Endoscopic ultrasonography-guided portal injection chemotherapy for hepatic metastases.

INTRODUCTION: We hypothesized that endoscopic ultrasonography-guided portal injection chemotherapy (EPIC) using irinotecan-loaded microbeads may achieve increased intrahepatic concentrations, while decreasing systemic exposure. This may achieve enhanced efficacy for the treatment of diffuse liver metastases, while decreasing systemic toxicities. MATERIALS AND METHODS: In eight anesthetized 35 kg pigs, EPIC was performed transgastrically using the linear-array echoendoscope and a 22 g fine-needle aspiration. In four animals, irinotecan (100 mg) loaded onto 75-150 micron liquid chromatography (LC) beads was injected. In four animals, saline was injected into the portal vein and unloaded irinotecan (100 mg) was injected into the jugular vein. Plasma (every 15 min), and at 1 h bone marrow, liver and skeletal muscle samples were obtained. Irinotecan and SN-38 (active metabolite) concentrations were assayed by LC/mass spectrometry. RESULTS: The procedure was performed safely in all eight animals. Compared with systemic administration, EPIC resulted in almost twice the hepatic concentration of irinotecan (6242 vs. 3692 ng/g) and half the systemic concentrations in plasma (1092 vs. 2762 ng/mL), bone marrow (815 vs. 1703 ng/mL) and skeletal muscle (521 vs. 1058 ng/g). SN-38 levels were lower with EPIC (liver: 166 vs. 681 ng/g; plasma: 1.8 vs. 2.4 ng/mL; bone marrow: 0.9 vs. 1.4 ng/mL; muscle 4.6 vs. 9.2 ng/g). Liver histology showed the beads within small portal venules. CONCLUSIONS: EPIC using irinotecan-loaded microbeads can enhance hepatic exposure to irinotecan, while decreasing systemic concentrations. SN-38 levels were lower with EPIC indicating that a substantial portion of the irinotecan was still loaded onto beads. The microbeads may act as a reservoir resulting in prolonged hepatic drug exposure.

Effect of fluoroscopy utilization monitoring on fluoroscopy times during ERCP.

AIM: The aim of the present study was to find whether informing endoscopists that their FT is being tracked would result in decreasing their overall fluoroscopy utilization as measured by FT. METHODS: We reviewed the medical charts of patients underwent ERCP from April 2011 to May 2012. On December 15, 2011, the endoscopists were informed about their mean FT during ERCP, were encouraged to decrease FT and were informed their FT would be monitored. We compared the mean FT of the endoscopists individually and as a group before and after December 15, 2011. RESULTS: The study included 293 patients and 3 endoscopists. Before informing the endoscopists that their FT was being tracked, utilization of fluoroscopy was significantly variable among endoscopists. The mean FT for all endoscopists was 9.04 minutes and for each endoscopist was 6.06, 11.43, and 7.67 minutes, respectively (P<0.02). After informing the endoscopists that their FT will be followed, there was a trend toward a decrease in FT among the group (9.04 vs. 7.4 minutes, P=0.06). However, the changes in FT among endoscopists individually were variable. The FT for first, second and third endoscopists changed from 6.06 min to 3.39 min, p<0.02, 11,43 min to 8.8 min, P=0.14 and 7.67 to 11.47 minutes, P=0.06, respectively. CONCLUSION: Fluoroscopic utilization during ERCP among endoscopists is variable. Endoscopists' knowledge that their FT during ERCP is being tracked leads to variable results among endoscopists. Nonetheless, overall it leads to a trend in reducing fluoroscopy utilization.

Comparison of transcolonic NOTES and laparoscopic peritoneoscopy for the detection of peritoneal metastases.

BACKGROUND AND AIMS: Peritoneoscopy by natural orifice transluminal endoscopic surgery (NOTES) could replace laparoscopic staging peritoneoscopy (LAP) if the yield were comparable to that from LAP. In previously performed porcine experiments, transgastric peritoneoscopy seemed inferior to LAP due to limited visualization of the liver. The aim of the present study was to improve liver visualization by using a colonic approach and to compare transcolonic peritoneoscopy (TCP) with the previously set LAP standard. METHODS: Small beads were stapled into porcine peritoneal cavities to simulate metastases. Previously in the same model LAP had detected 95% of beads (95% CI 87% -98%). Using a non inferiority design, a sample size of 33 beads was determined; these were distributed among six animals with randomization for numbers and location. TCP was performed using either standard endoscopic accessories (TCP-s) or a specially designed toolkit (TCP-t) in randomized order by one of two blinded endoscopists. Primary outcome was number of beads found and touched during peritoneoscopy. RESULTS: Locations of beads included abdominal peritoneum (6 beads), diaphragm (8), liver (18), and miscellaneous sites (1). TCP-s found 25 beads (yield 76%, 95% CI 59% -87%). TCP-t found 19 beads (yield 58%, 95% CI 41%-71%). The majority of missed beads were located at the inferior liver surface: TCP-s detected 8/15 (53%) and TCP-t 5/15 (33%) of these simulated metastases. CONCLUSIONS: In this prospective, experimental trial, transcolonic NOTES peritoneoscopy was inferior in comparison with the diagnostic laparoscopy done previously in the same model.

Celiac and perigastric lymph node metastasis of prostate cancer diagnosed with endoscopic ultrasound-guided fine-needle aspiration.

Endoscopic ultrasound has been used to diagnose and stage gastrointestinal and nongastrointestinal tumours. To our knowledge, the present report describes the first case of celiac and perigastric lymph node metastasis of prostate cancer diagnosed with endoscopic ultrasound-guided fine-needle aspiration.

Risk factors for cardiopulmonary events during propofol-mediated upper endoscopy and colonoscopy.

BACKGROUND: Propofol-mediated sedation for endoscopy is popular because of its rapid onset and recovery profile. AIM: To examine procedure-specific occurrence and risk factors for cardiopulmonary events during propofol-mediated upper endoscopy (EGD) and colonoscopy. DESIGN: A cohort study using the Clinical Outcomes Research Initiative database was used to determine the frequency of cardiopulmonary events. Clinical Outcomes Research Initiative consisted of 69 practice sites comprising 593 US endoscopists. Multivariate logistic regression analysis used variables, such as age, ASA classification and propofol administration by monitored anaesthesia care or gastroenterologist-administered propofol to determine the risk of cardiopulmonary events. RESULTS: The overall cardiopulmonary event rate for 5928 EGDs and 11 683 colonoscopies was 11.7/1000 cases. For colonoscopy, ascending ASA classification was associated with an increased risk. Monitored anaesthesia care was associated with a decreased adjusted relative risk (0.5, 95% CI: 0.36-0.72). ASA I and II patients receiving monitored anaesthesia care for EGD exhibited a significantly lower relative risk (ARR 0.29, 95% CI: 0.14-0.64). For subjects with ASA class III or greater, there was no difference in the risk between monitored anaesthesia care and gastroenterologist-administered propofol. CONCLUSIONS: There are procedure-specific risk factors for cardiopulmonary events during propofol-mediated EGD and colonoscopy. These should be taken into account during future prospective comparative trials.

The accuracy of PillCam ESO capsule endoscopy versus conventional upper endoscopy for the diagnosis of esophageal varices: a prospective three-center pilot study.

BACKGROUND AND STUDY AIMS: Variceal bleeding is a major complication of cirrhosis, and is associated with a 20 % mortality at 6 weeks. Current international guidelines recommend that patients with cirrhosis are screened by conventional upper endoscopy (esophagogastroduodenoscopy, EGD) in order to detect esophageal varices. The recently developed PillCam ESO esophageal capsule endoscope has been shown to be an accurate diagnostic tool in the investigation of patients with gastroesophageal reflux and Barrett's esophagus. We compared the PillCam ESO capsule endoscope with EGD for the detection of esophagogastric varices and portal hypertensive gastropathy in patients with cirrhosis. PATIENTS AND METHODS: A pilot trial was conducted at three sites. Patients with cirrhosis who were undergoing clinically indicated EGD for screening or surveillance for esophageal varices underwent a PillCam ESO study followed by an EGD within 48 hours. Capsule videos were assessed by an investigator who was blinded to the patient's medical history and EGD findings. RESULTS: A total of 23 of the 32 enrolled patients were found to have esophageal varices at both EGD and PillCam ESO endoscopy. In one patient PillCam ESO detected small varices that were not seen at EGD. The overall concordance between PillCam ESO and EGD was 96.9 % for the diagnosis of esophageal varices and 90.6 % for the diagnosis of portal hypertensive gastropathy. There were no adverse events related to PillCam ESO endoscopy. CONCLUSIONS: In a high-prevalence population, PillCam ESO may represent an accurate noninvasive alternative to EGD for the detection of esophageal varices and portal hypertensive gastropathy. A large-scale trial is underway to validate and expand these findings.

The No Endosonographic Detection of Tumor (NEST) Study: a case series of pancreatic cancers missed on endoscopic ultrasonography.

BACKGROUND AND STUDY AIMS: The purpose of this study was to identify possible associated factors that may have contributed to failure to detect a pancreatic neoplasm during endoscopic ultrasound (EUS) examinations by experienced endosonographers. PATIENTS AND METHODS: A multicenter retrospective study was organized, and 20 cases of pancreatic neoplasms missed by nine experienced endosonographers were identified. Careful analysis of each case was carried out to identify the factors that might have led to the missed diagnosis on EUS. RESULTS: Twelve patients with a missed pancreatic neoplasm had EUS features of chronic pancreatitis. Other factors that might have increased the likelihood of a false-negative EUS examination included a diffusely infiltrating carcinoma (n = 3), a prominent ventral/dorsal split (n = 2), and a recent episode (within the previous 4 weeks) of acute pancreatitis (n = 1). Five patients with a negative initial EUS underwent a follow-up EUS after 2-3 months, with a pancreatic mass being found in all cases. Three patients had a diffusely infiltrating pancreatic adenocarcinoma. CONCLUSIONS: EUS is not a foolproof method of detecting a pancreatic neoplasm. Possible associated factors that may increase the likelihood of a false-negative EUS examination include chronic pancreatitis, a diffusely infiltrating carcinoma, a prominent ventral/dorsal split and a recent episode (< 4 weeks) of acute pancreatitis. If there is a high clinical suspicion of pancreatic neoplasm, if EUS and other imaging methods are negative, and if the patient does not undergo surgery, this study suggests that a repeat EUS after 2-3 months may be useful for detecting an occult pancreatic neoplasm.

Outcomes of Helicobacter pylori treatment in community practice and impact of therapeutic effectiveness information on physician behaviour.

BACKGROUND: The effect of knowledge of Helicobacter pylori eradication rates on physician choice of treatment regimen is unknown. As practice variation results in differences in outcome, it is important to determine whether physician behaviour can be altered by such knowledge. AIMS: (i) To determine whether dissemination of practice variation and effectiveness data regarding H. pylori changes subsequent prescribing behaviour and (ii) whether this change results in an improvement in the effectiveness of therapy. METHODS: Community gastroenterologists in the Portland metropolitan area enrolled patients being treated for H. pylori. The regimen used, diagnostic method, indication and success in eradication was measured. Patient-centred factors were also measured, including symptoms, interest in post-treatment diagnostic testing and willingness to pay. RESULTS: Significantly more physicians participating in both studies used proton pump inhibitor-triple therapy based regimens in this trial (46% vs. 85%, P=0.01), although the overall difference between the two trials was not significant (62% vs. 83%, P=0.11). There was no change in overall eradication rates by per protocol analysis between trials (84% vs. 85%, P=0.78), but a significant decrease in effectiveness by intention-to-treat analysis observed in this study (80% vs. 71%, P=0.03). Significantly more patients were treated for reasons other than peptic ulcer disease in this study (P=0.0003). CONCLUSIONS: The overall effectiveness of H. pylori therapy in practice remains good. There has been a shift in the choice of treatment regimen and indication for therapy between the time periods of the two studies. Dissemination of treatment data appears to effect prescribing behaviour, but whether it has a beneficial effect on treatment outcome remains unproven.

A randomized trial of lansoprazole, amoxycillin, and clarithromycin versus lansoprazole, bismuth, metronidazole and tetracycline in the retreatment of patients failing initial Helicobacter pylori therapy.

BACKGROUND/AIM: 10-30% of the patients treated for Helicobacter pylori fail to clear the infection after initial therapy. Little is known as to the efficacy of retreatment regimens in these patients. Proton pump inhibitor (PPI) -based triple and quadruple therapies demonstrate efficacies of 80-90% as initial therapy for H. pylori infection, but whether these regimens are as effective when used for retreatment is unknown. The efficacy of a metronidazole-containing regimen in this situation is also unknown. Our aim was to compare the efficacy of a nonmetronidazole-containing PPI-based triple versus a PPI-based quadruple therapy containing metronidazole in patients failing previous H. pylori therapy. METHODS: 48 patients were enrolled in this study at two sites after failure of previous H. pylori therapy as determined by a positive (14)C-urea breath test. Patients were stratified by prior treatment with a metronidazole-containing regimen and were then randomized to either lansoprazole (L) 30 mg twice daily, amoxycillin (A) 1,000 mg twice daily, and clarithromycin (C) 500 mg twice daily for 14 days (LAC) or L 30 mg four times daily, bismuth subsalicylate (B) 2 tablets four times daily, metronidazole (M) 250 mg four times daily and tetracycline (T) 250 mg four times daily for 14 days (LBMT). Side effects and compliance (pill count) were assessed at the completion of therapy. A repeat (14)C-urea breath test was performed 4 or more weeks after completion of therapy, and cure was defined as a negative test result. RESULTS: 48 patients (16 males and 32 females) were enrolled in this study. 20 patients received LAC (18 prior M), and 28 received LBMT (23 prior M). Per protocol and intention-to-treat efficacies were 82% (95% CI 64-100%) and 75% (95% CI 56-94%) for LAC and 80% (96% CI 64-96%) and 71% (95% CI 54-88%) for LBMT (p = 0.85 per protocol and p = 0.78 intention to treat between LAC and LBMT), respectively. The compliance (> or =80% of pills taken) was found to be 89% in both treatment groups. Side effects were noted in 84% for LAC and in 82% for LBMT, but were mild and did not cause discontinuation of therapy. CONCLUSIONS: PPI-based triple and quadruple therapy with both LAC and LBMT are effective in retreating patients failing initial metronidazole-based H. pylori therapies. LAC was not statistically superior to LBMT as a 'retreatment' regimen in this clinical situation, but the small sample size and wide confidence limits do not preclude the possibility of a smaller but significant difference in efficacy between the regimens. To determine whether LAC or LBMT is as effective for retreating patients failing non-metronidazole-containing regimens requires further study.

Fine-needle aspiration biopsy diagnosis of gastrointestinal stromal tumors using morphology, immunocytochemistry, and mutational analysis of c-kit.

BACKGROUND: Differentiating gastrointestinal stromal tumors (GISTs) from other intramural mesenchymal tumors of the GI tract on fine-needle aspiration biopsies (FNABs) is difficult. Recent studies have shown that GISTs are immunophenotypically and genetically distinct. GISTs exhibit consistent immunohistochemical expression of CD-117 (KIT) and often express activating mutations of this protooncogene. The aim of the current study was to employ immunocytochemistry and mutational analysis of the c-kit gene to aid in the diagnosis of GISTs on FNAB. METHODS: Five endoscopic ultrasound-guided FNABs of gastrointestinal spindle cell neoplasms performed at the Veterans Affairs Medical Center (VAMC) in Portland, Oregon, from 1998-1999 were reviewed. A panel of immunocytochemical stains was performed on each cellblock including CD-117 (KIT), smooth muscle actin (SMA), desmin, S-100, and CD34. Genomic DNA (gDNA) was extracted, and amplification of exons 9, 11, 13 and 17 of c-kit was performed by polymerase chain reaction (PCR) on CD-117 (KIT) and CD34 positive cases. Direct sequencing of amplicons identified the mutations. RESULTS: Five patients were diagnosed with GISTs based on morphology and immunocytochemical positivity for CD-117 and CD34. PCR analysis of c-kit exon 11 revealed three cases with novel-sized PCR bands in addition to the expected wild-type-sized PCR product. Amplicons from these cases contained an in-frame deletion mutation. One of the two cases with wild-type-;sized exon 11 amplicons was found to be heterozygous for a point mutation producing an amino acid substitution (W557R). No mutations in exon 9, 11, 13, or 17 of c-kit were found in the remaining case. CONCLUSIONS: Ancillary techniques such as immunocytochemistry and c-kit gene mutational analysis may aid in the diagnosis of GISTs on FNABs.

Frequency of mediastinal lymph node metastases in patients undergoing EUS evaluation of pancreaticobiliary masses.

BACKGROUND: Mediastinal lymph node metastases have rarely been reported in patients with pancreatic cancer. Our aim was to determine the frequency of mediastinal lymph node metastases in patients with pancreaticobiliary masses by using EUS-guided fine needle aspiration. METHODS: Sixty-six consecutive patients with pancreatobiliary masses were evaluated on EUS for the presence of mediastinal lymph node metastases. All masses were staged by commonly used EUS criteria by using sector scanning echoendoscopes. Mediastinal lymph nodes with EUS features that suggested malignancy were aspirated. RESULTS: Of the 66 patients (mean age 65.6 years; 38 men), 4 had biliary masses, 5 had lesions of the major duodenal papilla, and 57 had pancreatic masses. Eleven patients (10 pancreatic masses, 1 biliary mass) had enlarged mediastinal lymph node (12-30 mm) on EUS; in 2 patients these had a benign appearance and were not aspirated. Nine patients underwent EUS-guided fine needle aspiration: in 1 the cytology was inconclusive (patient subsequently had a negative Whipple resection); in 4 the mediastinal lymph node cytology was benign; the remaining 4 patients had adenocarcinoma cells in the aspirate from mediastinal lymph node. These 4 pancreatic tumors were staged by EUS as T2N1M1 (1), as T4N0M1 (2, one later found to also have a lung mass), and T4N1M1 (1). CONCLUSION: Enlarged mediastinal lymph nodes were found on EUS in 16.6% (95% CI [7.7%, 25.6%]) of patients with pancreatobiliary masses and in 17.5% (95% CI [7.6%, 27.4%]) of patients with pancreatic masses. The frequency of mediastinal lymph node metastases in pancreatobiliary masses was 6.1% (95% CI [0.34%, 11.9%]) and in pancreatic masses 7.0% (95% CI [0.4%, 13.6%]). Routine EUS evaluation of the mediastinum in patients with pancreatic masses is warranted.

Does neoadjuvant chemoradiation downstage esophageal carcinoma?

BACKGROUND: Neoadjuvant chemoradiotherapy is administered to patients with esophageal carcinoma with the belief that this will both downstage the tumor and improve survival. Endoscopic ultrasound (EUS) is currently the most accurate method of staging esophageal cancer for tumor (T) and lymph node (N) status. Because both EUS and neoadjuvant therapy for esophageal carcinoma are relatively new, there are few data examining the relationship between EUS stage and histological stage (the stage after resection) in patients receiving neoadjuvant therapy. METHODS: To determine the effect of neoadjuvant chemoradiotherapy on T and N stage as determined by EUS, we retrospectively compared two groups of patients with esophageal cancer staged by EUS. One group (33 patients) underwent neoadjuvant therapy (Walsh protocol: 5-fluorouracil, cisplatin, and 4000 rads of external beam radiation) followed by resection. The second group (22 patients), a control group, underwent resection without neoadjuvant therapy. We then compared histological stage to determine if there was a downstaging in the patients receiving neoadjuvant therapy. Survival was evaluated as well. RESULTS: EUS accurately predicted histologic stage. In the control group EUS overestimated T stage in 3 of 22 (13%), underestimated N stage in 2 of 22 (9%), and overestimated N stage in 2 of 22 (9%) of patients. Preoperative radiochemotherapy downstaged (preoperative EUS stage versus pathologic specimen) 12 of 33 (36%) of patients whereas only 1 of 22 (5%) of patients in the control group was downstaged. Complete response (no tumor found in the surgical specimen) was observed in 5 of 33 (15%) of patients receiving radiochemotherapy. Survival was prolonged significantly in patients receiving radiochemotherapy: 20.6 months versus 9.6 months for those (stage II or III) patients not receiving radiochemotherapy (P <0.01). Operative time, operative blood loss, and length of stay were not significantly different between groups. Perioperative mortality was higher in the radiochemotherapy group (13%) compared with the no radiochemotherapy group (5%) but did not achieve statistical significance. CONCLUSIONS: EUS accurately stages esophageal carcinoma. Neoadjuvant radiochemotherapy downstages esophageal carcinoma for T and N status. In our nonrandomized study, neoadjuvant therapy conferred a significant survival advantage. Operative risk appears to be increased in patients receiving neoadjuvant radiochemotherapy prior to esophagectomy.