Esophageal verrucous carcinoma arising from hyperkeratotic plaques associated with human papilloma virus type 51.

Esophageal verrucous carcinoma is a rare variant of esophageal squamous cell carcinoma. We report a case of esophageal verrucous carcinoma associated with human papilloma virus (HPV) type 51. The patient had long-standing dysphagia and odynophagia, and white esophageal plaques showing hyperkeratosis on biopsy. At repeat endoscopy, the esophagus was covered with verrucous white plaques and areas of nodular mucosa with white fronds, with a distal 10-cm smooth mass protruding into the lumen. Biopsies demonstrated an atypical squamoproliferative lesion but no frank malignancy. HPV type 51 DNA was detected in endoscopic biopsy specimens by polymerase chain reaction. Because the size of the lesion favored an underlying verrucous carcinoma, our patient underwent minimally invasive esophagectomy with gastric pull-up and cervical anastomosis. The pathologic diagnosis was a well-differentiated esophageal verrucous carcinoma. One year after esophagectomy, the patient feels well and is free of disease. Although HPV DNA was not detected in the cancer tissue obtained at surgery, our case suggests an association between HPV type 51 and esophageal verrucous carcinoma. The clinical evolution in this case highlights the importance of endoscopic surveillance in patients with exuberant esophageal hyperkeratosis, and of definitive surgical resection when malignancy is suspected even if frank malignancy is not demonstrated on superficial biopsies.

Addressing the challenges of the clinical application of pharmacogenetic testing.

Pharmacogenomics aims to use molecular genetic markers to predict treatment outcome. Indeed, within the past decade there has been a rapid emergence of pharmacogenetic tests to aid clinicians in predicting efficacy or toxicity for some drugs. Despite this major advance in therapeutic drug management, there remain challenges to the appropriate use of pharmacogenetic tests. We discuss UGT1A1 pharmacogenetic testing to illustrate the knowledge gaps impeding widespread use of pharmacogenetic tests in the clinical setting.

As tests evolve and costs of cancer care rise: reappraising stool-based screening for colorectal neoplasia.

BACKGROUND: Colorectal cancer screening and treatment are rapidly evolving. Aims To reappraise stool-based colorectal cancer screening in light of changing test performance characteristics, lower test cost and increasing colorectal cancer care costs. METHODS: Using a Markov model, we compared faecal DNA testing every 3 years, annual faecal occult blood testing or immunochemical testing, and colonoscopy every 10 years. RESULTS: In the base case, faecal occult blood testing and faecal immunochemical testing gained life-years/person and cost less than no screening. Faecal DNA testing version 1.1 at $300 (the current PreGen Plus test) gained 5323 life-years/100 000 persons at $16 900/life-year gained and faecal DNA testing version 2 (enhanced test) gained 5795 life-years/100 000 persons at $15 700/life-year gained vs. no screening. In the base case and most sensitivity analyses, faecal occult blood testing and faecal immunochemical testing were preferred to faecal DNA testing. Faecal DNA testing version 2 cost $100 000/life-year gained vs. faecal immunochemical testing when per-cycle adherence with faecal immunochemical testing was 22%. Faecal immunochemical testing with excellent adherence was superior to colonoscopy every 10 years. CONCLUSIONS: As novel biological therapies increase colorectal cancer treatment costs, faecal occult blood testing and faecal immunochemical testing could become cost-saving. The cost-effectiveness of faecal DNA testing compared with no screening has improved, but faecal occult blood testing and faecal immunochemical testing are preferred to faecal DNA testing when patient adherence is high. Faecal immunochemical testing may be comparable to colonoscopy every 10 years in persons adhering to yearly testing.

Obstipation as a paraneoplastic presentation of small cell lung cancer: case report and literature review.

Paraneoplastic symptoms caused by abnormal gastrointestinal motility may be the initial manifestation of small cell lung cancer (SCLC). We report a case of a 63-year-old woman who presented with progressive constipation culminating in obstipation, and associated symptoms of more widespread dysmotility. A paraneoplastic syndrome was suspected. The only abnormality on chest computed tomography was a minimally enlarged paratracheal lymph node. Positron emission tomography demonstrated increased activity in the lymph node. The antinuclear neuronal antibody titer was elevated. Bronchoscopy with transtracheal biopsy confirmed the diagnosis of SCLC. One year after diagnosis, the patient had progressive symptoms of intestinal obstruction, and ultimately feculent vomiting. On abdominal radiography, colonic sitz markers ingested a year earlier were in virtually the same positions as after ingestion. Palliative colectomy with ileostomy was performed. The myenteric plexus in the terminal ileum and colon showed infiltration by a mixture of B-cell and T-cell lymphocytes and plasma cells, and no gross neuronal abnormalities. We review the clinical and pathologic features, clinical course, and management of paraneoplastic pseudoobstruction.

Serological testing for coeliac disease in patients with symptoms of irritable bowel syndrome: a cost-effectiveness analysis.

BACKGROUND: Patients diagnosed with irritable bowel syndrome may have coeliac disease. AIM: To evaluate the cost-effectiveness of coeliac disease testing in suspected irritable bowel syndrome. METHODS: We used decision analysis to estimate the number of coeliac disease cases detected, quality-adjusted life-years gained, and costs resulting from testing suspected irritable bowel syndrome patients for tissue transglutaminase antibody or an antibody panel (tissue transglutaminase, gliadin, total immunoglobulin A). Positive tests prompted endoscopic biopsy. A gluten-free diet improved quality of life in coeliac disease. RESULTS: Assuming a coeliac disease prevalence of 3%, tissue transglutaminase detected 28 and the panel detected 29 of 30 coeliac disease cases among 1000 suspected irritable bowel syndrome patients. The cost/case detected was $4600 with tissue transglutaminase and $8800 with the panel. The cost/quality-adjusted life-year gained with tissue transglutaminase was $7400, and the incremental cost/quality-adjusted life-year gained for the panel vs. tissue transglutaminase was $287 000. Tissue transglutaminase cost under $100 000/quality-adjusted life-year gained at a coeliac disease prevalence >/=1.1%, assuming a modest utility gain of 0.005 with coeliac disease diagnosis. CONCLUSIONS: Testing for coeliac disease in patients with suspected irritable bowel syndrome is likely to be cost-effective even at a relatively low coeliac disease prevalence and with small improvements in quality of life with a gluten-free diet.

Safety, efficacy and costs of pharmacotherapy for functional gastrointestinal disorders: the case of alosetron and its implications.

BACKGROUND: Functional gastrointestinal disorders cause substantial morbidity, but not mortality. Alosetron may achieve 'adequate relief ' in diarrhoea-predominant irritable bowel syndrome, but may cause major complications, including death. AIM: To appraise, quantitatively, the trade-off between possible symptomatic improvement and serious complications in the treatment of functional gastrointestinal disorders. METHODS: A decision analytical model was used to examine alosetron or standard treatment for 6 months in 45-year-old women with diarrhoea-predominant irritable bowel syndrome using the health care system's perspective. RESULTS: Assuming a 14% higher 'adequate relief' rate with alosetron compared to standard care, and a complication rate of four per 1000 persons in 6 months, alosetron gained 0.00081 quality-adjusted life-years (QALYs) per patient at a cost of 358,700 US dollars per QALY gained. Alosetron gained QALYs if 'adequate relief' increased the patients' utility by more than 0.01 in the base case. In probabilistic analysis, alosetron gained QALYs in 98.2% of iterations at a median cost of 212,600 US dollars per QALY (interquartile range, 138,000-338,900 US dollars per QALY). Results were highly sensitive to the utility gain with 'adequate relief' and alosetron's response and complication rates. CONCLUSIONS: Alosetron's benefit-to-risk profile appears to be favourable, but its cost per QALY gained may be substantial. Decision analyses on treatments for functional gastrointestinal disorders are likely to be highly sensitive to the utility estimates used. There is a pressing need for direct utility measurements in functional gastrointestinal disorders.

Effect of the selective serotonin reuptake inhibitor sertraline on gastric sensitivity and compliance in healthy humans.

Abstract Visceral hypersensitivity may contribute to symptoms in functional dyspepsia. Selective serotonin reuptake inhibitors (SSRIs) may be beneficial in functional gastrointestinal disorders. The aim of this study was to determine whether the SSRI sertraline affects gastric sensitivity and compliance in healthy humans. Ten healthy humans completed a 6-week randomized, double-blind, crossover trial of sertraline (50 mg day(-1)) vs. placebo. After each 2-week treatment, fullness, pain and nausea were rated at increasing gastric barostat distending pressures. Sensation thresholds above minimal distending pressure (MDP) were determined with a tracking method. Somatic sensory testing was performed by hand immersion in ice water. No differences were found between sertraline and placebo for symptoms as a function of distending pressure (fullness, P = 0.72; pain, P = 0.79; nausea, P = 0.41), gastric compliance (P = 0.15), median and interquartile range thresholds for first sensation [4.1 (3.5-5.7) vs. 6.2 (3.3-10.0) mmHg above MDP, P = 0.19] and pain [15.2 (8.3-21.0) vs. 15.3 (10.3-19.8) mmHg above MDP, P = 0.85], and median tolerance times for hand ice water immersion [27 (19-99) vs. 29 (20-180) s, P = 0.73]. In conclusion, sertraline had no effect on gastric sensitivity or compliance, or somatic pain tolerance in healthy humans. Studies are needed to assess the effects of SSRIs on visceral sensation and clinical symptoms in patients with functional dyspepsia.

Reappraisal of non-invasive management strategies for uninvestigated dyspepsia: a cost-minimization analysis.

BACKGROUND: The benefits of the Helicobacter pylori test-and-treat strategy are attributable largely to the cure of peptic ulcer disease while limiting the use of endoscopy. AIM: To reappraise the test-and-treat strategy and empirical proton pump inhibitor therapy for the management of uninvestigated dyspepsia in the light of the decreasing prevalence of H. pylori infection, peptic ulcer disease and peptic ulcer disease attributable to H. pylori. METHODS: Using a decision analytical model, we estimated the cost per patient with uninvestigated dyspepsia managed with the test-and-treat strategy ($25/test; H.pylori treatment, $200) or proton pump inhibitor ($90/month). Endoscopy ($550) guided therapy for persistent or recurrent symptoms. RESULTS: In the base case (25%H. pylori prevalence, 20% likelihood of peptic ulcer disease, 75% of ulcers due to H.pylori), the cost per patient is $545 with the test-and-treat strategy and $529 with proton pump inhibitor, and both strategies yield similar clinical outcomes at 1 year. H. pylori prevalence, the likelihood of peptic ulcer disease and the proportion of ulcers due to H.pylori are important determinants of the least costly strategy. At an H. pylori prevalence below 20%, proton pump inhibitor is consistently less costly than the test-and-treat strategy. CONCLUSIONS: As the H. pylori prevalence, the likelihood of peptic ulcer disease and the proportion of ulcers due to H. pylori decrease, empirical proton pump inhibitor becomes less costly than the test-and-treat strategy for the management of uninvestigated dyspepsia. Given the modest cost differential between the strategies, the test-and-treat strategy may be favoured if patients without peptic ulcer disease derive long-term benefit from H.pylori eradication.

Aspirin as an adjunct to screening for prevention of sporadic colorectal cancer. A cost-effectiveness analysis.

BACKGROUND: Aspirin may decrease colorectal cancer incidence, but its role as an adjunct to or substitute for screening has not been evaluated. OBJECTIVE: To examine the potential cost-effectiveness of aspirin chemoprophylaxis in relation to screening. DESIGN: Markov model. DATA SOURCES: Literature on colorectal cancer epidemiology, screening, costs, and aspirin chemoprevention (1980-1999). TARGET POPULATION: General U.S. population. TIME HORIZON: 50 to 80 years of age. PERSPECTIVE: Third-party payer. INTERVENTION: Aspirin therapy in patients screened with sigmoidoscopy every 5 years and fecal occult blood testing every year (FS/FOBT) or colonoscopy every 10 years (COLO). OUTCOME MEASURES: Discounted cost per life-year gained. RESULTS OF BASE-CASE ANALYSIS: When a 30% reduction in colorectal cancer risk was assumed, aspirin increased costs and decreased life-years because of related complications as an adjunct to FS/FOBT and cost $149 161 per life-year gained as an adjunct to COLO. In patients already taking aspirin, screening with FS/FOBT or COLO cost less than $31 000 per life-year gained. RESULTS OF SENSITIVITY ANALYSIS: Cost-effectiveness estimates depended highly on the magnitude of colorectal cancer risk reduction with aspirin, aspirin-related complication rates, and the screening adherence rate in the population. However, when the model's inputs were varied over wide ranges, aspirin chemoprophylaxis remained generally non-cost-effective for patients who adhere to screening. CONCLUSIONS: In patients undergoing colorectal cancer screening, aspirin use should not be based on potential chemoprevention. Aspirin chemoprophylaxis alone cannot be considered a substitute for colorectal cancer screening. Public policy should focus on improving screening adherence, even in patients who are already taking aspirin.

Outcomes of initial noninvasive Helicobacter pylori testing in U.S. primary care patients with uninvestigated dyspepsia.

OBJECTIVE: Recent European trials demonstrate that testing and treatment for Helicobacter pylori (H. pylori) is an effective alternative to prompt endoscopy in uninvestigated dyspepsia. The eventual endoscopy rate after H. pylori testing, which is a key determinant of cost-effectiveness, is unknown in the United States. Our aim was to determine the endoscopy rate after H. pylori testing in primary care practice in the United States and to compare outcomes among seropositive and seronegative patients. METHODS: We performed a retrospective review with mean 13 month follow-up of primary care patients with dyspeptic symptoms tested with office-based H. pylori serology. RESULTS: Of 268 adults tested (37+/-11 yr, 58% women), 57 (21%) were seropositive and 49/57 (86%) received eradication therapy. Endoscopy or contrast radiography was performed on 19% of seropositive and 19% of seronegative patients (p = 0.97). Annualized median disease-related expenditures were similar among seropositive and seronegative patients ($228 [$93-$654] vs $366 [$107-$1268], p = 0.19). However, aggregate expenditures were substantially lower than the cost of endoscopy alone ($816 [$296-$970]). On follow-up, seropositive and seronegative patients had similar numbers of primary care visits (2.9+/-3.2 vs 3.5+/-3.6, p = 0.23), prolonged antisecretory medication use (25 vs 33%, p = 0.27), and specialist referrals (23 vs 24%, p = 0.83). CONCLUSION: In a United States center, 81% of primary care patients tested for H. pylori did not undergo endoscopy, and patients incurred significantly lower median expenditures after noninvasive H. pylori testing than the cost of endoscopy alone. Seropositive and seronegative patients experienced comparable outcomes after H. pylori testing.

Effects of nutrients and serotonin 5-HT3 antagonism on symptoms evoked by distal gastric distension in humans.

Distal gastric distension may contribute to meal-related dyspeptic symptoms. This study's aims were to determine the effects of distinct nutrient classes on symptoms induced by distal gastric distension and their dependence on 5-hydroxytryptamine(3) (5-HT3) receptors. Nine healthy subjects rated pain, nausea, and bloating induced by isobaric distal gastric distensions (6-24 mmHg) during duodenal lipid, carbohydrate, protein, or saline perfusion after treatment with placebo or the 5-HT3 receptor antagonist granisetron (10 microg/kg iv). Distensions produced greater pain, nausea, and bloating with lipid at 1.5 kcal/min compared with saline (P < or = 0.02), primarily because of greater distal gastric volumes at each distending pressure. In contrast, carbohydrate and protein had no significant effect. At 3 kcal/min, lipid increased symptoms through a volume-independent as well as a volume-dependent effect. Granisetron did not affect symptom perception or gastric pressure-volume relationships. In conclusion, isobaric distal gastric distension produces more intense symptoms during duodenal lipid compared with saline perfusion. Symptom perception during distal gastric distension is unaffected by 5-HT3 receptor antagonism.

Gastric distention correlates with activation of multiple cortical and subcortical regions.

BACKGROUND & AIMS: The pathophysiology of functional dyspepsia may involve abnormal processing of visceral stimuli at the level of the central nervous system. There is accumulating evidence that visceral and somatic pain processing in the brain share common neuronal substrates. However, the cerebral loci that process sensory information from the stomach are unknown. The aim of this study was to localize the human brain regions that are activated by gastric distention. METHODS: Brain (15)O-water positron emission tomography was performed in 15 right-handed healthy volunteers during baseline and distal gastric distentions to 10 mm Hg, 20 mm Hg, threshold pain, and moderate pain. Pain, nausea, and bloating were rated during baseline and distentions (0-5 scale). Statistical subtraction analysis of brain images was performed between distentions and baseline. RESULTS: Symptoms increased with distending stimulus intensity (maximum pain, 2.1 +/- 0.4; nausea, 2.2 +/- 0.4; bloating, 3.7 +/- 0.2). Paralleling increases in distention stimulus and symptoms, progressive increases in activation (P < or = 0.05), were observed in the thalami, insula bilaterally, anterior cingulate cortex, caudate nuclei, brain stem periaqueductal gray matter, cerebellum, and occipital cortex. CONCLUSIONS: Symptomatic gastric distention activates structures implicated in somatic pain processing, supporting the notion of a common cerebral pain network.

Pathobiology of visceral pain: molecular mechanisms and therapeutic implications V. Central nervous system processing of somatic and visceral sensory signals.

Somatic and visceral sensation, including pain perception, can be studied noninvasively in humans with functional brain imaging techniques. Positron emission tomography and functional magnetic resonance imaging have identified a series of cerebral regions involved in the processing of somatic pain, including the anterior cingulate, insular, prefrontal, inferior parietal, primary and secondary somatosensory, and primary motor and premotor cortices, the thalamus, hypothalamus, brain stem, and cerebellum. Experimental evidence supports possible specific roles for individual structures in processing the various dimensions of pain, such as encoding of affect in the anterior cingulate cortex. Visceral sensation has been examined in the setting of myocardial ischemia, distension of hollow viscera, and esophageal acidification. Although knowledge regarding somatic sensation is more extensive than the information available for visceral sensation, important similarities have emerged between cerebral representations of somatic and visceral pain.

Motility of the small intestine.

Motility of the small intestine is controlled by myogenic, neural, and hormonal mechanisms and is modulated by external influences such as meals, central nervous system activation, and immune factors. Small-bowel dysmotility is recognized in a number of diseases, but its precise role in symptom generation remains unclear in many instances. We review publications that in the year under review added to the basic understanding of small-intestinal motility as well as its alteration in disease.

Novel approaches to the treatment of nausea and vomiting.

Nausea and vomiting are debilitating symptoms complicating many clinical conditions. Conventional antiemetic agents act as muscarinic, histamine, and dopamine receptor antagonists in the central nervous system. In a retrospective analysis, tricyclic antidepressant drugs demonstrated efficacy in long-term treatment of functional nausea. Some cases of vomiting result from impaired gastrointestinal motor activity. Agents which act on gastric serotonin (5-HT4), dopamine, and motilin receptors accelerate gastric emptying and relieve symptoms in gastroparesis. Recent investigations suggest that some patients with refractory gastroparesis may benefit from gastric electrical pacing. The treatment of acute chemotherapy-induced emesis was revolutionized by 5-HT3 receptor antagonists; however, these agents are less efficacious in delayed vomiting. Neurokinin (NK-1) receptor antagonists show promise in treating delayed chemotherapy-evoked emesis. Furthermore, animal studies indicate a broad spectrum of action for NK-1 antagonists in treating diverse causes of nausea and vomiting. The cyclic vomiting syndrome is characterized by discrete episodes of relentless vomiting separated by asymptomatic intervals and is associated with migraine headaches. Antimigraine therapies including the 5-HT1D receptor agonists sumatriptan reduce the severity of cyclic vomiting attacks. Investigations into these and other novel treatments may provide important advances in the care of difficult cases of nausea and vomiting resulting from disparate illnesses.

Differential symptomatic and electrogastrographic effects of distal and proximal human gastric distension.

Nausea and gastric dysrhythmias occur in conditions associated with gastric distension. The roles of distal and proximal gastric mechanoreceptors in these responses are unexplored. Because antral distension induces vomiting in animals and antral and fundic vagal afferent discharges differ, we hypothesized that distal gastric distension in humans leads to greater symptomatic and dysrhythmic responses than proximal distension. Symptoms and electrogastrograms were recorded in healthy humans during distal and proximal gastric distension with a barostat. Distal but not proximal distension induced nausea and a 747 +/- 250% increase in dysrhythmic power (P < 0.05), responses not affected by granisetron, indomethacin, or atropine, agents that block dysrhythmias in other settings. In the distal stomach, bloating and pain developed at lower pressures (P < 0.05) not modified by granisetron, and compliance was significantly lower (P < 0.05). In conclusion, gastric mechanoreceptor activation in the less-compliant distal stomach produces nausea and dysrhythmias via non-5-hydroxytryptamine3 (5-HT3), non-prostaglandin-dependent, and noncholinergic pathways. Distal mechanoreceptor activation induces greater bloating and pain than proximal mechanoreceptor activation via 5-HT3-independent pathways.

Differential 5-HT3 mediation of human gastrocolonic response and colonic peristaltic reflex.

Colonic motor function is modulated by extended and local neural reflexes involving unknown mediators. To test the role of serotonin (5-HT3) pathways, increases in colonic tone during antral distension and duodenal lipid perfusion (gastrocolonic responses) and changes in orad and caudad colonic tone in response to local colonic distension (peristaltic reflex) were measured after double-blind granisetron (10 microg/kg) or placebo infusion in healthy human volunteers. Antral distension evoked increases in colonic tone, which were blunted by granisetron (P < 0.05) without effects on antral compliance. Intraduodenal lipid perfusion also evoked increased colonic tone, which was reduced by granisetron (P < 0.05). In contrast, orad colonic contractions and caudad relaxations and contractions during colonic distension were unaffected by granisetron. In conclusion, 5-HT3 receptor antagonism blunts both the mechano- and chemoreceptor components of the human gastrocolonic response without altering antral compliance. In contrast, 5-HT3 pathways play no role in the ascending or descending components of the colonic peristaltic reflex. These findings demonstrate different roles for 5-HT3 receptors in the control of colonic motor function by the proximal gastrointestinal tract and by local neural reflexes.