Extended Use of Ciprofloxacin Markedly Decreases the Incidence of Severe BK Virus-Associated Hemorrhagic Cystitis In Allogeneic HSCT Recipients

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2317-2317
Author(s):  
Ashley N Miller ◽  
Ashley S Glode ◽  
Kathy Hogan ◽  
Christine Schaub ◽  
Robert K Stuart ◽  
...  
Keyword(s):  
Viral Replication ◽  
Hemorrhagic Cystitis ◽  
Conditioning Regimen ◽  
Bk Virus ◽  
Control Group ◽  
Control Groups ◽  
Hematopoietic Stem ◽  
Cox Regression Analysis ◽  
Allogeneic Hsct ◽  
And Control

Abstract Abstract 2317 Introduction: The polyoma virus BK is present in the urothelial tract of the majority of patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Urothelial damage by the conditioning regimen triggers early viral replication and subsequent immune mediated damage to the urothelium. Clinical manifestations of BK virus-associated hemorrhagic cystitis (BKHC), with typical onset in the first 100 days after HSCT, range from asymptomatic microscopic hematuria to massive life threatening blood loss and urinary obstruction. There is no standard prophylaxis or treatment for BKHC. The antibacterial fluoroquinolones have been shown in vitro to inhibit BK viral replication by direct inhibition of the BK encoded DNA gyrase. Therefore, we hypothesized that extended prophylaxis with the fluoroquinolone ciprofloxacin might decrease the incidence of severe BKHC after HSCT. Methods: In March 2009 we began prescribing prophylaxis for BKHC with ciprofloxacin 500 mg orally twice daily from day 0 until day 60 after transplantation in all allograft recipients (except patients allergic to ciprofloxacin). Patient and transplant variables, as well as incidence of severe BKHC, were collected retrospectively for all consecutive patients undergoing allogeneic HSCT between June 2006 and July 2010. Severe BKHC was defined as grades 3 or 4 hemorrhagic cystitis with evidence of urinary excretion of BK virus by polymerase chain reaction. We estimated the incidence of severe BKHC and the survival free of severe BKHC for patients receiving (ciprofloxacin group) or not (control group) prophylaxis. Additionally, we performed a multivariate analysis to assess the independent role of ciprofloxacin prophylaxis in preventing episodes of severe BKHC. Results: Eighty-one consecutive patients were included in the analysis, of which 33 received ciprofloxacin prophylaxis. Median age of patients was 50 years (range 19–70) and 37% were female. Overall 47% of patients received a myeloablative conditioning regimen and 60% had an alternative (not HLA-matched sibling) donor. Median follow up for patients in the ciprofloxacin and control groups were respectively 180 (range 33–504) and 515 days (range of 29–1645). There was no difference in overall survival between ciprofloxacin and control groups. Episodes of severe BKHC occurred after a median of 60 days (range 27–118) after transplantation and were less frequent in the ciprofloxacin than in the control group (2.9% vs. 22.9%, chi-square test P= 0.01). Survival free of severe BKHC was also significantly superior in the ciprofloxacin group (Log-rank test P=0.04; Figure). In a multivariate Cox-regression analysis including age, gender, intensity of the conditioning regimen, use of mesna during conditioning and alternative donor, only the use of ciprofloxacin prophylaxis was significantly associated with the endpoint survival free of severe BKHC (P=0.01). There were no complications associated with prolonged use of ciprofloxacin, in particular no increase in Clostridium difficile associated diarrhea. Conclusion: Ciprofloxacin prophylaxis appears safe and effective in reducing the incidence of severe BKHC after allogeneic HSCT. This finding requires confirmation with a prospective randomized trial. Disclosures: Off Label Use: Ciprofloxacin- prevention of BK associated hemorragic cystitis.

Immunotherapy with Autologous Anti-CD19 Chimeric Antigen Receptor T Cells Followed By Allogeneic Hematopoietic Stem Cell Transplantation Has Remarkably Improved Leukemia-Free Survival in Refractory/Relapsed B-Cell Acute Lymphoblastic Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 829-829
Author(s):  
Yan-Li Zhao ◽  
Tong Wu ◽  
De-Yan Liu ◽  
Jian-Ping Zhang ◽  
Zhi-Jie Wei ◽  
...  
Keyword(s):  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Control Group ◽  
Control Groups ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Allogeneic Hsct ◽  
Time Period ◽  
And Control

Abstract Introduction: The prognosis of refractory/relapsed acute lymphoblastic leukemia (ALL) is poor with chemotherapy or even allogeneic hematopoietic stem cell transplantation (HSCT). Although our immunotherapy with autologous anti-CD19 chimeric antigen receptor T cells (CART) has resulted in 88.6% complete remission (CR) in refractory/relapsed B-cell ALL (B-ALL), many patients relapsed at around 2 months after CART therapy (unpublished data). Our current strategy is to perform HSCT for refractory/relapsed B-ALL in CR by CART therapy to attain continuous leukemia-free survival (LFS). However, majority of the patients with CART therapy developed cytokine release syndrome which may increase transplant-related mortality (TRM). Moreover, all patients with CART therapy have very tough diseases which could result in higher relapse rate after transplant. Objective: In current study, the safety and efficacy of HSCT for refractory/relapsed B-ALL after CART therapy were investigated. The patients with B-ALL who received HSCT during the same time period without CART therapy were as control. Patients and Methods: Between July 2015 and May 2016, consecutive 22 patients with refractory/relapsed CD19+ B-ALL in CR by CART therapy followed by allogeneic HSCT in our hospital were analyzed as CART group; and consecutive 89 patients with B-ALL in CR who received allogeneic HSCT in our hospital during the same time period but without previous CART therapy were as control group. Clinical characteristics between two groups was comparable except more CR1 (22.7% vs. 57.3%) in control group and more CD3+ cells infused (1.93x108/kg vs. 1.46 x108/kg, p=0.026) in CART group. The median age was 8 (2-44) years, 15 (2-52) years in CART and control groups (p=0.147). The median disease course was 19.1 (3.9-53.7) months, 10.6 (3.7-123.0) months in CART and control groups (p=0.385). The median time from CART therapy to HSCT was 86 (31-172) days. Disease status was 22.7% cases in CR1, 54.5% in CR2, 18.2% in CR3 and 4.5% in CR4 in CART group; and 57.3% cases in CR1, 36.0% in CR2 and 6.7% in CR3 in control group (p=0.08). Minimal residual disease pre-conditioning by flow cytometry was positive in 22.7%, 31.5% patients in CART and control groups (p=0.422). Donor source was identical sibling (IS) in 13.6%, unrelated (UR) in 31.8% and haploidentical (HI) in 54.5% in CART group; and IS in 14.6%, UR in 16.9% and HI in 68.5% in control group (p=0.313). Myeloablative conditioning regimens were administered with either total body irradiation (TBI) plus cyclophosphamide (Cy)/ fludarabine (Flu)-based in 90.9% cases or busulfan (Bu) plus Cy/ Flu-based in 9.1% cases in CART group; and TBICY/Flu-based in 85.4% cases or BuCy/Flu-based in 14.6% cases in control group (p=0.498). Antithymocyte globulin was used in UR and HI transplants. Cyclosporine, short-term methotrexate, and mycophenolate mofetil were employed for GVHD prophylaxis. Results: The median time to neutrophil engraftment was similar between two groups (14 days vs. 13 days, p=0.196), but platelet engraftment was slower in CART group (14 days vs. 12 days, p=0.031). Cumulative incidence of grade II-IV acute GVHD (aGVHD) was higher in CART group (57.6% vs. 33.1%, p=0.009), which may related to higher CD3+ cells infused in CART cohort; but the incidences of grade III-IV aGVHD were no statistical significance (25.1% vs. 15.7%, p=0.564) in two groups. No remarkable differences were seen in CMV reactivation (45% vs. 51.7%, p=0.601) and transplant-associated thrombotic microangiopathy (13.6% vs. 9.0%, p=0.514) in two groups. No significant difference was found in TRM between CART and control groups (7.1% vs. 15.2%, p=0.808). Relapse rates were similar in two groups (5.0% vs. 6.9%, p=0.888). With a median follow-up 9 (2-12) months, LFS was comparable in CART and control groups (84.8% vs. 80.9%, p=0.937). Conclusions: Our preliminary results have shown that the strategy with CART therapy followed by allogeneic HSCT in refractory/relapsed B-ALL is very safe and effective with similar outcomes in TRM, relapse rate and LFS compared with control group. CART therapy has resulted in very good CR in refractory/relapsed B-ALL and allowed the patients to achieve continuous LFS by subsequent allogeneic HSCT, which is revolutionary modality for those patients who have otherwise incurable diseases. Disclosures No relevant conflicts of interest to declare.

Impact Of Prophylaxis With Defibrotide On The Occurrence Of Acute GvHD In Allogeneic HSCT

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4591-4591
Author(s):  
Selim Corbacioglu ◽  
Simone Cesaro ◽  
Maura Faraci ◽  
Bernd Gruhn ◽  
Jaap J Boelens ◽  
...  
Keyword(s):  
Acute Gvhd ◽  
Controlled Study ◽  
Control Group ◽  
Hematopoietic Stem ◽  
Allogeneic Hsct ◽  
Adjusted Risk ◽  
Gvhd Prophylaxis ◽  
Grade Ii ◽  
And Control ◽  
The Impact

Background Acute GvHD (aGvHD) remains one of the most significant complications of allogeneic hematopoietic stem cell transplantation (HSCT) with a persistently high incidence despite a plethora of prophylactic approaches. The medical need for effective drugs to prevent aGvHD remains substantial. Methods A prospective, randomized, open-label controlled study has been conducted in 356 children at high-risk for hepatic VOD post-HSCT to demonstrate efficacy of prophylaxis with defibrotide (DF) to reduce the incidence of VOD (180 in the DF arm and 176 in the control arm [Corbacioglu, Lancet 2012]). A secondary objective of the study was to analyze the impact of DF prophylaxis on the incidence and severity of aGvHD. Among children undergoing allogeneic HSCT (allo-subset) 122 patients received DF prophylaxis and 117 were in the control arm. Results Demographic and baseline characteristics were similar in the DF and control arm of the allo-subset. Mean age (± SD) was 6.47±5.28 and 6.54±5.49 in DF arm and in the controls respectively, with 29% and 30% being <2 years; 64% and 58%, respectively, were males. Busulfan was used in conditioning in 62% and 64% of patients in the two arms, and melphalan in 60% and 53%, respectively. Grafts were from related donors in 40% and 30%, respectively, in DF and control arm. Prophylaxis with DF was shown to significantly reduce the occurrence and severity of aGvHD. At day+100 post-HSCT the incidence of aGvHD was 47% in the DF arm vs. 65% in the control group (p=0.0046). DF did not seem to affect the incidence of aGvHD grade I (25% vs 28%, respectively). However, Defibrotide showed a consistent reduction of the more severe grade II–IV aGvHD from 37% to 22% (p=0.0130). Of note the use of corticosteroids was significantly lower in patients receiving DF prophylaxis (37% vs 48% in control arm, p=0.0363), likely reflecting the lower incidence of aGvHD in the DF arm. This has also previously been observed in the treatment studies [Richardson, ASH 2012]. Standard GvHD prophylaxis was allowed according to best practice and was generally comparable (cyclosporine A: 81% vs. 89%; methotrexate: 46% vs. 56%; in DF and control arm, respectively). However, there was a difference in patients who received antithymocyte globulin (ATG) in the DF arm compared to controls (55% vs 70%). Exploratory analysis performed adjusting for ATG as covariate confirmed the significant effects of defibrotide [Adjusted Risk Difference (DF vs control) for aGvHD grade II–IV: -0.1470 (95%CI: -0.2618; -0.0322), p =0.0121]. Defibrotide did not seem to interfere with a graft-versus-leukemia effect. Relapse rates of combined leukemias were 8% (ALL 1.5%, AML 5%, others 1.5%) in DF group compared with 10% (ALL 3%, AML 7%) in controls by day +100; while 10% (ALL 1.5%, AML 7%, others 1.5%) patients in DF group relapsed by day +180 compared with 13% (ALL 8%, AML 5%) in the control arm. Conclusions The study shows that DF prophylaxis can reduce the incidence and severity of aGvHD in children undergoing allogeneic HSCT. This reduction observed with defibrotide is additional to standard GvHD prophylaxis that was fully implemented in these patients. Defibrotide has been reported to protect endothelial cells from damage as well as to downregulate heparanase activity. These clinical data would therefore suggest a benefit of defibrotide to reduce the incidence and severity of aGvHD. Further studies may be conducted to strengthen preclinical and clinical evidence for the role of defibrotide in aGvHD prevention. Ref: Corbacioglu S et al, Lancet 2012; 379:1301-9. Richardson PG et al, Blood 2012; 120:738. Disclosures: Corbacioglu: Gentium : Consultancy. Cesaro:Pfizer SpA: Honoraria; Gilead: Honoraria; Merck: Honoraria. Tudone:Gentium : Employment. Ballabio:Gentium : Employment. Heringa:Gentium S.p.A.: Employment.

scholarly journals Moxibustion Therapy at CV4 Prevents Postoperative Dysuria after Procedure for Prolapse and Hemorrhoids

2013 ◽  
Vol 2013 ◽  
pp. 1-5 ◽  
Author(s):  
Xue-Mei Bian ◽  
Ling Lv ◽  
Wan-Bing Lin ◽  
Hai-Hong Liang ◽  
Ying Zhang ◽  
...  
Keyword(s):  
Nursing Care ◽  
Moxibustion Therapy ◽  
Cox Regression ◽  
Conventional Care ◽  
Control Group ◽  
Control Groups ◽  
Urethral Catheterization ◽  
Cox Regression Analysis ◽  
And Control ◽  
Experimental Group

Objective. To explore the intervention methods of the patients with dysuria after performing the procedure for prolapse and hemorrhoids (PPH).Methods. 100 cases with hemorrhoids were randomly divided into experimental and control groups. The control group received routine nursing care. As comparison, the experimental group, on the basis of conventional care, was treated with moxa roll moxibustion 1 hour after the operation for 30 minutes. The autonomous urination within 1 h, 2 h, 4 h, 6 h, and 8 h after operation and the catheterization rate 8 h after operation of two groups of patients were observed.Results. The median time of autonomous urination of control group (8 h) was significantly greater than that of the experimental group (6 h) (P<0.001). Cox regression analysis showed that the moxibustion therapy was positively correlated with automatic micturition in the patients after PPH. The probability of automatic micturition in the experimental group was 2.032 times that in the control group (RR = 2.032, 95% CI: 1.278~3.230). The catheterization rate of control group (38%) was significantly higher than that of the experimental group (10%) (P<0.001).Conclusion. The Guanyuan acupoint moxibustion can prevent dysuria after PPH and reduce the urethral catheterization.

Hemorrhagic Cystitis and BK Virus Infection in Children after Hematopoietic Stem Cell Transplantation.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2195-2195
Author(s):  
Bernd Gruhn ◽  
Loreen Maier ◽  
Renate Egerer ◽  
Dietlinde Fuchs ◽  
Felix Zintl ◽  
...  
Keyword(s):  
Risk Factors ◽  
Stem Cell ◽  
Virus Infection ◽  
Hemorrhagic Cystitis ◽  
Bk Virus ◽  
Unrelated Donor ◽  
Hematopoietic Stem ◽  
Allogeneic Hsct ◽  
Virus Load ◽  
Graft Versus Host

Abstract Hemorrhagic cystitis (HC) is a serious complication after hematopoietic stem cell transplantation (HSCT). The pathogenesis of HC in adults is not fully understood and may be influenced by BK virus infection, type of transplant, conditioning regimen, stem cell source, and graft-versus-host disease. Little is known about the development of HC in children after HCST, especially about the association with BK virus infection. Therefore, we retrospectively analyzed the incidence, risk factors and BK virus association of HC in 165 consecutive children (median age, 12 years) who underwent peripheral blood stem cell (n=97; T-cell depleted: n=48) or bone marrow transplantation (n=68) between 1/2000 and 12/2006 in a single center. Fifty nine patients received autologous HSCT and 106 patients underwent allogeneic HSCT. Nineteen of the 165 patients (11.5%) developed HC after a median of 33 days (range, 1–98 days). All 19 patients with HC underwent allogeneic HSCT and showed BK viruria after transplantation. An acute graft-versus-host disease was significantly more frequent in children with HC (P &lt; .001). Significant risk factors in univariate binary logistic analyses were age &gt; 12 years (OR, 3.275; P &lt; .031), use of busulfan (OR, 3.514; P &lt; .013), use of busulfan and cyclophosphamide in combination (OR, 4.935; P &lt; .002), and an unrelated donor (OR, 3.309; P &lt; .043). Independent risk factors in multivariate binary logistic analyses were age &gt; 12 years and the combination of busulfan and cyclophosphamide. We suggest that cyclophosphamide is toxic to the urinary bladder and busulfan enhances this effect. Furthermore, we analyzed the BK virus load in urine by real-time polymerase chain reaction. We found in patients without HC a significantly increased number of BK virus copies in urine in children older than 12 years (P &lt; .009) and in children who received antithymocyte globulin (P &lt; .001). In addition, BK virus load in urine was significantly increased in children who suffered from HC. Thirteen of 14 children with HC had a BK virus load in urine &gt;107 copies/mL (P &lt; .001). We observed in individual BK virus profiles an increase of BK virus copies in urine before the onset of HC. We conclude that HC in children is a disease of multiple etiologies. Allogeneic HSCT, the combination of busulfan and cyclophosphamide, age &gt; 12 years, and an unrelated donor are risk factors for the development of HC in childhood. Increased BK virus load in urine of more than 107 copies/mL may lead to HC. Therefore, it is useful to quantify BK virus in urine in those children with above mentioned risk factors to initiate early treatment or to prevent the development of HC.

The Effects of Super-Intensified Conditioning Regimen of Allogeneic Hematopoietic Stem Cell Transplantation for Refractory Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 5026-5026
Author(s):  
Qifa Liu ◽  
Jing Sun ◽  
Dan Xu ◽  
Yu Zhang ◽  
Zhiping Fan ◽  
...  
Keyword(s):  
Stem Cell ◽  
Conditioning Regimen ◽  
The Other ◽  
Control Group ◽  
Post Transplantation ◽  
Hematopoietic Stem ◽  
Incidence And Mortality ◽  
Leukemia Relapse ◽  
And Control ◽  
Experimental Group

Abstract Objective To explore the regimen related toxicity (RRT) and the effects of super-intensified conditioning regimen combined with inducing graft versus leukemia (GVL) in allogeneic hematopoietic stem cell transplantation (allo-HSCT) for refractory leukemia which can’t obtain complete remission (CR) pre- transplantation. Methods 18 patients who did not obtain CR before transplantation received super-intensity conditioning regimen protocol(experimental group), and 62 patients with acute leukemia who obtained CR or chronic myeloid leukemian (CML) who were in the chronic phase before transplantation received total body irradiation (TBI) plus cyclophosphamide (CTX) or modified BuCY (hydroxyurea, busulfan, Ara-C, CTX) protocol (control group). Cyclosporin A was reduced rapidly and gradually or donor lymphocytic infusion (DLI) was used to induced GVL if acute graft versus host disease (GVHD) did not happened in patients with refractory leukemia at 30 days post-transplantation. The incidence and mortality of RRT during transplantation, and the rate of CR, GVHD and leukemia relapse after transplantation was investigated. Kaplan-Meier survival analysis model was used to estimate the disease-free survival (DSF) rate at 3 years post-transplantation. Results Except one patient in experimental group and two patients in control group died of transplant-related complications, all the other patients obtained hematopoietic reconstitution.’ the total RRT incidence were both 100% in two groups. The RRT of stomach intestine were most common in all the organs and the RRT incidence of experimental group and control group was 83.3% and 85.5%, respectively, in stomach intestine. The RRT incidence was 44.4% and 62.9% in oral cavity and 16.7% and 33.9% in bladder, respectively, in the experimental group and control group. There was no significance and P value was 0.823, 0.172 and 0.244, respectively, in the RRT incidence of stomach intestine, oral cavity and bladder between the two groups. The RRT mortality was 0 and 5%, respectively, and was not different (P=0.341) in the experimental and control group. Except one patient died of infection, all the other patients obtained CR in patients who were treated with supper-intensified conditioning regimen. The incidences of acute or chronic GVHD were 58.8% and 40.0% or 92.6% and 55.8%, respectively, in the experimental and control group. The incidence of leukemia relapse was 11.8% and 18.3%, respectively, in the two groups. The DSF at 3 years after transplantation was 61.2±12.3% and 65.0±7.4% (P=0.6311), respectively, in the two groups. Conclusion The consecutive super-intensified conditioning regimen combined with inducing GVL post transplantation protocol can increase the rate of CR and DFS, and dose not increase RRT incidence and mortality in allo-HSCT for the refractory leukemia which can’t obtain CR pre- transplantation.

BKV Disease during the First 100 Days after Allogeneic Hematopoietic Stem Cell Transplantation - Results of a Screening Program and Retrospective Analysis

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3403-3403 ◽  
Author(s):  
Philip Posdzich ◽  
Marco Herling ◽  
Silke Leitzke ◽  
Laura Hamacher ◽  
Veronica Di Christanziano ◽  
...  
Keyword(s):  
Risk Factors ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Complete Remission ◽  
Acute Gvhd ◽  
Screening Program ◽  
Hemorrhagic Cystitis ◽  
Bk Virus ◽  
Hematopoietic Stem ◽  
Allogeneic Hsct

Abstract BK virus (BKV) is a human polyomavirus often acquired in childhood which can reactivate after allogeneic hematopoietic stem cell transplantation (HSCT). BKV reactivation may present indifferent ways from asymptomatic viruria to hemorrhagic cystitis or nephritis. Methods We evaluated 377 patients (159 male, 218 female, median age 52 years) who were transplanted at the University of Cologne between 2008 and 2013 to assess incidence and risk factors for BKV disease after allogeneic HSCT. All 377 patients were screened routinely for BKV in urine and serum. We defined BKV disease as hemorrhagic cystitis (HC) with BK virus >100.000/ml in urine, hematuria (2+ until 4+ in dipstick test) and negative urine microbiology. To find risk factors for BKV disease, the impact of conditioning, CMV status, graft-versus-host disease (GvHD), underlying disease, donor mismatch and stem cell source was analyzed. Results According to our definition, BKV cystitis occurred in 37 of 377 patients (9,8%) in the first 100 days after HSCT. In 14 of these 37 patients (37,8%) BKV was also detected in serum. BKV was detected in the urine of 194 patients (51,4%) at any time during the screening program, but only 19,1% developed hemorrhagic cystitis. Sixty-two percent of patients suffering from BKV disease were female, 37,8% male. BKV disease was diagnosed in 13,3% of patients not in complete remission as opposed to 5,4 % of patients in complete remission prior to conditioning (p = 0,010). BKV disease was less common in matched related or unrelated (7,7%) as compared to mismatched or haplo-identical donors (16,7%; p=0,012). Acute GvHD grade II to IV was described in 122 of 377 patients (32,36%). Of them, 13,9% suffered from BKV cystitis in comparison to 7,84% with no or grade I acute GvHD, which did not reach statistical significance. We could not detect any correlation between BKV disease and administration of cyclophosphamide, total body irradiation or anti-thymocyte globuline. There was no association with the graft source. BKV disease was no predictor for non-relapse mortality, overall and relapse-free survival. Conclusion BKV disease is a common complication after allogeneic HSCT. The virus can be found in the urine of about half of our transplanted patients, but only a small proportion developed an HC. State of remission before conditioning and donor mismatch are associated with the development of BKV disease, which had no impact on survival in our cohort. Disclosures Scheid: Novartis: Other: funding outside this work; Celgene: Other: funding outside this work; Janssen: Other: funding outside this work.

Risk Factors for BK Viruria and Hemorrhagic Cystitis in Hematopoietic Stem Cell Transplant (HSCT) Recipients.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1072-1072
Author(s):  
Wassim McHayleh ◽  
Rajesh Sehgal ◽  
Walid El-Ayass ◽  
Shahid Husain ◽  
Parmjeet Randhawa ◽  
...  
Keyword(s):  
Risk Factors ◽  
Hemorrhagic Cystitis ◽  
Conditioning Regimen ◽  
Fisher Exact Test ◽  
Cell Transplant ◽  
Myeloablative Conditioning ◽  
Hematopoietic Stem ◽  
Exact Test ◽  
Allogeneic Hsct ◽  
Conditioning Intensity

Abstract Polyomavirus BK associated hemorrhagic cystitis (HC) is becoming an increasingly recognized complication of HSCT. The pathogenesis of BK-associated HC is not fully understood, and it is not possible to predict the clinical course of BK reactivation in patients following HSCT. Multiple co-factors could play a role in the development of HC after HSCT in patients (pts) with BK viruria (BKV) including the type of transplant autologous (auto) vs. allogeneic (allo), conditioning regimen, development of Graft-Versus-Host Disease (GVHD), conditioning intensity and source of donor stem cells (Matched unrelated [MUD] vs. HLA-identical sibling [SIB]).We retrospectively analyzed the incidence, risk factors and outcome of BK reactivation and HC in pts who had HSCT at the Univ. of Pittsburgh Cancer Institute during the last 2 years. BKV was determined using a quantitative real-time PCR assay considered positive for titers higher than 10 copies. In total, 247 pts were studied, 63% (155/247) received an auto and 37% (92/247) an allo HSCT. BKV was observed in 20% (49/247) of pts. 3% (5/155) of pts undergoing auto and 48% of pts undergoing allo HSCT (44/92) developed BKV. 18% of pts (9/49) developed HC, 1 in the auto and 8 in the allo group. Three pts died from complications related to HC. Of the allo HSCT pts, 50% (46/92) received Sib and MUD HSCT. Non-myeloablative conditioning regimens (Flu/TBI, Flu/Cy, Flu/Bu/ATG, TLI/ATG, Flu/Csa/MMF) were used in 39% pts (36/92) and whereas 61% (56/92) of pts underwent myeloablative conditioning (BuCy, TBI/Cy). In pts undergoing allo HSCT with myeloablative regimen, 52% (29/56) had BKV with 28% (8/29) having HC, while 42% (16/35) of pts after nonmyeloablative conditioning had BKV with no pt developing HC. Of the allo HSCT pts, GVHD data was available for 67 pts, 69% (46/67) had grade 1-4 acute GVHD whereas 31% (21/67) had no evidence of GVHD. In pts with no GVHD, BKV was seen in 38% (8/21) with no pt developing HC while 52% (24/46) pts with GVHD had BKV with 13% (3/24) developing HC. In patients undergoing MUD HSCT, BKV and HC were present in 43% (20/46) and 5% (1/20) respectively, whereas in the SIB group, BKV and HC developed in 52% (24/46) and 29% (7/24), respectively. As calculated by Fisher exact test BKV was significantly associated with allo HSCT (p< 0.001) and Cyclophosphamide-containing non-myeloablative conditioning in allo HSCT recipients (p=0.03). In contrast we did not observe a significant impact of ATG vs. non-ATG-containing regimen, non-ablative vs. myeloablative conditioning or presence vs. absence of GVHD in our cohort of allo-HSCT patients. However, development of BK-induced HC in BKV+ allogeneic HSCT patients was significantly associated with the presence of myeloablative conditioning (p=0.03). Based on these findings we conclude that 1. Development of BKV occurs predominantly following allogeneic HSCT. 2. Conditioning intensity is an important risk factor for the development of HC in patients with BKV. 3. Cyclophosphamide is an important co-factor for the development of BKV in patients undergoing non-myeloablative conditioning. We hypothesize that cyclophosphamide-induced bladder damage might not only contribute to BKV-associated HC, but also to BK reactivation. Therefore, prospective trials addressing the value of prophylactic or pre-emptive therapy for BKV should focus on patients undergoing myeloablative allogeneic HSCT.

TLR4 Asp299Gly Variant Confers Strong Protection against BK Virus-Associated Hemorrhagic Cystitis After Hematopoietic Stem Cell Transplantation in Children.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 344-344 ◽  
Author(s):  
Bernd Gruhn ◽  
Norman Kloeppner ◽  
Nadine Pfaffendorf ◽  
Ilona Wolff ◽  
Daniel Steinbach ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Myeloid Leukemia ◽  
Hemorrhagic Cystitis ◽  
Conditioning Regimen ◽  
Bk Virus ◽  
Hematopoietic Stem

Abstract Abstract 344 Hemorrhagic cystitis is a serious complication after hematopoietic stem cell transplantation (HSCT). The pathogenesis of hemorrhagic cystitis is not fully understood and is influenced by BK virus infection, type of transplant, conditioning regimen, stem cell source, and graft-versus-host disease. Nothing is known about human genetic factors and the development of BK virus-associated hemorrhagic cystitis in patients after HSCT. Toll-like receptors (TLR) are essential components of the innate immune system. TLR have been discovered as the most important class of pattern recognition receptors, involved in the host defense against bacteria, viruses, fungi, and protozoa. C3H/HeJ mice that lack functional TLR4 receptors did not develop cystitis after intravesical instillation of E. coli. Individuals with the Asp299Gly polymorphism of the TLR4 gene showed a diminished inflammatory responsiveness to endotoxin. Because of the requirement of TLR4 in inflammatory response we hypothesized that TLR4 Asp299Gly reduces the risk of BK virus-associated hemorrhagic cystitis after hematopoietic stem cell transplantation (HSCT). 166 children (median age, 13 years) with acute lymphoblastic leukemia (n=72), acute myeloid leukemia (n=38), myelodysplastic syndrome (n=21), chronic myeloid leukemia (n=12), genetic disease (n=12) or severe aplastic anemia (n=11) who underwent allogeneic bone marrow (n=105) or peripheral blood stem cell transplantation (n=61; T-cell depleted: n=31) in a single center and their respective donors were genotyped of TLR4 for rs4986790 (A896G, Asp299Gly) using TaqMan real-time polymerase chain reaction. The donor was HLA-matched unrelated in 57% of transplants or HLA-identical related in 33% of transplants. Conditioning regimen was myeloablative in all cases and based on total body irradiation in 48% of transplants or busulfan in 47% of transplants. Two forms of post-transplant immunosuppression predominated, cyclosporine A and methotrexate in 64% of transplants and cyclosporine A alone in 25% of transplants. The Asp299Gly variant was present in 21 of the 166 patients (12.6%) and in 24 of the 166 donors (14.4%). Interestingly, we found a significantly reduced incidence of BK virus-associated hemorrhagic cystitis in patients with the Asp299Gly variant (0% versus 22.8%, p=0.009). In addition, we observed a significantly reduced incidence of BK virus-associated hemorrhagic cystitis in patients who were transplanted from a donor with this specific variant (4.2% versus 22.5%; p=0.05). In ten of the donor-patient pairs the variant was present in both individuals and no hemorrhagic cystitis was observed. The occurrence of the TLR4 Asp299Gly variant, in either recipients or donors, had no significant impact on acute and chronic GVHD, relapse rate, bacterial and fungal infectious complications, transplant related mortality, and overall survival. In conclusion, the TLR4 Asp299Gly variant in the recipient and/or the donor confers strong protection against BK virus-associated hemorrhagic cystitis after HSCT in children. This study provides the first evidence that the innate immune system through TLR4 signaling pathway seems to play an important role in the pathogenesis of BK virus-associated hemorrhagic cystitis after HSCT. Disclosures: No relevant conflicts of interest to declare.

Conjugated Linoleic Acid Causes a Marked Increase in Liver α-Tocopherol and Liver α-Tocopherol Transfer Protein in C57BL/6 J Mice

2010 ◽  
Vol 80 (1) ◽  
pp. 65-73 ◽  
Author(s):  
Pei-Min Chao ◽  
Wan-Hsuan Chen ◽  
Chun-Huei Liao ◽  
Huey-Mei Shaw
Keyword(s):  
Antioxidant Enzymes ◽  
Linoleic Acid ◽  
Conjugated Linoleic Acid ◽  
Thiobarbituric Acid ◽  
Control Group ◽  
Thiobarbituric Acid Reactive Substances ◽  
Control Groups ◽  
Protein Levels ◽  
Transfer Protein ◽  
And Control

Conjugated linoleic acid (CLA) is a collective term for the positional and geometric isomers of a conjugated diene of linoleic acid (C18:2, n-6). The aims of the present study were to evaluate whether levels of hepatic α-tocopherol, α-tocopherol transfer protein (α-TTP), and antioxidant enzymes in mice were affected by a CLA-supplemented diet. C57BL/6 J mice were divided into the CLA and control groups, which were fed, respectively, a 5 % fat diet with or without 1 g/100 g of CLA (1:1 mixture of cis-9, trans-11 and trans-10, cis-12) for four weeks. α-Tocopherol levels in plasma and liver were significantly higher in the CLA group than in the control group. Liver α-TTP levels were also significantly increased in the CLA group, the α-TTP/β-actin ratio being 2.5-fold higher than that in control mice (p<0.01). Thiobarbituric acid-reactive substances were significantly decreased in the CLA group (p<0.01). There were no significant differences between the two groups in levels of three antioxidant enzymes (superoxide dismutase, glutathione peroxidase, and catalase). The accumulation of liver α-tocopherol seen with the CLA diet can be attributed to the antioxidant potential of CLA and the ability of α-TTP induction. The lack of changes in antioxidant enzyme protein levels and the reduced lipid peroxidation in the liver of CLA mice are due to α-tocopherol accumulation.

Sri Lankan Cleft Lip and Palate Study Model Analysis: Clefts of the Secondary Palate

1993 ◽  
Vol 30 (2) ◽  
pp. 227-230 ◽  
Author(s):  
Andrew Mccance ◽  
David Roberts-Harry ◽  
Martyn Sherriff ◽  
Michael Mars ◽  
William J.B. Houston
Keyword(s):  
Cleft Lip ◽  
Cleft Lip And Palate ◽  
Model Analysis ◽  
Control Group ◽  
Tooth Size ◽  
Sri Lankan ◽  
Control Groups ◽  
Secondary Palate ◽  
Comparable Control ◽  
And Control

The study models of a group of adult Sri Lankan patients with clefts of the secondary palate were investigated. Tooth-size and arch-dimension comparisons were made with a comparable control group. Significant differences were found between the cleft and control groups in tooth sizes, chord lengths, and arch widths. The cleft group dimensions were generally smaller than those of the control group. Overjets were larger in the cleft group.

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