Polyp Burden In Patients Research Articles

Author commentary on Hideki Ishikawa et al.

Hideki Ishikawa et al. Intensive endoscopic resection for downstaging of polyp burden in patients with familial adenomatous polyposis (J-FAPP Study III): a multicenter prospective interventional study

Is there a role for endoscopic management of the large bowel in familial adenomatous polyposis?

In this issue of Endoscopy, Ishikawa et al. [1] describe intense endoscopic downstaging of colorectal polyp burden in patients with familial adenomatous polyposis (FAP) in a multicenter, prospective, interventional study. After 5 years, 90.4 % of patients with intact colon remained without surgical intervention and 83.9 % of those who had 10 cm or more residual large bowel did not require further surgical intervention. The authors conclude that their approach “could have the potential to be a useful means of preventing colorectal cancer without implementing colectomy.” This raises interesting questions about the role of endoscopy in the management of FAP and perhaps can be seen to challenge the paradigm of surgical management of this condition, in all except those with a very mild polyp burden.

Nonsteroidal Anti-inflammatory Drugs for Chemoprevention in Patients With Familial Adenomatous Polyposis: A Systematic Review and Meta-Analysis.

Published literature shows mixed reports of the benefits of nonsteroidal anti-inflammatory drugs (NSAIDs) on reducing colorectal polyps in patients with familial adenomatous polyposis (FAP). We conducted a systematic review and performed a meta-analysis to assess the impact of NSAIDs on colorectal polyp burden in patients with FAP. We searched PubMed, EMBASE, and Cochrane for randomized controlled trials (RCTs) comparing the effect of NSAIDs vs placebo on the percent change in polyp number and polyp size in patients with FAP. Mean differences between the 2 study arms were pooled using RevMan. The risk of bias (RoB) was assessed using the Cochrane Risk of Bias tool for RCTs, and certainty in the evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation methodology. The search strategy identified 1021 studies, out of which we included 8 RCTs with a total of 279 patients. Treatment for 6.4 ± 2.2 months with NSAIDs reduced polyp numbers by-17.4% (95% confidence interval-26.41%,-8.29%) (low certainty [I2 89%] due to imprecision and issues with RoB) and polyp size by-15.9% (95% confidence interval -24.98%,-6.73%) (very low certainty (I2 84%) due to imprecision, inconsistency, and issues with RoB). The most common gastrointestinal adverse events reported were stomatitis, diarrhea, and abdominal pain. Side effects leading to drug discontinuation were gastroenteritis and drug allergy. Short-term use of NSAIDs reduced polyp number and polyp size but with low to very low certainty of evidence. Further large multicenter studies are needed to further explore NSAIDs as a chemopreventive measure in patients with FAP.

Combination of Sulindac and Bexarotene for Prevention of Intestinal Carcinogenesis in Familial Adenomatous Polyposis.

Familial adenomatous polyposis (FAP) is a hereditary colorectal cancer syndrome, which results in the development of hundreds of adenomatous polyps carpeting the gastrointestinal tract. NSAIDs have reduced polyp burden in patients with FAP and synthetic rexinoids have demonstrated the ability to modulate cytokine-mediated inflammation and WNT signaling. This study examined the use of the combination of an NSAID (sulindac) and a rexinoid (bexarotene) as a durable approach for reducing FAP colonic polyposis to prevent colorectal cancer development. Whole transcriptomic analysis of colorectal polyps and matched normal mucosa in a cohort of patients with FAP to identify potential targets for prevention in FAP was performed. Drug-dose synergism of sulindac and bexarotene in cell lines and patient-derived organoids was assessed, and the drug combination was tested in two different mouse models. This work explored mRNA as a potential predictive serum biomarker for this combination in FAP. Overall, transcriptomic analysis revealed significant activation of inflammatory and cell proliferation pathways. A synergistic effect of sulindac (300 μmol/L) and bexarotene (40 μmol/L) was observed in FAP colonic organoids with primary targeting of polyp tissue compared with normal mucosa. This combination translated into a significant reduction in polyp development in ApcMin/+ and ApcLoxP/+-Cdx2 mice. Finally, the reported data suggest miRNA-21 could serve as a predictive serum biomarker for polyposis burden in patients with FAP. These findings support the clinical development of the combination of sulindac and bexarotene as a treatment modality for patients with FAP. PREVENTION RELEVANCE: This study identified a novel chemopreventive regimen combining sulindac and bexarotene to reduce polyposis in patients with FAP using in silico tools, ex vivo, and in vivo models. This investigation provides the essential groundwork for moving this drug combination forward into a clinical trial.

Safety and efficacy of an enteroscopy-based approach in reducing the polyp burden in patients with Peutz-Jeghers syndrome: experience from a tertiary referral center.

Background:Patients with Peutz–Jeghers syndrome develop hamartomatous polyps in the small bowel, possibly causing anemia, intussusception, and obstruction. We aimed to evaluate the impact of an enteroscopy-based approach, including both device-assisted and intraoperative enteroscopy, on the reduction of the polyp burden in a cohort of adult Peutz–Jeghers syndrome patients.Materials and methods:A retrospective study was conducted at Azienda Ospedaliero-Universitaria Città della Salute e della Scienza in Turin, Italy. Consecutive Peutz–Jeghers syndrome patients eligible for device-assisted or intraoperative enteroscopy, between January 2003 and November 2019, were included. Enteroscopy technical issues and complications were recorded. At the time of index enteroscopy, the patients’ clinical records were retrospectively reviewed, and clinical data were recorded until November 2019.Results:Overall, 24 patients were included. Before inclusion, 16/24 patients (66.7%) underwent small bowel surgery for polyp-related complications, 13 of which (81.2%) in an emergent setting. Two patients had a history of small bowel neoplasms. During the timeframe, 47 device-assisted enteroscopies and 9 intraoperative enteroscopies were performed, and 247 small bowel polyps were endoscopically removed. The overall complication rate was 12.8% (8.5% for device-assisted enteroscopy, 22.2% for intraoperative enteroscopy). The median observation time was 108 months: in this timeframe, two patients developed small bowel polyp-related complications requiring emergent surgery. No patients developed small bowel cancer, but nine extra-gastrointestinal neoplasms were recorded.Conclusion:An enteroscopy-based approach appears to be well tolerated and effective in decreasing polyp-related complications in Peutz–Jeghers syndrome patients, thus reducing the need for emergent surgery. Although the prevention of small bowel polyp-related complications remains the main goal in these patients, the high incidence of extra-gastrointestinal neoplasms appears to be a rising issue.

Dupilumab improves patient-reported outcomes in patients with chronic rhinosinusitis with nasal polyps and comorbid asthma

Dupilumab improves patient-reported outcomes in patients with chronic rhinosinusitis with nasal polyps and comorbid asthma

Effect of Subcutaneous Dupilumab on Nasal Polyp Burden in Patients With Chronic Sinusitis and Nasal Polyposis: A Randomized Clinical Trial.

Dupilumab has demonstrated efficacy in patients with asthma and atopic dermatitis, which are both type 2 helper T-cell-mediated diseases. To assess inhibition of interleukins 4 and 13 with dupilumab in patients with chronic sinusitis and nasal polyposis. A randomized, double-blind, placebo-controlled parallel-group study conducted at 13 sites in the United States and Europe between August 2013 and August 2014 in 60 adults with chronic sinusitis and nasal polyposis refractory to intranasal corticosteroids with 16 weeks of follow-up. Subcutaneous dupilumab (a 600 mg loading dose followed by 300 mg weekly; n = 30) or placebo (n = 30) plus mometasone furoate nasal spray for 16 weeks. Change in endoscopic nasal polyp score (range, 0-8; higher scores indicate worse status) at 16 weeks (primary end point). Secondary end points included Lund-Mackay computed tomography (CT) score (range, 0-24; higher scores indicate worse status), 22-item SinoNasal Outcome Test score (range, 0-110; higher scores indicating worse quality of life; minimal clinically important difference ≥8.90), sense of smell assessed using the University of Pennsylvania Smell Identification Test (UPSIT) score (range, 0-40; higher scores indicate better status), symptoms, and safety. Among the 60 patients who were randomized (mean [SD] age, 48.4 years [9.4 years]; 34 men [56.7%]; 35 with comorbid asthma), 51 completed the study. The least squares (LS) mean change in nasal polyp score was -0.3 (95% CI, -1.0 to 0.4) with placebo and -1.9 (95% CI, -2.5 to -1.2) with dupilumab (LS mean difference, -1.6 [95% CI, -2.4 to -0.7]; P < .001). The LS mean difference between the 2 groups for the Lund-Mackay CT total score was -8.8 (95% CI, -11.1 to -6.6; P < .001). Significant improvements with dupilumab were also observed for the 22-item SinoNasal Outcome Test (LS mean difference between groups, -18.1 [95% CI, -25.6 to -10.6]; P < .001) and sense of smell assessed by UPSIT (LS mean difference, 14.8 [95% CI, 10.9 to 18.7]; P < .001). The most common adverse events were nasopharyngitis (33% in the placebo group vs 47% in the dupilumab group), injection site reactions (7% vs 40%, respectively), and headache (17% vs 20%). Among adults with symptomatic chronic sinusitis and nasal polyposis refractory to intranasal corticosteroids, the addition of subcutaneous dupilumab to mometasone furoate nasal spray compared with mometasone alone reduced endoscopic nasal polyp burden after 16 weeks. Further studies are needed to assess longer treatment duration, larger samples, and direct comparison with other medications. clinicaltrials.gov Identifier: NCT01920893.

Su1289 Efficacy of Bowel Preparation With the Use of a General Diet Versus a Clear Liquid Diet With Polyethylene Glycol Electrolyte Solution

in a structured colonoscopy report with well-defined fields to capture all the data. Main Outcome Measurements: We analyzed the synchronous polyp burden rate in patients with 1cm polyps. Results: 137 patients were found to have 185 polyps measuring 1cm during 155 colonoscopies. Mean age: 61.23; SexMen : Women: 68:69; BMI: 27.1. Caucasians: 115 (83.9%); History of abdominal surgery: 85 (62%). Colonoscopy: 155 colonoscopies were performed in total (index endoscopy followup endoscopy within 6 months). Indication (n 155): Screening: 55; Surveillance of polyps: 51; Symptoms: 14; Referral for EMR: 35; Boston Bowel Preparation Scale: 8.95 0.37 EMR of 1 cm polyp: Size: 1-2cm: 140; 2cm: 45; Paris Classification of 1 cm polyps: Documented in the last 82 of 185 polyps: 0-IIa:72%; 0-IIb: 1.2%; 0-Is: 18.3%; 0-Ip: 8.5%. En-bloc EMR: 83.2% of lesions. APC of the edges: 51% of EMR defects; Prophylactic clip closure: 84.9% of EMR defects. Complications: Perforation: 0; Bleeding: 4 (2 required clip hemostasis). Local recurrence: 1 (tubular adenoma). Nature of pathology of 1cm polyp: Majority are serrated adenomas and tubular adenomas. See table 1. Synchronous Polyp Burden in patients with 1cm polyp : Majority are tubular adenomas, with a total adenoma burden per patient of 3.71. See table 2. Conclusions: Patients with large colon polyps are associated with a high polyp burden. Hence, it is critical to clear the colon of all the polyps in addition to confirming complete eradication of the large polyp after the EMR to prevent colon cancer in this high risk group.

Genetic polymorphisms of human flavin-containing monooxygenase 3: implications for drug metabolism and clinical perspectives.

Flavin-containing monooxygenase 3 (FMO3) is a hepatic microsomal enzyme that oxidizes a host of drugs, xenobiotics and other chemicals. Numerous variants in the gene encoding FMO3 have been identified, some of which result in altered enzymatic activity and, consequently, altered substrate metabolism. Studies also implicate individual and ethnic differences in the frequency of FMO3 polymorphisms. In addition, new variants continue to be identified with potentially important clinical implications. For example, the role of FMO3 variants in the pathophysiology of gastrointestinal diseases is an evolving area of research. Two commonly occurring polymorphisms of FMO3, E158K and E308G, have been associated with a reduction in polyp burden in patients with familial adenomatous polyposis who were treated with sulindac sulfide, an FMO3 substrate. These findings suggest a potential role for prospective genotyping of common FMO3 polymorphisms in the treatment of disease states that involve the use of drugs metabolized by FMO3. This review summarizes the current state of research on the genetic polymorphisms of FMO3, with a focus on their clinical implications in gastrointestinal diseases.

Prevention of colorectal cancer through the use of COX-2 selective inhibitors.

Colorectal cancer is a major cause of morbidity and mortality accounting for an estimated 550,000 deaths annually worldwide. Colonic neoplasia develops in a stepwise fashion progressing from normal mucosa to adenomatous polyps to carcinoma, a process that takes years, thereby providing a prime opportunity for intervention. Although early detection by fecal occult blood testing and sigmoidoscopy can decrease the risk of cancer-related death by 20-30%, most persons never undergo appropriate screening. Population-based studies have previously determined that long-term ingestion of aspirin or other nonsteroidal antiinflammatory drugs (NSAIDs) leads to a 40-50% reduction in mortality. from colorectal cancer. These observational studies fueled subsequent mechanistic investigations that led to the identification of a molecular target, cyclooxygenase-2 (COX-2). COX-2 has tumor-promoting properties. Expression of COX-2 is virtually undetectable in normal intestinal mucosa, but is increased in approximately 50% of colonic adenomas and in 90% of colorectal carcinomas. Experimental studies in mice have revealed that genetic ablation or pharmacologic inhibition of COX-2 attenuates the number and size of intestinal polyps that develop in animals harboring a mutation in Apc, which confers an increased risk for intestinal neoplasia. Recent clinical studies using specific COX-2 inhibitors have shown that these compounds can: (1) reduce intestinal polyp burden in patients with familial adenomatous polyposis; (2) prevent the occurrence and/ or recurrence of colorectal adenomas and cancers; and (3) negatively regulate angiogenesis in colorectal cancer liver metastases. Compared to nonselective NSAIDs, COX-2 specific inhibitors cause substantially fewer gastrointestinal side effects. These findings indicate that a widely used and relatively safe class of drugs may represent a viable and effective anticancer strategy for a disease that causes over a half-million deaths per year.

Celecoxib inhibits phorbol ester-induced expression of COX-2 and activation of AP-1 and p38 MAP kinase in mouse skin.

Celecoxib, the first US FDA-approved selective cyclooxygenase-2 (COX-2) inhibitor initially developed for the treatment of adult rheumatoid arthritis and osteoarthritis, was reported to reduce the polyp burden in patients with familial adenomatous polyposis. This specific COX-2 inhibitor also protects against experimentally induced carcinogenesis, but molecular mechanisms underlying its chemopreventive activities remain largely unresolved. In the present work, we found that celecoxib inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced expression of COX-2 in female ICR mouse skin when applied topically 30 min prior to TPA as determined by both immunoblot and immunohistochemical analyses. In another study, celecoxib attenuated the DNA binding activity of activator protein 1 (AP-1) through suppression of c-Jun and c-Fos expression in TPA-treated mouse skin. In addition, celecoxib inhibited both the catalytic activity and phosphorylation of p38 mitogen-activated protein (MAP) kinase. In the same animal model, TPA treatment resulted in rapid activation via phosphorylation of extracellular signal-regulated protein kinase (ERK)1/2 and p38 MAP kinase, which are upstream of AP-1 in mouse skin. In order to clarify the roles of p38 and ERK in TPA-induced AP-1 activation, we utilized the pharmacologic inhibitors of these enzymes. The p38 inhibitor SB203580 blocked TPA-mediated AP-1 activation, while the MEK1/2 inhibitor U0126 was not inhibitory despite suppression of c-Fos expression in mouse skin. Furthermore, SB203580 markedly inhibited COX-2 expression induced by TPA. Taken together, these findings suggest that celecoxib down-regulates COX-2 by blocking activation of p38 MAP kinase and AP-1, which may represent molecular mechanisms underlying antitumor promoting effects of this drug on mouse skin tumorigenesis.

Cyclooxygenase-2 inhibitors in colorectal cancer.

Cyclooxygenase (COX) enzyme-dependent arachidonic acid metabolites occupy key positions in important physiologic processes such as immunity, reproduction, and vascular integrity. Large retrospective and prospective population-based studies have shown that the use of both nonselective, nonsteroidal anti-inflammatory drugs and selective COX-2 inhibitors are associated with decreased colorectal cancer incidence and mortality rate. A majority of animal studies provide strong evidence that prevention of intestinal tumors is more efficiently accomplished by COX-2 selective inhibition rather than by COX-1 suppression. The inducible COX-2 isoform is overexpressed in colorectal tissues and is associated with critical events of tumorigenesis. COX-2 expression correlates with expression of angiogenic factors and new blood vessel formation. Inhibition of COX-2 favors apoptosis and causes a dose-dependent decline of tumor growth and metastasis in these models. These data, together with the fact that COX-2 inhibitors cause less toxic side effects compared with nonselective nonsteroidal anti-inflammatory drugs, render these new compounds promising candidates in chemoprevention and treatment of colorectal cancer. Results from initial clinical trials suggest that COX-2 inhibitors may be able to reduce the polyp burden in patients with familial polyposis coli. However, further clinical studies are needed to evaluate whether COX-2 inhibition will be effective in all types of colorectal tumor tissues. This is especially true for neoplastic lesions that express COX-2 at a lower level (eg, hereditary nonpolyposis colorectal cancer) and for colorectal tumors of patients with inflammatory bowel disease. In summary, COX-2 inhibitors represent a new and very promising group of chemotherapeutic agents with great potential for both colorectal cancer prevention and treatment.

Celecoxib as Adjunctive Therapy for Treatment of Colorectal Cancer

To describe the role of celecoxib as adjunctive therapy in the treatment of familial adenomatous polyposis (FAP), an inherited autosomal dominant predisposition syndrome for colorectal cancer. Literature was evaluated through MEDLINE search (1995-March 2000) and through secondary sources, using the search terms celecoxib, cyclooxygenase-2 inhibitors, and familial adenomatous polyps. Observational studies have found a decreased rate of colorectal cancer in people who regularly took aspirin or other nonsteroidal antiinflammatory drugs (NSAIDs). The Food and Drug Administration granted accelerated approval in December 1999 for the NSAID celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, for adjunctive therapy in patients with FAP, based on a six-month, randomized, controlled clinical trial. Aspirin and other NSAIDs reduce the incidence of colorectal cancer in the general population. Limited clinical studies in patients with FAP using nonaspirin NSAIDs have shown a reduction in polyp burden. A current clinical trial using celecoxib has also shown a reduction in polyp burden in patients with FAP. The long-term clinical impact of using a selective COX-2 inhibitor is not known, since celecoxib has not been studied beyond six months in patients with FAP. By reducing the polyp burden in FAP patients, celecoxib may be useful as adjunctive chemotherapy, in addition to routine endoscopic surveillance and surgery.