Expectations on mesenchymal stem cell (MSC) treatment are high, especially in the fields of sepsis, transplant medicine, and autoimmune diseases. Various pre-clinical studies have been conducted with encouraging results, although the mechanisms of action behind the observed immunomodulatory capacity of mesenchymal stem cells have not been fully understood. Previous studies have demonstrated that the immunomodulatory effect of MSCs is communicated via MSC-secreted cytokines and has been proven to rely on the local microenvironment as some of the observed effects depend on a pre-treatment of MSCs with inflammatory cytokines. Nonetheless, recent findings indicate that the cytokine-mediated effects are only one part of the equation as apoptotic, metabolically inactivated, or even fragmented MSCs have been shown to possess an immunomodulatory potential as well. Both cytokine-dependent and cytokine-independent mechanisms suggest a key role for regulatory T cells and monocytes in the overall pattern, but the principle as to why viable and non-viable MSCs have similar immunomodulatory capacities remains elusive. Here we review the current knowledge on cellular and molecular mechanisms involved in MSC-mediated immunomodulation and focus on the viability of MSCs, as there is still uncertainty concerning the tumorigenic potential of living MSCs.

Mesenchymal stem cells (MSCs) are used in various clinical and preclinical models for immunomodulation. However, it remains unclear how the immunomodulatory effect of MSC is communicated. MSC-induced immunomodulation is known to be mediated through both MSC-secreted cytokines and direct cell-cell interactions. Recently, it has been demonstrated that metabolically inactive, heat-inactivated MSCs (HI-MSCs) have similar anti-inflammatory capacities in LPS-induced sepsis compared with viable MSC.To further investigate the immunomodulatory effects of MSC, we introduced MSC and HI-MSC in two animal models with different immunological causes. In the first model, allogeneic hearts were transplanted from C57BL/6 mice to BALB/c recipients. MSC in combination with mycophenolate mofetil (MMF) significantly improved graft survival compared with MMF alone, whereas the application of HI-MSC had no effect on graft survival. We revealed that control MSC dose-dependently inhibited CD3 + and CD8 + T-cell proliferation in vitro, whereas HI-MSC had no effect. In the second model, sepsis was induced in mice via cecal ligation and puncture. HI-MSC treatment significantly improved the overall survival, whereas control MSCs had no effect. in vitro studies demonstrated that HI-MSCs are more effectively phagocytosed by monocytes than control MSCs and induced cell death in particular of activated CD16 + monocytes, which may explain the immune protective effect of HI-MSC in the sepsis model. The results of our study demonstrate that MSC-mediated immunomodulation in sepsis is dependent on a passive recognition of MSC by monocytes, whereas fully functional MSCs are required for inhibition of T-cell-mediated allograft rejection. K E Y W O R D S heat-inactivated mesenchymal stem

Traditionally, esophageal oncological resections have been performed via open approaches with well-documented levels of morbidity and mortality complicating the postoperative course. In contemporary terms, minimally invasive approaches have garnered sustained support in all areas of surgery, and there has been an exponential adaptation of this technology in upper GI surgery with the advent of laparoscopic and robotic techniques. The current literature, while growing, is inconsistent in reporting on the benefits of minimally invasive esophagectomies (MIEs) and this makes it difficult to ascertain best practice. The objective of this review was to critically appraise the current evidence addressing the safety, efficacy, and cost-effectiveness of MIEs versus open esophagectomies. A systematic review of the literature was performed by searching nine electronic databases to identify any systematic reviews published on this topic and recommended Joanna Briggs Institute approach to critical appraisal, study selection, data extraction and data synthesis was used to report the findings. A total of 13 systematic reviews of moderate to good quality encompassing 143 primary trials and 36,763 patients were included in the final synthesis. Eleven reviews examined safety parameters and found a generalized benefit of MIE. Efficacy was evaluated by eight systematic reviews and found each method to be equivalent. There were limited data to judiciously appraise cost-effectiveness as this was only evaluated in one review involving a single trial. There is improved safety and equivalent efficacy associated with MIE when compared with open esophagectomy. Cost-effectiveness of MIE cannot be sufficiently supported at this point in time. Further studies, especially those focused on cost-effectiveness are needed to strengthen the existing evidence to inform policy makers on feasibility of increased assimilation of this technology into clinical practice.

Esophageal reconstruction can be challenging when stomach and colon are not anatomically intact and their use as esophageal substitutes is therefore limited. Innovative individual approaches are then necessary to restore the intestinal passage. We describe a technique in which a short stump of the right hemicolon and 25 cm of ileum on a long, non-supercharged, fully mobilized ileocolic arterial pedicle were used for esophageal reconstruction to the neck. In this case, a 65 year-old male patient had accidentally indigested hydrochloric acid which caused necrosis of his upper digestive tract. An emergency esophagectomy, gastrectomy, duodenectomy, pancreatectomy and splenectomy had been performed in an outside hospital. A cervical esophagostomy and a biliodigestive anastomosis had been created and a jejunal catheter for enteral feeding had been placed. After the patient had recovered, a reconstruction of his food passage via the left and transverse colon failed for technical reasons due to an intraoperative necrotic demarcation of the colon. Our team then faced the situation that only a short stump of the right hemi-colon was left in situ when the patient was referred to our center. After intensified nutritional therapy, we reconstructed this patient's food passage with the right hemicolon-approach described herein. After treatment of a postoperative pneumonia, the patient was discharged from hospital on the 26(th) postoperative day in a good clinical condition on an oral-only diet. In conclusion, individual approaches for long-segment reconstruction of the esophagus can be technically feasible in experienced hands. They do not always require arterial supercharging or free intestinal transplantation.

Background Anastomotic leakages after esophagectomies continue to constitute significant morbidity and mortality. Intrathoracic anastomoses pose a high risk for mediastinitis, sepsis, and death, if a leak is not addressed timely and appropriately. However, there are no standardized treatment recommendations or algorithms as for how to treat these leakages. Methods The study included all patients at the University Hospital Regensburg, who developed an anastomotic leakage after esophagectomy with gastric pull-up reconstruction from 2007 to 2022. Patients receiving conventional treatment options for an anastomotic leakage (stents, drainage tubes, clips, etc.) were compared to patients receiving endoscopic vacuum-assisted closure (eVAC) therapy as their mainstay of treatment. Treatment failure was defined as cervical esophagostomy formation or death. Results In total, 37 patients developed an anastomotic leakage after esophagectomy with a gastric pull-up reconstruction. Twenty patients were included into the non-eVAC cohort, whereas 17 patients were treated with eVAC. Treatment failure was observed in 50% of patients (n = 10) in the non-eVAC cohort and in 6% of patients (n = 1) in the eVAC cohort (p < 0.05). The 90-day mortality in the non-eVAC cohort was 15% (n = 3) compared to 6% (n = 1) in the eVAC cohort. Cervical esophagostomy formation was required in 40% of cases (n = 8) in the non-eVAC cohort, whereas no patient in the eVAC cohort underwent cervical esophagostomy formation. Conclusion eVAC therapy for leaking esophagogastric anastomoses appears to be superior to other treatment strategies as it significantly reduces morbidity and mortality. Therefore, we suggest eVAC as an essential component in the treatment algorithm for anastomotic leakages following esophagectomies, especially in patients with intrathoracic anastomoses.