Integrative immune transcriptomic classification improves patient selection for precision immunotherapy in advanced gastro-oesophageal adenocarcinoma.

BACKGROUND: Advanced gastro-oesophageal cancer (GEA) treatment has been improved by the introduction of immune checkpoint inhibitors (CPIs), yet identifying predictive biomarkers remains a priority, particularly in patients with a combined positive score (CPS) < 5, where the benefit is less clear. Our study assesses certain immune microenvironment features related to sensitivity or resistance to CPIs with the aim of implementing a personalised approach across CPS < 5 GEA. DESIGN: Through integrative transcriptomic and clinicopathological analyses, we studied in both a retrospective and a prospective cohort, the immune tumour microenvironment features. We analysed the cell types composing the immune infiltrate highlighting their functional activity. RESULTS: This integrative study allowed the identification of four different groups across our patients. Among them, we identified a cluster whose tumours expressed the most gene signatures related to immunomodulatory pathways and immunotherapy response. These tumours presented an enriched immune infiltrate showing high immune function activity that could potentially achieve the best benefit from CPIs. Finally, our findings were proven in an external CPI-exposed population, where the use of our transcriptomic results combined with CPS helped better identify those patients who could benefit from immunotherapy than using CPS alone (p = 0.043). CONCLUSIONS: This transcriptomic classification could improve precision immunotherapy for GEA.

The characteristics of the stricture, but not the ongoing treatment, could influence the outcome of endoscopic dilation in recurrent Crohn's disease / Las características de la estenosis, pero no el tratamiento, podrían influir en el resultado de la dilatación endoscópica en la enfermedad de Crohn recurrente

Aim: Stricture is one of the main complications of Crohn's disease (CD). Among the main conservative therapeutic alternatives, endoscopic balloon dilation (EBD) of the strictures stands out, which can improve the symptoms and delay or even avoid the need for more surgeries. The main aim of this study was to evaluate the efficacy of the EBD in CD patients with post-surgical anastomotic strictures from a previous surgery. Patients and methods: An observational study of a cohort of 32 patients with CD who underwent EBD due to uncomplicated strictures at a tertiary hospital, since 2009. Demographic, clinical and disease variables, medical treatments and previous surgeries and types, analytical variables at the time of dilation, number of dilations, complications and need for subsequent surgery were collected by searching data in clinical records. Results: Thirty-two patients were included, performing a total of 63 endoscopic dilations. A technical success of 63.5%, a therapeutic success by dilation of 58.75% and a therapeutic success per patient of 62.5% were achieved. Regarding complications, the percentage of post-dilation adverse events was 3.2% and post-dilation incidents were 4.8%. Thirty EBD did not need any medical treatment modification, 9 EBD remained untreated and 12 EBD required further surgery. The length of the strictures, but not the ongoing treatment, was the only statistically significant factor of therapeutic success by dilation and per patient. Conclusions: EBD seems a safe technique in short post-surgical strictures, can avoid the need for new surgery and prevents unnecessary immunosuppression in patients with CD anastomotic strictures.(AU)

Objetivo: La estenosis es una de las principales complicaciones de la enfermedad de Crohn (EC). La dilatación endoscópica con balón (DEB) es una de las principales alternativas terapéuticas para mejorar los síntomas y retrasar o evitar nuevas cirugías. El objetivo principal fue evaluar la eficacia de la DEB en pacientes con EC y estenosis anastomótica posquirúrgica. Pacientes y métodos: Estudio observacional de una cohorte de 32 pacientes con EC tratados con DEB por estenosis no complicadas en un hospital terciario, desde 2009. Se recogieron variables demográficas, clínicas y de la enfermedad, tratamientos médicos y cirugías previas, variables analíticas en el momento de la dilatación, número de dilataciones, complicaciones y necesidad de cirugía posterior mediante la búsqueda de datos en las historias clínicas. Resultados: Se incluyó a 32 pacientes, con un total de 63 dilataciones endoscópicas. Se obtuvo un éxito técnico del 63,5%, un éxito terapéutico por dilatación del 58,75% y un éxito terapéutico por paciente del 62,5%. En cuanto a las complicaciones, el porcentaje de eventos adversos fue del 3,17% y de incidentes del 4,8%. No necesitaron ninguna modificación del tratamiento médico 30 DEB, 9 permanecieron sin tratamiento y 12 requirieron una nueva cirugía. La longitud de la estenosis, pero no el tratamiento en curso, fue el único factor estadísticamente significativo del éxito terapéutico por dilatación y por paciente. Conclusiones: La DEB parece una técnica segura en las estenosis posquirúrgicas cortas, ya que podría evitar nuevas cirugías y evitar la inmunosupresión innecesaria en pacientes con estenosis anastomóticas de EC.(AU)

The characteristics of the stricture, but not the ongoing treatment, could influence the outcome of endoscopic dilation in recurrent Crohn's disease.

AIM: Stricture is one of the main complications of Crohn's disease (CD). Among the main conservative therapeutic alternatives, endoscopic balloon dilation (EBD) of the strictures stands out, which can improve the symptoms and delay or even avoid the need for more surgeries. The main aim of this study was to evaluate the efficacy of the EBD in CD patients with post-surgical anastomotic strictures from a previous surgery. PATIENTS AND METHODS: An observational study of a cohort of 32 patients with CD who underwent EBD due to uncomplicated strictures at a tertiary hospital, since 2009. Demographic, clinical and disease variables, medical treatments and previous surgeries and types, analytical variables at the time of dilation, number of dilations, complications and need for subsequent surgery were collected by searching data in clinical records. RESULTS: Thirty-two patients were included, performing a total of 63 endoscopic dilations. A technical success of 63.5%, a therapeutic success by dilation of 58.75% and a therapeutic success per patient of 62.5% were achieved. Regarding complications, the percentage of post-dilation adverse events was 3.2% and post-dilation incidents were 4.8%. Thirty EBD did not need any medical treatment modification, 9 EBD remained untreated and 12 EBD required further surgery. The length of the strictures, but not the ongoing treatment, was the only statistically significant factor of therapeutic success by dilation and per patient. CONCLUSIONS: EBD seems a safe technique in short post-surgical strictures, can avoid the need for new surgery and prevents unnecessary immunosuppression in patients with CD anastomotic strictures.

Evaluation of the optical criteria for sessile serrated lesions of the colon: A prospective study on a colorectal cancer screening population.

Background and study aims We aimed to describe the presence and combination of Hazewinkel's optical diagnosis (OD) criteria for sessile serrated lesions (SSL), determining which lesion characteristics increase the probability of a correct OD, with a focus on diminutive lesions. Patients and methods This was a prospective study describing the presence of Hazewinkel's OD criteria for SSL in lesions found in consecutive CRC screening colonoscopies. The presence of each OD criterion and their diagnostic combinations in SSL, related to the lesion's NBI International Colorectal Endoscopic (NICE) classification category, size, and location, were described. The presence of two or more optical criteria was considered diagnostic of SSL. The OD was compared to pathology as the gold standard. Results Seventy-nine SSLs (5.6 %) were diagnosed. Cloud-like appearance was the most prevalent OD criterion (35, 44.3 %). OD criteria were more frequently identified in NICE type 1, ≥ 10 mm, and proximal lesions. Only 26 SLLs fulfilled the OD criteria (sensitivity 32.9 %, 95 % CI 29.1 %-36.7 %). The sensitivity for diminutive SSL was 14.7 %, (95 % CI 11.9 %-17.6 %). Eighty-five lesions were optically diagnosed as SSL. However, only in 26 SSL was this the definitive diagnosis (positive predictive value 30.6 %, 95 % CI 26.9 %-34.3 %). Size > 5 mm and proximal location increased the probability of a correct diagnosis. The overall accuracy of the optical criteria was 92.0 % (95 % CI, 89.8 %-94.2 %). Conclusions The Hazewinkel's optical criteria are not reliable for a positive diagnosis of SSL, particularly for diminutive lesions.

Periendoscopic management of antiplatelet therapy: Prospective evaluation of adherence to guidelines / Manejo perioendoscópico del tratamiento antiagregante plaquetario: evaluación prospectiva del cumplimiento de las guías clínicas

Introducción: Adherence to guidelines on the periendoscopic management of antiplatelet therapy (APT) has not been analyzed in detail. Our aim was to assess adherence to guidelines in patients referred to our Endoscopy Unit on a case-by-case basis, describing in detail the detected deviations and identifying areas of improvement. Patients and methods: Cross-sectional study of outpatients consecutively scheduled for an unsedated upper or lower gastrointestinal endoscopy between January and June 2015. Patients on anticoagulant therapy were excluded. Results: 675 patients were evaluated, including 91 (13.5%) patients on APT [upper GI endoscopy 25 (27.5%), lower GI endoscopy 66 (72.5%)]. Contrary to the clinical guidelines, aspirin was discontinued in 25 of the 77 patients previously prescribed the drug (32.5%) but this modification was patient's own decision in 11 cases. Most of the apparent deviations in the management of clopidogrel and dual antiplatelet therapy (DAPT) were not true non-adherence cases. The Primary Care physician modified an APT prescribed by another physician in 8 of 9 cases (88.9%), always in cases with aspirin. No relationship was found between the endoscopic procedure's predicted risk of bleeding or the patient's thrombotic risk and modification of therapy. Discussion: In many patients, the peri-procedural management of APT goes against current guidelines, but some of these inconsistencies cannot be considered true deviations from practice. Identified areas for improvement are increasing patient awareness about APT, disseminating the guidelines in Primary Care, and underscoring the significance of thrombotic risk related to APT withdrawal

Introducción: El cumplimiento de las guías clínicas sobre el manejo periendoscópico del tratamiento antiagregante plaquetario (TAP) no se ha analizado con detalle. Nuestro objetivo fue analizar caso por caso el cumplimiento de las guías en los pacientes que acuden a nuestra Unidad de Endoscopia, describiendo con detalle las desviaciones detectadas e identificando áreas de mejora. Pacientes y métodos: Estudio transversal sobre pacientes consecutivos programados para gastroscopia o colonoscopia realizadas sin sedación entre enero y junio de 2015. Se excluyeron los pacientes en tratamiento anticoagulante. Resultados: Se evaluaron 675 pacientes de los que se incluyeron 91 (13,5%) por estar en tratamiento con antiagregante plaquetario (gastroscopias 25 [27,5%], colonoscopias 66 [72,5%]). La aspirina se interrumpió contrariamente a las guías clínicas en 25 de los 77 pacientes que la llevaban (32,5%), pero esta modificación fue una decisión del propio paciente en 11 casos. Muchas de las aparentes desviaciones en el manejo del clopidogrel y del tratamiento antiagregante plaquetario doble (TAPD) no eran verdaderos casos de no cumplimiento. El médico de Atención Primaria modificó el TAP prescrito por otro especialista en 8 de 9 casos (88,9%), siempre en casos de aspirina. No se encontró relación entre el riesgo de sangrado del procedimiento endoscópico o el riesgo de trombosis del paciente y la modificación del tratamiento. Discusión: En una proporción significativa de pacientes el manejo periprocedimiento del TAP va en contra de las guías clínicas, pero algunas de estas desviaciones no pueden considerarse verdaderos incumplimientos. Áreas de mejora son aumentar la información al paciente sobre el TAP, extender la diseminación de las guías a atención primaria y resaltar la importancia del riesgo trombótico relacionado con la suspensión del TAP

Periendoscopic management of antiplatelet therapy: Prospective evaluation of adherence to guidelines.

INTRODUCCIóN: Adherence to guidelines on the periendoscopic management of antiplatelet therapy (APT) has not been analyzed in detail. Our aim was to assess adherence to guidelines in patients referred to our Endoscopy Unit on a case-by-case basis, describing in detail the detected deviations and identifying areas of improvement. PATIENTS AND METHODS: Cross-sectional study of outpatients consecutively scheduled for an unsedated upper or lower gastrointestinal endoscopy between January and June 2015. Patients on anticoagulant therapy were excluded. RESULTS: 675 patients were evaluated, including 91 (13.5%) patients on APT [upper GI endoscopy 25 (27.5%), lower GI endoscopy 66 (72.5%)]. Contrary to the clinical guidelines, aspirin was discontinued in 25 of the 77 patients previously prescribed the drug (32.5%) but this modification was patient's own decision in 11 cases. Most of the apparent deviations in the management of clopidogrel and dual antiplatelet therapy (DAPT) were not true non-adherence cases. The Primary Care physician modified an APT prescribed by another physician in 8 of 9 cases (88.9%), always in cases with aspirin. No relationship was found between the endoscopic procedure's predicted risk of bleeding or the patient's thrombotic risk and modification of therapy. DISCUSSION: In many patients, the peri-procedural management of APT goes against current guidelines, but some of these inconsistencies cannot be considered true deviations from practice. Identified areas for improvement are increasing patient awareness about APT, disseminating the guidelines in Primary Care, and underscoring the significance of thrombotic risk related to APT withdrawal.

A long-term prospective study of the efficacy and safety of endoscopic septotomy using the LigaSure(R) system for the treatment of Zenker's diverticulum

Background and objectives: endoscopic septotomy of the cricopharyngeal muscle (ESCM) is a technique used for the treatment of Zenker's diverticulum (ZD). The experience with computerized vascular sealing systems (LigaSure(R) type) is limited. The objective of this study was to evaluate the efficacy and safety of ESCM using LigaSure(R). Methods: this was a long-term prospective study of 18 patients with ZD, who were referred to our hospital due to ESCM between 2010 and 2016. The severity of the symptoms was determined using the Dakkak-Bennett validated scale for dysphagia and the rest with numerical scales. The rates of relapse and retreatment were evaluated. Results: ESCM with LigaSure(R) was performed in 17 cases, one case was excluded due to technical difficulties. The median age was 72 years and regurgitation, dysphagia and respiratory symptoms were found in 100%, 89% and 56% of cases, respectively. The median size of the diverticulum was 28 mm (20-60 mm). The median time of the procedure was 35 minutes (25-45 minutes). There were four complications, two hemorrhages and two perforations. The median follow-up was 13 months (range: 12-82 months). Clinical improvements were observed for all symptoms and were maintained 12 months after treatment (p < 0.05). There was no relapse during follow-up in 13 patients. A complete section was not achieved and clinical relapse occurred after a median time of seven months that required retreatment in the remaining patients. Conclusions: ESCM with LigaSure(R) may be a safe and effective technique in long-term follow-up situations, with low rates of relapse

No disponible

Non-guided self-learning program for high-proficiency optical diagnosis of diminutive and small colorectal lesions: A single-endoscopist pilot study.

BACKGROUND: The implementation of optical diagnosis (OD) of diminutive colorectal lesions in clinical practice has been hampered by differences in performance between community and academic settings. One possible cause is the lack of a standardized learning tool. Since the factors related to better learning are not well described, strong evidence upon which a consistent learning tool could be designed is lacking. We hypothesized that a self-designed learning program may be enough to achieve competency in OD of diminutive lesions of the colon. AIM: To assess the accuracy of OD of diminutive lesions in real colonoscopies after application of a self-administered learning program. METHODS: This was a single-endoscopist prospective pilot study, in which an experienced endoscopist followed a self-designed, self-administered learning program in OD of colorectal lesions. An assessment phase divided in two halves with a 6-mo period in between without performance of OD was developed in a population-based colorectal cancer screening program. The accomplishment of the Preservation and Incorporation of Valuable Endoscopic Innovations criteria and performance measures were calculated overall and in the two halves of the assessment phase, assessing their response to the 6-mo stopping period. The evolution of performance through blocks of 50 lesions was also assessed. RESULTS: Overall, 152 patients and 522 lesions (≤ 5 mm: 399, and 6-9 mm: 123) were included. The negative predictive value for the OD of adenoma in rectosigmoid lesions diagnosed with high confidence was 91.7% [95% confidence interval (CI): 87.3-96.6]. The proportion of agreement on surveillance interval between OD and pathological diagnosis was higher than 95%. Overall accuracy for diminutive lesions diagnosed with high confidence was 89.5% (95%CI: 86.3-92.7). The overall accuracy of OD was similar in the two halves of the assessment phase [90.1 (95%CI: 85.6-94.7) vs 88.2 (95%CI: 87.9-95.9)]. All the other performance parameters were also equivalent, except for specificity. Specificity, negative predictive value and accuracy were the parameters most affected by the stopping period between the two halves. Upon analyzing trends on blocks of 50 lesions, an improvement on sensitivity (P = 0.02) was detected only in the first half and an improvement on accuracy (P = 0.01) was detected only in the second half. CONCLUSION: A self-administered learning program is sufficient to achieve expert-level OD. To maintain performance, continuous practice is needed, with a refresher course following any long non-practice period.

A long-term prospective study of the efficacy and safety of endoscopic septotomy using the LigaSure® system for the treatment of Zenker's diverticulum.

BACKGROUND AND OBJECTIVES: endoscopic septotomy of the cricopharyngeal muscle (ESCM) is a technique used for the treatment of Zenker's diverticulum (ZD). The experience with computerized vascular sealing systems (LigaSure® type) is limited. The objective of this study was to evaluate the efficacy and safety of ESCM using LigaSure®. METHODS: this was a long-term prospective study of 18 patients with ZD, who were referred to our hospital due to ESCM between 2010 and 2016. The severity of the symptoms was determined using the Dakkak-Bennett validated scale for dysphagia and the rest with numerical scales. The rates of relapse and retreatment were evaluated. RESULTS: ESCM with LigaSure® was performed in 17 cases, one case was excluded due to technical difficulties. The median age was 72 years and regurgitation, dysphagia and respiratory symptoms were found in 100%, 89% and 56% of cases, respectively. The median size of the diverticulum was 28 mm (20-60 mm). The median time of the procedure was 35 minutes (25-45 minutes). There were four complications, two hemorrhages and two perforations. The median follow-up was 13 months (range: 12-82 months). Clinical improvements were observed for all symptoms and were maintained 12 months after treatment (p < 0.05). There was no relapse during follow-up in 13 patients. A complete section was not achieved and clinical relapse occurred after a median time of seven months that required retreatment in the remaining patients. CONCLUSIONS: ESCM with LigaSure® may be a safe and effective technique in long-term follow-up situations, with low rates of relapse.

Unravelling the lipocalin 2 interaction with aptamers: May rolling circle amplification improve their functional affinity?

Cancer diagnosis based on serum biomarkers requires receptors of extreme sensitivity and selectivity. Tunability of aptamer selection makes them ideal for that challenge. However, aptamer characterization is a time-consuming task, not always thoroughly addressed, leading to suboptimal aptamer performance. In this work, we report on the affinity characterization and potential usage of two aptamers against a candidate cancer biomarker, the neutrophil gelatinase-associated lipocalin (NGAL). Electrochemical sandwich assays on Au electrodes and SPR experiments showed a restricted capture ability of one of the aptamers (LCN2-4) and a small detectability of the other (LCN2-2). Interestingly, a truncated version of the signaling aptamer LCN2-2 selectively binds to NGAL covalently linked to magnetic beads due to high local protein concentration. The functional affinity of this aptamer is enhanced by three-orders of magnitude using rolling circle amplification (RCA), completed in only 15 min, followed by hybridization with short complementary fluorescein-tag probes, enzyme labeling and chronoamperometric measurement. Microscale thermophoresis experiments show a poor affinity for the protein in solution, which urges the importance of a full and in-depth characterization of aptamers to be used as diagnostic reagents.

Breast milk microRNAs harsh journey towards potential effects in infant development and maturation. Lipid encapsulation can help.

The possibility that diet-derived miRNAs survive the gastrointestinal tract and exert biological effects in target cells is triggering considerable research in the potential abilities of alimentary preventive and therapeutic approaches. Many validation attempts have been carried out and investigators disagree on several issues. The barriers exogenous RNAs must surpass are harsh and adequate copies must reach target cells for biological actions to be carried out. This prospect opened a window for previously unlikely scenarios concerning exogenous non-coding RNAs, such as a potential role for breast milk microRNAs in infants' development and maturation. This review is focused on the thorny path breast milk miRNAs face towards confirmation as relevant role players in infants' development and maturation, taking into consideration the research carried out so far on the uptake, gastrointestinal barriers and potential biological effects of diet-derived miRNAs. We also discuss the future pharmacological and pharma-nutritional consequences of appropriate miRNAs research.

Auditoría clínica de la administración de fármacos en una residencia de personas mayores enfermas de Alzheimer y otras demencias neurodegenerativas / Clinical audit regarding the administration of drugs in a residence for elderly people with Alzheimer’s disease and other neurodegenerative dementias

El equipo de enfermería de la Residencia El Sol observó cómo la administración de fármacos a los residentes conllevaba ciertos riesgos inherentes a la demencia. A partir de este hecho nos planteamos realizar una auditoría clínica para establecer qué tipo de incidencias se producía y determinar qué medidas tomar para minimizarlas. El estudio ha durado 12 meses y ha servido para identificar a los residentes con mayor riesgo, las incidencias de mayor frecuencia y buscar estrategias desde el equipo de enfermería que sean eficaces en la reducción del número de incidencias con la colaboración del resto del personal de la residencia

The Nursing Staff at the Residencia El Sol noticed there; were significant risks associated to the administration of; drugs to the residents given their condition of dementia; sufferers. This was the starting point for a Clinical Audit whose aims are to determine what kind of incident; take place whilst administering medication and what; measures can be implemented in order to minimize their; incidence. The study lasted 12 months and has served different purposes such as identifying the residents at a highest risk, determining the most frequent incidents and helping the Nursing Team develop startegies with a view to reduce the number of those incidents in close collaboration with the rest of the staff at the Residencia El Sol

Co-aggregation of enzymes and polyethyleneimine: a simple method to prepare stable and immobilized derivatives of glutaryl acylase.

We have developed a novel methodology that allowed the preparation of cross-linked enzyme aggregates (CLEAs) of glutaryl acylase (GAC) by co-aggregation of the enzyme with an aminated polymer: polyethyleneimine (PEI). The preparation of CLEAs of GAC from Pseudomonas sp. is not possible when using poly(ethylene glycol) and glutaraldehyde directly as precipitating and cross-linking agent, respectively. This problem arises probably from the low content of surface Lys groups of GAC which prevents an efficient cross-linking of the enzyme molecules in the aggregate. This fact was proven by the release of enzyme molecules from the aggregate and the solubilization of the enzyme when eliminating the precipitating agent. Our new co-aggregation system favors the cross-linking between the very reactive and abundant primary amino groups of the PEI and the primary amino groups on the enzyme surface. The use of PEI prevents the release of enzyme molecules from the aggregate. By this methodology, we prepared a very stable immobilized derivative of GAC. After optimization of the glutaraldehyde treatment conditions, the stability of the enzyme was significantly improved. It kept more than 60% of its initial activity after 72 h of incubation at 45 degrees C, whereas the soluble enzyme was fully inactivated in 2.5 h of incubation in the same conditions. Therefore, we have a new protocol for carrying out the preparation of cross-linked aggregates of enzymes with a low number of lysines on its surface.

Improved stabilization of chemically aminated enzymes via multipoint covalent attachment on glyoxyl supports.

The surface carboxylic groups of penicillin G acylase and glutaryl acylase were chemically aminated in a controlled way by reaction with ethylenediamine via the 1-ethyl-3-(dimethylamino-propyl) carbodiimide coupling method. Then, both proteins were immobilized on glyoxyl agarose. In both cases, the immobilization of the chemically modified enzymes improved the enzyme stability compared to the stability of the immobilized but non-modified enzyme (by a four-fold factor in the case of PGA and a 20-fold factor in the case of GA). The chemical modification presented a deleterious effect on soluble enzyme stability. Therefore, the improved stability should be related to a higher multipoint covalent attachment, involving both the lysine amino groups and also the new amino groups chemically introduced on the enzyme. Moreover, the lower pK(a) of the new amino groups permitted to immobilize the enzyme under milder conditions. In fact, the aminated proteins could be immobilized even at pH 9, while the non-modified enzymes could only be immobilized at pH over 10.