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Photoreceptor degeneration is a major cause of untreatable blindness worldwide and has recently been targeted by emerging technologies, including cell- and gene-based therapies. Cell types of neural lineage have shown promise for replacing either photoreceptors or retinal pigment epithelial cells following delivery to the subretinal space, while cells of bone marrow lineage have been tested for retinal trophic effects following delivery to the vitreous cavity. Here we explore an alternate approach in which cells from the immature neural retinal are delivered to the vitreous cavity with the goal of providing trophic support for degenerating photoreceptors. Rat and human retinal progenitor cells were transplanted to the vitreous of rats with a well-studied photoreceptor dystrophy, resulting in substantial anatomical preservation and functional rescue of vision. This work provides scientific proof-of-principle for a novel therapeutic approach to photoreceptor degeneration that is currently being evaluated in clinical trials.

The goal of this study was to determine if transplantation of enteric neural stem cells (ENSCs) can rescue the enteric nervous system, restore gut motility, reduce colonic inflammation, and improve survival in the Ednrb-KO mouse model of Hirschsprung disease (HSCR). ENSCs were isolated from mouse intestine, expanded to form neurospheres, and microinjected into the colons of recipient Ednrb-KO mice. Transplanted ENSCs were identified in recipient colons as cell clusters in neo-ganglia. Immunohistochemical evaluation demonstrated extensive cell migration away from the sites of cell delivery and across the muscle layers. Electrical field stimulation and optogenetics showed significantly enhanced contractile activity of aganglionic colonic smooth muscle following ENSC transplantation and confirmed functional neuromuscular integration of the transplanted ENSC-derived neurons. ENSC injection also partially restored the colonic migrating motor complex. Histological examination revealed a significant reduction in inflammation in ENSC-transplanted aganglionic recipient colon compared with that of sham-operated mice. Interestingly, mice that received cell transplant also had prolonged survival compared with controls. This study demonstrates that ENSC transplantation can improve outcomes in HSCR by restoring gut motility and reducing the severity of Hirschsprung-associated enterocolitis, the leading cause of death in human HSCR.

Regenerative cell therapy to replenish the missing neurons and glia in the aganglionic segment of Hirschsprung disease represents a promising treatment option. However, the success of cell therapies for this condition are hindered by poor migration of the transplanted cells. This limitation is in part due to a markedly less permissive extracellular environment in the postnatal gut than that of the embryo. Coordinated interactions between enteric neural crest-derived cells (ENCDCs) and their local environment drive migration along the embryonic gut during development of the enteric nervous system. Modifying transplanted cells, or the postnatal extracellular environment, to better recapitulate embryonic ENCDC migration could be leveraged to improve the engraftment and coverage of stem cell transplants. We compared the transcriptomes of ENCDCs from the embryonic intestine to that of postnatal-derived neurospheres and identified 89 extracellular matrix (ECM)-associated genes that are differentially expressed. Agrin, a heparin sulfate proteoglycan with a known inhibitory effect on ENCDC migration, was highly over-expressed by postnatal-derived neurospheres. Using a function-blocking antibody and a shRNA-expressing lentivirus, we show that inhibiting agrin promotes ENCDC migration in vitro and following cell transplantation ex vivo and in vivo. This enhanced migration is associated with an increased proportion of GFAP + cells, whose migration is especially enhanced.

Because derivation of retinal organoids (ROs) and transplantation are frequently split between geographically distant locations, we developed a special shipping device and protocol capable of the organoids' delivery to any location. Human embryonic stem cell (hESC)-derived ROs were differentiated from the hESC line H1 (WA01), shipped overnight to another location, and then transplanted into the subretinal space of blind immunodeficient retinal degeneration (RD) rats. Development of transplants was monitored by spectral-domain optical coherence tomography. Visual function was accessed by optokinetic tests and superior colliculus (SC) electrophysiology. Cryostat sections through transplants were stained with hematoxylin and eosin; or processed for immunohistochemistry to label human donor cells, retinal cell types, and synaptic markers. After transplantation, ROs integrated into the host RD retina, formed functional photoreceptors, and improved vision in rats with advanced RD. The survival and vision improvement are comparable with our previous results of hESC-ROs without a long-distance delivery. Furthermore, for the first time in the stem cell transplantation field, we demonstrated that the response heatmap on the SC showed a similar shape to the location of the transplant in the host retina, which suggested the point-to-point projection of the transplant from the retina to SC. In conclusion, our results showed that using our special device and protocol, the hESC-derived ROs can be shipped over long distance and are capable of survival and visual improvement after transplantation into the RD rats. Our data provide a proof-of-concept for stem cell replacement as a therapy for RD patients.

BACKGROUND: Autologous stem cell transplantation (ASCT) after induction therapy improves disease-free survival for patients with multiple myeloma (MM). While the goal of ASCT is to render a minimal disease state, it is also associated with eradication of immunosuppressive cells, and we hypothesize that early introduction of immunotherapy post-ASCT may provide a window of opportunity to boost treatment efficacy. METHODS: We conducted a phase 1 clinical trial to investigate the application of autologous lymphocyte infusion and anti-SLAMF7 monoclonal antibody, elotuzumab, after ASCT in patients with newly diagnosed MM previously treated with induction therapy. In addition to CD34+ stem cells, peripheral blood mononuclear cells were harvested prior to transplant and infused on day 3 after stem cell infusion to accelerate immune reconstitution and provide autologous natural killer (NK) cells that are essential to the mechanism of elotuzumab. Elotuzumab was administered starting on day 4 and then every 28 days after until 1 year post-ASCT. Cycles 4-12 were administered with standard-of-care lenalidomide maintenance. RESULTS: All subjects were evaluated for safety, and 13 of 15 subjects completed the treatment protocol. At 1 year post-ASCT, the disease status of enrolled subjects was as follows: five stringent complete responses, one complete response, six very good partial responses, one partial response, and two progressive diseases. The treatment plan was well tolerated, with most grade 3 and 4 AEs being expected hematologic toxicities associated with ASCT. Correlative analysis of the immune microenvironment demonstrated a trend toward reduced regulatory T cells during the first 3 months post-transplant followed by an increase in NK cells and monocytes in patients achieving a complete remission. CONCLUSIONS: This phase 1 clinical trial demonstrates that early introduction of immunotherapy after ASCT is well tolerated and shows promising disease control in patients with MM, accompanied by favorable changes in the immune microenvironment. TRIAL REGISTRATION NUMBER: NCT02655458.

Allogeneic hematopoietic stem cell transplantation (aHSCT) can cure patients with otherwise fatal leukemias and lymphomas. However, the benefits of aHSCT are limited by graft-versus-host disease (GVHD). Minnelide, a water-soluble analog of triptolide, has demonstrated potent antiinflammatory and antitumor activity in several preclinical models and has proven both safe and efficacious in clinical trials for advanced gastrointestinal malignancies. Here, we tested the effectiveness of Minnelide in preventing acute GVHD as compared with posttransplant cyclophosphamide (PTCy). Strikingly, we found Minnelide improved survival, weight loss, and clinical scores in an MHC-mismatched model of aHSCT. These benefits were also apparent in minor MHC-matched aHSCT and xenogeneic HSCT models. Minnelide was comparable to PTCy in terms of survival, GVHD clinical score, and colonic length. Notably, in addition to decreased donor T cell infiltration early after aHSCT, several regulatory cell populations, including Tregs, ILC2s, and myeloid-derived stem cells in the colon were increased, which together may account for Minnelides GVHD suppression after aHSCT. Importantly, Minnelides GVHD prevention was accompanied by preservation of graft-versus-tumor activity. As Minnelide possesses anti-acute myeloid leukemia (anti-AML) activity and is being applied in clinical trials, together with the present findings, we conclude that this compound might provide a new approach for patients with AML undergoing aHSCT.

Neurointestinal diseases cause significant morbidity and effective treatments are lacking. This study aimes to test the feasibility of transplanting autologous enteric neural stem cells (ENSCs) to rescue the enteric nervous system (ENS) in a model of colonic aganglionosis. ENSCs are isolated from a segment of small intestine from Wnt1::Cre;R26iDTR mice in which focal colonic aganglionosis is simultaneously created by diphtheria toxin injection. Autologous ENSCs are isolated, expanded, labeled with lentiviral-GFP, and transplanted into the aganglionic segment in vivo. ENSCs differentiate into neurons and glia, cluster to form neo-ganglia, and restore colonic contractile activity as shown by electrical field stimulation and optogenetics. Using a non-lethal model of colonic aganglionosis, our results demonstrate the potential of autologous ENSC therapy to improve functional outcomes in neurointestinal disease, laying the groundwork for clinical application of this regenerative cell-based approach.

Background Objective Methods Results Conclusion Dental pulp tissue engineering is expected to become an ideal treatment for irreversible pulpitis and apical periodontitis. However, angiogenesis and neurogenesis for functional pulp regeneration have not yet met the standard for large‐scale clinical application, and need further research.This review focused on the potential mechanisms of angiogenesis and neurogenesis in pulp regeneration, including stem cell types, upstream and downstream regulatory molecules and cascade signalling pathways, thereby providing a theoretical basis and inspiring new ideas to improve the effectiveness of dental pulp tissue engineering.An electronic literature search was carried out using the keywords of ‘pulp regeneration’, ‘stem cell transplantation’, ‘dental pulp stem cells’, ‘angiogenesis’ and ‘neurogenesis’. The resulting literature was screened and reviewed.Stem cells used in dental pulp tissue engineering can be classified as dental‐derived and non‐dental‐derived stem cells, amongst which dental pulp stem cells (DPSC) have achieved promising results in animal experiments and clinical trials. Multiple molecules and signalling pathways are involved in the process of DPSC‐mediated angiogenic and neurogenetic regeneration. In order to promote angiogenesis and neurogenesis in pulp regeneration, feasible measures include the addition of growth factors, the modulation of transcription factors and signalling pathways, the use of extracellular vesicles and the modification of bioscaffold materials.Dental pulp tissue engineering has had breakthroughs in preclinical and clinical studies in vivo. Overcoming difficulties in pulpal angiogenesis and neurogenesis, and achieving functional pulp regeneration will lead to a significant impact in endodontics. [ABSTRACT FROM AUTHOR]

Background: Ischemic cardiomyopathy, characterized by coronary artery atherosclerosis, impairs the myocardial tissue. Coronary artery bypass grafting (CABG) is commonly used to revascularize affected areas and improve patient survival rates; however, it can fail to enhance cardiac function. Impaired capillary blood flow may obstruct functional recovery, prompting interest in treatments, such as angiogenic factor administration. Adipose-derived stem cells (ADSCs), which are known for immune evasion, have shown the potential to construct capillary networks and improve myocardial function. This clinical trial aimed to evaluate the safety and efficacy of ADSC spray therapy combined with CABG. Methods: This single-center, randomized, double-blind study involved patients with ischemic cardiomyopathy who were scheduled for CABG and who had a left ventricular ejection fraction ≤ 40%. The participants were randomized to receive CABG as well as ADSC spray therapy or placebo. The primary endpoints were safety, changes in late gadolinium-enhanced (LGE) magnetic resonance imaging (MRI) volumes, and feasibility. The secondary endpoints included left ventricular function, exercise tolerance, and heart failure symptoms. Results: Seven patients were enrolled; of them, six were randomized to receive ADSC therapy (n = 3) or placebo (n = 3). The procedure was successfully completed with minimal adverse events. One patient in the ADSC group developed pleural effusion that was resolved with drainage. The LGE-MRI volumes decreased in the ADSC group but remained unchanged in the placebo group. Improvements in left ventricular function and exercise tolerance were noted in the ADSC group, with heart failure symptoms improving to New York Heart Association class I. In contrast, the placebo group showed no significant changes, with one patient experiencing worsening symptoms. Conclusions: ADSC spray therapy combined with CABG demonstrated safety and efficacy at enhancing cardiac function. ADSC likely contributes to capillary network reconstruction, thereby augmenting the benefits of CABG. Future phase II and III trials are warranted to confirm its therapeutic efficacy and long-term outcomes. This novel approach represents a significant advancement in the treatment of ischemic cardiomyopathy and offers a viable strategy for improving myocardial function and patient prognosis. Trial registration This study was registered with the Japan Registry of Clinical Trials (jRCT2053190103) and ClinicalTrials.gov (NCT04695522) [ABSTRACT FROM AUTHOR]

Cytomegalovirus (CMV) infections continue to be associated with significant morbidity and mortality following solid organ transplantation and haemopoietic stem cell transplantation. Advances in understanding the biology of CMV in the immunosuppressed host will translate into improved management approaches and better clinical outcomes. Updated definitions of resistant and refractory CMV infections will lead to more consistent reporting of CMV outcomes, better inform appropriate antiviral strategies and influence clinical trial design. Improved knowledge of the immunological control of CMV in the immunosuppressed host has led to novel diagnostics, emerging therapeutic cellular therapies and the development of an informed rationale for prophylactic and pre‐emptive strategies. As the boundaries of transplantation are extended, new patterns of CMV infection are being recognised. Finally, recent studies support the use of novel antiviral therapies in transplant recipients in the appropriate clinical setting. In this review, we provide an update on important new and emerging concepts in the management of CMV in immunosuppressed transplant recipients. [ABSTRACT FROM AUTHOR]

Summary: Philadelphia chromosome (Ph)‐like acute lymphoblastic leukaemia (ALL) is a high‐risk subtype with a gene expression profile similar to Ph‐positive ALL, due to activation of tyrosine kinase signalling. To understand the clinical implications of Ph‐like ALL, this single‐centre retrospective study evaluates outcomes in 268 adults, largely Hispanic ALL patients treated between 2013 and 2024, with a subgroup analysis of 139 haematopoietic stem cell transplantation (HSCT) patients. ALL subtypes included 68 (25.4%) Ph‐like, 89 (33.2%) Ph‐positive, and 111 (41.4%) Ph‐negative. Ph‐like patients were the youngest age at diagnosis (p = 0.007), most likely to have refractory disease (p < 0.001), and least likely to achieve minimal residual disease (MRD) negativity after induction (p = 0.031). Relative to Ph‐negative ALL, Ph‐like achieved worse event‐free survival (EFS) (HR = 1.66; 95% CI 1.12–2.46; p = 0.012), whereas Ph‐positive had improved EFS (HR = 0.60; 95% CI 0.38–0.93; p = 0.024) and cumulative incidence of relapse (CIR) (HR = 0.59; 95% CI 0.35–0.99; p = 0.046). Within the transplant subgroup, Ph status did not impact disease‐free survival (DFS), CIR, or overall survival (OS). However, patients who received blinatumomab within 1‐year pre‐HSCT had improved DFS (HR = 0.43; 95% CI 0.20–0.94; p = 0.034) and CIR (HR = 0.26; 95% CI 0.09–0.75; p = 0.13). In conclusion, our data suggest that Ph‐like is less likely to respond to standard induction therapy and HSCT may result in similar survival outcomes to Ph‐negative ALL. [ABSTRACT FROM AUTHOR]

Despite the approval of new drugs, the inclusion of -omics-derived data and the integration of machine learning in both the diagnostic and therapeutic process, the prognosis of acute myeloid leukemia (AML) remains dismal. The curative path is still aimed at achieving a successful allogeneic hematopoietic stem cell transplant (HSCT) in most patients. Nevertheless, access to this procedure is limited to eligible patients. Moreover, post-HSCT outcomes are influenced by AML heterogeneity and patient-related factors. The rise of venetoclax (VEN)-based combinations as standard of care in the treatment of older or unfit AML patients, together with their peculiar management profile, has led researchers to evaluate the feasibility of this approach in patients proceeding toward HSCT. We reviewed the available evidence to weigh up the advantages and pitfalls of this new therapeutic strategy. [ABSTRACT FROM AUTHOR]

Objectives: Diabetes mellitus has a negative impact on patients' lives and is a significant medical and social problem. Due to the high prevalence of diabetes mellitus, shortage of donor materials, immune rejection of the pancreas and limited efficacy of existing treatment methods, the study of promising and more effective approaches to the treatment of this disease, such as transplantation of fetal pancreatic islet cells, becomes relevant. The aim of the study is to determine the efficacy and necessity of fetal pancreatic islet cell transplantation in the treatment of type 2 diabetes mellitus. Methods: The study was carried out with the help of analytical-synthetic method, literature review and analysis of medical databases corresponding to the topic of work, clinical and experimental studies conducted by other authors were considered. Results: As a result of this work, it was found that the use of fetal stem cell transplantation is an effective method in the treatment of diabetes. Studies confirm that this method reduces hyperglycaemia and NOMA index, increases c-peptide values without serious side effects on the background of treatment. Conclusions: Fetal islet cells have advantages in cell culture, relatively low immunogenicity, effective engraftment, although they may produce less insulin relative to adult somatic stem cells. Transplanted islet cells are able to replace and renew the function of the recipient's own pancreatic β-cells, and prevent their destruction. Fetal pancreatic islet cell transplantation is a promising treatment option for type 2 diabetes that can complement or replace existing therapies, improving patients' glucose control. [ABSTRACT FROM AUTHOR]

Due to the limitations of organ transplantation and the urgent need for treatment of chronic diseases, the benefit of stem cells for treatment has been studied and evaluated as an effective approach worldwide. One of the leading countries in this field is Iran. In this respect, several research and treatment institutes, including endocrinology and metabolism research institute are active in the use of stem cells in Iran. Herein, the aim is to review strategies, challenges, and opportunities for stem cell research and treatment in endocrinology and metabolism research institute. [ABSTRACT FROM AUTHOR]

Background: Inflammatory bowel diseases are complex chronic disorders with a relapsing–remitting course that affect the gut due to dysregulated immune response. The incidence of these disorders is increasing globally along with an increase in the incidence in pediatric population. Very early onset inflammatory bowel diseases are seen in children with age less than 6 years, where monogenic causes predominate. With the advent of next‐generation sequencing methods, these disorders are being diagnosed more. Interleukin‐10 receptor mutation‐associated inflammatory bowel diseases is one such monogenic disorder where immunosuppression shows poor response. Methods: We report the case of an 8‐month‐old child of Indian origin who presented with severe enterocolitis and rectovaginal fistulas. She was evaluated on lines of a very early onset inflammatory bowel disease. She was found to have a mutation in the interleukin‐10 receptor causing severe enterocolitis. She underwent a diversion colostomy. She was admitted at 25 months of age for the hematopoietic‐stem‐cell‐transplant (HSCT). The conditioning regimen used consisted of busulfan, fludarabine, and anti‐thymocyte‐globulin (ATG). The child received a 10/10 human leukocyte antigen (HLA) matched from a matched‐unrelated adult female donor with bone marrow stem cell product at a dose of 5.6 million CD34+ cells per kg. Results: She was treated successfully by a matched unrelated donor HSCT. At present, she is 2 years and 4 months posttransplant and is cured. Conclusions: Early recognition and prompt genetic testing can help in diagnosing and establishing the cause of a very early onset inflammatory bowel disease. Very early onset inflammatory bowel disease caused due to interleukin‐10 receptor mutations can be cured by HSCT. [ABSTRACT FROM AUTHOR]

Purpose: Oral focus screening is recommended before HCT (haematopoietic cell transplantation). Acute foci are generally treated pre-HCT. However, it is unclear whether chronic foci should be treated pre-HCT. This study aimed to evaluate the association between number of foci and early post-HCT morbidity and mortality. Methods: Patients who received an oral screening pre-HCT at Radboudumc between 2013 and 2023, with a recent panoramic radiograph, were included. Foci were defined as teeth or implants with deep pockets, furcation radiolucencies, periapical radiolucencies, deep caries, partial eruption or retained roots. Dental interventions were provided pre-HCT if deemed necessary and possible. Hospital length of stay (LOS), mortality and oral exacerbations were assessed in the first hundred days post-HCT. Hospital LOS was log-transformed to normalize its skewed distribution. Multivariate regression analyses were performed. Results: Five hundred patients were included (median age 58 years, 37% female, 56% allogeneic). Four acute foci in two patients remained untreated pre-HCT. Forty-eight percent had at least one untreated chronic focus pre-HCT (mostly furcation radiolucencies and post-endodontic periapical lesions). Mean LOS was 22 days; 20 patients died, and four patients had an oral exacerbation before HCT day + 100. After adjustment for conditioning intensity, age, socioeconomic status and number of teeth, HCT recipients with ≥ 3 foci had five additional days in the hospital compared to those without foci (ratio of means 1.21; 95% CI 1.00 – 1.46). The number of foci was not associated with early post-HCT mortality. Conclusion: The presence of ≥ 3 oral foci is associated with extended hospital LOS in the first hundred days post-HCT. [ABSTRACT FROM AUTHOR]

Introduction: The complex nature of xerostomia prevents the establishment of a definite cure. Recently, research has pivoted towards stem cell transplantation for glandular reconstruction. The aim of this study is to provide an updated review of the existing research, to highlight the encountered challenges and research pathways, potentially enhancing the therapeutic applications of stem cell transplantation. Methods: This is a systematic review according to PRISMA guidelines, using the following databases: PubMed (PMC), PMC Europe, Scopus, Medline, Research Gate, Elsevier. The main question was whether stem cell therapies can contribute to the treatment of xerostomia. Results: 19 of 226 publications met the criteria for this review, including 'in vivo', 'in vitro' studies and clinical trials. All 19 studies described thoroughly the stem cell source and the transplantation method, and documented results based on analytical and statistical methods of confirmation. Data show that the various sources of stem cells play a significant role, with bone marrow or adipose tissue-derived pluripotent blasts being the most utilized. Human transplants in mice have also been accepted and reversed hyposalivation. The effects have been beneficial especially in models undergone radiotherapy (IR) or exhibit Sjogren Syndrome-like symptoms (SS), suggesting that with appropriate treatment and enrichment techniques, stem cell transplantation seems effective regardless of the cause of the disorder. Extracts and co-cultures of gland and stem cells also seem to improve gland function. Conclusion: Although in its initial stages, the use of stem cells seems to be a promising therapy to alleviate xerostomia regardless of its cause. [ABSTRACT FROM AUTHOR]

Lung transplantation is hindered by low donor lung utilization rates. Infectious complications are reasons to decline donor grafts due to fear of post-transplant primary graft dysfunction. Mesenchymal stem cells are a promising therapy currently investigated in treating lung injury. Full-term amniotic fluid-derived lung-specific mesenchymal stem cell treatment may regenerate damaged lungs. These cells have previously demonstrated inflammatory mediation in other respiratory diseases, and we hypothesized that treatment would improve donor lung quality and postoperative outcomes. In a transplantation model, donor pigs were stratified to either the treated or the nontreated group. Acute respiratory distress syndrome was induced in donor pigs and harvested lungs were placed on ex vivo lung perfusion (EVLP) before transplantation. Treatment consisted of 3 doses of 2 × 106 cells/kg: one during EVLP and 2 after transplantation. Donors and recipients were assessed on clinically relevant parameters and recipients were followed for 3 days before evaluation for primary graft dysfunction (PGD). Repeated injection of the cell treatment showed reductions in inflammation seen through lowered immune cell counts, reduced histology signs of inflammation, and decreased cytokines in the plasma and bronchoalveolar lavage fluid. Treated recipients showed improved pulmonary function, including increased PaO 2 /FiO 2 ratios and reduced incidence of PGD. Repeated injection of lung-specific cell treatment during EVLP and post transplant was associated with improved function of previously damaged lungs. Cell treatment may be considered as a potential therapy to increase the number of lungs available for transplantation and the improvement of postoperative outcomes. [ABSTRACT FROM AUTHOR]

PURPOSE: Given the high heterogeneity in survival for patients with multiple myeloma, it would be clinically useful to quantitatively predict the individual survival instead of attributing patients to two to four risk groups as in current models, for example, revised International Staging System (R-ISS), R2-ISS, or Mayo-2022-score. PATIENTS AND METHODS: Our aim was to develop a quantitative prediction tool for individual patient's 3-/5-year overall survival (OS) probability. We integrated established clinical and molecular risk factors into a comprehensive prognostic model and evaluated and validated its risk discrimination capabilities versus R-ISS, R2-ISS, and Mayo-2022-score. RESULTS: A nomogram for estimating OS probabilities was built on the basis of a Cox regression model. It allows one to translate the individual risk profile of a patient into 3-/5-year OS probabilities by attributing points to each prognostic factor and summing up all points. The nomogram was externally validated regarding discrimination and calibration. There was no obvious bias or overfitting of the prognostic index on the validation cohort. Resampling-based and external evaluation showed good calibration. The c-index of the model was similar on the training (0.76) and validation cohort (0.75) and significantly higher than for the R-ISS (P <.001) or R2-ISS (P <.01). CONCLUSION: In summary, we developed and validated individual quantitative nomogram-based OS prediction. Continuous risk assessment integrating molecular prognostic factors is superior to R-ISS, R2-ISS, or Mayo-2022-score alone. [ABSTRACT FROM AUTHOR]

PURPOSE: Decision about the optimal timing of a treatment procedure in patients with hematologic neoplasms is critical, especially for cellular therapies (most including allogeneic hematopoietic stem-cell transplantation [HSCT]). In the absence of evidence from randomized trials, real-world observational data become beneficial to study the effect of the treatment timing. In this study, a framework to estimate the expected outcome after an intervention in a time-to-event scenario is developed, with the aim of optimizing the timing in a personalized manner. METHODS: Retrospective real-world data are leveraged to emulate a target trial for treatment timing using multistate modeling and microsimulation. This case study focuses on myelodysplastic syndromes, serving as a prototype for rare cancers characterized by a heterogeneous clinical course and complex genomic background. A cohort of 7,118 patients treated according to conventional available treatments/evidence across Europe and United States is analyzed. The primary clinical objective is to determine the ideal timing for HSCT, the only curative option for these patients. RESULTS: This analysis enabled us to identify the most appropriate time frames for HSCT on the basis of each patient's unique profile, defined by a combination relevant patients' characteristics. CONCLUSION: The developed methodology offers a structured framework to address a relevant clinical issue in the field of hematology. It makes several valuable contributions: (1) novel insights into how to develop decision models to identify the most favorable HSCT timing, (2) evidence to inform clinical decisions in a real-world context, and (3) the incorporation of complex information into decision making. This framework can be applied to provide medical insights for clinical issues that cannot be adequately addressed through randomized clinical trials. How to personalize the timing of stem-cell transplantation for hematologic neoplasms with multistate decision models. [ABSTRACT FROM AUTHOR]

Ewing sarcoma (ES) is a malignant tumor of bone and soft tissue that most often occurs in children, adolescents, and young adults. Debate and controversy remain in the management of relapsed/refractory ES (RR‐ES). The authors leveraged the expertise assembled by the National Ewing Sarcoma Tumor Board, a multidisciplinary virtual tumor board that meets monthly to discuss challenging cases of ES. In this review, they focus on select topics that apply to the management of patients with RR‐ES. The specific topics covered include the initial approach of such patients and discussion of the goals of care, the role of molecular testing, chemotherapy regimens and novel agents to consider, the role of maintenance therapy, and the use of high‐dose chemotherapy with autologous stem cell rescue. The data referenced are often limited to subgroup analyses and/or compiled from multiple sources. Although not intended to replace the clinical judgement of treating physicians, these guidelines are intended to support clinicians and provide some clarity and recommendations for the management of patients with RR‐ES. Plain Language Summary: Ewing sarcoma (ES) is a bone and soft tissue cancer that most often occurs in teenagers and young adults.This article uses the experience of the National Ewing Sarcoma Tumor Board, a multi‐institution, multidisciplinary virtual tumor board that meets monthly to discuss challenging cases of ES and to address questions related to the treatment of patients with relapsed ES.Although not intended to replace the clinical judgement of treating physicians and limited by available data, these consensus recommendations will support clinicians who treat patients with this challenging malignancy, made even more difficult when it recurs. Debates remain in defining the standard of care for treating patients with relapsed Ewing sarcoma. This set of consensus recommendations from the National Ewing Sarcoma Tumor Board are intended to provide some clarity and recommendations for the management of patients with recurrent disease. [ABSTRACT FROM AUTHOR]

Introduction: Elderly acute myeloid leukemia (AML) patients with poor‐risk cytogenetics have a poor outcome with intensive chemotherapy (IC). While Venetoclax (VEN) has changed the outcomes of elderly unfit patients treatment, it is unknown whether it could be effective in poor‐risk cytogenetics 60–75 years old patients. Materials and Methods: We included 60–75‐year‐old AML patients eligible to allogenic stem cell transplantation (allo‐SCT) treated with VEN (combined with azacitidine or with Cladribin and Aracytine) at Institut Paoli Calmettes, between 2020 and 2023 and compared this cohort with patients treated by IC between 2010 and 2019. Results: Twenty six patients were treated with VEN (17 in combination with azacitidine and 9 with Cladribin and Aracytine) and 90 were treated with IC. Thirteen patients (50%) had a TP53 mutation. The median time for leucocyte and platelet counts recovery was 26 days (range 0–103) and 26 days (range, 0–63). The median duration of the first hospitalization was 32 days (ranges, 7–79). The composite response rate was 69% (CR = 50%, CRi = 4%, MLFS = 15%). Allo‐SCT could be performed in 42% of cases. Median overall survival (OS) was 7.9 months (20.9 months in the group of patients who transitioned to allo‐SCT). We found no difference with the historical cohort of patients treated with IC except a trend toward less lower and upper tract gastro‐intestinal (GI) tract infections in the VEN group (respectively 8% vs 26%, p =.06; and 0% vs. 13% p =.06). Conclusion: VEN‐based treatment was found to be effective in high risk AML can be considered as an alternative to IC in patients aged 60–75 with adverse cytogenetics. [ABSTRACT FROM AUTHOR]

Stem cell transplantation into seminiferous tubules of recipient testis could become a tool for fertility restoration, genetic improvement, or conservation of endangered species. Spermatogonial stem cells (SSCs) are primary candidates for transplantation; however, limited abundance, complexity for isolation and culture, and lack of specific markers have limited their use. Mesenchymal stromal/stem cells (MSCs) are multipotent progenitors that are simple to isolate and culture and possess specific markers for identification, and immune evasive and migratory capacities. The objective of the present study was to evaluate the potential for survival and colonization in seminiferous tubules of two different concentrations of bovine fetal adipose tissue-derived MSCs (AT-MSCs), native of pre-induced, and to compare the fate of bovine adult peripheral blood-derived MSCs (PB-MSCs) and SSCs after allogenic transplantation in testis of recipient bulls. In experiment 1, AT-MSCs at two concentrations (1x107 and 2x107; n = 3) or pre-exposed to 2 μM testosterone and 1 μM retinoic acid (RA) for 14 days (n = 5) were evaluated. In experiment 2, adult PB-MSCs and SSCs (4x107 cells each) pre-exposed to Sertoli cell conditioned media (SCs/CM; n = 4) for 14 days were compared. Each cell type was separately labelled with PKH26 and then transplanted into testes of 8-month-old recipient bulls. Four weeks (Exp. 1) and two weeks (Exp. 2) after transplantation, testicular tissue was processed for confocal microscopy detection of PKH26-positive cells. Mean number of PKH26-positive cells were higher (P < 0.05) in testis transplanted with 2x107 AT-MSCs in the proximal (6.7 ± 3.7) and medial (6.6 ± 3.2) sections compared to testis transplanted with 1x107 AT-MSCs (proximal: 1.9 ± 1; medial: 1.9 ± 1) sections or pre-induced AT-MSCs (proximal: 4.7 ± 5.6; medial: 3.8 ± 4.1). In Exp. 2, mean number of PKH26-positive SSCs in medial testicular section (22.5 ± 1.3) were higher (P < 0.05) compared to respective section in PB-MSCs group (17 ± 4.2). Thus, in vivo data indicates that a higher number of transplanted AT-MSCs resulted in more cells surviving and colonizing seminiferous tubules; however, pre-induction with testosterone and RA did not improve these capacities. SSCs displayed a greater capacity for survival and colonization in recipient seminiferous tubules; however, PB-MSCs were observed in all sections of testis after two weeks of transplantation. • MSCs are multipotent precursors with immune evasive capacity. • Bovine MSCs colonization capacity was evaluated in seminiferous tubules. • AT-MSCs were able to survive and colonize in allogenic recipient testis. • PB-MSCs were observed in all sections of testis after two weeks of transplantation. • SSCs had greater capacity for survival and colonization in recipient testis. [ABSTRACT FROM AUTHOR]

Background: Relapse/refractory B-cell acute lymphoblastic leukaemia (r/r B-ALL) represents paediatric cancer with a challenging prognosis. CAR T-cell treatment, considered an advanced treatment, remains controversial due to high relapse rates and adverse events. This study assessed the efficacy and safety of CAR T-cell therapy for r/r B-ALL. Methods: The literature search was performed on four databases. Efficacy parameters included minimal residual disease negative complete remission (MRD-CR) and relapse rate (RR). Safety parameters constituted cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Results: Anti-CD22 showed superior efficacy with the highest MRD-CR event rate and lowest RR, compared to anti-CD19. Combining CAR T-cell therapy with haploidentical stem cell transplantation improved RR. Safety-wise, bispecific anti-CD19/22 had the lowest CRS rate, and anti-CD22 showed the fewest ICANS. Analysis of the costimulatory receptors showed that adding CD28ζ to anti-CD19 CAR T-cell demonstrated superior efficacy in reducing relapses with favorable safety profiles. Conclusion: Choosing a more efficacious and safer CAR T-cell treatment is crucial for improving overall survival in acute leukaemia. Beyond the promising anti-CD22 CAR T-cell, exploring costimulatory domains and new CD targets could enhance treatment effectiveness for r/r B-ALL. [ABSTRACT FROM AUTHOR]

Purpose of Review: Given the poor outcomes for peripheral T-cell lymphomas (PTCL), stem cell transplant (SCT) remains an important therapeutic approach. Post-SCT relapse is common and maintenance therapy post-SCT is increasingly being utilized. Here we review the use of post-SCT maintenance therapy for PTCL patients. Recent Findings: Maintenance therapy is increasingly utilized to decrease post-SCT relapse and improve outcomes in PTCL. Ongoing and completed post-SCT maintenance trials utilizing agents such as romidepsin, brentuximab vedotin, duvelisib, and pembrolizumab have shown efficacy in decreasing relapse. Further, additional agents with efficacy in PTCL have emerged that may inform future maintenance approaches. Summary: Maintenance therapy is a promising approach to maintain response after SCT in PTCL. While several trials are ongoing to evaluate maintenance therapy in PTCL, current data suggests this may be an effective method to decrease post-SCT relapse. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a condition characterized by the gradual degeneration of the nervous system that poses significant challenges to cognitive function and overall mental health. Given the increasing global life expectancy, there is an urgent need for effective strategies to prevent and manage Alzheimer's disease, with a particular focus on anti-aging interventions. Recent scientific advancements have unveiled several promising strategies for combating Alzheimer's disease (AD), ranging from lifestyle interventions to cutting-edge pharmacological treatments and therapies targeting the underlying biological processes of aging and AD. Regular physical exercise, cognitive engagement, a balanced diet, and social interaction serve as key pillars in maintaining brain health. At the same time, therapies target key pathological mechanisms of AD, such as amyloid-beta accumulation, tau abnormalities, neuroinflammation, mitochondrial dysfunction, and synaptic loss, offering potential breakthroughs in treatment. Moreover, cutting-edge innovations such as gene therapy, stem cell transplantation, and novel drug delivery systems are emerging as potential game-changers in the fight against AD. This review critically evaluates the latest research on anti-aging interventions and their potential in preventing and treating Alzheimer's disease (AD) by exploring the connections between aging mechanisms and AD pathogenesis. It provides a comprehensive analysis of both well-established and emerging strategies, while also identifying key gaps in current knowledge to guide future research efforts. [ABSTRACT FROM AUTHOR]

The document discusses the impact of CDKN2A/B deletion as a negative prognostic factor for allogeneic hematopoietic stem cell transplantation in childhood B cell precursor acute lymphoblastic leukemia. The study examined 164 children with B-ALL who underwent transplantation, finding that CDKN2A/B deletion was significantly associated with lower leukemia-free survival and higher relapse rates. The study suggests that CDKN2A/B deletion may affect chemosensitivity and immune response, highlighting the need for further research and potential incorporation of cellular therapy or targeted agents in treatment strategies. [Extracted from the article]

Toxoplasmosis, a parasitic disease, can cause fatal multi-organ failure in immunocompromised patients. The lack of specificity in the symptoms and the need to confirm a diagnosis of tachyzoites in fluids or tissues through microscopic examination leads to a delay in reaching a diagnosis. A 28-year-old woman with severe aplastic anemia received stem cell transplantation seven months ago, presented with fever. Computed Tomography scan and ultrasonography showed moderate pleural, pericardial, peritoneal, and pelvic effusions. Metagenomic next-generation sequencing of blood and alveolar lavage fluid was done, 11,082 and 17,154 sequence readings of Toxoplasma gondii were detected, accounting for 1.34% and 17.09% of genome coverage, respectively. Then, marrow aspirate smears showed Toxoplasma gondii tachyzoites and pseudocyst. This case report alerts clinicians about Toxoplasma gondii infection in stem cell transplantation patients with multiple serous effusions and fever. Clinical trial: Not applicable. [ABSTRACT FROM AUTHOR]

Summary In 2014, the International Myeloma Working Group (IMWG) updated the criteria for diagnosing myeloma and added three additional criteria to the traditional Calcium elevation, Renal impairment, Anemia, Bone disease (CRAB) criteria, called the Sixty % marrow plama cells, Light chain ratio >60, Mri demonstates lytic lesions (SLiM) criteria (clonal bone marrow plasma cells ≥60%, involved to uninvolved free light chain ratio (FLCr) ≥100 and >1 focal lesion on magnetic resonance imaging (MRI)). We report on the outcomes of 30 patients who underwent autologous stem cell transplantation (ASCT) where therapy was initiated solely based on SLiM criteria and compared them to a matched cohort of 60 patients whose myeloma‐defining event was CRAB. The SLiM cohort had a shorter median time to neutrophil (15 vs. 16 days, p = 0.049) and platelet (15 vs. 17 days, p = 0.0004) engraftment. The 36‐month overall survival (OS) was 100% in the SLiM group and 93.27% in the control group (95% CI 83.06%–97.42%), with a trend towards longer OS in the SLiM cohort (p = 0.065). The 36‐month progression‐free survival (PFS) was 91.61% in the SLiM (95% CI 69.93%–97.87%) and 65.95% in the control group (95% CI 52.31%–76.53%). There was no difference in the PFS between the cohorts (p = 0.414). ASCT is efficacious and safe in MM patients transplanted only due to SLIM criteria. Early intervention in this asymptomatic cohort did not appear to result in deeper responses or better PFS compared to outcomes in symptomatic patients. [ABSTRACT FROM AUTHOR]

The letter to the editor published in Leukemia & Lymphoma discusses the clinical challenge of residual and relapsed FLT3-ITD mutated AML in extramedullary immunoprivileged sites. The authors present four cases illustrating different clinical scenarios of EM relapse, highlighting the need for further discussion and development of management strategies for this subset of patients. The study emphasizes the unmet clinical need in addressing EM relapse among FLT3-ITD mutated AML patients and calls for future research to tailor therapeutic strategies for this specific population. [Extracted from the article]

Introduction: Chimeric antigen receptor T-cell (CAR-T) therapy has emerged as a promising approach for treating relapsed/refractory (r/r) T-cell acute lymphoblastic leukemia (T-ALL). However, it is mostly used as a bridging therapy for allogeneic hematopoietic stem cell transplantation (allo-HSCT). Furthermore, secondary allo-HSCT is costly and associated with significantly high treatment-related mortality rate than the primary transplants. In this report, we present the case of an adult T-ALL patient who underwent CD7-targeted autologous CAR-T cell therapy that was not bridged with secondary allo-HSCT. Case presentation: The adult T-ALL patient relapsed for a third time after undergoing allogeneic peripheral blood stem cell transplantation (PBSCI) and achieving the first complete remission (CR1). Therefore, the patient was administered CD7-targeted autologous CAR-T cell therapy that was not bridged with secondary allo-HSCT. Towards this, the endogenous CD7-deleted CAR (CD7-CAR7) T cells were generated using CRISPR/Cas9 gene-editing technology. However, after the first infusion, the CD7 CAR-T cells did not show significant proliferation when analyzed at two weeks and the patient became positive for peripheral measurable residual disease (MRD). Therefore, after a two-week period, an augmented dose of CAR-T cells was administered. MRD was monitored in the peripheral blood and bone marrow samples. The patient achieved complete remission and did not require targeted treatment after the completion of CD7 CAR-T-cell therapy. The current follow-up data has shown that the patient is negative for MRD and has been disease-free for more than 42 months. Conclusion: The results of this case study provide evidence for the long-term efficacy of CD7-targeted autologous CAR-T-cell therapy without requiring secondary allo-HSCT in patients with r/r T-ALL that have relapsed after previous allogeneic PBSCT. [ABSTRACT FROM AUTHOR]

Objective: To describe the implementation of a multi-step antimicrobial stewardship program in a haemato-oncology and stem cell transplantation program unit. Methods: Pre-post quasi-experimental study with two interrupted time-series analyses, conducted between 01/01/2019 and 31/12/2022 in the Paediatric Haemato-Oncology Unit of the Padua Paediatric Hospital. The interventions were: (1) 02/2020: dissemination of febrile neutropenia clinical pathways, (2) April 2021: provision of the clinical pathways via a customized App (Firstline.org) and implementation of a twice-a-week prospective audit and feedback. The main outcome was antibiotic consumption measured by days of administered therapy (DOTs)/1000 patients’ days for all antibiotics and most used molecules. Results: The first intervention (clinical pathways) resulted in a decrease in the overall antibiotic use by the haemato-oncology unit, with an abrupt reduction of 3-gen cephalosporins in favor of piperacillin-tazobactam, as indicated by the clinical pathways. Meropenem and glycopeptide use did not vary. The second intervention (antimicrobial stewardship) further decreased total antibiotic consumption, and a significant decline in meropenem, amikacin, and glycopeptides was achieved. Conclusions: Multi-step stewardship based on guidelines dissemination, multidisciplinary team intervention and collaboration (“handshake” stewardship) was highly effective in optimizing guidelines adherence and reducing overprescriptions in a fragile patient cohort. [ABSTRACT FROM AUTHOR]

Brentuximab vedotin (BV) has been approved for CD30‐positive cutaneous T‐cell lymphoma (CTCL) after at least one previous systemic treatment in China. However, real clinical practice is still limited. We aim to retrospectively review our experience with BV in a cohort of Chinese patients with CTCL, focusing on its efficacy and safety. We included 17 CTCL patients treated with BV at Peking Union Medical College Hospital from January 2021 to June 2024, including 12 with mycosis fungoides (MF)/Sézary syndrome (SS) and five with primary cutaneous anaplastic large‐cell lymphoma (pc‐ALCL). Patients had previously received a median of three treatment regimens (including acitretin, interferon, methotrexate, histone deacetylase inhibitors, phototherapy, radiotherapy, and chemotherapy). Sixteen patients received BV treatment at an initial dose of 1.8 mg/kg intravenously every 3 weeks, either as monotherapy (7/17) or in combination with gemcitabine, chidamide, or multiagent chemotherapy. The median treatment cycle has six cycles. Two patients received BV as the last treatment before undergoing allogeneic stem cell transplantation (alloSCT). The overall response rate (ORR) was 71% (13/17), with 18% (3/17) achieving complete remission (CR). In the MF/SS group, the ORR was 58% (7/12), while in the pc‐ALCL group, it was 100% (5/5). Adverse events (AEs) were observed in 12 patients, including peripheral neuropathy (PN) in three cases, fever in six cases, neutropenia in three cases, exfoliative dermatitis in two cases, and abnormal liver function in one case. Only one patient experienced ≥ Grade 3 AEs. Based on clinical experience in our center, BV, either as monotherapy or combined with chemotherapy, showed a good response in the treatment of advanced CTCL patients with good tolerability. [ABSTRACT FROM AUTHOR]

The article discusses the use of salvage monotherapy with venetoclax for patients with acute myeloid leukemia (AML) who failed standard induction chemotherapy. Venetoclax has shown promising results in combination therapies for AML, but its use as a standalone salvage therapy after standard induction has not been reported. The study describes four patients who received venetoclax monotherapy after failing standard induction therapy, showing blast clearance and potential benefits in reducing toxicity compared to reinduction chemotherapy. The authors suggest that venetoclax monotherapy could be a valuable option for refractory AML patients, especially in the context of pre-allogeneic stem cell transplantation. [Extracted from the article]

ABSTRACT Solid organ transplant and hematopoietic cell transplant patients face an increased risk of infectious diseases, greater exposure to antibiotics, and heightened risk of multidrug‐resistant organisms (MDROs) due to their immunosuppressed state. Antimicrobial stewardship programs (ASP) are essential in reducing the incidence of MDRO by conserving antimicrobial use, minimizing treatment durations, and improving the appropriate use of diagnostic testing. However, the role of ASP in transplant infectious diseases (TID) is still evolving, necessitating greater collaboration between ASP and transplant programs. This collaboration will mitigate infection risks, reduce infection‐associated costs, and improve outcomes. This article reviews the key components for implementing ASP in TID, especially for those that are establishing or growing their ASP to include TID, including specific goals, structure and funding, ASP initiatives (including antibiotic allergy delabeling, diagnostic stewardship, and antiviral/antifungal stewardship), metrics, and educational opportunities. [ABSTRACT FROM AUTHOR]

PurposeMethodsResultsConclusionTo report a case of cytomegalovirus (CMV)-related hemorrhagic retinal vasculitis in a patient with multiple myeloma (MM) on daratumumab, a trial cereblon E3 ligase modulatory drug (CELMoD), dexamethasone, and acyclovir, and discuss clinical implications for CMV prophylaxis.Case report, narrative review of CMV reactivation risk in MM patients on daratumumab and antiviral agent efficacy for CMV prophylaxis.A 63-year-old female presented with 3 days of progressive unilateral vision loss in the right eye to the level of counting fingers. She had a history of relapsed and refractory MM and autologous stem cell transplant (ASCT). At the time of presentation, she was receiving daratumumab, a trial CELMoD, dexamethasone, and acyclovir. Posterior segment exam demonstrated trace vitreous cells (0.5+ vitritis as per SUN criteria) and scattered hemorrhages with multifocal intraluminal vascular whitening, aligned with infectious posterior uveitis and suggestive of panretinal occlusive vasculitis. Optical coherence tomography showed inner macular edema and epiretinal membrane formation. CMV reactivation was confirmed with PCR of anterior chamber fluid and blood.Patients with MM on daratumumab are at increased risk of opportunistic reactivations including CMV, potentially due to daratumumab’s immunomodulatory side effects. Our patient developed CMV-related hemorrhagic retinal vasculitis despite low-dose acyclovir, which provides limited protection against CMV reactivation in CMV seropositive individuals. This case report therefore offers casuistic support for ophthalmic screening for CMV reactivation or CMV prophylaxis with letermovir in this patient population. [ABSTRACT FROM AUTHOR]

Summary Accurate classification and risk prediction are critical for therapeutic decision‐making in patients with acute myeloid leukaemia (AML). Myelodysplasia‐related (MR) gene mutations are classified as adverse genetic factors by the European LeukaemiaNet‐2022 guidelines. However, their prognostic value in de novo AML remains controversial. This study retrospectively analysed 188 patients with de novo AML‐MR, stratifying them into four subgroups based on dynamic measurable residual disease (MRD) after induction, one or two courses of consolidation chemotherapy. The median follow‐up was 36.8 months (4.6–73.7). Patients with persistent or recurrent MRD positivity after the second consolidation had the poorest 3‐year relapse‐free survival (RFS), overall survival (OS) and cumulative incidence of relapse compared to the other groups (p < 0.001). Multivariable analysis identified this high‐risk group as an independent risk factor for both RFS and OS. We observed significant heterogeneity of OS benefit from allogeneic stem cell transplantation (allo‐SCT) by MRD‐risk groups, with substantial OS advantage for patients in subgroup D (3‐year OS: allo‐SCT 70.0% vs. 18.2% without, p < 0.001) but no benefit for others (p = 0.047 for interaction). This study underscores the importance of dynamic MRD in refining risk stratification and identifying de novo AML patients with MR mutations who would benefit from allo‐SCT during the first complete remission. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusions The decision‐making process between autologous hematopoietic stem cell transplant (autoHSCT) and less‐intensive treatments necessitates shared decision‐making between older patients with hematological malignancies and healthcare providers. However, there is limited knowledge from both perspectives. This qualitative study aimed to comprehensively understand the experiences of shared decision‐making regarding autoHSCT among older patients with hematological malignancies and physicians.Older patients and physicians were recruited from the hematology department at one of the affiliated general hospitals of Wuhan University. They participated in semi‐structured, in‐depth face‐to‐face individual interviews from August 2022 to March 2023. The interviews explored their experiences with shared decision‐making about autoHSCT. Interviews were transcribed verbatim and analyzed using Colaizzi's phenomenological method.Thirteen older patients and eight physicians were recruited. Two themes were identified: (1) Factors influencing AutoHSCT recommendations and decision‐making: Seven factors were categorized into three groups: physician‐driven factors (pretransplant assessments, experience‐based judgment, and communication approaches), patient‐driven factors (perceived benefits and risks, financial challenges, and family involvement), and mutual trust between patients and physicians, which is a bidirectional factor relying on both physicians' trust and the active participation of patients in the decision‐making process. (2) Treatment planning and outcome expectations: Regardless of treatment choices, patients focused on engaging in self‐management and prioritizing quality of life, and maintaining hope for positive outcomes.The shared decision‐making process for autoHSCT between older patients with hematological malignancies and physicians is shaped by physician‐driven factors, patient‐driven factors, and mutual trust. These findings provide a foundation for developing patient‐centered care strategies, including decision aids and enhanced communication training for physicians, aimed at improving outcomes for older patients facing complex treatment choices. Future research should explore how these factors interact over time, through longitudinal studies, to assess their long‐term impact on patient outcomes and quality of life. [ABSTRACT FROM AUTHOR]

Background: At present, fat transplantation is widely used in the plastic surgery industry, but the long-term preservation rate of transplanted fat decreases because of complications such as oil cysts due to the inability in macrophages to metabolize absorption. In cell-assisted lipotransfer technology, adipose-derived stem cells (ASCs) can influence the inflammatory response of grafts through the immunoregulation in macrophages, and the lipid metabolism in macrophages plays an important role in this process. Therefore, we hypothesized ASCs could improve the retention rate of fat grafts by regulating the progress of lipid metabolism in macrophages. Methods: We established fat transplantation and ASC-assisted fat transplantation model in C57BL/6 mice in vivo, and bone marrow-derived macrophages cocultured with apoptotic adipocytes were treated with or without ASCs in vitro. Graft retention, tissue structure, fibrosis, macrophage phenotype transformation, lipid deposition, mitochondrial morphology, oxygen consumption rate (OCR), fatty acid β-oxidation (FAO) level, and ATP production were assessed. Additionally, fat transplantation and ASC-assisted fat transplantation model was treated with etomoxir which inhibits mitochondrial FAO. Macrophages pretreated with etomoxir were co-cultured with apoptotic adipocytes and treated with or without ASCs. The method aboved was used for detection and verification. Results: In vivo, ASC-assisted fat transplantation improved macrophage mitochondrial expression and FAO level, promoted the early transformation of M2 macrophages, reduced the long-term lipid deposition of macrophages, and improved the retention rate of fat grafts. In vitro, ASCs up-regulated the level of mitochondrial FAO, OCR and ATP production in macrophages, reduced lipid deposition of macrophages and promoted M2 macrophages polarization by paracine function. The ability of ASCs in group pretreated with etomoxir to reduce the foaming of macrophages, promote the transformation to M2 macrophages, and improve the retention rate of fat transplantation was weakened. Conclusions: ASCs increased the retention rate of transplanted fat by upregulating mitochondrial FAO to promote M2 polaration in macrophages. In addition, ASCs up-regulate mitochondrial FAO by paracrine effect to reduce foam cells formation and promote M2 transformation in macrophages in vitro. [ABSTRACT FROM AUTHOR]

Aims Methods Results Conclusion Allogeneic haematopoietic stem cell transplantation (allo‐HSCT) is a vital treatment for various paediatric malignant and nonmalignant diseases. The conditioning treatment before allo‐HSCT is crucial for successful engraftment. Treosulfan, a cytotoxic prodrug, has gained popularity due to its lower toxicity compared to traditional alkylating agents used for conditioning treatment.We investigated the relationship between pharmacokinetics and pharmacodynamics of treosulfan in paediatric patients, in a substudy pooling from 2 multicentre phase 2 clinical trials. A total of 83 children with malignant and nonmalignant diseases received treosulfan‐based conditioning. Treosulfan exposure and its relationship with clinical outcomes, including survival, graft failure and graft‐vs.‐host disease, were investigated.Our findings reveal no significant association between treosulfan exposure and the key clinical outcomes or toxicity (P‐values between .22 and .99), if the dosing is based on the approved product information.These findings suggest that treosulfan exposure after standardized body surface area‐based dosing is appropriate in paediatric allo‐HSCT. [ABSTRACT FROM AUTHOR]

Background Objectives Materials and methods Results Discussion Conclusion It is not known whether bone marrow stem cells when injected intravenously for a bone marrow transplant colonize the human testicular epithelium. No previous studies of sperm genotype after bone marrow transplantation are reported.To differentiate host from donor genotype in spermatozoa of men who have undergone successful bone marrow transplants.Triplet DNA samples (spermatozoa, blood, and hair) obtained from men who had recovered sperm production after bone marrow transplant were genotyped using 44 autosomal and three sex‐related single nucleotide polymorphisms to determine the tissue genotype in pairwise comparisons of DNA profiles.Participants were 14 men at a median of 5.5 years after allogeneic bone marrow transplant who had a median sperm output of 77 million spermatozoa/ejaculate. In 14/14 the donor (leukocyte) DNA genotype differed significantly from the spermatozoa and hair genotypes whereas hair and sperm genotypes showed no variations.These data suggest that paternity after a successful bone marrow transplant is likely to be of the host and not the donor's genetic origins. The study's small sample size reflects the paucity of eligible man with recovered spermatogenesis after bone marrow transplant and represents preliminary evidence. A large‐scale epidemiological analysis to estimate the frequency of bone marrow donor stem cell colonization of the testicular germinal epithelium based on progeny sex ratio and frequency of female donors is proposed.Successful colonization of the testicular germinal and hair follicle epithelia by allogeneic bone marrow transplant donor stem cells is rare or does not occur. [ABSTRACT FROM AUTHOR]

We describe the case of a 27‐year‐old male, previously healthy though with a social history notable for recreational cocaine use, who developed bone marrow failure due to aplastic anemia (AA) with associated serous fat atrophy (SFA). After the SFA was corrected with nutritional supplementation, the patient underwent successful allogeneic, haploidentical stem cell transplantation with a regimen designed to treat AA. To our knowledge, this is the first case of hematopoietic stem cell transplantation (HSCT) performed following correction of SFA. Herein we propose our novel hypothesis that SFA, once resolved, is not a contraindication to stem cell transplantation, which we believe adds valuable insight toward an improved understanding of nutrition's role in HSCT. Additionally, the AA is thought to be toxin‐induced and specifically levamisole‐mediated after exposure to levamisole‐adulterated cocaine. We highlight potential connections between levamisole, AA, and SFA and call for further efforts to understand these relationships—especially as the use of levamisole as a cocaine adulterant continues to rise across the globe. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a global health concern and the leading cause of dementia in the elderly. The prevalence of this neurodegenerative condition is projected to increase concomitantly with increased life expectancy, resulting in a significant economic burden. With very few FDA-approved disease-modifying drugs available for AD, there is an urgent need to develop new compounds capable of impeding the progression of the disease. Given the unclear etiopathogenesis of AD, this review emphasizes the underlying mechanisms of this condition. It explores not only well-studied aspects, such as the accumulation of Aβ plaques and neurofibrillary tangles, but also novel areas, including glymphatic and lymphatic pathways, microbiota and the gut–brain axis, serotoninergic and autophagy alterations, vascular dysfunction, the metal hypothesis, the olfactory pathway, and oral health. Furthermore, the potential molecular targets arising from all these mechanisms have been reviewed, along with novel promising approaches such as nanoparticle-based therapy, neural stem cell transplantation, vaccines, and CRISPR-Cas9-mediated genome editing techniques. Taking into account the overlap of these various mechanisms, individual and combination therapies emerge as the future direction in the AD strategy. [ABSTRACT FROM AUTHOR]

The transplantation of injury/ischemia-induced stem cells (iSCs) extracted from post-stroke human brains can improve the neurological functions of mice after stroke. However, the usefulness of iSCs as an alternative stem cell source remains unclear. The current study aimed to assess the efficacy of iSC and mesenchymal stem cell (MSC) transplantation. In this experiment, equal numbers of human brain-derived iSCs (h-iSCs) (5.0 × 104 cells/μL) and human bone marrow-derived MSCs (h-MSCs) (5.0 × 104 cells/μL) were intracranially transplanted into post-stroke mouse brains after middle cerebral artery occlusion. Results showed that not only h-iSC transplantation but also h-MSC transplantation activated endogenous neural stem/progenitor cells (NSPCs) around the grafted sites and promoted neurological functional improvement. However, mice that received h-iSC transplantation experienced improvement in a higher number of behavioral tasks compared with those that received h-MSC transplantation. To investigate the underlying mechanism, NSPCs extracted from the ischemic areas of post-stroke mouse brains were cocultured with h-iSCs or h-MSCs. After coincubation, NSPCs, h-iSCs, and h-MSCs were selectively collected via fluorescence-activated cell sorting. Next, their traits were analyzed via microarray analysis. The genes related to various neuronal lineages in NSPCs after coincubation with h-iSCs were enriched compared with those in NSPCs after coincubation with h-MSCs. In addition, the gene expression patterns of h-iSCs relative to those of h-MSCs showed that the expression of genes related to synapse formation and neurotransmitter-producing neurons increased more after coincubation with NSPCs. Hence, cell–cell interactions with NSPCs promoted transdifferentiation toward functional neurons predominantly in h-iSCs. In accordance with these findings, immunohistochemistry showed that the number of neuronal networks between NSPCs and h-iSCs was higher than that between NSPCs and h-MSCs. Therefore, compared with h-MSC transplantation, h-iSC transplantation is associated with a higher neurological functional improvement, presumably by more effectively modulating the fates of endogenous NSPCs and grafted h-iSCs themselves. [ABSTRACT FROM AUTHOR]

Human CMV, regularly reactivated by simple triggers, results in asymptomatic viral shedding, powerful cellular immune responses, and memory inflation. Immunocompetent individuals benefit from a robust immune response, which aids in viral management without causing clinically significant illness; however, immunodeficient individuals are always at a higher risk of CMV reactivation and disease. Hematopoietic stem cell transplant (HSCT) recipients are consistently at higher risk of CMV reactivation and clinically significant CMV illness due to primary disease, immunosuppression, and graft vs. host disease. Early recovery of CMV-CMI responses may mitigate effects of viral reactivation in HSCT recipients. Immune reconstitution following transplantation occurs spontaneously and is mediated initially by donor-derived T cells, followed by clonal growth of T cells produced from graft progenitors. CMV-specific immune reconstitution post-transplant is related to spontaneous clearance of CMV reactivation and may eliminate the need for prophylactic or pre-emptive medication, making it a potential predictive marker for monitoring CMV reactivation. This review highlights current thoughts and therapeutic options for CMV reactivation in HSCT, with focus on CMV immune reconstitution and post-HSCT monitoring. Immune monitoring aids in risk stratification of transplant recipients who may progress from CMV reactivation to clinically significant CMV infection. Implementing this approach in clinical practice reduces the need for periodic viral surveillance and antiviral therapy in recipients who have a high CMV-CMI and thus may experience self-limited reactivation. Therefore, in the age of precision medicine, it is critical to incorporate CMV-specific cellular immune surveillance into conventional procedures and algorithms for the management of transplant recipients. [ABSTRACT FROM AUTHOR]

Introduction: Hepatic sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) is a major complication following hematopoietic stem cell transplantation, resulting from immune and chemical toxicity in the sinusoidal endothelium and hepatocellular damage. In the most severe cases, multiorgan dysfunction occurs, so it is essential to promptly identify patients at greater risk of SOS/VOD and to adopt prophylactic strategies. Objectives: This study aims to systematize the impact of different approaches as primary prophylaxes against SOS/VOD in patients undergoing hematopoietic stem cell transplantation (HSCT). Methods: A systematic review and meta-analysis of randomized clinical trials evaluating different strategies for primary prophylaxis of SOS/VOD was carried out in pairwise fashion and with a consistent network structure. The odds ratio (OR) and corresponding confidence intervals were calculated using the random-effects model. Heterogeneity was assessed by the I2 method and the efficacy of each approach was estimated by SUCRA (surface under the cumulative ranking curve). Results: Considering all patients undergoing HSCT, ursodeoxycholic acid (UDCA) [OR = 0.38, 95%CI 0.14–1.06, SUCRA = 0.720] was associated with a lower incidence of VOD while defibrotide reached a modest reduction in its incidence [OR = 0.64, 95%CI 0.23–1.67; SUCRA = 0.486]. Considering the subgroup of patients undergoing hematopoietic progenitors allotransplantation, defibrotide scored higher [OR = 0.51, 95%CI 0.09–2.85, SUCRA = 0.650] by comparison with UDCA [OR = 0.53, 95%CI 0.14–1.96, SUCRA = 0.639]. Conclusions: This is the first meta-analysis comparing primary prophylaxes against SOS/VOD. UDCA yielded more promising results when considering all patients undergoing hematopoietic stem cell transplantation, yet, in a subgroup analysis of the ones exposed to allogeneic grafts, it becomes not significantly overrun by defibrotide. [ABSTRACT FROM AUTHOR]

Background: The selection of the best donor for each specific patient is crucial for the success of allogeneic hematopoietic stem cell transplantation (HSCT). However, there is debate on the choice of the best donor when multiple suitable donors exist. Methods: By using own data from two transplant centers, we have developed a calculator able to provide the patients' 2-year overall survival (OS) associated with each of the potential donor options during the selection process, in order to support the transplant physician during the choice. Data on 737 HSCTs with HLA-identical siblings, and unrelated or related haploidentical donors from January 2010 to July 2022 have been retrospectively obtained. Results: Patients' age, disease, comorbidity index, and donor type were found to be significant variables able to predict the outcome with robustness (concordance index: 0.677). Estimates are provided within an example in the text showing outcomes with four donor options for a specific patient. Conclusions: We present the prototype of a tool supporting the selection of the best donor, guiding transplant physicians during the delicate process of donor selection before HSCT. This approach relies on real data from the centers, reflecting their local clinical experience. Improvements are underway with a larger, ongoing multicenter study. [ABSTRACT FROM AUTHOR]

Background: X-linked agammaglobulinaemia (XLA), caused by mutations in BTK, is characterised by low or absent peripheral CD19 + B lymphocytes and agammaglobulinaemia. The mainstay of treatment consists of immunoglobulin replacement therapy (IgRT). As this cannot fully compensate for the immune defects in XLA, patients may therefore continue to be at risk of complications. Objectives: To describe the clinical outcomes of XLA patients in the United Kingdom and Hong Kong and evaluate current treatment strategies. Methods: Patients with a definitive diagnosis of XLA were included in this cross-sectional and retrospective analysis of clinical health outcomes. Data pertaining to diagnosis, infection incidence, IgG trough levels and lung function were collected and analysed. Results: 99 patients with a median age of 29.02 years (IQR 12.83–37.41) and a total follow up of 1922 patient years, were included this study. The median age at diagnosis was 3.30 years (IQR 1.04–8.38) which decreased over time (p = 0.004). 40% of the cohort had radiological evidence of bronchiectasis. Risk of bronchiectasis was not significantly associated with clinical infection incidence (p = 0.880) or IgG trough levels (p = 0.407). Two patients demonstrated novel complications, namely persistent norovirus infection, leading to haemopoietic stem cell transplantation (HSCT). Conclusions: Despite modern therapy, most XLA patients continue to experience complications, most notably bronchiectasis, likely due to absence of IgA/M in current therapies, but lack of B lymphocytes may also lead to additional sequalae. These data strongly support the need for further research, particularly that of curative modalities including HSCT and gene therapy. [ABSTRACT FROM AUTHOR]

Despite therapeutic advancements, multiple myeloma (MM) remains incurable. NK cells have emerged as a promising option for the treatment of MM. NK cells are heterogenous and typically classified based on the relative expression of their surface markers (e.g., CD56 and CD16a). These cells elicit an antitumor response in the presence of low mutational burden and without neoantigen presentation via germline-encoded activating and inhibitory receptors that identify the markers of transformation present on the MM cells. Higher NK cell activity is associated with improved survival and prognosis, whereas lower activity is associated with advanced clinical stage and disease progression in MM. Moreover, not all NK cell phenotypes contribute equally toward the anti-MM effect; higher proportions of certain NK cell phenotypes result in better outcomes. In MM, the proportion, phenotype, and function of NK cells are drastically varied between different disease stages; this is further influenced by the bone marrow microenvironment, proportion of activating and inhibitory receptors on NK cells, expression of homing receptors, and bone marrow hypoxia. Antimyeloma therapies, such as autologous stem cell transplant, immunomodulation, proteasome inhibition, and checkpoint inhibition, further modulate the NK cell landscape in the patients. Thus, NK cells can naturally work in tandem with anti-MM therapies and be strategically modulated for improved anti-MM effect. This review article describes immunotypic and phenotypic differences in NK cells along with the functional changes in homeostatic and malignant states and provides expert insights on strategies to harness the potential of NK cells for improving outcomes in MM. [ABSTRACT FROM AUTHOR]

AbstractAllogeneic hematopoietic stem cell transplantation (AHSCT) is currently the only treatment modality that is capable of curing myelofibrosis (MF). Although outcomes of AHSCT have improved vastly in recent years owing to advancements in HLA typing, conditioning regimens, and supportive care, it remains a procedure with a considerable risk in MF patients due to conditioning regimen related toxicity, higher rates of graft failure, infections, and graft versus host disease (GVHD). Recent progress in the treatment and prevention of GVHD with post-transplant cyclophosphamide has also rendered transplantation from alternative donors feasible and safer, thus improving access to patients without HLA-identical donors. Accordingly, all patients with intermediate or high-risk MF today should be referred for potential transplant evaluation to consider the pros and cons of an early versus a delayed transplant strategy. Individual risk assessment in MF is best facilitated by contemporary prognostic models that incorporate both clinical and genetic risk factors. The current review highlights new information regarding risk stratification in MF, anchored by practical algorithms that facilitate patient selection for specific treatment actions, including AHSCT. [ABSTRACT FROM AUTHOR]