| 1. |
- Berglund, Sofia, et al.
(författare)
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Granulocyte transfusions could benefit patients with severe oral mucositis after allogeneic hematopoietic stem cell transplantation
- 2019
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Ingår i: Vox Sanguinis. - : Wiley-Blackwell. - 0042-9007 .- 1423-0410. ; 114:7, s. 769-777
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Tidskriftsartikel (refereegranskat)abstract
- Background and objectives Mucositis is a common complication after allogeneic hematopoietic stem cell transplantation (HSCT), and is caused by a combination of conditioning-induced mucosal damage and severe neutropenia. The symptoms include oral and abdominal pain, inability to swallow food and fluids, and severe diarrhoea. Severe mucositis is associated with increased risk of Graft-versus-Host disease and infection. Granulocyte transfusions (GCX) could be a treatment option, and our objective was to study its feasibility and potential benefits. Material and methods This retrospective, single-centre study included 30 patients receiving GCX because of severe oral mucositis after HSCT during 2005-2017. Clinical outcome, response to GCX, change in opiate administration and adverse events were studied. Results Twenty-seven patients received GCX from donors pre-treated with steroids and G-CSF, and three from donors pre-treated with steroids only. Overall response was 83% (24/29 evaluable patients). Fifteen patients reached a complete response. In 14 of 24 responders, a reduction of the administration of opiate pain relief was seen. In eight patients this reduction was >= 50% of the dose. Adverse events (AEs) were reported in 14 cases, and were mild to moderate, and well manageable with symptomatic treatment. No life-threatening or fatal AEs were recorded. Conclusions These results indicate that GCX could be a safe and effective treatment for oral mucositis after HSCT with the potential to reduce the necessity of opiate analgesic treatment in this disorder. No severe AEs were seen in this study, but the risk for severe pulmonary AEs after GCX needs to be considered.
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| 2. |
- Garming Legert, Karin
(författare)
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Conditioning associated effects on oral mucosa and salivary function in allogeneic stem cell recipients
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Allogeneic hematopoietic stem cell transplantation (HSCT) is an effective treatment for patients with a range of disorders of the immunohematopoietic system. In HSCT recipients, acute complications in the oral cavity are common. They are related to the disease itself, its treatment, the pre-transplant status of the oral cavity, and nutritional problems during the neutropenic phase. As the results of treatment improve and survival rates increase, not only cure of the disease but also a variety of delayed side effects become apparent that make the compromised patient require special oral care. In order to improve the patient’s quality of life, this problem must be solved. The aim of this thesis was to investigate conditioning related effects on salivary function and on the oral mucosa, and also the impact of other risk factors for salivary dysfunction and oral mucositis in allogeneic HSCT recipients. In patients conditioned with fractionated total body irradiation (fTBI) or single-dose total body irradiation (sTBI), we found that fTBI resulted in less reduction of salivary secretion rate one year after HSCT than sTBI, despite the higher total dose of radiation. In addition, we found that risk factors for a low stimulated salivary secretion rate (SSSR) one year after HSCT were sTBI and seropositivity of recipients for 3–4 herpes viruses. A cumulative increase in risk factors resulted in less salivary output. We found no difference in long-term salivary function after HSCT in 15-year olds who received conditioning with sTBI, fTBI, or busulfan (Bu). There was a negative correlation between age at conditioning with sTBI and salivary function. This correlation was not seen using fTBI or Bu. We also found a negative correlation between total systemic exposure to Bu and the SSSR. Female sex was a risk factor for salivary dysfunction at 15 years of age after HSCT. Comparing myeloablative conditioning (MAC) to reduced intensity conditioning (RIC), we found that MAC was associated with a higher prevalence of oral mucositis (OM). Severe OM prolonged hospitalization. The introduction of a new intensive oral hygiene protocol was associated with lower OM score and the two scoring systems used for grading of OM showed good correlation.We also identified several risk factors for OM. In multivariate analysis, all donor-recipient gender combinations except the female-donor-male-recipient situation and year of transplantation—especially before the year 2011 when oral care was intensified—was significantly associated with a higher OM score. In HSCT recipients, we found no difference in volume of gingival crevicular fluid (GCF) before, during, or after HSCT. When monitoring pro-inflammatory cytokines, we observed that cytokines are activated in the GCF. Patients conditioned with MAC or RIC had different patterns of pro-inflammatory cytokines, both in GCF and serum. There was a correlation between oral mucositis and an increase in IL-6 in the serum. Finally, we found no correlations between GCF and serum levels of cytokines at any time point. In conclusion, both acute and long-term oral side effects are common after allogeneic HSCT. There is a lack of comprehensive and effective oral management regimens. By developing evidence-based recommendations that might improve the appropriateness of clinical practice, the acute oral complications might be reduced, patient outcomes would be better, and cost-effectiveness and quality of life would improve. Our findings also suggest that it is necessary to have long-term follow-up after allogeneic stem cell transplantation because some children will have permanently reduced salivary function. These people may require additional preventive measures throughout their lives in order to maintain proper oral health.
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| 3. |
- Garming-Legert, Karin, et al.
(författare)
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Oral mucositis after tacrolimus/sirolimus or cyclosporine/methotrexate as graft-versus-host disease prophylaxis
- 2020
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Ingår i: Oral Diseases. - : Wiley. - 1354-523X .- 1601-0825. ; 27:5, s. 1217-1225
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: To determine whether treatment with tacrolimus plus sirolimus (Tac/Sir) as a prophylaxis for graft-versus-host disease worsens severe oral mucositis and delays healing compared to cyclosporine plus methotrexate (CsA/Mtx) following haematopoietic stem cell transplantation.Subjects and methods: The study comprised 141 patients: 73 randomized to receive Tac/Sir and 68 to receive CsA/Mtx. The oral mucositis assessment scale and toxicity grading according to WHO were used to assess the severity, peak and duration of oral mucositis from the day -3 to day 24 post-transplant.Results: Eighty-seven patients developed oral mucositis in the first 24 days post-transplant. No significant difference in oral mucositis severity between the Tac/Sir and CsA/Mtx groups was observed. The peak oral mucositis score occurred on day 10 in both groups. Although oral mucositis scores had returned to baseline in the CsA/Mtx group on day 24 post-transplant, no significant difference compared with the Tac/Sir group was found.Conclusions: The introduction of tacrolimus/sirolimus as a graft-versus-host disease prophylaxis in haematopoietic stem cell transplantation increased neither the incidence nor severity of oral mucositis compared with cyclosporine/methotrexate. Furthermore, oral mucositis healing was not prolonged and followed the same time pattern as cyclosporine/methotrexate.
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| 4. |
- Mougeot, Jean-Luc C., et al.
(författare)
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Identification of single nucleotide polymorphisms (SNPs) associated with chronic graft-versus-host disease in patients undergoing allogeneic hematopoietic cell transplantation
- 2023
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Ingår i: SUPPORTIVE CARE IN CANCER. - 0941-4355 .- 1433-7339. ; 31:10
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Tidskriftsartikel (refereegranskat)abstract
- Introduction Chronic graft-versus-host disease (cGVHD) is a debilitating side effect of allogeneic hematopoietic cell transplantation (HCT), affecting the quality of life of patients. We used whole exome sequencing to identify candidate SNPs and complete a multi-marker gene-level analysis using a cohort of cGVHD( +) (N = 16) and cGVHD( -) (N = 66) HCT patients.Methods Saliva samples were collected from HCT patients (N = 82) pre-conditioning in a multi-center study from March 2011 to May 2018. Exome sequencing was performed and FASTQ files were processed for sequence alignments. Significant SNPs were identified by logistic regression using PLINK2(v3.7) and Fisher's exact test. One cGVHD( -) patient sample was excluded from further analysis since no SNP was present in at least 10% of the sample population. The FUMA platform's SNP2GENE was utilized to annotate SNPs and generate a MAGMA output. Chromatin state visualization of lead SNPs was completed using Epilogos tool. FUMA's GENE2FUNC was used to obtain gene function and tissue expression from lead genomic loci.Results Logistic regression classified 986 SNPs associated with cGVHD( +). SNP2GENE returned three genomic risk loci, four lead SNPs, 48 candidate SNPs, seven candidate GWAS tagged SNPs, and four mapped genes. Fisher's exact test identified significant homozygous genotypes of four lead SNPs (p < 0.05). GENE2FUNC analysis of multi-marker SNP sets identified one positional gene set including lead SNPs for KANK1 and KDM4C and two curated gene sets including lead SNPs for PTPRD, KDM4C, and/or KANK1.Conclusions Our data suggest that SNPs in three genes located on chromosome 9 confer genetic susceptibility to cGVHD in HCT patients. These genes modulate STAT3 expression and phosphorylation in cancer pathogenesis. The findings may have implications in the modulation of pathways currently targeted by JAK inhibitors in cGVHD clinical trials.
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| 5. |
- Mougeot, Jean-Luc C., et al.
(författare)
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Single nucleotide polymorphisms conferring susceptibility to leukemia and oral mucositis: a multi-center pilot study of patients prior to conditioning therapy for hematopoietic cell transplant
- 2024
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Ingår i: SUPPORTIVE CARE IN CANCER. - 0941-4355 .- 1433-7339. ; 32:4
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Tidskriftsartikel (refereegranskat)abstract
- PurposeLeukemias have been associated with oral manifestations, reflecting susceptibility to cancer therapy-induced oral mucositis. We sought to identify SNPs associated with both leukemia and oral mucositis (OM).MethodsWhole exome sequencing was performed on leukemia and non-cancer blood disorder (ncBD) patients' saliva samples (N = 50) prior to conditioning therapy. WHO OM grading scores were determined: moderate to severe (OM2-4) vs. none to mild (OM0-1). Reads were processed using Trim Galorev0.6.7, Bowtie2v2.4.1, Samtoolsv1.10, Genome Analysis Toolkit (GATK)v4.2.6.1, and DeepVariantv1.4.0. We utilized the following pipelines: P1 analysis with PLINK2v3.7, SNP2GENEv1.4.1 and MAGMAv1.07b, and P2 [leukemia (N = 42) vs. ncBDs (N = 8)] and P3 [leukemia + OM2-4 (N = 18) vs. leukemia + OM0-1 (N = 24)] with Z-tests of genotypes and protein-protein interaction determination. GeneCardsSuitev5.14 was used to identify phenotypes (P1 and P2, leukemia; P3, oral mucositis) and average disease-causing likelihood and DGIdb for drug interactions. P1 and P2 genes were analyzed with CytoScape plugin BiNGOv3.0.3 to retrieve overrepresented Gene Ontology (GO) terms and Ensembl's VEP for SNP outcomes.ResultsIn P1, 457 candidate SNPs (28 genes) were identified and 21,604 SNPs (1016 genes) by MAGMAv1.07b. Eighteen genes were associated with "leukemia" per VarElectv5.14 analysis and predicted to be deleterious. In P2 and P3, 353 and 174 SNPs were significant, respectively. STRINGv12.0 returned 77 and 32 genes (C.L. = 0.7) for P2 and P3, respectively. VarElectv5.14 determined 60 genes from P2 associated with "leukemia" and 11 with "oral mucositis" from P3. Overrepresented GO terms included "cellular process," "signaling," "hemopoiesis," and "regulation of immune response."ConclusionsWe identified candidate SNPs possibly conferring susceptibility to develop leukemia and oral mucositis.
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| 6. |
- Remberger, Mats, et al.
(författare)
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Improved survival after allogeneic hematopoietic stem cell transplantation in recent years : A single-center study
- 2011
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Ingår i: Biology of blood and marrow transplantation. - : Elsevier BV. - 1083-8791 .- 1523-6536. ; 17:11, s. 1688-1697
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Tidskriftsartikel (refereegranskat)abstract
- We analyzed the outcome of allogeneic hematopoietic stem cell transplantation (HSCT) over the past 2 decades. Between 1992 and 2009, 953 patients were treated with HSCT, mainly for a hematologic malignancy. They were divided according to 4 different time periods of treatment: 1992 to 1995, 1996 to 2000, 2001 to 2005, and 2006 to 2009. Over the years, many factors have changed considerably regarding patient age, diagnosis, disease stage, type of donor, stem cell source, genomic HLA typing, cell dose, type of conditioning, treatment of infections, use of granulocyte-colony stimulating factor (G-CSF), use of mesenchymal stem cells, use of cytotoxic T cells, and home care. When we compared the last period (2006-2009) with earlier periods, we found slower neutrophil engraftment, a higher incidence of acute graft-versus-host disease (aGVHD) of grades II-IV, and less chronic GVHD (cGHVD). The incidence of relapse was unchanged over the 4 periods (22%-25%). Overall survival (OS) and transplant-related mortality (TRM) improved significantly in the more recent periods, with the best results during the last period (2006-2009) and a 100-day TRM of 5.5%. This improvement was also apparent in a multivariate analysis. When correcting for differences between the 4 groups, the hazard ratio for mortality in the last period was 0.59 (95% confidence interval [CI]: 0.44-0.79; P < .001) and for TRM it was 0.63 (CI: 0.43-0.92; P = .02). This study shows that the combined efforts to improve outcome after HSCT have been very effective. Even though we now treat older patients with more advanced disease and use more alternative HLA nonidentical donors, OS and TRM have improved. The problem of relapse still has to be remedied. Thus, several different developments together have resulted in significantly lower TRM and improved survival after HSCT over the last few years.
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| 7. |
- Tollemar, Victor, et al.
(författare)
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Histopathological Grading of Oral Mucosal Chronic Graft-versus-Host Disease : Large Cohort Analysis
- 2020
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Ingår i: Biology of blood and marrow transplantation. - : Elsevier. - 1083-8791 .- 1523-6536. ; 26:10, s. 1971-1979
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Tidskriftsartikel (refereegranskat)abstract
- Graft-versus-host disease (GVHD) can manifest as acute or chronic complications in patients after hematopoietic cell transplantation (HCT). Oral chronic GVHD (cGVHD) occurs in approximately 70% of HCT recipients and includes lichenoid-like mucosal reactions, restricted mouth opening, and salivary gland dysfunction. However, the underlying histopathological presentation remains to be validated in large cohorts. We characterized the histopathological features of oral mucosal cGVHD and devised a scoring model in a large patient cohort (n = 112). Oral mucosal biopsy sections (n = 303) with and without oral cGVHD were identified from archived and current HCT recipients with additional healthy controls. Histological screening was performed on hematoxylin and eosin-stained and periodic acid-Schiff-stained sections. A points-based grading tool (0 to 19, grade 0 to IV) was established based on intraepithelial lymphocytes and band-like inflammatory infiltrate, atrophic epithelium with basal cell liquefaction degeneration, including apoptosis, as well as separation of epithelium and pseudo-rete ridges. Validation involved 62 biopsy specimens, including post-HCT (n = 47) and healthy (n = 15) specimens. Remaining biopsy specimens (n = 199) were blindly graded by 3 observers. Histological severity was correlated with clinical diagnostic and distinctive features, demonstrating a spectrum of individual patient severity, including frequent signs of subclinical GVHD in healthy mucosa. However, oral cGVHD presented with significantly higher (P < .001) scores compared with HCT controls, with moderate to high positive likelihood ratios for inflammatory infiltrate, exocytosis, and basal membrane alterations. The grade II-IV biopsy specimens demonstrated a histopathological diagnosis of active mucosal lichenoid-like cGVHD, highlighting the importance of correlating clinical presentation with the dynamic histopathological processes for improved patient stratification. In addition, this tool could be used for assessing treatments, pathological processes, and immune cellular content to provide further insight into this debilitating disease.
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| 8. |
- Tollemar, Victor, et al.
(författare)
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Immunohistopathology of oral mucosal chronic graft-versus-host disease severity and duration
- 2023
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Ingår i: Oral Diseases. - : John Wiley & Sons. - 1354-523X .- 1601-0825. ; 29:8, s. 3346-3359
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Tidskriftsartikel (refereegranskat)abstract
- Objective Chronic graft-versus-host disease (cGVHD) is the main cause of late non-relapse mortality following hematopoietic cell transplantation. Oral mucosal (om-) cGVHD is common, but diagnosis and assessment rely on clinical interpretation and patient-reported symptoms. We investigated immunohistopathological profiles with respect to om-cGVHD severity disease duration. Material and methods Ninety-four transplant patients and 15 healthy controls (n = 212 biopsies) were investigated by quantitative immunohistochemistry for T cells (CD4, CD8, and CD5), B cells (CD19 and CD20), macrophages (CD68), and Langerhans cells (CD1a). Results We found significant increases in T (CD4, CD8) and monocytic (CD68) cells in om-cGVHD, and a notable absence of B (CD19 and CD20) cells. Histopathological activity correlated with increased CD4, CD8 and CD68. However, CD4 was associated with mild om-cGVHD, whereas CD8 and CD68 were found to be elevated in severe om-cGVHD. CD8 and CD68 levels were raised at disease onset, but during late phase, the predominant CD68 population was accompanied by CD4. Conclusion Oral cGVHD is a heterogenous clinical disorder, but our knowledge of the underlying biology remains limited. We highlight the importance of CD4, CD8 and CD68 immune profiling, together with histological grading for the staging of oral cGVHD, to broaden our understanding of the biology and individual disease course.
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| 9. |
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