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Background: Primary immunodeficiency diseases (inborn errors of immunity) with partial albinism are a group of autosomal recessive syndromes including Chediak Higashi Syndrome (CHS), Griscelli Syndrome type 2 (GS2), Hermansky-Pudlak Syndromes type 2 and 10 (HPS2, HPS10), Vici syndrome and P14/LAMTOR2 deficiency., Methods: Twenty-five patients including 10 CHS, 10 GS2, and 5 HPS2 were evaluated in this study within the last 10 years. Five cases with oculocutaneous albinism (OCA) and 5 healthy subjects without albinism were used as two control groups. Genetic analyses were performed by whole exome or panel sequencing or targeted Sanger sequencing. Subsequently, leukocyte granules in peripheral blood smear and hair shaft were examined as screening tests., Results: Giant granules were only presented in the leukocytes cytoplasm of 10/10 CHS patients. The uneven cluster of pigments and giant melanin granules in hair samples were observed in 10/10 GS2 and 10/10 CHS patients, respectively. In both 5/5 OCA and 5/5 HPS2 patients, there were regular pigments in the middle of hair shafts. Genetic analyses were performed for all patients, revealing 7 novel variants in LYST gene for CHS patients and 4 novel variants in AP3B1 for HPS2 patients., Conclusion: Receiving hematopoietic stem cell transplantation (HSCT) in a timely manner is crucial in CHS and GS2 patients; therefore, screening tests may provide a vital clue for early diagnosis in these patients. However, the final confirmation of CHS, GS2, and HPS2 disorders is done by genetic assay., (© 2024 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

C1q deficiency is a rare inborn error of immunity characterized by increased susceptibility to infections and autoimmune manifestations mimicking SLE, with an associated morbidity and mortality. Because C1q is synthesized by monocytes, to date, four patients treated with allogeneic HSCT have been reported, with a positive outcome in three. We conducted an international retrospective study to assess the outcome of HSCT in C1q deficiency. Eighteen patients, fourteen previously unreported, from eleven referral centres, were included. Two patients had two HSCTs, thus 20 HSCTs were performed in total, at a median age of 10 years (range 0.9-19). Indications for HSCT were autoimmune manifestations not controlled by ongoing treatment in seventeen, and early development of MALT lymphoma in one patient. Overall survival (OS) was 71% and event-free survival was 59% at two years (considering an event as acute GvHD ≥ grade III, disease recurrence and death). In eleven patients HSCT led to resolution of autoimmune features and discontinuation of immunosuppressive treatments (follow-up time range 3-84 months). Five patients died due to transplant-related complications. Patients with a severe autoimmune phenotype, defined as neurological and/or renal involvement, had the worst OS (40% vs 84%; p = 0.034). Reviewing data of 69 genetically confirmed C1q deficient patients, we found that anti-Ro antibodies are associated with neurologic involvement, and anti-RNP and anti-DNA antibodies with renal involvement. In conclusion, HSCT may be a valid curative option for C1q deficiency, but careful selection of patients, with an accurate assessment of risk and benefit, is mandatory., (© 2024. The Author(s).)

Competing Interests: Conflicts of interest The authors declare no conflict of interest.

Despite low incidence, neuroblastoma, an immunologically cold tumor, is the most common extracranial solid neoplasm in pediatrics. In relapsed/refractory cases, the benefits of autologous hematopoietic stem cell transplantation (auto-HSCT) and other therapies are limited. Natural killer (NK) cells apply cytotoxicity against tumor cells independently of antigen-presenting cells and the adaptive immune system. The primary endpoint of this trial was to assess the safety of the injection of allogenic, ex vivo-expanded and primed NK cells in relapsed/refractory neuroblastoma patients after auto-HSCT. The secondary endpoint included the efficacy of this intervention in controlling tumors. NK cells were isolated and primed ex vivo (by adding interleukin [IL]-2, IL-15, and IL-21) in a GMP-compliant CliniMACS system and administered to four patients with relapsed/refractory MYCN-positive neuroblastoma. NK cell injections (1 and 5 × 10 7 cells/kg in the first and second injections, respectively) were safe, and no acute or sub-acute adverse events were observed. During the follow-up period, one complete response (CR) and one partial response (PR) were observed, while two cases exhibited progressive disease (PD). In follow-up evaluations, two died due to disease progression, including the case with a PR. The patient with CR had regular growth at the 31-month follow-up, and another patient with PD is still alive and receiving chemotherapies 20 months after therapy. This therapy is an appealing and feasible approach for managing refractory neuroblastomas post-HSCT. Further studies are needed to explore its efficacy with higher doses and more frequent administrations for high-risk neuroblastomas and other immunologically cold tumors.Trial registration number: irct.behdasht.gov.ir (Iranian Registry of Clinical Trials, No. IRCT20201202049568N1)., (© 2024. The Author(s).)

Despite reaching enormous achievements in therapeutic approaches worldwide, GBM still remains the most incurable malignancy among various cancers. It emphasizes the necessity of adjuvant therapies from the perspectives of both patients and healthcare providers. Therefore, most emerging studies have focused on various complementary and adjuvant therapies. Among them, metabolic therapy has received special attention, and metformin has been considered as a treatment in various types of cancer, including GBM. It is clearly evident that reaching efficient approaches without a comprehensive evaluation of the key mechanisms is not possible. Among the studied mechanisms, one of the more challenging ones is the effect of metformin on apoptosis and senescence. Moreover, metformin is well known as an insulin sensitizer. However, if insulin signaling is facilitated in the tumor microenvironment, it may result in tumor growth. Therefore, to partially resolve some paradoxical issues, we conducted a narrative review of related studies to address the following questions as comprehensively as possible: 1) Does the improvement of cellular insulin function resulting from metformin have detrimental or beneficial effects on GBM cells? 2) If these effects are detrimental to GBM cells, which is more important: apoptosis or senescence? 3) What determines the cellular decision between apoptosis and senescence?, Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Hajimohammadebrahim-Ketabforoush, Zali, Shahmohammadi and Hamidieh.)

The eighth workshop of the Worldwide Network for Blood and Marrow Transplantation (WBMT) was held in Islamabad, Pakistan, from September 22 to 23, 2022, aiming to foster hematopoietic stem cell transplant (HSCT) activity in the World Health Organization (WHO) Eastern Mediterranean Region (EMRO). Participating countries, including Pakistan, Oman, Iran, and Saudi Arabia, reported increased HSCT in the last few years, whereas others from the EMRO and beyond, including Qatar, United Arab Emirates, Nepal, and Bangladesh, started HSCT recently and have developed HSCT programs with excellent results. During educational sessions and open dialog, participating teams and international experts from the WBMT shared their experience and discussed minimum essential requirements for establishing and expanding HSCT in emerging countries, indications for HSCT training and dissemination of knowledge, stem cell donor selection and safety, quality assurance in transplant centers, and the value and importance of transplant outcome databases. International support, collaboration, and local engagement, including government participation and WHO assistance, are valuable in increasing HSCT access worldwide., (Copyright © 2024 Hematology/Oncology and Stem Cell Therapy.)

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative strategy against a variety of malignant and nonmalignant disorders. However, acute and chronic graft-versus-host disease (aGVHD and cGVHD, respectively) commonly complicate this approach, culminating in substantial morbidities and mortalities. The integumentary system is the preponderant organ involved in cGVHD, and its response to existing treatments, including well-versed immunosuppressants and novel targeted therapies, is not desirable. Despite the rarity, ulcers of sclerotic skin cGVHD are treatment-refractory and associated with significant morbidities and an exaggerated risk of infectious complications. Platelet-rich plasma (PRP) and its derivatives are endowed with growth factors and proangiogenic molecules and hold regenerative potential. This study aimed to assess the safety and efficacy of the application of platelet gel-containing dressing against ulcerative skin cGVHD in pediatric patients. This randomized trial is conducted at the hematopoietic stem cell transplantation unit of the Children's Medical Center Hospital in Tehran, Iran. Twenty-one pediatric patients (aged between 5 and 15 years) were initially enrolled, and 16 met the inclusion criteria. All cases (4 females) were recipients of allo-HSCT who had been complicated with symmetrically or near-symmetrically ulcerative sclerotic skin cGVHD. Fresh umbilical cord blood (UCB) was obtained from healthy donors and underwent centrifugation using a novel PRP preparation kit in a single-step process. Platelet gel was produced by adding thrombin to the isolated buffy coat layer. Two similar ulcers of each patient were randomized to receive either conventional dressing or platelet gels up to 6 times. At each time point evaluation, ulcer size and its relative reduction compared to the basal size were recorded. Included patients received a total of 80 platelet gel-containing dressings. While the mean sizes of randomized ulcers at the beginning of the study were similar, their differences became significant 15 days after the initiation of intervention (P = .019). In addition, the mean reduction in the ulcers' surface area (in comparison to their baseline values) was significantly higher for the intervention arm at all evaluation points (P = .001 for day 5 and P < .001 for subsequent time points). At the end of the trial, the number of ulcers with a more than 50% reduction in size was 14 (87.5%) in the intervention arm (including 6 completely healed ulcers) versus 1 (6.25%, which was not completely healed) in the control arm (P < .001). None of the patients exhibited any localized or systemic treatment-related adverse events. In this study, using a relatively large number of cases, we showed that UCB-derived platelet gel is a safe, feasible, and effective curative approach for skin ulcers of sclerotic skin cGVHD in pediatric patients. Designing upcoming trials on the efficacy of this therapeutic approach for ocular, mucosal, and acute skin GVHD is prudent. Retrospectively registered at the Iranian Registry of Clinical Trials (registration number IRCT20190101042197N1) on August 24, 2020., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Conflicts of interest None.

Purpose: Pediatric Hematopoietic Stem Cell Transplant (HSCT) profoundly affects various dimensions of parents' lives. Effective coping strategies are essential for improving psychological well-being and overall quality of life. Therefore, this study aimed to explore parental coping strategies with their child's HSCT challenges., Design and Methods: This qualitative study was conducted in Iran from February to November 2023, utilizing conventional content analysis with purposive sampling. For data collection, unstructured interviews were conducted, followed by in-depth semi-structured interviews with open-ended questions. Saturation was reached after analyzing qualitative data from 20 participants., Results: Data analysis unveiled a main theme labeled "harmony in hardship". This overarching concept encapsulates the participants' endeavors to cope with the various hurdles and complexities stemming from their child's HSCT. This theme consisted of five categories: "emotional release", "positive coping", "avoidance coping", "spiritual coping", and "seeking support"., Conclusion: Parents utilized multifaceted coping strategies to manage the complexities of their child's HSCT journey. Understanding these mechanisms is crucial as they can positively influence parents' psychological well-being and improve their overall quality of life., Implications for Clinical Practice: Healthcare professionals should recognize the diverse coping strategies employed by parents of children undergoing HSCT and provide tailored interventions and support. Furthermore, implementing structured support programs and training initiatives for healthcare professionals can enhance their capacity to meet the diverse needs of parents during this challenging journey., Competing Interests: Declaration of competing interest The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Diamond-Blackfan anaemia (DBA), first described over 80 years ago, is a congenital disorder of erythropoiesis with a predilection for birth defects and cancer. Despite scientific advances, this chronic, debilitating, and life-limiting disorder continues to cause a substantial physical, psychological, and financial toll on patients and their families. The highly complex medical needs of affected patients require specialised expertise and multidisciplinary care. However, gaps remain in effectively bridging scientific discoveries to clinical practice and disseminating the latest knowledge and best practices to providers. Following the publication of the first international consensus in 2008, advances in our understanding of the genetics, natural history, and clinical management of DBA have strongly supported the need for new consensus recommendations. In 2014 in Freiburg, Germany, a panel of 53 experts including clinicians, diagnosticians, and researchers from 27 countries convened. With support from patient advocates, the panel met repeatedly over subsequent years, engaging in ongoing discussions. These meetings led to the development of new consensus recommendations in 2024, replacing the previous guidelines. To account for the diverse phenotypes including presentation without anaemia, the panel agreed to adopt the term DBA syndrome. We propose new simplified diagnostic criteria, describe the genetics of DBA syndrome and its phenocopies, and introduce major changes in therapeutic standards. These changes include lowering the prednisone maintenance dose to maximum 0·3 mg/kg per day, raising the pre-transfusion haemoglobin to 9-10 g/dL independent of age, recommending early aggressive chelation, broadening indications for haematopoietic stem-cell transplantation, and recommending systematic clinical surveillance including early colorectal cancer screening. In summary, the current practice guidelines standardise the diagnostics, treatment, and long-term surveillance of patients with DBA syndrome of all ages worldwide., Competing Interests: Declaration of interests AK declares honoraria from chiesi and Novartis and a research grant from Novaris. AK is on the advisory board of Chiesi and Novartis. FML declares honoraria from Chiesi and is on the advisory board of Chiesi. LK is on the advisory board of Agios, Amgen, Bayer, and Novartis. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Cancer is among the serious health problems of the medical world, for treatment of which severe treatments are used. However, the prognosis of cancer patients is still poor. The application of NK cell-derived exosomes (NK-Exo) is a new method for cancer immunotherapy. These nanoparticles with a size range of 30-120 nm are a small model of mother cells. In this study, the anti-tumor activity of NK-Exo and LAK-Exo (activated NK cell-derived exosome) against acute myeloid leukemia (AML) is investigated in vitro. Materials and Methods: The MACS method was performed for the separation of NK cells from the buffy coats of healthy donors, and an EXOCIBE kit was used for the isolation of NK-Exo. After treating the KG-1 cell line with different doses of NK-Exo, MTT assay, and annexin V-PE were done to evaluate cell proliferation and apoptosis, respectively, and for confirmation of involved proteins, Real-Time PCR and western blotting were performed. Results: Anti-tumor activity of NK-Exo and LAK-Exo was dose- and time-dependent. Their highest activities were observed following 48 hours of incubation with 50 µg/ml exosome (p<0.0001). However, this cytotoxic activity was also seen over a short period of time with low concentrations of NK-Exo (p<0.05) and LAK-Exo (p<0.001).The cytotoxic effect of LAK-Exo on target cells was significantly higher than NK-EXO. The induction of apoptosis by different pathways was time-point dependent. Total apoptosis was 34.56% and 51.6% after 48 hours of tumor cell coculture with 50µg/ml NK-Exo and LAK-Exo, respectively. Significant expression of CASPASE3 , P38, and CYTOCHROME C genes was observed in the cells treated with 50 µg/ml NK-Exo and LAK-Exo. Conclusion : Our study confirmed the antileukemia activity of NK-Exo against AML tumor cells in vitro. Therefore, NK-Exo can be considered as a promising and effective treatment for leukemia therapy., Competing Interests: The authors have no conflicts of interest for publication of this study., (Copyright © 2024 Tehran University of Medical Sciences.)

Objectives: Pediatric Hematopoietic Stem Cell Transplant (HSCT) profoundly impacts the physical, psychological, and social aspects of parents' lives. Thus, this study aimed to explore the experiences of parents living with a child with cancer who undergoes HSCT., Methods: This qualitative study involved 20 parents of children with cancer who were undergoing HSCT at a referral hospital in Iran. Purposive sampling was used to select the participants from February 2023 to November 2023. In-depth semi-structured interviews, featuring open-ended questions, were utilized for data collection. Data analysis was performed using conventional content analysis., Results: Data analysis revealed two main themes. "Surrounded by hardships" and "Self-actualization." The first theme encompassed participants' experiences of facing difficulties in life after being aware of their child's need for HSCT. This theme consisted of four categories: "uncertainty about the child's future," "exhaustion from the child's treatment process," "worrying about the healthy child(ren)," and "helplessness." The second theme "self-actualization" included with two categories: "transformation in life's philosophy" and "acquisition of new capabilities." These categories highlighted the positive outcomes experienced by the participants following their child's HSCT., Conclusion: Our findings underscore the importance of healthcare providers being attuned to parents' experiences throughout their child's HSCT trajectory. It is crucial for healthcare providers to encourage parents to articulate their concerns and feelings and seek support from healthcare providers, family, and friends. The development of psychological support services in healthcare settings can facilitate tailored interventions to alleviate parents' difficulties., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Maleki, Dehghan Nayeri, Hamidieh and Pouraboli.)

Objective: There is interest in using cytotoxic T lymphocyte antigen-4 (CTLA-4) immunotherapy to treat blood cancers. Unfortunately, patients with acute lymphoblastic leukaemia (ALL) frequently exhibit resistance to treatment and natural killer (NK) cell exhaustion. This study aims to increase the cytotoxic potency of natural killer cells by using CTLA-4 to block the Nalm-6 leukaemia cell line., Materials and Methods: In this experimental study, NK cells were purified from the peripheral blood mononuclear cells (PBMCs) of 10 healthy people and assessed by flow cytometry for purity and viability. The purified cells were activated overnight at 37°C and 5% CO2 with interleukin-15 (IL-15, 10 ng/ml) followed by evaluation of expressions of CTLA-4, activating and inhibitory receptors, and the release of interferon gamma (IFN-γ) and granzyme B (GZM B). CTLA-4 expression on NK cells from recurrent ALL patients was also evaluated. Finally, the cytotoxic activity of NK cells was assessed after the CTLA-4 blockade., Results: The purity of the isolated cells was 96.58 ± 2.57%. Isolated NK cells activated with IL-15 resulted in significantly higher CTLA-4 expression (8.75%, P<0.05). Similarly, CTLA-4 expression on the surface of NK cells from patients with ALL was higher (7.46%) compared to healthy individuals (1.46%, P<0.05). IL-15 reduced NKG2A expression (P<0.01), and increased expressions of NKP30 (P<0.05) and NKP46 (P<0.01). The activated NK cells released more IFN-γ (P<0.5) and GZM B (P<0.01) compared to unactivated NK cells. Blockade of CTLA-4 enhanced the NK cell killing potential against Nalm-6 cells (56.3%, P<0.05); however, IFN-γ and GZM B levels were not statistically different between the blocked and non-blocked groups., Conclusion: Our findings suggest that CTLA-4 blockage of Nalm-6 cells causes an increase in antitumour activity of NK cells against these cells. Our study also provides evidence for the potential of cancer immunotherapy treatment using blocking anti-CTLA-4 mAbs.

Background: Beta-thalassemia major patients frequently have endocrinopathies. We tried to determine relation between demographic and transfusion factor and endocrinopathies., Methods: Major beta-thalassemia patients (n=114 cases), 3-38 yr of age, entered this study. Female to male ratio was 51/63. Children (less than 20 yr) formed 57% of participants. Information about bone mineral density (BMD) and hormonal and biochemistry blood evaluation including fasting blood sugar (FBS), ferritin, triiodothyronine (T3), thyroxine (T4) and thyroid-stimulating hormone (TSH), luteinizing hormone (LH) and follicle-stimulating hormone (FSH), testosterone (males), and estradiol (females) entered data sheet., Results: Sex and ferritin level showed no significant correlation with above disorders. Age significantly correlated to short stature, diabetes, low BMD at femur and neck ( P , 0.031, 0.008, 0.009 and <0.001, respectively) . The risk of short stature had increased in 12 yr and older patients 7.71 times than younger patients ( P = 0.008). The risk of diabetes had increased in 35 yr and older patients 26.25 times than younger patients ( P = 0.03). The risk of Z-score ≤ -2 in femoral region has increased in 19 yr and older patients 5.84 times than younger patients ( P = 0.002). The risk of Z-score ≤ -2 in spinal region has increased in 14 yr and older patients 17 times than younger patients ( P = 0.007)., Conclusion: The main factor related with endocrinopathies was age. The correlation between age and short stature, diabetes and low BMD was positive. Therefore, we recommend early monitoring of thalassemia patients (in their late childhood and early teenage) for these complications., (Copyright© 2024 Mohajeri-Tehrani et al. Published by Tehran University of Medical Sciences.)

Background: One of the main reasons for cancer resistance to chemotherapy is the presence of cancer stem cells (CSCs) in cancer tissues. It is also believed that CSCs are the unique originators of all tumor cells. On the other hand, the Epithelial-Mesenchymal Transition pathway (EMT) can act as the main agent of metastasis. Therefore, it is possible that targeting CSCs as well as the EMT pathway could help in cancer therapy. Considering that CSCs constitute only a small percentage of the total tumor mass, enrichment before study is necessary. In our previous study, CSCs were enriched in the human colon cancer cell line HT29 by induction of EMT. These CSC-enriched HT29 cells with mesenchymal morphology were named "HT29-shE". In the present study, these cells were used to investigate the effect of pioglitazone (Pio) and Cetuximab (Cet) in order to find CSC and EMT targeting agents., Method: The viability and IC50 rate of cells treated with different concentrations of Pio and Cet were evaluated using the MTT test. EMT and CSC markers and cell morphology were assessed in Pio and Cet treated and untreated HT29-shE cells using flow cytometry, realtime PCR, immunocytochemistry, and microscopic monitoring., Results: The findings showed that Pio and Cet at concentrations of 250 μM and 40 μg/ml, respectively, decrease cell viability by 50%. Also, they were able to reduce the expression of CSC markers (CD133 and CD44) in the CSC enriched HT29 cell line. Furthermore, Pio and Cet could efficiently reduce the expression of vimentin as a mesenchymal marker and significantly upregulate the expression of E-cadherin as an epidermal marker of EMT and its reverse mesenchymal-- to-epithelial transition (MET). In addition, the mesenchymal morphology of HT29-shE changed into epithelial morphology after Cet treatment., Conclusion: Pio and Cet could inhibit EMT and reduce CSC markers in the EMT induced/CSC enriched cell line. We expect that focus on finding EMT/CSC-targeting agents like these drugs can be helpful for cancer treatment., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

A number of studies have been conducted on the application of 3D models for drug discovery, drug sensitivity assessment, and drug toxicity. Most of these studies focused on disease modelling and attempted to control cellular differentiation, heterogeneity, and key physiological features to mimic organ reconstitution so that researchers could achieve an accurate response in drug evaluation. Recently, organoids have been used by various scientists due to their highly organotypic structure, which facilitates the translation from basic research to the clinic, especially in cancer research. With this tool, researchers can perform high-throughput analyses of compounds and determine the exact effect on patients based on their genetic variations, as well as develop personalized and combination therapies. Although there is a lack of standardization in organoid culture, patientderived organoids (PDOs) have become widely established and used for drug testing. In this review, we have discussed recent advances in the application of organoids and tumoroids not only in cancer research for drug screening but also in clinical trials to demonstrate the potential of organoids in translational medicine., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Introduction: Allogeneic hematopoietic stem cell transplantation (HSCT) is the only definitive curative option for β-major thalassemia patients (β-MT). Posterior reversible encephalopathy syndrome (PRES) is a pervasive neurological complication which typically occurs following HSCT. β-MT patients are prone to a higher PRES incidence due to long-term immunosuppression; thus, it is imperative that these patients are closely monitored for PRES after HSCT., Patients and Methods: We included 148 pediatric patients with β-MT who underwent HSCT between March 2015 and August 2022 in Children's Medical Center. Patients in this study were divided into two groups. The association between PRES and class of β-MT and other risk factors were assessed and the overall survival rate was determined., Results: Fourteen out of 112 patients (12%) with class I and II β-MT developed PRES. However, PRES occurred in 11 out of 36 patients (30.5%) with β-MT-III. Our results indicated that there was a significant association between class III β-MT and the occurrence of (P = .004). Additionally, acute graft-versus-host disease (aGVHD) occurred in 80% and 44.7% of patients in the PRES and non-PRES groups, respectively (P = .001). The results of the Kaplan-Meier analysis revealed that the 5-year overall survival (OS) was 75.6% in the PRES group versus 95% in the non-PRES group, which was statistically significant (P = .001)., Conclusion: Based on our results, pediatric β-MT III patients are at a higher risk of developing PRES. Additionally, pediatric β-MT patients with a history of aGVHD, regardless of disease class, are more likely to develop PRES. Considering these results, PRES has a higher chance of being the etiology of symptoms and should be considered more often in these patients., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2), was declared a global pandemic in March 2020 and resulted in more than 6 million deaths worldwide to date. Although several vaccines were produced against COVID-19 and many therapeutic protocols were developed for the management of this respiratory infection, COVID-19 pandemic has still remained an unresolved problem with the emergence of new variants of SARS-CoV-2, especially vaccine-resistant variants. Probably, end of the COVID-19 needs effective and certain treatments which were undiscovered to date. According to immunomodulatory and regenerative properties, mesenchymal stem cells (MSCs) have been considered a therapeutic approach to suppressing cytokine storm caused by SARS-CoV-2 and the treatmet of severe COVID-19. Following intravenous (IV) infusion of MSCs, cells entrap in the lung, guard alveolar epithelial cells, suppress pulmonary fibrosis and improve lung dysfunction. The human menstrual blood-derived stem cells (hMenSCs) as a novel source of MSCs are collected by noninvasive, painless, and easy way without ethical issues. MenScs are an abundant and cheap source with a high proliferation rate and differentiation ability into multiple cell lineages. Regarding immunomodulatory and anti-inflammatory properties, regenerative ability and low immunogenicity, these cells exhibit great potential in the treatment of various diseases. Some clinical trial studies have begun using MenSCs to treat severe COVID-19. According to these trials, MenSC therapy showed promising and encouraging results in treating severe COVID-19. We reviewed published clinical trials and summarized the effects of MenSC therapy on severe COVID-19 with a focus on clinical and laboratory data, immune and inflammatory factors and concluded the advantages and possible risks of this procedure., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The use of cell therapy for clinical applications has seen a dramatic increase in recent years, primarily in oncology, especially with the use of chimeric antigen receptor (CAR) T-cell therapies. However, there are some barriers to the widespread adoption of CAR-T cell therapies globally, primarily because of the high cost of manufacturing these cells and clinical infrastructure considerations. We reviewed the different strategies adopted across Asia to implement CAR-T cell therapy and found that these included patient assistance programs, close engagement with funders, cost-effectiveness studies, on-site manufacturing of CAR-T cells, and joint ventures between local partners and foreign pharmaceutical companies. Although on-site manufacturing can reduce the cost of genetic engineering and expansion, it does not address many other hidden costs and quality considerations. Future growth in large-scale regional manufacturing, facilitated by cutting-edge science and innovation, could reduce costs through economies of scale and facilitate the eagerly needed global access., Competing Interests: The authors declare no conflict of interest. Disclosure forms provided by the authors are available on the website. WH, AS, AAH and ST are editorial board members of Blood Cell Therapy. They were not involved in the editorial evaluation or decision to accept this article for publication., (Copyright Ⓒ2024 Asia-Pacific Blood and Marrow Transplantation Group (APBMT).)

Introduction: We aimed to evaluate the efficacy, safety, and latent toxicity of total body irradiation (TBI)-based conditioning regimens compared to non-TBI regimens for pediatric patients (under 18 years old) with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (HSCT)., Methods: A systematic search was performed on MEDLINE, Scopus, WOS, and PMC. Also, a search for grey literature was performed on Google Scholar and relevant articles' references were included. Relevant articles which met the inclusion criteria were retrieved up to October 31th, 2022. CMA version 2 was used for the quantitative synthesis of the data., Results: Eight studies on efficacy and safety of TBI and non-TBI as a conditioning regimen were analyzed and six comparative studies on late toxicity were investigated. The meta-analysis revealed a hazard ratio (HR) of 1.508 (95% CI 0.96-2.35) for overall survival (OS) in instances of non-TBI conditioning. Also, an HR of 1.503 (95% CI 1.006-2.25) for disease-free- survival (DFS) favoring TBI-based conditioning. Late complications were reported to be significantly higher in the TBI conditioning regimen group than in the non-TBI group., Conclusion: It appears that non-TBI regimens are as effective as TBI regimens in pediatrics with ALL regarding OS. Occurrence of latent toxicity is higher with TBI conditioning regimen. Conversely, TBI-based regimens are superior to non-TBI conditioning regimens regarding DFS. Considering all aspects, non-TBI conditioning regimens can be an alternative treatment option for pediatric ALL undergoing HSCT., Competing Interests: Declaration of Competing Interest All of the authors declare that there is no conflict of interest., (Copyright © 2023. Published by Elsevier Ltd.)

We report here a newly and facile synthesis of the phospholipids@gold nanoflowers (AuNFs) from intact cells as a new biomimetic organic-inorganic hybrid. The most appealing feature of this nanostructure is its dual-absorbing peak in near infrared (NIR) and visible region of spectra, which makes them a potential light-sensitive agent for reactive oxygen species (ROS)-induced apoptosis. Here, in contrast to previous studies, proposed nanostructures are synthesized in a one-pot reaction using phospholipids present in living cell membranes (as a donor cell) with detectable micro process of AuNF formation. The properties of the resulting AuNFs were evaluated through transmission electron microscopy (TEM), as well as FT-IR, 31 P-NMR spectra and UV-Vis spectroscopy. Designed cell membrane-based nanostructure looks like an intact cell and would be able to interact with other cells (as a target cell) and also capable to produce cytotoxic singlet oxygen under NIR irradiation. Generated ROS act as a key player in initiation of programmed cell death (apoptosis) and progress of cancer photodynamic therapy (PDT). Cellular experiments on breast cancer MCF-7 cells demonstrated that they may be effective as photodynamic therapy agents., (Copyright © 2023. Published by Elsevier B.V.)

Background: Accumulating evidence has demonstrated that RDW (red blood cell distribution width) may independently predict clinically important outcomes in many populations. However, the role of RDW has not been elucidated in brain death. We conducted this study with the aim of evaluating the predictive value of RDW in brain death., Methods: A retrospective study of seventy-seven of brain death cases during 36 months were evaluated at university hospitals, affiliated in Tehran, Iran. Demographical data include age, sex, BMI and cause of brain death, also laboratory results (red blood cell distribution, mean corpuscular volume, hemoglobin) collected by checklists from patient records. Having the three RDW measurements (days of hospital admission, day of brain death, and day of cardiac arrest) required., Results: Time interval from hospital admission until brain death was 5.27±4.07. The mean age of brain death cases was 32.65±16.53. The mean RDW values on days of hospital admission, the day of brain death, and the day of cardiac arrest were 14.53±1.98, 15.12±1.93 and 15.18±2.07, respectively. Results of the repeated-measures ANOVA test reveal that RDW level was constantly higher in the traumatic patient group compared to the non-traumatic ones (P=0.008)., Conclusion: The frequency of brain death was high in patients with high RDW values. RDW might be a prognostic biomarker for brain death. More prospective studies with large sample size and long follow-up period should be carried out to determine the prognostic significance of RDW and brain death in future., Competing Interests: None declared.

Purpose: Major histocompatibility complex class II (MHC-II) deficiency is a rare inborn error of immunity (IEI). Impaired antigen presentation to CD4 + T cells results in combined immunodeficiency (CID). Patients typically present with severe respiratory and gastrointestinal tract infections at early ages. Hematopoietic stem cell transplantation (HSCT) is the only curative therapy., Methods: We describe the clinical, immunologic, and genetic features of eighteen unrelated Iranian patients with MHC-II deficiency., Results: Consanguinity was present in all affected families. The median age at the initial presentation was 5.5 months (range 7 days to 18 years). The main symptoms included failure to thrive, persistent diarrhea, and pneumonia. Autoimmune and neurologic features were also documented in about one-third of the patients, respectively. Thirteen patients carried RFXANK gene mutations, two carried RFX5 gene mutations, and three carried a RFXAP gene mutation. Six patients shared the same RFXANK founder mutation (c.162delG); limited to the Iranian population and dated to approximately 1296 years ago. Four of the patients underwent HSCT; three of them are alive. On the other hand, nine of the fourteen patients who did not undergo HSCT had a poor prognosis and died., Conclusion: MHC-II deficiency is not rare in Iran, with a high rate of consanguinity. It should be considered in the differential diagnosis of CID at any age. With the limited access to HSCT and its variable results in MHC-II deficiency, implementing genetic counseling and family planning for the affected families are mandatory. We are better determined to study the c.162delG RFXANK heterozygous mutation frequency in the Iranian population., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The number of hematopoietic stem cell transplantations (HCTs) is increasing annually worldwide, and the Asia-Pacific (AP) region is no exception. We report on the absolute number of HCTs in 2018 and 2019 and the trends in graft selection and disease indication in the past few decades. In 2018, 24,292 HCTs were performed in the AP region, of which 8,754 (36.0%) were autologous and 15,538 (64.0%) were allogeneic. Among the allogeneic HCTs, 10,552 (67.9%) of the recipients were related to their donors, whereas 4,986 (32.1%) were unrelated. In 2019, 27,583 HCTs were reported, of which 17,613 (63.9%) were allogeneic and 9,970 (36.1%) were autologous. Although, in 2010, there was a nearly equal number of related and unrelated HCTs, the difference has shown an annual increase, with more than double (2.05) the number of related than unrelated HCTs in 2019. Recent trends in the AP region show that peripheral blood has overwhelmingly surpassed the bone marrow as a graft source for both related and unrelated HCTs, with the haploidentical donor type being preferred; however, their trends in each country/region were quite different among countries/regions. In 2019, the main conditions requiring HCT were acute myelogenous leukemia (n=6,629 [24.0%]), plasma cell disorders (PCD) (n=4,935 [17.9%]), malignant lymphoma (ML) (n=4,106 [14.9%]), acute lymphoblastic leukemia (AML) (n=3,777 [13.7%]), myelodysplastic syndrome or myelodysplastic/myeloproliferative neoplasm (n=1,913 [6.9%]), severe aplastic anemia (n=1,671 [6.1%]), and hemoglobinopathy (n=910 [3.3%]). PCD and ML were the main indications for autologous HCT, and the number of PCD cases has grown more prominent than the corresponding of ML. The increased number of allogeneic transplants for hemoglobinopathy remains prominent, as well as that of AML and acute lymphocytic leukemia for the past 5 years. There was a significant regional variation in the number of facilities performing HCTs, ranging from one in Mongolia and Nepal to 313 in Japan, and differing regional densities varying from 0.1 in Indonesia and Pakistan to 24.7 in Japan. The total transplant density per 10 million population in each country/region also differed (0.2 in Indonesia and 627 in New Zealand). This annual Activity Survey aims to help all participating countries/regions understand the changes in HCT, serve as an asset in promoting HCT activities in the AP region, and be used as a reference for comparison with other registries from Europe and the United States., Competing Interests: The authors declare no conflict of interest. Disclosure forms provided by the authors are available on the website. MI, AS, MB, AAH, and SO are editors of Blood Cell Therapy. They were not involved in the editorial evaluation and the decision to accept this article for publication., (Copyright Ⓒ2023 Asia-Pacific Blood and Marrow Transplantation Group (APBMT).)

Background: Allo-HSCT is a definite approach for the management of a wide variety of lethal and debilitating malignant and non-malignant disorders. However, its two main complications, acute and chronic graft-versus-host disease (GVHD), exert significant morbidities and mortalities. BoS, as a manifestation of chronic lung GVHD, is a gruesome complication of allo-HSCT, and for those with steroid-refractory disease, no approved second-line therapies exist. Mesenchymal stem cells (MSCs) exert anti-inflammatory and growth-promoting effects, and their administration against a wide range of inflammatory and neurologic disorders, as well as GVHD, has been associated with promising outcomes. However, literature on the safety and effectiveness of MSC therapy for BoS and pediatric cGVHD is scarce., Methods: We designed a single-arm trial to administer adipose tissue (AT)-derived MSCs to pediatric patients with refractory BoS after allo-HSCT. AT-MSCs from obese, otherwise healthy donors were cultured in an ISO class 1 clean room and injected into the antecubital vein of eligible patients with a dose of 1 × 10 6 /kg. The primary endpoints included a complete or partial response to therapy [in terms of increased forced expiratory volume in one second (FEV1) values and steroid dose reduction] and its safety profile., Results: Four eligible patients with a median age of 6.5 years were enrolled in the study. Steroid-induced osteoporosis and myopathy were present in three cases. A partial response was evident in three cases after a single injection of AT-MSCs. The treatment was safe and tolerable, and no treatment-related adverse events were noted. Two patients developed manageable COVID-19 infections one and 4 months after AT-MSC injection. After a median follow-up duration of 19 months, all cases are still alive and have had no indications for lung transplantation., Conclusions: AT-MSCs could be safely administered to our pediatric cases with BoS post-allo-HSCT. Considering their advanced stage of disease, their sub-optimal functional capacity due to steroid-induced complications, and COVID-19 infection post-treatment, we believe that AT-MSC therapy can have possible efficacy in the management of pediatric BoS. The conduction of further studies with larger sample sizes and more frequent injections is prudent for further optimization of AT-MSC therapy against BoS. Trial registration Iranian Registry of Clinical Trials (IRCT), IRCT20201202049568N2. Registered 22 February 2021, https://en.irct.ir/trial/53143 ., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Chimeric antigen receptor T (CAR-T) cell therapy represents a breakthrough in personalized cancer treatments. In this regard, synthetic receptors comprised of antigen recognition domains, signaling, and stimulatory domains are used to reprogram T-cells to target tum or cells and destroy them. Despite the success of this approach in refractory B-cell malignancies, the optimal potency of CAR T-cell therapy for many other cancers, particularly solid tumors, has not been validated. Natural killer cells are powerful cytotoxic lymphocytes specialized in recognizing and dispensing the tumor cells in coordination with other anti-tumor immunity cells. Based on these studies, many investigations are focused on the accurate designing of CAR T-cells with clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system or other novel gene editing tools that can induce hereditary changes with or without the presence of a double-stranded break into the genome. These methodologies can be specifically focused on negative controllers of T-cells, induce modifications to a particular gene, and produce reproducible, safe, and powerful allogeneic CAR T-cells for on-demand cancer immunotherapy. The improvement of the CRISPR/Cas9 innovation offers an adaptable and proficient gene-editing capability in activating different pathways to help natural killer cells interact with novel CARs to particularly target tumor cells. Novel achievements and future challenges of combining next-generation CRISPR-Cas9 gene editing tools to optimize CAR T-cell and natural killer cell treatment for future clinical trials toward the foundation of modern cancer treatments have been assessed in this review., Competing Interests: The authors declare no conflict of interests., (© 2023 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co., Ltd.)

Background: The reconstitution of different T-cell subsets following allogeneic hematopoietic stem cell transplantation (allo-HSCT) is critical for efficient pathogen protection and the prevention of graft-versus-host disease (GvHD). In particular, studies have highlighted the importance of balanced ratios of regulatory T-cells (Tregs) and distinct functionally T-cells in preventing acute and chronic GvHD., Methods: We evaluated the regeneration of CD4 and CD8 T-cell subpopulations in nine pediatric patients with non-malignant disorders following allo-HSCT from a fully HLA-identical donor., Results: CD4 and CD8 T-cells were higher 12 months after the transplant but still lower than in healthy controls and pre-transplant. However, we found after allo-HSCT, central memory and effector memory cell subsets were the predominant phenotypes in the CD4 and CD8 T-cell populations, respectively. In patients who had developed acute GvHD, there was an increase in the frequency of TEMRA (effector memory T cells that re-express CD45RA) cells within the CD4 T-cell population. Meanwhile, in patients with chronic GvHD, we observed a decrease in Th1 cells in CD4 T-cells and effector memory cells within the CD8 T-cell population. In addition, we found decreased TEMRA cell subsets in CD4 and CD8 T-cell populations in chronic GvHD., Conclusion: Our findings suggest a possible relationship between the influence of acute GvHD and its prevention on delayed CD4 T-cell reconstitution and, reciprocally, unbalanced regeneration of CD4 and CD8 T-cell subsets in the development of chronic GvHD., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2023. Published by Elsevier B.V.)

Background: In order to support the comprehensive classification of Leukocyte Adhesion Deficiency-I (LAD-I) severity by simultaneous screening of CD11a/CD18, this study assessed clinical, laboratory, and genetic findings along with outcomes of 69 LAD-I patients during the last 15 years., Methods: Sixty-nine patients (40 females and 29 males) with a clinical phenotype suspected of LAD-I were referred to Immunology, Asthma, and Allergy research institute, Tehran, Iran between 2007 and 2022 for further advanced immunological screening and genetic evaluations as well as treatment, were enrolled in this study., Results: The diagnosis median age of the patients was 6 months. Delayed umbilical cord separation was found in 25 patients (36.2%). The median diagnostic delay time was 4 months (min-max: 0-82 months). Forty-six patients (66.7%) were categorized as severe (CD18 and/or CD11a: below 2%); while 23 children (33.3%) were in moderate category (CD18 and/or CD11a: 2%-30%). During the follow-ups, 55.1% of children were alive with a mortality rate of 44.9%. Skin ulcers (75.4%), omphalitis (65.2%), and gingivitis (37.7%) were the most frequent complaints. Genetic analysis of the patients revealed 14 previously reported and three novel pathogenic mutations in the ITGB2 gene. The overall survival of patients with and without hematopoietic stem cell transplantation was 79.3% and 55.6%, respectively., Conclusion: Physicians' awareness of LAD-I considering delayed separation of umbilical cord marked neutrophilic leukocytosis, and variability in CD11 and CD18 expression levels, and genetic analysis leads to early diagnosis and defining disease severity. Moreover, the prenatal diagnosis would benefit families with a history of LAD-I., (© 2023 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Despite multi-modal therapies for patients with malignant brain tumors, their median survival is < 2 years. Recently, NK cells have provided cancer immune surveillance through their direct natural cytotoxicity and by modulating dendritic cells to enhance the presentation of tumor antigens and regulate T-cell-mediated antitumor responses. However, the success of this treatment modality in brain tumors is unclear. The main reasons are; the brain tumor microenvironment, the NK cell preparations and administration, and the donor selection. Our previous study showed that intracranial injection of activated haploidentical NK cells resulted in the eradication of glioblastoma tumor mass in the animal model without any evidence of tumor recurrence. Therefore, in the present study, we evaluated the safety of intra-surgical cavity or intra cerebrospinal fluid (CSF) Injectionofex vivoactivated haploidentical NK cells in six patients with recurrent glioblastoma multiform (GBM) and malignant brain tumors resistance to chemo/radiotherapy. Our results indicated that activated haploidentical NK cells express activator and inhibitor markers and can kill the tumor cells. However, their cytotoxic potential on patient-derived GBM (PD-GBM) was more than that of its cell line. Also, their infusion increased the overall disease control rate by about 33.3%, with a mean survival of 400 days. Moreover, we showed that local administration of the activated haploidentical NK cells in malignant brain tumors is safe, feasible, tolerated at higher doses, and cost-effective., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Griscelli syndrome type 2 (GS2) is an autosomal recessive immunodeficiency characterized by hair hypopigmentation, recurrent fever, hepatosplenomegaly and pancytopenia. This study aims to find new genetic changes and clinical features in 18 children with GS2 caused by the RAB27A gene defect. In all, 18 Iranian children with GS2 who presented with silver grey hair and frequent pyogenic infection were included in this study. After recording demographic and clinical data, PCR sequencing of the RAB27A gene was performed for all exons and exon-intron boundaries. Two patients in this study were subjected to whole-exome sequencing followed by Sanger sequencing. Light microscopy study of hair showed large irregular clumps of pigment with the absence of giant granules on the blood smear. Mutation analysis of the RAB27A gene identified two novel missense mutations as homozygous in a patient, one in exon 2, c.140G>C and another in exon 4, c.328G>T. In addition, for 17 other patients, 6 reported mutations were obtained including c.514&#95;518delCAAGC, c.150&#95;151delAGinsC, c.400&#95;401delAA, c.340delA, c.428T>C and c.221A>G. The mutation c.514&#95;518delCAAGC was the most frequent and found in 10 patients; this mutation may be considered a hotspot in Iran. Early diagnosis and treatment of RAB27A deficiency can contribute to better disease outcomes. In affected families, genetic results could be urgently needed to make a timely decision about haematopoietic stem cell transplantation and prenatal diagnosis., (© 2023 The Scandinavian Foundation for Immunology.)

Background: Acute lymphoblastic leukemia (ALL) is the most prevalent childhood cancer under the age of 15 years. Despite the recent advances in therapeutic regimens, relapse occurs in 15%-20% of pediatric patients after chemotherapy, and hematopoietic stem cell transplantation (HSCT) is the best treatment option. However, donor availability is one of the major challenges. Over the last decade, haploidentical donor (HID) transplantation has evolved as an alternative option. Herein, we aimed to compare the transplant outcomes in pediatric patients receiving total body irradiation (TBI)-free myeloablative regimens, between non-HID and HID transplant., Patients and Methods: The study included 60 pediatric ALL patients who had undergone HSCT from October 2016 until September 2020. Forty-three patients received non-HID HSCT, while 17 patients received HID. The sources of stem cells (SC) were peripheral blood stem cells (PBSC) for all the patients. The conditioning regimen was based on busulfan and cyclophosphamide. For graft-versus-host disease (GvHD) prophylaxis, patients received cyclosporine and methotrexate in the setting of non-HID transplantation, where HIDs received post-transplant cyclosporine and cyclophosphamide., Results: The cumulative incidences of 3-year overall survival (OS) were 73.1%, 66.6%, and 69.5%, for matched sibling donor-matched related donor (MSD-MRD), matched unrelated donor-mismatched unrelated donor (MUD-MMUD), and HID groups, respectively (p = .85). The cumulative incidences of grade II-IV acute GvHD for the MRD, MUD-MMUD, and HID groups were 29%, 41%, and 49%, respectively (p = .47). Furthermore, the 3-year cumulative incidence of chronic GvHD was MSD-MRD: 70% versus MUD-MMUD: 42% versus HID: 45% (p = .64). The 3-year cumulative incidence of relapse post transplantation was 45%, 18%, and 45%, respectively, for the MSD-MRD, MUD-MMUD, and HID groups, and the differences were not statistically significant (p = .55). There was a higher risk for cytomegalovirus (CMV) infection in patients receiving HID transplants compared to those of non-HIDs (p < .01)., Conclusion: Our results indicate that PBSC-HID transplant outcomes in the setting of non-TBI conditioning are comparable to those of non-HIDs in pediatric ALL patients., (© 2023 Wiley Periodicals LLC.)

Risk factors for severe SARS-Cov-2 infection course are poorly described in children following hematopoietic cell transplantation (HCT). In this international study, we analyzed factors associated with a severe course (intensive care unit (ICU) admission and/or mortality) in post-HCT children. Eighty-nine children (58% male; median age 9 years (min-max 1-18)) who received an allogeneic (85; 96%) or an autologous (4; 4%) HCT were reported from 28 centers (18 countries). Median time from HCT to SARS-Cov-2 infection was 7 months (min-max 0-181). The most common clinical manifestations included fever (37; 42%) and cough (26; 29%); 37 (42%) were asymptomatic. Nine (10%) children following allo-HCT required ICU care. Seven children (8%) following allo-HCT, died at a median of 22 days after SARS-Cov-2 diagnosis. In a univariate analysis, the probability of a severe disease course was higher in allo-HCT children with chronic GVHD, non-malignant disease, immune suppressive treatment (specifically, mycophenolate), moderate immunodeficiency score, low Lansky score, fever, cough, coinfection, pulmonary radiological findings, and high C-reactive protein. In conclusion, SARS-Cov-2 infection in children following HCT was frequently asymptomatic. Despite this, 10% needed ICU admission and 8% died in our cohort. Certain HCT, underlying disease, and SARS-Cov-2 related factors were associated with a severe disease course., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Objectives: Fanconi anemia (FA) is a rare, heterogeneous, inherited disorder. Allogeneic hematopoietic stem cell transplantation (HSCT) represents the only therapeutic option to restore normal hematopoiesis. This study reports the outcomes of FA-HSCT patients and identifies factors, including clinical phenotype. Our team examined more than 95% of Iranian FA patients during the last decade., Study Design: One hundred and six FA patients (age range: 2-41) who underwent HSCT from March 2007 to February 2018 were enrolled. Clinical characteristics of genetic disease, pre-HSCT findings, HSCT indication, and long-term follow-up evaluated and recorded. Data were analyzed using SPSS 19.0., Results: The mean follow-up period for survivors was 36 months (range, 1-101). The 3-year overall survival (OS) and disease-free survival were 72.2% and 71.2%, respectively. The 3-year OS rate for patients with limited and extensive malformations was 78.8% and 56.6%, respectively ( p  = 0.025). Acute graft versus host disease incidence was 60.52% for patients with limited malformations versus 70% for patients with extensive ones ( p  = 0.49). Chronic graft versus host disease incidence for these two groups was 9.21% and 10%, respectively ( p  = 0.91)., Conclusions: OS was not associated with each of the malformations singly; however, it was lower in the extensive group. The younger age of patients at the HSCT time leads to a higher OS. The differences in FA patients' outcomes and the various genotypes were probably related. These data provide a powerful tool for further studies on genotype-phenotype association with HSCT results., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors. Health Science Reports published by Wiley Periodicals LLC.)

The World Health Organization-designated Eastern Mediterranean region (EMRO) consists of 22 countries in North Africa and Western Asia with a collective population of over 679 million. The area comprises some of the wealthiest countries per capita income and some of the poorest. The population structure is also unique and contrasts with western countries, with a much younger population. The region sits in the heart of the thalassemia belt. Many countries have a significant prevalence of sickle cell disease, and cancer is on the rise in the region. Therefore, the strategic priorities for the growth and development of hematopoietic stem cell transplantation (HSCT) differ from country to country based on resources, healthcare challenges, and prevalent infrastructure. Thirty-one reporting teams to the Eastern Mediterranean Blood and Marrow Transplantation Group have active HSCT programs in 12 countries; allogeneic transplants outnumber autologous transplants, and the proportion of allotransplants for non-malignant conditions is higher in the EMRO region than in Western Europe and North America. The vast majority (99%) of allotransplants are from matched related donors. Matched unrelated donors and other alternate donor transplants are underutilized. The chance of finding a matched related donor for allografts is higher, with a significant chance of finding matched donors among non-sibling related donors. Reasons for relatively lower rates of transplants compared with other countries are multifactorial. Capacity building, development of newer centers, innovative funding, and better utilization of information technology are required to make transplantation as an accessible modality to more patients. Cost-effectiveness and cost-containment, regulation, and ensuring quality will all be priorities in planning HSCT development in the region.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment option for hereditary hemoglobin disorders, such as beta-thalassemia; However, this procedure is not without constraints, mainly engendering complications such as acute graft-versus-host disease (aGvHD), chronic GvHD (cGvHD), and susceptibility to infections. The clinical outcomes of allo-HSCT are highly dependant on the quality and quantity of T-cell subsets reconstitution. Following the allo-HSCT of six pediatric patients afflicted with beta-thalassemia, their mononuclear cells were isolated, and then cultured with a combination of phorbol myristate acetate (PMA)/ionomycin and Brefeldin A. The content of CD4 T-cell subsets, including T helper 17 (Th17) cells and regulatory T cells (Tregs), were determined by specific conjugated-monoclonal antibodies three and six months post-HSCT. An increased frequency of total CD4 T-cells, Tregs and Th17 cells was observed at day 90 and 180 after allo-HSCT, albeit the numbers were still lower than that of our healthy controls. In patients who developed cGvHD, a lower Th17/Treg ratio was observed, owing it to a decreased proportion of Th17 cells. In conclusion, creating balance between Th17 and Treg subsets may prevent acute and chronic GvHD in patients after allo-HSCT., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)

CRISPR/Cas9 is an effective gene editing tool with broad applications for the prevention or treatment of numerous diseases. It depends on CRISPR (clustered regularly interspaced short palindromic repeats) as a bacterial immune system and plays as a gene editing tool. Due to the higher specificity and efficiency of CRISPR/Cas9 compared to other editing approaches, it has been broadly investigated to treat numerous hereditary and acquired illnesses, including cancers, hemolytic diseases, immunodeficiency disorders, cardiovascular diseases, visual maladies, neurodegenerative conditions, and a few X-linked disorders. CRISPR/Cas9 system has been used to treat cancers through a variety of approaches, with stable gene editing techniques. Here, the applications and clinical trials of CRISPR/Cas9 in various illnesses are described. Due to its high precision and efficiency, CRISPR/Cas9 strategies may treat gene-related illnesses by deleting, inserting, modifying, or blocking the expression of specific genes. The most challenging barrier to the in vivo use of CRISPR/Cas9 like off-target effects will be discussed. The use of transfection vehicles for CRISPR/Cas9, including viral vectors (such as an Adeno-associated virus ( AAV )), and the development of non-viral vectors is also considered., (© 2023 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co., Ltd.)

The eminence of Bacillus Calmette-Guerin (BCG) vaccine in newborn vaccination programs has been conspicuous throughout the years, especially in low-income developing countries where tuberculosis is prevalent; however, application of the BCG vaccine is not without constraints, especially in patients afflicted with immunodeficiency diseases, such as severe combined immunodeficiency (SCID). The present study aimed to evaluate whether the administration of BCG vaccine at birth could improve the outcomes of hematopoietic stem cell transplantation (HSCT) in pediatric patients with SCID. In this study, 30 SCID patients who underwent HSCT using a reduced-intensity conditioning regimen (RIC) were followed-up for 2 years post-HSCT. The outcomes of HSCT were evaluated in both non-BCG-vaccinated patients (n = 12) and BCG-vaccinated patients (n = 18). Our results show a higher incidence of acute graft-versus-host disease (aGVHD), but not of chronic GVHD, in the BCG-vaccinated patients, and a similar overall survival (OS) rate in the 2 groups. We speculate that the similar OS rate in the 2 groups, despite the risk of BGC vaccination, was because this group received an RIC conditioning regimen. There was no other difference between the 2 groups. Considering the effect of the BCG vaccine on HSCT outcome, we suggest that the administration of BCG vaccine be deferred until age 3 months so that APT testing without the interference of maternal antibodies can be performed. However, this study could benefit from a larger cohort to further validate our findings, as the possible reason for some factors not being statistically significant was our small sample size., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Introduction: The oral cavity is one of the most common sites impacted by hematopoietic stem cell transplantation (HSCT) with acute complications including mucositis, bleeding, salivary gland dysfunction, infection, and taste alteration. These complications may result in significant morbidity and can negatively impact outcomes such as length of stay and overall costs. As such, oral care during HSCT for prevention and management of oral toxicities is a standard component of transplant protocols at all centers. The objective of this study was to evaluate the current oral care practices for patients during HSCT at different transplant centers within the Eastern Mediterranean region., Material and Methods: An internet-based survey was directed to 30 transplant centers in the Eastern Mediterranean region. The survey included five sections asking questions related to (1) transplant center demographics; (2) current oral care protocol used at the center and type of collaboration (if any) with a dental service; (3) use of standardized oral assessment tools and grading systems for mucositis; (4) consultations for management of oral complications; and (5) oral health needs at each center. Data are presented as averages and percentages., Results: A total of 16 responses from 11 countries were collected and analyzed, indicating a response rate of 53%. Eight centers reported that a dentist was part of the HSCT team, with four reporting oral medicine specialists specifically being part of the team. Almost all centers (15/16; 93%) had an affiliated dental service to facilitate pre-HSCT dental clearance with an established dental clearance protocol at 14 centers (87%). Dental extraction was associated with the highest concern for bleeding and the need for platelet transfusion. With respect to infection risk, antibiotic prophylaxis was considered in the setting of low neutrophil counts with restorative dentistry and extraction. All centers provide daily reinforcement of oral hygiene regimen. The most frequently used mouth oral rinses included sodium bicarbonate (68%) and chlorhexidine gluconate (62%), in addition to ice chips for dry mouth (62%). The most frequently used mucositis assessment tools were the World Health Organization scale (7/16; 43%) and visual analogue scale for pain (6/16; 37%). Mucositis pain was managed with lidocaine solution (68.8%), magic mouth wash (68.8%) and/or systemic pain medications (75%)., Conclusions: Scope and implementation of oral care protocols prior to and during HSCT varied between transplant centers. The lack of a universal protocol may contribute to gaps in oral healthcare needs and management for this group of patients. Further dissemination of and education around available oral care guidelines is warranted., Clinical Relevance: Considering oral care during HSCT a standard component of transplant protocols, the current study highlights the common oral care practices for patients at centers within the Eastern Mediterranean region.

Introduction: T cells that recognize WT1 peptides have been shown to efficiently eliminate WT1-expressing tumor cells. This study was designed to investigate the feasibility of isolating WT1-reactive T cells from peripheral blood mononuclear cells (PBMCs) from healthy donors and patients with Wilms tumor, and to assess the cytotoxicity mediated by these cells against Wilms tumor cells (WiTu cells)., Methods: WT1-reactive T cells were enriched and isolated by stimulating PBMCs with a WT1 peptide pool and interferon-γ capture-based immunomagnetic separation (IMS). Using the lactate dehydrogenase release assay, the in vitro cytotoxicity of the isolated cells and standard chemotherapy was evaluated on WiTu cells., Results: Higher proportions of WT1-reactive T cells were isolated from patients with Wilms tumor compared to those isolated from HDs. WT1-reactive T cells produced > 50% specific lysis when co-cultured with WT1 + WiTu cells at the highest effector-to-target (E:T) ratio in this study (i.e., 5:1), compared to <23% when co-cultured with WT1 - WiTu cells at the same ratio. WT1-reactive T cells showed anti-tumoral activity in a dose-dependent manner and mediated significantly greater cytotoxicity than the non-WT1-reactive fraction of PBMCs on WT1 + WiTu cells. The cytotoxicity of standard chemotherapy was significantly lower than that of WT1-reactive T cells when co-cultured with WT1 + WiTu cells at E:T ratios of 2:1 and 5:1., Conclusion: WT1-reactive T cells can be effectively enriched from the PBMCs of patients with Wilms tumor. Ex vivo generated WT1-reactive T cells might be considered an adoptive immunotherapeutic option for WT1 + Wilms tumors., Competing Interests: The authors declare no conflict of interest., (© 2023 The Author(s).)

Introduction: Graft-versus-host disease (GvHD) is a life-threatening syndrome commonly associated with hematopoietic stem cell transplantation (HSCT). Preventing the incidence of GVHD after HSCT along with minimizing long-term immunosuppression is currently under investigation with regulatory T cells (Tregs). As Tregs are a low-frequency population and the yield of all memory Tregs is not sufficient for clinical application, an initial Treg expansion is essential., Methods: Thirty milliliters of peripheral blood from the β-thalassemia major (beta-TM) patients and healthy controls were obtained and Tregs were isolated using MACS. Isolated cells were cultured in the presence of rapamycin and rIL-2 followed by activated with anti-CD3/CD28-coated beads. To evaluate Treg plasticity, expanded Tregs were cultured in a medium containing IL1β, IL6, TGFβ, and IL2, with or without 500 nM rapamycin for 72 h. To assess the functional properties of Tregs, CFSE dilution assays were performed to evaluate the ability of in vivo expanded Tregs from beta-TM patients. Statistical analysis was performed using paired t-test and independent t-test, with the aid of SPSS version 12.0. p-value ≤0.05 was considered significant., Results: The percentage of Tregs isolated from the control group was significantly higher than the Tregs isolated from patients (p-value = 0.01), which is probably due to the iron overload in beta-TM patients as a result of continuous blood transfusion. Also, the percentage of Tregs after 5 days of expansion had a significant increase in both groups compared to before expansion (p-value = 0.03). Our results also showed that the expansion of Tregs after 72 h in the presence of inflammatory cytokines and in the absence of rapamycin led to the increase in the intracellular expression of IL-17 (p-value = 0.01), while intracellular expression of IL-17 remained low following the addition of 100 nM rapamycin to the culture medium (pvalue = 0.073). The results of the functional evaluation of expanded Tregs showed relatively differences in both patient and control groups. Thus, expanded Tregs inhibited the proliferation of responder T cells in a dose-dependent manner in the control group (p-value = 0.028), while in the patient group this inhibitory effect was not significant (p-value = 0.055)., Conclusion: Tregs isolated from beta-TM patients have poorer inhibitory performance than Tregs isolated from healthy individuals. Also, we concluded that rapamycin stabilizes the Treg population by inhibiting the production of IL-17, all necessitating the administration of appropriate immunosuppressive drugs in patients receiving Treg therapy., (© 2022 S. Karger AG, Basel.)

Objective/background: Mixed chimerism is a major concern after allogenic hematopoietic stem cell transplantation (HSCT) using a reduced-intensity conditioning (RIC) regimen in primary immunodeficiencies (PIDs). A donor lymphocyte infusion (DLI) escalating dose regimen has been developed with the aim of reducing toxicity while preserving efficacy. However, the graft-versus-host disease (GvHD) development remains the most common and adverse effect of DLI and continues to be a limiting factor in its application, especially nonmalignant diseases such as PIDs. We prospectively evaluated PID patients after HSCT using RIC in Childrens Medical Center, who were candidates for an escalating dose of DLI for MC from 2016 to 2018., Methods: With the median follow-up of 16.4 months, 12 patients (nine males and three females) with a median age of 3.72 years received DLI. The median number of DLI was 3.2 (range, 1-5), the maximum and total dose of DLIs administered per patient were 3.6 × 10 7 (range, 1-5) cells/kg CD3 + and 9.3 × 10 7 (range, 1-15) cells/kg CD3 + cells, respectively., Results: Median donor chimerism at baseline before the DLIs was 41% (range, 11-73%), patients received DLIs at a median of 105 (range, 37-230) days and 52 (range, 3-168) days after the HSCT and onset of the MC, respectively. At the final assessment, six (54.5%) patients improved after DLIs at a median of 47.3 days., Conclusion: PID patients may benefit from DLI with an escalating dose regimen, but the GvHD development remains a concern during the DLI, and the optimum dose and frequency must be standardized.

Background and Purpose: Given the high mortality rate of invasive candidiasis in hospitalized pediatric patients, it is crucial to establish a predictive system to achieve early diagnosis and treatment of patients who are likely to benefit from early antifungal treatment. This study aimed to assess the Candida colonization index, species distribution, and antifungal susceptibility pattern of Candida strains isolated from pediatric patients with high Candida colonization index (CI)., Materials and Methods: This study was carried out at the Children's Medical Center in Tehran-Iran. In total, 661 samples were collected from 83 patients. The Candida CI was calculated according to the descriptions of previous studies. The isolates were identified using polymerase chain reaction-based techniques. The Clinical and Laboratory Standard Institute protocol M60 was used to conduct the antifungal susceptibility test., Results: A colonization index greater than 0.5 was confirmed in 29 cases (58% of positive samples) with two children developing candidemia. Candida albicans (n=53, 49.5%) was the most common Candida species in patients with CI > 0.5. Except for acute lymphoblastic leukemia, no risk factors were linked to a high index in colonized children ( P > 0.05). Twelve isolates (7.01%) were multi-azole resistant with high MICs against both isavuconazole and ravuconazole and seven strains (4.09%) were echinocandins resistant., Conclusion: In pediatric intensive care units, patients are at risk of fungal infection, particularly candidemia. In this study, more than half of the children with positive yeast cultures had CI > 0.5, and 6.8% developed candidemia., Competing Interests: There is no conflict of interest., (Copyright: © 2021, Published by Mazandaran University of Medical Sciences on behalf of Iranian Society of Medical Mycology and Invasive Fungi Research Center.)

Platelets (PLTs) are small anucleate blood cells that release from polyploidy megakaryocytes(MKs). PLT transfusion is standard therapy to prevent hemorrhage. PLT transfusion is donor-dependent way which have limitations including the inadequate donor blood supply, poor quality, and issues related to infection and immunity. Overcoming these obstacles is possible with in vitro production of human PLTs. Currently several cells have been considered as source to in vitro production of PLTs such as hematopoietic stem cells (HSCs), embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). However, HSCs are a limited source for PLT production and large-scale expansion of HSC-derived PLT remains difficult. Alternative sources can be ESCs which have unlimited expansion capacity. But ESCs have ethical issues related to destroying human embryos. iPSCs are considered as an ideal unlimited source for PLT production. They are able to differentiate into any cells and have the capacity of self-renewal. Moreover, iPSCs can be acquired from any donor and easily manipulated. Due to new advances in development of MK cell lines, bioreactors, feeder cell-free production and the ability of large scale generation, iPSC-based PLTs are moving toward clinical applicability and considering the minimal risk of alloimmunization and tumorigenesis of these products, there is great hopefulness they will become the standard source for blood transfusions in the future. This review will focus on how to progress of in vitro generation of PLT from stem cell especially iPSCs and some of the successful strategies that can be easily used in clinic will be described., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Natural killer (NK) cell therapy has been shown to be effective in the treatment of some cancers. However, the effects of this adoptive immunotherapy have not been investigated for Wilms tumor (WT). In this study, the effects of adoptive NK-cell transfer on a patient-derived xenograft (PDX) model of anaplastic WT were evaluated, and the impacts of cell source and ex vivo activation strategy on the therapeutic efficacy of NK-cell product were appraised., Methods: NK cells were isolated from human peripheral blood mononuclear cells (NK PB ) and human cord blood (NK CB ), and were expanded and activated using a cytokine cocktail. Another group of NK cells (NK ET ) was produced through activation with the exosomes extracted from previously challenged NK PB cells with WT. PDX-bearing mice were treated with clinically relevant doses of NK PB , NK CB , NK ET , standard chemotherapy, and placebo (phosphate-buffered saline)., Results: PDX models treated with NK CB showed a better survival rate, though the difference among the study groups was not significant. Compared with the placebo control group, NK CB significantly improved the histopathologic response, NK PB significantly inhibited the proliferation of neoplastic cells, and NK ET led to a significant decrease in the metastasis score (all p-values <.05). Standard chemotherapy provided the greatest tumor growth inhibition and the lowest mitotic count, though it did not show any significant advantage over NK-cell therapies in any of the outcome parameters in two-by-two comparisons., Conclusions: This study spotlights the efficacy of adoptive NK-cell transfer as a potential treatment candidate for high-risk WT., (© 2022 Wiley Periodicals LLC.)

The Asia-Pacific Blood and Marrow Transplantation Group (APBMT) has been conducting annual surveys on the activity of hematopoietic stem cell transplants since 2007. The APBMT Data Center collected the following data in 2017. A total of 21,504 transplants were registered from 733 transplant centers of 20 countries/regions in the Asia-Pacific (AP) region. Five countries/regions comprised 89.4% of all transplants - China (6,979), Japan (5,794), South Korea (2,626), India (2,034), and Australia (1,789). The number of centers in these five countries/regions also comprised 88.9% of all centers: Japan (373), China (123), India (66), Australia (45), and South Korea (44). The overall ratio between autologous and allogeneic transplants was 37.0% and 63.0%, respectively, but the ratios varied significantly among countries/regions. Autologous transplants have surpassed allogeneic transplants in Thailand, Australia, Vietnam, New Zealand, Singapore, and Iran. In contrast, the proportion of allogeneic transplants comprised over 70% of all transplants in Pakistan, China, and Hong Kong. These ratios were compared by the Data Center among countries/regions that performed more than 50 transplants. The proportion of related and unrelated transplants also differed among countries/regions. The number of unrelated transplants was more than related ones in Japan (2,551 vs. 1,202) and Australia (329 vs. 291), whereas more than 80% of all transplants were related transplants in Malaysia (90.9%), India (89.5%), Iran (87.2%), Vietnam (85.7%), China (80.9%), and Thailand (80.6%). All transplant activities were related transplants in Pakistan, the Philippines, Myanmar, and Nepal, and no allogeneic transplants were performed in Bangladesh and Mongolia. Regarding the indications for transplants, acute myeloid leukemia (AML) was the most common disease for allogeneic transplant (4,759, 35.1% of allogeneic transplants), while plasma cell disorder (PCD) was the most common disease for autologous transplant (3,701, 27.3% of all autologous transplants). Furthermore, the number of transplants for hemoglobinopathy has steeply increased in this region compared with the rest of disease indications (677, 3.1% of all transplants). APBMT covers a broad area globally, including countries/regions with diverse disease distribution, development of HSCT programs, population, and economic power. Consistent and continuous activity surveys considering those elements in each country/region revealed the HSCT field's diverse characteristics and background factors in this region., Competing Interests: The authors declare no conflict of interest. Disclosure forms provided by the authors are available on the website. MI, AS, and SO are members of the Editor of Blood Cell Therapy. They were not involved in the editorial evaluation or the decision to accept this article for publication., (Copyright Ⓒ2022 Asia-Pacific Blood and Marrow Transplantation Group (APBMT).)

Human cytomegalovirus (HCMV) is ubiquitously prevalent. Immune system in healthy individuals is capable of controlling HCMV infection; however, HCMV can be life-threatening for immunocompromised individuals, such as transplant recipients. Both innate and adaptive immune systems are critically involved in the HCMV infection. Recent studies have indicated that regulatory immune cells which play essential roles in maintaining a healthy immune environment are closely related to immune response in HCMV infection. However, the exact role of regulatory immune cells in immune regulation and homoeostasis during the battle between HCMV and host still requires further research. In this review, we highlight the protective and pathological roles of regulatory immune cells in HCMV infection following hematopoietic stem cell transplantation (HSCT)., (© 2021 John Wiley & Sons Ltd.)

The Worldwide Network of Blood and Marrow Transplantation (WBMT) pursues the mission of promoting hematopoietic cell transplantation (HCT) for instance by evaluating activities through member societies, national registries and individual centers. In 2016, 82,718 first HCT were reported by 1,662 HCT teams in 86 of the 195 World Health Organization member states representing a global increase of 6.2% in autologous HCT and 7.0% in allogeneic HCT and bringing the total to 1,298,897 procedures. Assuming a frequency of 84,000/year, 1.5 million HCT were performed by 2019 since 1957. Slightly more autologous (53.5%) than allogeneic and more related (53.6%) than unrelated HCT were reported. A remarkable increase was noted in haploidentical related HCT for leukemias and lymphoproliferative diseases, but even more in non-malignant diseases. Transplant rates (TR; HCT/10 million population) varied according to region reaching 560.8 in North America, 438.5 in Europe, 76.7 in Latin America, 53.6 in South East Asia/Western Pacific (SEA/WPR) and 27.8 in African/East Mediterranean (AFR/EMR). Interestingly, haploidentical TR amounted to 32% in SEA/WPR and 26% in Latin America, but only 14% in Europe and EMR and 4.9% in North America of all allogeneic HCT. HCT team density (teams/10 million population) was highest in Europe (7.7) followed by North America (6.0), SEA/WPR (1.9), Latin America (1.6) and AFR/EMR (0.4). HCT are increasing steadily worldwide with narrowing gaps between regions and greater increase in allogeneic compared to autologous activity. While related HCT is rising, largely due to increase in haploidentical HCT, unrelated HCT is plateauing and cord blood HCT is in decline.

Chronic granulomatous disease (CGD) is a life-threatening immunodeficiency condition. To date, hematopoietic stem cell transplantation (HSCT) is the only curative modality. We prospectively studied the outcomes of fifteen CGD patients undergoing HSCT with fludarabine and melphalan plus anti-thymocyte globulin (ATG). Most of the donors were fully matched siblings (n = 12). Cyclosporine A and methylprednisolone were used for graft-versus-host disease (GVHD) prophylaxis. CGD diagnosis had been suspected upon clinical symptoms and was confirmed in all patients by an abnormal neutrophil functional assay. The three-year overall survival (OS) and event-free survival (EFS) rates were 73.3% and 46.7%, respectively. With the median follow-up time of 33.12 months, the mean OS and EFS were 42.6 and 26.8 months; respectively. Eleven patients (73.33%) achieved full donor chimerism. Two stable mixed chimerisms with no sign of the underlying disease (13.33%) and two secondary graft failure (13.33%) occurred as well. The cumulative incidence of transplant-related mortality was 23.1% and it was two times more in adults compared with children. Three years GVHD-FS (free survival) was 57.8% in all patients and it was 70% and 42.9% in children and adults, respectively. Our results indicate that fludarabine, melphalan, and ATG have relatively favorable outcomes in CGD patients. Also, we suggest that HSCT should be performed as soon as a suitably matched donor is found., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Mucopolysaccharidoses (MPSs) are rare, heterogeneous inborn errors of metabolism (IEM) diagnosed through a combination of clinical, biochemical, and genetic investigations. The aim of this study was molecular characterization of the largest cohort of Iranian MPS patients (302 patients from 289 unrelated families), along with tracking their ethnicity and geographical origins. 185/289 patients were studied using an IEM-targeted NGS panel followed by complementary Sanger sequencing, which led to the diagnosis of 154 MPS patients and 5 non-MPS IEMs (diagnostic yield: 85.9%). Furthermore, 106/289 patients who were referred with positive findings went through reanalysis and confirmatory tests which confirmed MPS diagnosis in 104. Among the total of 258 MPS patients, 225 were homozygous, 90 harbored novel variants, and 9 had copy number variations. MPS IV was the most common type (34.8%) followed by MPS I (22.7%) and MPS VI (22.5%). Geographical origin analysis unveiled a pattern of distribution for frequent variants in ARSB (c.430G>A, c.962T>C [p.Leu321Pro], c.281C>A [p.Ser94*]), GALNS (c.319G>A [p.Ala107Thr], c.860C>T [p.Ser287Leu], c.1042A>G [p.Thr348Ala]), and IDUA (c.1A>C [p.Met1Leu], c.1598C>G [p.Pro533Arg], c.1562&#95;1563insC [p.Gly522Argfs*50]). Our extensive patient cohort reveals the genetic and geographic landscape of MPS in Iran, which provides insight into genetic epidemiology of MPS and can facilitate a more cost-effective, time-efficient diagnostic approach based on the region-specific variants., (© 2022 Wiley Periodicals LLC.)