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The broad differential diagnosis of neonatal erythroderma often poses a diagnostic challenge. Mortality of neonatal erythroderma is high due to complications of the erythroderma itself and the occasionally severe and life-threatening underlying disease. Early correct recognition of the underlying cause leads to better treatment and prognosis. Currently, neonatal erythroderma is approached on a case-by-case basis. The purpose of this scoping review was to develop a diagnostic approach in neonatal erythroderma. After a systematic literature search in Embase (January 1990 - May 2020, 74 cases of neonatal erythroderma were identified, and 50+ diagnoses could be extracted. Main causes were the ichthyoses (40%) and primary immunodeficiencies (35%). Congenital erythroderma was present in 64% (47/74) of the cases, predominantly with congenital ichthyosis (11/11; 100%), Netherton syndrome (12/14, 86%) and Omenn syndrome (11/23, 48%). Time until diagnosis ranged from 102 days to 116 days for cases of non-congenital erythroderma and congenital erythroderma respectively. Among the 74 identified cases a total of 17 patients (23%) died within a mean of 158 days and were related to Omenn syndrome (35%), graft-versus-host disease (67%) and Netherton syndrome (18%). Disease history and physical examination are summarized in this paper. Age of onset and a collodion membrane can help to narrow the differential diagnoses. Investigations of blood, histology, hair analysis, genetic analysis and clinical imaging are summarized and discussed. A standard blood investigation is proposed, and the need for skin biopsies with lympho-epithelial Kazal-type related Inhibitor staining is highlighted. Overall, this review shows that diagnostic procedures narrow the differential diagnosis in neonatal erythroderma. A 6-step flowchart for the diagnostic approach for neonatal erythroderma during the first month of life is proposed. The approach was made with the support of expert leaders from international multidisciplinary collaborations in the European Reference Network Skin-subthematic group Ichthyosis.

The broad differential diagnosis of neonatal erythroderma often poses a diagnostic challenge. Mortality of neonatal erythroderma is high due to complications of the erythroderma itself and the occasionally severe and life-threatening underlying disease. Early correct recognition of the underlying cause leads to better treatment and prognosis. Currently, neonatal erythroderma is approached on a case-by-case basis. The purpose of this scoping review was to develop a diagnostic approach in neonatal erythroderma. After a systematic literature search in Embase (January 1990 - May 2020, 74 cases of neonatal erythroderma were identified, and 50+ diagnoses could be extracted. Main causes were the ichthyoses (40%) and primary immunodeficiencies (35%). Congenital erythroderma was present in 64% (47/74) of the cases, predominantly with congenital ichthyosis (11/11; 100%), Netherton syndrome (12/14, 86%) and Omenn syndrome (11/23, 48%). Time until diagnosis ranged from 102 days to 116 days for cases of non-congenital erythroderma and congenital erythroderma respectively. Among the 74 identified cases a total of 17 patients (23%) died within a mean of 158 days and were related to Omenn syndrome (35%), graft-versus-host disease (67%) and Netherton syndrome (18%). Disease history and physical examination are summarized in this paper. Age of onset and a collodion membrane can help to narrow the differential diagnoses. Investigations of blood, histology, hair analysis, genetic analysis and clinical imaging are summarized and discussed. A standard blood investigation is proposed, and the need for skin biopsies with lympho-epithelial Kazal-type related Inhibitor staining is highlighted. Overall, this review shows that diagnostic procedures narrow the differential diagnosis in neonatal erythroderma. A 6-step flowchart for the diagnostic approach for neonatal erythroderma during the first month of life is proposed. The approach was made with the support of expert leaders from international multidisciplinary collaborations in the European Reference Network Skin-subthematic group Ichthyosis.

Nucleophosmin-1 (NPM1) mutations in acute myeloid leukemia (AML) confer a survival advantage in the absence of FLT3-internal tandem duplication (FLT3-ITD). Here, we investigated the main predictors of outcome after allogeneic hematopoietic stem cell transplantation (allo-HCT). We identified 1572 adult (age >= 18 year) patients with NPM1-mutated AML in first complete remission (CR1:78%) or second complete remission (CR2:22%) who were transplanted from matched sibling donors (30.8%) or unrelated donors (57.4%) between 2007 and 2019 at EBMT participating centers. Median follow-up for survivors was 23.7 months. FLT3-ITD was present in 69.3% of patients and 39.2% had detectable minimal/measurable residual disease (MRD) at transplant. In multivariate analysis, relapse incidence (RI) and leukemia-free survival (LFS) were negatively affected by concomitant FLT3-ITD mutation (HR 1.66 p = 0.0001, and HR 1.53, p < 0.0001, respectively), MRD positivity at transplant (HR 2.18, p < 10(-5) and HR 1.71, p < 10(-5), respectively), and transplant in CR2 (HR 1.36, p = 0.026, and HR 1.26, p = 0.033, respectively), but positively affected by Karnofsky score >= 90 (HR 0.74, p = 0.012, and HR 0.7, p = 0.0002, respectively). Overall survival (OS) was also negatively influenced by concomitant FLT3-ITD (HR 1.6, p = 0.0001), MRD positivity at transplant (HR 1.61, p < 10(-5)), and older age (HR 1.22 per 10 years, p < 0.0001), but positively affected by matched sibling donor (unrelated donor: HR 1.35, p = 0.012; haploidentical donor: HR 1.45, p = 0.037) and Karnofsky score >= 90 (HR 0.73, p = 0.004). These results highlight the independent and significant role of FLT3-ITD, MRD status, and disease status on posttransplant outcomes in patients with NPM1-mutated AML allowing physicians to identify patients at risk of relapse who may benefit from posttransplant prophylactic interventions.

Colitis is a common, but poorly understood, adverse event of immune checkpoint inhibitors that are standard-of-care for an expanding range of cancer types. This explorative study aimed to describe the immune infiltrates in the colon from individuals developing checkpoint inhibitor colitis and compare them to well-known immunophenotypes of acute graft-versus-host disease, ulcerative colitis, and Crohn’s disease. Colon biopsies (n = 20 per group) of patients with checkpoint inhibitor colitis, acute graft-versus-host disease, ulcerative colitis and Crohn’s disease, all colitis treatment-naïve, and of individuals with a normal colon were analyzed using immunohistochemistry: CD8 for cytotoxic T cells, CD4 for T helper cells, and CD68 to identify cells of macrophage lineage. CD8 + T cell, CD4 + T cell, and CD68 + cell counts were performed. Cell infiltration was scored as scattered/patchy or band-like in the superficial and deep gut mucosa. Checkpoint inhibitor colitis was found to be heavily infiltrated by CD8 + T cells. Comparative analysis between groups showed that both CD8 + T cell counts (P

Contains fulltext : 241342.pdf (Publisher’s version ) (Closed access) Nonmyeloablative regimens are used for allogeneic hematopoietic cell transplantation (HCT) of older or medically unfit patients, but successful outcome is still hindered by graft-versus-host disease (GVHD), especially in the setting of HLA-mismatched HCT. New GVHD prophylaxis strategies are emerging, including the triple drug strategy, that improve the GVHD-free and relapse-free survival (GRFS). Because the impact of ATG in HLA-mismatched Flu-TBI-based nonmyeloablative HCT has not been investigated, we did a retrospective analysis in three Dutch centers. 67 patients were evaluable, with a median age of 56 years. Overall survival, relapse-free survival and GRFS at 4 years were 52%, 43%, and 38%, respectively. NRM findings and cumulative incidence of relapse at 4 years were 26% and 31%, respectively. At 1-year grade II-IV had occurred in 40% of the patients, and the incidence of moderate-severe chronic GVHD incidence was 16%. Acknowledging the limitations of retrospective analyses, we conclude that the use of ATG for HLA-mismatched truly nonmyeloablative Flu-TBI HCT is feasible and results in acceptable long term outcomes, especially with regards to GRFS. We consider ATG in combination with cyclosporin and mycophenolate mofetil as an alternative for the triple drug strategy that uses sirolimus for GVHD prophylaxis in this particular setting.

The impact of GVHD and graft-versus-leukemia effect in unrelated cord blood transplantation (UCBT) is controversial. In the Eurocord/ALWP EBMT and JSTCT/JDCHCT collaborative study, we evaluated the impact of GVHD on UCBT outcomes in Japanese and European registries. A total of 3, 690 adult patients with acute leukemia who received their first single UCBT were included. A multivariate analysis of overall survival (OS) revealed a positive impact of grade II acute GVHD compared with grade 0-I GVHD, in the Japanese cohort (hazard ratio (HR), 0.81; P = 0.001), and an adverse impact in the European cohort (HR, 1.37; P = 0.007). A negative impact of grade III-IV acute GVHD on OS was observed regardless of registries. In the analysis of relapse, a positive impact of grade II acutes GVHD compared with grade 0–I GVHD was observed only in the Japanese cohort, regardless of disease risk. The positive impact of limited chronic GVHD on OS was observed only in the Japanese cohort. In conclusion, a positive impact of mild GVHD after a single UCBT was observed only in the Japanese cohort. This could explain the ethnic difference in UCBT outcomes and might contribute to the preference usage of UCBT in Japan., 急性白血病治療における臍帯血移植後の合併症が及ぼす予後への影響 --国際共同研究から明らかになった日欧での違い--. 京都大学プレスリリース. 2021-10-19.

Hematopoietic stem cell transplantation-associated thrombotic microangiopathy (HSCT-TMA) is a common complication occurring post-HSCT and is associated with substantial morbidity and mortality if not promptly identified and treated. Emerging evidence suggests a central role for the complement system in the pathogenesis of HSCT-TMA. The complement system has also been shown to interact with other pathways and processes including coagulation and inflammation, all of which are activated following HSCT. Three endothelial cell-damaging "hits" are required for HSCT-TMA genesis: a genetic predisposition or existing damage, an endothelial cell-damaging conditioning regimen, and additional damaging insults. Numerous risk factors for the development of HSCT-TMA have been identified (including primary diagnosis, graft type, and conditioning regimen) and validated lists of relatively simple diagnostic signs and symptoms exist, many utilizing routine clinical and laboratory assessments. Despite the relative ease with which HSCT-TMA can be screened for, it is often overlooked or masked by other common post-transplant conditions. Recent evidence that patients with HSCT-TMA may also concurrently present with these differential diagnoses only serve to further confound its identification and treatment. HSCT-TMA may be treated, or even prevented, by removing or ameliorating triggering "hits", and recent studies have also shown substantial utility of complement-targeted therapies in this patient population. Further investigation into optimal management and treatment strategies is needed. Greater awareness of TMA post-HSCT is urgently needed to improve patient outcomes; the objective of this article is to clarify current understanding, explain underlying complement biology and provide simple tools to aid the early recognition, management, and monitoring of HSCT-TMA.

DisclaimerThis article is based on recommendations from the 12(th) WALT Congress, Nice, October 3-6, 2018, and a follow-up review of the existing data and the clinical observations of an international multidisciplinary panel of clinicians and researchers with expertise in the area of supportive care in cancer and/or PBM clinical application and dosimetry. This article is informational in nature. As with all clinical materials, this paper should be used with a clear understanding that continued research and practice could result in new insights and recommendations. The review reflects the collective opinion and, as such, does not necessarily represent the opinion of any individual author. In no event shall the authors be liable for any decision made or action taken in reliance on the proposed protocols. Objective: This position paper reviews the potential prophylactic and therapeutic effects of photobiomodulation (PBM) on side effects of cancer therapy, including chemotherapy (CT), radiation therapy (RT), and hematopoietic stem cell transplantation (HSCT). Background: There is a considerable body of evidence supporting the efficacy of PBM for preventing oral mucositis (OM) in patients undergoing RT for head and neck cancer (HNC), CT, or HSCT. This could enhance patients' quality of life, adherence to the prescribed cancer therapy, and treatment outcomes while reducing the cost of cancer care. Methods: A literature review on PBM effectiveness and dosimetry considerations for managing certain complications of cancer therapy were conducted. A systematic review was conducted when numerous randomized controlled trials were available. Results were presented and discussed at an international consensus meeting at the World Association of photobiomoduLation Therapy (WALT) meeting in 2018 that included world expert oncologists, radiation oncologists, oral oncologists, and oral medicine professionals, physicists, engineers, and oncology researchers. The potential mechanism of action of PBM and evidence of PBM efficacy through reported outcomes for individual indications were assessed. Results: There is a large body of evidence demonstrating the efficacy of PBM for preventing OM in certain cancer patient populations, as recently outlined by the Multinational Association for Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO). Building on these, the WALT group outlines evidence and prescribed PBM treatment parameters for prophylactic and therapeutic use in supportive care for radiodermatitis, dysphagia, xerostomia, dysgeusia, trismus, mucosal and bone necrosis, lymphedema, hand-foot syndrome, alopecia, oral and dermatologic chronic graft-versus-host disease, voice/speech alterations, peripheral neuropathy, and late fibrosis amongst cancer survivors. Conclusions: There is robust evidence for using PBM to prevent and treat a broad range of complications in cancer care. Specific clinical practice guidelines or evidence-based expert consensus recommendations are provided. These recommendations are aimed at improving the clinical utilization of PBM therapy in supportive cancer care and promoting research in this field. It is anticipated these guidelines will be revised periodically.

The targeted inhibition of effector cytokines such as interleukin 17 (IL-17) in psoriasis and IL-13 in atopic dermatitis offers impressive efficacy with a favorable side effect profile. In contrast, the downregulation of interferon gamma (IFN-γ) in T helper (Th) 1-dominant skin disorders may lead to more adverse events, given the crucial role of IFN-γ in antiviral and antitumoral immunity. Modulating Th17 and Th2 cell differentiation is performed by blocking IL-23 and IL-4, respectively, whereas anti-IL-12 antibodies are only moderately effective in downregulating Th1 lymphocyte differentiation. Therefore, a targeted approach of IFN-γ-driven disorders remains challenging. Recent literature suggests that certain pathogenic Th17 cell subsets with Th1 characteristics, such as CD4+CD161+CCR6+CXCR3+IL-17+IFN-y+ (Th17.1) and CD4+CD161+CCR6+CXCR3+IL-17-IFN-y+ (exTh17), are important contributors in Th1-mediated autoimmunity. Differentiation to a Th17.1 or exTh17 profile results in the upregulation of IFN-y. Remarkably, these pathogenic Th17 cell subsets are resistant to glucocorticoid therapy and the dampening effect of regulatory T cells (Treg). The identification of Th17.1/exTh17 cells in auto-immune disorders may explain the frequent treatment failure of conventional immunosuppressants. In this review, we summarize the current evidence regarding the cellular plasticity of Th17 cells in inflammatory skin disorders. A deeper understanding of this phenomenon may lead to better insights into the pathogenesis of various skin diseases and the discovery of a potential new treatment target.

The broad differential diagnosis of neonatal erythroderma often poses a diagnostic challenge. Mortality of neonatal erythroderma is high due to complications of the erythroderma itself and the occasionally severe and life-threatening underlying disease. Early correct recognition of the underlying cause leads to better treatment and prognosis. Currently, neonatal erythroderma is approached on a case-by-case basis. The purpose of this scoping review was to develop a diagnostic approach in neonatal erythroderma. After a systematic literature search in Embase (January 1990 - May 2020, 74 cases of neonatal erythroderma were identified, and 50+ diagnoses could be extracted. Main causes were the ichthyoses (40%) and primary immunodeficiencies (35%). Congenital erythroderma was present in 64% (47/74) of the cases, predominantly with congenital ichthyosis (11/11; 100%), Netherton syndrome (12/14, 86%) and Omenn syndrome (11/23, 48%). Time until diagnosis ranged from 102 days to 116 days for cases of non-congenital erythroderma and congenital erythroderma respectively. Among the 74 identified cases a total of 17 patients (23%) died within a mean of 158 days and were related to Omenn syndrome (35%), graft-versus-host disease (67%) and Netherton syndrome (18%). Disease history and physical examination are summarized in this paper. Age of onset and a collodion membrane can help to narrow the differential diagnoses. Investigations of blood, histology, hair analysis, genetic analysis and clinical imaging are summarized and discussed. A standard blood investigation is proposed, and the need for skin biopsies with lympho-epithelial Kazal-type related Inhibitor staining is highlighted. Overall, this review shows that diagnostic procedures narrow the differential diagnosis in neonatal erythroderma. A 6-step flowchart for the diagnostic approach for neonatal erythroderma during the first month of life is proposed. The approach was made with the support of expert leaders from international multidisciplinary collaborations in the European Reference Network Skin-subthematic group Ichthyosis.

Background: Post-transplant cyclophosphamide (PTCY) is increasingly used for allogeneic peripheral blood stem cell transplantation (allo-PBSCT) from an HLA-matched unrelated donor (MUD) as an alternative to the standard anti-thymocyte globulin (ATG) graft-versus-host disease (GvHD) prophylaxis. Following the demonstration that the use of PBSC haploidentical grafts results in more GvHD than bone marrow grafts, groups have attempted to reduce GvHD in haploidentical-PBSCT by adding ATG to PTCY. The experience of combined PTCY+ATG in the MUD allo-PBSCT is minimal and whether ATG brings any added value when PTCY is used in this setting is still unclear. Methods: In this registry-based study, we compared outcomes of 421 patients with PTCY and 151 patients with PTCY+ATG who underwent a first MUD allo-PBSCT for acute myeloid leukemia (AML) in complete remission. Results: Characteristics of PTCY and PTCY+ATG patients were well balanced, including the number of additional immunosuppressive drugs, with the only significant difference between the two cohorts being the median year of transplant, and the follow-up period (19.6 versus 31.1 months, respectively, pConclusions: To date, the question of the best combination of GvHD-preventing drugs in the MUD-PBSCT setting remains unanswered. Our results highlight that in PTCY-based MUD-PBSCT for AML, the addition of ATG does not provide any extra benefit in terms of further GvHD reduction, better GRFS or better survival.

To discuss and evaluate new technologies for a better diagnosis of corneal diseases and limbal stem cell deficiency, the outcomes of a consensus process within the European Vision Institute (and of a workshop at the University of Cologne) are outlined. Various technologies are presented and analyzed for their potential clinical use also in defining new end points in clinical trials. The disease areas which are discussed comprise dry eye and ocular surface inflammation, imaging, and corneal neovascularization and corneal grafting/stem cell and cell transplantation. The unmet needs in the abovementioned disease areas are discussed, and realistically achievable new technologies for better diagnosis and use in clinical trials are outlined. To sum up, it can be said that there are several new technologies that can improve current diagnostics in the field of ophthalmology in the near future and will have impact on clinical trial end point design.

Pretreatment dental screening aims to locate and eliminate oral foci of infection in order to eliminate local, loco-regional, or systemic complications during and after oncologic treatment. An oral focus of infection is a pathologic process in the oral cavity that does not cause major infectious problems in healthy individuals, but may lead to severe local or systemic inflammation in patients subjected to oncologic treatment. As head and neck radiotherapy patients bear a lifelong risk on oral sequelae resulting from this therapy, the effects of chemotherapy on healthy oral tissues are essentially temporary and reversible. This has a large impact on what to consider as an oral focus of infection when patients are subjected to, for example, head and neck radiotherapy for cancer or intensive chemotherapy for hematological disorders. While in patients subjected to head and neck radiotherapy oral foci of infection have to be removed before therapy that may cause problems ultimately, in patients that will receive chemotherapy such, so-called chronic, foci of infection are not in need of removal of teeth but can be treated during a remission phase. Acute foci of infection always have to be removed before or early after the onset of any oncologic treatment.

We performed a study to find out how advances in modern medicine have improved the mortality risk of allogeneic stem cell transplantation. We analyzed major transplantation outcome parameters in adult patients on the European Society for Blood and Marrow Transplantation (EBMT) registry who had hematologic malignancies and had received transplants from matched sibling donors. We performed multivariate analyses using the Cox proportional-hazards model including known risk factors for nonrelapse mortality and a matched-pairs analysis. We identified 38 800 patients who fulfilled the inclusion criteria. Considerable changes in patient characteristics have occurred in the past decades, such as older age, different underlying diseases, and a higher proportion of patients with advanced disease. Major reasons for transplantation-related death in the 1980s were infectious complications and graft-versus-host disease. Nonrelapse mortality, measured at 1 year after transplantation, has decreased over time: 29.7% from 1980 through 1989, 24.4% from 1990 through 1999, 14.8% from 2000 through 2009, and 12.2% from 2010 through 2016. On multivariate analysis, the year of transplantation was associated with reduced nonrelapse mortality (P < .0001; hazard ratio [HR] [95% confidence interval (CI)], 0.8 [0.79-0.82], for 5-year intervals) and decreased overall mortality (P < .0001; HR [95% CI], 0.87 [0.86-0.88]. In the matched-pairs analysis of 3718 patients in each group, nonrelapse mortality at 1 year was 24.4% in the 1990s and 9.5% from 2013 through 2016 (P < .0001; HR [95% CI], 0.39 [0.34-0.43]). Transplantation-related mortality has decreased significantly in the past 40 years. These favorable data facilitate evidence-based treatment decisions on transplantation indications in the context of the availability of novel immunotherapies. ispartof: BLOOD ADVANCES vol:4 issue:24 pages:6283-6290 ispartof: location:United States status: published

Allogeneic hematopoietic stem cell transplantation (alloSCT) for myeloid leukemia remains one of the most effective anti-tumor treatments available, capable of curing an increasingly higher proportion of patients. Alloreactivity generated by T cells has limited efficacy in the early post-transplant period while most patients will relapse within 6 months after transplantation. Prior studies in T cell depleted grafts showed that, with the elimination of T cells, natural killer (NK) cells provide most of the anti-tumor effect in the early post-transplant period. Administration of unmodified T cells to mitigate infections and relapse will expose the patient to a high risk of graft-vs-host disease (GvHD). Post-transplant cyclophosphamide (PTCy), initially used for haploidentical (haplo) donor transplants, is now also increasingly utilized in HLA matched donor transplants to prevent GvHD. In most patients, PTCy eliminates, at least in part, alloreactive T and NK cells early post-transplant. Administration of modified NK cells in the early post-transplant period makes intuitive sense to enhance the anti-tumor effect of the graft and thereby prevent relapse. Effective application of cellular therapy early after transplant has opened a new direction and could revolutionize the field of hematopoietic stem cell transplantation.

Indications for autologous (auto-HCT) and allogeneic transplantation (allo-HCT) in relapsed/refractory Hodgkin lymphoma (rrHL) have been long established. The expectation is that long-term outcomes have significantly improved over time with increased experience in these procedures. The objective of this study was to assess whether this is the case and to identify further areas of improvement. A total of 13,639 adult patients receiving an auto-HCT or allo-HCT for rrHL were reported to the European Society for Blood and Marrow Transplantation (EBMT) over a 25-year period. Regarding auto-HCT, recipients are younger, interval between diagnosis and transplant shorter, peripheral blood has become the universal stem cell source and the use of total body irradiation is almost non-existent in recent years. Allo-HCT is currently mostly used as a second transplant; recipients are younger, fitter and less frequently, chemorefractory. Reduced intensity conditioning protocols have vastly replaced myeloablative protocols. Increasing numbers of haplo-HCT have been reported. Both in auto-HCT and allo-HCT, NRM, PFS and OS have significantly improved but relapse remains the main cause of treatment failure. A better selection of patients and improvements in the supportive care has resulted in a reduction in the NRM. Relapse after HCT remains unchanged and further research is needed.

Previously, the outcome of paediatric Philadelphia-chromosome-positive (Ph+) ALL treated with conventional chemotherapy alone was poor, necessitating the use of haematopoietic stem cell transplantation (HSCT) for the best outcomes. The recent addition of tyrosine kinase inhibitors (TKIs) alongside the chemotherapy regimens for Ph+ ALL has markedly improved outcomes, replacing the need for HSCT for lower risk patients. An additional poor prognosis group of Philadelphia-chromosome-like (Ph-like) ALL has also been identified. This group also can be targeted by TKIs in combination with chemotherapy, but the role of HSCT in this population is not clear. The impact of novel targeted immunotherapies (chimeric antigen receptor T cells and bispecific or drug-conjugated antibodies) has improved the outcome of patients, in combination with chemotherapy, and made the role of HSCT as the optimal curative therapy for Ph+ ALL and Ph-like ALL less clear. The prognosis of patients with Ph+ ALL and persistent minimal residual disease (MRD) at the end of consolidation despite TKI therapy or with additional genetic risk factors remains inferior when HSCT is not used. For such high-risk patients, HSCT using total-body-irradiation-containing conditioning is currently recommended. This review aims to provide an update on the current and future role of HSCT for Ph+ ALL and addresses key questions related to the management of these patients, including the role of HSCT in first complete remission, MRD evaluation and related actions post HSCT, TKI usage post HSCT, and the putative role of HSCT in Ph-like ALL.

The mechanisms underlying operational tolerance after hematopoietic stem cell transplantation in humans are poorly understood. We studied two independent cohorts of patients who underwent allogeneic hematopoietic stem cell transplantation from human leukocyte antigen–identical siblings. Primary tolerance was associated with long-lasting reshaping of the recipients’ immune system compared to their healthy donors with an increased proportion of regulatory T cell subsets and decreased T cell activation, proliferation, and migration. Transcriptomics profiles also identified a role for nicotinamide adenine dinucleotide biosynthesis in the regulation of immune cell functions. We then compared individuals with operational tolerance and nontolerant recipients at the phenotypic, transcriptomic, and metabolomic level. We observed alterations centered on CD38+-activated T and B cells in nontolerant patients. In tolerant patients, cell subsets with regulatory functions were prominent. RNA sequencing analyses highlighted modifications in the tolerant patients’ transcriptomic profiles, particularly with overexpression of the ectoenzymeNT5E(encoding CD73), which could counterbalance CD38 enzymatic functions by producing adenosine. Further, metabolomic analyses suggested a central role of androgens in establishing operational tolerance. These data were confirmed using an integrative approach to evaluating the immune landscape associated with operational tolerance. Thus, balance between a CD38-activated immune state and CD73-related production of adenosine may be a key regulator of operational tolerance.

Introduction: BK polyomavirus (BKPyV) infections are an important cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT). The aim of the study was to assess the clinical characteristics of BKPyV infections after HSCT.Materials and Methods: The study was conducted in the adult HSCT clinics of a tertiary hospital in the central of Turkey between January 2017 and December 2019. Results: A total of 54 patients with HSCT were retrospectively evaluated and BKPyV disease was seen in 24 (44%). Hemorrhagic cystitis (HC) was seen in 19 (79.2%) of these patients. The median age was 42 and 50% of them were male. The most common underlying disease was acute myeloid leukemia. Five patients had autologous and 15 patients had allogeneic HSCT. The median time to engraft-ment was 15 days. Graft Versus Host disease (GVHD) was seen in seven patients. The median time elapsed to BKPyV disease after HSCT was found as 60 days. Nineteen patients with BKPyV disease had grade three and one patient had grade two HC. While BKPyV viremia was positive in five patients, viruria was detected in all patients. Eighteen of the patients with BKPyV disease were treated with cidofovir and 11 with ciprofloxacin. Four of the patients received intravesical cidofovir. The complete response was obtained in 53% of patients with BKPyV disease.Conclusion: We found that coincidental BKPyV disease and CMV activation may occur after HSCT with haematological malignancies. It is thought that follow-up in patients with suspected activation, especially in terms of hematuria and cystitis, may be important. Also, immunosuppressive agents used for GVHD prophylaxis can trigger BKPyV disease.

The optimal reduced-intensity conditioning (RIC) for patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains unclear. We retrospectively analyzed 417 patients > 45 years with ALL in first complete remission who underwent a matched sibling or unrelated allo-HSCT and compared outcomes between fludarabine/busulfan (FLUBU, n = 127), fludarabine/melphalan (FLUMEL, n = 190), and fludarabine-TBI (FLUTBI, n = 100) conditioning. At 2 years, there were no differences between the groups in terms of cumulative incidence (CI) of relapse (40% for FLUBU vs 36% for FLUMEL vs 41% for FLUTBI, p = 0.21); transplant-related mortality (TRM) (18% for FLUBU, 22% for FLUMEL, 14% for FLUTBI, p = 0.09); overall survival (55% for FLUBU, 50% for FLUMEL, 60% for FLUTBI, p = 0.62) or leukemia-free survival (43% for FLUBU, 42% for FLUMEL, 45% for FLUTBI, p = 0.99), but GVHD-relapse-free survival was significantly lower in the FLUTBI group than FLUBU and FLUMEL group (18% vs 35% vs 28%, p = 0.02). However, this difference was lost in the multivariate analysis when adjusted for the in vivo T-cell depletion. Finally, the FLUMEL regimen was shown to be an independent risk factor for a higher TRM (HR 1.97, 95% CI 1.05-3.72, p = 0.04). We conclude that the three most popular RIC regimens yield similar transplant outcomes.

To discuss and evaluate new technologies for a better diagnosis of corneal diseases and limbal stem cell deficiency, the outcomes of a consensus process within the European Vision Institute (and of a workshop at the University of Cologne) are outlined. Various technologies are presented and analyzed for their potential clinical use also in defining new end points in clinical trials. The disease areas which are discussed comprise dry eye and ocular surface inflammation, imaging, and corneal neovascularization and corneal grafting/stem cell and cell transplantation. The unmet needs in the abovementioned disease areas are discussed, and realistically achievable new technologies for better diagnosis and use in clinical trials are outlined. To sum up, it can be said that there are several new technologies that can improve current diagnostics in the field of ophthalmology in the near future and will have impact on clinical trial end point design.

Pretreatment dental screening aims to locate and eliminate oral foci of infection in order to eliminate local, loco‐regional, or systemic complications during and after oncologic treatment. An oral focus of infection is a pathologic process in the oral cavity that does not cause major infectious problems in healthy individuals, but may lead to severe local or systemic inflammation in patients subjected to oncologic treatment. As head and neck radiotherapy patients bear a lifelong risk on oral sequelae resulting from this therapy, the effects of chemotherapy on healthy oral tissues are essentially temporary and reversible. This has a large impact on what to consider as an oral focus of infection when patients are subjected to, for example, head and neck radiotherapy for cancer or intensive chemotherapy for hematological disorders. While in patients subjected to head and neck radiotherapy oral foci of infection have to be removed before therapy that may cause problems ultimately, in patients that will receive chemotherapy such, so‐called chronic, foci of infection are not in need of removal of teeth but can be treated during a remission phase. Acute foci of infection always have to be removed before or early after the onset of any oncologic treatment.

Reduced-intensity conditioning (RIC) regimens developed to extend the use of allogeneic hematopoietic stem cell transplantation (HSCT) to older patients have resulted in encouraging outcomes. We aimed to compare the 2 most commonly used RIC regimens, i.v. fludarabine with busulfan (FluBu) and fludarabine with melphalan (FluMel), in patients with myelodysplastic syndrome (MDS). Through the Center for International Blood and Marrow Transplant Research (CIBMTR), we identified 1045 MDS patients age >= 60 years who underwent first HSCT with a matched related or matched (8/8) unrelated donor using an RIC regimen. The CIBMTR's definition of RIC was used: a regimen that incorporated an i.v. busulfan total dose

The thymus plays a key role in adaptive immunity by generating a diverse population of T cells that defend the body against pathogens. Various factors from disease and toxic insults contribute to the degeneration of the thymus resulting in a fewer output of T cells. Consequently, the body is prone to a wide host of diseases and infections. In this review, first, the relevance of the thymus is discussed, followed by thymic embryological organogenesis and anatomy as well as the development and functionality of T cells. Attempts to regenerate the thymus include in vitro methods, such as forming thymic organoids aided by biofabrication techniques that are transplantable. Ex vivo methods that have shown promise in enhancing thymic regeneration are also discussed. Current regenerative technologies have not yet matched the complexity and functionality of the thymus. Therefore, emerging techniques that have shown promise and the challenges that lie ahead are explored., T cells defend the body against pathogens. They are developed in a factory, which is called the thymus. During very early in life the thymus starts to shrink leading to higher risks of infections. In this review, ways that can regenerate the thymus are discussed.

The thymus plays a key role in adaptive immunity by generating a diverse population of T cells that defend the body against pathogens. Various factors from disease and toxic insults contribute to the degeneration of the thymus resulting in a fewer output of T cells. Consequently, the body is prone to a wide host of diseases and infections. In this review, first, the relevance of the thymus is discussed, followed by thymic embryological organogenesis and anatomy as well as the development and functionality of T cells. Attempts to regenerate the thymus include in vitro methods, such as forming thymic organoids aided by biofabrication techniques that are transplantable. Ex vivo methods that have shown promise in enhancing thymic regeneration are also discussed. Current regenerative technologies have not yet matched the complexity and functionality of the thymus. Therefore, emerging techniques that have shown promise and the challenges that lie ahead are explored.

Data on whether the T cell dose of allogeneic peripheral blood stem cell (PBSC) products influences transplantation outcomes are conflicting. Using the Center for International Blood and Marrow Transplant Research database, we identified 2736 adult patients who underwent first allogeneic PBSC transplantation for acute leukemia or myelodysplastic syndrome between 2008 and 2014 using an HLA-matched sibling donor (MSD) or an 8/8-matched unrelated donor (MUD). We excluded ex vivo and in vivo T cell-depleted transplantations. Correlative analysis was performed between CD3(+) T cell dose and the risk of graft-versus-host-disease (GVHD), relapse, nonrelapse mortality (NRM), disease-free survival (DFS), and overall survival (OS). Using maximum likelihood estimation, we identified CD3(+) T cell dose cutoff that separated the risk of acute GVHD (aGVHD) grade II-IV in both the MSD and MUD groups. A CD3(+) T cell dose cutoff of 14 x 10(7) cells/kg identified MSD/low CD3(+) (n = 223) and MSD/high CD3(+) (n = 1214), and a dose of 15 x 107 cells/kg identified MUD/low (n = 197) and MUD/high CD3(+) (n = 1102). On univariate analysis, the MSD/high CD3(+) group had a higher cumulative incidence of day +100 aGVHD grade II-IV compared with the MSD/low CD3(+) group (33% versus 25%; P=.009). There were no differences between the 2 groups in engraftment rate, risk of aGVHD grade III-IV or chronic GVHD (cGVHD), NRM, relapse, DFS, or OS. The MUD/high CD3(+) group had a higher cumulative incidence of day +100 aGVHD grade II-IV compared with the MUD/low CD3(+) group (49% versus 41%; P=.04). There were no differences between the 2 groups in engraftment rate, risk of severe aGVHD or cGVHD, NRM, relapse, DFS, or OS. Multivariate analysis of the MSD and MUD groups failed to show an association between CD3(+) T cell dose and the risk of either aGVHD grade II-IV (P=.10 and .07, respectively) or cGVHD (P = .80 and .30, respectively). Subanalysis of CD4(+) T cells, CD8(+) T cells, and CD4+/CD8+ ratio failed to identify cutoff values predictive of transplantation outcomes; however, using the log-rank test, the sample size was suboptimal for identifying a difference at this cutoff cell dose. In this registry study, the CD3(+) T cell dose of PBSC products did not influence the risk of aGVHD or cGVHD or other transplantation outcomes when using an MSD or an 8/8-matched MUD. Subset analyses of CD4(+) and CD8(+) T cell doses were not possible given our small sample size. (C) 2019 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

BACKGROUND: Allogeneic haematopoietic cell transplantation (HCT) is often associated with poor oral intake due to painful mucositis and gastrointestinal sequalae that occur following a preparative regimen of intensive chemotherapy and/or total body radiation. Although attractive to assume that optimal nutrition improves HCT outcomes, there are limited data to support this. It is also unclear whether artificial nutrition support should be provided as enteral tube feeding or parenteral nutrition (PN). METHODS: We analysed day-100 non-relapse mortality (NRM), incidence of acute graft-versus-host disease (GvHD), acute gastrointestinal GvHD, 5-year survival and GvHD-free/relapse-free survival (GRFS) according to both route and adequacy of nutritional intake prior to neutrophil engraftment, together with other known prognostic factors, in a retrospective cohort of 484 patients who underwent allogeneic HCT for haematologic malignancy between 2000 and 2014. RESULTS: Multivariate analyses showed increased NRM with inadequate nutrition (hazard ratio (HR) 4.1; 95% confidence interval (CI) 2.2-7.2) and adequate PN (HR 2.9; 95% CI 1.6-5.4) compared to adequate enteral nutrition (EN) both P

Purpose Adult T-cell leukemia-lymphoma (ATL) is a distinct mature T-cell malignancy caused by chronic infection with human T-lymphotropic virus type 1 with diverse clinical features and prognosis. ATL remains a challenging disease as a result of its diverse clinical features, multidrug resistance of malignant cells, frequent large tumor burden, hypercalcemia, and/or frequent opportunistic infection. In 2009, we published a consensus report to define prognostic factors, clinical subclassifications, treatment strategies, and response criteria. The 2009 consensus report has become the standard reference for clinical trials in ATL and a guide for clinical management. Since the last consensus there has been progress in the understanding of the molecular pathophysiology of ATL and risk-adapted treatment approaches. Methods Reflecting these advances, ATL researchers and clinicians joined together at the 18th International Conference on Human Retrovirology—Human T-Lymphotropic Virus and Related Retroviruses—in Tokyo, Japan, March, 2017, to review evidence for current clinical practice and to update the consensus with a new focus on the subtype classification of cutaneous ATL, CNS lesions in aggressive ATL, management of elderly or transplantation-ineligible patients, and treatment strategies that incorporate up-front allogeneic hematopoietic stem-cell transplantation and novel agents. Results As a result of lower-quality clinical evidence, a best practice approach was adopted and consensus statements agreed on by coauthors (> 90% agreement). Conclusion This expert consensus highlights the need for additional clinical trials to develop novel standard therapies for the treatment of ATL

The use of antihuman T-lymphocyte immunoglobulin in the setting of transplantation from an HLA-matched related donor is still much debated. Acute and chronic graft-versus-host disease are the main causes of morbidity and mortality after allogeneic hematopoietic stem cell transplantation in patients with myelofibrosis. The aim of this study was to evaluate the effect of antihuman T-lymphocyte immunoglobulin in a large cohort of patients with myelofibrosis (n=287). The cumulative incidences of grade II-IV acute graft-versus-host disease among patients who were or were not given antihuman T-lymphocyte immunoglobulin were 26% and 41%, respectively. The corresponding incidences of chronic graft-versus-host disease were 52% and 55%, respectively. Non-adjusted overall survival, disease-free survival and non-relapse mortality rates were 55% versus 53%, 49% versus 45%, and 32% versus 31%, respectively, among the patients who were or were not given antihuman T-lymphocyte immunoglobulin. An adjusted model confirmed that the risk of acute graft-versus-host disease was lower following antihuman T-lymphocyte immunoglobulin (hazard ratio, 0.54; P=0.010) while it did not decrease the risk of chronic graft-versus-host disease. The hazard ratios for overall survival and non-relapse mortality were 0.66 and 0.64, with P-values of 0.05 and 0.09, respectively. Antihuman T-lymphocyte immunoglobulin did not influence disease-free survival, graft-versus-host disease, relapse-free survival or relapse risk. In conclusion, in the setting of matched related transplantation in myelofibrosis patients, this study demonstrates that antihuman T-lymphocyte immunoglobulin decreases the risk of acute graft-versus-host disease without increasing the risk of relapse. ispartof: HAEMATOLOGICA vol:104 issue:6 pages:1230-1236 ispartof: location:Italy status: published

Diabetic retinopathy (DR) is a multifactorial microvascular disease induced by hyperglycemia and subsequent metabolic abnormalities. The resulting cell stress causes a sequela of events that ultimately can lead to severe vision impairment and blindness. The early stages are characterized by activation of glia and loss of pericytes, endothelial cells (EC) and neuronal cells. The integrity of the retinal microvasculature becomes affected, and, as a possible late response, macular edema may develop as a common reason for vision loss in patients with non proliferative DR. Moreover, the local ischemia can trigger vasoproliferation leading to vision-threating proliferative DR (PDR) in humans. Available treatment options include control of metabolic and hemodynamic factors. Timely intervention of advanced DR stages with laser photocoagulation, intraocular anti-vascular endothelial growth factor (VEGF) or glucocorticoid drugs can reduce vision loss.As the pathology involves cell loss of both the vascular and neuroglial compartments, cell replacement strategies by stem and progenitor cells have gained considerable interest in the past years. Compared to other disease entities, so far little is known about the efficacy and potential mode of action of cell therapy in treatment of DR. In preclinical models of DR different cell types have been applied ranging from embryonic or induced pluripotent stem cells, hematopoietic stem cells, and endothelial progenitor cells to mesenchymal stromal cells (MSC). The latter cell population can combine various modes of action (MoA), thus they are among the most intensely tested cell types in cell therapy. The aim of this review is to discuss the rationale for using MSC as potential cell therapy to treat DR. Accordingly, we will revise identified MoA of MSCs and speculate how these may support the repair of the damaged retina.

Purpose: Posttransplant cyclophosphamide (PTCy) is increasingly being utilized as a principle GvHD prophylaxis strategy in allogeneic hematopoietic cell transplantation (allo-HCT). A haploidentical (haplo) or matched unrelated donor (UD) is a valid option in the absence of a matched related donor. Experimental Design: We compared the outcomes of patients with acute leukemia who underwent haplo bone marrow (haplo-BM, N = 401) versus UD mobilized peripheral blood stem cells (UD-PB, N = 192) transplantation in the setting of PTCy. Results: The median follow-up duration was 36 months in the haplo-BM group and 16.6 months in the UD-PB group, respectively (P < 0.01). Myeloablative conditioning was used in 64.6% and 42.7% of haplo-BM and UD-PB patients, respectively (P < 0.01). Cumulative incidence of neutrophil engraftment at day 30 was 87% in haplo-BM versus 94% in UD-PB, respectively (P = 0.21). In the multivariate analysis, the risk of grade 2–4 acute GvHD (HR = 0.53, P = 0.01) and chronic GvHD (HR = 0.50, P = 0.02) was significantly lower in the haplo-BM group compared with the UD-PB group. There was no significant difference between the study groups with respect to relapse incidence, nonrelapse mortality, leukemia-fee survival, overall survival, or GvHD-free and relapse-free survival. Conclusions: The use of a haplo donor with a BM graft resulted in a lower incidence of GvHD compared with a UD-PB stem cell graft in the setting of PTCy for patients with acute leukemia. However, differences in GvHD did not translate into a difference in survival outcomes. Based upon these data, UD-PB or haplo-BM should be considered equally acceptable sources for allo-HCT.

Niemann–Pick type C (NPC) disease is a rare neurovisceral lipid storage disease with progressive neurodegeneration, leading to premature death. The disease is caused by loss-of-function mutations either in the NPC1 or NPC2 gene which results in lipid accumulation in the late endosomes and lysosomes. The involved disease mechanisms are still incompletely understood, making the design of a rational treatment very difficult. Since the disease is characterized by peripheral inflammation and neuroinflammation and it is shown that extracellular vesicles (EVs) obtained from mesenchymal stromal cells (MSCs) provide immunomodulatory capacities, we tested the potential of MSC-EV preparations to alter NPC1 disease pathology. Here, we show that the administration of an MSC-EV preparation with in vitro and in vivo confirmed immune modulatory capabilities is able to reduce the inflammatory state of peripheral organs and different brain regions of NPC1-diseased mice almost to normal levels. Moreover, a reduction of foamy cells in different peripheral organs was observed upon MSC-EV treatment of NPC1−/− mice. Lastly, the treatment was able to decrease microgliosis and astrogliosis, typical features of NPC1 patients that lead to neurodegeneration. Altogether, our results reveal the therapeutic potential of MSC-EVs as treatment for the genetic neurovisceral lipid storage disease NPC, thereby counteracting both central and peripheral features.

The introduction of advanced therapy medicinal products (ATMPs) to the global pharma market has been revolutionizing the pharmaceutical industry and has opened new routes for treating various types of cancers and incurable diseases. In the past two decades, a noticeable part of clinical practices has been devoting progressively to these products. The first step to develop such an ATMP product is to be familiar with other approved products to obtain a general view about this industry trend. The present paper depicts an overall perspective of approved ATMPs in different countries, while reflecting the degree of their success in a clinical point of view and highlighting their main safety issues and also related market size as a whole. In this regard, published articles regarding safety, efficacy, and market size of approved ATMPs were reviewed using the search engines PubMed, Scopus, and Google Scholar. For some products which the related papers were not available, data on the relevant company website were referenced. In this descriptive study, we have introduced and classified approved cell, gene, and tissue engineering-based products by different regulatory agencies, along with their characteristics, manufacturer, indication, approval date, related regulatory agency, dosage, product description, price and published data about their safety and efficacy. In addition, to gain insights about the commercial situation of each product, we have gathered accessible sale reports and market size information that pertain to some of these products. ispartof: FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY vol:8 ispartof: location:Switzerland status: published

Research efforts on nanomaterial-based therapies for the treatment of autoimmune diseases and cancer have spiked and have made rapid progress over the past years. Nanomedicine has been shown to contribute significantly to overcome current therapeutic limitations, exhibiting advantages compared to conventional therapeutics, such as sustained drug release, delayed drug degradation and site-specific drug delivery. Multiple nanodrugs have reached the clinic, but translation is often hampered by either low targeting efficiency or undesired side effects. Nanomaterials, and especially inorganic nanoparticles, have gained criticism due to their potential toxic effects, including immunological alterations. However, many strategies have been attempted to improve the therapeutic efficacy of nanoparticles and exploit their unique properties for the treatment of inflammation and associated diseases. In this review, we elaborate on the immunomodulatory effects of nanomaterials, with a strong focus on the underlying mechanisms that lead to these specific immune responses. Nanomaterials to be discussed include inorganic nanoparticles such as gold, silica and silver, as well as organic nanomaterials such as polymer-, dendrimer-, liposomal- and protein-based nanoparticles. Furthermore, various approaches for tuning nanomaterials in order to enhance their efficacy and attenuate their immune stimulation or suppression, with respect to the therapeutic application, are described. Additionally, we illustrate how the acquired insights have been used to design immunotherapeutic strategies for a variety of diseases. The potential of nanomedicine-based therapeutic strategies in immunotherapy is further illustrated by an up to date overview of current clinical trials. Finally, recent efforts into enhancing immunogenic cell death through the use of nanoparticles are discussed. ispartof: NANOSCALE ADVANCES vol:2 issue:11 pages:5046-5089 ispartof: location:England status: published

International audience; Full text linksfull-text provider logoActionsFavoritesSharePage navigation Title & authors Abstract Conflict of interest statement Figures References Related information LinkOut - more resourcesJ Hematol Oncol. 2020 Jul 3;13(1):87.doi: 10.1186/s13045-020-00923-0.Post-transplant cyclophosphamide versus antithymocyte globulin in patients with acute myeloid leukemia in first complete remission undergoing allogeneic stem cell transplantation from 10/10 HLA-matched unrelated donorsEolia Brissot 1 2 , Myriam Labopin 3 , Ian Moiseev 4 , J J Cornelissen 5 , Ellen Meijer 6 , Gwendolyn Van Gorkom 7 , Montserrat Rovira 8 , Fabio Ciceri 9 10 , Laimonas Griskevicius 11 , Didier Blaise 12 , Edouard Forcade 13 , Martin Mistrik 14 , Stephan Mielke 15 , Claude Eric Bulabois 16 , Riitta Niittyvuopio 17 , Eric Deconinck 18 , Annalisa Ruggeri 9 10 , Jaime Sanz 19 20 , Alexandros Spyridonidis 21 , Bipin Savani 22 , Sebastian Giebel 23 , Arnon Nagler 24 , Mohamad Mohty 25 26Affiliations PMID: 32620146 PMCID: PMC7333262 DOI: 10.1186/s13045-020-00923-0 Free PMC articleAbstractBackground: Graft-versus-host disease (GVHD) remains a major contributor to mortality and morbidity after allogeneic stem-cell transplantation (allo-HSCT). The updated recommendations suggest that rabbit antithymocyte globulin or anti-T-lymphocyte globulin (ATG) should be used for GVHD prophylaxis in patients undergoing matched-unrelated donor (MUD) allo-HSCT. More recently, using post-transplant cyclophosphamide (PTCY) in the haploidentical setting has resulted in low incidences of both acute (aGVHD) and chronic GVHD (cGVHD). Therefore, the aim of our study was to compare GVHD prophylaxis using either PTCY or ATG in patients with acute myeloid leukemia (AML) who underwent allo-HSCT in first remission (CR1) from a 10/10 HLA-MUD.Methods: Overall, 174 and 1452 patients from the EBMT registry receiving PTCY and ATG were included. Cumulative incidence of aGVHD and cGVHD, leukemia-free survival, overall survival, non-relapse mortality, cumulative incidence of relapse, and refined GVHD-free, relapse-free survival were compared between the 2 groups. Propensity score matching was also performed in order to confirm the results of the main analysis RESULTS: No statistical difference between the PTCY and ATG groups was observed for the incidence of grade II-IV aGVHD. The same held true for the incidence of cGVHD and for extensive cGVHD. In univariate and multivariate analyses, no statistical differences were observed for all other transplant outcomes. These results were also confirmed using matched-pair analysis.Conclusion: These results highlight that, in the10/10 HLA-MUD setting, the use of PTCY for GVHD prophylaxis may provide similar outcomes to those obtained with ATG in patients with AML in CR1.

Overcoming graft-versus-host disease (GvHD) without increasing relapse and severe infections is a major challenge after allogeneic hematopoietic stem-cell transplantation (HSCT). ATIR101 is a haploidentical, naïve cell-enriched T-cell product, depleted of recipient-alloreactive T cells to minimize the risk of GvHD and provide graft-versus-infection and -leukemia activity. Safety and efficacy of ATIR101 administered after T-cell-depleted haploidentical HSCT (TCD-haplo + ATIR101) without posttransplant immunosuppressors were evaluated in a Phase 2, multicenter study of 23 patients with acute leukemia and compared with an observational cohort undergoing TCD-haplo alone (n = 35), matched unrelated donor (MUD; n = 64), mismatched unrelated donor (MMUD; n = 37), and umbilical cord blood (UCB; n = 22) HSCT. The primary endpoint, 6-month non-relapse mortality (NRM), was 13% with TCD-haplo + ATIR101. One year post HSCT, TCD-haplo + ATIR101 resulted in lower NRM versus TCD-haplo alone (P = 0.008). GvHD-free, relapse-free survival (GRFS) was higher with TCD-haplo + ATIR101 versus MMUD and UCB (both P < 0.03; 1-year rates: 56.5%, 27.0%, and 22.7%, respectively) and was not statistically different from MUD (1 year: 40.6%). ATIR101 grafts with high third-party reactivity were associated with fewer clinically relevant viral infections. Results suggest that haploidentical, selective donor-cell depletion may eliminate requirements for posttransplant immunosuppressors without increasing GvHD risk, with similar GRFS to MUD. Following these results, a randomized Phase 3 trial versus posttransplant cyclophosphamide had been initiated., SCOPUS: ar.j, info:eu-repo/semantics/published

Allogeneic hematopoietic stem cell transplantation (alloSCT) for myeloid leukemia remains one of the most effective anti-tumor treatments available, capable of curing an increasingly higher proportion of patients. Alloreactivity generated by T cells has limited efficacy in the early post-transplant period while most patients will relapse within 6 months after transplantation. Prior studies in T cell depleted grafts showed that, with the elimination of T cells, natural killer (NK) cells provide most of the anti-tumor effect in the early post-transplant period. Administration of unmodified T cells to mitigate infections and relapse will expose the patient to a high risk of graft-vs-host disease (GvHD). Post-transplant cyclophosphamide (PTCy), initially used for haploidentical (haplo) donor transplants, is now also increasingly utilized in HLA matched donor transplants to prevent GvHD. In most patients, PTCy eliminates, at least in part, alloreactive T and NK cells early post-transplant. Administration of modified NK cells in the early post-transplant period makes intuitive sense to enhance the anti-tumor effect of the graft and thereby prevent relapse. Effective application of cellular therapy early after transplant has opened a new direction and could revolutionize the field of hematopoietic stem cell transplantation.

Human cytomegalovirus (HCMV) can cause significant disease in immunocompromised patients, and treatment options are limited by toxicities. CSJ148 is a combination of two anti-HCMV human monoclonal antibodies (LJP538 and LJP539) that bind to and inhibit the functions of viral HCMV glycoprotein B (gB) and the pentameric complex, consisting of glycoproteins gH, gL, UL128, UL130, and UL131. In this phase 2, randomized, placebo-controlled trial, we evaluated the safety and efficacy of CSJ148 for prophylaxis of HCMV in patients undergoing allogeneic hematopoietic stem cell transplantation., Human cytomegalovirus (HCMV) can cause significant disease in immunocompromised patients, and treatment options are limited by toxicities. CSJ148 is a combination of two anti-HCMV human monoclonal antibodies (LJP538 and LJP539) that bind to and inhibit the functions of viral HCMV glycoprotein B (gB) and the pentameric complex, consisting of glycoproteins gH, gL, UL128, UL130, and UL131. In this phase 2, randomized, placebo-controlled trial, we evaluated the safety and efficacy of CSJ148 for prophylaxis of HCMV in patients undergoing allogeneic hematopoietic stem cell transplantation. As would be expected in the study population, all the patients (100%) reported at least one treatment-emergent adverse event. There were 22 deaths during this study, and over 80% of the patients receiving placebo or CSJ148 developed at least one adverse event of grade 3 or higher severity. No subject who received antibody developed a hypersensitivity- or infusion-related reaction. CSJ148-treated patients showed trends toward decreased viral load, shorter median duration of preemptive therapy, and fewer courses of preemptive therapy. However, the estimated probability that CSJ148 decreases the need for preemptive therapy compared to placebo was 69%, with a risk ratio of 0.89 and a 90% credible interval of 0.61 to 1.31. The primary efficacy endpoint was therefore not met, indicating that CSJ148 did not prevent clinically significant HCMV reactivation in recipients of allogeneic hematopoietic cell transplants. (This study has been registered at ClinicalTrials.gov under identifier NCT02268526 and at EudraCT under number 2017-002047-15.)

Graft-vs.-host disease (GvHD) is a major complication after allogeneic hematopoietic stem cell transplantation that causes mortality and severe morbidity. Genetic disparities in human leukocyte antigens between the recipient and donor are known contributors to the risk of the disease. However, the overall impact of genetic component is complex, and consistent findings across different populations and studies remain sparse. To gain a comprehensive understanding of the genes responsible for GvHD, we combined genome-wide association studies (GWAS) from two distinct populations with previously published gene expression studies on GvHD in a single gene-level meta-analysis. We hypothesized that genes driving GvHD should be associated in both data modalities and therefore could be detected more readily through their combined effects in the integrated analysis rather than in separate analyses. The meta-analysis yielded a total of 51 acute GvHD-associated genes (false detection rate [FDR]

Large differences in patient and transplant backgrounds make it difficult to identify consistent prognostic factors of unrelated cord blood transplantation (UCBT) among different populations. Thus, we performed a collaborative study between Eurocord/ALWP-EBMT and JSHCT/JDCHCT. Adults with acute leukaemia who underwent a single UCBT were eligible. In total, 3764 and 1027 patients of the JSHCT/JDCHCT and Eurocord/ALWP-EBMT registries, respectively, were included. The median ages of the Japanese and European cohorts were 51 and 38 years, respectively. Three or more HLA mismatches were more frequently observed in the Japanese cohort. The median total nucleated cell (TNC) counts were 2.58 and 3.51 10 7 /kg in the Japanese and European cohorts, respectively. Anti-thymocyte globulin was used in only 2% of the Japanese cohort compared with 65% of the European cohort. The 3-year overall survival (OS) was 41% in JSHCT/JDCHCT and 33% in Eurocord/ALWP-EBMT. In the multivariate analysis, TNC dose and HLA matching had no significant effect on OS in either cohort, whereas year of transplantation, age, and refined disease risk index affected OS in both cohorts. Despite considerable differences in characteristics between the Japanese and European cohorts, we observed similar prognostic factors affecting UCBT outcomes in adult patients with acute leukaemia in both registries.

A total of 192 pediatric patients, median age 8.6 years, with high‐risk hematological malignancies, underwent haploidentical stem cell transplantation (haplo‐HSCT) using post‐transplantation cyclophosphamide (PT‐Cy), or ex vivo T cell‐depleted (TCD) graft platforms, from January 1999 to December 2016 in 10 centers in Spain. Some 41 patients received an unmanipulated graft followed by PT‐Cy for graft‐vs‐host disease (GvHD) prophylaxis. A total of 151 patients were transplanted with CD3‐depleted peripheral blood stem cells (PBSCs) by either CD34+ selection, CD3+CD19+ depletion, TCRαβ+CD19+ depletion or CD45RA+ depletion, added to CD34+ selection for GvHD prophylaxis. The PBSCs were the only source in patients following ex vivo TCD haplo‐HSCT; bone marrow was the source in 9 of 41 patients following PT‐CY haplo‐HSCT. Engraftment was achieved in 91.3% of cases. A donor younger than 30 years, and the development of chronic GvHD were positive factors influencing survival, whereas positive minimal residual disease (MRD) before transplant and lymphoid disease were negative factors. The probability of relapse increased with lymphoid malignancies, a donor killer‐cell immunoglobulin‐like receptor (KIR) haplotype A and positive MRD pretransplant. No difference was found in overall survival, disease‐free survival or relapse incidence between the two platforms. Relapse is still of concern in both platforms, and it should be the focus of future efforts. In conclusion, both platforms for haplo‐HSCT were effective and could be utilized depending on the comfort level of the center., Research funding: National Health Service of Spain, Instituto de Salud Carlos III (ISCIII), FONDOS FEDER grant (FIS). Grant Number: PI18/01301, the CRIS Cancer Foundation, the Association Pablo Ugarte.

The effect of timing of community acquired respiratory virus (CARV) infection after allogeneic hematopoietic stem cell transplant (allo-HCT) is an as yet unsettled issue. We evaluate this issue by including all consecutive allo-HCT recipients with molecularly-documented CARV infection during the first year after transplant. The study cohort was drawn from a prospective longitudinal survey of CARV in allo-HCT recipient having respiratory symptoms conducted from December 2013 to December 2018 at two Spanish transplant centers. Respiratory viruses in upper and/or lower respiratory specimens were tested using multiplex PCR panel assays. The study cohort comprised 233 allo-HCT recipients with 376 CARV infection episodes diagnosed during the first year after allo-HCT. Overall, 60% of CARV episodes occurred within the first 6 months (227 out of 376). Thirty patients (13%) had died at 3 months after CARV detection, of which 25 (83%) were recipients developing CARV within the first 6 months after transplant. Multivariate analysis identified four risk factors for mortality: ATG used as part of conditioning regimen [odds ratio (OR) 2.8, 95% confidence interval (C.I.) 1.21-6.4, p = 0.01], CARV lower respiratory tract disease (OR 3.4, 95% C.I. 1.4-8.4, p = 0.007), CARV infection within the first 6 months of transplant (OR 3.04, 95% C.I. 1.1-8.7, p = 0.03), and absolute lymphocyte count

Uric acid is a danger signal contributing to inflammation. Its relevance to allogeneic stem cell transplantation (alloSCT) derives from preclinical models where the depletion of uric acid led to improved survival and reduced graft-versus-host disease (GvHD). In a clinical pilot trial, peri-transplant uric acid depletion reduced acute GvHD incidence. This prospective international multicenter study aimed to investigate the association of uric acid serum levels before start of conditioning with alloSCT outcome. We included patients with acute leukemia, lymphoma or myelodysplastic syndrome receiving a first matched sibling alloSCT from peripheral blood, regardless of conditioning. We compared outcomes between patients with high and low uric acid levels with univariate- and multivariate analysis using a cause-specific Cox model. Twenty centers from 10 countries reported data on 366 alloSCT recipients. There were no significant differences in terms of baseline comorbidity and disease stage between the high- and low uric acid group. Patients with uric acid levels above median measured before start of conditioning did not significantly differ from the remaining in terms of acute GvHD grades II-IV incidence (Hazard ratio [HR] 1.5, 95% Confidence interval [CI]: 1.0-2.4, P=0.08). However, they had significantly shorter overall survival (HR 2.8, 95% CI: 1.7-4.7, P

High-risk chronic lymphocytic leukemia (CLL) has been defined by clinical and/or genetic resistance (TP53 abnormalities) to treatment with chemoimmunotherapy (CIT). With the availability of pathway inhibitors (PIs), such as kinase inhibitors and BCL2 antagonists, the outlook of CIT-resistant patients has dramatically improved. Here, we propose a revision of the concept of high-risk CLL, driven by TP53 abnormalities and response to treatment with PI. CLL high-risk-I, CIT-resistant is defined by clinically CIT-resistant disease with TP53 aberrations, but fully responsive to PI. This category is largely the domain of PI-based therapy, and cellular therapy (ie, allogeneic hematopoietic cell transplantation) remains an option only in selected patients with low individual procedure-related risk. In CLL high-risk-II, CIT- and PI-resistant, characterized by increasing exhaustion of pharmacological treatment possibilities, cellular therapies (including chimeric antigen receptor-engineered T cells) should be considered in patients eligible for these procedures. Moreover, molecular and cellular therapies are not mutually exclusive and could be used synergistically to exploit their full potential.

The immunomodulatory potential of mesenchymal stromal cells (MSCs) and regulatory T cells (T‐reg) is well recognized by translational scientists in the field of regenerative medicine and cellular therapies. A wide range of preclinical studies as well as a limited number of human clinical trials of MSC therapies have not only shown promising safety and efficacy profiles but have also revealed changes in T‐reg frequency and function. However, the mechanisms underlying this potentially important observation are not well understood and, consequently, the optimal strategies for harnessing MSC/T‐reg cross‐talk remain elusive. Cell‐to‐cell contact, production of soluble factors, reprogramming of antigen presenting cells to tolerogenic phenotypes, and induction of extracellular vesicles (“exosomes”) have emerged as possible mechanisms by which MSCs produce an immune‐modulatory milieu for T‐reg expansion. Additionally, these two cell types have the potential to complement each other's immunoregulatory functions, and a combinatorial approach may exert synergistic effects for the treatment of immunological diseases. In this review, we critically assess recent translational research related to the outcomes and mechanistic basis of MSC effects on T‐reg and provide a perspective on the potential for this knowledge base to be further exploited for the treatment of autoimmune disorders and transplants., Mesenchymal stromal cells (MSCs) promote regulatory T cell numbers and immune suppressive functions through mechanisms involving cell‐cell contact, production of soluble mediators, reprogramming of antigen presenting cells, and release of extracellular vesicles that likely represent important components of MSC therapeutic effects in immune/inflammatory diseases.

The subcommittee reviewed the prevalence, incidence, risk factors, natural history, morbidity and questionnaires reported in epidemiological studies of dry eye disease (DED). A meta-analysis of published prevalence data estimated the impact of age and sex. Global mapping of prevalence was undertaken. The prevalence of DED ranged from 5 to 50%. The prevalence of signs was higher and more variable than symptoms. There were limited prevalence studies in youth and in populations south of the equator. The meta-analysis confirmed that prevalence increases with age, however signs showed a greater increase per decade than symptoms. Women have a higher prevalence of DED than men, although differences become significant only with age. Risk factors were categorized as modifiable/nonmodifiable, and as consistent, probable or inconclusive. Asian ethnicity was a mostly consistent risk factor. The economic burden and impact of DED on vision, quality of life, work productivity, psychological and physical impact of pain, are considerable, particularly costs due to reduced work productivity. Questionnaires used to evaluate DED vary in their utility. Future research should establish the prevalence of disease of varying severity, the incidence in different populations and potential risk factors such as youth and digital device usage. Geospatial mapping might elucidate the impact of climate, environment and socioeconomic factors. Given the limited study of the natural history of treated and untreated DED, this remains an important area for future research.

The subcommittee reviewed the prevalence, incidence, risk factors, natural history, morbidity and questionnaires reported in epidemiological studies of dry eye disease (DED). A meta-analysis of published prevalence data estimated the impact of age and sex. Global mapping of prevalence was undertaken. The prevalence of DED ranged from 5 to 50%. The prevalence of signs was higher and more variable than symptoms. There were limited prevalence studies in youth and in populations south of the equator. The meta-analysis confirmed that prevalence increases with age, however signs showed a greater increase per decade than symptoms. Women have a higher prevalence of DED than men, although differences become significant only with age. Risk factors were categorized as modifiable/non-modifiable, and as consistent, probable or inconclusive. Asian ethnicity was a mostly consistent risk factor. The economic burden and impact of DED on vision, quality of life, work productivity, psychological and physical impact of pain, are considerable, particularly costs due to reduced work productivity. Questionnaires used to evaluate DED vary in their utility. Future research should establish the prevalence of disease of varying severity, the incidence in different populations and potential risk factors such as youth and digital device usage. Geospatial mapping might elucidate the impact of climate, environment and socioeconomic factors. Given the limited study of the natural history of treated and untreated DED, this remains an important area for future research.

Dedicator-of-cytokinesis 8 (DOCK8) deficiency, a primary immunodeficiency disease, can be reversed by allogeneic hematopoietic stem cell transplantation (HSCT); however, there are few reports describing the use of alternative donor sources for HSCT in DOCK8 deficiency. We describe HSCT for patients with DOCK8 deficiency who lack a matched related or unrelated donor using bone marrow from haploidentical related donors and post-transplantation cyclophosphamide (PT/Cy) for graft-versus-host disease (GVHD) prophylaxis. Seven patients with DOCK8 deficiency (median age, 20 years; range, 7 to 25 years) received a haploidentical related donor HSCT. The conditioning regimen included 2 days of low-dose cyclophosphamide, 5 days of fludarabine, 3 days of busulfan, and 200 cGy total body irradiation. GVHD prophylaxis consisted of PT/Cy 50 mg/kg/day on days +3 and +4 and tacrolimus and mycophenolate mofetil starting at day +5. The median times to neutrophil and platelet engraftment were 15 and 19 days, respectively. All patients attained >90% donor engraftment by day +30. Four subjects developed acute GVHD (1 with maximum grade 3). No patient developed chronic GVHD. With a median follow-up time of 20.6 months (range, 9.5 to 31.7 months), 6 of 7 patients are alive and disease free. Haploidentical related donor HSCT with PT/Cy represents an effective therapeutic approach for patients with DOCK8 deficiency who lack a matched related or unrelated donor. Published by Elsevier Inc. on behalf of the American Society for Blood and Marrow Transplantation.

In the last decade, extracellular vesicles (EVs) have emerged as a key cell-free strategy for the treatment of a range of pathologies, including cancer, myocardial infarction and inflammatory diseases. Indeed, the field is rapidly transitioning from promising in vitro reports towards in vivo animal models and early clinical studies. These investigations exploit the high physicochemical stability and biocompatibility of EVs, as well as their innate capacity to communicate with cells over long distances via signal transduction and membrane fusion. This review will focus on methods in which EVs can be chemically or biologically modified to broaden, alter or enhance their therapeutic capability. We will examine two broad strategies, which have been used to introduce a wide range of nanoparticles, reporter systems, targeting peptides, pharmaceutics and functional RNA molecules. First, we will explore how EVs can be modified by manipulating their parent cells; either through genetic or metabolic engineering, or by introducing exogenous material that is subsequently incorporated into secreted EVs. Second, we consider how EVs can be directly functionalized using strategies such as hydrophobic insertion, covalent surface chemistry and membrane permeabilization. We will discuss the historical context of each specific technology, present prominent examples and evaluate the complexities, potential pitfalls and opportunities presented by different re-engineering strategies.

Mesenchymal stromal cells (MSCs) possess reparative, regenerative and immunomodulatory properties. The current literature suggests that MSCs could improve kidney transplant outcome via immunomodulation. In many clinical domains, research has also focussed on the regenerative and reparative effects of therapies with MSCs. However, in the field of transplantation, data on this subject remain scarce. This review provides an overview of what is known about the regenerative and reparative effects of MSCs in various fields ranging from wound care to fracture healing and also examines the potential of these promising MSC properties to improve the outcome of kidney transplantations.