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1.
Molecular Biomarkers in Ocular Graft-versus-Host Disease: A Systematic Review
Bohlen, J., Gomez, C., Zhou, J., Martinez Guasch, F., Wandvik, C., Sunshine, S. B.
Biomolecules. 2024;14(1)
Abstract
Ocular graft-versus-host disease (oGVHD) affects ~50% of post-stem cell transplant patients and is the only form of GVHD diagnosed without a biopsy. As it must be distinguished from other dry eye diseases, there is a need to identify oGVHD biomarkers to improve diagnosis and treatment. We conducted a systematic review of 19 scholarly articles published from 2018 to 2023 including articles focused on adult patients diagnosed with oGVHD following allogeneic hematopoietic stem cell transplant and used biomarkers as the outcome measure. Articles that were not original investigations or were not published in English were excluded. These clinical investigations explored different molecular oGVHD biomarkers and were identified on 3 October 2023 from the Scopus, PubMed, and Embase databases by using search terms including ocular graft-versus-host disease, biomarkers, cytokines, proteomics, genomics, immune response, imaging techniques, and dry-eye-related key terms. The Newcastle-Ottawa scale for case-control studies was used to assess bias. From the 19 articles included, cytokine, proteomic, lipid, and leukocyte profiles were studied in tear film, as well as ocular surface microbiota and fluorescein staining. Our findings suggest that cytokine profiling is the most studied oGVHD biomarker. Additionally, variations correlating these biomarkers with disease state may lead to a more targeted diagnosis and therapeutic approach. Limitations include language bias, publication bias, and sampling bias, as well as a lack of appropriate controls for included studies.
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2.
A genome-wide association study on hematopoietic stem cell transplantation reveals novel genomic loci associated with transplant outcomes
Rosenberger, A., Crossland, R. E., Dressel, R., Kube, D., Wolff, D., Wulf, G., Bickeböller, H., Dickinson, A., Holler, E.
Frontiers in immunology. 2024;15:1280876
Abstract
INTRODUCTION Data on genomic susceptibility for adverse outcomes after hematopoietic stem cell transplantation (HSCT) for recipients are scarce. METHODS We performed a genome wide association study (GWAS) to identify genes associated with survival/mortality, relapse, and severe graft-versus-host disease (sGvHD), fitting proportional hazard and subdistributional models to data of n=1,392 recipients of European ancestry from three centres. RESULTS The single nucleotide polymorphism (SNP) rs17154454, intronic to the neuronal growth guidant semaphorin 3C gene (SEMA3C), was genome-wide significantly associated with event-free survival (p=7.0x10(-8)) and sGvHD (p=7.5x10(-8)). Further associations were detected for SNPs in the Paxillin gene (PXN) with death without prior relapse or sGvHD, as well as for SNPs of the Plasmacytoma Variant Translocation 1 gene (PVT1, a long non-coding RNA gene), the Melanocortin 5 Receptor (MC5R) gene and the WW Domain Containing Oxidoreductase gene (WWOX), all associated with the occurrence of sGvHD. Functional considerations support the observed associations. DISCUSSION Thus, new genes were identified, potentially influencing the outcome of HSCT.
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3.
Diagnostic and prognostic role of elafin in skin acute graft versus host disease: a systematic review
Bhattarai, A., Shah, S., Yadav, R., Dhakal, G., Neupane, R., Paudel, S., Bhandari, P., Abu Serhan, H., Sah, R., Sah, S., et al
Hematology (Amsterdam, Netherlands). 2024;29(1):2293497
Abstract
BACKGROUND AND OBJECTIVE Graft versus host disease (GVHD) is the common complication seen after allogeneic hematopoietic stem cell transplantation (HSCT) and a pleomorphic syndrome that resembles autoimmune and other immunologic disorders, leading to profound immune dysregulation and organ dysfunction. The most common targets of GVHD are skin, gastrointestinal tract and liver. GVHD is classified as acute graft versus host disease (aGvHD) if it occurs within the first 100 days after HSCT and chronic graft versus host disease(cGVHD) if it occurs after day 100. The skin is most frequently and earliest affected by aGvHD, followed by the gastrointestinal tract and liver. An ideal biomarker would predict the onset and severity of clinical acute GVHD and help to direct management, and this is an area of active research regarding the use of biomarkers for diagnosis and prognosis of acute GVHD. Recently, elafin has been identified as a potential plasma biomarker for aGVHD. METHOD We searched the databases PubMed, Cochrane library, and medRxiv for all studies investigating the Diagnostic or prognostic role of elafin in GVHD. We set the search strategy incorporating the search terms, 'elafin', 'graft versus host', and 'GVHD', and operated using the Boolean operators 'AND', and 'OR'. Thus, retrieved articles were then exported on an Excel® sheet, and duplicates were removed. The systematic review was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. After selecting the study based on inclusion criteria, data on study characteristics and biomarker description was extracted on a pre-determined data extraction table on the Microsoft Excel version. The quality assessment of the included studies was determined using the QUIPS tool. RESULT The search revealed 547 studies and 6 studies that met the eligibility criteria of this review have been included. The major finding of our study is the significant elevation of elafin in skin aGVHD. CONCLUSION Elafin is a significant biomarker for diagnosis and prognosis of skin aGVHD and should be assessed within 2 weeks of the onset of the disease.
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4.
Can Cytokine Detection Predict the Occurrence and Outcome of aGVHD after Allo-HCT? A Retrospective Study
Gao, Q., Zhang, W., Zhang, D., Hao, Q., An, Y., Liang, G.
Discovery medicine. 2023;35(176):242-250
Abstract
BACKGROUND Many cytokines play essential roles in the occurrence and development of acute graft-versus-host-disease (aGVHD). This study aims to validate whether 11 proinflammatory and anti-inflammatory cytokines can be a candidate for aGVHD biomarkers to predict its occurrence and outcome. METHODS Out of 178 patients who underwent allogeneic hematopoietic stem cell transplantation, we retrospectively enrolled 32 cases into the pre-transplant cohort and 45 cases into the post-transplant cohort. The serum cytokine concentrations were determined by flow cytometry. The control and experimental groups were non-aGVHD, I-II aGVHD and III-IV aGVHD groups, respectively. Risk factors and overall survival (OS) were also evaluated. RESULTS In the pre-transplant cohort, interleukin (IL)-2 decreased in patients with aGVHD, and IL-4 only reduced in patients with III-IV aGVHD. In the post-transplant cohort, only IL-4 increased 1.79 times more in patients with III-IV aGVHD than in the other two groups. Patients with gastrointestinal (GI) aGVHD had lower IL-2, IL-4 and IL-17F levels pre-transplant and lower IL-2 post-transplant. None of the other cytokines was significantly different. Logistic regression analysis showed that no cytokine could predict the occurrence and outcome of aGVHD. Diarrhea within 15 days post-transplant is an independent risk factor for the occurrence of aGVHD and a risk factor for a fatal outcome. Patients without diarrhea had longer survival time of 672 (586-757) days vs 444 (229-548) days and better 2-year OS (85.7% vs 46.4%) than those with diarrhea. Compared to patients with aGVHD, patients without aGVHD had a longer survival time of 618 (530-706) days vs 449 (353-545) days and better 2-year OS (76.2% vs 47.1%). CONCLUSIONS Proinflammatory and anti-inflammatory cytokines can provide specific indications for the occurrence and progression of aGVHD. However, to truly guide the diagnosis and prognosis, cytokines with larger sample sizes, more detection time points and more accurate diagnostic efficacy need to be further studied.
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5.
miR-155 and miR-92 levels in ALL, post-transplant aGVHD, and CMV: possible new treatment options
Saadi, M. I., Nikandish, M., Ghahramani, Z., Valandani, F. M., Ahmadyan, M., Hosseini, F., Rahimian, Z., Jalali, H., Tavasolian, F., Abdolyousefi, E. N., et al
Journal of the Egyptian National Cancer Institute. 2023;35(1):18
Abstract
BACKGROUND Acute lymphoblastic leukemia (ALL) is a malignancy that leads to altered blast cell proliferation, survival, and maturation and eventually to the lethal accumulation of leukemic cells. Recently, dysregulated expression of various micro-RNAs (miRNAs) has been reported in hematologic malignancies, especially ALL. Cytomegalovirus infection can induce ALL in otherwise healthy individuals, so a more detailed evaluation of its role in ALL-endemic areas like Iran is required. METHODS In this cross-sectional study, 70 newly diagnosed adults with ALL were recruited. The expression level of microRNA-155(miR-155) and microRNA-92(miR-92) was evaluated by real-time SYBR Green PCR. The correlations between the miRNAs mentioned above and the severity of disease, CMV infection, and acute graft vs. host disease after hematopoietic stem cell transplantation (HSCT) were assessed. B cell and T cell ALL distinction in the level of miRNAs was provided. RESULTS After the statistical analysis, our results indicated a marked increase in the expression of miR-155 and miR-92 in ALL patients vs. healthy controls (*P = 0.002-*P = 0.03, respectively). Also, it was shown that the expression of miR-155 and miR-92 was higher in T cell ALL compared to B cell ALL (P = 0.01-P = 0.004, respectively), CMV seropositivity, and aGVHD. CONCLUSION Our study suggests that the plasma signature of microRNA expression may act as a powerful marker for diagnosis and prognosis, providing knowledge outside cytogenetics. Elevation of miR-155 in plasma can be a beneficial therapeutic target for ALL patients, with consideration of higher plasma levels of miR-92 and miR-155 in CMV + and post-HSCT aGVHD patients.
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6.
A Pilot Trial of Patient-Reported Outcomes for Acute Graft-Versus-Host-Disease
Patel, S. S., Hong, S., Rybicki, L., Farlow, S., Dabney, J., Kalaycio, M., Sobecks, R., Majhail, N. S., Hamilton, B. K.
Transplantation and cellular therapy. 2023
Abstract
BACKGROUND Acute graft-versus-host disease (GVHD) is a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). Acute GVHD is associated with severe physical and psychosocial symptoms. OBJECTIVES We sought to evaluate the feasibility of capturing patient-reported outcome (PRO) measures in acute GVHD to better measure symptom burden and quality of life (QOL). STUDY DESIGN We conducted a pilot study of adult patients undergoing first allogeneic HCT. Questions from FACT-BMT, PROMIS-10, and PRO-CTCAE were selected, and the survey was administered electronically pre-HCT, at days 14, 50, and 100 post-HCT. In addition, patients who developed grade 2-4 acute GVHD received it weekly for four weeks and then monthly up to 3 months. RESULTS From 2018 to 2020, 73 patients were consented, of which 66 went on to receive HCT and were included in the analysis. Median age at transplant was 63 years, and 92% were Caucasian. Only 47% of expected surveys were completed (range 0-67% for each time point). Descriptive exploratory analysis demonstrate an expected trajectory of QOL using the FACT-BMT and PROMIS-10 scores throughout transplant. Patients who developed acute GVHD (N=15) generally had lower QOL scores compared to those with no or mild GVHD post-HCT. The PRO-CTCAE captured several physical and mental/emotional symptoms in all patients and those with GVHD. Fatigue (100%), decreased appetite (92%), problem tasting (85%), loose stools (77%), pain (77%), skin itching (77%) and depression (feeling sad) (69%) were the most prevalent symptoms among patients with grade 2-4 acute GVHD. Patients with acute GVHD generally reported worse symptoms than those with no/mild GVHD in frequency, severity, and interference in normal activities. Several challenges were identified including poor access/literacy of electronic surveys, acute illness, and need for extensive research/resource support. CONCLUSIONS We demonstrate the challenges yet potential of using PRO measures in acute GVHD. We demonstrate that the PROMIS-10 and PRO-CTCAE measures are able to capture several symptoms and QOL domains of acute GVHD. Further investigation into making PROs feasible in acute GVHD are needed.
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7.
Ikaros expression is associated with an increased risk of chronic graft-versus-host disease
Pereira, A. D., de Molla, V. C., Fonseca, Arbm, Tucunduva, L., Novis, Y., Pires, M. S., Popi, A. F., Arrais-Rodrigues, C. A.
Scientific reports. 2023;13(1):8458
Abstract
Immune reconstitution after hematopoietic stem cell transplantation (HSCT) is a complex and extremely variable process. The Ikaros transcription factor plays an important role in hematopoiesis in several cell lines, especially in the lymphoid lineage. We hypothesized that Ikaros might influence immune reconstitution, and consequently, the risk of opportunistic infections, relapse, and graft versus host disease (GVHD). Samples were collected from the graft and from the peripheral blood (PB) of the recipients 3 weeks after neutrophil recovery. Real-time polymerase chain reaction (RT-PCR) was performed to analyze the absolute and relative Ikaros expression. Patients were divided into two groups, according to Ikaros expression in the graft and in the recipients' PB based on the ROC curves for moderate/severe cGVHD. A cutoff of 1.48 was used for Ikaros expression in the graft, and a cutoff of 0.79 was used for Ikaros expression in the recipients' PB. Sixty-six patients were included in this study. Median age of patients was 52 years (range 16-80 years), 55% of them were male, and 58% of them had acute leukemia. Median follow-up period was 18 months (range 10-43 months). There was no association between Ikaros expression and the risk of acute GVHD, relapse, or mortality. However, a significant association was observed with the risk of chronic GVHD. Higher Ikaros expression in the graft was associated with a significantly higher cumulative incidence (CI) of moderate/severe chronic GVHD according to the National Institute of Health (NIH) classification at two years (54% vs. 15% for patients with lower expression, P = 0.03). A higher Ikaros expression in the recipients' PB 3 weeks after engraftment was also associated with a significantly higher risk of moderate/severe chronic GVHD (65% vs. 11%, respectively, P = 0.005). In conclusion, Ikaros expression in the graft and in the recipients' PB after transplantation was associated with a higher risk of moderate/severe chronic GVHD. Ikaros expression should be evaluated in larger prospective trials as a potential biomarker for chronic GVHD.
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8.
Longitudinal dynamics of gut microbiota in the pathogenesis of acute graft-versus-host disease
Qi, L., Peng, J., Huang, X., Zhou, T., Tan, G., Li, F.
Cancer medicine. 2023
Abstract
AIM: The gut microbiota has been reported to be associated with acute graft-versus-host disease (aGvHD) in hematopoietic stem cell transplantation (HSCT). Dynamic surveillance of the microbiota is required to understand the detailed pathogenesis involved in the process of aGvHD. METHODS Fecal samples were collected prospectively at four timepoints, including pre-HSCT (T1), graft infusion (T2), neutrophil engraftment (T3), and 30 days after transplantation (T4). Fecal samples were profiled by 16S ribosomal RNA gene sequencing to assess the microbiota composition. RESULTS From the T1 to T4 timepoint, the diversity of the gut microbiota decreased, and the dominant species also changed, with a decrease in the obligate anaerobic bacteria and a shift toward a "pathogenic community". Compared with non-aGvHD patients, aGvHD patients had a lower abundance of Roseburia at T1 and a higher abundance of Acinetobacter johnsonii at T2. Furthermore, Acinetobacter johnsonii was negatively correlated with the secretion of IL-4 and TNF-α. At T3, Rothia mucilaginos was demonstrated to be linked with a decreased risk of aGvHD, which was accompanied by decreased secretion of IL-8. At T4, higher abundances of Lactobacillus paracasei and Acinetobacter johnsonii were identified to be related with aGvHD. Lactobacillus paracasei was associated with the downregulation of IL-10, and Acinetobacter johnsonii was associated with the downregulation of IL-2 and TNF-α. CONCLUSIONS Dynamic changes in gut microbiota composition and related cytokines were found to be related to aGvHD, including pathogenic or protective changes. These findings suggested that manipulation of gut microbiota at different timepoints might be a promising avenue for preventing or treating this common complication.
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9.
The macrophage activation marker sCD163 in acute and chronic graft-versus-host disease after pediatric hematopoietic stem cell transplantation
Hergel, L. L. F., Kielsen, K., Weischendorff, S., Ifversen, M., Kamari-Kany, N., Møller, H. J., Rittig, S., Grønbæk, H., Müller, K.
Bone marrow transplantation. 2023
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10.
Chronic GVHD after steroid-sensitive, -dependent, and -refractory acute GVHD: incidence and clinical outcomes
Herzog, S., Weisdorf, D. J., Shanley, R., Rayes, A., Holtan, S. G., Young, J. A., MacMillan, M. L., El Jurdi, N.
Blood advances. 2023
Abstract
Chronic graft-versus-host disease (cGVHD) is a major limitation to the long-term success of allogeneic hematopoietic cell transplant (HCT). Our prior study of acute graft-versus-host disease (aGVHD) defined distinct treatment-response groups based on response to first-line corticosteroids: steroid-sensitive (SS), steroid-resistant (SR), and steroid-dependent (SD) aGVHD. We conducted a retrospective, single-institution, cohort study to assess the incidence, risk factors, and clinical outcomes of patients with cGVHD after a previous diagnosis of SS, SD, or SR aGVHD compared to those with no history of aGVHD. Among 784 consecutive adult and pediatric HCT recipients for hematologic malignancies between 2008 and 2016, 347 (44%) developed aGVHD with 13% SS, 12% SD, and 19% SR aGVHD. 3-year cumulative incidence of cGVHD was 25%. Among those with cGVHD, 39% had no prior aGVHD diagnosis, while those with a prior aGVHD diagnosis, 16% had SS, 24% had SD, and 21% had SR aGVHD. Mild or moderate cGVHD was highest among those with preceding SD aGVHD, while severe cGVHD was most frequent among those with previous SR aGVHD. We identified SD acute GVHD and SR acute GVHD as independent significant risk factors for development of chronic GVHD after allogeneic HCT, whereas SS acute GVHD is not a risk factor. Our study demonstrates that cGVHD after SD aGVHD did not have an intermediate prognosis between SR and SS groups as hypothesized, rather chronic GVHD following both SD and SR acute GVHD have similar prognosis. Our findings suggest that previous aGVHD response states are important predictors of cGVHD severity and outcomes.