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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).

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) potentially renders thalassemia patients disease-free with presumably cessation of associated complications. This study analyzes the liver fibrosis status and the determinants of its progression in ex-thalassemic patients. The liver fibrosis status of 108 pediatric transfusion-dependent β-thalassemia major patients was evaluated before and one year after allo-HSCT using transient elastography (TE). All patients achieved normal hematopoiesis. In univariate analyses, not in all, but in patients developing significant post-HSCT iron overload or hepatic graft-versus-host disease (GvHD), as well as recipients of bone marrow stem cells (BMSC), significant TE increment occurred. In multivariable analyses, through a model with large effect size (Adj.R2 = 26%, F(3,104) = 13.53, P < 0.001), post-HSCT serum ferritin and hepatic GvHD were ascertained as independent determinants of significant TE increase, and the effect of stem cell graft source approached the level of significance. Excluding the patients with intermediate/high Lucarelli risk classes, the TE increase was significantly greater only in BMSC recipients (P = 0.033). Although the risk impact of allograft source on liver fibrosis progression requires further evaluation; hepatic status of ex-thalassemic patients can be preserved after HSCT, if hepatic GvHD is controlled and adequate post-transplantation iron depletion is ensured.

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.

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 .

Diamond–Blackfan anemia (DBA) is a rare, congenital bone marrow failure syndrome characterized by hypoplastic anemia. Earliest descriptions of this disease date back to 1936, and since then, a plethora of treatment strategies have been used to control or treat the disease. In recent decades, hematopoietic stem cell transplantation (HSCT) has been declared the only curative treatment. Despite the time elapsing from the first time HSCT has been used in this setting, no unified standard preparative and prophylactic protocol has been established. In this article, for the first time, the published articles concerning the efficacy of the most verified conditioning regimens established for these patients, the myeloablative conditioning regimen (MAC), were systematically reviewed. A comparison of two groups, based on the presence or absence of radiation in their protocol, was performed. Electronic and manual searches were conducted on PubMed, Scopus, and Web of Science. The primary study domains, selection, and outcome were assessed using the JBI Scale quality assessment for cohort and case series studies. Cohorts were categorized into treatment groups, and the characteristics of patients and donors, in addition to intervention characteristics and outcomes, were synthesized. Among a total of 196 studies reviewed, we included five cohorts in our systematic review. The studies were heterogeneous in various aspects. In conclusion, our analysis suggests that DBA patients who underwent a MAC non‐total body irradiation (TBI) conditioning regimen may experience better post‐HSCT outcomes; however, the findings are inconclusive.

Severely immunocompromised NOD.Cg‐PrkdcscidIl2rgtm1Sug (NOG) mice are among the ideal animal recipients for generation of human cancer models. Transplantation of human solid tumors having abundant tumor‐infiltrating lymphocytes (TILs) can induce xenogeneic graft‐versus‐host disease (xGvHD) following engraftment and expansion of the TILs inside the animal body. Wilms' tumor (WT) has not been recognized as a lymphocyte‐predominant tumor. However, 3 consecutive generations of NOG mice bearing WT patient‐derived xenografts (PDX) xenotransplanted from a single donor showed different degrees of inflammatory symptoms after transplantation before any therapeutic intervention. In the initial generation, dermatitis, auto‐amputation of digits, weight loss, lymphadenopathy, hepatitis, and interstitial pneumonitis were observed. Despite antibiotic treatment, no response was noticed, and thus the animals were prematurely euthanized (day 47 posttransplantation). Laboratory and histopathologic evaluations revealed lymphoid infiltrates positively immunostained with anti‐human CD3 and CD8 antibodies in the xenografts and primary tumor, whereas no microbial infection or lymphoproliferative disorder was found. Mice of the next generation that lived longer (91 days) developed sclerotic skin changes and more severe pneumonitis. Cutaneous symptoms were milder in the last generation. The xenografts of the last 2 generations also contained TILs, and lacked lymphoproliferative transformation. The systemic immunoinflammatory syndrome in the absence of microbial infection and posttransplant lymphoproliferative disorder was suggestive of xGvHD. While there are few reports of xGvHD in severely immunodeficient mice xenotransplanted from lymphodominant tumor xenografts, this report for the first time documented serial xGvHD in consecutive passages of WT PDX‐bearing models and discussed potential solutions to prevent such an undesired complication. Three consecutive generations of NOG mice bearing Wilms tumor patient‐derived xenografts from a single donor showed different degrees of immunoinflammatory symptoms. Histopathologic evaluations of the xenografts and parental tumor showed lymphoid infiltrates and human‐originated CD3 and CD8 positive cells in the tissue blocks, while no lymphoproliferative disorder was evident (suggestive of a lymphodominant tumor graft). In the absence of microbial infection and lymphoproliferative disorder, the syndrome was suggestive of xenogeneic graft‐versus‐host disease.

There are many types of leukocytes reside in subcutaneous adipose tissue (SAT), and among them, natural killer cells (NKs) comprise a major part. We show that the NKs that reside in the SAT (adipose tissue-derived NK cells; ADNKs) of the abdominal region found with phenotypic differences from the NKs circulating in the peripheral blood derived NK cells (PBNKs). In this survey, flow cytometry phenotyping was used to study the differences between the natural cytotoxicity receptor expression on ADNKs and PBNKs of both obese and lean persons. Also, their cytotoxicity and cytokine production patterns were evaluated. The activation experiments on isolated and expanded NKs with IL-2, IL-15, and IL-21 cytokines revealed the main population of the CD56 within the total ADNKs of obese persons has an under-expression of NKp30 and NKp44 despite the unchanged levels of NKG2D. The data suggest the suppressive condition of the adipose tissue niche on the NKs response against sensitive major histocompatibility complex class I non-expressing neoplastic cells. As the NKs are the first line of the body's defense vs tumor formation, this change may lead to the development of transformed cells into the tumors.

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. Key points The younger age of FA patients at the HSCT time leads to a higher OS. OS was lower in the congenital malformations extensive group. The malformations’ scope affects aGvHD incidence significantly, while not cGvHD. Various HSCT outcomes in different centers can be due to distinct genotypes.

Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT) is the only known curative option for hematologic manifestations of Diamond-Blackfan anemia (DBA) as a rare inherited bone marrow failure syndrome. This treatment may be considered for DBA patients with corticosteroid-resistance, transfusion dependence, and/or progression to severe aplastic anemia or myelodysplastic syndrome (MDS)/ Acute myleloid leukemia (AML). In this prospective study, 10 pediatric DBA patients (age < 15 years) who underwent allo-HSCT from HLA-matched donors using non-TBI myeloablative conditioning regimen (intravenous busulfan and cyclophosphamide ± antithymocyte globulin) during September 2010 to February 2014 are reported. For Graft versus Host Disease (GvHD) prophylaxis cyclosporine A. and a short course of methotrexate were administered. Except one patient who received transplantation from his sibling cord blood, engraftment occurred in all the other patients (9 out of 10) with full donor chimerism ( > 95%). The median neutrophil and platelet engraftment times were 11 (range, 10- 13) days and 23 (range, 15-50) days, respectively. Acute GvHD developed in 7 patients. After a median follow-up of 53.3 months, 8 patients are still alive, of whom 7 patients are disease-free. The other two patients died due to grade III-IV acute GvHD. Our data suggests that allo-HSCT using busulan-based non-TBI myeloablative conditioning regimen could be a long-term effective treatment for DBA patients. Early transplantation especially before having multiple transfusions leading to iron overload, particularly from an HLAmatched sibling donor would be associated with favorable outcomes.

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.