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Briefings in Bioinformatics Mar 2024Gliomas are the most common type of malignant brain tumors, with glioblastoma multiforme (GBM) having a median survival of 15 months due to drug resistance and relapse....
Gliomas are the most common type of malignant brain tumors, with glioblastoma multiforme (GBM) having a median survival of 15 months due to drug resistance and relapse. The treatment of gliomas relies on surgery, radiotherapy and chemotherapy. Only 12 anti-brain tumor chemotherapies (AntiBCs), mostly alkylating agents, have been approved so far. Glioma subtype-specific metabolic models were reconstructed to simulate metabolite exchanges, in silico knockouts and the prediction of drug and drug combinations for all three subtypes. The simulations were confronted with literature, high-throughput screenings (HTSs), xenograft and clinical trial data to validate the workflow and further prioritize the drug candidates. The three subtype models accurately displayed different degrees of dependencies toward glutamine and glutamate. Furthermore, 33 single drugs, mainly antimetabolites and TXNRD1-inhibitors, as well as 17 drug combinations were predicted as potential candidates for gliomas. Half of these drug candidates have been previously tested in HTSs. Half of the tested drug candidates reduce proliferation in cell lines and two-thirds in xenografts. Most combinations were predicted to be efficient for all three glioma types. However, eflornithine/rifamycin and cannabidiol/adapalene were predicted specifically for GBM and low-grade glioma, respectively. Most drug candidates had comparable efficiency in preclinical tests, cerebrospinal fluid bioavailability and mode-of-action to AntiBCs. However, fotemustine and valganciclovir alone and eflornithine and celecoxib in combination with AntiBCs improved the survival compared to AntiBCs in two-arms, phase I/II and higher glioma clinical trials. Our work highlights the potential of metabolic modeling in advancing glioma drug discovery, which accurately predicted metabolic vulnerabilities, repurposable drugs and combinations for the glioma subtypes.
Topics: Humans; Glioma; Cannabidiol; Brain Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Animals; Models, Biological; Cell Line, Tumor; Organophosphorus Compounds
PubMed: 38701414
DOI: 10.1093/bib/bbae199 -
The Cochrane Database of Systematic... May 2024The risk of cytomegalovirus (CMV) infection in solid organ transplant recipients has resulted in the frequent use of prophylaxis to prevent the clinical syndrome... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The risk of cytomegalovirus (CMV) infection in solid organ transplant recipients has resulted in the frequent use of prophylaxis to prevent the clinical syndrome associated with CMV infection. This is an update of a review first published in 2005 and updated in 2008 and 2013.
OBJECTIVES
To determine the benefits and harms of antiviral medications to prevent CMV disease and all-cause death in solid organ transplant recipients.
SEARCH METHODS
We contacted the information specialist and searched the Cochrane Kidney and Transplant Register of Studies up to 5 February 2024 using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal, and ClinicalTrials.gov.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) and quasi-RCTs comparing antiviral medications with placebo or no treatment, comparing different antiviral medications or different regimens of the same antiviral medications for CMV prophylaxis in recipients of any solid organ transplant. Studies examining pre-emptive therapy for CMV infection are studied in a separate review and were excluded from this review.
DATA COLLECTION AND ANALYSIS
Two authors independently assessed study eligibility, risk of bias and extracted data. Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes and mean difference (MD) and 95% CI for continuous outcomes. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.
MAIN RESULTS
This 2024 update found four new studies, bringing the total number of included studies to 41 (5054 participants). The risk of bias was high or unclear across most studies, with a low risk of bias for sequence generation (12), allocation concealment (12), blinding (11) and selective outcome reporting (9) in fewer studies. There is high-certainty evidence that prophylaxis with aciclovir, ganciclovir or valaciclovir compared with placebo or no treatment is more effective in preventing CMV disease (19 studies: RR 0.42, 95% CI 0.34 to 0.52), all-cause death (17 studies: RR 0.63, 95% CI 0.43 to 0.92), and CMV infection (17 studies: RR 0.61, 95% CI 0.48 to 0.77). There is moderate-certainty evidence that prophylaxis probably reduces death from CMV disease (7 studies: RR 0.26, 95% CI 0.08 to 0.78). Prophylaxis reduces the risk of herpes simplex and herpes zoster disease, bacterial and protozoal infections but probably makes little to no difference to fungal infection, acute rejection or graft loss. No apparent differences in adverse events with aciclovir, ganciclovir or valaciclovir compared with placebo or no treatment were found. There is high certainty evidence that ganciclovir, when compared with aciclovir, is more effective in preventing CMV disease (7 studies: RR 0.37, 95% CI 0.23 to 0.60). There may be little to no difference in any outcome between valganciclovir and IV ganciclovir compared with oral ganciclovir (low certainty evidence). The efficacy and adverse effects of valganciclovir or ganciclovir were probably no different to valaciclovir in three studies (moderate certainty evidence). There is moderate certainty evidence that extended duration prophylaxis probably reduces the risk of CMV disease compared with three months of therapy (2 studies: RR 0.20, 95% CI 0.12 to 0.35), with probably little to no difference in rates of adverse events. Low certainty evidence suggests that 450 mg/day valganciclovir compared with 900 mg/day valganciclovir results in little to no difference in all-cause death, CMV infection, acute rejection, and graft loss (no information on adverse events). Maribavir may increase CMV infection compared with ganciclovir (1 study: RR 1.34, 95% CI: 1.10 to 1.65; moderate certainty evidence); however, little to no difference between the two treatments were found for CMV disease, all-cause death, acute rejection, and adverse events at six months (low certainty evidence).
AUTHORS' CONCLUSIONS
Prophylaxis with antiviral medications reduces CMV disease and CMV-associated death, compared with placebo or no treatment, in solid organ transplant recipients. These data support the continued routine use of antiviral prophylaxis in CMV-positive recipients and CMV-negative recipients of CMV-positive organ transplants.
Topics: Humans; Acyclovir; Antiviral Agents; Bias; Cause of Death; Cytomegalovirus Infections; Ganciclovir; Organ Transplantation; Postoperative Complications; Randomized Controlled Trials as Topic; Transplant Recipients; Valacyclovir; Valganciclovir
PubMed: 38700045
DOI: 10.1002/14651858.CD003774.pub5 -
Journal of Clinical Virology : the... Jun 2024Valganciclovir (valG), a cytomegalovirus (CMV) prophylactic agent, has dose-limiting side effects. The tolerability and effectiveness of valacyclovir (valA) as CMV... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Valganciclovir (valG), a cytomegalovirus (CMV) prophylactic agent, has dose-limiting side effects. The tolerability and effectiveness of valacyclovir (valA) as CMV prophylaxis is unknown.
METHODS
We conducted a randomized, open-label, single-center trial of valA versus valG for all posttransplant CMV prophylaxis in adult and pediatric kidney recipients. Participants were randomly assigned to receive valA or valG. Primary endpoints were the incidence of CMV viremia and side-effect related drug reduction with secondary assessment of incidence of EBV viremia.
RESULTS
Of the 137 sequential kidney transplant recipients enrolled, 26 % were positive and negative for CMV antibody in donor and recipient respectively. The incidence of CMV viremia (4 of 71 [6 %]; 8 of 67 [12 %] P = 0.23), time to viremia (P = 0.16) and area under CMV viral load time curve (P = 0.19) were not significantly different. ValG participants were significantly more likely to require side-effect related dose reduction (15/71 [21 %] versus 1/66 [2 %] P = 0.0003). Leukopenia was the most common reason for valG dose reduction and granulocyte-colony stimulating factor was utilized for leukopenia recovery more frequently (25 % in valG vs 5 % in valA: P = 0.0007). Incidence of EBV viremia was not significantly different.
CONCLUSIONS
ValA has significantly less dose-limiting side effects than valG. In our study population, a significant increase in CMV viremia was not observed, in adults and children after kidney transplant, compared to valG.
TRIAL REGISTRATION NUMBER
NCT01329185.
Topics: Humans; Valacyclovir; Cytomegalovirus Infections; Valganciclovir; Kidney Transplantation; Antiviral Agents; Male; Female; Adult; Transplant Recipients; Child; Middle Aged; Adolescent; Ganciclovir; Viremia; Viral Load; Young Adult; Valine; Cytomegalovirus; Child, Preschool; Acyclovir; Aged; Treatment Outcome; Incidence
PubMed: 38688164
DOI: 10.1016/j.jcv.2024.105678 -
Clinical Transplantation May 2024Cytomegalovirus (CMV) remains the predominant opportunistic infection following solid organ transplantation (SOT). While valganciclovir is the drug of choice for CMV... (Observational Study)
Observational Study
INTRODUCTION
Cytomegalovirus (CMV) remains the predominant opportunistic infection following solid organ transplantation (SOT). While valganciclovir is the drug of choice for CMV prophylaxis, its utility can be compromised due to the risk of cytopenia. Letermovir, a novel agent approved for CMV prophylaxis in allogeneic hematopoietic stem cell transplant recipients and high-risk kidney transplant recipients, exhibits reduced toxicity. This study aims to present the practical application of letermovir as both primary and secondary prophylaxis against CMV in heart transplant recipients (HTR).
METHODS
In this observational, retrospective, single-center study, we included all consecutive adult HTRs from June 2020 to January 2022 who were administered letermovir for CMV prophylaxis. We documented instances of CMV breakthrough infections, side effects related to letermovir, changes in neutropenia following the switch from valganciclovir to letermovir, and any drug interactions with the immunosuppressive regimen.
RESULTS
The study comprised 10 patients: two received primary prophylaxis with letermovir due to a high risk of CMV infection (donor-positive, recipient-negative serostatus), and eight received it as secondary prophylaxis following a CMV infection. The median duration of letermovir administration was 8 months (range 3-12 months). No CMV breakthrough infections were reported while on prophylaxis. However, three patients experienced CMV breakthrough infections after discontinuing letermovir prophylaxis (30%). No significant side effects were observed, although one patient reported digestive intolerance. Among the nine patients on tacrolimus, six needed reduced doses after switching to letermovir.
CONCLUSION
This real-life study appears to support the effectiveness of letermovir prophylaxis in HTR. Nonetheless, the risk of CMV infection post-treatment cessation is notable. Further drug monitoring and research on the efficacy of letermovir for CMV prophylaxis in SOT patients is warranted.
Topics: Humans; Cytomegalovirus Infections; Heart Transplantation; Male; Retrospective Studies; Antiviral Agents; Female; Middle Aged; Follow-Up Studies; Cytomegalovirus; Adult; Aged; Prognosis; Acetates; Quinazolines; Transplant Recipients; Postoperative Complications; Risk Factors; Graft Rejection
PubMed: 38686437
DOI: 10.1111/ctr.15327 -
Diagnostics (Basel, Switzerland) Apr 2024An association between subtle changes in T2 white matter hyper-intense signals (WMHSs) detected in fetal brain magnetic resonance imaging (fbMRI) and congenital...
An association between subtle changes in T2 white matter hyper-intense signals (WMHSs) detected in fetal brain magnetic resonance imaging (fbMRI) and congenital cytomegalovirus (CMV) infection has been established. The research aim of this study is to compare children with congenital CMV infection with neurodevelopment outcome and hearing deficit with and without WMHSs in a historic prospective case study cohort of 58 fbMRIs. Of these, in 37 cases, fbMRI was normal (normal group) and WMHSs were detected in 21 cases (WMHS group). The median infection week of the WMHS group was earlier than the normal fbMRI group (8 and 17 weeks of gestation, respectively). The proportion of infants treated with valganciclovir in the WMHS group was distinctly higher. Hearing impairment was not significantly different between the groups. VABS scores in all four domains were within normal range in both groups. The median score of the motor skills corrected for week of infection was better in the WMHS group. A multivariate analysis using the week of infection interaction variable of WMHS and valganciclovir treatment showed better motor score outcomes in the valganciclovir treatment group despite an earlier week of infection. WMHSs were not associated with neurodevelopmental outcome and hearing deficit. In our cohort, valganciclovir treatment may have a protective effect on fetuses with WMHSs by improving neurodevelopmental outcome.
PubMed: 38667443
DOI: 10.3390/diagnostics14080797 -
Journal of Medical Virology Apr 2024This study evaluated the cost-effectiveness of maribavir versus investigator-assigned therapy (IAT; valganciclovir/ganciclovir, foscarnet, or cidofovir) for... (Comparative Study)
Comparative Study
Cost-effectiveness of maribavir versus conventional antiviral therapies for post-transplant refractory cytomegalovirus infection with or without genotypic resistance: A US perspective.
This study evaluated the cost-effectiveness of maribavir versus investigator-assigned therapy (IAT; valganciclovir/ganciclovir, foscarnet, or cidofovir) for post-transplant refractory cytomegalovirus (CMV) infection with or without resistance. A two-stage Markov model was designed using data from the SOLSTICE trial (NCT02931539), real-world multinational observational studies, and published literature. Stage 1 (0-78 weeks) comprised clinically significant CMV (csCMV), non-clinically significant CMV (n-csCMV), and dead states; stage 2 (78 weeks-lifetime) comprised alive and dead states. Total costs (2022 USD) and quality-adjusted life years (QALYs) were estimated for the maribavir and IAT cohorts. An incremental cost-effectiveness ratio was calculated to determine cost-effectiveness against a willingness-to-pay threshold of $100 000/QALY. Compared with IAT, maribavir had lower costs ($139 751 vs $147 949) and greater QALYs (6.04 vs 5.83), making it cost-saving and more cost-effective. Maribavir had higher acquisition costs compared with IAT ($80 531 vs $65 285), but lower costs associated with administration/monitoring ($16 493 vs $27 563), adverse events (AEs) ($11 055 vs $16 114), hospitalization ($27 157 vs $33 905), and graft loss ($4516 vs $5081), thus making treatment with maribavir cost-saving. Maribavir-treated patients spent more time without CMV compared with IAT-treated patients (0.85 years vs 0.68 years), leading to lower retreatment costs for maribavir (cost savings: -$42 970.80). Compared with IAT, maribavir was more cost-effective for transplant recipients with refractory CMV, owing to better clinical efficacy and avoidance of high costs associated with administration, monitoring, AEs, and hospitalizations. These results can inform healthcare decision-makers on the most effective use of their resources for post-transplant refractory CMV treatment.
Topics: Humans; Cost-Benefit Analysis; Cytomegalovirus Infections; Antiviral Agents; Ribonucleosides; Benzimidazoles; Quality-Adjusted Life Years; United States; Cytomegalovirus; Drug Resistance, Viral; Male; Female; Middle Aged; Adult; Genotype; Transplant Recipients; Dichlororibofuranosylbenzimidazole
PubMed: 38647051
DOI: 10.1002/jmv.29609 -
Cureus Mar 2024Cytomegalovirus (CMV) retinitis is commonly associated with immunosuppression and can cause irreversible vision loss. Chimeric antigen receptor T-cell (CAR-T) therapy...
Cytomegalovirus (CMV) retinitis is commonly associated with immunosuppression and can cause irreversible vision loss. Chimeric antigen receptor T-cell (CAR-T) therapy has emerged as an effective cancer treatment option but requires immunosuppression, thereby increasing the possibility of acquiring opportunistic infections such as CMV. We present the case of a 76-year-old female with a history of hypertension and type 2 diabetes mellitus who initially presented with shortness of breath and was diagnosed with the activated B-cell subset of diffuse large B-cell lymphoma (DLBCL). She received multiple cycles of chemotherapy and experienced relapses with cardiac involvement. The patient developed vision loss in the right eye and was diagnosed with bilateral posterior vitritis. She underwent various treatments, including radiotherapy, systemic chemotherapy, cataract extraction, and vitrectomy. After CAR-T therapy, she developed bilateral CMV retinitis, confirmed through polymerase chain reaction testing and managed by valganciclovir. Overall, this case report describes the first reported case of bilateral CMV retinitis following CAR-T therapy for DLBCL. It emphasizes the need for early recognition and treatment of CMV retinitis to prevent permanent vision loss. The report also underscores the importance of regular ocular screening and consideration of prophylactic measures in patients undergoing CAR-T therapy.
PubMed: 38646322
DOI: 10.7759/cureus.56637 -
Journal of Cardiology Cases Apr 2024Inflammatory bowel disease (IBD) is a complex chronic inflammatory intestinal disease. The development of de novo IBD after solid organ transplantation with...
UNLABELLED
Inflammatory bowel disease (IBD) is a complex chronic inflammatory intestinal disease. The development of de novo IBD after solid organ transplantation with immunosuppressive agents has been rarely reported. We present the case of a 65-year-old man with repeated colitis after heart transplantation (HTx) who was diagnosed with Crohn's disease (CD). The patient underwent HTx due to non-ischemic dilated cardiomyopathy. Six months after HTx, he developed serious diarrhea and a transient fever, which persisted for about 6 months. Valganciclovir or any antibiotic agents were not effective for his symptoms and longitudinal ulcers in colonoscopy aggravated during the course, so that we made a diagnosis of CD. We started 5-aminosalicylic acid and found improvement in his symptoms and colonoscopic findings. However, 7 months after improvement, CD worsened. We started ustekinumab by which his condition successfully went into remission again. While oral immunosuppressive drugs are thought to suppress autoimmune diseases in general, IBD should be included in the differential diagnoses for recurring enterocolitis after HTx. Poorly controlled CD can lead to serious and potentially fatal complications, but in this case, ustekinumab has been used safely and effectively for the treatment of CD.
LEARNING OBJECTIVE
Colitis is a common complication after heart transplantation (HTx). Although cytomegalovirus colitis or posttransplant lymphoproliferative disorder are observed commonly, de novo inflammatory bowel disease (IBD) should be considered when serious refractory colitis occurs. Not only 5-aminosalicylic acid but also ustekinumab, which is a monoclonal antibody to the p40 subunit of interleukin (IL)-12 and IL-23, may be a safe and effective treatment for de novo IBD after HTx.
PubMed: 38646076
DOI: 10.1016/j.jccase.2023.12.005 -
Pediatric Transplantation May 2024
Topics: Child; Humans; Valganciclovir; Neutropenia; Organ Transplantation
PubMed: 38623879
DOI: 10.1111/petr.14754 -
Ocular Immunology and Inflammation Apr 2024To describe the spectrum of clinical features of cytomegalovirus-related anterior uveitis (CMV-AU) along with potential comorbidities, to calculate complication rates,...
PURPOSE
To describe the spectrum of clinical features of cytomegalovirus-related anterior uveitis (CMV-AU) along with potential comorbidities, to calculate complication rates, and to determine risk factors and biomarkers affecting prognosis in a cohort of a Southern European Mediterranean population.
MATERIALS AND METHODS
It is a retrospective, multicenter case series of consecutive patients with persisting hypertensive AU, unresponsive to topical steroids therapy, and CMV-positive essays from two uveitis referral centers were collected and analyzed.
RESULTS
Fifty-seven eyes of 53 patients with polymerase chain reaction-verified CMV-AU over a period of 8 years were included with a mean age of 48 ± 18. Four presentation patterns were identified: 26.3% as Posner-Schlossman-like, 31.6% as chronic AU, 19.3% as presumed herpetic uveitis, 12.3% as Fuchs uveitis syndrome-like, and 10.5% without specific initial classification. About 15.8% received oral valganciclovir, 22.8% received topical valganciclovir, and 61.4% received both, for a mean duration of treatment of 44 months. AU recurrences were observed in 23 eyes with a mean of 1.5 (±1.5) recurrences per year. The only finding significantly associated with recurrence was the presence of posterior synechiae (PS) ( = 0.034). Fewer keratic precipitates (KPs) were indicative for the need of longer treatment, and endotheliitis was strongly associated with the need for filtration surgery.
CONCLUSION
In this immunocompetent southern European population, four distinct clinical presentation patterns were further confirmed, and possible biomarkers such as PS, KPs, and endotheliitis were newly reported to influence treatment outcomes. Large-scale studies could provide a more effective customized treatment protocol.
PubMed: 38621024
DOI: 10.1080/09273948.2024.2329315