6-week Mortality Research Articles

Effectiveness of Adjunctive Drug Therapy to Endoscopic Stenting in Liver Cirrhosis Complicated by Refractory Variceal Bleeding

AIM OF THE STUDY. Comparative clinical analysis of the efficacy of terlipressin and octreotide as additional drug therapy to mechanical hemostasis with nitinol stent in patients with liver cirrhosis complicated by bleeding from esophageal varices refractory to endoscopic treatment.MATERIAL AND METHODS. Thirty-one patients with liver cirrhosis complicated by esophageal variceal bleeding refractory to endoscopic treatment , in whose complex treatment program, as a first-line life­saving measure, hemostasis with a self-expanding hemostasis was performed nitinol stent were randomly assigned to two groups. In group A, 20 patients were treated with terlipressin as an adjuvant to mechanical hemostasis, and in group B, 11 patients were treated with octreotide. Unpaired Student’s t-test was used for statistical analysis of the results. Graphs for assessing the survival function of patients for 8 weeks after the end of treatment were constructed using the Kaplan-Meier method.RESULTS. In the acute observation period terlipressin and octreotide were equally effective in treating refractory variceal bleeding. In the subacute observation period, the administration of octreotide was generally accompanied by a greater number of side effects (54.5%) than terlipressin (30.0%) (p=0.453). In the remote observation period, 8-week survival in the group of patients receiving terlipressin was higher than in the group of patients receiving octreotide.CONCLUSION. Terlipressin is as effective as octreotide as an adjunct to endoscopic stenting in drug therapy for liver cirrhosis complicated by esophageal variceal bleeding refractory to endoscopic treatment. At the same time, terlipressin has a greater effect than octreotide on reducing 8-week mortality, which approaches statistical significance. In this regard, terlipressin may be the vasoactive drug of choice in acute refractory variceal bleeding.

Invasive Candidiasis in Pediatric Hematologic Malignancy: Increased Risk of Dissemination With Candida tropicalis.

Candida species are the most common cause of invasive fungal disease, and children with hematologic malignancy are at increased risk. Non-albicans Candida (NAC) now account for more than half of all invasive candidiasis (IC) and carry a worse prognosis. We aimed to compare the epidemiology, risk factors, organ dissemination, biomarkers and outcomes in IC based on the species implicated and evaluate trends in antifungal resistance over time. Patients 0-18 years of age with hematologic malignancy and IC at 2 centers were included. Fifty-three patients from 2011 to 2022 were identified. Information related to demographics, host and risk factors, Candida species and antifungal susceptibilities, treatment and outcomes was collected via retrospective chart review. Data were analyzed at the species level. The incidence rate of IC was 29 per 1000 patients with leukemia and lymphoma. The median time to infection from diagnosis of malignancy was 38 days. Candida tropicalis (n = 17; 30%) was the most identified species followed by Candida albicans (n = 14; 25%). Patients with C. tropicalis infection were more likely to have dissemination to the eyes (P = 0.035), spleen (P = 0.001) and skin (P = 0.003) than patients with C. albicans or other NAC. Of the 34 patients who underwent dilated retinal examination, 24% (n = 8) had evidence of intraocular candidiasis. Seven of the 8 patients with intraocular disease had prolonged candidemia (3 or more days; P = 0.003). The 12-week crude mortality rate was 16.9%. NAC, specifically C. tropicalis, accounted for most of the IC in children with hematological malignancies. Screening for intraocular candidiasis continues to play an important role in patients with IC, and future studies are needed to determine if screening can be limited to patients with select risk factors.

Transjugular intrahepatic portosystemic shunting in patients over 60 years with cirrhosis and comorbidities when liver transplantation is reasonably denied

Aim. To determine the potential of TIPS that provides effective portal decompression for longevity and quality of life of patients over 60 years with cirrhosis and concomitant pathology when liver transplantation is reasonably denied.Materials and methods. The study included 27 patients aged over 60 with comorbidities, who underwent TIPS in 2016–2023 due to life-threatening manifestations of complicated portal hypertension of cirrhotic origin.Results. TIPS provided effective portal decompression in all 27 patients, confirmed by a 55.4 ± 5.2% reduction in portal pressure gradient. No hospital and 6-week mortality was recorded. 2 deaths (7.4%) were registered within one year after shunt surgery.Conclusion. In addition to lessening the risk of life-threatening complications, reduction of portal hypertension in liver cirrhosis provides favorable conditions for therapy of concomitant diseases, limited by concerns regarding hepatic decompensation. Due to the achieved stabilization of comorbidities, the denial to include the patient in the waiting list for liver transplantation can be reconsidered.

Elevated Plasma Matrix Metalloproteinases Are Associated With Mycobacterium tuberculosis Bloodstream Infection and Mortality in Human Immunodeficiency Virus-Associated Tuberculosis.

Mortality from human immunodeficiency virus (HIV)-associated tuberculosis (TB) is high, particularly among hospitalized patients. In 433 people with HIV hospitalized with symptoms of TB, we investigated plasma matrix metalloproteinases (MMP) and matrix-derived biomarkers in relation to TB diagnosis, mortality, and Mycobacterium tuberculosis (Mtb) bloodstream infection (BSI). Compared to other diagnoses, MMP-8 was elevated in confirmed TB and in Mtb-BSI, positively correlating with extracellular matrix breakdown products. Baseline MMP-3, -7, -8, -10, and PIIINP were associated with Mtb-BSI and 12-week mortality. These findings implicate MMP dysregulation in pathophysiology of advanced HIV-TB and support MMP inhibition as a host-directed therapeutic strategy for HIV-TB.

Regional citrate anticoagulation versus LMWH anticoagulation for CRRT in liver failure patients without increased bleeding risk.

The optimal anticoagulation regimen for continuous renal replacement therapy (CRRT) in liver failure (LF) patients without increased bleeding risk remains controversial. Therefore, we conducted a monocentric retrospective study to evaluate the efficacy and safety of the regional citrate anticoagulation (RCA) versus low molecular weight heparin (LMWH) anticoagulation for CRRT in LF without increased bleeding risk. According to the anticoagulation strategy for CRRT, patients were divided into the RCA and LMWH-anticoagulation groups. The evaluated endpoints were patient survival, filter lifespan, bleeding, citrate accumulation, and totCa/ionCa ratio. Totally 167 and 164 filters were used in the RCA and LMWH group, respectively. The median filter lifespan was significantly longer in the RCA group (34 h (IQR = 24-54) versus 24 h (IQR = 18-45.5) [95%CI, 24.5-33]; p < 0.001). The 4-week mortality rate was significantly higher in the LMWH-anticoagulation group (71 (57.72%) vs 53 (40.46%); p = 0.006). After adjusted the important parameters in the multivariate COX regression model, the mortality risk was significantly reduced in the RCA group (HR = 0.668 [95%CI, 0.468-0.955]; p = 0.027). In the LMWH group, 30 bleeding episodes (24,19%) were observed, whereas only 7 (5.34%) occurred in the RCA group (p < 0.001). Two patients (1.5%) in the RCA group occurred citrate accumulation. In LF patients without increased bleeding risk who underwent CRRT, RCA significantly extended the filter lifespan and improved patient survival rate. There was no significant difference in the rate of adverse events between the two groups.

Impact of perioperative hemoglobin-related parameters on clinical outcomes in patients with spinal metastases: identifying key markers for blood management.

Patients with spinal metastases undergoing surgical treatment face challenges related to preoperative anemia, intraoperative blood loss, and frailty, emphasizing the significance of perioperative blood management. This retrospective analysis aimed to assess the correlation between hemoglobin-related parameters and outcomes, identifying key markers to aid in blood management. A retrospective review was performed to identify patients who underwent surgical treatment for spinal metastases. Hb-related parameters, including baseline Hb, postoperative nadir Hb, predischarge Hb, postoperative nadir Hb drift, and predischarge Hb drift (both in absolute values and percentages) were subjected to univariate and multivariate analyses. These analyses were conducted in conjunction with other established variables to identify independent markers predicting patient outcomes. The outcomes of interest were postoperative short-term (6-week) mortality, long-term (1-year) mortality, and postoperative 30-day morbidity. A total of 289 patients were included. Our study demonstrated that predischarge Hb (OR 0.62, 95% CI 0.44-0.88, P = 0.007) was an independent prognostic factor of short-term mortality, while baseline Hb (OR 0.76, 95% CI 0.66-0.88, P < 0.001) was identified as an independent prognostic factor of long-term mortality. Additionally, nadir Hb drift (OR 0.82, 95% CI 0.70-0.97, P = 0.023) was found to be an independent prognostic factor for postoperative 30-day morbidity. This study demonstrated that predischarge Hb, baseline Hb, and nadir Hb drift are prognostic factors for outcomes. These findings provide a foundation for precise blood management strategies. It is crucial to consider Hb-related parameters appropriately, and prospective intervention studies addressing these markers should be conducted in the future.

Predicting early rebleeding and mortality after endoscopic hemostasis of esophagogastric varices: Diagnostic performance of aspartate aminotransferase-to-platelet ratio index and model for end-stage liver disease-Na score.

Endoscopic variceal ligation and sclerotherapy are recommended for esophagogastric variceal bleeding (EGVB) in cirrhosis but can be complicated by early rebleeding and death. This study aimed to identify noninvasive markers accurately predicting early rebleeding and mortality after endoscopic hemostasis for EGVB. Among 116 patients with endoscopically confirmed EGVB and endoscopic hemostasis, various noninvasive markers were calculated, and their predictive accuracy was compared by receiver-operating characteristic curve analysis. Endpoints included 5-day rebleeding, 5-day mortality, 6-week rebleeding, and 6-week mortality. The median age was 63 years. Child-Pugh class B and C patients accounted for 40.5% and 34.5%, respectively. Only the aspartate aminotransferase-to-platelet ratio index (APRI) significantly predicted 5-day rebleeding, with an area under the curve (AUC) of 0.777 (95% confidence interval [CI]: 0.537-1). The model for end-stage liver disease-Na (MELD-Na) score showed good predictive accuracy for 5-day mortality (AUC: 0.839, 95% CI: 0.681-0.997), 6-week rebleeding (AUC: 0.797, 95% CI: 0.663-0.932), and 6-week mortality (AUC: 0.888, 95% CI: 0.797-0.979). Patients with cirrhosis with a high APRI and MELD-Na score were at high risk of early rebleeding and death after EGVB. Allocating appropriate monitoring and care for those patients is necessary.

Outcomes of Patients With Newly Diagnosed AML and Hyperleukocytosis.

AML presenting with hyperleukocytosis is associated with poor outcomes. We aim to understand the factors associated with early mortality and overall survival (OS) to help guide management and improve early mortality. We retrospectively reviewed data from 129 consecutive patients with newly diagnosed AML and a WBC count ≥100 × 109/L between January 2010 and April 2020. Logistic regression models estimated odds ratios for 4-week mortality. Cox proportional hazard models estimated hazard ratios for OS. The median age was 65 years (range, 23-86); the median WBC was 146 × 109/L (range, 100-687). Seventy-five (58%) patients had clinical leukostasis (CL). FLT3, NPM1, and RAS pathway mutations were detected in 63%, 45%, and 27% of patients, respectively. Cytoreduction consisted of hydroxyurea in 124 (96%) patients, cytarabine in 69 (54%), and leukapheresis in 31 (24%). The cumulative 4-week and 8-week mortality rates were 9% and 13%, respectively, all in patients age 65 years and older. By multivariate analysis, older age, CL, and thrombocytopenia <40 × 109/L were independently associated with a higher 4-week mortality rate. After a median follow-up of 49.4 months, the median OS was 14.3 months (95% CI, 7 to 21.6), with 4-year OS of 29%. Age 65 years and older, CL, tumor lysis syndrome, elevated LDH ≥2,000 U/L, elevated lactate ≥2.2 mmol/L, and poor-risk cytogenetics were independent factors associated with worse OS. Hyperleukocytosis is a life-threatening hematologic emergency. Early recognition and intervention including cytoreduction, blood product support, antibiotics, and renal replacement therapy may help mitigate the risk of morbidity and early mortality.

Prognostic scores for predicting clinical outcomes in upper gastrointestinal bleeding

Background and aimsThis study aimed to determine the performance of AIMS65, Rockall score, and Glasgow-Blatchford score (GBS) in patients presenting with upper gastrointestinal bleeding (UGIB) and to compare results between patients with nonvariceal UGIB (NVUGIB) and variceal UGIB (VUGIB).MethodsWe conducted a single-center prospective cohort study between December 2021 and December 2022. A total of 400 patients who met the inclusion criteria were included in the study, out of which 232 patients (58%) had NVUGIB and 168 patients (42%) had VUGIB. Receiver operating characteristic curve analysis was performed for all outcomes for comparison.ResultsOf the total of 400 patients with UGIB, 232 patients (58%) had NVUGIB, and 168 patients (42%) had VUGIB. The present study showed that GBS (AUROC 0.729, 95% CI: 0.598–0.859, p = 0.001) and RS (AUROC 0.693, 95% CI: 0.579–0.807, p = 0.005) but not AIMS65 (AUROC, 0.545, 95% CI: 0.412–0.679, p = 0.500) predicted in-hospital and overall 6-week mortality in patients with UGIB. All the three scores predicted need for blood transfusion and poor composite outcomes (p < 0.05). The need for endoscopic intervention was predicted by all the three scores in overall UGIB (OUGIB) patients (p < 0.05), only GBS and RS in NVUGIB patients (p < 0.05). Rebleeding was best predicated by RS in both OUGIB and NVUGIB patients (p < 0.05). None of the scores predicted the need for endoscopic intervention, rebleeding, need for surgical and radiological intervention, and composite outcomes in VUGIB patients (p > 0.05).ConclusionsGBS and RS were superior to AIMS65 in predicted in-hospital and overall 6-week mortality in all the three categories: OUGIB, NVUGIB, and VUGIB patients.

A retrospective comparison of abbreviated course “7+7” vs standard hypomethylating agent plus venetoclax doublets in older/unfit patients with newly diagnosed acute myeloid leukemia.

6507 Background: Hypomethylating agent (HMA) plus venetoclax (VEN) regimens are standard of care in older/chemotherapy ineligible patients with acute myeloid leukemia (AML). While the VEN label recommends continuous 28-day cycles, shortened VEN durations may mitigate cytopenias and improve tolerability. It is unknown how shorter VEN cycles compare to standard HMA+VEN in terms of efficacy/safety. Methods: We performed a retrospective comparison of patients with newly diagnosed (ND) AML treated with azacitidine (AZA) x 7 days plus VEN x 7 days (“7+7” regimen) at 7 French centers (n=82, Willekens, ASH 2022) vs patients treated with standard dose HMA+VEN (s-HMA/VEN) at a US center (n=173), generally consisting of 21-28 days of VEN. We compared composite complete remission rate (CRc, consisting of CR + CRi), overall survival (OS), event-free survival (EFS), and myelosuppression between regimens. Results: Baseline characteristics are shown in the table. The s-HMA-VEN group consisted of 10-day decitabine (DAC) in 59% with the remaining patients receiving 5-day DAC or 7-day AZA. The CRc rate was similar; 72% with “7+7” vs 71% with s-HMA/VEN (p=0.89). The CR rate was 57% with “7+7” vs 55% with s-HMA/VEN (p=0.72). Median cycles to first response was 1 in both groups, however 42% of responders on “7+7” required more than 1 cycle for first response whereas almost all responders on s-HMA-VEN (99%) had a first response after cycle 1. Median cycles to best response was 2 with “7+7” vs 1 with s-HMA-VEN (p=0.02). 4-week mortality was similar (2% with “7+7”, 6% with s-HMA-VEN; p=0.24). 8-week mortality was higher with s-HMA-VEN (17%) compared to “7+7” (6%) (p=0.02). The median OS was 11.2 months (2-year 28%) with “7+7” vs 10.1 months (2-year 33%) with s-HMA/VEN (p=0.93). Outcomes stratified by molecular groups will be updated at the meeting. Fewer patients required platelet transfusions during cycle 1 with “7+7” compared to s-HMA/VEN (62% vs 77%, p=0.01). The cycle 1 rates of neutropenic fever and red cell transfusion requirements were similar. Conclusions: Acknowledging the limitations of a retrospective comparison across multiple centers, we did not observe a signal for a difference in efficacy between "7+7" vs standard VEN-based HMA doublets in ND-AML. The “7+7” regimen was associated with lower platelet transfusion requirements and lower 8-week mortality. [Table: see text]

Predictive Modeling for Spinal Metastatic Disease.

Spinal metastasis is exceedingly common in patients with cancer and its prevalence is expected to increase. Surgical management of symptomatic spinal metastasis is indicated for pain relief, preservation or restoration of neurologic function, and mechanical stability. The overall prognosis is a major driver of treatment decisions; however, clinicians' ability to accurately predict survival is limited. In this narrative review, we first discuss the NOMS decision framework used to guide decision making in the treatment of patients with spinal metastasis. Given that decision making hinges on prognosis, multiple scoring systems have been developed over the last three decades to predict survival in patients with spinal metastasis; these systems have largely been developed using expert opinions or regression modeling. Although these tools have provided significant advances in our ability to predict prognosis, their utility is limited by the relative lack of patient-specific survival probability. Machine learning models have been developed in recent years to close this gap. Employing a greater number of features compared to models developed with conventional statistics, machine learning algorithms have been reported to predict 30-day, 6-week, 90-day, and 1-year mortality in spinal metastatic disease with excellent discrimination. These models are well calibrated and have been externally validated with domestic and international independent cohorts. Despite hypothesized and realized limitations, the role of machine learning methodology in predicting outcomes in spinal metastatic disease is likely to grow.

Risk factors and predictive nomograms for bedside emergency endoscopic treatment following endotracheal intubation in cirrhotic patients with esophagogastric variceal bleeding

Data on emergency endoscopic treatment following endotracheal intubation in patients with esophagogastric variceal bleeding (EGVB) remain limited. This retrospective study aimed to explore the efficacy and risk factors of bedside emergency endoscopic treatment following endotracheal intubation in severe EGVB patients admitted in Intensive Care Unit. A total of 165 EGVB patients were enrolled and allocated to training and validation sets in a randomly stratified manner. Univariate and multivariate logistic regression analyses were used to identify independent risk factors to construct nomograms for predicting the prognosis related to endoscopic hemostasis failure rate and 6-week mortality. In result, white blood cell counts (p = 0.03), Child-Turcotte-Pugh (CTP) score (p = 0.001) and comorbid shock (p = 0.005) were selected as independent clinical predictors of endoscopic hemostasis failure. High CTP score (p = 0.003) and the presence of gastric varices (p = 0.009) were related to early rebleeding after emergency endoscopic treatment. Furthermore, the 6-week mortality was significantly associated with MELD scores (p = 0.002), the presence of hepatic encephalopathy (p = 0.045) and postoperative rebleeding (p < 0.001). Finally, we developed practical nomograms to discern the risk of the emergency endoscopic hemostasis failure and 6-week mortality for EGVB patients. In conclusion, our study may help identify severe EGVB patients with higher hemostasis failure rate or 6-week mortality for earlier implementation of salvage treatments.

Tranexamic acid in upper gastrointestinal bleed in patients with cirrhosis: A randomized controlled trial.

Patients with Child-Turcotte-Pugh class B and C cirrhosis with upper gastrointestinal bleeding (UGIB) have systemic as well as localized (in the mucosa of the esophagus and stomach) fibrinolysis. The aim of this study was to evaluate the efficacy and safety of tranexamic acid in the treatment of acute UGIB in patients with cirrhosis. A total of 600 patients with advanced liver cirrhosis (Child-Turcotte-Pugh class B or C) presenting with UGIB were randomly allocated to either the tranexamic acid (n=300) or the placebo group (n=300). The primary outcome measure was the proportion of patients developing 5-day treatment failure. Failure to control bleeding by day 5 was seen in 19/300 (6.3%) patients in the tranexamic acid group and 40/300 (13.3%) patients in the placebo group ( p =0.006). Esophageal endoscopic variceal ligation (EVL) site as a source of failure to control bleeding by day 5 among patients undergoing first-time esophageal EVL (excluding patients with a previous post-EVL ulcer as a source of bleed) was seen in 11/222 (4.9%) patients in the tranexamic acid group and 27/225 (1212.0%) patients in the placebo group ( p =0.005). However, 5-day and 6-week mortality was similar in the tranexamic acid and placebo groups. Tranexamic acid significantly reduces the failure to control bleeding by day 5 and failure to prevent rebleeding after day 5 to 6 weeks in patients with advanced liver cirrhosis (Child-Turcotte-Pugh class B or C) presenting with UGIB, by preventing bleeding from the EVL site.

Combination Antifungal Therapy for Invasive Mucormycosis in Immunocompromised Hosts: A Single-Center Experience.

Combination antifungal therapy for invasive mucormycosis remains controversial and is inconsistently defined in prior studies. In a cohort of patients with immunocompromised status and invasive mucormycosis, we found no difference in 6-week mortality with up-front or salvage combination therapy as compared with monotherapy.

Full adherence to cirrhosis quality indicators is associated with lower mortality in acute variceal bleeding: Nationwide audit.

Acute variceal bleeding (AVB) is a major complication in patients with cirrhosis. Using a nationwide AVB audit, we performed a nested cohort study to determine whether full adherence to the AVB quality indicator (QI) improves clinical outcomes in patients with cirrhosis and AVB. We assessed real-world adherence to AVB QI among patients with cirrhosis admitted for AVB in all public hospitals in Singapore between January 2015 and December 2020. Full adherence was considered when all 5 QIs were fulfilled: prophylactic antibiotics, vasoactive agents, timely endoscopy, endoscopic hemostasis during index endoscopy, and nonselective beta-blockers after AVB. We compare 6-week mortality between the full adherence and suboptimal adherence groups using a propensity-matched cohort.A total of 989 patients with AVB were included. Full adherence to all AVB QI was suboptimal (56.5%). Analysis of the propensity-matched cohort with comparable baseline characteristics showed that full adherence was associated with a lower risk of early infection (20.0% vs. 26.9%), early rebleeding (5.2% vs. 10.2%), and mortality at 6 weeks (8.2% vs. 19.7%) and 1 year (21.3% vs. 35.4%) ( p <0.05 for all). While full adherence was associated with a lower 6-week mortality regardless of the MELD score, nonadherence was associated with a higher 6-week mortality despite a lower predicted risk of 6-week mortality. Despite high adherence to the recommended process measures, patients with CTP-C remain at a higher risk of rebleeding, 6-week and 1-year mortality. Full adherence to the AVB QI should be the target for quality improvement in patients with cirrhosis.

Curative surgical treatment of common bile duct stones: Retrospective cohort study.

In the event of symptomatic common bile duct (CBD) stones with dilated CBD, one possible curative treatment option is stone extraction through choledocotomy associated with cholecystectomy. Endoscopic treatment is only reserved for residual stones at 6weeks. The aim of this study was to evaluate the results from laparoscopic curative surgical treatment of CBD stones with dilated CBD. This is a retrospective single-centered cohort study. All consecutive patients admitted for laparoscopic cholecystectomy with evidence of CBD stones with dilated CBD from January 2010 to December 2020 at our center were included. Success was defined by CBD clearance at 6weeks. Need for additional procedures, such as endoscopic sphincterotomy, immediate, and end-of-procedure morbi-mortality as well as factors associated with procedure failure, were also studied. A total of 246 patients who received curative treatment were included in the study. The success rate for the curative treatment was 93.1% (229 patients). Immediate postoperative morbidity was 24.4% with a 5.3% reintervention rate. Immediate and 6-week postoperative mortality rates were zero and 0.4%, respectively. The mean length of stay was 11.3days. Factors associated with procedure failure appeared to be the occurrence of an early postoperative complication and the need for readmission during the period between surgery and drain removal. This study indicates that laparoscopic curative surgical treatment for symptomatic CBD stones may be performed with acceptable results without routine need for additional procedures.

Clinical presentation and outcome of invasive mould disease in paediatric patients with acute lymphoblastic leukaemia

BackgroundChildhood acute lymphoblastic leukaemia (ALL) cure rates have improved, but invasive mould disease (IMD) remains a life-threatening complication. Here, we evaluate the epidemiology, clinical presentation, treatment and outcome of IMD in paediatric patients with ALL. MethodsPatients (1–18 years) treated according to the Dutch Childhood Oncology Group (DCOG) ALL-11 protocol from 2012–2021 were analysed for probable and proven IMD. Data was extracted from the Dutch national registry and the electronic health care system. ResultsAmong 643 patients with ALL, 47 (7.3%) were diagnosed with a probable (n = 29) or proven (n = 18) IMD. Aspergillosis was diagnosed in 42 (89%) patients. Forty-one episodes (87%) occurred during the induction (n = 20) and first consolidation (n = 21) course. The median age at ALL diagnosis was 5 years [IQR 3–10] in the overall group versus 14 years [IQR 7–16] in the IMD group. Two-third of the patients did not receive mould-active prophylaxis. The most prevalent clinical symptoms at presentation were persistent fever and respiratory symptoms. The lungs were the most common site of infection with involvement in 44 (94%) patients, followed by the CNS in 16 (34%) patients. The 6-week and 12-week mortality rate after IMD diagnosis was 10.6% and 14.9%, respectively. Discussion and conclusionIn our paediatric cohort a notable incidence of probable and proven IMD was observed during the early stages of treatment. Remarkable is the high frequency of CNS involvement. These findings highlight the importance of effective prophylactic strategies and warrant early brain imaging.

Vitamin K2 sensitizes the efficacy of venetoclax in acute myeloid leukemia by targeting the NOXA-MCL-1 pathway.

Promising outcomes have been reported in elder patients with acute myeloid leukemia (AML) using combined therapy of venetoclax (VEN) and azacytidine (AZA) in recent years. However, approximately one-third of patients appear to be refractory to this therapy. Vitamin K2 (VK2) shows apoptosis-inducing activity in AML cells, and daily oral VK2 (menaquinone-4, GlakayR) has been approved for patients with osteoporosis in Japan. We observed a high response rate to AZA plus VEN therapy, with no 8-week mortality in the newly diagnosed AML patients consuming daily VK2 in our hospital. The median age of the patients was 75.9 years (range 66-84) with high-risk features. Patients received AZA 75 mg/m2 on D1-7, VEN 400 mg on D1-28, and daily VK2 45 mg. The CR/CRi ratio was 94.7% (18/19), with a CR rate of 79%. Complete cytogenetic CR was achieved in 15 of 19 (79%) patients, and MRD negativity in 2 of 15 (13%) evaluable CR patients. Owing to the extremely high response rate in clinical settings, we further attempted to investigate the underlying mechanisms. The combination of VK2 and VEN synergistically induced apoptosis in all five AML cell lines tested. VK2, but not VEN, induced mitochondrial reactive oxygen species (ROS), leading to the transcriptional upregulation of NOXA, followed by MCL-1 repression. ROS scavengers repressed VK2 induced-NOXA expression and led to the cancellation of pronounced apoptosis and the downregulation of MCL-1 by VK2 plus VEN. Additionally, knockdown and knockout of NOXA resulted in abrogation of the MCL-1 repression as well as enhanced cytotoxicity by the two-drug combination, indicating that VK2 suppresses MCL-1 via ROS-mediated NOXA induction. These data suggest that the dual inhibition of BCL-2 by VEN and MCL-1 by VK2 is responsible for the remarkable clinical outcomes in our patients. Therefore, large-scale clinical trials are required.

Bleeding from Varices: Still a Heavy Burden in Patients with Cirrhosis

Introduction: Bleeding from varices is a severe complication in patients with cirrhosis. Despite its treatment has been well established in the last three decades the mortality can be still high. This study compares the epidemiological features and the bleeding-related outcomes of a group of patients published about ten years ago with a more recent group of 168 consecutive patients. Methods: The diagnosis, the treatment, and the main outcomes (5-day failure, 5-day and 6-week rebleeding, 5-day and 6-week mortality) of variceal bleeding were evaluated according to the current guidelines. Results: The number of patients with cirrhosis admitted for variceal bleeding every year has progressively decreased in the last ten years. The age sex and severity of liver disease, evaluated with Child Pugh and MELD scores, were comparable in the two series. In the more recent series, there were significantly fewer patients with HCV infection and more patients with alcohol-related cirrhosis. The main outcomes of bleeding were comparable too. Overall, at 6 weeks 36.4% of patients did not overcome the bleeding episode. Conclusion: The decreasing incidence of bleeding from varices is likely attributable to antiviral treatment of HCV and HBV and the larger diffusion of beta-blockers in primary prophylaxis. Despite the larger application of the gold standard therapy, the mortality of variceal bleeding remains high in patients with cirrhosis.

Serum heme oxygenase-1 as a prognostic biomarker in patients with acute exacerbation of interstitial lung disease

Serum heme oxygenase (HO)-1 level has been reported as a clinically reliable diagnostic biomarker for acute exacerbation of interstitial lung disease (ILD); however, its utility for predicting mortality among these patients is unclear. Serum HO-1 levels of patients newly diagnosed with acute exacerbation of ILD were measured at the time of initiating steroid pulse therapy. The relationship between serum HO-1 and various other serum biomarkers, change in HRCT findings, and disease prognosis at 12 weeks after diagnosis of acute exacerbation was evaluated in 51 patients, of whom 17 (33%) had idiopathic pulmonary fibrosis (IPF). Serum HO-1 was higher in patients with acute exacerbation of IPF than in patients with acute exacerbation of other ILDs. Serum HO-1 levels were higher in patients who died within these 12 weeks than in survivors. Among age, sex, comorbidities, IPF diagnosis, HRCT findings, and blood biomarkers, serum HO-1 was a primary predictor of 12-week mortality. In 41 patients who underwent repeat HRCT, serum HO-1 was higher in patients with honeycomb progression than in those without. Serum HO-1 measurement could be useful for evaluating disease mortality and morbidity of patients with acute exacerbation of ILDs.