Use Of COX-2 Inhibitors Research Articles

HPV-associated penile cancer: Impact of copy number alterations in miRNA/mRNA interactions and potential druggable targets.

Penile cancer (PeCa) is a rare disease, but its incidence has increased worldwide, mostly in HPV+ patients. Nevertheless, there is still no targeted treatment for this carcinoma. To predict the main signaling pathways involved in penile tumorigenesis and its potential drug targets. Genome-wide copy number profiling was performed in 28 PeCa. Integration analysis of CNAs and miRNAs and mRNA targets was performed by DIANA-TarBase v.8. The potential impact of the miRNAs/target genes on biological pathways was assessed by DIANA-miRPath v.3.0. For each miRNA, KEGG pathways were generated based on the tarbase and microT-CDS algorithms. Pharmaco-miR was used to identify associations between miRNAs and their target genes to predict druggable targets. 269 miRNAs and 2,395 genes were mapped in cytobands with CNAs. The comparison of the miRNAs mapped at these cytobands and the miRNAs that were predicted to regulate the genes also mapped in these regions, resulted in a set of common 35 miRNAs and 292 genes. Enrichment pathway revealed their involvement in five top signaling pathways. EGFR and COX2 were identified as potential druggable targets. Our data indicate the potential use of EGFR and COX2 inhibitors as a target treatment for PeCa patients.

Structural and functional state of Heren carcinoma after local fractional X-irradiation and irradiation combined with meloxicam

Background. One of the most important problems of oncology is the overcoming of therapeutic resistance of tumors, which occurs in particular due to increased levels of the enzyme cyclooxygenase 2 (COX-2). It is known that the growth of COX-2 and the product of its activity, prostaglandin-E2 in cancer, promotes such processes in the body as tumor growth, stimulation of proliferation, induction of cancer stem cells, inhibition of apoptosis, activation of angiogenesis, invasion, metastasis and development of chemoresistance. The use of COX-2 inhibitors, which are nonsteroidal anti-inflammatory drugs (NSAIDs), significantly limits these processes and improves survival and mortality in cancer patients, and in combination with chemotherapeutics eliminates the resistance they cause. Purpose – study of the structural and functional state of Guerin’s carcinoma cells after the combined use of nonsteroidal anti-inflammatory drug meloxicam and local X-irradiation in total doses of 1.0 and 10 Gy. Materials and methods. On 33 rats with inoculated Guerin’s carcinoma, the ultrastructure of tumor cells (TC) was studied using standard methods of electron microscopy 24 hours after the combined use of the meloxicam drug at a dose of 0.2 mg per 1 kg of body weight one day before the first and 2 hours before the second session fractional local X-irradiation in total doses of 1 and 10 Gy (twice daily at 0.5 and 5.0 Gy, respectively. The mitotic index (the number of cells in the state of mitosis per 100 TC,%), the apoptosis index (the number of cells in the state of apoptotic death per 100 TC,%) and the frequency of TC with small nuclei (%). Results. It was found that irradiation of Guerin’s tumor in a total dose of 10 Gy causes disturbances in the ultrastructure associated with damage to the nuclear apparatus of the TC. Pleiomorphism of the nuclei, the appearance of binucleated cells and micronuclei, a significant decrease in mitotic activity and a slight increase in the apoptosis index are observed. Stimulation of the functional activity of macrophages is also noted. Under irradiation in a total dose of 1 Gy, such effects are less pronounced or completely absent, such as, for example, the processes of phagocytosis. The frequency index of TC with small nuclei is equally reliably increased at both radiation doses. The administration of the drug meloxicam leads to a significant decrease in mitotic activity and an increase in the frequency of small cells, while the ultrastructural picture of the tumor remains almost unchanged. With the combined action of the drug and radiation in both doses, violations of the fine structure of the OC are identical to those found during irradiation. At the same time, the mitotic index in the group with the combined effect of the drug and radiation at a dose of 10 Gy is significantly lower than with only irradiation.In addition, at both doses, the frequency of small forms of PC significantly increases in comparison with the indicators of both the intact control group and the corresponding irradiation groups. Only in combination with radiation does meloxicam reliably stimulate apoptosis, while in other groups its index remains at the level of control values. The relationship was confirmed, which was constantly revealed in all experimental groups, between a decrease in the level of the mitotic index and an increase in the frequency of TC with small nuclei in Guerin’s carcinoma. An inverse correlation was found between these indicators (r = 0.80, P = 0.05). Conclusions. The combined action of the drug and irradiation significantly increases the effectiveness of both therapeutic factors due to the property of meloxicam to reliably inhibit proliferative activity and promote post-radiation development of apoptosis in tumor tissue. The presence of a correlation between the mitotic index and the frequency of cells with small nuclei in Guerin’s tumor may indicate the relationship between cell growth and division. Under the combined action of both investigated factors, changes in the tumor ultrastructure are mainly caused by irradiation. The administration of meloxicam increases the efficiency of the combined use of both therapeutic agents due to its ability to reliably inhibit proliferative activity and promote post-radiation development of apoptosis in tumor tissue. The presence of a correlation dependence between the mitotic index and the frequency of cells with small nuclei in Guerin’s tumor may indicate the relationship between the processes of cell growth and division.

Evaluating the Safety of Non-Steroidal Anti-inflammatory Drugs use in Asthmatic Patients: A Systematic, Critical Review of Literature

Background: Evidence suggest avoidance of Non-steroidal anti-inflammatory drugs (NSAID) in aspirinintolerantasthmatics due to the risk of triggering exacerbation attack; however, evidence around avoidingNSAIDs in all other asthmatic patients are unclear. This study aimed to evaluate the evidence surroundingthe safety of using NSAIDs, including selective COX-2 inhibitors, among asthmatic patients.Methods: A systematic review used Medline (OVID), Scopus and Embasefrom January-2008 toJanuary-2019. Inclusion criteria includedEnglish, and human studies that evaluated the use of NSAID inasthmatics. Data was screened/extracted using a pre-designed data extraction form using Covidence®,thenwere critically appraised.Conclusion: Of the 49 identified studies,eight were eligible. Prevalence of NSAID-induced asthmaexacerbation was 9%(95%CI:6.0–12.0%)-9.9% (95%CI:9.4-10.5%). Asthmatics who were aspirin/NSAIDintolerant had 37% higher risk of hospitalisation compared to tolerant patients (RR:1.37; 95%CI:1.12–1.67).Use of COX-2 inhibitors showed non-significant associations with worsening respiratory symptoms/exacerbation. Only low-quality evidence was found for the safety of topical NSAID. NSAIDs-inducedrespiratory reactions/symptoms is relatively uncommon with the majority of asthmatic patients couldtolerate NSAIDs therapy. Asthmatic patients who suffer from aspirin-induced asthma or NSAIDsexacerbatedrespiratory disease (NSAIDs intolerant) should be avoided NSAIDs prescribing but could besafely prescribed selective COX-2 inhibitors as an alternative.

Periconceptional nonsteroidal anti-inflammatory drug use, folic acid intake, and the risk of spina bifida.

Use of nonsteroidal anti-inflammatory drugs (NSAIDs) during pregnancy may increase risk for neural tube defects (NTDs), including spina bifida. Folic acid intake can prevent NTDs, but it is not known whether it modifies any risks associated with NSAID use. To assess the impact of periconceptional NSAID use on the risk of spina bifida overall and stratified by folic acid intake. We analyzed 1998-2015 data from the Slone Epidemiology Center Birth Defects Study, a multi-site, case-control study. Mothers were interviewed to identify sociodemographic factors, behaviors, and exposures during pregnancy. Periconceptional NSAID use was defined as use of aspirin, ibuprofen, naproxen, or COX2 inhibitors within the month before or after the last menstrual period. Logistic regression models were used to estimate adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for NSAID use, adjusted for study center and race/ethnicity stratified by average daily folic acid intake above ("high FA") or below ("low FA") 400 mcg/day. We compared mothers of 267 infants with spina bifida to mothers of 6,233 nonmalformed controls. Among control mothers, 20% used NSAIDS periconceptionally (16% ibuprofen, 4% aspirin, 3% naproxen, and <1% COX-2 inhibitors). For any NSAID use, the aORs among low FA and high FA women were 1.70 (95% CI [1.13, 2.57]) and 1.09 (95% CI [0.69, 1.71]), respectively. We observed a small increase in the risk for spina bifida among infants born to women who used NSAIDs periconceptionally, but this risk was limited to those who had inadequate folic acid intake.

Genetic variant of cyclooxygenase-2 in gastric cancer: More inflammation and susceptibility.

Gastric cancer accounts for the majority cancer-related deaths worldwide. Although various methods have considerably improved the screening, diagnosis, and treatment of gastric cancer, its incidence is still high in Asia, and the 5-year survival rate of advanced gastric cancer patients is only 10%-20%. Therefore, more effective drugs and better screening strategies are needed for reducing the incidence and mortality of gastric cancer. Cyclooxygenase-2 (COX-2) is considered to be the key inducible enzyme in prostaglandins (PGs) synthesis, which is involved in multiple pathways in the inflammatory response. For example, inflammatory cytokines stimulate innate immune responses via Toll-like receptors and nuclear factor-kappa B to induce COX-2/PGE2 pathway. In these processes, the production of an inflammatory microenvironment promotes the occurrence of gastric cancer. Epidemiological studies have also indicated that non-steroidal anti-inflammatory drugs can reduce the risk of malignant tumors of the digestive system by blocking the effect of COX-2. However, clinical use of COX-2 inhibitors to prevent or treat gastric cancer may be limited because of potential side effects, especially in the cardiovascular system. Given these side effects and low treatment efficacy, new therapeutic approaches and early screening strategies are urgently needed. Some studies have shown that genetic variation in COX-2 also play an important role in carcinogenesis. However, the genetic variation analysis in these studies is incomplete and isolated, pointing out only a few single nucleotide polymorphisms (SNPs) and the risk of gastric cancer, and no comprehensive study covering the whole gene region has been carried out. In addition, copy number variation (CNV) is not mentioned. In this review, we summarize the SNPs in the whole COX-2 gene sequence, including exons, introns, and both the 5’ and 3’ untranslated regions. Results suggest that COX-2 does not increase its expression through the CNV and the SNPs in COX-2 may serve as the potential marker to establish risk stratification in the general population. This review synthesizes emerging insights of COX-2 as a biomarker in multiple studies, summarizes the association between whole COX-2 sequence variation and susceptibility to gastric cancer, and discusses the future prospect of therapeutic intervention, which will be helpful for early screening and further research to find new approaches to gastric cancer treatment.

Non-steroidal Anti-inflammatory Drug Use and Risk of Age-Related Macular Degeneration in the California Teachers Study.

PurposeThe aim of this study was to examine whether use of regular aspirin and/or other non-steroidal anti-inflammatory drugs (NSAIDs) is associated with the development of age-related macular degeneration (AMD).MethodsIn the California Teachers Study cohort (N = 88,481) we identified diagnoses of AMD up to December 31, 2012 by linkage to statewide hospital discharge records. Aspirin, ibuprofen, other NSAIDs, and acetaminophen use and comprehensive risk factor information were collected via self-administered questionnaires at baseline in 1995–1996 and a follow-up questionnaire in 2005–2006. We employed Cox proportional hazard regression to model AMD risk.ResultsWe did not find any associations between AMD and frequency and duration of aspirin or ibuprofen use reported at baseline. In the subsample with more specific information on medication use, we observed a 20% decrease in risk of AMD among low-dose aspirin users (HR 0.81, 95% CI 0.70–0.95) and a 55% decrease among cyclooxygenase-2 (COX-2) inhibitor users (HR 0.45, 95% CI 0.26–0.78) during 6.3 years of average follow-up.ConclusionThe decrease in risk of intermediate- or late-stage AMD among women who reported regular use of low-dose aspirin or specific COX-2 inhibitors suggests a possible protective role for medications with COX-2 inhibitory properties or aspirin at doses used for cardiovascular disease prevention.

Dual Effects of Cyclooxygenase Inhibitors in Combination With CD19.CAR-T Cell Immunotherapy.

Chimeric antigen receptor T (CAR-T) cells targeting CD19 came into clinical practice for the treatment of B cell lymphoma in 2018. However, patients being treated for B cell lymphoma often suffer from comorbidities such as chronic pain, cardiovascular diseases and arthritis. Thus, these patients frequently receive concomitant medications that include nonsteroidal anti-inflammatory drugs (NSAIDs) like cyclooxygenase (COX) inhibitors. Celecoxib, a selective COX-2 inhibitor, and aspirin, a non-selective COX-1 and COX-2 inhibitor, are being used as anti-inflammatory, analgesic and anti-pyretic drugs. In addition, several studies have also focused on the anti-neoplastic properties of COX-inhibitors. As the influence of COX-inhibitors on CD19.CAR-T cells is still unknown, we investigated the effect of celecoxib and aspirin on the quantity and quality of CD19.CAR-T cells at different concentrations with special regard to cytotoxicity, activation, cytokine release, proliferation and exhaustion. A significant effect on CAR-T cells could be observed for 0.1 mmol/L of celecoxib and for 4 mmol/L of aspirin. At these concentrations, we found that both COX-inhibitors could induce intrinsic apoptosis of CD19.CAR-T cells showing a significant reduction in the ratio of JC-10 red to JC-10 green CAR-T cells from 6.46 ± 7.03 (mean ± SD) to 1.76 ± 0.67 by celecoxib and to 4.41 ± 0.32 by aspirin, respectively. Additionally, the ratios of JC-10 red to JC-10 green Daudi cells were also decreased from 3.41 ± 0.30 to 0.77 ± 0.06 by celecoxib and to 1.26 ± 0.04 by aspirin, respectively. Although the cytokine release by CD19.CAR-T cells upon activation was not hampered by both COX-inhibitors, activation and proliferation of CAR-T cells were significantly inhibited via diminishing the NF-ĸB signaling pathway by a significant down-regulation of expression of CD27 on CD4+ and CD8+ CAR-T cells, followed by a clear decrease of phosphorylated NF-ĸB p65 in both CD4+ and CD8+ CAR-T cells by a factor of 1.8. Of note, COX-inhibitors hampered expansion and induced exhaustion of CAR-T cells in an antigen stress assay. Collectively, our findings indicate that the use of COX-inhibitors is a double-edged sword that not only induces apoptosis in tumor cells but also impairs the quantity and quality of CAR-T cells. Therefore, COX-inhibitors should be used with caution in patients with B cell lymphoma under CAR-T cell therapy.

Does concurrent COX inhibition and immune checkpoint blockade improve clinical outcome in patients with metastatic renal cell carcinoma?

e16558 Background: Cyclooxygenase (COX) inhibition is postulated to restore the immune environment and synergizes with immune checkpoint inhibitors (ICI). The concurrent use of COX inhibitors (COXi) and ICI was associated with longer disease control in metastatic melanoma and non-small cell lung cancer. However, its role in mRCC remains unclear. Methods: We retrospectively reviewed 194 patients with mRCC treated with ICI (PD-(L)1 inhibitors +/- CTLA-4 inhibitors or TKIs) at Moffitt Cancer Center between 6/2014-7/2019. Concurrent use of COXi (aspirin [ASA] or NSAIDs) was defined as at least 3 weeks of COXi use during the first ICI course. Clinical characteristics of both arms were compared using Chi-squared or Kruskal-Wallis Rank Sum test. Time to progression (TTP) and Overall survival (OS) were compared using Kaplan Meier’s estimates. Univariate and multivariate Cox proportional hazards model was performed to evaluate the association between clinical factors, TTP, and OS. Results: Of 194 patients, 126 patients (64.9%) took COXi. Median age was 59.7 years and 80.4% were male. COXi arm had fewer patients with &lt; 1 year from diagnosis to systemic treatment (45.9% vs 69.5%, p = 0.006) and more advanced age (median: 66 years vs 60 years, p = 0.01). IDMC risk group, number of prior therapies, neutrophil to lymphocytes ratio were similar between both arms. Median TTP was 8 months (m) for COXi arm and 12m for ICI only (HR 1.38; 95% CI [0.98, 1.94]). Median OS was 27m for COXi arm and 33m for ICI only (HR 1.05, 95% CI [0.69, 1.59]). Early mortality rate (within 3m of ICI treatments) were similar between both arms. Conclusions: In contrast to melanoma and lung cancer, concurrent use of COXi and ICI did not improve TTP and OS in patients with mRCC. The dual blockade showed a trend for shorter TTP. Further validation studies with larger cohorts are needed to confirm this finding.[Table: see text]

Oral cancer chemoprevention: COX-2 inhibitor a covenant

&lt;p&gt;Oral cancer survival remains poor despite advancement in treatment modalities. In oral cancer and oral premalignant lesions, cyclooxygenase-2 (COX-2) is widely expressed and tends to be enhanced especially in high-risk oral lesions. Numerous researches suggests that the inflammation pathway of cyclooxygenase/prostaglandin E2 (PGE2) leads to the development and progression of a number of cancers, including oral squamous cell carcinoma (OSCC). With an emphasis on research data, this article discusses the relationship between inflammation and cancer, summarizes the use of anti-inflammatory agents COX-2 inhibitors for cancer chemoprevention and treatment, and explains the mechanisms underlying the anti-cancer effects of anti-inflammatory agents (COX-2 inhibitors).&lt;/p&gt;

The Effect of Nonsteroidal Anti-inflammatory Drugs and Selective COX-2 Inhibitors on Bone Healing.

A recently published study, "Risk of Nonunion With Nonselective NSAIDs, COX-2 Inhibitors, and Opioids" by George et al (J Bone Joint Surg Am. 2020;102:1230-1238), assesses whether the use of nonselective nonsteroidal anti-inflammatory drugs (NSAIDs), selective cyclooxygenase 2 (COX-2) enzyme inhibitors, or opioids was associated with a risk of long bone fracture nonunion in Optum's deidentified private health database. This review analyzes the study, including strengths, weaknesses, and areas for future research. The study found an association between COX-2 inhibitor and opioid use with fracture nonunion but not with nonselective NSAID use. Although the literature on this topic is varied, these results are at least partially aligned with several animal studies that show COX-2 inhibitors to be associated with fracture nonunion. The George et al study design has several important limitations, indicating that further research is needed on this topic.

Preemptive analgesia using selective cyclooxygenase-2 inhibitors alleviates postoperative pain in patients undergoing total knee arthroplasty: A protocol for PRISMA guided meta-analysis of randomized controlled trials.

Background:The postoperative pain associated with total knee arthroplasty (TKA) is severe for most patients. The analgesic efficacy and safety of preoperative use of selective cyclooxygenase-2 (COX-2) inhibitors for patients undergoing TKA are unclear.Objectives:We conducted a systematic review and meta-analysis to assess whether the use of selective COX-2 inhibitors before TKA decreases the postoperative pain intensity.Methods:Data sources: The PubMed, Embase, EBSCO, Web of Science, and Cochrane Controlled Register of Trials databases from inception to January 2020.Study eligibility criteria:All randomized controlled trials (RCTs) in which the intervention treatment was preoperative selective COX-2 vs placebo in patients undergoing TKA and that had at least one of the quantitative outcomes mentioned in the following section of this paper were included. Letters, review articles, case reports, editorials, animal experimental studies, and retrospective studies were excluded.Interventions:All RCTs in which the intervention treatment was preoperative selective COX-2 vs placebo in patients undergoing TKA.Study appraisal and synthesis methods:The quality of the RCTs was quantified using the Newcastle–Ottawa quality assessment scale. RevMan 5.3 software was used for the meta-analysis.Results:Six RCTs that had enrolled a total of 574 patients were included in the meta-analysis. The visual analog scale pain score at rest was significantly different between the experimental group and control group at 24 hours (P < .05) and 72 hours (P < .05) postoperatively. The experimental group exhibited a significant visual analog scale pain score during flexion at 24 hours postoperatively (P < .05), and it was not different at 72 hours postoperatively (P = .08). There was a significant difference in opioid consumption (P < .05), but there was no difference in the operation time (P = .24) or postoperative nausea/vomiting (P = .64) between the groups.Conclusion:The efficacy of preoperative administration of selective COX-2 inhibitors to reduce postoperative pain and opioid consumption after TKA is validated.Systematic review registration number:INPLASY202090101

Cyclooxygenase Inhibition Safety and Efficacy in Inflammation-Based Psychiatric Disorders.

According to the World Health Organization, the major psychiatric and neurodevelopmental disorders include major depression, bipolar disorder, schizophrenia, and autism spectrum disorder. The potential role of inflammation in the onset and progression of these disorders is increasingly being studied. The use of non-steroidal anti-inflammatory drugs (NSAIDs), well-known cyclooxygenase (COX) inhibitors, combined with first-choice specific drugs have been long investigated. The adjunctive administration of COX inhibitors to classic clinical treatments seems to improve the prognosis of people who suffer from psychiatric disorders. In this review, a broad overview of the use of COX inhibitors in the treatment of inflammation-based psychiatric disorders is provided. For this purpose, a critical analysis of the use of COX inhibitors in the last ten years of clinical trials of the major psychiatric disorders was carried out.

Effects of Therapies on Cardiovascular Events in Ankylosing Spondylitis: A Systematic Review and Meta-Analysis.

IntroductionNon-steroidal anti-inflammatory drugs (NSAIDs) and tumor necrosis factor inhibitors (TNFi) are the most common therapies used in AS, however, the associated long-term cardiovascular risk is unclear. We performed a systematic review and meta-analysis on the association of therapies used for ankylosing spondylitis (AS) such as NSAIDs and TNFi on cardiovascular events (CVE) in AS.MethodsA comprehensive search was performed from database inception to May 29, 2020 to include controlled studies of AS treated with NSAIDs, oral small molecules, or biologics reporting CVE. Study-specific risk ratios (RR) were pooled using a random effects model.ResultsNine non-randomized studies from 1570 studies screened fulfilled inclusion criteria. Among NSAID users as a whole versus no NSAIDs, no increased risk of CVE (composite outcome) was observed; however, the risk of cerebrovascular accident was significantly lower (RR 0.58, 95% CI 0.37–0.93, I2 = 66%). Cox-2 inhibitor use was associated with reduced risk of all CVE (RR 0.48, 95% CI 0.33–0.70, I2 = 0%). Non-selective NSAIDs were not associated with any increased/decreased risk of any CVE. Meta-analysis of three studies of MI did not show a significant association with TNFi (RR 0.88, 95% CI 0.57–1.35, I2 = 76%).ConclusionsIn this meta-analysis of non-randomized studies, NSAID users as a whole and users of non-selective NSAIDs did not seem to have a higher risk of any CVE. Limited data suggest a lower risk of composite CVE outcome with Cox-2 inhibitors, unlike the increased risk reported in the general population. No significant association between TNFi and MI was observed. The certainty in evidence was very low due to all studies being observational. More studies are needed to study the association between TNFi use and CVE in general to evaluate a possible protective role in AS.Electronic Supplementary MaterialThe online version of this article (10.1007/s40744-020-00248-x) contains supplementary material, which is available to authorized users.

Efeitos adversos do uso prolongado de anti-inflamatórios não esteroidais inibidores da COX-2 em equinos: revisão

Os antiinflamatórios não esteroidais (AINE's), por serem comercializados, suprimidos-se entre os medicamentos mais prescritos no mundo, possuindo ação anti-inflamatória, analgésica e antipirética por inibição das prostaglandinas mediante bloqueio das cicloxigenases (COX). Atualmente sabe-se da existência de três enzimas COX com ações distintas. Postulou-se que as propriedades farmacológicas dos AINE's decorrem principalmente da ação inibitória da COX-2, enquanto que as reações adversas são geradas da inibição da COX-1, criando subgrupos de AINE's: preferenciais, seletivos e não seletivos para COX-2. A introdução dos inibidores da COX-2 na prática clínica visa manter a eficácia antiinflamatória sem os efeitos adversos indesejáveis. Todavia, estudos comprovados toxidade associada ao seu uso. Objetivou-se com este trabalho levantar informações sobre os efeitos do uso prolongado de inibidores da COX-2 na espécie de AINE. Para isso, foi realizada uma revisão bibliográfica buscando estudos sobre os efeitos do uso de inibidores da COX-2 em cavalos. Foi observado que esta classe de medicamentos diversos efeitos tóxicos para uma espécie, principalmente em situações onde existiram sobredosagens, uso por tempo prolongado e associação com outros AINE's. São necessárias para o controle de comercialização desses fármacos. A escolha do fármaco no tratamento deve ser individualizada a cada paciente, levando em consideração seus fatores de risco e benefícios. Seu uso de forma racional é um importante aliado dos clínicos veterinários na promoção da saúde e bem-estar-animal.

Abstract 3491: COX-2 inhibitor use and risk of skin cancer: three prospective cohort studies

Abstract Skin cancer is the most commonly diagnosed type of cancer, with continually rising incidence rates. Cyclooxygenase-2 (COX-2) inhibitor use has been associated with lower risk of several cancers, though epidemiological studies on skin cancer risk have been limited and inconclusive. To evaluate whether COX-2 inhibitor use is associated with decreased risk of basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (cSCC), and melanoma, we analyzed COX-2 inhibitor use and risk of skin cancer based on three prospective cohorts–the Nurses' Health Study (NHS, 2000-2012), NHS II (2001-2011), and the Health Professionals Follow-up Study (HPFS, 2002-2012). COX-2 inhibitor use and duration were assessed by biennial questionnaires, with cSCC and melanoma cases verified by pathological records. Over 1.54 million person-years of follow-up, 16,098 BCC, 1,973 cSCC, and 625 invasive melanoma cases were documented. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) for the association of COX-2 inhibitor use with risk of BCC, cSCC, and melanoma were estimated using Cox proportional hazards models. We pooled the results between the three cohorts using a fixed effects model. For ever vs. never users, COX-2 inhibitor use was associated with a modestly increased risk of BCC (multivariable HR 1.10, 95% CI 1.06–1.15) and cSCC (multivariable HR 1.12, 95% CI 1.00–1.27). The effect estimate was similar for melanoma, but was non-significant (multivariable HR 1.10, 95% CI 0.89–1.38). In conclusion, COX-2 inhibitor use was not associated with decreased skin cancer risk and instead was associated with modestly increased risk of BCC and cSCC. Further investigation is necessary to replicate these results. Citation Format: Hsuan Yen, Hsi Yen, Aaron Drucker, Jiali Han, Wen-Qing Li, Tricia Li, Abrar Qureshi, Eunyoung Cho. COX-2 inhibitor use and risk of skin cancer: three prospective cohort studies [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3491.

Abstract 2754: Inhibition of nitric oxide synthase and cyclooxygenase potentiate immune responses that control aggressive mammary tumor in a murine model

Abstract Progression of aggressive, triple negative breast cancers (TNBC) is driven by inflammation and the presence of tumor infiltrating lymphocytes (TIL) improves survival. Recent studies show that TNBCs show high levels of TILs but these cells are exhausted as evident from decreased IFNγ, Ki67 and granzyme B. High expression of the inflammation-associated protein, inducible nitric oxide synthase (NOS2) and co-expression with high cyclooxygenase 2 (COX2) means poor prognosis in ER- breast cancer. Interestingly, NOS2 and COX2 are upregulated in different cells in the tumor microenvironment (TME). Thus, we hypothesized that the tandem use of NOS2 and COX2 inhibitors would curtail tumor progression by targeting different cell types within the TME simultaneously. As COX2 has also been reported to regulate tumor infiltration of myeloid cells, this could regulate both the lymphoid and myeloid arms of the immune system for better response. We investigated the effects of NOS2 and COX2 on tumorigenesis and pulmonary metastasis in a murine model of TNBC by injecting 4T1 cells into the fourth mammary fat pad of wild type (WT) and NOS2 knockout (NOS2-/-) BALB/c mice followed by treatment with COX inhibitor, indomethacin. Changes in infiltrating immune cells was analyzed using flow cytometry and confocal microscopy. We measured the levels of serum cytokines using bead-based, LegendPlex assay. We found that NOS2-/- mice developed fewer pulmonary metastatic lesions than WT mice while indomethacin directly reduced primary tumor growth in both WT and NOS2-/- mice. Indomethacin treated NOS2-/- mice showed better median survival (60 days compared 51 in WT mice). Two NOS2-/-, indomethacin treated mice showed complete remission and long term (5-months) tumor growth delay after 4T1 re-challenge, indicating immune activation in mice lacking NOS2 and COX2 function. Flow cytometry of primary tumors showed higher infiltration of activated CD4, CD8 cells, macrophages and reduction of Tregs in treated mice. Microscopy revealed a physical ‘walling -off' of TILs by CD11b+ cells in untreated tumors that was abrogated upon indomethacin treatment. As many TNBC patients succumb to pulmonary metastasis and because we found reduced metastasis in NOS2-/- mice, we studied the immune cells in metastatic lungs. Lung niche of NOS2-/- mice had more activated T-cells, bone marrow-derived macrophages and neutrophils that are not conducive to establishment of metastasis. Serum of NOS2-/- mice had elevated IL-6 that drove increased IL17A subsequently contributing to reduced metastasis and this effect was improved upon indomethacin treatment. IL6 is also a potential inhibitor of Tregs thus further improving immune surveillance. COX inhibition can treat aggressive TNBC directly by reducing cancer cell proliferation and indirectly by immune activation. Tandem NOS2 inhibition can render the pulmonary microenvironment unfavorable for metastatic spread and induce a favorable systemic cytokine storm that further improves outcome. Citation Format: Veena Somasundaram, Debashree Basudhar, Christopher McGinity, Robert Y. Cheng, Lisa A. Ridnour, Stephen J. Lockett, David A. Wink. Inhibition of nitric oxide synthase and cyclooxygenase potentiate immune responses that control aggressive mammary tumor in a murine model [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2754.

Biochemical control of the combination of cyclooxygenase-2 inhibitor and 125 I-brachytherapy for prostate cancer: Post hoc analysis of an open-label controlled randomized trial.

To evaluate the use of cyclooxygenase-2 inhibitors in patients receiving low-dose-rate brachytherapy for prostate cancer. A total of 310 patients with prostate cancer (cT1c-3aN0M0) who received low-dose-rate brachytherapy between May 2010 and July 2013 were enrolled and allocated to one of the two treatment groups (tamsulosin alone 0.2mg/day for 6months vs tamsulosin 0.2mg/day for 6months plus celecoxib 200mg/day for 3months). The primary end-point was the chronological change in international prostate symptom score, and the number of patients was assessed for the primary end-point. Biochemical recurrence-free, cancer-specific survival and overall survival rates 5years after the last patient received low-dose-rate brachytherapy were retrospectively examined. The median follow-up period after low-dose-rate brachytherapy was 72.0months (range 3-99months). A total of 12 (3.9%) patients experienced biochemical recurrence. The biochemical recurrence-free rate in the celecoxib group (5-year biochemical recurrence-free rate 98.5%) was significantly better (log-rank test P=0.023, 95% confidence interval 0.07-0.63, hazard ratio 0.20) than that in the tamsulosin group (5-year biochemical recurrence-free rate 93.4%). None of the patients died from prostate cancer. However, 14 (4.5%) patients died of other causes. No significant difference was observed in terms of overall survival between the celecoxib and tamsulosin groups. The combination of cyclooxygenase-2 inhibitor and low-dose-rate brachytherapy can contribute to a better biochemical control of prostate cancer.

Risk of Nonunion with Nonselective NSAIDs, COX-2 Inhibitors, and Opioids.

Cyclooxygenase-2 (COX-2) has been found to be important for fracture-healing in animal models, raising concerns about use of nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors after fractures. We evaluated associations of NSAIDs, COX-2 inhibitors, and opioids with nonunion after long-bone fracture. Using private health insurance claims data from Optum's de-identified Clinformatics Data Mart database from January 1, 2000, to September 30, 2015, we identified adults with a single long-bone fracture or commonly paired long-bone fractures who had 1 year of available follow-up data. Using multivariable logistic regression models, we examined associations between NSAID, COX-2-inhibitor, or opioid prescription fills after the fracture and the risk of nonunion within 1 year, defined as a nonunion diagnosis with a procedure to treat the nonunion. A nonunion diagnosis with a procedure to treat the nonunion was identified after 2,996 (0.9%) of the 339,864 fracture episodes, with rates varying by fracture site. The risk of that outcome was greater in patients who had filled COX-2-inhibitor prescriptions (adjusted odds ratio = 1.84 [95% confidence interval = 1.38 to 2.46]) or opioid prescriptions (1.69 [1.53 to 1.86]), but not in patients who had filled nonselective-NSAID prescriptions (1.07 [0.93 to 1.23]) after the fracture. Results were similar when the outcome definition was changed to just a nonunion diagnosis. COX-2 inhibitors, but not nonselective NSAIDs, were associated with a greater risk of nonunion after fracture. Opioids were also associated with nonunion risk, although patients filling prescriptions for opioids may have had more severe fractures. Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

COMBINED NSAID-INDUCED LESIONS OF THE GASTROINTESTINAL TRACT: FREQUENCY, CLINICAL AND ENDOSCOPIC FEATURES, TREATMENT

Purpose: to study the frequency of lesions of the gastrointestinal tract in NSAIDs users with rheumatoid diseases, as well as to increase the effectiveness of therapeutic and preventivestrategies. Matherials and methods: 112 patients (50 men, 62 women) with various rheumatic diseases and long-term NSAIDs were examined. All patients underwent upper and lower endoscopy, in some patients video capsule endoscopy of the small intestine was also performed. Results: аccording to the data obtained, the most common NSAID-induced gastrointestinal damage was NSAID-gastropathy, observed in 43 % of all NSAID users. 68.6 % of patients with NSAID gastropathy during video capsule endoscopy were additionally diagnosed with NSAID enteropathy, and 9 % of patients with NSAID gastropathy were also diagnosed with NSAID colopathy, which were significantly more common in patients receiving non-selective NSAIDs. Combined lesions of all sections of the gastrointestinal tract, the gastroduodenal zone, small and large intestine, were observed in a significant number of patients — in 27 % of cases, most often in patients with rheumatic diseases who took non-selective NSAIDs. A generalization of the existing experience in the treatment of patients with NSAID-induced gastrointestinal lesions showed that in the case of a combination of NSAID-gastropathy and NSAID-enteropathy, the preferred preventive strategies should be H. pylori eradication, the use of rebamipide and the use of selective COX-2 inhibitors. With the combination of NSAIDs with concomitant excess bacterial growth syndrome and NSAIDs-colopathy, rifaximin, rebamipid and sulfalazine are effective. Conclusions: the data obtained confirm the high prevalence of combined lesions of the proximal and distal gastrointestinal tract in rheumatological patients, which may indicate a universal damaging effect of NSAIDs on the entire gastrointestinal tract.

Relative risk of end-stage renal disease requiring dialysis in treated ankylosing spondylitis patients compared with individuals without ankylosing spondylitis: A nationwide, population-based, matched-cohort study.

To examine the relative risk of end-stage renal disease (ESRD) requiring dialysis among treated ankylosing spondylitis (AS) patients compared with non-AS individuals. We used claims data from Taiwan's National Health Insurance Research Database obtained between 2003 and 2012, and enrolled 37,070 newly treated AS patients and randomly selected 370,700 non-AS individuals matched (1:10) for age, sex and year of index date. Those with a history of chronic renal failure or dialysis were excluded. After adjusting for age, sex, diabetes mellitus, hypertension, IgA nephropathy, frequency of serum creatinine examinations, use of methotrexate, sulfasalazine, ciclosporis, corticosteroid, aminoglycoside, amphotericin B, cisplatin, contrast agents and annual cumulative defined daily dose (cDDD) of traditional NSAIDs, selective cyclooxygenase-2 inhibitors (COX-2i) and preferential COX-2i, we calculated the adjusted hazard ratios (aHRs) with 95% confidence intervals using the Cox proportional hazard model to quantify the risk of ESRD in AS patients. We re-selected 6621 AS patients and 6621 non-AS subjects by further matching (1:1) for cDDDs of three groups of NSAIDs to re-estimate the aHRs for ESRD. Fifty-one (0.14%) of the 37,070 AS patients and 1417 (0.38%) of the non-AS individuals developed ESRD after a follow-up of 158,846 and 1,707,757 person-years, respectively. The aHR for ESRD was 0.59 (0.42-0.81) in AS patients compared with non-AS individuals. However, after further matching for cDDD of NSAIDs, the aHR of ESRD was 1.02 (0.41-2.53). Significant risk factors included hypertension, IgA nephropathy and use of COX-2i. The risk of ESRD was not significantly different between treated AS patients and non-AS individuals matched for age, sex, year of index date and dose of NSAID.