Selective association of nonaspirin NSAIDs with risk of diverticulitis.

PURPOSE: The purpose of this study is to investigate the association of intake of nonsteroidal anti-inflammatory drugs (NSAIDs) and in particular nonaspirin NSAIDs and compare it with other risk factors for the progression of diverticulosis to diverticulitis in patients who underwent colonoscopy. METHODS: A total of 194 patients who underwent complete colonoscopy in our center between 2012 and 2016 were recruited: 144 with diverticulosis without prior diverticulitis (median age 71 years, 59.7% men) and 50 with diverticulitis (median age 64 years, 54.0% men). Data concerning current and previous medication as well as concomitant diseases were collected using a structured questionnaire and by revision of patients medical charts. RESULTS: Patients with diverticulitis were significantly (p < 0.001) younger as compared to individuals with plain diverticulosis (median age 64 versus 71 years, respectively). The intake of NSAIDs significantly (p = 0.002) increased the risk of prior diverticulitis (OR 3.2, 95% CI 1.5-6.9). In the multivariate model, both age (p < 0.001) and NSAIDs (p = 0.03) proved to be independent determinants of diverticulitis. When analyzing aspirin intake, it was not associated with diverticulitis. CONCLUSIONS: Our study demonstrates, in line with previous reports, that intake of NSAIDs is associated with diverticulitis. We show in particular that nonaspirin NSAIDs might be selectively associated with diverticulitis. These results point to divergent role of aspirin and nonaspirin NSAIDs in the development of diverticulitis.

Association between use of proton pump inhibitors and occurrence of colon diverticulitis.

BACKGROUND: Some recent studies have described the adverse effects of proton pump inhibitors (PPIs). PPI use and colonic diverticulitis are both associated with bacterial enteric infection and translocation. The aim of this study was to assess the association between PPI use and colonic diverticulitis. METHODS: We conducted a population-based nested case-control study in part by use of data retrospectively collected from the National Health Insurance Research Database. Diverticulitis patients were identified using inpatient discharge records with International Classification of Diseases, Ninth Revision, Clinical Modification codes (562.11 and 562.13), and were recruited as the study cohort. The controls were matched to the study patients by age, sex, nonsteroidal anti-inflammatory drugs use, laxative use, and index date. The cumulative defined daily dose (DDD) was estimated as the sum of the dispensed DDD of any PPI. The adjusted odds ratio and 95% confidence interval (CI) were estimated using multiple logistic regression. RESULTS: We enrolled 690 patients with acute diverticulitis, along with 2760 patients who comprised the control group. The adjusted odds ratios for the study cohort compared with PPI nonusers, after adjusting for possible confounders (including sex, age, comorbidities, and medication), were 1.29 (95% CI = 0.70-2.36) and 1.02 (95% CI = 0.59-1.76) for the group with cumulative PPI use ≥42 and ≥55 DDDs over an exposure period of 90 and 180 days, respectively, prior to the claimed date of hospitalization for colonic diverticulitis. CONCLUSION: The study showed that use of PPIs did not increase the risk of colon diverticulitis.

Zenker's diverticulitis secondary to alendronate ingestion: a rare cause of recurrent dysphagia.

OBJECTIVE: Acute dysphagia/odynophagia developed in a 79-year-old female patient secondary to what we believe was a caustic injury to a large Zenker's diverticulum (ZD) in the setting of long-term alendronate use. She reported severe dysphagia and odynophagia of 1-week duration. She had experienced a similar episode 10 months earlier that had resolved after stopping alendronate temporarily. Although she was able to handle secretions, she was unable to swallow solids or liquids. She was noted to be dehydrated. On endoscopy, a large and markedly inflamed ZD was identified. There was no visual esophageal mucosal injury within the esophagus. Alendronate therapy was discontinued, and parenteral nutrition and proton pump inhibitors were initiated. Her symptoms resolved within 1 week, and she was able to resume oral intake. DESIGN: Case report. SETTING: University Hospital. LIMITATIONS: Case report. DISCUSSION: Bisphosphonate therapy is commonly used to treat osteoporosis and is therefore an increasingly prevalent component of the medication list of elderly patients. These medications may cause significant caustic injury and are therefore administered with strong caution in the setting of dysphagia or known structural abnormalities of the esophagus. The fear is that tablets may become entrapped within a diverticulum and lead to intense acute inflammatory changes. CONCLUSIONS: Health care providers should be aware of potential complications with ulcerogenic medications in patients with ZD. These medications should be administered with caution in the setting of dysphagia or known structural abnormalities of the esophagus. When patients with history of dysphagia are evaluated for their suitability to receive oral bisphosphonate therapy, care should be taken to investigate the etiology of dysphagia. Evaluation should focus not only on the tubular esophagus, but also on excluding a Zenker's pharyngeal diverticulum with appropriate contrast imaging.

Use of aspirin or nonsteroidal anti-inflammatory drugs increases risk for diverticulitis and diverticular bleeding.

BACKGROUND & AIMS: Nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, have been implicated in diverticular complications. We examined the influence of aspirin and NSAID use on risk of diverticulitis and diverticular bleeding in a large prospective cohort. METHODS: We studied 47,210 US men in the Health Professionals Follow-up Study cohort who were 40-75 years old at baseline in 1986. We assessed use of aspirin, nonaspirin NSAIDs, and other risk factors biennially. We identified men with diverticulitis or diverticular bleeding based on responses to biennial and supplementary questionnaires. RESULTS: We documented 939 cases of diverticulitis and 256 cases of diverticular bleeding during a 22-year period of follow-up evaluation. After adjustment for risk factors, men who used aspirin regularly (≥2 times/wk) had a multivariable hazard ratio (HR) of 1.25 (95% confidence interval [CI], 1.05-1.47) for diverticulitis and a HR of 1.70 (95% CI, 1.21-2.39) for diverticular bleeding, compared with nonusers of aspirin and NSAIDs. Use of aspirin at intermediate doses (2-5.9 standard, 325-mg tablets/wk) and frequency (4-6 days/wk) were associated with the highest risk of bleeding (multivariable HR, 2.32; 95% CI, 1.34-4.02, and multivariable HR, 3.13; 95% CI, 1.82-5.38, respectively). Regular users of nonaspirin NSAIDs also had an increased risk of diverticulitis (multivariable HR, 1.72; 95% CI, 1.40-2.11) and diverticular bleeding (multivariable HR, 1.74; 95% CI, 1.15-2.64), compared with men who denied use of these medications. CONCLUSIONS: Regular use of aspirin or NSAIDs is associated with an increased risk of diverticulitis and diverticular bleeding. Patients at risk of diverticular complications should carefully consider the potential risks and benefits of using these medications.

The incidence of gastrointestinal perforations among rheumatoid arthritis patients.

OBJECTIVE: Gastrointestinal (GI) perforation has emerged as a novel safety concern in relation to medications used to treat rheumatoid arthritis (RA). This study was undertaken to characterize the incidence and risk factors for GI perforation in RA patients. METHODS: Using administrative databases of a large US health plan, we identified RA patients treated with biologic agents, methotrexate (MTX), oral glucocorticoids, and nonsteroidal antiinflammatory drugs (NSAIDs). Additional risk factors we evaluated included diverticulitis. Hospitalization with GI perforation was identified using a validated algorithm. Incidence rates and risk factors were evaluated using Cox proportional hazards models. RESULTS: Among 40,841 RA patients, 37 hospitalizations with GI perforation were identified. The rate of GI perforation among patients currently being treated with biologic agents who were also receiving oral glucocorticoids was higher (1.12 per 1,000 person-years [95% confidence interval (95% CI) 0.50-2.49]) than for patients being treated with biologic agents who were not also receiving glucocorticoids (0.47 per 1,000 person-years [95% CI 0.22-0.98]) or for patients being treated with MTX who were also receiving glucocorticoids (0.87 per 1,000 person-years [95% CI 0.36-2.10]). Neither biologic agents nor MTX was significantly associated with GI perforation, in contrast to current treatment with glucocorticoids and NSAIDs together (hazard ratio 4.7 [95% CI 1.9-12.0]) or glucocorticoids alone (hazard ratio 2.8 [95% CI 1.3-6.1]). Diverticulitis also was a strong risk factor (hazard ratio 9.1 [95% CI 3.1-26.4]). Seventy percent of patients with GI perforation received glucocorticoids, had antecedent diverticulitis, or both. CONCLUSION: GI perforation is an uncommon but serious adverse event among RA patients. Because a majority of patients with GI perforation were being treated with glucocorticoids or had previously experienced diverticulitis, these individuals should be considered at higher risk.

Phase I study of vandetanib with radiotherapy and temozolomide for newly diagnosed glioblastoma.

PURPOSE: Increasing evidence has suggested that angiogenesis inhibition might potentiate the effects of radiotherapy and chemotherapy in patients with glioblastoma (GBM). In addition, epidermal growth factor receptor inhibition might be of therapeutic benefit, because the epidermal growth factor receptor is upregulated in GBM and contributes to radiation resistance. We conducted a Phase I study of vandetanib, an inhibitor of vascular endothelial growth factor receptor 2 and epidermal growth factor receptor, in patients with newly diagnosed GBM combined with RT and temozolomide (TMZ). METHODS AND MATERIALS: A total of 13 GBM patients were treated with vandetanib, radiotherapy, and concurrent and adjuvant TMZ, using a standard "3 + 3" dose escalation. The maximal tolerated dose was defined as the dose with <1 of 6 dose-limiting toxicities during the first 12 weeks of therapy. The eligible patients were adults with newly diagnosed GBM, Karnofsky performance status of >or=60, normal organ function, who were not taking enzyme-inducing antiepileptic drugs. RESULTS: Of the 13 patients, 6 were treated with vandetanib at a dose of 200mg daily. Of the 6 patients, 3 developed dose-limiting toxicities within the first 12 weeks, including gastrointestinal hemorrhage and thrombocytopenia in 1 patient, neutropenia in 1 patient, and diverticulitis with gastrointestinal perforation in 1 patient. The other 7 patients were treated with 100 mg daily, with no dose-limiting toxicities observed, establishing this dose as the maximal tolerated dose combined with TMZ and RT. CONCLUSION: Vandetanib can be safely combined with RT and TMZ in GBM patients. A Phase II study in which patients are randomized to vandetanib 100 mg daily with RT and TMZ or RT and TMZ alone is underway.

Ruptured Meckel diverticulum mimicking mucositis in a patient receiving induction therapy for high-risk acute lymphoblastic leukemia.

A Meckel diverticulum is an embryonic remnant of the vitellointestinal duct. It is present in approximately 2% of the population and is estimated to cause symptoms<5% of the time. It generally results in painless bleeding or abdominal pain. Rarely, it can rupture, resulting in peritonitis and gram-negative sepsis. We present the case of a 17-year-old male who ruptured his Meckel diverticulum 23 days after the beginning of induction chemotherapy for high-risk acute lymphoblastic leukemia. We postulate that gastritis caused by dexamethasone, mucositis caused by doxorubicin, and the unique anatomic nature of a Meckel diverticulum may have contributed to this extremely unlikely and previously unreported event.

Chemo-biotherapy with 5-fluorouracil, leucovorin, and alpha interferon in metastatic carcinoma of the colon--a Cancer Biotherapy Research Group [CBRG] phase II study.

BACKGROUND: Biochemical modulation of 5-Fluorouracil activity with Leucovorin has been well documented in colorectal cancer. Several studies have shown increased efficacy of 5-fluorouracil in combination with alpha interferon. We therefore initiated a phase II trial of dual modulation of 5-fluorouracil with leucovorin and alpha interferon to evaluate outcomes in patients with metastatic carcinoma of the colon. METHODS: Patients with metastatic colon carcinoma with expected survival > 4 months and performance status of ECOG < or = 2 were treated weekly with Leucovorin 400 mg i.v. followed by 5-FU 600 mg/m2 i.v. bolus. Alpha interferon 3-9 million units was administered subcutaneously every Monday, Wednesday and Friday. Patients were analyzed for toxicity, tumor response and survival. RESULTS: Sixteen patients with a median age of 66 years were treated. Three patients were not evaluable for response but were evaluable for toxicity. Grades 3 and 4 toxicities were neutropenia, diarrhea, mucositis, nausea and vomiting, fatigue, fever, asthenia and elevated hepatic enzymes. One patient died from complications associated with diverticulitis and neutropenia. Objective response rate was 23% (95% confidence interval 4-46%) and median survival was 11.5 months (95% confidence interval 6.3-19 months). Thirty-eight percent of the patients were alive at one year and 19% at two years. CONCLUSION: The combination of 5-fluorouracil, leucovorin and alpha interferon as administered in this phase II study did not result in enhanced response rate or survival. However this regimen was associated with considerable toxicity.

Use of acetaminophen and nonsteroidal anti-inflammatory drugs: a prospective study and the risk of symptomatic diverticular disease in men.

OBJECTIVE: To examine prospectively the relationship between self-reported regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen and the risk of symptomatic diverticular disease. DESIGN: Prospective cohort study using a mailed baseline questionnaire in 1986, and follow-up every 2 years through 1992. SETTING: Male health professionals residing in 50 US states. PATIENTS: A total of 35 615 male health professionals (dentists, optometrists, veterinarians, physicians, pharmacists, osteopathic physicians, podiatrists) 40 to 75 years of age at baseline and free of diagnosed diverticular disease, colon or rectal polyp, ulcerative colitis, and cancer prior to 1988. MAIN OUTCOME MEASURES: Follow-up questionnaires in 1988, 1990, and 1992 about use of NSAIDs, acetaminophen, and other variables including the diagnosis of symptomatic diverticular disease. RESULTS: During 4 years of follow-up, we documented 310 newly diagnosed cases of symptomatic diverticular disease. After adjustment for age, physical activity, and energy-adjusted dietary fiber and total fat intake, regular and consistent use of NSAIDs and acetaminophen was positively associated with the overall risk of symptomatic diverticular disease (for users vs nonusers, relative risk [RR] for NSAIDs = 2.24, 95% confidence interval [CI], 1.28-3.91; RR for acetaminophen = 1.81, 95% CI, 0.79-4.11). Most of this positive association was attributable to cases associated with bleeding, particularly for acetaminophen (for users vs nonusers, RR for NSAIDs = 4.64, 95% CI, 0.99-21.74; RR for acetaminophen = 13.63, 95% CI, 3.53-52.60). CONCLUSIONS: These results suggest that regular and consistent use of NSAIDs in general and acetaminophen is associated with symptoms of severe diverticular disease, particularly bleeding. Further research is needed to investigate the potentially deleterious effect of NSAIDs and other medications on the lower gastrointestinal tract.

Morphologic classification of inflammatory, nonspecific, and proliferative lesions of the urinary bladder of mice.

A morphologic classification of inflammatory, nonspecific, and proliferative lesions of the urinary bladder of mice has been developed. The system was developed over a period of several years in order to tabulate and summarize the lesions for review. The classification has successfully met the needs of the National Center for Toxicological Research and has also provided useful information in understanding the biologic significance of urothelial lesions in mice.