Use of Darvadstrocel (Allogenic Stem Cell Therapy) for Crohn's Fistulas in Real Clinical Practice: The National Project to Implement Mesenchymal Stem Cell for the Treatment of Perianal Crohn's Fistula (the PRIME Study).

BACKGROUND: Perianal fistulas may affect 15% to 50% of patients with Crohn's disease. Treatment is complex, requiring a multidisciplinary approach. Darvadstrocel (allogenic mesenchymal cells obtained from lipoaspirates) was approved in 2018 by the European and Spanish Agencies of Medicines and Medical Products as a treatment for fistulas in Crohn's disease. Recent guidelines from the European Crohn's and Colitis Organisation and Spanish Working Group on Crohn's Disease and Ulcerative Colitis state that darvadstrocel is effective with a favorable safety profile and a strong level of evidence (n = 2). OBJECTIVE: Presenting real-world effectiveness data for darvadstrocel in a Spanish population. DESIGN: Observational retrospective cohort study with prospective data gathering. SETTINGS: The study was conducted at 14 institutions in Spain. PATIENTS: From November 2019 to April 2022, all patients (n = 73) treated with darvadstrocel in these institutions were included, fulfilling the following criteria: 1) complex fistula/s in a patient with Crohn's disease; 2) failure of conventional and antitumor necrosis factor treatment; and 3) the absence of collections of >2 cm confirmed by pelvic MRI at the time of surgery. INTERVENTIONS: Darvadstrocel treatment. MAIN OUTCOME MEASURES: Clinical response (closure of 50% or more of external openings), complete clinical closure (100% of external openings), and radiological closure (no fluid collection >2 cm, edema, or inflammation) evaluated 6 months after treatment. RESULTS: Clinical response was observed in 63 patients (86.3%), complete clinical closure in 50 patients (68.5%), and radiological closure in 45 patients (69.2%). Combined clinical and radiological response was observed in 41 patients (63.1%). Not all clinically healed patients had radiological closure, and vice versa. No serious adverse events were reported. LIMITATIONS: Retrospective nature of the study. CONCLUSIONS: Study results were consistent with those reported in previous clinical trials, real-world efficacy findings from the INSPIRE study (assessing darvadstrocel effectiveness in Europe, Israel, Switzerland, United Kingdom, and Japan), and previously published literature. Darvadstrocel was effective and demonstrated a favorable safety profile when used in normal clinical practice for the treatment of fistulas in Crohn's disease. See Video Abstract . USO DE DARVADSTROCEL TERAPIA CON CLULAS MADRE ALOGNICAS PARA FSTULA EN ENFERMEDAD DE CROHN EN LA PRCTICA CLNICA REAL EL PROYECTO NACIONAL PARA IMPLEMENTAR DE CLULAS MADRE MESENQUIMALES PARA EL TRATAMIENTO DE LA FSTULA DE CROHN PERIANAL EL ESTUDIO PRIME: ANTECEDENTES:Las fístulas perianales pueden afectar entre el 15 y el 50% de los pacientes con enfermedad de Crohn. El tratamiento es complejo y requiere un enfoque multidisciplinario. El darvadstrocel (células mesenquimales alogénicas obtenidas a partir de lipoaspirados) fue aprobado en 2018 por las Agencias Europea y Española de Medicamentos y Productos Sanitarios como tratamiento de las fístulas en la EC. Las recientes directrices de la Organización Europea de Crohn y Colitis y del Grupo de Trabajo Español sobre la Enfermedad de Crohn y Colitis Ulcerosa afirman que darvadstrocel es eficaz con un perfil de seguridad favorable y un sólido nivel de evidencia (2).OBJETIVO:Presentar datos de eficacia real de darvadstrocel en población española.DISEÑO:Estudio de cohorte retrospectivo observacional con recopilación prospectiva de datos.ESCENARIO:14 instituciones.PACIENTES:Desde noviembre de 2019 hasta abril de 2022, se incluyeron todos los pacientes (73) tratados con darvadstrocel en estas instituciones, que cumplieron los siguientes criterios: 1) fístula/s compleja/s en un paciente con enfermedad de Crohn; 2) fracaso del tratamiento convencional y anti factor de necrosis tumoral; 3) ausencia de colecciones > 2 cm confirmada por resonancia magnética pélvica en el momento de la cirugía.INTERVENCIONES:Tratamiento con Darvadstrocel.PRINCIPALES MEDIDAS DE RESULTADO:Respuesta clínica (cierre de ≥50% de las aberturas externas), cierre clínico completo (100% de las aberturas externas) y cierre radiológico (sin acumulación de líquido >2 cm, sin edema ni inflamación) evaluados 6 meses después del tratamiento.RESULTADOS:Se observó respuesta clínica en 63 pacientes (86.3%), cierre clínico completo en 50 pacientes (68.5%) y cierre radiológico en 45 pacientes (69.2%). Se observó respuesta clínica y radiológica combinada en 41 pacientes (63.1%). No todos los pacientes clínicamente curados tuvieron cierre radiológico y viceversa. No hubo eventos adversos graves reportados.LIMITACIONES:Estudio retrospectivoCONCLUSIONES:Los resultados del estudio fueron consistentes con los informados en ensayos clínicos anteriores, los hallazgos de eficacia en el mundo real del estudio INSPIRE (que evalúa la efectividad de darvadstrocel en Europa, Israel, Suiza, el Reino Unido y Japón) y la literatura publicada anteriormente. Darvadstrocel fue eficaz y demostró un perfil de seguridad favorable cuando se utiliza en la práctica clínica habitual para el tratamiento de fístulas en la enfermedad de Crohn. (Traducción-Dr. Jorge Silva Velazco ).

Serpine1 mRNA confers mesenchymal characteristics to the cell and promotes CD8+ T cells exclusion from colon adenocarcinomas.

Serine protease inhibitor clade E member 1 (SERPINE1) inhibits extracellular matrix proteolysis and cell detachment. However, SERPINE1 expression also promotes tumor progression and plays a crucial role in metastasis. Here, we solve this apparent paradox and report that Serpine1 mRNA per se, independent of its protein-coding function, confers mesenchymal properties to the cell, promoting migration, invasiveness, and resistance to anoikis and increasing glycolytic activity by sequestering miRNAs. Expression of Serpine1 mRNA upregulates the expression of the TRA2B splicing factor without affecting its mRNA levels. Through transcriptional profiling, we found that Serpine1 mRNA expression downregulates through TRA2B the expression of genes involved in the immune response. Analysis of human colon tumor samples showed an inverse correlation between SERPINE1 mRNA expression and CD8+ T cell infiltration, unveiling the potential value of SERPINE1 mRNA as a promising therapeutic target for colon tumors.

Efficacy of Sacral Nerve Stimulation in Non-constipated Irritable Bowel Syndrome Patients: A Systematic Review.

BACKGROUND AND AIMS: Irritable bowel syndrome (IBS) is a prevalent disorder with a complex and heterogeneous physiopathology, including a dysregulation of gut-brain axis. Treatment for IBS is targeted to the predominant symptom and requires a multidisciplinary approach. This review aims to evaluate the efficacy and safety of sacral nerve stimulation in non-constipated IBS patients Methods: A literature search was carried out on MEDLINE, The Cochrane Central Register of Controlled Trials (CENTRAL) and Web of Science databases for all relevant articles. Quality of included papers was assessed using standardized guidelines Results: Of 129 initial citations, 7 articles met our predefined inclusion criteria, including five randomized trials, a pilot study and a descriptive follow-up study. Five of 7 studies reported a positive effect of sacral nerve stimulation on symptoms and quality of life improvement in non-constipated IBS patients. No study reported serious adverse events. CONCLUSIONS: Despite initial promising results of sacral nerve stimulation in non-constipated IBS patients, studies with larger sample sizes and longer follow-up are required.

Multicriteria Decision Analysis for Updating of Quality Indicators for Inflammatory Bowel Disease Comprehensive Care Units in Spain.

BACKGROUND AND AIMS: Management of inflammatory bowel disease [IBD] is complex and IBD Comprehensive Care Units [ICCUs] facilitate the delivery of quality care to IBD patients. The objective of this study was to update the existing set of quality indicators [QIs] for ICCUs, based on a nationwide quality certification programme carried out in Spain, from a multi-stakeholder perspective and using multicriteria decision analysis [MCDA] methodology. METHODS: An MCDA comprising three different phases was conducted. In phase 1, a systematic literature review was performed, and after validation by a scientific committee comprising 11 experts, a preliminary set of QIs was developed. In phase 2, a larger group of 49 experts determined the relevance and relative importance of each QI by prioritising and weighing the preliminary set. Finally in phase 3, the scientific committee reviewed the results and made a final selection via a deliberative process. RESULTS: The final set comprised 67 QIs, classified as Structure [23 QIs], Process [35 QIs] and Outcome [9 QIs], which were ranked according to their relative importance. Multidisciplinary management was the most important requirement in ICCUs, followed by continuity of care, standardisation of clinical care and, especially, the incorporation of patients' reported outcomes. CONCLUSIONS: This updated set of QIs comprises a weighted and prioritised set of items that represent the essential minimum of criteria for ensuring appropriate quality of care in the management of IBD patients.

Changes in the management of IBD patients since the onset of COVID-19 pandemic. A path toward the implementation of telemedicine in Spain?

BACKGROUND: COVID-19 pandemic increased medical services demand aside from interrupting daily clinical practice for other diseases such as inflammatory bowel disease (IBD). Here we present the results of a survey to gain the perception of IBD specialists in their patient-management using telemedicine in their daily practice. METHODS: This was an observational survey study among physicians focused on IBD (gastroenterologist, surgeons, and pediatricians) members of the Spanish Working Group on Crohn's Disease and Ulcerative Colitis (GETECCU), the Spanish Association of Gastroenterology (AEG), and the Spanish Association of Coloproctology (AECP), regarding changes of management of IBD patients. RESULTS: We received a total of 269 responses to the survey (from May to June 2020). Before the pandemic, nearly all the respondents reported performing very frequently their visits face-to-face (n=251, 93.3%) while, during the pandemic, the telephone visits were the most frequent visits performed (n=138, 51.3%). Regarding communication difficulties, 157 (58.4%) respondents reported the impossibility of performing a proper examination as the most relevant issue. Also, 114 (42.4%) respondents considered remote visits more time-consuming than face-to-face visits. Most gastroenterologists (n=188, 83.2%) considered patients with active perianal disease in special need of face-to-face consultation and more than half of the surgeons (n=35, 50.7%) reported having performed an immediate postoperative follow-up remotely. CONCLUSIONS: Most IBD units have implemented remote visits during the pandemic, but most professionals found them more time-consuming and unsuitable for some disease profiles. Therefore, there is a need for the development of better telemedicine systems that can meet professionals' and patients' requirements.

Incorporation of Elastin to Improve Polycaprolactone-Based Scaffolds for Skeletal Muscle via Electrospinning.

Skeletal muscle regeneration is increasingly necessary, which is reflected in the increasing number of studies that are focused on improving the scaffolds used for such regeneration, as well as the incubation protocol. The main objective of this work was to improve the characteristics of polycaprolactone (PCL) scaffolds by incorporating elastin to achieve better cell proliferation and biocompatibility. In addition, two cell incubation protocols (with and without dynamic mechanical stimulation) were evaluated to improve the activity and functionality yields of the regenerated cells. The results indicate that the incorporation of elastin generates aligned and more hydrophilic scaffolds with smaller fiber size. In addition, the mechanical properties of the resulting scaffolds make them adequate for use in both bioreactors and patients. All these characteristics increase the biocompatibility of these systems, generating a better interconnection with the tissue. However, due to the low maturation achieved in biological tests, no differences could be found between the incubation with and without dynamic mechanical stimulation.

Fabrication of hybrid scaffolds obtained from combinations of PCL with gelatin or collagen via electrospinning for skeletal muscle tissue engineering.

The creation of skeletal muscle tissue in vitro is a major topic of interest today in the field of biomedical research, due to the lack of treatments for muscle loss due to traumatic accidents or disease. For this reason, the intrinsic properties of nanofibrillar structures to promote cell adhesion, proliferation, and cell alignment presents an attractive tool for regenerative medicine to recreate organized tissues such as muscle. Electrospinning is one of the processing techniques often used for the fabrication of these nanofibrous structures and the combination of synthetic and natural polymers is often required to achieve optimal mechanical and physiochemical properties. Here, polycaprolactone (PCL) is selected as a synthetic polymer used for the fabrication of scaffolds, and the effect of protein addition on the final scaffolds' properties is studied. Collagen and gelatin were the proteins selected and two different concentrations were analyzed (2 and 4 wt/vol%). Different PCL/protein systems were prepared, and a structural, mechanical and functional characterization was performed. The influence of fiber alignment on the properties of the final scaffolds was assessed through morphological, mechanical and biological evaluations. A bioreactor was used to promote cell proliferation and differentiation within the scaffolds. The results revealed that protein addition produced a decrease in the fiber size of the membranes, an increase in their hydrophilicity, and a softening of their mechanical properties. The biological study showed the ability of the selected systems to harbor cells, allow their growth and, potentially, develop musculoskeletal tissues.

Feasibility and safety of calcium alginate hydrogel sealant for the treatment of cryptoglandular fistula-in-ano: phase I/IIa clinical trial.

AIM: Complex perianal fistulas pose a challenge to the surgeon since the fistulous tract must be eliminated without impairing continence. Although without strong scientific evidence, some bibliography has demonstrated the efficacy of some sealants in the treatment of anal fistulas. We aimed to assess the feasibility and safety of calcium alginate hydrogel injections into the fistulous tract as treatment for trans-sphincteric cryptoglandular fistulas. METHODS: A prospective, single-centre, case series of this novel technique was conducted in a level 3 Spanish hospital, including patients diagnosed with trans-sphincteric perianal fistulas and treated with a calcium alginate hydrogel sealant. A strict follow-up was performed by an independent surgeon at 1, 3, 6 and 12 months. The main outcome measures were feasibility, safety (number of adverse events) and efficacy of the treatment. RESULTS: Twenty patients were treated. The treatment was performed for all patients. Seven adverse events related to the injection product or the surgical procedure were identified. After a 12-month follow-up, 12 patients were completely cured and eight were not cured, with a greater response in the first 6 months. These findings were confirmed by endoanal ultrasound, with a Cohen's kappa concordance rate of 0.89. No statistically significant differences were observed in pain measured using the visual analogue scale, faecal incontinence measured using the Wexner scoring system, and quality of life analysed by the SF-36 Health Survey. CONCLUSION: The treatment was feasible, safe and with discrete satisfactory healing results. It also demonstrated an acceptable safety profile, without worsening of faecal incontinence, quality of life and pain following treatment.

Validation of a Novel Fecal Incontinence Scale: The Rapid Assessment Fecal Incontinence Score (RAFIS).

OBJECTIVE: The development and validation of a new version of the fecal incontinence (FI) scale "Rapid Assessment Fecal Incontinence Score" (RAFIS) incorporating domains for severity, type of stool loss, and global perception of the effect of incontinence on quality of life (QoL). BACKGROUND: FI negatively impacts on QoL. Currently used incontinence questionnaires have outstanding limitations on the global assessment of the impact of the disease on QoL that patients perceive. We developed a new version of RAFIS with a more complete questionnaire. MATERIALS AND METHODS: A 3-phase study was performed to evaluate the applicability and reliability of our questionnaire as a tool for assessing FI. Our score was completed by 98 patients (78 women; mean age: 57±13 y) who presented with FI and who were referred from 4 colorectal surgery centers. The RAFIS was assessed for internal consistency, test-retest reliability, and sensitivity to change. A multivariate analysis was performed. Comparisons were made with the Wexner Cleveland Clinic Incontinence Score and the Fecal Incontinence Quality of Life Scale. RESULTS: The RAFIS showed good internal consistency and test-retest reliability, differentiating the severity of incontinence but not the etiology. There was a moderate-high correlation between the new scale and the reference scales. Sensitivity to change, compared with the Wexner Score, was moderate. Comparison with established QoL instruments showed a moderate negative correlation. Logistic regression of the RAFIS discriminated between mild and moderate-severe impact on QoL. No correlation was detected with the new score to the presence of an anal sphincter defect or sphincter hypotonia. CONCLUSION: The RAFIS scale is easy to administer and compares well with other validated incontinence instruments.

Treatment of faecal incontinence with autologous expanded mesenchymal stem cells: results of a pilot study.

AIM: Management of faecal incontinence (FI) remains challenging because no definitive optimal treatment for this condition has yet been determined. Regenerative medicine could be an attractive therapeutic alternative for treating FI. Here, we aimed to determine the safety and feasibility of autologous expanded mesenchymal stem cells derived from adipose tissue (AdMSCs) in the treatment of patients diagnosed with structural FI. METHOD: This was a randomized, multicentre, triple-blinded, placebo-controlled pilot study conducted at four sites in Spain with 16 adults with FI and a sphincter defect. Autologous AdMSCs were obtained from patients from surgically excised adipose tissue. These patients were intralesionally infused with a single dose of 4 × 107 AdMSCs or a placebo while under anaesthesia. We assessed the safety and feasibility of the treatment as the cumulative incidence of adverse events and the treatment efficacy using the Cleveland Clinic Faecal Incontinence Score, Faecal Incontinence Quality of Life score and Starck criteria to classify sphincter defects and anorectal physiology outcomes. RESULTS: Adipose tissue extraction, cell isolation and intralesional infusion procedures were successful in all the patients. There was only one adverse event connected to adipose tissue extraction (a haematoma), and none was associated with the injection procedure. There were no significant differences in any of the assessed clinical, manometric or ultrasonographic parameters. CONCLUSION: This study indicates that this infusion procedure in the anal sphincter is feasible and safe. However, it failed to demonstrate efficacy to treat patients with structural FI.

Electrical Modeling of the Growth and Differentiation of Skeletal Myoblasts Cell Cultures for Tissue Engineering.

In tissue engineering, of utmost importance is the control of tissue formation, in order to form tissue constructs of clinical relevance. In this work, we present the use of an impedance spectroscopy technique for the real-time measurement of the dielectric properties of skeletal myoblast cell cultures. The processes involved in the growth and differentiation of these cell cultures in skeletal muscle are studied. A circuit based on the oscillation-based test technique was used, avoiding the use of high-performance circuitry or external input signals. The effect of electrical pulse stimulation applied to cell cultures was also studied. The technique proved useful for monitoring in real-time the processes of cell growth and estimating the fill factor of muscular stem cells. Impedance spectroscopy was also useful to study the real-time monitoring of cell differentiation, obtaining different oscillation amplitude levels for differentiated and undifferentiated cell cultures. Finally, an electrical model was implemented to better understand the physical properties of the cell culture and control the tissue formation process.

Influence of robotics in surgical complication rate in elderly population with rectal cancer.

BACKGROUND: Rectal cancer surgery is a technically complex procedure. Moreover, short-term outcomes show high rate of complications especially in elderly and laparoscopic surgery has not demonstrated to be able to reduce this complication rate. Robotics has several advantages in pelvic surgical procedures, which could have an impact in complication rates in elderly patients. AIMS: The aim of our study is to demonstrate whether robotic surgery has any influence on the reduction of complications in the aged population undergoing rectal cancer. METHODS: We performed a retrospective analysis of a prospective database of 151 patients who underwent robotic surgery for rectal cancer. We divided our population into three groups: under 65-year-old, between 65- and 80-year-old and above 80-year-old. We recorded complications in each group intra and post procedure. RESULTS: The present study included 151 patients (94 males). Of them, 77 patients were under 66 year old, 63 patients were between 66 and 79 year old and 11 patients were 80 year old and above. The analysis showed conversion rates of 10.38%, 13.69%, 27.27%, and the complication rate of 23.4%, 23.8%, and 27.3% in each group. Univariate analysis showed no differences between the three groups. Nevertheless, there were statistical differences from BMI, ASA and neoadjuvant therapy. In multivariant analysis only neoadjuvant therapy was significant. CONCLUSIONS: Robotic approach does not decrease complications in elderly population and conversion is similar in these age groups. So we should not rule out robotic surgery in elderly patients, although we must select each case with a multidisciplinary approach.

Autologous adipose-derived stem cells for the treatment of complex cryptoglandular perianal fistula: A randomized clinical trial with long-term follow-up.

The aim of this clinical trial (ID Number NCT01803347) was to determine the safety and efficacy of autologous adipose-derived stem cells (ASCs) for treatment of cryptoglandular fistula. This research was conducted following an analysis of the mistakes of a same previous phase III clinical trial. We designed a multicenter, randomized, single-blind clinical trial, recruiting 57 patients. Forty-four patients were categorized as belonging to the intent-to-treat group. Of these, 23 patients received 100 million ASCs plus intralesional fibrin glue (group A) and 21 received intralesional fibrin glue (group B), both after a deeper curettage of tracks and closure of internal openings. Fistula healing was defined as complete re-epithelialization of external openings. Those patients in whom the fistula had not healed after 16 weeks were eligible for retreatment. Patients were evaluated at 1, 4, 16, 36, and 52 weeks and 2 years after treatment. Results were assessed by an evaluator blinded to the type of treatment. After 16 weeks, the healing rate was 30.4% in group A and 42.8% in group B, rising to 55.0% and 63.1%, respectively, at 52 weeks. At the end of the study (2 years after treatment), the healing rate remained at 50.0% in group A and had reduced to 26.3% in group B. The safety of the cellular treatment was confirmed and no impact on fecal continence was detected. The main conclusion was that autologous ASCs for the treatment of cryptoglandular perianal fistula is safe and can favor long-term and sustained fistula healing.