Treatment-emergent adverse events after infusion of adherent stem cells: the MiSOT-I score for solid organ transplantation

BACKGROUND: Cellular therapy after organ transplantation is emerging as an intriguing strategy to achieve dose reduction of classical immunosuppressive pharmacotherapy. Here, we introduce a new scoring system to assess treatment-emergent adverse events (TEAEs) of adherent stem cell therapies in the clinical setting of allogeneic liver transplantation (for example, the MiSOT-I trial Eudract CT: 2009-017795-25). METHODS: The score consists of three independent modalities (set of parameters) that focus on clinically relevant events early after intravenous or intraportal stem cell infusion: pulmonary toxicity, intraportal-infusional toxicity and systemic toxicity. For each modality, values between 0 (no TEAE) and 3 (severe TEAE) were defined. The score was validated retrospectively on a cohort of n=187 recipients of liver allografts not receiving investigational cell therapy between July 2004 and December 2010. These patients represent a control population for further trials. Score values were calculated for days 1, 4, and 10 after liver transplantation. RESULTS: Grade 3 events were most commonly related to the pulmonary system (3.5% of study cohort on day 4). Almost no systemic-related TEAEs were observed during the study period. The relative frequency of grade 3 events never exceeded 5% over all modalities and time points. A subgroup analysis for grade 3 patients provided no descriptors associated with severe TEAEs. CONCLUSION: The MiSOT-I score provides an assessment tool to score specific adverse events that may occur after adherent stem cell therapy in the clinical setting of organ transplantation and is thus a helpful tool to conduct a safety study

A simplified regimen of targeted antifungal prophylaxis in liver transplant recipients: A single-center experience

Background: Invasive fungal infection (IFI) is a severe complication of liver transplantation burdened by high mortality. Guidelines recommend targeted rather than universal antifungal prophylaxis based on tiers of risk. Methods: We aimed to evaluate IFI incidence, risk factors, and outcome after implementation of a simplified two-tiered targeted prophylaxis regimen based on a single broad-spectrum antifungal drug (amphotericin B). Patients presenting 1 or more risk factors according to literature were administered prophylaxis. Prospectively collected data on all adult patients transplanted in Turin from January 2011 to December 2015 were reviewed. Results: Patients re-transplanted before postoperative day 7 were considered once, yielding a study cohort of 581 cases. Prophylaxis was administered to 299 (51.4%) patients; adherence to protocol was 94.1%. Sixteen patients developed 18 IFIs for an overall rate of 2.8%. All IFI cases were in targeted prophylaxis group; none of the non-prophylaxis group developed IFI. Most cases (81.3%) presented within 30 days after transplantation during prophylaxis; predominant pathogens were molds (94.4%). Only 1 case of candidemia was observed. One-year mortality in IFI patients was 33.3% vs 6.4% in patients without IFI (P =.001); IFI attributable mortality was 6.3%. At multivariate analysis, significant risk factors for IFI were renal replacement therapy (OR = 8.1) and re-operation (OR = 5.2). Conclusions: The implementation of a simplified targeted prophylaxis regimen appeared to be safe and applicable and was associated with low IFI incidence and mortality. Association of IFI with re-operation and renal replacement therapy calls for further studies to identify optimal prophylaxis in this subset of patients

Effect on post-operative pulmonary complications frequency of high flow nasal oxygen versus standard oxygen therapy in patients undergoing esophagectomy for cancer: study protocol for a randomized controlled trial—OSSIGENA study

Background: Postoperative pulmonary complications (PPCs) remain a challenge after esophagectomy. Despite improvement in surgical and anesthesiological management, PPCs are reported in as many as 40% of patients. The main aim of this study is to investigate whether early application of high-flow nasal cannula (HFNC) after extubation will provide benefit in terms of reduced PPC frequency compared to standard oxygen therapy. Methods: Patients aged 18–85 years undergoing esophagectomy for cancer treatment with radical intent, excluding those with American Society of Anesthesiologists (ASA) score >3 and severe systemic comorbidity (cardiac, pulmonary, renal or hepatic disease) will be randomized at the end of surgery to receive HFNC or standard oxygen therapy (Venturi mask or nasal goggles) after early extubation (within 12 hours after the end of surgery) for 48 hours. The main postoperative goals are to obtain SpO2 ≥94% and adequate pain control. Oxygen therapy after 48 hours will be stopped unless the physician deems it necessary. In case of respiratory clinical worsening, patients will be supported with the most appropriate tool (noninvasive ventilation or invasive mechanical ventilation). Pulmonary [pneumonia, pleural effusion, pneumothorax, atelectasis, acute respiratory distress syndrome (ARDS), tracheo-bronchial injury, air leak, reintubation, and/or respiratory failure] complications will be recorded as main outcome. Secondary outcomes, including cardiovascular, surgical, renal and infective complications will also be recorded. The primary analysis will be carried out on 320 patients (160 per group) and performed on an intention-to-treat (ITT) basis, including all participants randomized into the treatment groups, regardless of protocol adherence. The primary outcome, the PPC rate, will be compared between the two treatment groups using a chi-square test for categorical data, or Fisher’s exact test will be used if the assumptions for the chi-square test are not met. Discussion: Recent evidence demonstrated that early application of HFNC improved the respiratory rate oxygenation index (ROX index) after esophagectomy but did not reduce PPCs. This randomized controlled multicenter trial aims to assess the potential effect of the application of HFNC versus standard oxygen over PPCs in patients undergoing esophagectomy. Trial Registration: This study is registered at clinicaltrial.gov NCT05718284, dated 30 January 2023

Effect on post-operative pulmonary complications frequency of high flow nasal oxygen versus standard oxygen therapy in patients undergoing esophagectomy for cancer: study protocol for a randomized controlled trial—OSSIGENA study

Background: Postoperative pulmonary complications (PPCs) remain a challenge after esophagectomy. Despite improvement in surgical and anesthesiological management, PPCs are reported in as many as 40% of patients. The main aim of this study is to investigate whether early application of high-flow nasal cannula (HFNC) after extubation will provide benefit in terms of reduced PPC frequency compared to standard oxygen therapy. Methods: Patients aged 18–85 years undergoing esophagectomy for cancer treatment with radical intent, excluding those with American Society of Anesthesiologists (ASA) score >3 and severe systemic comorbidity (cardiac, pulmonary, renal or hepatic disease) will be randomized at the end of surgery to receive HFNC or standard oxygen therapy (Venturi mask or nasal goggles) after early extubation (within 12 hours after the end of surgery) for 48 hours. The main postoperative goals are to obtain SpO2 ≥94% and adequate pain control. Oxygen therapy after 48 hours will be stopped unless the physician deems it necessary. In case of respiratory clinical worsening, patients will be supported with the most appropriate tool (noninvasive ventilation or invasive mechanical ventilation). Pulmonary [pneumonia, pleural effusion, pneumothorax, atelectasis, acute respiratory distress syndrome (ARDS), tracheo-bronchial injury, air leak, reintubation, and/or respiratory failure] complications will be recorded as main outcome. Secondary outcomes, including cardiovascular, surgical, renal and infective complications will also be recorded. The primary analysis will be carried out on 320 patients (160 per group) and performed on an intention-to-treat (ITT) basis, including all participants randomized into the treatment groups, regardless of protocol adherence. The primary outcome, the PPC rate, will be compared between the two treatment groups using a chi-square test for categorical data, or Fisher’s exact test will be used if the assumptions for the chi-square test are not met. Discussion: Recent evidence demonstrated that early application of HFNC improved the respiratory rate oxygenation index (ROX index) after esophagectomy but did not reduce PPCs. This randomized controlled multicenter trial aims to assess the potential effect of the application of HFNC versus standard oxygen over PPCs in patients undergoing esophagectomy