Clinical characteristics of membranous nephropathy after allogeneic hematopoietic stem cell transplantation: A real-world multicenter study.

Membranous nephropathy (MN) is a rare complication that can occur after allogeneic hematopoietic stem cell transplantation (allo-HSCT). MN patients may develop nephrotic syndrome or even kidney failure, which greatly affects their quality of life and prognosis. However, current knowledge regarding MN after allo-HSCT is limited. Thus, a multicenter nested case‒control study was conducted. Patients who had been diagnosed with MN after allo-HSCT were retrospectively identified at 8 HSCT centers. A total of 51 patients with MN after allo-HSCT were included. The median age of MN patients after allo-HSCT was 38 years, and the median duration from HSCT to MN was 18 months. The use of HLA-matched donors (P = 0.0102) and peripheral blood as the graft source (P = 0.0060) were identified as independent predisposing risk factors for the onset of MN after allo-HSCT. Compared to those in the control group, the incidence of extensive chronic graft-versus-host disease was greater in the MN patients (P = 0.0002). A total of 31 patients developed nephrotic syndrome. Patients receiving combination treatments of corticosteroids and immunosuppressants appeared to have better outcomes. In conclusion, MN is a rare but occasionally severe complication following HSCT and may require active treatment.

Cytomegalovirus infection is associated with thymic dysfunction and chronic graft-versus-host disease after pediatric hematopoietic stem cell transplantation.

Pediatric hematopoietic stem cell transplantation (HSCT) is challenged by chronic graft-versus-host disease (cGvHD) significantly affecting survival and long-term morbidity, but underlying mechanisms including the impact of post-HSCT CMV infection are sparsely studied. We first investigated the impact of CMV infection for development of cGvHD in 322 children undergoing standard myeloablative HSCT between 2000 and 2018. Clinically significant CMV infection (n = 61) was an independent risk factor for chronic GvHD in a multivariable Cox regression analysis (HR = 2.17, 95% CI = 1.18-3.97, P = 0.013). We next explored the underlying mechanisms in a subcohort of 39 children. CMV infection was followed by reduced concentration of recent thymic emigrants (17.5 vs. 51.9 × 106/L, P = 0.048) and naïve CD4+ and CD8+ T cells at 6 months post-HSCT (all P < 0.05). Furthermore, CD25highFOXP3+ Tregs tended to be lower in patients with CMV infection (2.9 vs. 9.6 × 106/L, P = 0.055), including Tregs expressing the naivety markers CD45RA and Helios. CD8+ T-cell numbers rose after CMV infection and was dominated by exhausted PD1-expressing cells (66% vs. 39%, P = 0.023). These findings indicate that post-HSCT CMV infection is a main risk factor for development of chronic GvHD after pediatric HSCT and suggest that this effect is caused by reduced thymic function with a persistently impaired production of naïve and regulatory T cells in combination with increased peripheral T-cell exhaustion.

Disseminated Mycobacterium kansasii infection due to surgical site infection following allogeneic hematopoietic stem cell transplantation: A case report and literature review.

This report details a rare case of surgical site infection (SSI) caused by Mycobacterium kansasii following allogeneic hematopoietic stem cell transplantation (allo-HSCT) in a 53-year-old patient with IgA-κ type multiple myeloma. After undergoing multiple chemotherapy regimens and two stem cell transplants, the patient developed an SSI 31-month post-transplantation, manifesting as an intracranial abscess at the site of a previous craniotomy. M. kansasii was isolated from the drainage fluid, marking this instance as a unique case in the literature of nontuberculous mycobacteria (NTM) infection post-allo-HSCT with such a delayed onset. The patient's treatment included targeted antimicrobial therapy based on susceptibility testing, resulting in eventual resolution of the infection, although the patient later succumbed to multiple myeloma relapse. This case underscores the critical need to consider NTM infections in the differential diagnosis of persistent fevers and SSIs in immunocompromised patients, particularly those with chronic graft-versus-host disease. It highlights the importance of early diagnostic and therapeutic interventions to manage these infections effectively. This report contributes to the limited but growing body of literature on NTM infections post-allo-HSCT and emphasizes the need for vigilance in monitoring postoperative patients, especially those with prolonged immunosuppression.

Efficacy and safety of ruxolitinib in the treatment of chronic graft-versus-host disease: a retrospective analysis.

Steroid-refractory chronic graft-versus-host disease (cGvHD) is associated with significant morbidity and mortality, with ruxolitinib being the first drug approved for its treatment. We retrospectively analyzed the safety and efficacy of ruxolitinib for treatment of cGvHD at our center between 07/2015 and 12/2022 and identified 48 patients receiving ruxolitinib as second (18/48) or advanced (30/48) treatment line. Ruxolitinib was started on median day 340 (range 119-595) after cGvHD onset; median duration of administration was 176 (range, 79-294) days with 16/48 patients continuing treatment at last follow-up. National Institutes of Health organ grading and the intensity of immunosuppression were assessed at the start of ruxolitinib treatment and repeated after 1, 3, 6, and 12 months. Response assessment was terminated at the start of any additional new immunosuppressant treatment. The median time of follow-up was 582 (range, 104-1161) days. At the primary analysis after six months on ruxolitinib treatment, the overall response rate was 33%, and failure-free survival was 58%. Infectious adverse events ≥ CTCAE grade III were observed in 10/48 patients. The response rate was not associated with the severity of cGvHD, number of previous treatment lines, or number of additional agents combined with ruxolitinib applying a univariate regression model. At the time of the 12-month follow-up, four patients experienced recurrence of the underlying malignancy and two patients had experienced non-relapse-related mortality. Overall, ruxolitinib was relatively well-tolerated and showed outcomes comparable to the REACH3 trial in a heavily pretreated patient population.

Repeated Infusions of Bone-Marrow-Derived Mesenchymal Stem Cells over 8 Weeks for Steroid-Refractory Chronic Graft-versus-Host Disease: A Prospective, Phase I/II Clinical Study.

Chronic graft-versus-host disease (cGVHD) is a long-term complication of allogeneic hematopoietic stem cell transplantation associated with poor quality of life and increased morbidity and mortality. Currently, there are several approved treatments for patients who do not respond to steroids, such as ruxolitinib. Nevertheless, a significant proportion of patients fail second-line treatment, indicating the need for novel approaches. Mesenchymal stem cells (MSCs) have been considered a potential treatment approach for steroid-refractory cGVHD. To evaluate the safety and efficacy of repeated infusions of MSCs, we administered intravenous MSCs every two weeks to ten patients with severe steroid-refractory cGVHD in a prospective phase I clinical trial. Each patient received a total of four doses, with each dose containing 1 × 106 cells/kg body weight from the same donor and same passage. Patients were assessed for their response to treatment using the 2014 National Institutes of Health (NIH) response criteria during each visit. Ten patients with diverse organ involvement were enrolled, collectively undergoing 40 infusions as planned. Remarkably, the MSC infusions were well tolerated without severe adverse events. Eight weeks after the initial MSC infusion, all ten patients showed partial responses characterized by the amelioration of clinical symptoms and enhancement of their quality of life. The overall response rate was 60%, with a complete response rate of 20% and a partial response (PR) rate of 40% at the last follow-up. Overall survival was 80%, with a median follow-up of 381 days. Two patients died due to relapse of their primary disease. Immunological analyses revealed a reduction in inflammatory markers, including Suppression of Tumorigenicity 2 (ST2), C-X-C motif chemokine ligand (CXCL)10, and Secreted phosphoprotein 1(SPP1), following the MSC treatment. Repeated MSC infusions proved to be both feasible and safe, and they may be an effective salvage therapy in patients with steroid-refractory cGVHD. Further large-scale clinical studies with long-term follow-up are needed in the future to determine the role of MSCs in cGVHD.

Disability Associated with Chronic Graft-Versus-Host Disease After Allogeneic Hematopoietic Stem Cell Transplantation: Analysis of a Cross-Sectional US Patient Survey.

INTRODUCTION: Chronic graft-versus-host disease (GVHD) following hematopoietic stem cell transplantation (HSCT) is associated with poor health-related quality of life (HRQoL) and functional status. However, few studies have evaluated chronic GVHD-related disability and specific activity limitations from a patient perspective. The objective of this analysis was to assess physical, cognitive, and work disability, and describe factors predictive of disability in patients with chronic GVHD in the potentially employable general workforce. METHODS: The cross-sectional, online, Living With Chronic GVHD Patient Survey was administered in 2020 to adult US patients who reported an active chronic GVHD diagnosis (i.e., within the previous 5 years) following HSCT. Data included demographics, diagnosis, work status, chronic GVHD symptoms per the Lee Symptom Scale (LSS), and effects on daily living activities. Descriptive and correlational analyses informed composite disability definitions: (1) severe cognitive disability, (2) severe physical disability, and (3) work disability. RESULTS: Of 137 respondents with GVHD included in this analysis, 47.0% reported severe cognitive disability, and approximately two-thirds each reported severe physical disability (67.4%) and work disability (62.8%). Chronic GVHD severity/duration, symptoms (Lee Symptom Scale), and number of transplant specialists consulted were associated with all types of disability (univariable analyses). Severe cognitive disability was associated with the number of transplant specialists consulted, severe physical disability with female sex, and work disability with nonwhite race. CONCLUSIONS: In this analysis, we found that the presence of specific symptoms and the number of transplant specialists consulted were associated with all types of severe disability; female sex was predictive of severe physical disability and nonwhite race of work disability. These findings add to the understanding of chronic GVHD-associated disability, suggest a need for improved social support for patients, and highlight potential indicators for those most in need.

Chronic graft-versus-host disease (GVHD) is a possible serious complication that can occur after someone has received a bone marrow or stem cell transplant from another person. Symptoms of chronic GVHD can be severe and can affect quality of life. To better understand exactly how chronic GVHD affects quality of life, we asked adults in the USA with chronic GVHD to fill out a survey. The objective of this research was to find out how chronic GVHD affects daily activities and work. The survey asked about physical activities including personal hygiene, eating, shopping, and ability to use the restroom, and the survey asked about mental tasks including managing personal finances and interactions with other people. The survey also asked questions about work, such as the need to take disability leave or to leave a job due to chronic GVHD. Many people with chronic GVHD who completed the survey said they had severe difficulty with mental and/or physical tasks, and many had work-related disability. People with more severe chronic GVHD who had met with many transplant specialists were more likely to have difficulty with mental and physical tasks and also to have work disability. Women who completed the survey were more likely to report severe physical disability than men, and nonwhite participants were more likely to report work disability. The results of this survey highlight a need for improved social support for patients with chronic GVHD.

[Recent advances in prevention and treatment of chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation].

Chronic graft-versus-host disease (cGVHD) negatively impacts long-term survival and quality of life (QOL) after allogeneic hematopoietic cell transplantation. Corticosteroids are the first-line treatment for cGVHD, but approximately 30% to 70% of patients develop steroid-refractory cGVHD (SR-cGVHD), which has an extremely poor prognosis. The pathophysiology of cGVHD is more complicated than acute GVHD, but recent advances using murine models in conjunction with human studies indicate three major phases: 1) acute inflammation, 2) chronic inflammation with loss of immune tolerance, and 3) disrupted target organ homeostasis and fibrosis. Strategies that help prevent cGVHD include optimal donor selection and choice of conditioning regimen as well as pharmacologic and graft manipulation strategies. The key cellular mediators of SR-cGVHD are T cells, B cells, antigen-presenting cells, and fibroblasts. T cells and B cells are now targetable with the inhibitors ibrutinib and ruxolitinib, respectively. Recently, promising results have been obtained by modulating pathologic T cell responses with Rock2 inhibitors and targeting fibrosis with CSF-1R inhibitors. To optimize the use of these medications, a better understanding of the biological and target organ-specific mechanisms of cGVHD is needed. Here we review recent advances in cGVHD pathogenesis and discuss how best to implement recently approved biology-driven treatments for cGVHD.

Late Presentation of Oral Chronic Graft Versus Host Disease Manifesting As Hyperkeratotic Plaque: A Case Report.

Hematopoietic stem cell transplantation is the only curative intervention for myelodysplastic syndrome, with graft-versus-host disease (GVHD) being a frequently encountered consequence. GVHD is classified as acute (aGVHD) or chronic (cGVHD). The oral cavity is the most impacted by chronic. Oral manifestations of cGVHD are variable and include plaque, Wickham striae, and lichenoid patches. In order to prevent malignant misdiagnosis, the 2014 NIH consensus report decided to exclude white plaque as a diagnostic indicator for oral cGVHD. Nevertheless, it is still possible to classify a white plaque lesion as cGVHD through histological confirmation. The performance of a biopsy should be undertaken following meticulous consideration and a thorough evaluation of the associated risks and benefits. The in-depth review of oral cancer risk assessment is crucial, necessitating a careful review of multiple factors to accurately estimate the likelihood of malignant transformation in individuals with oral cGVHD. This report describes a case of oral cGVHD manifesting as hyperkeratotic plaque lesions confirmed by histopathology in a 62-year-old man who received an allogeneic hematopoietic stem cell transplant over a decade ago.

A Novel JAK1 Inhibitor SHR0302 Combined With Prednisone for First-Line Treatment of Chronic Graft-Versus-Host Disease: A Phase I Clinical Trial.

Chronic graft-versus-host disease (cGVHD) is a potentially life-threatening complication after allogeneic hematopoietic stem cell transplantation. Standard steroid first-line treatment could not satisfy therapeutic needs due to limited efficacy. As a highly selective Janus kinase (JAK) 1 inhibitor, SHR0302 exhibits a reduced inhibition effect on JAK2 and might have less effect on hematopoiesis. This phase I clinical trial investigated the tolerability and safety of SHR0302 in combination with prednisone, and its early efficacy evidence as a potential first-line treatment to moderate/severe cGVHD. The standard 3 + 3 dose escalation was implemented to find the optimal dose of SHR0302. And prednisone was concurrently administrated with a dose of 1 mg/kg/d and then gradually tapered after 2 weeks. Eighteen patients were enrolled into the study. Grade ≥ 3 treatment-related adverse events were observed in 38.9% of patients. Only one patient developed DLT (grade ≥ 3 hypercholesterolemia) in the highest dose-level group who had pre-existing hypercholesterolemia. The maximum tolerated dose was not reached. No patient discontinued treatment due to AEs. Sixteen out of 18 patients were evaluable for responses, the ORR at week 4 and week 24 were 94.4 and 87.5%, respectively. Overall, the treatment of SHR0302 combined with prednisone was safe and well-tolerated, preliminary clinical results presented a high response for previously untreated cGVHD and a significant reduction in prednisone use in this study. A phase II trial will be conducted to further investigate its therapeutic effects clinically.

Tongue cancer developing after haematopoietic stem cell transplantation for treatment of acute promyelocytic leukaemia: A case report.

Acute promyelocytic leukaemia (APL) is a form of acute myelogenous leukaemia. APL is characterised by anaemia due to suppression of normal haematopoiesis and infection. Haematopoietic stem cell transplantation (HSCT) is current option for the treatment of haematopoietic malignancies and is proving to be successful. Although HSCT has been effective for the treatment of haematopoietic malignant tumours, chronic graft-versushost disease (GVHD) but secondary cancers can occur, which is a serious complication and frequently involves the oral cavity and skin. Here, we report the case of tongue cancer occurring 17 years after transplantation in a patient who developed GVHD after haematopoietic stem cell transplantation and APL remission. To the best of our knowledge, this is the first report of secondary oral cancer after HSCT with APL as the primary disease.

The history of haploidentical stem cell transplantation: a trip from the bench to the bedside.

Allogeneic bone marrow transplantation is a curative intervention for both neoplastic and non-malignant conditions. However, not all patients have an HLA-matched donor. Therefore, the development of an approach that expand the donor pool was of paramount relevance. The development of post-transplantation cyclophosphamide as graft versus host disease prophylaxis allows the safe use of haploidentical donors, solving the donor availability problem to the vast majority of patients in need. The present paper reviews the history of the development of haploidentical transplantation at Johns Hopkins University, from the bench to the bedside.

Acute calcareous corneal degeneration in a patient with chronic graft-versus-host disease.

Objective: To describe acute calcareous corneal degeneration as a complication of chronic graft-versus-host disease. Materials and methods: Clinical case and review of the literature. Results: We presented a case of bilateral acute calcareous corneal degeneration in a patient with chronic graft-versus-host disease. Conclusions: Chronic graft-versus-host disease (cGVHD) occurs in 50-70% of bone marrow transplantation patients, the most frequent ocular complication being keratoconjunctivitis sicca (KCS). Calcareous corneal degeneration is a type of calcium deposition that can be secondary to chronic ocular inflammation or dry eye, but there are few cases reported of acute calcareous corneal degeneration and recurrent perforation in cGVHD. Abbreviations: GVHD = Chronic graft-versus-host disease, aGVHD = Acute graft-versus-host disease, cGVHD = Chronic graft-versus-host disease, KCS = Keratoconjunctivitis sicca, PKP = Penetrating keratoplasty, AMT = Amniotic membrane transplantation, PRGF = Plasma rich in growth factors, OD = Right eye, OS = Left eye.

[Pathogenesis and Therapeutic Prospects of Chronic Graft-Versus-Host Disease --Review].

Chronic graft-versus-host disease (cGVHD) is one of a major complication that affecting the long-term survival and living quality of patients after allogeneic hematopoietic stem cell transplantation, with the incidence of 30%-70%. Unlike acute GVHD, cGVHD involves a large number of immune cells and cytokines in addition to T cell, which is activated abnormally by the donor, and cytokine storms, which characterized by infiltration of donor lymphocytes and damage to host target organ. Recent studies have further made progress in targeting related immune cells and cytokines. In this review, the pathogenesis and therapeutic prospects of cGVHD were summarized from the perspectives of classical innate and adaptive immunity.

Concomitant use of interleukin-2 and tacrolimus suppresses follicular helper T cell proportion and exerts therapeutic effect against lupus nephritis in systemic lupus erythematosus-like chronic graft versus host disease.

Introduction: Defective interleukin-2 (IL-2) production contributes to immune system imbalance in patients with systemic erythematosus lupus (SLE). Recent clinical studies suggested that low-dose IL-2 treatment is beneficial for SLE and the therapeutic effect is associated with regulatory T cell (Treg) expansion. Pharmacological calcineurin inhibition induces a reduction in the number of Tregs because they require stimulation of T cell receptor signaling and IL-2 for optimal proliferation. However, the activation of T cell receptor signaling is partially dispensable for the expansion of Tregs, but not for that of conventional T cells if IL-2 is present. Aim: We examined whether addition of IL-2 restores the Treg proportion even with concurrent use of a calcineurin inhibitor and if the follicular helper T cell (Tfh) proportion is reduced in an SLE-like murine chronic graft versus host disease model. Methods: Using a parent-into-F1 model, we investigated the effect of IL-2 plus tacrolimus on Treg and Tfh proportions and the therapeutic effect. Results: Treatment with a combination of IL-2 and tacrolimus significantly delayed the initiation of proteinuria and decreased the urinary protein concentration, whereas tacrolimus or IL-2 monotherapy did not significantly attenuate proteinuria. Phosphorylation of signal transducer and activator of transcription 3, a positive regulator of Tfh differentiation, was reduced by combination treatment, whereas phosphorylation of signal transducer and activator of transcription 5, a negative regulator, was not reduced. Conclusion: Addition of calcineurin inhibitors as adjunct agents may be beneficial for IL-2-based treatment of lupus nephritis.

Therapeutic response of oral chronic graft-versus-host disease to topical corticosteroids according to the 2014 National Institutes of Health (USA) consensus criteria / Respuesta terapéutica de la enfermedad de injerto contra huésped crónica oral a los corticosteroides tópicos según los criterios de consenso de los Institutos Nacionales de Salud (EE. UU.) de 2014

Background: Chronic graft-versus-host-disease (cGVHD) is a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. The oral cavity is one of the most frequently affected anatomic sites and is affected in 70% of all patients who develop cGVHD. The objective of this study was to determine the therapeutic response to topical corticosteroids and clinical outcome of patients with oral cGVHD using the 2014 NIH consensus criteria. Material and Methods: The oral manifestations of cGVHD were collected at the first and the follow-up (FU) visits after the therapeutic treatment of oral GVHD. The FU intervals were: FU0, first visit; FU1, 0-1 month; FU2, 1-3 months; FU3, 3-6 months; FU4, 6-9 months; and FU5, 9-12 months. The oral cGVHD activity was assessed using the NIH modification of the Schubert Oral Mucosa Rating Scale (OMRS) and Thongprasom sign score. The functional impact was assessed by the organ-specific severity score. Results: Fourteen patients (93.3%) at FU0 were being treated with at least one form of systemic immunosuppressive therapy, i.e., prednisolone, cyclosporin, and tacrolimus. The OMRS was reduced between FU0 and FU3 (p < 0.001), FU0 and FU4 (p < 0.001), and FU0 and FU5 (p = 0.004). The organ-specific severity scores were also reduced between FU0 and FU4 (p = 0.016), and FU0 and FU5 (p = 0.001). There was no significant difference in the highest Thongprasom sign score between all follow-up intervals (FU0-FU5) (p = 0.201). One patient (6.7%) at FU4 and three patients (20.0%) at FU5 did not receive topical corticosteroid therapy for oral cGVHD....(AU)

[Evaluation of differences in quality of life in patients with chronic graft-versus-host disease].

Objective: To evaluate the status of, differences in, and factors influencing quality of life (QoL) in patients with chronic graft-versus-host disease (GVHD). Methods: From September 2021 to February 2023, a cross-sectional study of 140 patients with chronic GVHD was conducted at our center. Symptom burden was assessed by the Lee Symptomatology Scale (LSS), and QoL was assessed by the Medical Outcome Study 36-Item Short-Form Health Survey (SF-36) (version 1) and five-level EuroQoL five-dimensional questionnaire (EQ-5D-5L). Results: Data from 140 respondents, including 32 (22.9%) with mild chronic GVHD, 87 (62.1%) with moderate chronic GVHD, and 21 (15.0%) with severe chronic GVHD, were analyzed. Of the respondents, 61.4% were male, and the median transplantation age was 34 (15-68) years. The primary diagnoses were acute myeloid leukemia (50.0%), acute lymphoblastic leukemia (20.0%), and myelodysplastic syndrome (15.0%). The common chronic GVHD-affected organs included the skin in 74 patients (52.9%), the eyes in 57 patients (40.7%), and the liver in 50 patients (35.7%). Among the whole cohort, the eye (20.48±23.75), psychological (16.13±17.00), and oral (13.66±20.55) scores were highest in the LSS group. The physiological function (36.07±11.13), social function (36.10±10.68), and role-emotional functioning (38.36±11.88) scores were lowest in the SF-36 group. The EQ-5D index was 0.764. The total LSS scores for mild, moderate, and severe chronic GVHD were 6.51±6.15, 10.07±5.61, and 20.90±10.09, respectively. The SF-36 physical component scores (PCSs) were 43.12±6.38, 40.73±7.14, and 36.97±6.97, respectively, and the mental component scores (MCSs) were 43.00±8.47, 38.90±9.52, and 28.96±9.63, respectively. The EQ-5D values were 0.810±0.124, 0.762±0.179, and 0.702±0.198, respectively. The multivariate analysis showed that the overall symptom burden (ß=-0.517), oral symptom burden (ß=-0.456), National Institute of Health (NIH) criteria for the eyes (ß=-0.376), and nutrition-related symptom burden (ß=-0.211) were significantly negatively correlated with the PCS. The NIH score (ß=-0.260) was negatively correlated with the MCS score. Oral symptom burden (ß=-0.400), joint/fascia NIH criteria (ß=-0.332), number of involved systems (ß=-0.253), overall NIH criteria (ß=-0.205), and number of immunosuppressants taken (ß=-0.171) were significantly negatively correlated with the EQ-5D score (all P<0.05). Medium to strong correlations were found between the EQ-5D score and the SF-36 score (|r|=0.384-0.571, P<0.001). Conclusions: The QoL of patients with chronic GVHD is impaired, and the more severe the disease, the poorer the QoL. Overall symptom burden, severity of eyes, and oral symptom burden were the most important factors affecting QoL.

Differential expression of miRNA-769-5p and Smad2 in patients with or without oral cGVHD.

BACKGROUND: Oral chronic graft-versus-host disease (cGVHD) impacts quality of life of patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, its precise pathogenesis remains unknown, with potential associations with differential microRNA (miRNA) expression and the TGF-â/Smad signaling pathway. OBJECTIVES: This study aims to explore miRNA expression profiles in the peripheral blood of oral cGVHD patients, focusing on miRNA-769-5p and its relationship with Smad2. MATERIAL AND METHODS: Peripheral venous blood samples were collected for RNA extraction from 8 patients with oral cGVHD, 8 patients without cGVHD and 8 participants from the healthy control group. The miRNA library was constructed using the Illumina Hiseq 2500 platform. We focused on identifying miRNAs associated with the TGF-â/Smad signaling pathway and subsequently conducted validation experiments. The oral cGVHD and without cGVHD groups were each expanded to include 15 individuals. Peripheral blood samples were subjected to polymerase chain reaction (PCR) analysis to assess miRNA levels and to evaluate Smad2 mRNA levels in peripheral blood mononuclear cells (PBMC). Additionally, enzyme-linked immunosorbent assay (ELISA) was conducted to determine the Smad2 protein levels in peripheral blood. RESULTS: The most significantly differentially expressed miRNAs among the 3 groups were miRNA-505-5p and miRNA-769-5p. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated an enrichment of the target genes of miRNA-769-5p in the TGF-â signaling pathway. It was observed that miRNA-769-5p expression was higher in patients without oral cGVHD in comparison to those with oral cGVHD. Receiver operating characteristic (ROC) analysis demonstrated that miRNA-769-5p holds diagnostic value for oral cGVHD. As a target of miRNA-769-5p, Smad2 mRNA exhibited a negative correlation with it. Moreover, both Smad2 mRNA and protein levels were higher in patients with oral cGVHD as opposed to those without cGVHD. CONCLUSIONS: Differential expression of miRNAs, particularly the downregulation of miRNA-769-5p, may influence the development of oral cGVHD by diminishing its inhibitory effect on the TGF-â/Smad signaling pathway through its interaction with Smad2.

Impact of Center Volume on Chronic Graft Versus Host Disease in Patients With Allogeneic Stem Cell Transplantation.

Chronic graft-versus-host disease (cGVHD) is a complication of allogeneic hematopoietic stem cell transplantation (HSCT), negatively impacting quality of life (QoL) and increasing the risk of death. Complexity in cGVHD diagnosis and treatment causes significant variations in cGVHD management strategies across medical centers and physicians despite the existence of published guidelines. Thus, we hypothesized that center volume is associated with cGVHD incidence and outcomes after cGVHD develops. This study aimed to evaluate the effect of center volume on the incidence of cGVHD in patients who underwent HSCT and outcomes in patients with cGVHD. Our retrospective study included 28,786 patients who underwent their first HSCT (overall cohort) and 7664 who developed cGVHD (cGVHD cohort). We categorized institutions into quartiles (very low, low, high, and very high) using the number of HSCTs performed during the study period. We assessed cGVHD incidence in overall cohort and overall survival (OS) in cGVHD cohort. The very high-volume group showed significantly higher cGVHD incidence (adjusted hazard ratio [HR], 1.38; 95% confidence interval [CI]: 1.30 to 1.46) compared to the very low-volume group. However, the cGVHD incidence was similar among very low-, low- and high-volume groups. Low, high, and very high-volume groups showed significantly higher OS with adjusted HRs of 0.83 (95% CI: 0.73 to 0.94), 0.69 (95% CI: 0.61 to 0.79), and 0.68 (95% CI: 0.60 to 0.76), respectively, compared with the very low-volume group. In conclusion, we revealed a higher incidence of cGVHD in the very high-volume group and a poor survival outcome in the very low-volume group in patients with cGVHD.

Chronic Graft-versus-Host Disease-Associated Muscle Cramps: Severity and Response to Immunomodulatory Therapies.

Muscle cramps in patients with chronic graft-versus-host disease (cGVHD) are common and associated with impaired quality of life and symptom burden. Muscle cramps are not currently captured in the 2014 National Institutes of Health (NIH) response criteria, and thus characterization and response to immunomodulatory therapies are lacking. The objective of this study was to characterize muscle cramp frequency, duration, and pain level in patients with steroid-refractory cGVHD undergoing extracorporeal photopheresis (ECP). A single-center cohort of patients who underwent ECP for the indication of steroid-refractory cGVHD with muscle cramps at treatment initiation were followed from April 2021 to April 2023. Of 22 patients receiving ECP for cGVHD during the study period, 9 (41%) had muscle cramps at ECP initiation (6 males [66%]; median age, 59 years; range, 25 to 66 years). Seven of these 9 patients (78%) had multiple organs involved, and 7 (78%) had severe disease by the NIH Global Severity scale. Over a median treatment duration of 28 weeks (range, 10 to 48 weeks), 8 patients (89%) had decreased frequency of muscle cramps from a median of 5 episodes per week (range, 3 per day to 2 per week) to a median of <1 episode per week (range, 1 per month to 3 per week). The pain and duration of muscle cramps were not changed meaningfully. The NIH Global Severity score remained unchanged in 6 patients (67%) and was improved in 3 patients (33%). Muscle cramping is a morbid feature of cGVHD that may be sensitive to change with standard immunomodulatory therapies. Muscle cramp frequency should be further validated as a response measure in cGVHD.