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OBJECTIVES - Symptom eradication in patients with Barrett's esophagus (BE) does not guarantee control of acid or duodenogastroesophageal reflux (DGER). Continued reflux of acid and/or DGER may increase risk of neoplastic progression and may decrease the likelihood of columnar mucosa eradication after ablative therapy. To date, no study has addressed whether both complete acid and DGER control is possible in patients with BE. This prospective study was designed to assess the effect of escalating-dose proton pump inhibitor (PPI) therapy on esophageal acid and DGER.
METHODS - Patients with BE (≥3 cm in length) underwent simultaneous ambulatory prolonged pH and DGER monitoring after at least 1 week off PPI therapy followed by testing on therapy after 1 month of twice-daily rabeprazole (20 mg). In those with continued acid and/or DGER, the tests were repeated after 1 month of double-dose (40 mg twice daily) rabeprazole. The primary study outcome was normalization of both acid and DGER. Symptom severity was assessed on and off PPI therapy employing a four-point ordinal scale.
RESULTS - A total of 29 patients with BE consented for pH monitoring, of whom 23 also consented for both pH and DGER monitoring off and on therapy (83% male; mean age 58 years; mean body mass index 29; mean Barrett's length 6.0 cm). Median (interquartile range) total % time pH <4 and bilirubin absorbance >0.14 off PPI therapy were 18.4 (11.7-20.0) and 9.7 (5.0-22.2), respectively. In addition, 26/29 (90%) had normalized acid and 18/23 (78%) had normalized DGER on rabeprazole 20 mg. Among those not achieving normalization on 20 mg twice daily, 3/3 (100%) had normalized acid and 4/5 (80%) had normalized DGER on rabeprazole 40 mg twice daily. All subjects had symptoms controlled on rabeprazole 20 mg twice daily. Univariate analysis found no predictor for normalization of physiologic parameters based on demographics.
CONCLUSIONS - Symptom control does not guarantee normalization of acid and DGER at standard dose of twice-daily PPI therapy. Normalization of acid and DGER can be achieved in 79% of BE patients on rabeprazole 20 mg p.o. twice daily, and in the majority of the remainder at high-dose twice-daily PPI. In patients undergoing ablative therapy, pH or DGER monitoring may not be needed to ensure normalization of reflux if patients are treated with high-dose PPI therapy.
BACKGROUND & AIMS - Chronic unexplained nausea and vomiting (CUNV) is a debilitating disease of unknown cause. Symptoms of CUNV substantially overlap with those of gastroparesis, therefore the diseases may share pathophysiologic features. We investigated this hypothesis by quantifying densities of interstitial cells of Cajal (ICCs) and mapping slow-wave abnormalities in patients with CUNV vs controls.
METHODS - Clinical data and gastric biopsy specimens were collected from 9 consecutive patients with at least 6 months of continuous symptoms of CUNV but normal gastric emptying who were treated at the University of Mississippi Medical Center, and from 9 controls (individuals free of gastrointestinal disease or diabetes). ICCs were counted and ultrastructural analyses were performed on tissue samples. Slow-wave propagation profiles were defined by high-resolution electrical mapping (256 electrodes; 36 cm(2)). Results from patients with CUNV were compared with those of controls as well as patients with gastroparesis who were studied previously by identical methods.
RESULTS - Patients with CUNV had fewer ICCs than controls (mean, 3.5 vs 5.6 bodies/field, respectively; P < .05), with mild ultrastructural abnormalities in the remaining ICCs. Slow-wave dysrhythmias were identified in all 9 subjects with CUNV vs only 1 of 9 controls. Dysrhythmias included abnormalities of initiation (stable ectopic pacemakers, unstable focal activities) and conduction (retrograde propagation, wavefront collisions, conduction blocks, and re-entry), operating across bradygastric, normal (range, 2.4-3.7 cycles/min), and tachygastric frequencies; dysrhythmias showed velocity anisotropy (mean, 3.3 mm/s longitudinal vs 7.6 mm/s circumferential; P < .01). ICCs were less depleted in patients with CUNV than in those with gastroparesis (mean, 3.5 vs 2.3 bodies/field, respectively; P < .05), but slow-wave dysrhythmias were similar between groups.
CONCLUSIONS - This study defined cellular and bioelectrical abnormalities in patients with CUNV, including the identification of slow-wave re-entry. Pathophysiologic features of CUNV were observed to be similar to those of gastroparesis, indicating that they could be spectra of the same disorder. These findings offer new insights into the pathogenesis of CUNV and may help to inform future treatments.
Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.
Gastric arrhythmia continues to be of uncertain diagnostic and therapeutic significance. However, recent progress has been substantial, with technical advances, theoretical insights and experimental discoveries offering new translational opportunities. The discoveries that interstitial cells of Cajal (ICC) generate slow waves and that ICC defects are associated with dysmotility have reinvigorated gastric arrhythmia research. Increasing evidence now suggests that ICC depletion and damage, network disruption and channelopathies may lead to aberrant slow wave initiation and conduction. Histological and high-resolution (HR) electrical mapping studies have now redefined the human 'gastric conduction system', providing an improved baseline for arrhythmia research. The application of HR mapping to arrhythmia has also generated important new insights into the spatiotemporal dynamics of arrhythmia onset and maintenance, resulting in the emergence of new provisional classification schemes. Meanwhile, the strong associations between gastric functional disorders and electrogastrography (EGG) abnormalities (e.g. in gastroparesis, unexplained nausea and vomiting and functional dyspepsia) continue to motivate deeper inquiries into the nature and causes of gastrointestinal arrhythmias. In future, technical progress in EGG methods, new HR mapping devices and software, wireless slow wave acquisition systems and improved gastric pacing devices may achieve validated applications in clinical practice. Neurohormonal factors in arrhythmogenesis also continue to be elucidated and a deepening understanding of these mechanisms may open opportunities for drug design for treating arrhythmias. However, for all translational goals, it remains to be seen whether arrhythmia can be corrected in a way that meaningfully improves organ function and symptoms in patients.
© 2014 Wiley Publishing Asia Pty Ltd.
PURPOSE - The objective of this first-in-human trial included the safety, maximum tolerated dose (MTD), pharmacokinetics, immunogenicity and antitumour effects of KRN330, a novel fully-human monoclonal antibody directed against A33, a membrane bound glycoprotein uniformly expressed in 95% of colorectal cancers.
METHODS - Patients with advanced or metastatic colorectal cancer (CRC) refractory to standard therapy were eligible. Twenty-nine patients received weekly intravenous KRN330 (0.1-10mg/kg) for a minimum of 4 weeks in a standard 3+3 design, and nine patients received q2 week doses at 3mg/kg with pre- and post-biopsies to evaluate tumour binding and safety on this schedule.
RESULTS - The most common KRN330 related adverse events (all grades) were nausea (66%), diarrhoea (61%) and vomiting (47%). The MTD was 3mg/kg weekly, with dose-limiting grade 3 gastrointestinal toxicities at 10mg/kg and the intermediate dose level of 6 mg/kg. Pharmacokinetics of KRN330 was linear. Stable disease was reported in 12/38 patients (32%), with a median duration of 155 days. There was no evidence of human anti-human antibodies, and immunohistochemistry on biopsy samples demonstrated that KRN330 remained bound to tumour 2 weeks after dosing.
CONCLUSIONS - KRN330 is safe and tolerable at the MTD of 3mg/kg once weekly in patients with advanced CRC. Dosing on alternate weeks is supported by tumour binding. The long treatment durations and lack of immunogenicity warrant further investigation of KRN330 in combination.
Copyright © 2012 Elsevier Ltd. All rights reserved.
PURPOSE - Gemcitabine is effective in the treatment of pancreatic cancer and is a potent radiosensitizer. This study assessed safety and efficacy of full-dose gemcitabine administered before and during concurrent three-dimensional conformal radiation (3D-CRT) in patients with nonmetastatic pancreatic cancer.
PATIENTS AND METHODS - During cycles 1 and 3, patients received gemcitabine at 1,000 mg/m(2) on days 1 and 8 of each 21-day cycle. Cycle 2 included the same dose of gemcitabine on days 1, 8, and 15 of a 28-day cycle with concurrent 3D-CRT at 36 Gy, administered in 15 fractions of 2.4 Gy, over 3 weeks. Resectable patients underwent surgery 4 to 6 weeks after treatment. The primary objective was evaluation of toxicity. Tumor response, CA 19-9, and 1-year survival were also assessed.
RESULTS - Forty-one patients enrolled at six institutions between April 2002 and October 2003. Among the 39 treated patients, the most common toxicities were grade 3 neutropenia (12.8%), grade 3 nausea (10.3%), and grade 3 vomiting (10.3%). The response rate was 5.1% and disease control rate was 84.6%. Mean post-treatment CA 19-9 levels (228 +/- 347 U/mL) were significantly (P = .006) reduced compared with pretreatment levels (1,241 +/- 2,124 U/mL). Thirteen (81%) of 16 patients initially judged resectable, three (33%) of nine borderline-resectable patients, and one (7%) of 14 unresectable patients underwent resection after therapy. One-year survival rates were 73% for all patients, 94% for resectable patients, 76% for borderline-resectable patients, and 47% for unresectable patients.
CONCLUSION - Full-dose gemcitabine with concurrent radiotherapy was well tolerated and active. Evaluation of this regimen in a larger, randomized trial for patients with resectable or borderline-resectable disease may be warranted.
BACKGROUND - Chemotherapy-induced nausea and vomiting (CINV) is one of the most distressing side effects of moderately or highly emetogenic chemotherapy. Diphenhydramine, lorazepam, and dexamethasone have been used individually to treat CINV. The objective of this study was to evaluate the safety and potential efficacy of those drugs administered via a patient controlled pump (BAD pump) to control CINV.
PROCEDURE - A retrospective chart review was conducted of all pediatric oncology patients who received the BAD pump. Emetic episodes, doses of rescue medications to treat breakthrough nausea or vomiting, and occurrence of adverse events were recorded. Complete response (CR) was defined as no emesis or rescue medications, partial response (PR) as emesis but no rescue medications, and failure (F) as rescue medications required.
RESULTS - Thirty patients received a total of 141 courses. Adverse events occurred in 4.2% of the courses; confusion (n = 2), depressed mood (n = 1), dysphoria (n = 1), agitation (n = 1), and restlessness (n = 1). All side effects resolved after decreasing the infusion rate, and the pump was not discontinued in any patients. Eighteen patients failed conventional prophylaxis and received BAD pump for identical subsequent chemotherapy cycles; they spent more days in CR with BAD pump than without it, 21 versus 45 days (P = .003) respectively. Patients receiving BAD pump had significantly shorter hospital stay with BAD pump than those not receiving it, 68 days versus 76 (P = .046).
CONCLUSIONS - BAD pump is well tolerated in pediatric patients receiving chemotherapy and may be more effective than conventional prophylaxis in controlling CINV in some patients.
(c) 2006 Wiley-Liss, Inc.
Cluster analysis was used to validate headache diagnostic criteria of the International Headache Society (IHS). Structured diagnostic interviews were conducted on 443 headache sufferers from a community sample, which was randomly split to allow replication. Hierarchical cluster analysis of symptoms in both subsamples revealed two distinct (P<.001) clusters: (1) unilateral pulsating pain, pain aggravated by activity, and photophobia and phonophobia, and (2) bilateral pressing/tightening pain, mild to moderate intensity, and absence of nausea/vomiting. These clusters were consistent with IHS migraine and tension-type classifications, respectively. Replication using a non-hierarchical clustering technique, k-means cluster analysis, revealed a migrainelike patient cluster, reflecting more frequent pulsating, unilateral pain; more severe pain; and pain aggravated by activity; nausea, vomiting, photophobia, and phonophobia. A tensionlike patient cluster was also identified, reflecting more frequent pressing/tightening pain, mild to moderate pain, bilateral location, and absence of nausea/vomiting. These patient clusters were consistent across subsamples. International Headache Society diagnoses corresponded with classification based upon statistically derived clusters (P<.001). These results indicate that headache symptoms cluster empirically in a manner consistent with IHS criteria for migraine and tension-type headaches. Criterion overlap problems regarding pain intensity and duration were identified. Overall, these data support migraine and tension-type headache as distinct entities, and provide support for the IHS diagnostic criteria with minor modifications.
In studies conducted by the Eastern Cooperative Oncology Group, treatment with either paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) or carboplatin was associated with an improvement in 1-year survival in patients with stage IV non-small cell lung cancer (NSCLC). Based on these findings, a phase II trial of carboplatin plus paclitaxel was conducted in patients with advanced NSCLC to determine the activity and toxicity of this regimen. Eligibility requirements included stage IIIB or IV histologically confirmed NSCLC, Eastern Cooperative Oncology Group performance status of 0 to 2, no prior chemotherapy, and adequate hematologic, renal, hepatic, and cardiac functions. Paclitaxel was administered intravenously over 24 hours at a dose of 135 mg/m2 (28 patients) or 175 mg/m2 (23 patients), followed by a 1-hour infusion of carboplatin on day 2. Carboplatin was administered at a dose of 300 mg/m2 (16 patients) or, using the Calvert formula, a dose calculated to achieve an area under the concentration-time curve of 6 mg/mL x min (35 patients). Treatment was repeated every 28 days for a total of six cycles. Among the 51 eligible patients, 34 were men and 17 were women; their median age was 60 years and their median Eastern Cooperative Oncology Group performance status was 1. Six patients had stage IIIB and 45 had stage IV disease. Grade 3 or 4 granulocytopenia and thrombocytopenia were observed in 47% and 3% of treatment cycles, respectively. The most common nonhematologic toxicities noted included nausea and emesis, neuropathy, and arthralgia and myalgia. There were no complete responses and 14 partial responses, for an overall response rate of 27% (95% confidence interval, 17% to 41%). Median survival was 38 weeks and the survival rate at 1 year was 32%. Paclitaxel plus carboplatin, as given in this study, was found to be a moderately active regimen in patients with advanced NSCLC. This regimen warrants comparison with existing cisplatin-based regimens in a prospective randomized trial.