Optimizing aspirin dose for colorectal cancer patients through deep phenotyping using novel biomarkers of drug action.

Background: Low-dose aspirin's mechanism of action for preventing colorectal cancer (CRC) is still debated, and the optimal dose remains uncertain. We aimed to optimize the aspirin dose for cancer prevention in CRC patients through deep phenotyping using innovative biomarkers for aspirin's action. Methods: We conducted a Phase II, open-label clinical trial in 34 CRC patients of both sexes randomized to receive enteric-coated aspirin 100 mg/d, 100 mg/BID, or 300 mg/d for 3 ± 1 weeks. Biomarkers were evaluated in blood, urine, and colorectal biopsies at baseline and after dosing with aspirin. Novel biomarkers of aspirin action were assessed in platelets and colorectal tissues using liquid chromatography-mass spectrometry to quantify the extent of cyclooxygenase (COX)-1 and COX-2 acetylation at Serine 529 and Serine 516, respectively. Results: All aspirin doses caused comparable % acetylation of platelet COX-1 at Serine 529 associated with similar profound inhibition of platelet-dependent thromboxane (TX)A2 generation ex vivo (serum TXB2) and in vivo (urinary TXM). TXB2 was significantly reduced in CRC tissue by aspirin 300 mg/d and 100 mg/BID, associated with comparable % acetylation of COX-1. Differently, 100 mg/day showed a lower % acetylation of COX-1 in CRC tissue and no significant reduction of TXB2. Prostaglandin (PG)E2 biosynthesis in colorectal tumors and in vivo (urinary PGEM) remained unaffected by any dose of aspirin associated with the variable and low extent of COX-2 acetylation at Serine 516 in tumor tissue. Increased expression of tumor-promoting genes like VIM (vimentin) and TWIST1 (Twist Family BHLH Transcription Factor 1) vs. baseline was detected with 100 mg/d of aspirin but not with the other two higher doses. Conclusion: In CRC patients, aspirin 300 mg/d or 100 mg/BID had comparable antiplatelet effects to aspirin 100 mg/d, indicating similar inhibition of the platelet's contribution to cancer. However, aspirin 300 mg/d and 100 mg/BID can have additional anticancer effects by inhibiting cancerous tissue's TXA2 biosynthesis associated with a restraining impact on tumor-promoting gene expression. EUDRACT number: 2018-002101-65. Clinical Trial Registration: ClinicalTrials.gov, identifier NCT03957902.

Impact of the COVID-19 pandemic in colorectal cancer diagnosis and presentation / Impacto de la pandemia del COVID-19 en el diagnóstico y la presentación del cáncer colorrectal

Background and objective: The COVID-19 pandemic has been associated with a decrease in the colorectal cancer (CRC) incidence, due to the disruption of screening programmes and a downscaling of endoscopic activity. The endpoint of this study is to evaluate if the pandemic has led to a change in CRC diagnostic rate and presentation in our population. Methods: Multicenter retrospective study of all public hospitals of the Aragon region, attending a population of 1,329,391 inhabitants. We have analyzed all CRC cases detected and endoscopic units workload the year before the pandemic onset (1 March 2019–14 March 2020) and the first year of the COVID-19 pandemic (15 March 2020–28 February 2021). Results: The diagnosis of CRC cases dropped a 38.9% (888 pre-pandemic vs 542 pandemic cases). Also, there were 30.3% less colonoscopies performed (24,860 vs 17,337). During the pandemic, CRC cases were diagnosed in older patients (72.4±12.2 vs 71.2±12.1 years, p=0.021), and had more frequently severe complications at diagnosis (14.6% vs 10.4%, p=0.019). Moreover, most CRC cases were diagnosed in symptomatic patients (81.4%). No significant difference was found in CRC stage at diagnosis, although stage IV was more frequent (20.1% vs 16.1%). Most hospitals reported a lower workload of endoscopic activity. Conclusion: CRC diagnostic rate was lower after the onset of the pandemic. CRC was diagnosed in older patients and was more frequently associated with complications. After the onset of the pandemic, the endoscopic units did not reach the workload performed previously. (AU)

Introducción y objetivo: La pandemia del COVID-19 ha provocado una disminución en la incidencia de cáncer colorrectal (CCR) tras la suspensión de los programas de cribado y la reducción de la actividad endoscópica. El objetivo del estudio es evaluar si la pandemia se ha asociado a un cambio en la incidencia y presentación del CCR en nuestra población. Métodos: Estudio multicéntrico, retrospectivo de todos los hospitales públicos de Aragón, con 1.329.391 habitantes. Analizamos todos los CRC detectados y la carga laboral de las unidades de endoscopia del año prepandémico (1 marzo 2019 – 14 marzo 2020) y el primer año de la pandemia (15 marzo 2020 – 28 febrero 2021). Resultados: El diagnóstico de CRC descendió un 38,9% (888 casos prepandemia vs. 542 en pandemia). Se realizaron un 30,3% menos de colonoscopias (24.860 vs. 17.337). El CRC en pandemia se diagnosticó en pacientes de mayor edad (72,4±12,2 vs 71,2±12,1 años; p=0,021) y presentaron más complicaciones graves en el momento del diagnóstico (14,6 vs. 10,4%; p=0.019). La mayoría de los CRC se diagnosticaron en pacientes sintomáticos (81,4%). No hubo diferencias en el estadio al diagnóstico aunque el estadio iv fue más frecuente (20,1 vs. 16,1%). La mayoría de los hospitales reiniciaron la actividad endoscópica con una menor carga laboral. Conclusión: La tasa diagnóstica de CRC descendió tras el inicio de la pandemia, el CRC fue diagnosticado en pacientes mayores y se asoció con más complicaciones al diagnóstico. Tras el inicio de la pandemia, la mayoría de los hospitales reiniciaron su actividad con una menor carga laboral. (AU)

Fecal occult blood and calprotectin testing to prioritize primary care patients for colonoscopy referral: The advantage study.

BACKGROUND: Colonoscopy is the gold standard for colorectal cancer (CRC) diagnosis and screening, but endoscopy services are usually overburdened. This study aims to investigate the usefulness of fecal hemoglobin (fHb) and calprotectin (FC) for the identification of patients with high probability of CRC who need urgent referral. METHODS: In a multicenter prospective study, we enrolled symptomatic patients referred from primary care for colonoscopy. Prior to bowel preparation, fHb and FC quantitative tests were performed. The diagnostic performance was estimated for each biomarker/combination. We built a multivariable predictive model based on logistic regression, translated to a nomogram and a risk calculator to assist clinicians in the decision-making process. RESULTS: The study included 1224 patients, of whom 69 (5.6%) had CRC. At the fHb cut-offs of >0 and 10 µg/g, the negative predictive values for CRC were 98.8% (95% confidence interval 97.8%-99.3%) and 98.6% (95%CI 97.7%-99.1%), and the sensitivities were 85.5% (95%CI 75.0%-92.8%) and 79.7% (95%CI 68.3%-88.4%), respectively. When we added the cut-off of 150 µg/g of FC to both fHb thresholds, the sensitivity of fecal tests improved. In the multivariate logistic regression model, the concentration of fHb was an independent predictor for CRC; age and gender were also independently associated with CRC. CONCLUSIONS: fHb and FC are useful as part of a triage tool to identify those symptomatic patients with high probability of CRC. This can be easily applied by physicians to prioritize high-risk patients for urgent colonoscopy.

A Point-of-Care Faecal Test Combining Four Biomarkers Allows Avoidance of Normal Colonoscopies and Prioritizes Symptomatic Patients with a High Risk of Colorectal Cancer.

Most colonoscopies performed to evaluate gastrointestinal symptoms detect only non-relevant pathologies. We aimed to evaluate the diagnostic accuracy of a qualitative point-of-care (POC) test combining four biomarkers (haemoglobin, transferrin, calprotectin, and lactoferrin), a quantitative faecal immunochemical test (FIT) for haemoglobin, and a quantitative faecal calprotectin (FC) test in symptomatic patients prospectively recruited. Colorectal cancer (CRC), adenoma requiring surveillance, inflammatory bowel disease (IBD), microscopic colitis, and angiodysplasia were considered significant pathologies. A total of 571 patients were included. Significant pathology was diagnosed in 118 (20.7%), including 30 CRC cases (5.3%). The POC test yielded the highest negative predictive values: 94.8% for a significant pathology and 100% for CRC or IBD if the four markers turned negative (36.8% of the patients). Negative predictive values of FIT, FC, and its combination for diagnosis of a significant pathology were 88.4%, 87.6%, and 90.8%, respectively. Moreover, the positive predictive value using the POC test was 82.3% for significant pathology when all biomarkers tested positive (6% of the patients), with 70.6% of these patients diagnosed with CRC or IBD. The AUC of the POC test was 0.801 (95%CI 0.754-0.848) for the diagnosis of a significant pathology. Therefore, this POC faecal test allows the avoidance of unnecessary colonoscopies and prioritizes high risk symptomatic patients.

Impact of the COVID-19 pandemic in colorectal cancer diagnosis and presentation.

BACKGROUND AND OBJECTIVE: The COVID-19 pandemic has been associated with a decrease in the colorectal cancer (CRC) incidence, due to the disruption of screening programmes and a downscaling of endoscopic activity. The endpoint of this study is to evaluate if the pandemic has led to a change in CRC diagnostic rate and presentation in our population. METHODS: Multicenter retrospective study of all public hospitals of the Aragon region, attending a population of 1,329,391 inhabitants. We have analyzed all CRC cases detected and endoscopic units workload the year before the pandemic onset (1 March 2019-14 March 2020) and the first year of the COVID-19 pandemic (15 March 2020-28 February 2021). RESULTS: The diagnosis of CRC cases dropped a 38.9% (888 pre-pandemic vs 542 pandemic cases). Also, there were 30.3% less colonoscopies performed (24,860 vs 17,337). During the pandemic, CRC cases were diagnosed in older patients (72.4±12.2 vs 71.2±12.1 years, p=0.021), and had more frequently severe complications at diagnosis (14.6% vs 10.4%, p=0.019). Moreover, most CRC cases were diagnosed in symptomatic patients (81.4%). No significant difference was found in CRC stage at diagnosis, although stage IV was more frequent (20.1% vs 16.1%). Most hospitals reported a lower workload of endoscopic activity. CONCLUSION: CRC diagnostic rate was lower after the onset of the pandemic. CRC was diagnosed in older patients and was more frequently associated with complications. After the onset of the pandemic, the endoscopic units did not reach the workload performed previously.

The impact of COVID-19 pandemic in the diagnosis and management of colorectal cancer patients.

The novel coronavirus disease 2019 (COVID-19) pandemic has posed an unprecedented challenge to healthcare systems worldwide, causing downscaling of almost all other activities, especially in its early stages. Currently, the availability of vaccines along with the spread of new viral variants has modified the epidemiology of the disease, and the previous activity is being gradually resumed in most healthcare facilities. In this review, we have summarized the influence of the COVID-19 pandemic in the diagnosis and management of colorectal cancer (CRC) patients. Population-based screening with either colonoscopy or fecal occult blood tests has proven to reduce CRC incidence and mortality, so screening programs have been implemented in most western countries. However, during the first COVID-19 wave, most of these programs had to be disrupted temporarily. In this review, we have thoroughly analyzed the consequences of these disruptions of screening programs as well as of the forced delays in diagnostic and therapeutic services on CRC prognosis, although its exact impact cannot be exactly measured yet. In any way, strategies to minimize its effect, such as catch-up strategies expanding the colonoscopy capacity or using fecal occult blood concentration and other risk factors to prioritize patients, are urgently needed. The COVID-19 pandemic has also led to a change in CRC patient presentation, with an overall temporary decreased incidence due to postponed diagnoses, but with more patients presenting in need of an emergency admission or with symptoms. Finally, changes in treatment approaches in CRC patients have been reported during the pandemic, namely a drop in the proportion of laparoscopic surgeries or a rise in short-term radiotherapy courses. We have therefore aimed to summarize the available evidence to guide the healthcare professionals treating CRC patients to choose the best treatment options in the current pandemic situation.

Self-medication with analgesics reported by patients with ulcerative colitis: An anonymous survey / Automedicación con analgésicos en pacientes con colitis ulcerosa: encuesta anónima

Introduction: Analgesics are widely used, but evidence regarding whether their use increases the risk of inflammatory bowel disease (IBD) flares or complications is unclear. Therefore, self-medication with analgesics in IBD is usually not recommended. The aim of this study was to explore the prevalence of self-medication with analgesics in a cohort of ulcerative colitis (UC) patients and to identify reasons and factors associated with self-medication. Methods: This cross-sectional study included consecutive unselected adult patients with UC. Participants were asked to complete an anonymous web-based survey with multiple-choice questions and closed responses. No clinical data were collected. Results: A total of 546 patients (61.2% women, mean age 39.9 years) completed the survey. The prevalence of self-medication with analgesics was 49.8% (272/546). Paracetamol (45.2%) and metamizole (21.2%) were the most frequently used drugs; frequencies of self-medication were <5% for other analgesics (nonsteroidal anti-inflammatory drugs, opioids). The most frequent reasons for self-medication were the need for quick symptom relief and that it had been agreed with/prescribed by the treating physician. Multivariable analysis identified female sex (odds ratio [OR]=1.9), sick leave (OR=2.2), treatment with intravenous drugs (OR=2.9), and emergency room visit (OR=2.3) as variables associated with self-medication, whilst follow-up by a nurse was associated with less self-medication (OR=0.6). Conclusion: The frequency of self-medication with analgesics in UC patients is high and appears to be associated with variables suggesting worse disease control. Closer follow-up, including a specialized nurse, could decrease self-medication. Strategies to improve disease control, including close monitoring of symptoms such as pain, are needed.(AU)

Introducción: Los analgésicos son medicamentos ampliamente utilizados, pero las evidencias sobre si su uso aumenta el riesgo de brotes o complicaciones de la enfermedad inflamatoria intestinal (EII) no están claras; por lo tanto, en general, no se recomienda la automedicación con analgésicos en la EII. El objetivo de este estudio fue explorar la prevalencia de automedicación con analgésicos en una cohorte de pacientes con colitis ulcerosa (CU) e identificar los motivos y los factores asociados a la automedicación. Métodos: En este estudio transversal se incluyeron pacientes adultos con CU consecutivos y no seleccionados. Se pidió a los participantes que completasen una encuesta anónima por Internet con preguntas de elección múltiple y respuestas cerradas. No se recogieron datos clínicos. Resultados: Completaron la encuesta un total de 546 pacientes (61,2% mujeres; edad media 39,9 años). La prevalencia de automedicación con analgésicos fue del 49,8% (272/546). El paracetamol (45,2%) y metamizol (21,2%) fueron los fármacos utilizados con más frecuencia; la tasa de automedicación con otros analgésicos (antiinflamatorios no esteroideos, opioides) fue <5%. Los motivos más frecuentes para la automedicación fueron la necesidad de alivio sintomático rápido y que había sido acordado con/prescrito por el médico responsable del tratamiento. El análisis multivariante identificó el sexo femenino (odds ratio [OR]=1,9), la baja laboral (OR=2,2), el tratamiento con fármacos intravenosos (OR=2,9) y las visitas a urgencias (OR=2,3) como variables asociadas a la automedicación, mientras que el seguimiento por el personal de enfermería se asoció a menos automedicación (OR=0,6). Conclusión: La frecuencia de automedicación con analgésicos en pacientes con CU es alta y parece estar asociada a variables que sugieren peor control de la enfermedad. Un seguimiento más estrecho, incluyendo personal de enfermería especializado, podría disminuir la automedicación.(AU)

AINE, toxicidad gastrointestinal y enfermedad inflamatoria intestinal / NSAIDs, gastrointestinal toxicity and inflammatory bowel disease

Los antiinflamatorios no esteroideos (AINE) son uno de los grupos de fármacos más frecuentemente utilizados en la actualidad. Su uso implica riesgo de toxicidad gastrointestinal, que puede afectar tanto al tracto superior (úlcera péptica) como al inferior (gastroenteropatía por AINE).La toma de AINE se ha relacionado con un empeoramiento clínico en pacientes con enfermedad inflamatoria intestinal. En este artículo realizamos una revisión acerca de la toxicidad gastrointestinal alta y baja de los AINE, centrada especialmente en los riesgos y datos característicos de estos fármacos en pacientes con enfermedad inflamatoria intestinal y establecemos recomendaciones para su uso en la práctica clínica. Aunque la evidencia es limitada, pautas cortas a dosis bajas de AINE parecen seguras y los datos indican que los inhibidores selectivos de la COX-2 son la opción más segura. Se debe evitar su uso a largo plazo o a dosis altas, sobre todo en pacientes con inflamación activa.(AU)

Non-steroidal antiinflammatory drugs (NSAIDs) are currently one of the most widely used drugs. The use of NSAIDs is associated with gastrointestinal toxicity, affecting both upper gastrointestinal tract (peptic ulcer disease) and lower gastrointestinal tract (NSAID-induced enteropathy).NSAIDs use has been associated with an increased risk of clinical relapse in inflammatory bowel disease patients. In this article, we review the upper and lower gastrointestinal toxicity of NSAIDs, with a focus on the risks and specific data of these drugs in inflammatory bowel disease patients, giving recommendations for its appropriate use in the clinical practice. Although evidence is scarce, short-term use of NSAIDs appears to be safe, and the data available suggest that selective COX-2 inhibitors are the safer option. NSAIDs should be avoided as long-term treatment or with high doses, especially in patients with active inflammation.(AU)

Gastrointestinal and cardiovascular adverse events associated with NSAIDs.

INTRODUCTION: Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most prescribed pharmacological groups, especially in elderly patients. AREAS COVERED: The main GI and CV adverse events associated with NSAID use are reviewed. Risk factors and prophylactic strategies are also covered. EXPERT OPINION: COX-2 selective agents are safer to the GI tract but have a worst CV profile. On the contrary, naproxen seems safer for CV system, but it is one of the NSAIDs with higher GI toxicity. Co-therapy with aspirin reduces the GI benefits of COX-2 selective agents, whereas ibuprofen and naproxen may neglect the antiplatelet effect of aspirin. NSAIDs increase the risk of both upper and lower GI complications. Co-therapy with PPI reduces the risk of upper but not lower GI complications, and seems to induce dysbiosis in the small bowel, which may be implicated in the damage induced by NSAIDs. Celecoxib, a COX-2 selective agent, seems safer for both the upper and the lower GI tract. Prescription of type and dose of NSAIDs must be individualized based on the stratification of the CV and GI risk of patients.

Self-medication with analgesics reported by patients with ulcerative colitis: An anonymous survey.

INTRODUCTION: Analgesics are widely used, but evidence regarding whether their use increases the risk of inflammatory bowel disease (IBD) flares or complications is unclear. Therefore, self-medication with analgesics in IBD is usually not recommended. The aim of this study was to explore the prevalence of self-medication with analgesics in a cohort of ulcerative colitis (UC) patients and to identify reasons and factors associated with self-medication. METHODS: This cross-sectional study included consecutive unselected adult patients with UC. Participants were asked to complete an anonymous web-based survey with multiple-choice questions and closed responses. No clinical data were collected. RESULTS: A total of 546 patients (61.2% women, mean age 39.9 years) completed the survey. The prevalence of self-medication with analgesics was 49.8% (272/546). Paracetamol (45.2%) and metamizole (21.2%) were the most frequently used drugs; frequencies of self-medication were <5% for other analgesics (nonsteroidal anti-inflammatory drugs, opioids). The most frequent reasons for self-medication were the need for quick symptom relief and that it had been agreed with/prescribed by the treating physician. Multivariable analysis identified female sex (odds ratio [OR]=1.9), sick leave (OR=2.2), treatment with intravenous drugs (OR=2.9), and emergency room visit (OR=2.3) as variables associated with self-medication, whilst follow-up by a nurse was associated with less self-medication (OR=0.6). CONCLUSION: The frequency of self-medication with analgesics in UC patients is high and appears to be associated with variables suggesting worse disease control. Closer follow-up, including a specialized nurse, could decrease self-medication. Strategies to improve disease control, including close monitoring of symptoms such as pain, are needed.

NSAIDs, gastrointestinal toxicity and inflammatory bowel disease. / AINE, toxicidad gastrointestinal y enfermedad inflamatoria intestinal.

Non-steroidal antiinflammatory drugs (NSAIDs) are currently one of the most widely used drugs. The use of NSAIDs is associated with gastrointestinal toxicity, affecting both upper gastrointestinal tract (peptic ulcer disease) and lower gastrointestinal tract (NSAID-induced enteropathy). NSAIDs use has been associated with an increased risk of clinical relapse in inflammatory bowel disease patients. In this article, we review the upper and lower gastrointestinal toxicity of NSAIDs, with a focus on the risks and specific data of these drugs in inflammatory bowel disease patients, giving recommendations for its appropriate use in the clinical practice. Although evidence is scarce, short-term use of NSAIDs appears to be safe, and the data available suggest that selective COX-2 inhibitors are the safer option. NSAIDs should be avoided as long-term treatment or with high doses, especially in patients with active inflammation.

A Patient Self-Made Point-of-Care Fecal Test Improves Diagnostic Accuracy Compared with Fecal Calprotectin Alone in Inflammatory Bowel Disease Patients.

BACKGROUND: Monitoring inflammatory bowel disease patients may be challenging. Fecal calprotectin is one of the most performed tests. Other fecal biomarkers are less used in clinical practice. Rapid fecal tests that could be performed by patients may be a useful strategy to closely monitor disease activity. METHODS: We performed a prospective observational study including consecutive inflammatory bowel disease patients referred for colonoscopy in a single center. Certest FOB + Transferrin + Calprotectin + Lactoferrin® (Certest Biotec S.L, Zaragoza, Spain), a one-step point-of-care test which simultaneously detects these four biomarkers was performed. Endoscopic inflammatory activity was defined using the Mayo score (≥1) in ulcerative colitis, SES-CD (>3) and Rutgeerts scores (≥1) for Crohn's disease. RESULTS: Out of a total of 106 patients (56.5% female, mean age 51 years), 54 (50.9%) were diagnosed with ulcerative colitis and 52 (49.1%) with Crohn's disease. Endoscopic activity was detected in 42 patients (39.0%). Fecal calprotectin provided the best sensitivity (97.6%), with limited specificity (34.4%). Compared to calprotectin, the other 3 fecal biomarkers showed better specificity (87.5-92.1%) and lower sensitivity (45.2-59.5%). Patients with a negative result in all biomarkers (19/106-17.9%) had 100% (CI 95% 97.4-100) negative predictive value, while patients with the 4 biomarkers positive (13/106-12.3%) had 100% (CI 95% 96.1-100) positive predictive value of endoscopic inflammatory activity. AUROC of this 4 biomarker point-of-care test was 0.845 (95% CI 0.771-0.920), significantly higher than the AUROCs of any of the 4 biomarkers. CONCLUSIONS: This test may be a useful strategy to monitor inflammatory activity in clinical practice by excluding or prioritizing patients in need of a colonoscopy.