scholarly journals The Association of Combined GSTM1 and CYP2C9 Genotype Status with the Occurrence of Hemorrhagic Cystitis in Pediatric Patients Receiving Myeloablative Conditioning Regimen Prior to Allogeneic Hematopoietic Stem Cell Transplantation

2017 ◽  
Vol 8 ◽  
Author(s):  
Chakradhara Rao S. Uppugunduri ◽  
Flavia Storelli ◽  
Vid Mlakar ◽  
Patricia Huezo-Diaz Curtis ◽  
Aziz Rezgui ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Pediatric Patients ◽  
Hemorrhagic Cystitis ◽  
Conditioning Regimen ◽  
Myeloablative Conditioning ◽  
Hematopoietic Stem ◽  
Cyp2c9 Genotype

Sulfolane (a metabolite of busulfan) Levels Could Predict Occurrence Of Hemorrhagic Cystitis In Children Receiving Busulfan Based Myeloablative Conditioning Before Hematopoietic Stem Cell Transplantation

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4574-4574
Author(s):  
Chakradhara Rao S Uppugunduri ◽  
Mohamed Aziz Rezgui ◽  
Yves Theoret ◽  
Patricia Huezo Diaz ◽  
Anuj Kumar Tyagi ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Hemorrhagic Cystitis ◽  
Conditioning Regimen ◽  
Myeloablative Conditioning ◽  
Hematopoietic Stem ◽  
Post Transplant

Background One of the complications of myeloablative conditioning regimen with busulfan (BU) and cyclophosphamide (CY) in children undergoing hematopoietic stem cell transplantation (HSCT) is the occurrence of hemorrhagic cystitis (HC). Pathophysiology of HC involves multiple factors, such as damage to the bladder's transitional epithelium and the endothelium of blood vessels by BU, CY and their metabolites, viruses, bacterial infections, or other disease processes. It is well established fact that damage to the urothelium is the initial step during pathogenesis of HC. Though it is known about acrolein (metabolite of CY) contribution to HC development, the role of BU or its metabolites is not yet known completely. We recently developed an analytical method for sulfolane (Su) quantification, a water soluble metabolite of BU. Using this method we explored the relation of Su levels in plasma with HC before day 30 post-transplant, in 39 children (20 females, 19 males) receiving BU-CY conditioning prior to HSCT. Methods Hospital ethics committee approved the study, and all patients or their parents have signed the informed consent. Out of 39 patients 16 were diagnosed with nonmalignant disease. BU was administered in 16 dose infusions, with each infusion lasting two hours for every six hours. Bone marrow and cord blood were graft sources in 18 and 21 patients, respectively. Twenty patients had HLA–matched donor. HC was defined as the presence of hematuria (both microscopic and macroscopic) for more than a week from the initiation of the conditioning regimen up to 30 days post-transplant. All patients received MESNA as prophylaxis for HC. Plasma from patients collected before dose 7 and after dose 9 infusions of BU was used for measuring Su levels using gas-chromatography. Plasma levels of Su adjusted to cumulative BU dose up to Su level measurements (upto dose 6 for before dose 7 levels, upto dose 9 for after dose 9 levels) in mg/kg were used in the analysis. Mann-Whitney U test was used to analyze the relation of Su levels (ng/mL//mg/kg) and HC. A receiver–operator characteristic curve (ROC) for Su levels was plotted to show the trade-off in sensitivity versus 1- specificity rates for HC, as the cut-off of the test was shifted from low to high. Two sided p values were represented and probability at 0.05 was considered as statistically significant. Cumulative incidences of HC were estimated using Kaplan-Meier curves and log-rank test was used to compare the difference between groups divided based on cutoff defined in ROC curves, in univariate analysis. Univariate cox-regression was used to estimate hazard ratios with 95% confidence intervals. Results The overall cumulative incidence of HC was 20.5 %. We observed higher Su levels before dose 7 (mean±SD; 48.3±11.2 vs. 35.1±15.3 – p=0.02) and after dose 9 (40.5±9.6 vs. 30.9±14.4 – p=0.03) in patients diagnosed with early HC (n=8) compared to those with no HC (n=31-Figure 1A, Figure 1B), respectively. Cutoff values of 49.44 and 36.28 were chosen in ROC analysis for Su levels before dose 7 and after dose 9, respectively with better sensitivity and specificity to diagnose HC (Figure 1C). Patients with Su levels above the cutoff value defined (before dose 7, 41.7 %; after dose 9 42.9 %) had higher incidence of HC compared to those below the cutoff (before dose 7, 11.0 %; after dose 9, 8.0 %) at both dose levels (Figure 2A, Figure 2B). Age and Weight were also correlated with the incidence of HC, with higher incidence in patients older than 10 years, and weighed above 30 kg. Higher levels of Su correlated with the weight and age of the patients. Out of 8 individuals diagnosed with HC, 6 were detected positive for BK virus and one patient was positive for JC virus. Conclusion Higher plasma Su levels might also explain availability of Su and its hydroxyl metabolite in bladder to cause damaging effect similar to that of acrolein. We hypothesize that formation of Su is related to the volume of liver and enzyme activity which is usually correlated with weight and age of the patient. These levels might also predict the extent for acrolein formation, and might serve as surrogate marker to identify patients predisposed to HC. A functional study to elucidate the effect of Su on bladder urothelium is underway at our laboratory to understand its role in pathogenesis of HC. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Aetiology of hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation

2018 ◽  
Vol 20 (3) ◽  
pp. 232-238
Author(s):  
Vera A. Vasilieva ◽  
E.N. Parovichnikova ◽  
M.Yu. Drokov ◽  
L.A. Kuzmina ◽  
Galina A. Klyasova ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Clinical Symptoms ◽  
Hemorrhagic Cystitis ◽  
Conditioning Regimen ◽  
Hematopoietic Stem ◽  
Viral Aetiology

Incidence, severity, and risk factors for hemorrhagic cystitis (HC) were assessed in 267 patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). HC was diagnosed in 14.6% (39 patients) within 1-139 days after allo-HSCT (median duration – 39 days). Chemotherapy-related HC was diagnosed in 4 patients only. The majority (19⁄35) of patients developed late HC of viral aetiology. Median time from a day of HC diagnosis to clinical symptoms resolution was 25 days (range: 6 to 133 days). Using a multivariate analysis, allo-HSCT from mismatched unrelated/haploidentical donor was found to be a risk factor of HC (р=0.01). The analysis also showed that 82.1% of patients with HC received cyclophosphamide as a part of conditioning regimen or +3/+4 days after allo-HSCT.

Monitoring JAK3 mRNA Levels in Patients with GVHD after Allogeneic Hematopoietic Stem Cell Transplantation by Real-Time Quantitative PCR.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5273-5273
Author(s):  
Qihui Li ◽  
Xin Du ◽  
Suxia Geng ◽  
Jianyu Weng ◽  
Rong Guo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Quantitative Pcr ◽  
Conditioning Regimen ◽  
Myeloablative Conditioning ◽  
Hematopoietic Stem ◽  
Real Time Quantitative Pcr

Abstract Background: Graft-versus-host disease (GVHD) represents a major hurdle impeding the efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT). JAK3 plays pivotal roles in the initiation of cytokine-triggered signaling transduction. Recent studies about the murine GVHD model show that targeting JAK3 in donor lymphocytes with a chemical inhibitor such as WHI-P131 may be useful in the prevention of severe GVHD. However, the level of JAK3 expression in patients with GVHD has not been reported. The current study is to develop a reliable and rapid real-time quantitative PCR (Q-PCR) method using Taqman Probe for detecting JAK3 in allo-HSCT recipients. Methods: 20 patients who received myeloablative-conditioning regimen for hematological malignancies and cyclosporine for GVHD prophylaxis have been investigated in this still ongoing study clinically. One of these patients developed acute GVHD (aGVHD), 9 patients developed chronic GVHD (cGVHD), and 10 patients showed no evidence of GVHD during the first 365 days post-transplant. RNA was extracted from white blood cells and cDNA templates were synthesized using 1μg RNA. The standard curve method was used for relative quantitation of JAK3. Results: There is a clear trend for a increasing expression of JAK3 in 9 patients with GVHD. Interestingly, a significant decrease of JAK3 gene expression when the severity of GVHD was remission (P=0.04). One of the patient with cGVHD, the level of JAK3 gene expression has no changed before and after treatment. However, these patients post HSCT without GVHD have a comparable level of JAK3 expression before myeloablative conditioning regimen(P>0.05). Conclusion: Based on our preliminary results, JAK3 mRNA level was obviously correlated with the development of GVHD. Analysis JAK3 mRNA expression may be useful in evaluating GVHD patients with allogeneic stem cell transplantation.

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