Primary refractory acute myeloid leukaemia (AML) remains a major clinical challenge, with poor outcomes despite salvage chemotherapy. Allogeneic haematopoietic cell transplantation (HCT) continues to be a potentially curative option for these patients. However, recent data on outcomes and prognostic factors specific to primary refractory AML remain limited. We conducted a retrospective analysis of 2600 adult patients with primary refractory AML who underwent their first allogeneic HCT between 2013 and 2022, using data from the Japanese national registry. The 3-year overall survival (OS) and leukaemia-free survival (LFS) rates were 28.5% and 24.4% respectively. The multivariate analysis identified older age (≥50 years), poor performance status (≥2), adverse cytogenetics, extramedullary disease at diagnosis and higher peripheral blood blast count at HCT (≥10%) as significant risk factors for worse OS and LFS. The cumulative incidences of relapse and non-relapse mortality at 3 years were 49.8% and 25.8% respectively. Based on the five significant risk factors, we developed a scoring system that effectively stratified patients into distinct prognostic groups for OS and LFS. This nationwide analysis demonstrated that allogeneic HCT offers the potential for long-term survival in adult patients with primary refractory AML. The proposed risk-scoring system may support clinical decision-making and patient counselling.
Future pandemic threats may be caused by novel coronaviruses and influenza A viruses. Here we show that when directly added to a cell culture, 12mer guanine RNA (G12) and its phosphorothioate-linked derivatives (G12(S)), rapidly entered cytoplasm and suppressed the propagation of human coronaviruses and influenza A viruses to between 1/100 and nearly 1/1000 of normal virus infectivity without cellular toxicity and induction of innate immunity. Moreover, G12(S) alleviated the weight loss caused by coronavirus infection in mice. G12(S) might exhibit a stable G-tetrad with left-handed parallel-stranded G-quadruplex, and inhibit the replication process by impeding interaction between viral nucleoproteins and viral RNA in the cytoplasm. Unlike previous antiviral strategies that target the G-quadruplexes of the viral genome, we now show that excess exogenous G-quadruplex-forming small RNA displaces genomic RNA from ribonucleoprotein, effectively inhibiting viral replication. The approach has the potential to facilitate the creation of versatile middle-molecule antivirals featuring lipid nanoparticle-free delivery. Phosphorothioate-linked guanosine 12mer inhibits the interaction of viral genomic RNA with nucleoprotein in the cytoplasm, suppressing the proliferation of coronaviruses and influenza A viruses that have the potential to cause future pandemics.
Delayed administration of polymyxin B hemoperfusion (PMX-HP) for septic shock could diminish its efficacy in real-world clinical settings. BEAT-SHOCK (BEst Available Treatment for septic SHOCK) registry is a prospective registry consisting of 309 adult patients with septic shock requiring high-dose norepinephrine (≥ 0.2 μg/kg/min). This predetermined analysis included 82 patients treated with PMX-HP. They were grouped according to the median time from intensive care unit (ICU) admission to administration of PMX-HP: the early administration group (n = 40) and the late administration group (n = 42). The primary outcome was short-term hemodynamic status, including mean arterial pressure and vasoactive-inotropic score (VIS; calculated from doses of dopamine, dobutamine, norepinephrine, epinephrine, vasopressin, milrinone, and levosimendan) within 48 h after ICU admission. The median time from ICU admission to administration of PMX-HP was 265 min (interquartile range [IQR]: 113–480). The median ages were 70 (IQR: 59–81) and 72 (IQR: 64–80) years (P = 0.77), and 21/40 (53
There are conflicting results regarding the efficacy of clazosentan, a selective endothelin A receptor antagonist, on cerebral vasospasm after subarachnoid hemorrhage (SAH). As the effectiveness of clazosentan for patients over 75 years old and those with World Federation of Neurosurgical Societies grade V has not been established, we aimed to evaluate its efficacy in real-world clinical settings. This study utilized prospectively collected data from consecutive SAH patients across 4 stroke centers, comparing 187 patients treated with clazosentan to 223 patients receiving standard of care. The incidence of favorable functional outcomes (modified Rankin Scale score 0-2) at 90 days after SAH, occurred more frequently in patients receiving clazosentan (74.9% vs 65.0%, p = 0.032). Multiple logistic analyses identified clazosentan administration as independently associated with favorable functional outcomes (49.1% vs 37.6%, odds ratio 2.17 [1.22-3.85], p = 0.008). Angiographic vasospasm (25.7% vs 48.9%, p < 0.001) and vasospasm-related infarcts (11.8% vs 20.2%, p = 0.023) were less frequent among patients receiving clazosentan. Stratification analyses revealed that clazosentan usage increased the incidence of favorable functional outcomes regardless of age, sex, SAH severity, and clot volume. These results underscore the therapeutic potential of clazosentan against cerebral vasospasm independent of patient characteristics.
Umbilical cord blood transplantation (CBT) is accepted as an effective treatment for acute myeloid leukemia (AML), and reduced-intensity conditioning (RIC), rather than myeloablative conditioning (MAC) regimens allowed elderly patients to be treated safely. However, appropriate intensities of conditioning regimens are still unclear, especially for middle-aged patients. To compare outcomes after RIC and MAC regimens, we analyzed AML patients aged 16 years or older in the Japanese registry database, who underwent single cord unit CBT between 2010-2019. Median ages of the RIC group (n = 1353) and the MAC group (n = 2101) were 59 and 51 years (P < 0.001), respectively. 5-year overall survival (OS) after MAC was superior to that of RIC (38.3% vs 27.7%, P < 0.001) with lower incidence of relapse (33.9% vs 37.4%, P = 0.029) and better neutrophil engraftment (84.7% vs 75.9%, P < 0.001). Detailed subgroup analysis revealed that age at transplantation is the most important factor affecting 5-year OS in RIC and MAC. This analysis identified a threshold of 55 years, beyond which the superiority of MAC disappeared, irrespective of other factors such as disease status or performance status. In conclusion, RIC may be preferable for patients aged 56 or older in CBT for AML due to higher potential toxicities.
