Association Of Nonsteroidal Anti-inflammatory Drugs Research Articles

Abstract 2159: A prospective study of non-steroidal anti-inflammatory drug use and colorectal adenoma and colorectal cancer

Abstract Background: Use of non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin and ibuprofen, has been shown to yield a chemopreventive effect against colorectal cancer. Whether NSAIDs protect against the initiation vs. the progression of colorectal cancer remains a debate. To explore its role in the course of colorectal carcinogenesis, we evaluated the associations of NSAIDs with incident adenoma, recurrent adenoma, and colorectal cancer in the context of a large population-based screening trial, where participants were randomized to undergo endoscopic examinations in a controlled setting. Methods: We prospectively evaluated the associations between self-reported baseline NSAIDs use and risk of incident distal adenoma (1,127 cases), recurrent adenoma (755 cases), and colorectal cancer (840 cases) among men and women, ages 55-74, enrolled between 1993-2001, and randomized to receive flexible sigmoidoscopy screening (n=77,445) as part of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Incident adenoma cases were those with a negative sigmoidoscopy at baseline, but then were found to have adenoma on a follow-up sigmoidoscopy 3 or 5 years later. Recurrent adenoma cases were identified via an ancillary study nested within the PLCO among participants who had an adenoma at baseline and another adenoma on a surveillance colonoscopy 6 months to 10 years after their baseline screen. Participants were followed for cancer incidence for the median of 11.9 years following the baseline screen. All diagnoses of colorectal adenoma and cancer were pathologically confirmed through medical record review. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) for adenoma incidence and recurrence and hazard ratios (HRs) and 95% CIs for colorectal cancer incidence using multivariable-adjusted models. Results: Compared to no or infrequent use (<4 times/month), we found aspirin use ≥2 times/day to be associated with a reduced risk of incident adenoma (OR=0.72, 95% CI:0.52-1.00). Although not significantly associated with recurrent adenoma (OR=1.00) or colorectal cancer (OR=0.80), a marginally significant dose trend was observed for colorectal cancer (P=0.05). Similarly, ibuprofen use ≥2 times/day was associated with a reduced risk for incident adenoma (OR=0.72, 95% CI:0.54-0.97), but not associated with adenoma recurrence or cancer. No systematic differences in risk patterns were found by anatomic site, i.e., proximal colon, distal colon or rectum. Conclusion: Our data suggest that use of aspirin and ibuprofen significantly reduces adenoma initiation, but benefit against progression to adenoma recurrence or cancer growth may be weaker. Given the recognized adverse effects of NSAIDs, such as gastric ulcer perforation and upper gastrointestinal bleeding, any chemopreventive recommendations associated with NSAID use need to be tailored by individual cost-benefit assessment. Citation Format: Wen-Yi Huang, L. Joseph Su, Christine C. Johnson, Mark P. Purdue, Sonja I. Berndt. A prospective study of non-steroidal anti-inflammatory drug use and colorectal adenoma and colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2159. doi:10.1158/1538-7445.AM2014-2159

Synergistic effect of the interaction between curcumin and diclofenac on the formalin test in rats

The association of non-steroidal anti-inflammatory drugs with certain plant extracts can increase antinociceptive activity, permitting the use of lower doses and thus limiting side effects. Therefore, the aim objective of the current study was to examine the effects of curcumin on the nociception and pharmacokinetics of diclofenac in rats. Antinociception was assessed using the formalin test. Diluted formalin was injected subcutaneously into the dorsal surface of the right hind paw. Nociceptive behavior was quantified as the number of flinches of the injected paw during 60min after injection, and a reduction in formalin-induced flinching was interpreted as an antinociceptive response. Rats were treated with oral diclofenac (1–31mg/kg), curcumin (3.1–100mg/kg) or the diclofenac–curcumin combination (2.4–38.4mg/kg). To determine the possibility of a pharmacokinetic interaction, the oral bioavailability of diclofenac (10mg/kg) was studied in presence and the absence of curcumin (31mg/kg). Diclofenac, curcumin, or diclofenac–curcumin combination produced an antinociceptive effect on the formalin test. ED30 values were estimated for the individual drugs, and an isobologram was constructed. The derived theoretical ED30 for the antinociceptive effect (19.2mg/kg) was significantly different from the observed experimental ED30 value (9.8mg/kg); hence, the interaction between diclofenac and curcumin that mediates the antinociceptive effect was synergistic. Notwithstanding, the interaction does not appear to involve pharmacokinetic mechanisms, as oral curcumin failed to produce any significant alteration in oral diclofenac bioavailability. Data suggest that the diclofenac–curcumin combination can interact at the systemic level and may have therapeutic advantages for the clinical treatment of inflammatory pain.

Non-steroidal anti-inflammatory drugs and the risk of atrial fibrillation: a population-based follow-up study

ObjectiveTo investigate the association of non-steroidal anti-inflammatory drugs (NSAIDs) and the risk of atrial fibrillation in a prospective community-based follow-up study of elderly individuals with uniform case assessment and data...

Bronchiolitis Obliterans Associated with Stevens-Johnson Syndrome and Response to Azathioprine

To the Editor: Stevens-Johnson syndrome (SJS) is an acute, self-limiting, immune-complex mediated hypersensitivity disorder of skin and mucus membranes. Though acute pulmonary complications are well described, persistent pulmonary sequelae associated with SJS are rare [1]. We describe severe progressive form of bronchiolitis obliterans (BO) following SJS and good response to azathioprine. A 9-y-old boy developed SJS following oral ibuprofen prescribed for febrile illness. A week later, he developed persistent cough, wheezing and progressive respiratory distress. At admission, he had tachypnea, retractions, extensive wheezing and crepitations with hyperpigmented scars, cicatrical ectropion in the left eye and dystrophic changes in nails. Oxygen-saturation was 87 % in room-air. Pulmonary function test showed severe obstruction with no response to bronchodilators. Chest-radiograph and high-resolution computerized tomography were consistent with BO (Figs. 1 and 2). He received supplemental oxygen, β2-agonist and budesonide inhalations, chest-physiotherapy and prednisolone. Azithromycin three times a week was also added. At 2-mo follow-up, he had persistent cough, exertional dyspnea and wheeze for which azathioprine was added as a steroid sparing agent. At 1-year follow-up, the patient improved clinically and was able to do his daily activities at home. Oxygenation and PFT improved. Although, he had dyspnea on moderate exertion, intermittent cough with wheeze, the symptoms had not worsened and the disease appeared to be controlled. BO may occur within days after SJS even when the initial pulmonary involvement is not severe [1]. The association of non-steroidal anti-inflammatory drugs like ibuprofen with SJS is well known [2]. The findings of mosaic perfusion, vascular attenuation and central bronchiectasis onHRCTare diagnostic of BO obviating the need for lung-biopsy in a consistent clinical setting, as in index case [3]. The anti-inflammatory effects of corticosteroids justify their use in the early phases. We added immune-modulator azathioprine which suppresses lymphocyte proliferation and decreases CD8+ lymphocyte subpopulation, as a corticosteroid sparing agent for control of inflammation. Previous anaecdotal reports in adults have suggested that azathioprine might be useful as a corticosteroidsparing agent for the treatment of organizing pneumonia [4]. Moreover, drugs like mycophenolate mofetil and azathioprine have also been used for prevention of bronchiolitis obliterans

Effect of Non-Steroidal Anti-Inflammatory Drugs on Bone Turnover: An Evidence-Based Review

Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used for acute and chronic pain control and treatment of inflammation, osteoarthritis and rheumatoid arthritis. NSAIDs have been shown to inhibit bone healing in animal studies due to the inhibition of prostaglandin synthesis. However, little evidence exists regarding the effect of NSAID exposure on human bone metabolism. This systematic review summarizes the current literature of randomized controlled trials (RCTs) investigating NSAIDs with bone remodeling-related outcomes in humans. After performing computerized searches in the most widely indexed databases, study selection, data abstraction and risk of bias assessment were conducted in duplicate. The results were controversial regarding the association of NSAID with bone formation or resorption. Increased bone mineral density following NSAID exposure was reported by some studies. Based on the levels of biochemical markers, no effect was seen on bone formation, while some evidence was found for a decreased rate of bone resorption in NSAID patients. Trials investigating the effects of NSAID treatment on bone metabolism outcomes of human patients are limited. Further research is required to confirm or refute the findings of this systematic review.

The Interplay Between NSAIDs and Candida albicans on the Gastrointestinal Tract of Guinea Pigs

Recent studies suggest that Candida albicans colonization is associated with several gastrointestinal inflammatory disorders and is also responsible for the delay in ulcer healing. No data are reported about the effects of C. albicans on the nonsteroidal anti-inflammatory drugs (NSAIDs)-induced necroinflammatory lesions. On the other hand, beneficial effects of NSAIDs regarding the colonization potential with C. albicans have been reported. Our aim was to investigate whether the association between NSAIDs and C. albicans could potentially induce necroinflammatory lesions in the guinea pigs gastric and enteral mucosa. Three interventional groups of 11 guinea pigs each were investigated after 5 days of receiving indomethacin, C. albicans or the association of both. C. albicans and necroinflammatory lesions were graded based on histological examinations. Statistical analysis used Mann-Whitney nonparametric test. NSAIDs did not significantly decrease C. albicans colonization grades on gastrointestinal mucosa. Administration of indomethacin subsequent to C. albicans determined significantly more severe necroinflammatory lesions compared to group that only received C. albicans. The association of NSAIDs and C. albicans did not cause significantly more severe degenerative or inflammatory lesions compared to the administration of only NSAIDs in this experimental model. Associations between NSAIDs and C. albicans caused significantly more severe necroinflammatory injuries than the lesions produced by C. albicans, without enhancing the mucosal injury or inflammation caused by NSAIDs.

Structural Association of Nonsteroidal Anti-Inflammatory Drugs with Lipid Membranes

The location and distribution of ibuprofen, a model nonsteroidal anti-inflammatory drug, in a phospholipid bilayer was examined in molecular detail by a combination of neutron diffraction and computer simulations. In addition to their use as antipyretic, analgesic, and anti-inflammatory drugs, such nonsteroidal anti-inflammatory drugs are used in the treatment of a number of diseases including cancer and Alzheimer's. As a side effect, they have been known to cause gastrointestinal toxicity, although the molecular mechanism of their action is poorly understood. In this study, we have used contrast variation-based neutron diffraction to determine the position of the drug in a 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine lipid bilayer and explore changes to the bilayer structure upon drug incorporation. In its charged state, the drug was found to locate in the polar headgroup region of the phospholipid bilayer, to induce bilayer thinning, and to increase the number of water molecules closely associated with the bilayer. These structural insights are consistent with molecular dynamics simulations and earlier macroscopic experiments of vesicle structure and dynamics. Using MD simulations, the neutral ibuprofen, typically observed at low pH and inaccessible to the diffraction studies, was found to locate deeper within the bilayer than the charged form.

Peripheral Synergistic Interaction Between Lidocaine and Lumiracoxib on the 1% Formalin Test in Rats

It has been shown that the association of non-steroidal anti-inflammatory drugs (NSAIDs) with analgesic agents can increase their antinociceptive activity, allowing the use of lower doses and thus limiting side effects. Therefore, the aim of the present study was to examine the possible pharmacological interaction between lumiracoxib and lidocaine at the local peripheral level in the rat using the 1% formalin test and isobolographic analysis. Lumiracoxib, lidocaine or fixed-dose ratio (1:1) lumiracoxib-lidocaine combinations were administered locally in the formalin-injured paw and the antinociceptive effect was evaluated. All treatments produced a dose-dependent antinociceptive effect. ED40 values were estimated for the individual drugs and an isobologram was constructed. The derived theoretical ED40 for the lumiracoxiblidocaine combination was 599.3 ± 58.8 μg/paw, being significantly higher than the actually observed experimental ED40 value, 393.6 ± 39.7 μg/paw. This result correspond to a synergistic interaction between lumiracoxib and lidocaine at the local peripheral level, potency being about one and half times higher with regard to that expected from the addition of the effects of the individual drugs. Data suggest that low doses of the lumiracoxib-lidocaine combination can interact synergistically at the peripheral level and therefore this drug association may represent a therapeutic advantage for the clinical treatment of procedural or inflammatory pain.

Risk of ST versus non-ST elevation myocardial infarction associated with non-steroidal anti-inflammatory drugs

ObjectiveThe objective of this study was to explore the association of non-steroidal anti-inflammatory drugs (NSAID) with ST-segment elevation myocardial infarction (STEMI) and non-ST segment elevation myocardial infarction (NSTEMI).Design, Setting &...

The combination of naproxen and citral reduces nociception and gastric damage in rats

It has been shown that the association of non-steroidal anti-inflammatory drugs with plant extracts can increase their antinociceptive activity, allowing the use of lower doses and, thus, limiting side effects. Therefore, the aim of this study was to examine the effects of the interaction between naproxen and citral on nociception and gastric injury in rats. Naproxen, citral, or combinations of naproxen and citral produced an antinociceptive effect. The administration of naproxen produced significant gastric damage, but this effect was not obtained with either citral or the naproxen-citral combination. The ED(50) value was estimated for the individual drugs and an isobologram was constructed. The derived theoretical ED(50) for the antinociceptive effect (423.8 mg/kg) was not significantly different from the observed experimental value (359.0 mg/kg); hence, the interaction between naproxen and citral mediating the antinociceptive effect is additive. These data suggest that the naproxen-citral combination interacts at the systemic level, produces minor gastric damage, and potentially has therapeutic advantages for the clinical treatment of inflammatory pain.

Association of Nonsteroidal Anti-Inflammatory Drugs with Lung Cancer: Results from a Large Cohort Study

Lung cancer is the most common cause of cancer-related mortality. Smoking cessation is crucial to decrease risk, but additional prevention modalities are needed. The use of nonsteroidal anti-inflammatory drugs (NSAID) may be promising. The study was a prospective cohort of 77,125 men and women, ages 50 to 76 years, from Washington state recruited in 2000 to 2002 (the VITamin And Lifestyle study). Lung cancer cases were identified through the Seattle-Puget Sound Surveillance, Epidemiology and End Results cancer registry during 5 years of follow-up. Hazard ratios (HR) associated with 10-year average use of total NSAIDs (excluding low-dose aspirin) and specific categories of NSAIDs were calculated for total incident lung cancer and specific morphologies. A total of 665 lung cancer cases were identified. After adjusting for smoking, age, gender, and acetaminophen use, there was a borderline-significant inverse trend with total NSAID use [>4.2 d/wk for >10 years versus none: HR, 0.82; 95% confidence interval (95% CI), 0.64-1.04; P for trend = 0.05]. The association was strongest for adenocarcinoma (HR, 0.59; 95% CI, 0.37-0.94; P for trend = 0.01) and seemed to be limited to men (HR, 0.66; 95% CI, 0.47-0.92; P for trend = 0.01) and to long-term (> or =10 years) former smokers (HR, 0.65; 95% CI, 0.44-0.96; P for trend = 0.04). There were no appreciable differences by NSAID type. Total NSAID use was associated with a small reduced risk of lung cancer, which was strongest for adenocarcinoma, men, and long-term former smokers. These findings are supported by known lung carcinogenesis mechanisms and suggest that NSAIDS may be useful for chemoprevention.

Association of Nonsteroidal Anti-Inflammatory Drugs, Prostate Specific Antigen and Prostate Volume

Nonsteroidal anti-inflammatory drugs such as aspirin prevent cardiovascular disease and several prior studies suggest that nonsteroidal anti-inflammatory drugs also decrease prostate inflammation and prostate cancer risk. We investigated the association between nonsteroidal anti-inflammatory drug use, prostate specific antigen and prostate volume, hypothesizing that there would be lower prostate specific antigen and prostate volume with nonsteroidal anti-inflammatory drug use. The Nashville Men's Health Study uses a multicenter, rapid recruitment protocol to collect clinical, biological, behavioral and body measurement data on 1,277 men older than 40 years who are scheduled for diagnostic prostate biopsy. Nonsteroidal anti-inflammatory drug use was ascertained by survey and clinical interview. Medical charts were reviewed to ascertain current prostate specific antigen, prostate volume and clinical diagnoses following biopsy. Approximately 46% of patients reported receiving nonsteroidal anti-inflammatory drugs, primarily aspirin (37%). After adjusting for age, race and other factors prostate volume was similar between aspirin users and nonusers (47.6 vs 46.0 ml, p = 0.16). In contrast, prostate specific antigen was significantly lower in aspirin users (7.3 vs 8.0 ng/ml, p = 0.01). The association between prostate specific antigen and aspirin was significant in men with latent prostate cancer (6.1 vs 7.3 ng/ml, p <0.01), marginal in patients with high grade prostatic intraepithelial neoplasia (5.0 vs 5.9 ng/ml, p = 0.09) and nonsignificant in those with a negative biopsy (5.6 vs 5.7 ng/ml, p = 0.64). The strongest prostate specific antigen-aspirin association was in men with cancer and a prostate volume of 60 ml or more (7.3 vs 12.7 ng/ml, p <0.01). Prostate specific antigen was significantly lower in aspirin users with latent cancer. Prostate volume was not associated with nonsteroidal anti-inflammatory drug use. Results suggest that aspirin may affect prostate cancer detection, suggesting a potential detection bias to address in future studies of nonsteroidal anti-inflammatory drugs and prostate cancer prevention.

Association of Nonsteroidal Anti-Inflammatory Drugs with Lung Cancer: Results from a Large Cohort Study

Association of Nonsteroidal Anti-Inflammatory Drugs with Lung Cancer: Results from a Large Cohort Study

Association of non-steroidal anti-inflammatory drugs with outcomes in patients with ST-segment elevation myocardial infarction treated with fibrinolytic therapy: an ExTRACT-TIMI 25 analysis

Non-steroidal anti-inflammatory drugs (NSAIDs) may be prothrombotic, may worsen hypertension or congestive heart failure and obstruct access to the binding site of aspirin to cyclooxygenase-1 and thereby interfere with aspirin's mechanism of action in reducing death and recurrent myocardial infarction (MI). We hypothesized that treatment with NSAIDs prior to an index MI would be associated with an increase in the risk of death, heart failure and recurrent MI among patients with ST-segment elevation MI (STEMI) treated with fibrinolytic therapy. In ExTRACT-TIMI 25, patients with STEMI were treated with aspirin and fibrinolytic therapy and randomized to either enoxaparin or unfractionated heparin. We included patients who had received NSAIDs within 7 days of enrollment and evaluated the incidence of MI, the composite of death and MI and the composite of death, MI, severe heart failure and shock through 30 days. Of 20,479 patients enrolled, 572 (2.8%) received an NSAID within 7 days of enrollment. NSAID treatment prior to entry was associated with a higher incidence of 30-day death or nonfatal recurrent MI (15.9% vs. 10.8%, univariate P < 0.001). In multivariable models adjusting for randomization group and differences in baseline characteristics, NSAID use was associated with higher odds of MI (adjusted odds ratio [OR(adj)] 1.44, 95% confidence interval [CI] 1.01-2.07, P = 0.047), the composite of death and MI (OR(adj) 1.29, 95% CI 1.00-1.66, P = 0.051), and the composite of death, MI, severe heart failure and shock (OR(adj) 1.29, 95% CI 1.02-1.65, P = 0.037). Among STEMI patients treated with a fibrinolytic agent and aspirin, use of NSAIDs in the week preceding the incident event was associated with a higher incidence of MI, the composite of death and MI as well as the composite of death, MI, severe heart failure and shock at 30 days.

Examination of the interaction between peripheral lumiracoxib and opioids on the 1% formalin test in rats

It has been shown that the association of non-steroidal anti-inflammatory drugs (NSAIDs) with opioid analgesic agents can increase their antinociceptive activity, allowing the use of lower doses and thus limiting side effects. Therefore, the aim of the present study was to examine the possible pharmacological interaction between lumiracoxib and codeine or nalbuphine at the local peripheral level in the rat using the 1% formalin test and isobolographic analysis. Lumiracoxib, codeine, nalbuphine or fixed-dose ratios lumiracoxib–codeine or lumiracoxib–nalbuphine combinations were administrated locally in the formalin-injured paw and the antinociceptive effect was evaluated using the 1% formalin test. All treatments produced a dose-dependent antinociceptive effect. ED 40 values were estimated for the individual drugs and an isobologram was constructed. The derived theoretical ED 40’s for the lumiracoxib–codeine and lumiracoxib–nalbuphine combinations were 423.4 ± 31.3 μg/paw and 310.9 ± 24.2 μg/paw, respectively, being significantly higher than the actually observed experimental ED 40 values, 233.2 ± 30.9 μg/paw and 132.7 ± 11.6 μg/paw, respectively. These results correspond to a synergistic interaction between lumiracoxib and opioids at the local peripheral level, potency being about two times higher with regard to that expected from the addition of the effects of the individual drugs. Data suggest that low doses of the lumiracoxib–opioids combination can interact synergistically at the peripheral level and therefore this drug association may represent a therapeutic advantage for the clinical treatment of inflammatory pain.

Effect of non‐steroidal anti‐inflammatory medications on the risk of amyotrophic lateral sclerosis

Inflammatory processes may be involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). We examined the association of non-steroidal anti-inflammatory drugs (NSAIDs) with the risk of ALS in case-control study of incident cases (n = 111) conducted within the Kaiser Permanente Medical Care Program of Northern California during the years 1996-2000. Controls (n = 258) randomly selected from the same population were frequency matched by age and gender to the ALS cases. Information regarding use of NSAIDs (non-aspirin and aspirin) and three classes of 'control' medications was collected by in-person structured interview. Subjects who used medication at least twice a week for at least a month were classified as 'ever users'. Multivariable logistic regression models were adjusted for age, gender, history of osteoarthritis/rheumatoid arthritis and pain, and other medication use. Overall, there was no association between NSAID use and ALS; however, some sex differences were noted for non-aspirin NSAID use. Among men, non-aspirin NSAID use was associated with a two-fold increased risk of ALS (adjusted odds ratio (OR) 2.0, 95% confidence interval (CI) 1.0-3.9), whereas among women, non-aspirin NSAID use was not associated with increased ALS risk (adjusted OR 0.5, 95% CI 0.2-1.2). ALS risk was not associated with aspirin use or with 'control' medications. This study did not find any evidence to suggest that NSAID use reduces the risk of ALS. The observed sex differences with non-aspirin NSAID use could be due to chance or an unmeasured confounder.

Case-control study on the association of upper gastrointestinal bleeding and nonsteroidal anti-inflammatory drugs in Japan

Studies in Western populations have shown the association of nonsteroidal anti-inflammatory drugs (NSAIDs) and upper gastrointestinal bleeding (UGIB). The role of Helicobacter pylori infection in NSAIDs-related UGIB remains to be studied. We conducted a case-control study in Japan to investigate these related topics. Cases of UGIB due to duodenal or gastric ulcer, or gastritis were identified in 14 study hospitals in various areas of Japan. For each case, two controls were identified from population registries in the same district. Information on drugs and other risk factors was obtained from 175 cases and 347 controls by telephone interviews. Anti-H. pylori antibody in the urine was measured in a single laboratory for all the cases and 225 controls. The odds ratio (OR) of UGIB was 5.5 for aspirin and 6.1 for other NSAIDs (NANSAIDs) (p<0.01). The OR for regular use was higher than for occasional use both for aspirin (7.7 vs 2.0) and NANSAIDs (7.3 vs 4.1). Loxoprofen (5.9), frequently used in Japan as a safe 'prodrug', was significantly associated with UGIB. The odds ratio for H. pylori infection was 4.9 and the relative excess risk due to the interaction between H. pylori and the use of NSAID was 1.2 (95% CI: -5.8-8.1). NSAIDs including loxoprofen increase the risk of UGIB in Japan as in Western countries, with a similar magnitude of association. There was no evidence of biological interaction between NSAIDs and H. pylori infection.

Evidence for a Biopsy Derived Grade Artifact Among Larger Prostate Glands

The PCPT has demonstrated a higher incidence of high grade (Gleason pattern 4 or greater) prostate cancers among men randomized to finasteride. One plausible explanation for this finding is that tumor grade as assigned by TRUS guided biopsy is artifactually associated with prostate volume. We evaluated our institutional data set of TRUS guided biopsies in the last 3 years and identified 369 cases of prostate cancer that fit the criteria of PSA less than 10 ng/ml, biopsy at our center and RP at our center. We identified risk factors for Gleason pattern 4 or greater on biopsy and then on RP specimens from the same patients using univariate and multiple logistic regression analyses. Assessed covariates included patient age, PSA and TRUS volume. Risk factors for Gleason pattern 4 or greater in the biopsy specimens included age (p = 0.01), hypoechoic lesions on TRUS (p <0.001) and TRUS volume (p = 0.008). However, among RP specimens TRUS volume (p = 0.60) became nonsignificant of Gleason pattern 4 or greater on multivariable analysis. Although prostate volume was a predictor for biopsy derived high grade disease it was not predictive of true histological grade. These data suggest that simply having a larger prostate results in fewer high grade cancers diagnosed at biopsy. Prostatectomy results in the same men suggest sampling artifact, as the distribution of cancer grade is not associated with prostate volume. These findings provide evidence that the increase in higher grade tumors among men in the finasteride arm of PCPT may simply result from prostate volume reduction.

Stercoral Perforation of the Sigmoid Colon: Report of a Rare Case and Its Possible Association with Nonsteroidal Anti-Inflammatory Drugs

Stercoral perforation of the colon is a rare phenomenon with fewer than 90 cases reported in the literature to date. The pathogenesis of stercoral ulceration is thought to result from ischemic pressure necrosis of the bowel wall caused by a stercoraceous mass. Stercoral perforation in more than 90 per cent of cases involves the sigmoid or rectosigmoid colon with associated fecal mass causing localized mucosal ulceration and bowel wall thinning due to localized pressure effect. We report the case of a 45-year-old woman who presented with a 12-hour history of epigastric pain. Significant comorbidities included systemic lupus erythematosus, sarcoidosis, hypertension, and previous history of congestive heart failure. The patient was also on prednisone and a nonsteroidal anti-inflammatory drug for joint pains. On physical examination the patient had signs of generalized peritonitis. Chest X-ray showed significant free air under the diaphragm. Emergency laparotomy revealed localized perforation over the antimesenteric border of the sigmoid colon with associated stercoral mass at the site of perforation. A segmental resection of the sigmoid colon with end colostomy (Hartmann's procedure) was performed. The patient made an uneventful recovery. Stercoral perforation is often a consequence of chronic constipation; however, there are other predisposing factors as the condition is rare compared with the frequency of severe constipation. One of the hypotheses includes the association of nonsteroidal anti-inflammatory drugs (NSAIDs) with stercoral perforation of the colon. Our case report lends support to this association with NSAID use; thus there need to be greater awareness and caution when using NSAIDs in chronically constipated patients.

Inverse association of non-steroidal anti-inflammatory drugs and malignant melanoma among women.

Recent human epidemiologic studies suggest that non-steroidal anti-inflammatory drugs (NSAIDs) have preventive effects against cancers of the colon, breast, and prostate. Laboratory and animal studies also provide evidence of antineoplastic effects of NSAIDs against a variety of solid tumors, including skin cancer. We studied the effects of NSAIDs on malignant melanoma in women utilizing a case control experimental design involving 110 women with histologically proven malignant melanoma, and 609 female controls frequency matched to the cases on age, and place of residence. We observed a significant decrease in the relative risk (RR) of malignant melanoma with regular intake of common over the counter NSAIDs such as aspirin and ibuprofen (RR = 0.45, 95% CI = 0.22-0.92, p < 0.05). Adjustment for sun exposure did not change the magnitude of the estimate. Our results are the first to show that NSAIDs may have value in the chemoprevention of malignant melanoma.