancreatic adenocarcinoma were enrolled in an open-label, dose-escalation trial. Subjects were entered into one out of two cohorts with escalating doses of BC-819. Each cohort received 2 weeks of twice weekly intratumoral injection of BC-819 under computerized tomography (CT) (n = 3) or endoscopic ultrasound (EUS) (n = 6) guidance. Patients were assessed by CT or positron emission tomography (PET)/CT during week 4 for tumor response. The maximum tolerated dose of BC-819 was not reached in this study at the highest dose. Asymptomatic elevation of lipase, which was considered as an adverse event with dose-limiting toxicity, occurred in only one subject in the high-dose group and was resolved spontaneously. The tumors did not increase in size 4 weeks after initiating treatment. Two weeks after completing the treatment, the two subjects who went on to receive subsequent chemotherapy or chemoradiation therapy, pancreatic tumors were downstaged and considered surgically resectable. Remarkably, three of the six subjects in cohort no. 2 evaluated at month 3 had a partial response. BC-819 can be safely administered intratumorally via EUS- or CT-guided injection at a dose of at least 8 mg per injection weekly twice. BC-819 given locally in combination with systemic chemotherapy may provide an additional therapeutic benefit for the treatment of pancreatic cancer.

Value of EUS-FNA cytological preparations compared with cell block sections in the diagnosis of pancreatic solid tumours.

OBJECTIVE: Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is performed in order to achieve a definite tissue diagnosis of pancreatic lesions. This in turn is a guide to the appropriate treatment for the patient. Tissue samples collected by the same needle for cytological preparations and cell block histological sections (often referred to as FNA-cytology and FNA-biopsy, respectively) are handled differently. The specific contribution of each of these tests was evaluated. METHODS: One hundred and two consecutive patients underwent EUS-FNA while being investigated for pancreatic solid lesions. Diagnosis was made by cytology, cell block sections or both. The diagnosis was confirmed by clinical outcome. RESULTS: Male/female ratio was 61/41. Mean age was 65±12 years (range, 22-94). Mean lesion size was 3.1±1.8 cm (range, 0.6-10 cm); 68% were >2 cm and 75% were located in the pancreatic head. The average number of needle passes was two (range, 1-4 passes). Final tissue diagnosis was malignant in 66 (65%) patients. Sensitivity, specificity and accuracy were 73%, 94% and 81%, respectively, for cytology alone, and 63%, 100% and 78%, for cell blocks alone. Eighty-two patients (80%) had cytology and cell blocks, which matched in 64 (78%) patients. EUS-FNA results that relied on both techniques had 84% sensitivity, 94% specificity and 88% accuracy. Cytology revealed 13 malignancies not diagnosed on cell blocks, while cell blocks revealed five malignancies not diagnosed by cytology. Malignant lesions were more common in men; they were larger in size and located in the pancreatic head. CONCLUSION: EUS-FNA cytology was more sensitive than cell blocks but less specific for the diagnosis of solid pancreatic lesions. The two methods are complementary and implementing both improves the diagnostic value of EUS-FNA.

Prospective multicenter performance evaluation of the second-generation colon capsule compared with colonoscopy.

BACKGROUND AND STUDY AIMS: A second-generation capsule endoscopy system, using the PillCam Colon 2, was developed to increase sensitivity for colorectal polyp detection compared with the first-generation system. The performance of this new system is reported. PATIENTS AND METHODS: In a five-center feasibility study, second-generation capsule endoscopy was prospectively compared with conventional colonoscopy as gold standard for the detection of colorectal polyps and other colonic disease, in a cohort of patients scheduled for colonoscopy and having known or suspected colonic disease. Colonoscopy was independently performed within 10 hours after capsule ingestion. Capsule-positive but colonoscopy-negative cases were counted as false-positive. RESULTS: 104 patients (mean age 49.8 years) were enrolled; data from 98 were analyzed. Patient rate for polyps of any size was 44 %, 53 % of these patients having adenomas. No adverse events related to either procedure were reported. The capsule sensitivity for the detection of patients with polyps >or= 6 mm was 89 % (95 % confidence interval [CI] 70 - 97) and for those with polyps >or= 10 mm it was 88 % (95 %CI 56 - 98), with specificities of 76 % (95 %CI 72 - 78) and 89 % (95 %CI 86 - 90), respectively. Both polyps missed by colonoscopy and mismatch in polyp size by study definition lowered specificity. Overall colon cleanliness for capsule endoscopy was adequate in 78 % of patients (95 %CI 68 - 86). CONCLUSIONS: The new second-generation colon capsule endoscopy is a safe and effective method for visualizing the colon and detecting colonic lesions. Sensitivity and specificity for detecting colorectal polyps appear to be very good, suggesting a potential for improved accuracy compared with the first-generation system. Further prospective and comparative studies are needed.

The colon - the latest terrain for capsule endoscopy.

Colonoscopy is the gold standard for evaluating pathologies of the large bowel, including screening for colorectal cancer. The technological features of current colonoscopes have not progressed much in recent years except for improved image and video display. The technique requires intubation and insufflation of the colon which are operator-dependent and involve a learning curve. Colonoscopy is an invasive procedure whose overall risk of complications is approximately 0.3%, increasing to 2% when polypectomy is performed. The PillCam Colon capsule endoscope (Given Imaging Ltd., Yoqneam, Israel) was developed for use as a safe, minimally invasive, non-sedation requiring, patient-friendly modality to visualize the colon. Only the interpretation of findings requires expertise. PillCam capsule endoscopy could be an alternative approach to colonoscopy for screening large populations. We report the first clinical investigations of the safety, feasibility and performance of colon capsule endoscopy compared with standard colonoscopy.

Evaluation of the PillCam Colon capsule in the detection of colonic pathology: results of the first multicenter, prospective, comparative study.

BACKGROUND AND STUDY AIMS: Population-based screening for colorectal cancer is widely recommended, with conventional colonoscopy considered to be the preferred diagnostic modality. However, compliance with screening colonoscopy is low and manpower capacity is limited. Capsule endoscopy might therefore represent a desirable alternative strategy. PATIENTS AND METHODS: The PillCam Colon capsule endoscope was prospectively tested in a multicenter setting. The indications for endoscopy in the enrolled patients included colorectal cancer screening (43 %), postpolypectomy surveillance (26 %), and lower gastrointestinal signs and symptoms (31 %). Study subjects underwent colon preparation and then ingested the capsule on the morning of the examination, with conventional colonoscopy being performed the same day. The PillCam Colon capsule findings were reviewed by three experts in capsule endoscopy who were blinded to the conventional colonoscopy findings. RESULTS: A total of 91 subjects were enrolled in three Israeli centers (55 men, 36 women; mean age 57), and the results were evaluable in 84 cases. The capsule was excreted within 10 hours in 74 % of the patients and reached the rectosigmoid colon in the other 16 %. Of the 84 evaluable patients, 20 (24 %) had significant findings, defined as at least one polyp of 6 mm or more in size or three or more polyps of any size: 14/20 (70 %) were identified with the capsule and 16/20 (80 %) were identified by conventional colonoscopy. Polyps of any size were found in 45 patients, 34/45 (76 %) found by the capsule and 36/45 (80 %) by conventional colonoscopy. In comparison with conventional colonoscopy, false-positive findings on PillCam Colon capsule examination were recorded in 15/45 cases (33 %). There were no adverse events related to the capsule endoscopy. CONCLUSIONS: PillCam Colon capsule endoscopy appears to be a promising new modality for colonic evaluation. Further improvements in the procedure will probably increase capsule examination completion and polyp detection rates. Additional studies are needed to evaluate the accuracy of PillCam Colon endoscopy in other patient populations with different prevalence levels of colonic disease.

Capsule endoscopy: improving transit time and image view.

AIM: To evaluate the effect of various methods of small bowel preparation on the transit time and the quality of visualization of the entire small bowel mucosa. METHODS: Ninety-five patients underwent capsule endoscopy (CE) by easily swallowing the capsule. They were divided into three study groups according to the preparation used: group A (n = 26) by polyethylene glycol (PEG) liter or with sodium phosphate (SP) 12 h prior to the CE study; group B (n = 29) by erythromycin 1 h prior to the CE study; and group C (n = 40) without any preparation. Visualization ranged from good to satisfactory to poor. RESULTS: The gastric emptying time in the group prepared with erythromycin was shorter but without statistical significance and the small bowel transit time was unaffected. In elderly subjects prepared by PEG or SP, the gastric emptying time was significantly longer (163.7 min, P = 0.05). The transit times of the three sub-groups were not affected by gender or pathology. The grade of cleaning of the entire study group was 3.27+/-1.1. The erythromycin group presented significantly the worst quality of images (P = 0.05) compared to the other sub-groups. Age, gender, and pathology had no effect on the quality of the cleaning of the small bowel in the sub-groups. One (1.05%) case had no natural excretion. CONCLUSION: Erythromycin markedly reduces gastric emptying time, but has a negative effect on the quality of the image in the small bowel. The preparation of elderly subjects with PEG or SP has a negative effect on the small bowel transit time.

The role of video capsule endoscopy in the evaluation of iron deficiency anaemia.

It is widely accepted that chronic occult blood loss from the gastrointestinal tract is a major cause of iron deficiency anaemia. Endoscopists are often asked to evaluate iron deficiency anaemia and identify the source of bleeding. This review offers an effective diagnostic strategy for this common clinical problem. After investigating the normal upper and lower parts of the gastrointestinal tract, the source of bleeding remains unidentified in about 10% of patients. The existing guidelines for evaluation of iron deficiency anaemia in patients above the age of 45, who have undergone standard upper and lower gastrointestinal examinations, are limited to a "treat and observe" phase. Small bowel X-ray series fail to detect many mucosal lesions, particularly vascular ectasias. While enteroscopy offers direct visual inspection of the small bowel mucosa beyond the reach of the standard upper endoscopes, this instrument reaches only 80-120 cm beyond the ligament of Treitz and its sensitivity in identifying the source of bleeding varies (24-75% of patients). A new and conceptually simple approach to examining the entire small intestine is video capsule endoscopy of the small bowel. This review addresses the optimal role of video capsule endoscopy in iron deficiency anaemia patients and offers guidelines for the appropriate gastrointestinal evaluation in such patients.

Diagnosing small bowel Crohn's disease with wireless capsule endoscopy.

BACKGROUND: The small bowel is the most commonly affected site of Crohn's disease (CD) although it may involve any part of the gastrointestinal tract. The current methodologies for examining the small bowel are x ray and endoscopy. AIMS: To evaluate, for the first time, the effectiveness of wireless capsule endoscopy in patients with suspected CD of the small bowel undetected by conventional modalities, and to determine the diagnostic yield of the M2A Given Capsule. PATIENTS: Seventeen patients (eight males, mean age 40 (15) years) with suspected CD fulfilled study entry criteria: nine had iron deficiency anaemia (mean haemoglobin 10.5 (SD 1.8) g%), eight had abdominal pain, seven had diarrhoea, and three had weight loss. Small bowel x ray and upper and lower gastrointestinal endoscopic findings were normal. Mean duration of symptoms before diagnosis was 6.3 (SD 2.2) years. METHODS: Each subject swallowed an M2A Given Capsule containing a miniature video camera, batteries, a transmitter, and an antenna. Recording time was approximately eight hours. The capsule was excreted naturally in the patient's bowel movement, and the data it contained were retrieved and interpreted the next day. RESULTS: Of the 17 study participants, 12 (70.6%, six males, mean age 34.5 (12) years) were diagnosed as having CD of the small bowel according to the findings of the M2A Given Capsule. CONCLUSIONS: Wireless capsule endoscopy diagnosed CD of the small bowel (diagnostic yield of 71%). It was demonstrated as being an effective modality for diagnosing patients with suspected CD undetected by conventional diagnostic methodologies.

Acupuncture treatment for irritable bowel syndrome. A double-blind controlled study.

BACKGROUND/AIM: Irritable bowel syndrome is one of the most common gastrointestinal disorders in Western society, affecting around 15% of the population, especially young adults. The cause(s) of irritable bowel syndrome and effective treatment(s) have remained elusive. This study aimed at exploring the therapeutic value of acupuncture by comparing the responses of irritable bowel syndrome sufferers to true acupuncture versus sham acupuncture in a controlled double-blind study. METHODS: Twenty-five patients who fulfilled the Rome criteria (irritable bowel syndrome symptoms persisting for more than 1 year) comprised the final study population. They were recruited through a 'call for' bulletin sent to gastroenterologists practicing in the region of our medical center. True acupuncture was performed at LI-4 (colonic meridian, needle only) and sham acupuncture at BL-60 (urinary vesicle meridian, needle only). Patient assignment to one of the two groups was random. RESULTS: The effect of the first true acupuncture on overall symptoms and abdominal pain was a clear and significant improvement (p = 0.05). No comparable effect was seen in the second session. CONCLUSIONS: Although the true acupuncture results were consistently better, no difference was found between the two groups in the overall statistical analysis. We could not show a therapeutic benefit of this treatment modality in irritable bowel syndrome.

Prevalence of short-segment Barrett's epithelium.

BACKGROUND/AIMS: The incidence of adenocarcinoma of the oesophagus has increased. Its major risk factor is Barrett's epithelium of which the sine qua non is microscopically diagnosed intestinal metaplasia. Short segment Barrett's epithelium may often be overlooked during routine endoscopy. In routine biopsies taken from normal-appearing mucosa of the distal oesophagus, the reported rates of short segment Barrett's epithelium in the distal oesophagus reached 36%. We compared these rates with the results obtained in a community hospital in Israel. METHODS: Consecutive patients undergoing oesophagogastroduodenoscopy were enrolled. Biopsy specimens taken from cardia, oesophagogastric junction and 2 cm above the oesophagogastric junction were stained with haematoxylin & eosin and Alcian blue. RESULTS: There were 112 study patients (mean age +/- SD 48. 9+/-18.3 years, 51.8% males). Nine (8.04%) patients had intestinal metaplasia (according to specimen from 2 cm above oesophagogastric junction), and symptoms of gastro-oesophageal reflux were found in only four (44.4%) of them. Of these nine patients, six (6.66%) had normal-appearing mucosa and three (3.33%) had macroscopic Barrett's epithelium. Alcian blue staining revealed two patients with intestinal metaplasia that haematoxylin & eosin staining had missed. CONCLUSION: We found an 8% prevalence of intestinal metaplasia compared to 18-36% reported in the literature. We also determined that the added advantage of routine biopsy was 5.4%.

Ethnic differences in colorectal cancer among Arab and Jewish neighbors in Israel.

OBJECTIVES: Migrant studies indicate that the differences in the incidence of colorectal cancer (CRC) are probably environmental and not genetic. There is epidemiological documentation that Israeli-born Arabs have much less CRC than Israeli-born Jews. We investigated these differences among Jews and Arabs living within the same central coastal region in Israel. METHODS: The files of pathology-diagnosed patients with CRC hospitalized from 1988 to 1996 were reviewed, and demographic data and incidence and location of malignancies were retrieved for this relative frequency study. RESULTS: Of the 527 patients (51.4% men) diagnosed as having CRC, 489 (92.8%) were Jews and 38 (7.2%) were Arabs (p < 0.001), representing 0.46% and 0.04% of the respective populations in the region. The average age at disease diagnosis of the Jews was 73.8 yr and that of the Arabs 61.4 yr (p < 0.001). Both groups shared identical health facilities and habits of attending them. The Arab patients were or had been employed in occupations that involved more physical activity. The site of lesion was on the right colon in 24.9% of all the cases-23.5% of the Jewish patients and 42.1% of the Arab patients (p < 0.001). Rectal cancer was found in 25.7% of the former and 15.8% of the latter (p < 0.001). CONCLUSIONS: The lower incidence of CRC among the Arabs persisted over time, and that group had greater right side and lesser rectal involvement than their Jewish neighbors, possible indications of genicity. The incidence of CRC among the Jews rose concomitantly with "Westernization" of their lifestyle, supporting a role for environmental influences.

Helicobacter pylori: seroprevalence and colorectal cancer.

BACKGROUND: Previous studies have published controversial results regarding a connection between Helicobacter pylori infection and colorectal cancer. One possible mechanism is increased gastrin secretion in subjects infected with H. pylori, insofar as gastrin is known to be a trophic factor for the colonic mucosa. OBJECTIVES: To investigate a possible role of gastrin secretion in H. pylori infection associated with colorectal cancer, and determine whether H. pylori infection is a factor in this disease. METHODS: The serum gastrin levels and the presence of H. pylori IgG antibodies were measured in 51 colorectal cancer patients and 51 control subjects. The cancer patients were also tested for carcinoembryonic antigen and CA 19-9. RESULTS: H. pylori IgG antibodies were found in the serum of 41 (80.4%) of the cancer patients compared to 32 (62.7%) of the control subjects (P = 0.05). A significant correlation was found between CA 19-9 (r = 0.3432, n = 49, P = 0.01) and seropositive H. pylori IgG antibodies in the serum of the cancer patients (odds ratio 2.43, and 95% confidence limit 0.99-5.95), but none between CEA and H. pylori IgG antibodies nor between the serum gastrin level and the presence of colorectal cancer. CONCLUSIONS: The results of this study indicate a significant association between seropositive H. pylori IgG antibodies and elevated CA 19-9 in colorectal cancer patients, but no correlation between the serum gastrin level and the presence of this cancer. H. pylori seropositivity is more prevalent in patients with colorectal cancer.

The use of induced sputum in the assessment of pulmonary involvement in Crohn's disease.

OBJECTIVE: Our aim was to evaluate lung involvement in Crohn's disease (CRD) patients by induced sputum (IS). Extraintestinal manifestations are frequent in CRD, but lung involvement is rare. Induced sputum is a reliable noninvasive method of investigating the pathogenesis, pathophysiology, and treatment of lung disease. METHODS: Twenty-four CRD patients and nine control subjects (all nonsmokers) without respiratory symptoms were tested. Sputum was induced by 20' inhalation of 3.5% saline using ultrasonic nebulizer. Samples were studied by differential counts of 200 cells on cytopreps stained by Giemsa. T-lymphocyte subset analyses were done by FACS using three monoclonal antibodies: CD3 = total T cells, CD4 = T helper cells, and CD8 = T suppressor-cytotoxic cells. CD4/CD8 >2.5 was considered abnormal. RESULTS: Four patients did not produce sputum. Of the remaining 20 patients, seven had active CRD and 13 were in remission. They were divided into two groups: Group A patients had abnormal CD4/CD8 ratio of 6.7 +/- 2.5; Group B (seven patients) had normal CD4/CD8 ratio of 1.7 +/- 0.52 (p = 0.0001). The differential counts of IS samples were similar in both groups, but lymphocyte count was significantly higher in CRD patients than in the control group (13.2 +/- 11.2 vs 4.8 +/- 3.6, p = 0.036). There were no differences in spirometry, treatment, extent, or activity of CRD. CONCLUSION: Using a simple noninvasive method, we found that among CRD patients without respiratory symptoms there was a high (65%) incidence of lung involvement.

Results of gastrointestinal evaluation in 90 hospitalized iron deficiency anemia patients.

BACKGROUND: Chronic occult blood loss from the gastrointestinal tract is widely accepted as a major cause of iron deficiency anemia. OBJECTIVES: To evaluate the diagnostic yield of gastroscopy, colonoscopy and fecal occult blood testing of hospitalized IDA patients, plus follow-up. METHODS: IDA was defined as hemoglobin < 12.5 g/dl (men) and 11 g/dl (women), and serum iron < 50 g/dl. The study group comprised 90 patients (42% male) with a mean age of 65 +/- 15 years and mean Hb 8.1 g/dl. RESULTS: Gastroscopy and colonoscopy revealed a bleeding source in 28.8% and 14.4% respectively. Gastrointestinal symptoms were found in 23% of patients with diseases of the upper gastrointestinal tract and in 15.3% of the lower. The sensitivity of fecal occult blood tests in detecting lesions in the lower and upper GI tracts was 100% and 30.7% respectively. Forty-four patients (48.9%) were discharged from the hospital with IDA of unknown origin. Over the following year, 20 of the 44 patients required further hospitalization, and of these, 13 were found to have anemia. Of the remaining 24 patients who were not hospitalized again, 15 had anemia. Four patients (9%) had significant gastrointestinal lesions and two died during the follow-up. CONCLUSIONS: Fecal occult blood is a sensitive examination for lower but not for upper GI tract lesions.

Helicobacter pylori and peptic ulcer disease therapies: a survey of gastroenterologists in Israel.

BACKGROUND: Eradication of Helicobacter pylori has become a therapeutic option in the treatment of patients with peptic ulcer disease. The aim of this study was to evaluate the current management strategies of Israeli gastroenterologists in the diagnosis and treatment of H. pylori-related peptic ulcer disease, 14 years after the discovery of H. pylori. MATERIALS AND METHODS: A questionnaire was mailed to all specialists in gastroenterology, members of the Israel Gastroenterological Association (IGA). Replies were received from 60% of Israel Board-certified gastroenterology specialists. RESULTS: Over 89% of the gastroenterologists (89.1%) noted that they recommend anti-H. pylori treatment. 94.5% said that they treat duodenal ulcer in the first presentation with anti-H. pylori medication and 75% said that they do so in cases of recurrent duodenal ulcer. According to the replies received, there is a strong consensus towards triple treatment as the favored anti-H. pylori treatment; no one noted the use of dual treatment. Seven-day triple treatment was prescribed by 83.6% of the gastroenterologists who responded. Of these, the great majority, 89.1%, stated that they use proton pump inhibitors (PPI) in combination with any two of the following antibiotics: metronidazole (47.3%), tinidazole (29.1%), clarithromycin (61.8%), and amoxicillin (40%). CONCLUSION: At the time of the survey, most Israel Board-certified gastroenterology specialists prescribed triple anti-H. pylori treatment of one-week's duration.