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Symptomatic cytomegalovirus (CMV) disease has been the standard endpoint for clinical trials in organ transplant recipients. Viral load may be a more relevant endpoint due to low frequency of disease. We performed a meta-analysis and systematic review of the literature. We found several lines of evidence to support the validity of viral load as an appropriate surrogate end-point, including the following: (1) viral loads in CMV disease are significantly greater than in asymptomatic viremia (odds ratio, 9.3 95% confidence interval, 4.6-19.3); (2) kinetics of viral replication are strongly associated with progression to disease; (3) pooled incidence of CMV viremia and disease is significantly lower during prophylaxis compared with the full patient follow-up period (viremia incidence: 3.2% vs 34.3%; P < .001) (disease incidence: 1.1% vs 13.0%; P < .001); (4) treatment of viremia prevented disease; and (5) viral load decline correlated with symptom resolution. Based on the analysis, we conclude that CMV load is an appropriate surrogate endpoint for CMV trials in organ transplant recipients.

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Background. Strict definition of invasive aspergillosis (IA) cases is required to allow precise conclusions about the efficacy of antifungal therapy. The Global Comparative Aspergillus Study (GCAS) compared voriconazole to amphotericin B (AmB) deoxycholate for the primary therapy of IA. Because predefined definitions used for this trial were substantially different from the consensus definitions proposed by the European Organization for Research and Treatment of Cancer/Mycoses Study Group in 2008, we recategorized the 379 episodes of the GCAS according to the later definitions. Methods. The objectives were to assess the impact of the current definitions on the classification of the episodes and to provide comparative efficacy for probable/proven and possible IA in patients treated with either voriconazole or AmB. In addition to original data, we integrated the results of baseline galactomannan serum levels obtained from 249 (65.7%) frozen samples. The original response assessment was accepted unchanged. Results. Recategorization allowed 59 proven, 178 probable, and 106 possible IA cases to be identified. A higher favorable 12-week response rate was obtained with voriconazole (54.7%) than with AmB (29.9%) (P < .0001). Survival was higher for voriconazole for mycologically documented (probable/proven) IA (70.2%) than with AmB (54.9%) (P = .010). Higher response rates were obtained in possible IA treated with voriconazole vs AmB with the same magnitude of difference (26.2%; 95% confidence interval [CI], 7.2%–45.3%) as in mycologically documented episodes (24.3%; 95% CI, 11.9%–36.7%), suggesting that possible cases are true IA. Conclusions. Recategorization resulted in a better identification of the episodes and confirmed the higher efficacy of voriconazole over AmB deoxycholate in mycologically documented IA.

Background. Invasive candidiasis is the third most common bloodstream infection in the intensive care unit (ICU) and is associated with morbidity and mortality. Prophylaxis and preemptive therapy are attractive strategies for this setting. Methods. We conducted a multicenter, randomized, double-blind, placebo-controlled trial of caspofungin as antifungal prophylaxis in 222 adults who were in the ICU for at least 3 days, were ventilated, received antibiotics, had a central line, and had 1 additional risk factor (parenteral nutrition, dialysis, surgery, pancreatitis, systemic steroids, or other immunosuppressants). Subjects' (1,3)-β-D-glucan levels were monitored twice weekly. The primary endpoint was the incidence of proven or probable invasive candidiasis by EORTC/MSG criteria in patients who did not have disease at baseline. Patients who had invasive candidiasis were allowed to break the blind and receive preemptive therapy with caspofungin. The preemptive approach analysis included patients all patients who received study drug, including those positive at baseline. Results. The incidence of proven/probable invasive candidiasis in the placebo and caspofungin arms was 16.7% (14/84) and 9.8% (10/102), respectively, for prophylaxis (P = .14), and 30.4% (31/102) and 18.8% (22/117), respectively, for the preemptive approach (P = .04); however, this analysis included patients with baseline disease. There were no significant differences in the secondary endpoints of mortality, antifungal use, or length of stay. There were no safety differences. Conclusions. Caspofungin was safe and tended to reduce the incidence of invasive candidiasis when used for prophylaxis, but the difference was not statistically significant. A preemptive therapy approach deserves further study. Clinical Trials Registration. NCT00520234.

Disease recurrence is the leading cause of treatment failure in patients with RUNX1::RUNXT1-positive acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Post-transplant maintenance therapy, guided by monitoring minimal residual disease (MRD), is commonly administered; however, relapse rates remain high. This prospective study aimed to assess the effectiveness and safety of epigenetic agents as prophylactic therapy in patients with RUNX1::RUNXT1-positive AML. Thirty high-risk patients received prophylactic therapy (n = 17 and n = 13 in the chidamide and AZA groups, respectively) between January 2019 and July 2023. 34 high-risk patients who received preemptive treatment due to molecular relapse were included in the analysis. The two-year relapse-free survival (RFS) and overall survival (OS) were significantly higher in the prophylactic group compared to the preemptive group (82.82% vs. 51.38%, P = 0.014; 86.42% vs. 56.16%, P = 0.025, respectively); 2-year cumulative incidence of relapse rates were 13.8% and 36.40%, respectively (P = 0.037). In conclusion, prophylactic therapy with epigenetic agents may improve long-term prognosis and is well-tolerated in patients with RUNX1::RUNXT1-positive high-risk AML. Timely post-transplant prophylactic therapy may be more effective than preemptive therapy based on positive MRD results.

BackgroundTo conduct a meta-analysis with the aim of comparing the outcomes of antiviral prophylaxis and preemptive therapy for the prevention of cytomegalovirus (CMV) infection in liver transplant (LT) recipients.MethodsWe searched databases for qualified studies up until March 2022. Finally, a meta-analysis was carried out using a fixed-effect or random-effect model based on the heterogeneity.ResultsWith a total of 1834 LT patients, the pooled incidence of CMV infection and CMV disease in the overall LT recipients using antiviral prophylaxis and preemptive therapy were 24.7% vs. 40.4% and 6.4% vs. 9.4%, respectively. Our meta-analysis exhibited a significant reduction in the incidence of CMV infection due to antiviral prophylaxis when compared to preemptive therapy in the high-risk group (OR: 6.67, 95% CI: 1.73, 25.66; p = 0.006). In contrast, there was a significant reduction in the incidence of late-onset of CMV disease in preemptive therapy compared to antiviral prophylaxis in the high-risk group (OR: 0.29, 95% CI: 0.12, 0.74; p = 0.009). However, the incidence of CMV disease, allograft rejection, graft loss, drug related adverse effects, opportunistic infections and mortality did not differ significantly between both the interventions (all p> 0.05).ConclusionsWe found the use of antiviral prophylaxis, compared with preemptive therapy, is superior in controlling CMV infection and prolonging the time to CMV disease in LT recipients without an increased risk of opportunistic infections, allograft rejection, graft loss, drug related adverse effects, development of drug resistance, and mortality.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is theoretically the only curative option for high-risk myelodysplastic syndrome (HR MDS) patients. However, the management of patients with relapsed disease post allo-HSCT remains a challenge with few standard treatments. Chidamide, a new selective histone deacetylase, has shown synergistic anti-leukemia effect combined with azacitidine in acute myeloid leukemia patients. Herein, we reported a 50-year-old HR MDS patient who experienced molecular relapse post allo-HSCT and was successfully salvaged by preemptive treatment of chidamide combined with azacitidine (CHI-AZA). This patient maintained a deep remission lasting over 2 years by regular maintenance treatment of CHI-AZA, without sever treatment-related adverse events or increased risk of graft versus host disease. This case report demonstrated that double epigenetic regimen of CHI-AZA was effective and tolerable. Formally evaluating this regimen in HR MDS patients post allo-HSCT may be meaningful.

Background In the absence of an adequate prevention strategy, up to 20% of CMV IgG+ liver transplant recipients (LTR) will develop CMV disease. Despite improved reporting in CMV-DNAemia, there is no consensus as to what the ideal CMV-DNAemia cutoff for a successful preemptive strategy is. Each transplant centre establishes their own threshold. We aimed to determine the effectiveness of our preventive strategy in CMV IgG+ LTR, and evaluate CMV replication kinetics. Methods In this retrospective study we determined the incidence of CMV disease in the first 6 months following transplantation in CMV seropositive LTR in a tertiary-care centre in Mexico. Secondary outcomes were determining the number of patients who required preemptive therapy (treatment cutoff ≥ 4000 UI/ml), adherence to the centre’s prevention protocol and calculation of viral replication kinetics. Results One-hundred and twenty-four patients met inclusion criteria. Four patients (3.2%) developed CMV disease. Ninety-six (85%) had detectable DNAemia and 25 (22%) asymptomatic patients received preemptive therapy, none of them developed CMV disease. The highest viral loads were observed on the second posttransplant month. The number of viral load measurements decreased over time. Patients with DNAemia ≥ 4000 UI/ml had a faster viral load growth rate, shorter viral load duplication time, and higher basic reproductive number. Viral load growth rate and autoimmune hepatitis were associated with development of DNAemia ≥ 4000 UI/ml. Conclusion Cytomegalovirus disease occurred in 3.2% of the study subjects. Preemptive therapy using a threshold of CMV ≥ 4000 UI/ml was effective in reducing the incidence of end-organ disease. The viral replication parameters described in this population highlight the importance of frequent monitoring, a challenging feat for transplant programs in low- and middle-income countries.

Background Magnesium is an antagonist of the N-methyl-D-aspartate receptor. This study aimed to investigate the anti-edematous effect of magnesium sulfate (MS) in different protocols of use and the possible mechanism of its action. Methods In a rat model of carrageenan-induced paw inflammation, the anti-edematous activity of MS was assessed with a plethysmometer. The effects of the nonselective inhibitor (L-NAME), selective inhibitor of neuronal (L-NPA) and inducible (SMT) nitric oxide synthase on the effects of MS were evaluated. Results MS administered systemically before or after inflammation reduced edema by 30% (5 mg/kg, P < .05) and 55% (30 mg/kg, P < .05). MS administered locally (.5 mg/paw, P < .05) significantly prevented the development of inflammatory edema by 60%. L-NAME, intraperitoneally administered before MS, potentiated (5 mg/kg, P < .05) or reduced (3 mg/kg, P < .05), while in the highest tested dose L-NPA (2 mg/kg, P < .01) and SMT (.015 mg/kg, P < .01) reduced the anti-edematous effect of MS. Conclusions Magnesium is a more effective anti-edematous drug in therapy than for preventing inflammatory edema. The effect of MS is achieved after systemic and local peripheral administration and when MS is administered as a single drug in a single dose. This effect is mediated at least in part via the production of nitric oxide.