CTNND1 is involved in germline predisposition to early-onset gastric cancer by affecting cell-to-cell interactions.

BACKGROUND: CDH1 and CTNNA1 remain as the main genes for hereditary gastric cancer. However, they only explain a small fraction of gastric cancer cases with suspected inherited basis. In this study, we aimed to identify new hereditary genes for early-onset gastric cancer patients (EOGC; < 50 years old). METHODS: After germline exome sequencing in 20 EOGC patients and replication of relevant findings by gene-panel sequencing in an independent cohort of 152 patients, CTNND1 stood out as an interesting candidate gene, since its protein product (p120ctn) directly interacts with E-cadherin. We proceeded with functional characterization by generating two knockout CTNND1 cellular models by gene editing and introducing the detected genetic variants using a lentiviral delivery system. We assessed ß-catenin and E-cadherin levels, cell detachment, as well as E-cadherin localization and cell-to-cell interaction by spheroid modeling. RESULTS: Three CTNND1 germline variants [c.28_29delinsCT, p.(Ala10Leu); c.1105C > T, p.(Pro369Ser); c.1537A > G, p.(Asn513Asp)] were identified in our EOGC cohorts. Cells encoding CTNND1 variants displayed altered E-cadherin levels and intercellular interactions. In addition, the p.(Pro369Ser) variant, located in a key region in the E-cadherin/p120ctn binding domain, showed E-cadherin mislocalization. CONCLUSIONS: Defects in CTNND1 could be involved in germline predisposition to gastric cancer by altering E-cadherin and, consequently, cell-to-cell interactions. In the present study, CTNND1 germline variants explained 2% (3/172) of the cases, although further studies in larger external cohorts are needed.

Risk stratification and treatment of primary biliary cholangitis.

Primary biliary cholangitis is a chronic liver disorder characterized by progressive cholestasis that may evolve to liver cirrhosis. While ursodeoxycholic acid is the treatment of choice, around 30% of patients do not respond to this therapy. These patients have a poorer prognosis, hence should be identified early in order to be offered therapy options. Along these lines, improved understanding of the condition's pathophysiology has allowed the development of newer drugs, including obeticholic acid and fibrates. This review offers a perspective on risk stratification and treatment for these patients, from ursodeoxycholic acid to second-line treatments.

What is the real-life maintenance mesalazine dose in ulcerative colitis?

OBJECTIVE: To describe how mesalazine (MSZ) is used in our practice in ulcerative colitis (UC), at what dose, and the success rate (regarding adherence to therapy). METHODS: Observational, transversal study, including all patients with UC and with MSZ maintenance therapy seen from September 2014 to February 2015 at two IBD units in Spain. Treatment adherence was measured by the Morisky-Green scale. RESULTS: We included 203 patients (mean MSZ dose: 2.6 ± 1.0 g/d; median of treatment: 19.5 months [IQR: 8-48]). Doses < 2 g/d were used in 15.3% of cases, 2-2.9 g/d doses in 35.0%, 3-3.9 doses in 29.5%, and ≥ 4 g/d doses in the remaining 20.2%. A single daily dose was preferred in 51.2% of cases, two doses in 33.0% and three doses in 15.8%. A different MSZ brand had been previously used in 36.6% of patients. In 134 cases (66%), the maintenance dose had been increased during a flare-up, and in 49 (36.6% of cases) this higher dose had been kept for maintenance (dose ≥ 4 g/d in 36 patients). During the MSZ therapy, 14 patients (6.9%) suffered mild side effects (21.4% altered liver function tests). Therapy adherence was good in 81.8% of cases. CONCLUSIONS: Half of our UC patients take high MSZ doses (≥ 3 g/d) as maintenance therapy, with acceptable safety and good adherence. Half of all patients take a single daily dose, and one third needed a different commercial brand during therapy. Opting for a higher MSZ maintenance dose is a possible strategy for a satisfactory maintenance therapy.

Effect of the SARS-CoV-2 pandemic on colorectal cancer diagnosis and prognosis.

BACKGROUND AND STUDY AIMS: Our aim was to determine the impact of the SARS-CoV-2 pandemic on the diagnosis and prognosis of colorectal cancer (CRC). PATIENTS AND METHODS: This prospective cohort study included individuals diagnosed with CRC between March 13, 2019 and June 20, 2021 across 21 Spanish hospitals. Two time periods were compared: prepandemic (from March 13, 2019 to March 13, 2020) and pandemic (from March 14, 2020 to June 20, 2021, lockdown period and 1 year after lockdown). RESULTS: We observed a 46.9% decrease in the number of CRC diagnoses (95% confidence interval (CI): 45.1%-48.7%) during the lockdown and 29.7% decrease (95% CI: 28.1%-31.4%) in the year after the lockdown. The proportion of patients diagnosed at stage I significantly decreased during the pandemic (21.7% vs. 19.0%; p = 0.025). Centers that applied universal preprocedure SARS-CoV-2 PCR testing experienced a higher reduction in the number of colonoscopies performed during the pandemic post-lockdown (34.0% reduction; 95% CI: 33.6%-34.4% vs. 13.7; 95% CI: 13.4%-13.9%) and in the number of CRCs diagnosed (34.1% reduction; 95% CI: 31.4%-36.8% vs. 26.7%; 95% CI: 24.6%-28.8%). Curative treatment was received by 87.5% of patients diagnosed with rectal cancer prepandemic and 80.7% of patients during the pandemic post-lockdown period (p = 0.002). CONCLUSIONS: The COVID-19 pandemic has led to a decrease in the number of diagnosed CRC cases and in the proportion of stage I CRC. The reduction in the number of colonoscopies and CRC diagnoses was higher in centers that applied universal SARS-CoV-2 PCR screening before colonoscopy. In addition, the COVID-19 pandemic has affected curative treatment of rectal cancers.

Identification of Lynch Syndrome Carriers among Patients with Small Bowel Adenocarcinoma.

BACKGROUND: Small bowel adenocarcinoma (SBA) is a rare disease which can be associated with Lynch syndrome (LS). LS tumors are characterized by the presence of microsatellite instability (MSI) and/or the loss of mismatch repair (MMR) protein expression. In SBA, the frequency of MMR deficient (MMRd) tumors varies from 5% to 35%. This study aims to describe the prevalence of LS carriers among patients with MMRd small bowel adenocarcinomas. METHODS: A multicenter retrospective study with identification and MMR testing of all consecutive SBA between 2004 and 2020 in a multicenter Spanish study. Demographical data, tumor characteristics, follow-up and survival information were collected. Germline testing was driven by identification of MMRd tumors. RESULTS: A total of 94 individuals diagnosed with SBA were recruited. We observed 20 (21.3%) MMRd tumors. In 9/15 (60%) patients with MMRd tumors, a pathogenic variant was identified (three MLH1, four MSH2, one MSH6 and one PMS2). Accordingly, the prevalence of LS among all SBA cases was 10.1%. CONCLUSIONS: More than one-fifth of SBA display MMRd and in more than a half is due to LS. Our data supports the implementation of universal MMR tumor testing among SBA for the identification of LS families.

Current allocation policy is favorable for patients with hepatocellular carcinoma waiting for liver transplantation.

BACKGROUND: Patients with hepatocellular carcinoma (HCC) are a growing population of the transplantation waiting list (WL) for orthotopic liver transplantation (OLT). There is no consensus to prioritize these patients while on the WL. AIMS: To assess whether patients with HCC were more prioritized than non-HCC patients based on their WL survival as primary outcome. METHODS: Restrospective cohort study including patients listed for elective OLT from January 2013 to January 2016. RESULTS: 165 patients with cirrhosis were listed for OLT: 64 in the HCC group (38.78%) and 101 in the non-HCC group (61.22%). Outcomes (HCC vs. non-HCC) were: OLT in 75.51% vs. 64.37%; death or dropout due to worsening in 20.41% vs. 27.59%, and delisting because of improvement in 4.08% vs. 8.05%. HCC patients had a significantly higher WL survival rate (HR = 0.45; 95% CI: 0.21-0.96); lower MELD score at transplantation (21 [20-24] vs. 24 [20-30]; p = 0.021); higher delta-MELD - the difference between MELD at transplantation and MELD at listing time - (3 [2-6] vs. 0 [0-5]; p = 0.024) and longer waiting time until OLT (143 [70-233] vs. 67 [21-164] days; p = 0.008). CONCLUSION: Despite having to wait longer, patients with HCC showed higher WL survival than non-HCC patients.

What is the real-life maintenance mesalazine dose in ulcerative colitis?

Objective: To describe how mesalazine (MSZ) is used in our practice in ulcerative colitis (UC), at what dose, and the success rate (regarding adherence to therapy). Methods: Observational, transversal study, including all patients with UC and with MSZ maintenance therapy seen from September 2014 to February 2015 at two IBD units in Spain. Treatment adherence was measured by the Morisky-Green scale. Results: We included 203 patients (mean MSZ dose: 2.6 ± 1.0 g/d; median of treatment: 19.5 months [IQR: 8-48]). Doses < 2 g/d were used in 15.3% of cases, 2-2.9 g/d doses in 35.0%, 3-3.9 doses in 29.5%, and ≥ 4 g/d doses in the remaining 20.2%. A single daily dose was preferred in 51.2% of cases, two doses in 33.0% and three doses in 15.8%. A different MSZ brand had been previously used in 36.6% of patients. In 134 cases (66%), the maintenance dose had been increased during a flare-up, and in 49 (36.6% of cases) this higher dose had been kept for maintenance (dose ≥ 4 g/d in 36 patients). During the MSZ therapy, 14 patients (6.9%) suffered mild side effects (21.4% altered liver function tests). Therapy adherence was good in 81.8% of cases. Conclusions: Half of our UC patients take high MSZ doses (≥ 3 g/d) as maintenance therapy, with acceptable safety and good adherence. Half of all patients take a single daily dose, and one third needed a different commercial brand during therapy. Opting for a higher MSZ maintenance dose is a possible strategy for a satisfactory maintenance therapy (AU)

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Efectos adversos de los inhibidores de la bomba de protones: revisión de evidencias y posicionamiento de la Sociedad Española de Patología Digestiva / Proton-pump inhibitors adverse effects: a review of the evidence and position statement by the Sociedad Española de Patología Digestiva

Introducción: en los últimos años, numerosos artículos relacionan el uso de los inhibidores de la bomba de protones (IBP) con posibles efectos adversos serios que han creado cierta alarma social. Objetivo: el objetivo de este trabajo es revisar la literatura de cara a elaborar un documento institucional de posicionamiento de la Sociedad Española de Patología Digestiva (SEPD) sobre la seguridad de los IBP a largo plazo. Material y métodos: se ha realizado una revisión exhaustiva de la literatura orientada a la presentación de conclusiones tras una valoración crítica sobre los siguientes temas: a) indicaciones actuales de los IBP; b) déficit de vitamina B12 y alteraciones neurológicas; c) déficit de magnesio; d) fracturas óseas; e) infecciones entéricas y neumonías; f) interacción con los derivados de las tienopiridinas; y e) complicaciones en pacientes cirróticos. Resultados: las indicaciones actuales de los IBP no han variado en los últimos años y están bien establecidas. No se recomienda la realización de un cribado generalizado de los niveles de vitamina B12 en todos los pacientes tratados de forma crónica con estos medicamentos; sin embargo, sí parece necesario controlar los niveles de magnesio al inicio del tratamiento y monitorizarlos en pacientes con toma de otros fármacos que puedan inducir hipomagnesemia. Existe mayor riesgo de fracturas óseas, aunque no se puede concluir que esta asociación sea causal. La asociación IBP e infección por Clostridium difficile es débil o moderada y el riesgo de neumonía es bajo. En pacientes con riesgo cardiovascular y tratados con derivados de las tienopiridinas -dada la ausencia de evidencias definitivas en relación a posibles interacciones medicamentosasparece que lo prudente sea sopesar adecuadamente los riesgos gastrointestinales y los riesgos cardiovasculares de cada paciente; cuando el riesgo gastrointestinal sea moderado/alto, debemos ejercer una acción terapéutica de prevención efectiva utilizando un IBP. En cirróticos descompensados deben ser indicados con cautela. Conclusiones: los IBP son fármacos seguros y los beneficios de su empleo, tanto a corto como a largo plazo superan los posibles efectos secundarios, siempre que la indicación, dosis y duración sean las adecuadas (AU)

Introduction: In the last few years a significant number of papers have related the use of proton-pump inhibitors (PPIs) to potential serious adverse effects that have resulted in social unrest. Objective: The goal of this paper was to provide a literature review for the development of an institutional position statement by Sociedad Española de Patología Digestiva (SEPD) regarding the safety of long-term PPI use. Material and methods: A comprehensive review of the literature was performed to draw conclusions based on a critical assessment of the following: a) current PPI indications; b) vitamin B12 deficiency and neurological disorders; c) magnesium deficiency; d) bone fractures; e) enteric infection and pneumonia; f) interactions with thienopyridine derivatives; e) complications in cirrhotic patients. Results: Current PPI indications have remained unchanged for years now, and are well established. A general screening of vitamin B12 levels is not recommended for all patients on a PPI; however, it does seem necessary that magnesium levels be measured at therapy onset, and then monitored in subjects on other drugs that may induce hypomagnesemia. A higher risk for bone fractures is present, even though causality cannot be concluded for this association. The association between PPIs and infection with Clostridium difficile is mild to moderate, and the risk for pneumonia is low. In patients with cardiovascular risk receiving thienopyridines derivatives it is prudent to adequately consider gastrointestinal and cardiovascular risks, given the absence of definitive evidence regardin potential drug-drug interactions; if gastrointestinal risk is found to be moderate or high, effective prevention should be in place with a PPI. PPIs should be cautiously indicated in patients with decompensated cirrhosis. Conclusions: PPIs are safe drugs whose benefits outweigh their potential side effects both short-term and long-term, provided their indication, dosage, and duration are appropriate (AU)

Estratificación del riesgo y tratamiento de la colangitis biliar primaria / Risk stratification and treatment of primary biliary cholangitis

La colangitis biliar primaria es una enfermedad hepática crónica caracterizada por colestasis progresiva que puede evolucionar hacia cirrosis hepática. El tratamiento de elección es el ácido ursodesoxicólico, aunque en torno al 30% de los pacientes no responde. Estos pacientes presentan un peor pronóstico, por lo que deben ser detectados precozmente para ofrecerles alternativas terapéuticas. En esta línea, el mejor conocimiento de la fisiopatología de la enfermedad ha permitido el desarrollo de nuevos fármacos, como el ácido obeticólico y los fibratos. Esta revisión ofrece una perspectiva sobre la estratificación del riesgo de los pacientes y del tratamiento de esta enfermedad, desde el ácido ursodesoxicólico a las terapias de segunda línea

Primary biliary cholangitis is a chronic liver disorder characterized by progressive cholestasis that may evolve to liver cirrhosis. While ursodeoxycholic acid is the treatment of choice, around 30% of patients do not respond to this therapy. These patients have a poorer prognosis, hence should be identified early in order to be offered therapy options. Along these lines, improved understanding of the condition's pathophysiology has allowed the development of newer drugs, including obeticholic acid and fibrates. This review offers a perspective on risk stratification and treatment for these patients, from ursodeoxycholic acid to second-line treatments

The ability of selected cladoceran species to utilize domestic wastewaters in Mexico City.

The population growth patterns of four cladocerans, viz. Alona rectangula, Ceriodaphnia dubia, Moina macrocopa and Daphnia pulex on wastewaters from a treatment plant at Iztacalco, Mexico City were analyzed in this study. Crude wastewater (tank A) did not support A. rectangula and all animals in the replicates died after 5 days. A. rectangula with partially treated wastewater (tank B) showed growth curves similar to controls where algal density was 1 x 10(6) cells ml(-1). With wastewater from tank C (last stage before treatment with purifying agents such as chlorine), the populations maintained a low density (7 ind. ml(-1)). In wastewaters from tanks A and B, C. dubia showed no positive population growth, but in water from tank C, they maintained a low density (2 ind. ml(-1)). D. pulex showed no positive growth in all replicates involving wastewater. Only in controls (diet of algae Chlorella), the population density increased with time. M. macrocopa showed higher population growth in crude wastewaters than controls. Partially treated wastewater from tank B also resulted in a greater population growth than in the controls. However, when wastewater from the tank C was used, the population declined after day 12. Under comparable conditions, A. rectangula reached much higher peak abundances (55 ind. ml(-1)) than the rest of the cladoceran species. The rates of population growth (r) of the tested cladoceran species followed trends similar to the peak population densities. A. rectangula had the highest growth rates (0.25 per day) in controls and from the wastewater from tank B. The r-values were negative for A. rectangula and C. dubia in crude wastewater. For M. macrocopa the r-values were higher (0.19) in crude wastewater than in algae (0.15). However, r-values of M. macrocopa became negative when cultured in treated wastewater from tank C.