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 ).

PD-L1 as a Prognostic Factor in Early-Stage Colon Carcinoma within the Immunohistochemical Molecular Subtype Classification.

BACKGROUND: There is a patent need to better characterize early-stage colorectal cancer (CRC) patients. PD-1 ligand (PD-L1) expression has been proposed as a prognostic factor but yields mixed results in different settings. The Consensus Molecular Subtype (CMS) classification has yet to be integrated into clinical practice. We sought to evaluate the prognostic value of PD-L1 expression overall and within CMS in early-stage colon cancer patients, in the hope of assisting treatment choice in this setting. METHODS: Tissue-microarrays were constructed from tumor samples of 162 stage II/III CRC patients. They underwent automatic immunohistochemical staining for PD-L1 and the proposed CMS panel. Primary endpoints were overall survival (OS) and disease-free survival (DFS). RESULTS: PD-L1 expression was significantly and independently associated with better prognosis (HR = 0.46 (0.26-0.82), p = 0.009) and was mostly seen in immune cells of the tumor-related stroma. CMS4 five-folds the risk of mortalitycompared with CMS1 (HR = 5.58 (1.36, 22.0), p = 0.034). In the subgroup CMS2/CMS3 analysis, PD-L1 expression significantly differentiated individuals with better OS (p = 0.004) and DFS (p < 0.001). CONCLUSIONS: Our study suggests that PD-L1 expression is an independent prognostic factor in patients with stage II/III colon cancer. Additionally, it successfully differentiates patients with better prognosis in the CMS2/CMS3 group and may prove significant for the clinical relevance of the CMS classification.

Safety of nonoperative management after acute diverticulitis.

PURPOSE: The role of surgery in the management of diverticular disease after an episode of acute diverticulitis (AD) managed in a conservative form is evolving. Age, number of episodes of AD, type of episode, and symptoms after the episodes are factors related to the need for elective surgery. The aim of this study is to evaluate the safety of conservative management and the risk factors for emergency surgery after a first episode of AD managed without surgery. METHODS: We retrospectively evaluated 405 patients diagnosed as having had a first episode of AD. Sixty-nine patients underwent emergency surgery on the first admission, and 69 patients had an elective operation in the follow-up (group A). The remaining 267 patients were managed initially without surgery (group B). Thirteen of these 267 patients needed a further urgent surgical procedure. Factors involved in the decision of elective surgery and the probability of emergency surgery after the first episode of AD managed without surgery were evaluated in relation to demographic factors, risk factors, presence of recurrences, and type of the first episode. RESULTS: Patients, mean age was 62.7 years, 71 were aged less than 51, and 151 were males. The mean follow-up for patients with nonoperative management was 91.2 months. An elective operation was performed in 69 patients. Compared to patients in group B, those in group A more frequently had a first episode of complicated acute diverticulitis (CAD) (37.1% vs. 16.4%; P = 0.000) and were more likely to be smokers (46.3% vs. 19.3%; P = 0.000) and to suffer more than one episode of AD (42% vs. 26.9%; P = 0.027). Nonoperative management was chosen for 267 patients, but 13 patients needed an emergency operation later. In the multivariate analysis, we found a significant relation between the presence of CAD in the first episode and the need for emergency surgery. There were no differences in surgical mortality between the patients in the two groups, but patients treated with elective surgery had a higher rate of stoma than patients treated non-operatively (7.2% vs. 1.4%; P = 0.028); this difference was not observed in the subgroup of patients with CAD (15.3% vs. 6.8%; P = 0.458). CONCLUSION: After an episode of AD, nonoperative management is safe because fewer than 5% of patients will need an emergent procedure in a subsequent attack of AD. A first episode of CAD is the only risk factor for emergency surgery in patients managed conservatively.

[Training periods with experts improve results in colorectal laparoscopic surgery]. / Las estancias de formación con expertos mejoran los resultados en cirugía laparoscópica colorrectal.

OBJECTIVE: To analyse the effects of training in elective colorectal laparoscopic surgery with a minimum 6 months follow up to assess early and delayed complications, and comparing the first 40 cases in the 1st Period (P-1: 1996-2002) with the 100 cases in the 2nd Period (P-2: 2003-2008). One of the surgeons had two training courses between P-1 and P-2. MATERIAL AND METHODS: A total of 66 colorectal resections due to cancer were performed and 74 operations for benign disease. The cases of malignant diseases increased between P-1 and P-2 (P<0.001). (Odds-Ratio=0.16). RESULTS: There number of complex cases increased between P-1 and P-2 (Anterior resection-amputation, left hemicolectomy, total colectomy, rectopexy) vs. Others (Sigmoidectomy, right resections) (P<0.05), but the mean duration of the operations was reduced by 29 minutes P<0.01). There were 24% conversions, with no change in P-2 (P=0.85). Surgical mortality at 3 months (1.4%) showed no differences (P=0.49). The total complications rate (31%) was significantly lower in P-2 (P=0.001), because medical complications (P=0.05), the more serious surgical complications (with reintervention) (P=0.05) and wound infections (P=0.0001) were lower. There was no change in the other surgical complications (P=0.61). The overall mean stay was 7.8 days (3-36) (median=6 days), with no differences between P-1 and P-2 (P=0.165). Conversion significantly lengthened the mean hospital stay (P=0.015) (from 7.2+/-5 days to 10.1+/-7 days), but there was no increase in complications (P=0.31). CONCLUSION: Training in colorectal laparoscopy and training periods with experts improve results (duration, complications, more complex surgery). Conversions did not decrease with experience and the hospital stays lengthened, but they were not associated with more complications.