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Several food contact materials (FCMs) contain non-intentionally added substances (NIAS), and most of the substances that migrate from plastic food packaging are unknown. This review aimed to situate the main challenges involving unknown NIAS in plastic food packaging in terms of identification, migration tests, prediction, sample preparation, determination methods and risk assessment trials. Most studies have identified NIAS in plastic materials as polyurethane adhesives (PU), polyethylene terephthalate (PET), polyester coatings, polypropylene materials (PP), multilayers materials, plastic films, polyvinyl chloride (PVC), recycled materials, high-density polyethylene (HDPE) and low-density polyethylene (LDPE). Degradation products are almost the primary source of NIAS in plastic FCMs, most from antioxidants as Irganox 1010 and Irgafos 168, following by oligomers and side reaction products. The NIAS assessment in plastics FCMs is usually made by migration tests under worst-case conditions using food simulants. For predicted NIAS, targeted analytical methods are applied using GC-MS based methods for volatile NIAS and GC-MS and LC-MS based methods for semi- and non-volatile NIAS; non-targeted methods to analyze unknown NIAS in plastic FCMs are applied using GC and LC techniques combined with QTOF mass spectrometry (HRMS). In terms of NIAS risk assessment and prioritization, the threshold of toxicological concern (TTC) concept is the most applied tool for risk assessment. Bioassays with sensitive analytical techniques seem to be an efficient method to identify NIAS and their hazard to human exposure; the combination of genotoxicity testing with analytical chemistry could allow the Cramer class III TTC application to prioritize unknown NIAS. The scientific justification for implementing a molecular weight-based cut-off (<1000 Da) in the risk assessment of FCMs should be reevaluated. Although official guides and opinions are being issued on the subject, the whole chain’s alignment is needed, and more specific legislation on the steps to follow to get along with NIAS.

We retrospectively evaluated the incidence, factors, and clinical outcomes of the discontinuation of immunosuppressive treatment (IST) after single-unit unrelated cord blood transplantation (CBT) in adults receiving cyclosporine-based graft-versus-host disease (GVHD) prophylaxis at our institute. Among the 309 patients who achieved engraftment, 247 were able to discontinue IST with a median follow-up of 121 months for survivors. The cumulative incidence of the discontinuation of IST was 46.2% at 180 days, 72.8% at 2 years, and 79.3% at 5 years post-CBT. In the multivariate analysis, discontinuation of IST after CBT was significantly associated with the requirement for steroid therapy (hazard ratio [HR]: 0.46; P < 0.001) and the recent calendar year of CBT (HR: 1.79; P < 0.001). In the conditional landmark analysis at 180 days, discontinuation of IST was not associated with the development of extensive chronic GVHD (HR: 1.00; P = 0.989), non-relapse mortality (HR: 0.49; P = 0.122), relapse (HR: 1.46; P = 0.388), or overall survival (HR: 1.91; P = 0.065). Our data showed that successful discontinuation of IST is common after single-unit CBT in adults. Discontinuation of IST did not affect subsequent outcomes, suggesting that discontinuation of IST is both feasible and safe in adults undergoing single-unit CBT.

Severe bacterial infections are a serious problem after cord blood transplantation (CBT). Colonization with multidrug-resistant Gram-negative rods (MRGNR) is associated with increased morbidity and mortality after allogeneic hematopoietic cell transplantation. However, its impact on outcomes after CBT is unclear. We aim to explore the impact of colonization with MRGNRs in adult patients undergoing CBT. We retrospectively analyzed 145 adult patients who received single-unit CBT in our institute. As a standard practice in our institute, all patients were screened for colonization with MRGNR by oral cavity swabs, urine, and stool specimens between the day of admission for CBT and the day of discharge or day 100 after CBT. There were 62 incidents of colonization with MRGNR in 52 patients, of which 25 involved Stenotrophomonas maltophilia, 19 multidrug-resistant Pseudomonas spp., and 18 extended-spectrum beta-lactamase-producing Enterobacteriaceae. On multivariate analysis, MRGNR persistence significantly affected increase in non-relapse mortality (NRM) (hazard ratio [HR], 8.96; 95% CI 1.85–43.46; P = 0.006) and the subsequent development of bloodstream infection due to MRGNR (HR 11.82; 95% CI 2.15–64.87; P = 0.004), but not MRGNR clearance, compared with non-colonized patients. These data suggest that persistent colonization with MRGNR is significantly associated with higher NRM in CBT for adults.

Augmented renal clearance (ARC) is a phenomenon characterized by increased renal functionality, which can impact the pharmacokinetics and pharmacodynamics of antimicrobial drugs eliminated by the kidneys. It is a potential concern for infection treatment. Cord blood transplantation (CBT) is primarily impeded by delayed neutrophil recovery and immune reconstitution, thereby increasing susceptibility to infection. However, the clinical implications of ARC following CBT remain unexplored. We retrospectively assessed the influence of ARC on post-transplant outcomes at various time points in 194 adult recipients of single-unit unrelated CBT between 2007 and 2022 at our institution. ARC was observed in 52.9% of patients at 1 day, 39.8% at 15 days, and 26.5% at 29 days post-CBT. ARC was not significantly associated with bloodstream infection, acute graft-versus-host disease, or veno-occlusive disease/sinusoidal obstruction syndrome at any time point. ARC at 1 day, 15 days, and 29 days post-CBT was not significantly associated  with overall survival, non-relapse mortality, or relapse rates. These findings suggest that ARC is common in adults during the early stages of CBT, but does not discernibly influence clinical outcomes or post-CBT complications.

Even though hematopoietic stem cell transplantation (HSCT) allows successful treatment for many malignant and non-malignant disorders, its curative potential remains limited by severe side effects, including infections and other transplant-related complications such as graft-versus-host disease (GvHD). This study examined changes in serum proteome via high-performance two-dimensional gel electrophoresis (2-DE) during HSCT to search for diagnostic biomarkers for post-HSCT complications. Longitudinal proteomic analysis revealed proteins related to metabolic complications and hemolytic anemia. Retinol-binding protein 4 (RBP4), a reliable marker of insulin resistance, was identified, and is possibly associated with the onset mechanism of acute graft-versus-host disease (aGvHD) and/or skin GvHD. Although the cause of insulin resistance is not fully understood, it is thought to be associated with adipocytes inflammation induced by RBP4, iron overload and hemolytic anemia after HSCT, as observed in this study. The present study has demonstrated that insulin resistance and metabolic complications could be immediate complications after transplantation and are associated with aGvHD. The biomarkers revealed in this study are promising tools to be used for improving the early diagnosis of HSCT-associated complications, especially aGvHD, possibly even before clinical manifestations.

This study investigated the safety, efficacy, and immunological influence of allogeneic umbilical cord-derived mesenchymal stromal cells (IMSUT-CORD) processed in serum-free medium and cryoprotectant, for treating steroid-resistant acute graft-versus-host disease (aGVHD). In a phase I dose-escalation trial, IMSUT-CORD were infused intravenously twice weekly over two cycles with up to two additional cycles. Four patients received a dose of 1 × 106 cells/kg, while three received 2 × 106/kg. Of 76 total adverse events, fourteen associated or possibly associated adverse events included 2 cases of a hot flash, headache, and peripheral neuropathy, 1 each of upper abdominal pain, hypoxia, increased γ-GTP, somnolence, peripheral vascular pain at the injection site, thrombocytopenia, hypertension, and decreased fibrinogen. At 16 weeks after the initial IMSUT-CORD infusion, three patients showed complete response (CR), two partial response (PR), one mixed response, and one no response. The overall response rate was 71.4%, and the continuous CR/PR rate was 100% for over 28 days after CR/PR. NK cell count significantly increased and correlated with treatment response, whereas IL-12, IL-17, and IL-33 levels decreased, but did not correlate with treatment response. CCL2 and CCL11 levels increased during IMSUT-CORD therapy. IMSUT-CORD are usable in patients with steroid-resistant aGVHD (UMIN000032819: https://www.umin.ac.jp/ctr).

Although daily higher urinary sodium (Na) and potassium (K) excretion ratio is associated with the risk of cardiovascular disease in the general population, a low Na/K ratio is associated with renal dysfunction in critically ill patients. Thus, we retrospectively analyzed the impact of daily urinary Na and K excretion and their ratio on non-relapse mortality (NRM) and overall mortality in 172 adult single-unit cord blood transplantation (CBT) patients treated at our institution between 2007 and 2020. Multivariate analysis showed that a low urinary Na/K ratio at both 14 days (hazard ratio [HR], 4.82; 95% confidence interval [CI], 1.81–12.83; P  = 0.001) and 28 days (HR, 4.47; 95% CI 1.32–15.12; P  = 0.015) was significantly associated with higher NRM. Furthermore, a low urinary Na/K ratio at 28 days was significantly associated with higher overall mortality (HR, 2.38; 95% CI 1.15–4.91; P  = 0.018). Patients with a low urinary Na/K ratio had decreased urine volume, more weight gain, experienced more grade III–IV acute graft-versus-host disease, and required corticosteroids by 28 days after CBT. These findings indicate that a low urinary Na/K ratio early after single-unit CBT is associated with poor NRM and survival in adults.

Abstract An intensified myeloablative conditioning regimen, involving the addition of granulocyte colony-stimulating factor (G-CSF)-combined high-dose cytarabine (12 g/m2) to standard total body irradiation and cyclophosphamide, has been performed for adult patients with myeloid malignancies in single-unit cord blood transplantation (CBT) since 1998 in our institute. We update the results of CBT, as the first allogeneic hematopoietic cell transplantation after this conditioning regimen, in 169 patients with a median long-term follow-up of 10.4 years. The median age was 43 years (range, 16 to 59 years). Ninety-four patients (56%) were in non-remission at the time of CBT, and 124 patients (73%) were acute myeloid leukemia. The median cryopreserved cord blood total nucleated cell dose and CD34+ cell dose was 2.40 × 107/kg and 0.93 × 105/kg, respectively. The cumulative incidence of neutrophil recovery at 42 days was 94.4% (95% confidence interval [CI]: 88.6–97.3%). Among the whole cohort, 105 patients were still alive at the end of the study period. The cumulative incidences of relapse and non-relapse mortality at 10 years were 26.0% (95% CI: 19.5–33.0%) and 16.9% (95% CI: 11.4–23.4%), respectively. There was an overall survival probability of 62.5% (95% CI: 54.3–69.7%) at 10 years. Higher disease risk index alone significantly affected higher overall mortality (hazard ratio 2.21, P = 0.003) in multivariate analysis. These outcomes demonstrate that G-CSF-combined myeloablative conditioning could have favorable long-term remission rates for adult patients with myeloid malignancies undergoing single-unit CBT.