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 15-50% 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 European Crohn's and Colitis Organisation and Spanish Working Group on Crohn's Disease and Ulcerative Colitis guidelines state that darvadstrocel is effective with a favorable safety profile and a strong level of evidence (2). OBJECTIVE: Presenting real-world effectiveness data for darvadstrocel in a Spanish population. DESIGN: Observational retrospective cohort study with prospective data gathering. SETTINGS: Fourteen institutions. PATIENTS: From November 2019-April 2022, all patients (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; 3) absence of collections >2 cm confirmed by pelvic MRI scan at the time of surgery. INTERVENTIONS: Darvadstrocel treatment. MAIN OUTCOME MEASURES: Clinical response (closure of ≥50% of external openings), complete clinical closure (100% of external openings) and radiological closure (no fluid collection >2 cm, no 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. 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, UK, and Japan) and previously published literature. Darvadstrocel was effective and demonstrated a favorable safety profile when used in normal clinical practice for treatment of fistulas in Crohn's disease. See Video Abstract.

Funduplicatura con disección extensa de la unión esofagogástrica: lecciones aprendidas y resultados tras 178 pacientes consecutivos / Fundoplication with extensive dissection of the esophagogastric junction: Lessons learned and outcomes from 178 consecutives patients

Introducción: La cirugía antirreflujo se asocia con frecuencia a tasas significativas de recurrencia y complicaciones, habiéndose propuesto varias técnicas quirúrgicas para minimizarlas. El objetivo del estudio es evaluar los resultados a tres años de una funduplicatura con disección extensa de la unión esofagogástrica (UEG). Métodos: Estudio observacional retrospectivo que incluyó a 178 pacientes con enfermedad por reflujo gastroesofágico (ERGE) o hernia de hiato (HH) a los que se les realizó una funduplicatura con disección extensa de la UEG entre 2015 y 2020. La recidiva herniaria, los síntomas y la calidad de vida al primer año y a los tres siguientes de la cirugía fueron evaluados mediante tránsito baritado, endoscopia y cuestionarios para síntomas y calidad de vida (Gastro Esophageal Reflux Disease-Health Related Quality of Life [GERD-HRQL]). Resultados: La tasa de pirosis fue de 7,5 y 10,7% al año y a los tres siguientes, respectivamente, regurgitación de 3,8 y 6,9% y disfagia de 3,7 y 7,6%. La presencia de hernia hiatal se evidenció preoperatoriamente en 55,1% y en 7,8 y 9,6% en el seguimiento y la mediana de la escala GERD-HRQL fue de 27, 2 y 0, respectivamente. No aparecieron casos de telescopaje de la funduplicatura ni síntomas que sugieran lesión vagal. No se encontraron diferencias al comparar los distintos tipos de funduplicatura en términos de recidiva del reflujo, complicaciones o recurrencia de la hernia. Conclusiones: La funduplicatura con disección extensa de la UEG contribuye a su correcto posicionamiento y mejor anclaje, lo que asocia bajas tasas de recidiva herniaria y del reflujo, así como disminuye la posibilidad de telescopaje y lesión vagal.(AU)

Introduction: Antireflux surgery is commonly associated with significant recurrence and complication rates, and several surgical techniques have been proposed to minimize them. The aim of this study is to evaluate the results of a fundoplication with extensive dissection of the esophagogastric junction 1 and 3 years after the procedure.Methods: Retrospective observational study including 178 patients with gastroesophageal reflux disease or hiatal hernia who underwent fundoplication with extensive dissection of the esophagogastric junction between 2015 and 2020. Hernia recurrence, symptoms and quality of life at 1 and 3 years after surgery were assessed by barium transit, endoscopy and questionnaires for symptoms and quality of life (GERD-HRQL). Results: Heartburn rate was 7.5% and 10.7% at 1 and 3 years respectively, regurgitation 3.8% and 6.9% and dysphagia was 3.7% and 7.6%. The presence of hiatal hernia was evident preoperatively in 55.1% and in 7.8% and 9.6% at follow-up and the median GERD-HRQL scale was 27, 2 and 0, respectively. There were no cases of slippage of the fundoplication or symptoms suggestive of vagal injury. No differences were found when comparing the different types of fundoplication in terms of reflux and recurrence or complications. Conclusions: Fundoplication with extensive dissection of the esophagogastric junction contributes to correct positioning and better anchorage of the fundoplication, which is associated with low rates of hiatal hernia and reflux recurrence, as well as absence of slippage and lower possibility of vagal injury.(AU)

Intraperitoneal administration of carcinoembryonic antigen-directed chimeric antigen receptor T cells is a robust delivery route for effective treatment of peritoneal carcinomatosis from colorectal cancer in pre-clinical study.

BACKGROUND AIMS: Peritoneal carcinomatosis (PC) from colorectal cancer (CRC) is a highly challenging disease to treat. Systemic chimeric antigen receptor (CAR) T cells have shown impressive efficacy in hematologic malignancies but have been less effective in solid tumors. We explored whether intraperitoneal (i.p.) administration of CAR T cells could provide an effective and robust route of treatment for PC from CRC. METHODS: We generated second-generation carcinoembryonic antigen (CEA)-specific CAR T cells. Various animal models of PC with i.p. and extraperitoneal metastasis were treated by i.p. or intravenous (i.v.) administration of CEA CAR T cells. RESULTS: Intraperitoneally administered CAR T cells exhibited superior anti-tumor activity compared with systemic i.v. cell infusion in an animal model of PC. In addition, i.p. administration conferred a durable effect and protection against tumor recurrence and exerted strong anti-tumor activity in an animal model of PC with metastasis in i.p. or extraperitoneal organs. Moreover, compared with systemic delivery, i.p. transfer of CAR T cells provided increased anti-tumor activity in extraperitoneal tumors without PC. This phenomenon was further confirmed in an animal model of pancreatic carcinoma after i.p. administration of our newly constructed prostate stem cell antigen-directed CAR T cells. CONCLUSIONS: Taken together, our data suggest that i.p. administration of CAR T cells may be a robust delivery route for effective treatment of cancer.

Fundoplication with extensive dissection of the esophagogastric junction: Lessons learned and outcomes from 178 consecutives patients.

INTRODUCTION: Antireflux surgery is commonly associated with significant recurrence and complication rates, and several surgical techniques have been proposed to minimize them. The aim of this study is to evaluate the results of a fundoplication with extensive dissection of the esophagogastric junction 1 and 3 years after the procedure. METHODS: Retrospective observational study including 178 patients with gastroesophageal reflux disease or hiatal hernia who underwent fundoplication with extensive dissection of the esophagogastric junction between 2015 and 2020. Hernia recurrence, symptoms and quality of life at 1 and 3 years after surgery were assessed by barium transit, endoscopy and questionnaires for symptoms and quality of life (GERD-HRQL). RESULTS: Heartburn rate was 7.5% and 10.7% at 1 and 3 years respectively, regurgitation 3.8% and 6.9% and dysphagia was 3.7% and 7.6%. The presence of hiatal hernia was evident preoperatively in 55.1% and in 7.8% and 9.6% at follow-up and the median GERD-HRQL scale was 27, 2 and 0 respectively. There were no cases of slippage of the fundoplication or symptoms suggestive of vagal injury. No differences were found when comparing the different types of fundoplication in terms of reflux and recurrence or complications. CONCLUSIONS: Fundoplication with extensive dissection of the esophagogastric junction contributes to correct positioning and better anchorage of the fundoplication, which is associated with low rates of hiatal hernia and reflux recurrence, as well as absence of slippage and lower possibility of vagal injury.

Corrigendum: MSC therapy ameliorates experimental gouty arthritis hinting an early COX-2 induction.

[This corrects the article DOI: 10.3389/fimmu.2023.1193179.].

The history of Crohn's perianal fistula treatment with mesenchymal stem cells: the story of darvadstrocel.

INTRODUCTION: This study provides an overview of the development of the first drug authorized for use in cell therapy. AREAS COVERED: We analyze the case of darvadstrocel, an example of a successful cell-therapy drug used worldwide to treat Crohn's perianal fistula. A bibliographic-historical analysis of the first cellular treatment approved by the EMA, including relevant aspects concerning the authors, who were involved in the whole process. We would like to highlight the following messages: Development: The article describes the development process of the drug, from initial concept through the clinical trial phases. Learning from failure: In describing the development of darvadstrocel, the authors highlight the importance of learning from failures, which is crucial to achieving successful outcomes. Collaboration: The article underscores the need for collaboration between public and private institutions to facilitate the advancement of cell-therapy drugs and ensure efficiency while adhering to regulatory guidelines. EXPERT OPINION: Regulatory requirements play a crucial role in the design and development of advanced therapies such as cell-therapy drugs. The findings of this study underscore the significance of appropriate disease application, meticulous donor selection, robust manufacturing processes, and proper therapy administration. Only by adopting these measures can cell-therapy drugs successfully complete all phases of the clinical trial process.

MSC therapy ameliorates experimental gouty arthritis hinting an early COX-2 induction.

Objective: The specific effect of Adipose-Derived Mesenchymal Stem Cells (Ad-MSC) on acute joint inflammation, where the response mostly depends on innate immunity activation, remains elusive. The pathogenesis of gouty arthritis, characterized by the deposition of monosodium urate (MSU) crystals in the joints, associated to acute flares, has been associated to NLRP3 inflammasome activation and subsequent amplification of the inflammatory response. Our aim was to study the effect of human Ad-MSC administration in the clinical inflammatory response of rabbits after MSU injection, and the molecular mechanisms involved. Methods: Ad-MSC were administered by intraarterial route shortly after intraarticular MSU crystal injections. Joint and systemic inflammation was sequentially studied, and the mechanisms involved in NLRP3 inflammasome activation, and the synthesis of inflammatory mediators were assessed in the synovial membranes 72h after insult. Ad-MSC and THP-1-derived macrophages stimulated with MSU were co-cultured in transwell system. Results: A single systemic dose of Ad-MSC accelerated the resolution of local and systemic inflammatory response. In the synovial membrane, Ad-MSC promoted alternatively M2 macrophage presence, inhibiting NLRP3 inflammasome and inducing the production of anti-inflammatory cytokines, such as IL-10 or TGF-ß, and decreasing nuclear factor-κB activity. Ad-MSC induced a net anti-inflammatory balance in MSU-stimulated THP-1 cells, with a higher increase in IL-10 and IDO expression than that observed for IL-1ß and TNF. Conclusion: Our in vivo and in vitro results showed that a single systemic dose of Ad-MSC decrease the intensity and duration of the inflammatory response by an early local COX-2 upregulation and PGE2 release. Ad-MSCs suppressed NF-kB activity, NLRP3 inflammasome, and promoted the presence of M2 alternative macrophages in the synovium. Therefore, this therapeutic approach could be considered as a pharmacological alternative in patients with comorbidities that preclude conventional treatment.

Understanding CAR T cell therapy and its role in ovarian cancer and peritoneal carcinomatosis from ovarian cancer.

Ovarian cancer is the seventh most common cancer worldwide in women and the most lethal gynecologic malignancy due to the lack of accurate screening tools for early detection and late symptom onset. The absence of early-onset symptoms often delays diagnosis until the disease has progressed to advanced stages, frequently when there is peritoneal involvement. Although ovarian cancer is a heterogeneous malignancy with different histopathologic types, treatment for advanced tumors is usually based on chemotherapy and cytoreduction surgery. CAR T cells have shown promise for the treatment of hematological malignancies, though their role in treating solid tumors remains unclear. Outcomes are less favorable owing to the low capacity of CAR T cells to migrate to the tumor site, the influence of the protective tumor microenvironment, and the heterogeneity of surface antigens on tumor cells. Despite these results, CAR T cells have been proposed as a treatment approach for peritoneal carcinomatosis from colorectal and gastric origin. Local intraperitoneal administration of CAR T cells has been found to be superior to systemic administration, as this route is associated with increased tumor reduction, a more durable effect, protection against local relapse and distant metastases, and fewer systemic adverse effects. In this article we review the application of CAR T cells for the treatment of ovarian cancer and peritoneal carcinomatosis from ovarian cancer.

Under the Hood: Understanding the Features of Mucin in Pseudomyxoma Peritonei.

Pseudomyxoma peritonei (PMP) is a rare malignant growth characterized by the production of mucin and the potential for peritoneal relapse. This study aimed to investigate the immunohistochemical and biological characteristics of mucin in patients with cellular and acellular PMP. We prospectively analyzed mucin specimens obtained from our patient cohort and described the composition and type of mucin present in each sample. A metagenomic analysis of the samples was performed to investigate the bacterial composition of the PMP microbiome. Secreted mucins 2 and 5AC and membrane-associated mucin-1 were the primary components of mucin in both cellular and acellular tumor specimens. The metagenomic study revealed a predominance of the phylum Proteobacteria and the genus Pseudomonas. Notably, Pseudomonas plecoglossicida, a species not previously reported in the human microbiome, was found to be the most abundant organism in the mucin of pseudomyxoma peritonei. Our findings suggest that the presence of MUC-2 and mucin colonization by Pseudomonas are characteristic features of both cellular and acellular disease. These results may have significant implications for the diagnosis and treatment of this rare entity.

Differential presence of exons (DPE): sequencing liquid biopsy by NGS. A new method for clustering colorectal Cancer patients.

Differential presence of exons (DPE) by next generation sequencing (NGS) is a method of interpretation of whole exome sequencing. This method has been proposed to design a predictive and diagnostic algorithm with clinical value in plasma from patients bearing colorectal cancer (CRC). The aim of the present study was to determine a common exonic signature to discriminate between different clinical pictures, such as non-metastatic, metastatic and non-disease (healthy), using a sustainable and novel technology in liquid biopsy.Through DPE analysis, we determined the differences in DNA exon levels circulating in plasma between patients bearing CRC vs. healthy, patients bearing CRC metastasis vs. non-metastatic and patients bearing CRC metastasis vs. healthy comparisons. We identified a set of 510 exons (469 up and 41 down) whose differential presence in plasma allowed us to group and classify between the three cohorts. Random forest classification (machine learning) was performed and an estimated out-of-bag (OOB) error rate of 35.9% was obtained and the predictive model had an accuracy of 75% with a confidence interval (CI) of 56.6-88.5.In conclusion, the DPE analysis allowed us to discriminate between different patho-physiological status such as metastatic, non-metastatic and healthy donors. In addition, this analysis allowed us to obtain very significant values with respect to previous published results, since we increased the number of samples in our study. These results suggest that circulating DNA in patient's plasma may be actively released by cells and may be involved in intercellular communication and, therefore, may play a pivotal role in malignant transformation (genometastasis).

Study of the Effect of Wild-Type and Transiently Expressing CXCR4 and IL-10 Mesenchymal Stromal Cells in a Mouse Model of Peritonitis.

Sepsis due to peritonitis is a process associated with an inflammatory state. Mesenchymal stromal cells (MSCs) modulate the immune system due to the paracrine factors released and may be a therapeutic alternative. Three treatment groups were developed in a murine model of peritonitis to verify the effect of human adipose mesenchymal stem cell (hASCs). Additionally, a temporary modification was carried out on them to improve their arrival in inflamed tissues (CXCR4), as well as their anti-inflammatory activity (IL-10). The capacity to reduce systemic inflammation was studied using a local application (peritoneal injection) as a treatment route. Comparisons involving the therapeutic effect of wild-type ASCs and ASCs transiently expressing CXCR4 and IL-10 were carried out with the aim of generating an improved anti-inflammatory response for sepsis in addition to standard antibiotic treatment. However, under the experimental conditions used in these studies, no differences were found between both groups with ASCs. The peritoneal administration of hASCs or genetically modified hASCs constitutes an efficient and safe therapy in our model of mouse peritonitis.

Searching for the Optimal Donor for Allogenic Adipose-Derived Stem Cells: A Comprehensive Review.

Adipose-derived stem cells comprise several clinically beneficial qualities that have been explored in basic research and have motivated several clinical studies with promising results. After being approved in the European Union, UK, Switzerland, Israel, and Japan, allogeneic adipose-derived stem cells (darvadstrocel) have been recently granted a regenerative medicine advanced therapy (RMAT) designation by US FDA for complex perianal fistulas in adults with Crohn's disease. This huge scientific step is likely to impact the future spread of the indications of allogeneic adipose-derived stem cell applications. The current knowledge on adipose stem cell harvest describes quantitative and qualitative differences that could be influenced by different donor conditions and donor sites. In this comprehensive review, we summarize the current knowledge on the topic and propose donor profiles that could provide the optimal initial quality of this living drug, as a starting point for further applications and studies in different pathological conditions.

An international consensus for mitigation of the detrimental effects of the COVID-19 pandemic on laparoscopic training.

AIM: Achieve an international consensus on how to recover lost training opportunities. The results of this study will help inform future EAES guidelines about the recovery of surgical training before and after the pandemic. BACKGROUND: A global survey conducted by our team demonstrated significant disruption in surgical training during the COVID-19 pandemic. This was wide-spread and affected all healthcare systems (whether insurance based or funded by public funds) in all participating countries. Thematic analysis revealed the factors perceived by trainees as barriers to training and gave birth to four-point framework of recovery. These are recommendations that can be easily achieved in any country, with minimal resources. Their implementation, however, relies heavily on the active participation and leadership by trainers. Based on the results of the global trainee survey, the authors would like to conduct a Delphi-style survey, addressed to trainers on this occasion, to establish a pragmatic step-by-step approach to improve training during and after the pandemic. METHODS: This will be a mixed qualitative and quantitative study. Semi-structured interviews will be performed with laparoscopic trainers. These will be transcribed and thematic analysis will be applied. A questionnaire will then be proposed; this will be based on both the results of the semi structured interviews and of the global trainee survey. The questionnaire will then be validated by the steering committee of this group (achieve consensus of >80%). After validation, the questionnaire will be disseminated to trainers across the globe. Participants will be asked to consent to participate in further cycles of the Delphi process until more than 80% agreement is achieved. RESULTS: This study will result in a pragmatic framework for continuation of surgical training during and after the pandemic (with special focus on minimally invasive surgery training).

Familial component of early-onset colorectal cancer: opportunity for prevention.

BACKGROUND: Individuals with a non-syndromic family history of colorectal cancer are known to have an increased risk. There is an opportunity to prevent early-onset colorectal cancer (age less than 50 years) (EOCRC) in this population. The aim was to explore the proportion of EOCRC that is preventable due to family history of colorectal cancer. METHODS: This was a retrospective multicentre European study of patients with non-hereditary EOCRC. The impact of the European Society of Gastrointestinal Endoscopy (ESGE), U.S. Multi-Society Task Force (USMSTF), and National Comprehensive Cancer Network (NCCN) guidelines on prevention and early diagnosis was compared. Colorectal cancer was defined as potentially preventable if surveillance colonoscopy would have been performed at least 5 years before the age of diagnosis of colorectal cancer, and diagnosed early if colonoscopy was undertaken between 1 and 4 years before the diagnosis. RESULTS: Some 903 patients with EOCRC were included. Criteria for familial colorectal cancer risk in ESGE, USMSTF, and NCCN guidelines were met in 6.3, 9.4, and 30.4 per cent of patients respectively. Based on ESGE, USMSTF, and NCCN guidelines, colorectal cancer could potentially have been prevented in 41, 55, and 30.3 per cent of patients, and diagnosed earlier in 11, 14, and 21.1 per cent respectively. In ESGE guidelines, if surveillance had started 10 years before the youngest relative, there would be a significant increase in prevention (41 versus 55 per cent; P = 0.010). CONCLUSION: ESGE, USMSTF, and NCCN criteria for familial colorectal cancer were met in 6.3, 9.4, and 30.4 per cent of patients with EOCRC respectively. In these patients, early detection and/or prevention could be achieved in 52, 70, and 51.4 per cent respectively. Early and accurate identification of familial colorectal cancer risk and increase in the uptake of early colonoscopy are key to decreasing familial EOCRC.

Implication of stem cells from adipose tissue in wound healing in obese and cancer patients.

OBJECTIVE: Certain diseases such as obesity and cancer can cause impaired wound healing. Adipose tissue derived stem cells (ASCs) are a novel field of research. Many studies have evidenced their high degree of safety and potential for wound repair due to their immunomodulatory and tissue-regeneration properties. The purpose of this study is to determine the impact of obesity and cancer on the therapeutic potential of ASCs. MATERIALS AND METHODS: We isolated and characterized the phenotype, differentiation capacities, secretome, and in vitro migration capacities of ASCs. Furthermore, we analyze their capacity of in vitro migration associated with the plasma of the different patients. RESULTS: We observed that ASCs isolated from obese and cancer patients have the same phenotype, cell proliferation, and migration capacities as ASCs derived from healthy donors. However, they do not have the same differentiation potential and exhibit distinct profiles of both pro-inflammatory and regulatory secreted cytokines, which, together with the signals received from the bloodstream, could account for the impaired healing in patients with these diseases. CONCLUSIONS: We consider the ASCs from patients with either obesity or cancer are slightly altered, and this may be the cause of worse wound healing in these patients.

OBJETIVO: Enfermedades como la obesidad y el cáncer pueden alterar la cicatrización de las heridas. Las células madre derivadas del tejido adiposo (ASC) abren un nuevo campo de investigación ya que muchos estudios han demostrado su utilidad y alto grado de seguridad para la reparación de heridas debido a sus propiedades inmunomoduladoras y de regeneración tisular. El propósito de este estudio es determinar el impacto de la obesidad y el cáncer en el potencial terapéutico de las ASCs. MATERIAL Y MÉTODOS: Aislamos y caracterizamos el fenotipo, la capacidad de diferenciación, el secretoma y la capacidad de migración in vitro de las ASC. Asimismo, analizamos la capacidad de migración in vitro asociada al plasma de los diferentes pacientes. RESULTADOS: Observamos que las ASC aisladas de pacientes obesos y con cáncer tienen el mismo fenotipo, proliferación celular y capacidades de migración que las ASCaisladas de donantes sanos. Sin embargo, no tienen el mismo potencial de diferenciación y exhiben perfiles distintos de citoquinas secretadas tanto proinflamatorias como reguladoras. CONCLUSIONES: Consideramos que las ASC de pacientes con obesidad o cáncer están levemente alteradas. Esta puede ser la causa de una peor cicatrización de las heridas en este tipo de pacientes.