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BackgroundHemorrhagic cystitis (HC) is an inflammatory disease of the bladder with sustained hematuria for which there is currently no approved drug treatment. We evaluated a liposomal tacrolimus preparation (LP-10) in patients with refractory moderate to severe sterile HC.MethodsThis phase 2a dose-escalation study assessed the safety and efficacy of up to 2 intravesical instillations of LP-10 (2, 4, or 8 mg tacrolimus) in 13 patients with HC. Primary efficacy outcomes were changes from baseline in the number of bleeding sites on cystoscopy, microscopic urine analysis for red blood cells (RBCs), and hematuria on dipstick. Additional efficacy measures included urinary incontinence, frequency, and urgency on a 3-day diary and cystoscopy global response assessment (GRA). Blood samples for pharmacokinetic (PK) assessment were obtained in all patients.ResultsIntravesical LP-10 was well tolerated, with no treatment-related severe or serious adverse events (AEs) and only 3 drug-related AEs (artificial urinary sphincter malfunction, dysuria, and bladder spasms). LP-10 blood levels showed short durations of minimal systemic uptake. Treatment resulted in significant improvements in bleeding on cystoscopy, RBC counts in urine, hematuria on dipstick, and urinary incontinence. Bleeding on cystoscopy and urinary incontinence showed dose-dependent improvements that were more pronounced in the 4 mg and 8 mg dose groups. All dose groups showed a significant improvement in cystoscopy GRA.ConclusionLP-10 was well tolerated, with clinically relevant efficacy seen in improvements in cystoscopic bleeding, hematuria, and urinary incontinence. The benefit-risk profile supports the further clinical development of LP-10 at a tacrolimus dose of 4 mg.

BACKGROUND: Hemorrhagic cystitis (HC) is an inflammatory disease of the bladder with sustained hematuria for which there is currently no approved drug treatment. We evaluated a liposomal tacrolimus preparation (LP-10) in patients with refractory moderate to severe sterile HC. METHODS: This phase 2a dose-escalation study assessed the safety and efficacy of up to 2 intravesical instillations of LP-10 (2, 4, or 8 mg tacrolimus) in 13 patients with HC. Primary efficacy outcomes were changes from baseline in the number of bleeding sites on cystoscopy, microscopic urine analysis for red blood cells (RBCs), and hematuria on dipstick. Additional efficacy measures included urinary incontinence, frequency, and urgency on a 3-day diary and cystoscopy global response assessment (GRA). Blood samples for pharmacokinetic (PK) assessment were obtained in all patients. RESULTS: Intravesical LP-10 was well tolerated, with no treatment-related severe or serious adverse events (AEs) and only 3 drug-related AEs (artificial urinary sphincter malfunction, dysuria, and bladder spasms). LP-10 blood levels showed short durations of minimal systemic uptake. Treatment resulted in significant improvements in bleeding on cystoscopy, RBC counts in urine, hematuria on dipstick, and urinary incontinence. Bleeding on cystoscopy and urinary incontinence showed dose-dependent improvements that were more pronounced in the 4 mg and 8 mg dose groups. All dose groups showed a significant improvement in cystoscopy GRA. CONCLUSION: LP-10 was well tolerated, with clinically relevant efficacy seen in improvements in cystoscopic bleeding, hematuria, and urinary incontinence. The benefit-risk profile supports the further clinical development of LP-10 at a tacrolimus dose of 4 mg.

Abstract Objective To review current literature to support the use of mesna as a preventive therapy for hemorrhagic cystitis and bladder cancer in patients with systemic autoimmune diseases and systemic vasculitis treated with cyclophosphamide. Materials and methods The search for articles was conducted systematically through MEDLINE, LILACS, Cochrane Library, and Embase databases. Only articles in English were selected. For available records, titles and abstracts were selected independently by two investigators. Results Eighteen studies were selected for analysis. The known adverse effects of cyclophosphamide were hematological toxicity, infections, gonadal toxicity, teratogenicity, increased risk for malignancy and hemorrhagic cystitis. Long-term toxicity was highly dependent on cyclophosphamide cumulative dose. The risk of bladder cancer is especially higher in long-term exposure and with cumulative doses above 36 g. The risk remains high for years after drug discontinuation. Hemorrhagic cystitis is highly correlated with cumulative dose and its incidence ranges between 12 and 41%, but it seems to be lower with new regimens with reduced cyclophosphamide dose. No randomized controlled trials were found to analyze the use of mesna in systemic autoimmune rheumatic diseases and systemic vasculitis. Retrospective studies yielded conflicting results. Uncontrolled prospective studies with positive results were considered at high risk of bias. No evidence was found to support the use of mesna during the treatment with cyclophosphamide for autoimmune diseases or systemic vasculitis to prevent hemorrhagic cystitis and bladder cancer. In the scenarios of high cumulative cyclophosphamide dose (i.e., > 30 g), patients with restricted fluid intake, neurogenic bladder, therapy with oral anticoagulants, and chronic kidney disease, mesna could be considered. Conclusion The current evidence was found to be insufficient to support the routine use of mesna for the prophylaxis of hemorrhagic cystitis and bladder cancer in patients being treated for systemic autoimmune diseases and systemic vasculitis with cyclophosphamide. The use may be considered for selected cases.

Abstract Background The risk factors for hemorrhagic cystitis (HC) in children undergoing hematopoietic stem cell transplantation (HSCT) are unclear. Therefore, we conducted this systematic review and meta-analysis to investigate the risk factors for HC in children undergoing HSCT. Methods We performed this meta-analysis by retrieving studies from PubMed, EMBASE, and the Cochrane Library up to October 10, 2023, and analyzing those that met the inclusion criteria. I2 statistics were used to evaluate heterogeneity. Results Twelve studies, including 2,764 patients, were analyzed. Male sex (odds ratio [OR] = 1.52; 95% confidence interval [CI], 1.16–2.00; p = 0.003, I2 = 0%), allogeneic donor (OR = 5.28; 95% CI, 2.60–10.74; p

Abstract JC polyomavirus (JCPyV) is a human polyomavirus that can establish lifelong persistent infection in the majority of adults. It is typically asymptomatic in immunocompetent individuals. However, there is a risk of developing progressive multifocal leukoencephalopathy (PML) in immunocompromised or immunosuppressed patients. Though JCPyV commonly resides in the kidney-urinary tract, its involvement in urinary system diseases is extremely rare. Here, we reported a case of a 60-year-old male patient with coronavirus disease 2019 (COVID-19) infection who developed hemorrhagic cystitis after receiving treatment with nirmatrelvir 300 mg/ritonavir 100 mg quaque die (QD). Subsequent metagenomic next-generation sequencing (mNGS) confirmed the infection to be caused by JCPyV type 2. Then, human immunoglobulin (PH4) for intravenous injection at a dose of 25 g QD was administered to the patient. Three days later, the hematuria resolved. This case illustrates that in the setting of compromised host immune function, JCPyV is not limited to causing central nervous system diseases but can also exhibit pathogenicity in the urinary system. Moreover, mNGS technology facilitates rapid diagnosis of infectious etiology by clinical practitioners, contributing to precise treatment for patients.

Background: The risk factors for hemorrhagic cystitis (HC) in children undergoing hematopoietic stem cell transplantation (HSCT) are unclear. Therefore, we conducted this systematic review and meta-analysis to investigate the risk factors for HC in children undergoing HSCT. Methods: We performed this meta-analysis by retrieving studies from PubMed, EMBASE, and the Cochrane Library up to October 10, 2023, and analyzing those that met the inclusion criteria. I2 statistics were used to evaluate heterogeneity. Results: Twelve studies, including 2,764 patients, were analyzed. Male sex (odds ratio [OR] = 1.52; 95% confidence interval [CI], 1.16–2.00; p = 0.003, I2 = 0%), allogeneic donor (OR = 5.28; 95% CI, 2.60–10.74; p < 0.00001, I2 = 0%), human leukocyte antigen (HLA) mismatched donor (OR = 1.86; 95% CI, 1.00–3.44; p = 0.05, I2 = 31%), unrelated donor (OR = 1.58; 95% CI, 1.10–2.28; p = 0.01, I2 = 1%), myeloablative conditioning (MAC) (OR = 3.17; 95% CI, 1.26–7.97; p = 0.01, I2 = 0%), busulfan (OR = 2.18; 95% CI, 1.33–3.58; p = 0.002, I2 = 0%) or anti-thymoglobulin (OR = 1.65; 95% CI, 1.07–2.54; p = 0.02, I2 = 16%) use, and cytomegalovirus (CMV) reactivation (OR = 2.64; 95% CI, 1.44–4.82; p = 0.002, I2 = 0%) were risk factors for HC in children undergoing HSCT. Conclusions: Male sex, allogeneic donor, HLA-mismatched, unrelated donor, MAC, use of busulfan or anti-thymoglobulin, and CMV reactivation are risk factors for HC in children undergoing HSCT. [ABSTRACT FROM AUTHOR]

Although it is known that BK polyomavirus (BKPyV) causes hemorrhagic cystitis (HC) after allogeneic hematopoietic stem cell transplantation (HSCT), the clinical significance of BKPyV viremia has not been fully evaluated. We retrospectively analyzed the results of quantitative polymerase chain reaction (PCR) evaluations for detecting BKPyV in the whole blood samples of patients undergoing allogeneic HSCT during the period from January 2010 to June 2020 at a single institute, Tokyo Medical and Dental University. BKPyV was detected in the blood of 28 of the 107 evaluated patients, and the cumulative incidence of was 27.9% (95%CI: 20.2–37.9%). HC due to BKPyV developed in four of the 28 patients with BKPyV viremia (14.3%) and in two of the 79 patients without it (2.5%; P < 0.05). BKPyV viremia itself did not affect the patients' post-transplant estimated glomerular filtration rate (eGFR), but BKPyV viremia with a high viral load was significantly associated with decreased eGFR values (P < 0.05). BKPyV viremia was also associated with significantly lower progression-free survival at 3 years (35.1% [95%CI: 17.8–53.1%] vs. 60.4% [95%CI: 48.4–70.5], P < 0.05). Our findings demonstrated that BKPyV viremia was associated with onset of HC, an early decline of renal function, and poorer survival after allogeneic HSCT. Further studies are needed to test these results and elucidate the mechanisms of renal dysfunction associated with BKPyV viremia. [ABSTRACT FROM AUTHOR]

JC polyomavirus (JCPyV) is a human polyomavirus that can establish lifelong persistent infection in the majority of adults. It is typically asymptomatic in immunocompetent individuals. However, there is a risk of developing progressive multifocal leukoencephalopathy (PML) in immunocompromised or immunosuppressed patients. Though JCPyV commonly resides in the kidney-urinary tract, its involvement in urinary system diseases is extremely rare. Here, we reported a case of a 60-year-old male patient with coronavirus disease 2019 (COVID-19) infection who developed hemorrhagic cystitis after receiving treatment with nirmatrelvir 300 mg/ritonavir 100 mg quaque die (QD). Subsequent metagenomic next-generation sequencing (mNGS) confirmed the infection to be caused by JCPyV type 2. Then, human immunoglobulin (PH4) for intravenous injection at a dose of 25 g QD was administered to the patient. Three days later, the hematuria resolved. This case illustrates that in the setting of compromised host immune function, JCPyV is not limited to causing central nervous system diseases but can also exhibit pathogenicity in the urinary system. Moreover, mNGS technology facilitates rapid diagnosis of infectious etiology by clinical practitioners, contributing to precise treatment for patients. [ABSTRACT FROM AUTHOR]

Introduction: To analyze the characteristics of early clinical symptoms of hemorrhagic cystitis (HC) after hematopoietic stem cell transplantation (HSCT) and the risk factors of severe HC. Methods: We retrospectively analyzed 77 children with post‐HSCT HC treated at our hospital between June 2013 and June 2021. Clinical characteristics were collected and catalogued. Results: Among the children with urinary tract irritation symptoms (UTIS) as the first symptom, symptoms appeared earlier than hematuria symptoms (28 day vs. 31 day, p = 0.027), and the time progressing to severe HC was significantly longer in these children (12 day vs. 7 day, p = 0.038), but there was no significant difference in the number of participants (57.8% vs. 59.4%, p = 0.889). BK polyomavirus (BKV) infection was an independent risk factor (hazard ratio [HR] = 2.782, p = 0.035) for severe HC, which was also positively associated with multi‐viral infection (HR = 2.215, p = 0.020). Conclusions: In HC children, when the first urinary tract symptom was UTIS, it appeared earlier than hematuria, and the time of progression to severe HC was significantly longer, suggesting that we still need more aggressive treatment for these children to prevent the worsening of symptoms. The severity of HC was positively correlated with BKV infection and multiple infections. [ABSTRACT FROM AUTHOR]

Hemorrhagic cystitis (HC) is a highly impacting complication in allogeneic hematopoietic stem cell transplantation (HSCT), occurring in 12%–37% of patients. The impact of transplant‐ and patient‐specific variables has been described, with a possible role for JCV and BKV, which may be cooperating with cytomegalovirus (CMV). Here, we analyze 134 letermovir‐exposed, CMV‐free patients, treated with the same cyclophosphamide‐based graft‐versus‐host disease (GVHD) prophylaxis, describing risk factors for HC. The overall incidence of HC was 23%. Patients with HLA mismatched transplant, higher comorbidity score, and receiving three alkylating agents with TBF (thiotepa, busulfan, and fludarabine) conditioning regimen had a higher risk of HC in multivariate analysis (OR: 4.48, 6.32, and 1.32, respectively). A HC‐score including male gender, TBF conditioning, and HLA‐mismatch stratifies the risk of HC in the first 100 days after HSCT. The role of BKV and JCV was not highly impacting in those patients, suggesting a possible synergistic effect between CMV and JCV in causing HC. HC can be interpreted as the combination of patient‐related factors, chemotherapy‐related toxicities—especially due to alkylating agents—and immunological elements. [ABSTRACT FROM AUTHOR]

ABSTRACTObjective This study aims to investigate the efficacy and safety of hyperbaric oxygen therapy (HBOT) in the treatment of late-onset hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation.Methods This retrospective analysis included 16 patients with late-onset hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation between 2016 and 2022. Among them, 8 patients received HBOT in addition to conventional treatment, while the other 8 received only conventional treatment. The clinical efficacy and safety of HBOT were evaluated by comparing the Numeric Rating Scale pain scores and clinical grades of hematuria before and after treatment, reflecting the patients’ urinary pain and hematuria status.Results The patients were divided into two groups based on whether they received HBOT. The group that received HBOT (n = 8) had a shorter duration of illness compared to the non-HBOT group (n = 8) (p

ObjectivesTo describe mesenchymal stromal cells (MSCs) in the treatment of hematopoietic stem cell transplantation (HSCT) complications and to assess its safety and efficacy.MethodsSingle-center retrospective study (2016–2023). Patients under 20 years who received MSCs for the treatment of HSCT-related complications were included.ResultsThirty patients (53.7% boys), median age at transplant 11 years (range 2–19) were included. MSCs indications were: graft-vs.-host disease (GVHD) in 18 patients (60%), of them 13 had acute GVHD (43.3%) and 5 chronic GVHD (16.7%); Grade 3–4 hemorrhagic cystitis (HC) in 4 (13.3%); poor graft function (PGF) in 6 (20%), 5 of them receiving MSCs with a CD34 stem cell-boost coinfusion; graft failure (GF) in 2 (6.7%), to enhance engraftment after a subsequent HSCT. Infusion-related-adverse-events were not reported. Overall response (OR) was 83% (25/30); 44% of responders (11/25) showed complete response (CR). OR for GVHD, HC, PGF and GF was 83.3%, 100%, 66.7% and 100% respectively. Response rate was 40% (95% CI: 20–55) and 79% (95% CI: 57–89) at 15 and 30 days. With a median follow-up of 21 months (IQR11–52.5), overall survival (OS) was 86% (95% CI: 74–100) and 79% (95% CI: 65–95) at 6 and 12 months post-MSCs infusion.ConclusionIn our study, the most frequent indication of MSCs was refractory aGVHD (43.3%). Response rates were high (OR 83%) and safety profile was good.

Cyclophosphamide is commonly used in the treatment of various cancers and autoimmune diseases, while concurrently imposing substantial toxicity on the bladder, frequently manifesting hemorrhagic cystitis. Intravesical interventions, such as hyaluronic acid supplementation, present a therapeutic strategy to reinstate bladder barrier function and alleviate the effects of metabolic toxicants. However, it remains a great challenge to achieve efficient cyclophosphamide-induced hemorrhagic cystitis (CHC) management with accelerated tissue repair owing to the low wet-adhesion, poor hemostasis, and acute inflammatory responses. To address these issues, a hemostatic and anti-inflammatory hydrogel adhesive of chitosan methylacryloyl/silk fibroin methylacryloyl (CHMA/SFMA) is developed for promoting the healing of CHC. The obtained hydrogels show a high adhesive strength of 26.21 N/m with porcine bladder, facilitating the rapid hemostasis within 15 s, and reinstate bladder barrier function. Moreover, this hydrogel adhesive promotes the proliferation and aggregation of SV-HUC-1 and regulates macrophage polarization. Implanting the hydrogels into CHC bladders of a SD rat model, they not only can be completely biodegraded in 14 days, but also effectively control hematuria and inflammation, and accelerate angiogenesis, thereby significantly promote the healing of bladder injury. Overall, CHMA/SFMA hydrogels exhibit rapid hemostasis for treating CHC and accelerate muscle tissue repair via angiogenesis and inflammation amelioration, which may provide a new path for managing severe hemorrhagic cystitis in the clinics.

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Background: The aim of this study was to evaluate whether cyclophosphamide administered after allogeneic stem cell transplantation (ASCT) from 9/10 HLA-Matched Unrelated Donors (MMUD) increases the rates of bloodstream infections (BSI) (fungal, viral (CMV, BK, hepatitis), bacterial), infectious complications (hemorrhagic cystitis(HC)) and infection-related mortality compared to allogeneic stem cell transplantation from matched related donors (MRD). Metods: This is a retrospective multicenter study. 45 MMUD ASCT patients who received posttransplant cyclophosphamide + methotrexate + calcineurin inhibitor compared with 45 MRD ASCT patients who received methotrexate + calcineurin inhibitor. Results: Although there was a statistically significant prolongation of neutrophil engraftment time in the PTCy arm, there was no statistically significant difference in bacterial BSI frequencies between the groups (PTCy; 9(20%), control;8 (17.8%), p=0.778). The distribution of CMV infection in the first 100 days was similar (p=0.827) but the distribution of CMV infection rate between the 100th and 365th days, was observed more frequently in the control group (p=0.005). HC rates and their grades were similar in both groups (PTCy; 4 (8.8%), control;6 (13.3%) p=0.502). The rates of VZV infection and invasive aspergillosis were similar in the PTCy and control groups (13.3% in the PTCy, and 17.8% in the control group p=0.561). IRM rate was statistically similar in both groups (13.3% in the PTCy arm and 17.8% in the control arm) Conclusions: The addition of PTCy to standard GvHD prophylaxis in MMUD ASCT does not lead to an increase in CMV reactivation, bacterial BSI, invasive fungal infection, viral hemorrhagic cystitis or infection-related mortality.

In hematopoietic stem cell transplantation (HSCT) recipients, BK virus-related hemorrhagic cystitis is a well-known complication. It increases the risk of death and morbidity of HSCT recipients with simultaneous increase in healthcare cost burden, as a result of prolonged hospital admissions. There are many conservative therapeutic strategies available for the treatment that are effective in treatment of milder forms of hemorrhagic cystitis. Vesical artery embolization is one of the nonsurgical bailout procedure in patient's refractory to medical therapy with added advantage of avoidance of high-risk definitive surgical procedure of cystectomy or urinary diversion in these critical immunosuppressed patients.

Rats manifest a condition called hemorrhagic cystitis after spinal cord injury (SCI). The mechanism of this condition is unknown, but it is more severe in male rats than in female rats. We assessed the role of sex regarding hemorrhagic cystitis and pathological chronic changes in the bladder. We analyzed the urine of male and female Sprague-Dawley and Fischer 344 rats after experimental spinal cord contusion, including unstained microscopic inspections of the urine, differential white blood cell counts colored by the Wright stain, and total leukocyte counts using fluorescent nuclear stains. We examined bladder histological changes in acute and chronic phases of SCI, using principal component analysis (PCA) and clustered heatmaps of Pearson correlation coefficients to interpret how measured variables correlated with each other. Male rats showed a distinct pattern of macroscopic hematuria after spinal cord injury. They had higher numbers of red blood cells with significantly more leukocytes and neutrophils than female rats, particularly hypersegmented neutrophils. The histological examination of the bladders revealed a distinct line of apoptotic umbrella cells and disrupted bladder vessels early after SCI and progressive pathological changes in multiple bladder layers in the chronic phase. Multivariate analyses indicated immune cell infiltration in the bladder, especially hypersegmented neutrophils, that correlated with red blood cell counts in male rats. Our study highlights a hitherto unreported sex difference of hematuria and pathological changes in males and females’ bladders after SCI, suggesting an important role of immune cell infiltration, especially neutrophils, in SCI-induced hemorrhagic cystitis.

Francis A Jefferson, Brian J Linder Department of Urology, Mayo Clinic, Rochester, MN, USACorrespondence: Brian J Linder, Email Linder.Brian@mayo.eduAbstract: Hemorrhagic cystitis (HC) can be one of the most challenging clinical scenarios for urologists to manage. It most commonly occurs as a toxicity of pelvic radiation therapy or in patients treated with the oxazaphosphorine class of chemotherapy. Successful management of HC necessitates a stepwise approach with a thorough understanding of the various treatment options. Once ensuring hemodynamic stability, conservative management includes establishing bladder drainage, manual clot evacuation, and continuous bladder irrigation through a large-bore urethral catheter. If gross hematuria persists, operative cystoscopy with bladder clot evacuation is often required. There are multiple intravesical options for treating HC, including alum, aminocaproic acid, prostaglandins, silver nitrate, and formalin. Formalin is an intravesical option that has caustic effects on the bladder mucosa and is most often reserved as a last-line intravesical treatment. Non-intravesical management tools include hyperbaric oxygen therapy and oral pentosan polysulfate. If needed, nephrostomy tube placement or superselective angioembolization of the anterior division of the internal iliac artery can be performed. Finally, cystectomy with urinary diversion is a definitive, albeit invasive, treatment option for refractory HC. While there is no standardized algorithm, treatment modalities typically progress from less to more invasive. Clinical judgement and shared decision-making with the patient are required when choosing therapies for managing HC, as success rates are variable and some treatments may have significant or irreversible effects.Keywords: hemorrhagic cystitis, hematuria, cystectomy, formalin, bladder cancer, radiation

Rats manifest a condition called hemorrhagic cystitis after spinal cord injury (SCI). The mechanism of this condition is unknown, but it is more severe in male rats than in female rats. We assessed the role of sex regarding hemorrhagic cystitis and pathological chronic changes in the bladder. We analyzed the urine of male and female Sprague-Dawley and Fischer 344 rats after experimental spinal cord contusion, including unstained microscopic inspections of the urine, differential white blood cell counts colored by the Wright stain, and total leukocyte counts using fluorescent nuclear stains. We examined bladder histological changes in acute and chronic phases of SCI, using principal component analysis (PCA) and clustered heatmaps of Pearson correlation coefficients to interpret how measured variables correlated with each other. Male rats showed a distinct pattern of macroscopic hematuria after spinal cord injury. They had higher numbers of red blood cells with significantly more leukocytes and neutrophils than female rats, particularly hypersegmented neutrophils. The histological examination of the bladders revealed a distinct line of apoptotic umbrella cells and disrupted bladder vessels early after SCI and progressive pathological changes in multiple bladder layers in the chronic phase. Multivariate analyses indicated immune cell infiltration in the bladder, especially hypersegmented neutrophils, that correlated with red blood cell counts in male rats. Our study highlights a hitherto unreported sex difference of hematuria and pathological changes in males and females' bladders after SCI, suggesting an important role of immune cell infiltration, especially neutrophils, in SCI-induced hemorrhagic cystitis. [ABSTRACT FROM AUTHOR]

In hematopoietic stem cell transplantation (HSCT) recipients, BK virus-related hemorrhagic cystitis is a well-known complication. It increases the risk of death and morbidity of HSCT recipients with simultaneous increase in healthcare cost burden, as a result of prolonged hospital admissions. There are many conservative therapeutic strategies available for the treatment that are effective in treatment of milder forms of hemorrhagic cystitis. Vesical artery embolization is one of the nonsurgical bailout procedure in patient's refractory to medical therapy with added advantage of avoidance of high-risk definitive surgical procedure of cystectomy or urinary diversion in these critical immunosuppressed patients. [ABSTRACT FROM AUTHOR]

Acrolein is the main toxic metabolite of ifosfamide (IFO) that causes urothelial damage by oxidative stress and inflammation. Here, we investigate the molecular mechanism of action of gingerols, Zingiber officinale bioactive molecules, as an alternative treatment for ifosfamide-induced hemorrhagic cystitis. Female Swiss mice were randomly divided into 5 groups: control; IFO; IFO + Mesna; and IFO + [8]- or [10]-gingerol. Mesna (80 mg/kg, i.p.) was given 5 min before, 4 and 8 h after IFO (400mg/kg, i.p.). Gingerols (25 mg/kg, p.o.) were given 1 h before and 4 and 8 h after IFO. Animals were euthanized 12 h after IFO injection. Bladders were submitted to macroscopic and histological evaluation. Oxidative stress and inflammation were assessed by malondialdehyde (MDA) or myeloperoxidase assays, respectively. mRNA gene expression was performed to evaluate mesna and gingerols mechanisms of action. Mesna was able to protect bladder tissue by activating NF-κB and NrF2 pathways. However, we demonstrated that gingerols acted as an antioxidant and anti-inflammatory agent stimulating the expression of IL-10, which intracellularly activates JAK/STAT/FOXO signaling pathway. [ABSTRACT FROM AUTHOR]

Hemorrhagic cystitis (HC) is a common complication after transplantation. The purpose of this study was to examine the incidence and risk factors for HC after hematopoietic stem cell transplantation (HSCT). The records of patients who underwent allogenic HSCT from January 2012 to December 2018 at our institution were retrospectively reviewed. Cox proportional regression and Kaplan–Meier analyses were performed to determine independent risk factors for HC. The statistical analysis was performed in May 2020. A total of 173 patients underwent HSCT, and 53 (30.6%) developed grade 2 or 3 HC cystitis at a median of 37 days (range − 5 to 98 days) after transplantation. Thirty-two patients developed moderate (grade 2) cystitis and 21 severe (grade 3) cystitis. Of the 173 patients, 61 developed acute graft-versus-host disease (GVHD) (median onset day 24) and 79 experienced cytomegalovirus (CMV) reactivation (median onset day 35). The relative risk (RR) of developing a CMV infection for patients with acute GVHD was 2.77 times that of patients without acute GVHD (P < 0.001). CMV infection was the only independent variable significantly associated with HC in both univariate and multivariate analyses. The estimated hazard ratio (HR) of CMV infection for the development of HC was 5.57 (95% confidence interval [CI]: 2.52 to 12.33, P < 0.001). CMV infection is an independent risk factor for the development of HC after HSCT, and acute GVHD is a risk factor for CMV reactivation. Decreasing the frequency of GVHD after HSCT may result in a lower frequency of HC. [ABSTRACT FROM AUTHOR]

Background: High-level BK polyomavirus (BKPyV) replication in allogeneic hematopoietic cell transplantation (HCT) predicts failing immune control and BKPyV-associated hemorrhagic cystitis (BKPyV-HC).Methods: To identify molecular markers of BKPyV-replication and disease, we scrutinized BKPyV-DNA loads in longitudinal urine and plasma pairs from 20 HCT-patients using quantitative nucleic-acid-testing (QNAT), DNase-I treatment prior to QNAT, next-generation-sequencing (NGS) and tested cell-mediated immunity.Results: We found that larger QNAT amplicons led to under-quantification and false-negatives results (p < 0.001). DNase-I reduced urine and plasma BKPyV-loads by >90% (p < 0.001) indicating non-encapsidated BKPyV-genomes. DNase-resistant urine BKPyV-loads remained infectious in cell culture. BKPyV-genome fragmentation of ≤250 bp impaired NGS-coverage of genetic variation using 1000 bp and 5000 bp targets. Conversely, 250bp-amplicons captured viral minority variants. We identified genotype-specific and genotype-independent changes in capsid-Vp1 or large T-antigen predicted to escape from antibody neutralization or HLA-presentation to CD8 T-cells, respectively. Genotype-specific changes in immunodominant 9mers were associated with reduced or absent CD8 T-cell responses. Thus, failure to control BKPyV-replication in HCT-patients may involve insufficient genotype-specific cytotoxic CD8 T-cell responses potentially predictable by low neutralizing antibodies as well as genotype-independent immune escape of variants.Conclusion: Our results provide new insights for patient evaluation and for designing immune protection through neutralizing antibodies, adoptive T-cell therapy or vaccines. [ABSTRACT FROM AUTHOR]

Background Hemorrhagic cystitis (HC) is a severe complication of allo-HSCT, characterized by irritative symptoms of the urinary tract and a higher morbidity rate. The risk factors and prognosis of HC are still unclear.Objective The objective of this study is to identify risk factors and outcomes to improve treatment in pediatric SAA patients undergoing HSCTs in the Children's Hospital of Soochow University.Methods A total of 97 SAA patients as a cohort were enrolled from 2010 to 2019 in the Children's Hospital of Soochow University and a number of factors related to HC and outcomes were analysed. In all transplants (except UCBT), patients received a combination of G-CSF stimulated bone marrow (BM) and peripheral blood stem cell (PBSC). The minimum number of CD34 + cells is 5 × 106 cells/kg.Results Mononuclear cells dose (MNC, cut off: 8.53 × 108/kg) and grade II–IV acute graft versus host disease (aGVHD) were identified as independent risk factors for HC. Patients without HC had better overall survival (OS) than with HC (No HC: 98.6%±1.4% vs HC: 87.4% ± 6.8%, p = 0.03).Conclusion We concluded that aGVHD and MNC dose in graft might play an important role in the development of HC in pediatric SAA patients undergoing allo-HSCT. HC is also a key complication affecting the prognosis of children with SAA after allo-HSCT.

Introduction BK virus‐associated hemorrhagic cystitis is a significant complication of hematopoietic stem cell transplantation. Although severe BK virus‐associated hemorrhagic cystitis is associated with treatment‐related mortality, sufficient evidence regarding its management is lacking. Case presentation A 14‐year‐old boy presented with BK virus‐associated hemorrhagic cystitis and bladder clot retention after hematopoietic stem cell transplantation. Various urological interventions failed to improve cystitis. While bladder clot retention frequently recurred, surgical intervention was difficult because of the underlying hematological disorder. Hence, bilateral single‐J ureteral stenting followed by Foley catheter placement was performed as a urinary diversion. The bladder clot completely disappeared 27 days after stenting. No additional procedure was required. BK virus‐associated hemorrhagic cystitis did not recur after the blood clot disappeared. Conclusion Bilateral single‐J ureteral stenting followed by Foley catheter placement is a simple and effective treatment method and should be considered before surgical intervention for severe BK virus‐associated hemorrhagic cystitis.

Hemorrhagic cystitis is a common complication following the use of cyclophosphamide. Associated dysuria can be painful and there are few good options to relieve pain. Phenazopyridine has historically been utilized for dysuria and is available over the counter. However, it is associated with hematologic side effects with prolonged use. Here we present a case of a patient who developed Heinz body hemolysis following prolonged administration of phenazopyridine to treat cyclophosphamide‐induced hemorrhagic cystitis following hematopoietic stem cell transplant. [ABSTRACT FROM AUTHOR]

Introduction: Hemorrhagic cystitis (HC) is a common complication of haploidentical hematopoietic stem cell transplantation (haplo-HSCT), characterized by irritative symptoms of the urinary tract and a higher morbidity and mortality rate. The worldwide incidence is reported between 10% and 70%. The use of alkylating agents and BK viral infection are the most frequent etiologies. The aim of this study was to report the HC incidence in an outpatient haplo-HCST program with a reduced intensity-conditioning (RIC) regimen, cataloguing risk factors, complications and final outcomes. Methods: The medical database of patients who received a haplo-HSCT between January 2012 and November 2017 was retrospectively analyzed. Demographic variables, general characteristics and HC incidence were included. Results: One hundred and eleven patients were included, 30 (27%) of whom developed HC, most of them (70%) being grade II, with a 30-day (7–149) median time of post-transplant HC onset. The BK virus was detected in 71% of the urine samples analyzed. All HC patients responded to treatment, except two (6.6%), who died due to HC complications. Conclusions: There was no difference in the HC incidence or severity, compared to that reported when performing haplo-HSCT in hospitalized patients, although the donor-recipient sex mismatch did relate to a higher HC incidence.

Abstract Hemorrhagic cystitis is a common complication following the use of cyclophosphamide. Associated dysuria can be painful and there are few good options to relieve pain. Phenazopyridine has historically been utilized for dysuria and is available over the counter. However, it is associated with hematologic side effects with prolonged use. Here we present a case of a patient who developed Heinz body hemolysis following prolonged administration of phenazopyridine to treat cyclophosphamide‐induced hemorrhagic cystitis following hematopoietic stem cell transplant.

Hemorrhagic cystitis (HC) is a severe complication of allo-HSCT, characterized by irritative symptoms of the urinary tract and a higher morbidity rate. The risk factors and prognosis of HC are still unclear. The objective of this study is to identify risk factors and outcomes to improve treatment in pediatric SAA patients undergoing HSCTs in the Children's Hospital of Soochow University. A total of 97 SAA patients as a cohort were enrolled from 2010 to 2019 in the Children's Hospital of Soochow University and a number of factors related to HC and outcomes were analysed. In all transplants (except UCBT), patients received a combination of G-CSF stimulated bone marrow (BM) and peripheral blood stem cell (PBSC). The minimum number of CD34 + cells is 5 × 106 cells/kg. Mononuclear cells dose (MNC, cut off: 8.53 × 108/kg) and grade II–IV acute graft versus host disease (aGVHD) were identified as independent risk factors for HC. Patients without HC had better overall survival (OS) than with HC (No HC: 98.6%±1.4% vs HC: 87.4% ± 6.8%, p = 0.03). We concluded that aGVHD and MNC dose in graft might play an important role in the development of HC in pediatric SAA patients undergoing allo-HSCT. HC is also a key complication affecting the prognosis of children with SAA after allo-HSCT. [ABSTRACT FROM AUTHOR]

Introduction: Hemorrhagic cystitis can commonly occur following an allogeneic hematopoietic cell transplant and treatment options are currently limited. Pentosan polysulfate, a heparin-like, sulfated polysaccharide, is used to relieve bladder pain and discomfort associated with interstitial cystitis. Initial reports in patients with hemorrhagic cystitis demonstrate that pentosan polysulfate may hasten hemorrhagic cystitis resolution and control symptoms. Methods and results: This report includes a retrospective case series of six patients who received pentosan polysulfate for the treatment of hemorrhagic cystitis following an allogeneic hematopoietic cell transplant. Pentosan polysulfate was initiated at a median of 4.5 days (range: 3–18) following hemorrhagic cystitis onset and continued for a median duration of 17.5 days (range: 7–64). Four patients were tested for BK virus and all were found to have BK viremia and viruria around the time of pentosan polysulfate initiation. The median number of red blood cell transfusions seemed to decrease in the patients initiated on pentosan polysulfate. All patients received a multi-agent treatment regimen, which included pentosan polysulfate, and half the patients had symptom resolution. The median time to symptom resolution from pentosan polysulfate initiation was 9 days (range: 7–10). Conclusion: Pentosan polysulfate was well-tolerated and seemed to assist with symptom resolution. Future studies are needed to confirm the impact of pentosan polysulfate on the treatment of hemorrhagic cystitis. [ABSTRACT FROM AUTHOR]

Aim of the research. Description of a clinical case using the various methods of diagnosis and treatment of hemorrhagic cystitis in the extracorporeal program fertilization. Object and methods of research. A 29-year-old patient К. presented with hemorrhagic cystitis complicated by bladder hemotamponade, which was a result of in vitro fertilization. For the purpose of investigation and monitoring of the patient condition complete blood count, basic metabolic panel, urine test and ultrasonography of the abdomen and the cystoscopy were performed. Management was based on the current Ukrainian medical guidelines. Research results and discussion. After a thorough investigation of this clinical case, we can say that the patient had hemorrhagic cystitis complicated by hemotamponade of the bladder as a result of in vitro fertilization. Each individual patient should have an individual approach when choosing protocols for medical ovarian stimulation in an in vitro fertilization program. Conclusions. When using assisted reproductive technologies in patients in the in vitro fertilization program, complications may occur during and after transvaginal follicle puncture. Transvaginal puncture of the follicles carries the risk of bleeding, damage to the bladder, intestines or blood vessels. To date, a large number of clinical studies have been conducted in the in vitro fertilization program in order to ensure the safety of these procedures and with minimal risk to the patient. The variety of diseases manifested by hematuria, the features of the development and clinical course of these pathological processes require an integrated approach based on a multidisciplinary approach in the field of therapy, urology, gynecology, oncology and infectious pathology. The choice of protocol for medical ovarian stimulation should be based on individual approach, taking into account the degree of risk of any complication.

Introduction: BK polyomavirus-associated hemorrhagic cystitis (BKPyV-HC) is a well-recognized infective complication of hematopoietic cell transplant (HCT) with increased organ dysfunction and mortality. This study was performed to describe the local incidence, risk factors, and outcomes of BKPyV infection. Methods: This retrospective case–control study was conducted between 2007 and 2016 from a tertiary hospital in South India. We identified HCT recipients diagnosed with BKPyV-HC and compared them with recipients over the same period who did not develop BK virus infection matched for age, sex, diagnosis, and donor type. We collected data from central electronic medical records and databases maintained in the departments of hematology and virology. Results: Over the study period, 1276 transplants were performed, of which 262 patients (20.5%) developed HC and 105 (8.2%) were BKPyV-positive. Grade 3 HC was most commonly (57.1%) seen, and the median time to develop BKPyV-HC was 35 (range 0–858) days. Survival was significantly lower in the cases (42.9% vs. 61%, P < 0.05). On univariate analysis, the protective effect of nonmyeloablative conditioning (P = 0.04), residual disease at the time of transplant in malignant conditions (P = 0.001), lower CD34 dose (P = 0.006), presence of acute graft versus host disease (GVHD, P < 0.001), reactivation of cytomegalovirus infection (P < 0.001), and presence of bacterial urinary tract infection (UTI) (P < 0.001) were significant factors. Multivariate logistic regression confirmed the presence of acute GVHD (P = 0.041), bacterial UTI (P < 0.001), and residual disease (P = 0.009) at HCT as significant risk factors for BKPyV-HC. Conclusions: Our study affirms the homogeneity of BKPyV-HC disease in low- and middle-income HCT settings with prior reports and the need for therapeutic strategies to reduce its resultant mortality.

Purpose: Hemorrhagic cystitis (HC) which occurs in 9%–31% of recipients after hematopoietic stem cell transplantation (HSCT) is an important cause of morbidity and mortality. Various treatment approaches have been applied for such as conservative treatments (hydration, analgesic agents, antibiotics), intravesical treatments (bladder irrigation, hyaluronic acid, and prostaglandin E), intravenous or intravesical antiviral agents, hyperbaric oxygen, and surgical treatments. Materials and Methods: This retrospective study included two hundred thirty-three children who underwent HSCT in Pediatric Bone Marrow Transplantation unit between April 2010 and June 2017. Results: Ten patients (4.2%) developed HC. The mean age of patients was 12.8 years and the mean duration of the onset of HC was 20 days. Urine and blood BK polyomavirus were positive in nine and four patients, respectively. Six patients received intravesical hyaluronic acid, three patients received intravesical prostaglandin E, three patients received intravenous ganciclovir, two patients received intravenous and/or intravesical cidofovir and hyperbaric oxygen treatment. The mean time of recovery from hematuria was 43 days. This study showed that the BK polyomavirus has an important role in the development of HC in HSCT patients, as in harmony with the literature. HC has been successfully treated in eight patients with supportive measures and/or intravesical hyaluronic acid. Conclusions: BK polyomavirus plays an important role in the development of HC pediatric patients. Intravesical hyaluronic acid, besides supportive measures, was effective for the treatment of HC and hyperbaric oxygen may be reserved for refractory cases.

Ayman M Mousa,1,2 Khaled S Allemailem,1,3 Fahad A Alhumaydhi,3 Faris Alrumaihi,3 Ahmad Almatroudi,3 Ameen S Alwashmi,3 Mohammad Aljasir,3 Osamah Al Rugaie,4 Abdullah SM Aljohani,5 Khaled EA Soliman,4,6 Mohamad Y Rezk,4,7 Ahmed MS Hegazy,8,9 Hanan S Seleem4,10 1Department of Basic Health Sciences, College of Applied Medical Sciences, Qassim University, Buraydah, 51452, Saudi Arabia; 2Department of Histology and Cell Biology, Faculty of Medicine, Benha University, Benha, 13518, Egypt; 3Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah, 51452, Saudi Arabia; 4Department of Basic Medical Sciences, College of Medicine and Medical Sciences, Qassim University, Unaizah, 51452, Saudi Arabia; 5Department of Veterinary Medicine, College of Agricultural and Veterinary Medicine, Qassim University, Buraydah, 51452, Saudi Arabia; 6Department of Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Sohag University, Sohag, 82524, Egypt; 7Department of Medical Physiology, Faculty of Medicine, Zagazig University, Al-Sharquia, 44519, Egypt; 8Department of Anatomy, Faculty of Medicine, Northern Border University, Arar, Saudi Arabia; 9Department of Anatomy and Embryology, Faculty of Medicine, Benha University, Benha, 13518, Egypt; 10Department of Histology and Cell Biology, Faculty of Medicine, Menoufia University, Shebin Elkoum, EgyptCorrespondence: Ayman M MousaDepartment of Basic Health Sciences, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi ArabiaTel +966 598146171Email a.mousa@qu.edu.saBackground: Ifosfamide (IFS) has potential complications such as nephropathy and hemorrhagic cystitis (HC). Although mesna can prevent IFS-induced cystitis by direct binding and neutralization of acrolein, HC symptoms have still been observed clinically in most of these cases. Celery is a powerful healing vegetable that has antioxidant, anti-inflammatory, and anticancer effects. The current study evaluated the synergistic effects of mesna and celery seed on IFS-induced HC in rabbits.Methods: Twenty male rabbits (four groups) were administered distilled water, IFS, mesna, and mesna+celery seed cotherapy (MCC) for three weeks. The serum and urinary bladder of experimental rabbits underwent biochemical (TNF-α, MDA, iNOS, SOD, GPx, and CAT), histopathological and ultrastructural investigations to evaluate the structural changes of the urinary bladder (UB).Results: IFS injection resulted in severe cystitis with a remarkable increase in the scale of hematuria, elevations of TNF-α, MDA, and iNOS activity, and reduced activity of SOD, GPx, and CAT antioxidants. Additionally, the structure of UB exhibited evident mucosal edema and ulceration. In contrast, the MCC regimen group revealed partial synergistic improvement of all mentioned parameters.Conclusion: IFS induced cystitis by releasing acrolein, which exerted a significant role in the pathogenesis of HC. In contrast, the MCC intake partially ameliorated the UB damage through its antioxidant and anti-inflammatory effects.Keywords: ifosfamide, mesna, celery, hemorrhagic cystitis, antioxidants, anti-inflammatory

This study is to investigate the effect of late-onset hemorrhagic cystitis (LOHC) on progression-free survival (PFS) of patients after haploidentical peripheral blood hematopoietic stem cell transplantation (haplo-PBSCT).

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