BACKGROUND: The importance of early intravenous (IV) antibiotic use for Mycobacterium abscessus complex lung diseases (MABC-LD) treatment remains unknown. METHODS: A retrospective multi-centre observational study was conducted in Taiwan. Patients who were diagnosed with and received treatment for MABC-LD from January 2007 to April 2021 were included. Treatment outcome was defined as modified microbiological cure of MABC-LD. RESULTS: Of the 89 enrolled patients, 34 (38.2%) received IV antibiotics as part of the treatment regimen. The median time to IV initiation was 1 day (IQR 1-49); 24 (70.6%) of these patients received IV agents within 4 weeks, defined as early-use. Forty-two (47.2%) patients achieved modified microbiological cure. In the multivariable logistic analysis, early IV antibiotic use was an independent factor associated with modified microbiological cure (aOR 5.32, 95% CI 1.66-17.00), whereas high radiological score (aOR 0.86, 95% CI 0.73-1.00) demonstrated negative association. CONCLUSIONS: In the present study, early use of effective IV antibiotic was prescribed in a low percentage (27%) for MABC-LD. By contrast, early IV antibiotic use was correlated with higher microbiological cure than were late or non-use. Future larger and prospective studies are needed to validate the association.

Background: More and more gene mutations have been identified in patients with de novo acute myeloid leukemia (AML). Among them, a set of gene mutations, including SRSF2, ZRSR2, SF3B1, U2AF1, ASXL1, EZH2, STAG2, and BCOR mutation, are categorized as secondary AML (sAML)-type mutations, for their distinct distribution in secondary AML, compared to primary AML (Lindsley et al, Blood 2015), but the reports regarding the prognostic impact have been scanty, especially in younger patients. Aims: In this study, we aimed to explore the clinical significance and prognostic implication of sAML-type mutations in non-M3 AML patients. Methods: We consecutively enrolled 921 de novo non-M3 AML patients; 368 were 60 years or older (older patients) and 553 were younger. Patients with an antecedent history of hematologic diseases, or therapy-related AML were excluded. sAML-type mutations were identified by targeted next-generation sequencing of 54 myeloid malignancies related gene mutations. Results: A total of 243 (26.4%) patients harbored sAML-type mutations (ST group), 40.2% in older patients and 17.2% in younger ones. Patients in the ST group were significantly older, had a lower WBC count, peripheral blast count and lactate dehydrogenase level at diagnosis. sAML-type mutations were negatively correlated with inv(16), monosomy 17, and complex karyotype, but positively associated with 2017 European LeukemiaNet (ELN)-defined unfavorable-risk genetic category. Among the patients receiving standard chemotherapy (n=686, 74.5%), the ST group had a significantly lower CR rate (62.9% vs. 81.5%, P< 0.01), especially among younger patients (70.8% vs. 86.7%, P<0.01), but only a trend in older patients (49.0% vs. 59.6, P=0.17). With a median follow-up of 4.7 years, patients in the ST group had a shorter overall survival (OS, median, 2.1 years vs. not reached, P< 0.01) and disease-free survival (DFS, median, 0.4 years vs. 0.9 years, P< 0.01) than the non-ST group. Subgroup analyses showed that sAML-type mutations conferred a significantly poorer DFS (median, 0 years vs. 0.5, P=0.03) and a trend of shorter OS (0.8 years vs. 1.1 years, P=0.08) in older patients, and a significantly worse OS (not reached vs. not reached, P=0.03) and a trend of shorter DFS (0.7 years vs. 1.0 years, P=0.16) in younger patients. The numbers of sAML-type mutations had prognostic impacts on both OS (median, 5.8 years vs. 1.5 vs. 1.3 for patients with 0, 1, and ≥2 mutations, respectively, P<0.01) and DFS (median, 0.9 years vs. 0.6 vs. 0 for those with 0, 1, and ≥2 mutations, respectively, P< 0.01). Intriguingly, these findings were valid among both the younger and older patients. Furthermore, the ELN-defined intermediate-risk patients with sAML-type mutations had similar poor OS and DFS to the ELN unfavorable-risk patients in total cohort (Figure 1), as well as in the older and younger patients. Among the patients with sAML-type mutations, allogeneic hematopoietic stem cell transplantation did improve their outcome (median OS 3.0 vs. 0.8 years, P< 0.01). Image:Summary/Conclusion: AML patients with sAML-type mutations had distinct clinical features and poorer outcomes. Incorporating sAML-type mutations can further refine the 2017 ELN risk stratification. It is suggested that AML patients with sAML-type mutations receive more intensive treatment, such as allo-HSCT, and/or novel therapies.

Objectives: Evidence of false-positive galactomannan enzyme immunoassay (GM-EIA) results associated with intravenous immunoglobulin (IVIG) administration is scarce. Here, we aimed to determine the false-positive rate of GM-EIA after IVIG administration and to identify the related factors. Methods: Standard GM-EIA was performed using diluted and pure human IVIG samples with and without heat treatment. We also included adult patients who had at least one GM-EIA result within 1 week of IVIG administration for analysis. Those who had prior invasive aspergillosis within 1 year before IVIG therapy were excluded. The clinical characteristics and galactomannan index (GMI) kinetics between patients with false-positive and true-positive GMI were compared. Results: All diluted and pure IVIG samples tested positive for GM. Heat treatment resulted in the considerable elevation of GMI. Of 48 patients with positive GM-EIA results within 1 week of IVIG administration, 22 (45.8%) were considered to have false-positive antigenaemia (false-positive group, FPG). After the completion of IVIG administration, a decline in GMI was observed in all FPG patients but in only 18 out of 26 patients (69.2%) with true-positive results (true-positive group, TPG). By 7, 14, and 18 days of IVIG administration, GMI reverted to negative values in 7/15 (46.7%), 18/20 (90%) and 22/22 (100%) FPG patients, respectively, and 6/24 (25%), 14/24 (58.3%), and 16/26 (61.5%) of TPG patients, respectively. The TPG was more likely to have two or more consecutively positive GMIs after IVIG administration than the FPG (adjusted odds ratio, 9.01; 95% confidence interval, 1.99-40.9). Conclusions: IVIG treatment may produce false-positive GM-EIA results. A positive GMI among patients receiving human IVIG should be interpreted with caution. (c) 2020 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Background:Myelodysplastic syndromes (MDS) are heterogeneous clonal myeloid disorders with increased risk of transformation to acute myeloid leukemia (AML). To understand the role of genetic evolution in the progression of MDS and its prognostic implication, comprehensive mutation analyses of large MDS cohorts sequentially by next generation sequencing during the clinical course are mandatory.Aims:The study was aimed to explore the evolution profile of genetic alterations and its clinic‐prognostic impact in MDS patients.Methods:Totally, 161 de novo MDS patients diagnosed according to the 2016 WHO classification who had paired samples both at diagnosis and subsequent follow‐ups were recruited. Among them, 81 patients had disease progression: 24 patients progressed to high‐risk MDS and 57 progressed to AML. Gene mutations were analyzed by targeted next generation sequencing of 54 genes involving in myeloid malignancies using TruSight Myeloid Panel.Results:The most prevalent gene mutations at diagnosis and progression were similar, including ASXL1, followed by RUNX1, SRSF2, and U2AF1 mutations. The most common genetic evolution was acquisition of NRAS mutation (16.0%), followed by that of chromosome 8 abnormalities (14.8%), and RUNX1 mutations (13.5%). Among the 81 patients with disease progression, 57 (70.4%) patients had genetic evolution: 18 patients had only cytogenetic evolution, 22 had only mutation shift (either acquisition or loss), and 17 had both cytogenetic evolution and mutation shift. The patients with disease progression had a higher frequency of mutation shift than those with stable disease (48.1% vs. 30.0%, P = 0.024). The gene mutation numbers were not associated with the risk of disease at diagnosis, but at progression, patients with acute myeloid leukemia (AML) had more gene mutation numbers than those with high risk MDS. Progression to AML rather than to high‐risk MDS and presence of cytogenetic or genetic evolution predicted poorer overall survival (OS) after progression (Fig 1A), irrespective of the original subtypes of MDS.We used SciClone to analyze the clonal architecture of gene mutations at diagnosis and at disease progression and identified two clusters of gene mutations. Cluster 1 gene mutations, including DNMT3A, NRAS, RUNX1, WT1, IDH2, splicing factors (including SRSF2, SF3B1, and U2AF1), and TET2 mutations, tended to have increasing allelic burdens or be acquired at progression; cluster 2 gene mutations, including ASXL1, SETBP1, STAG2, BCOR, and TP53 mutations, tended to be stationary, decreasing, or lost at disease progression. At diagnosis, the cluster 1 gene mutations were significantly more prevalent in MDS with subsequent progression to secondary AML but the cluster 2 gene mutations were more common in those with progression to high‐risk MDS. We risk‐stratified patients into three groups at diagnosis: the group 1 patients with cluster 1 ± cluster 2 gene mutations, the group 2 patients with the only cluster 2 gene mutations, and the group 3 patients with neither cluster 1 nor cluster 2 gene mutations. The group 3 patients had the longest OS, followed by the group 1, and the group 2 patients had the worst OS (Fig 1B).Summary/Conclusion:More than two‐thirds of MDS patients experienced genetic evolution during disease progression and the presence of the genetic evolution had a poor prognostic impact. It is necessary to develop novel treatment strategies for patients with genetic evolution in the near future.image

Background:The cause of hepatitis B virus (HBV) reactivation in patients with chronic myeloid leukemia (CML) treated with tyrosine kinase inhibitors (TKIs) is unclear.Aims:Taiwan has a high prevalence of HBV infection, and this study aimed to investigate the epidemiology of HBV reactivation in patients with CML treated with TKIs.Methods:We retrospectively reviewed 175 adult patients with CML who were treated using TKIs at National Taiwan University Hospital between January 2008 and July 2018. HBV infection status and reactivation were reviewed during follow‐up.Results:A total of 99 men and 76 women with a median age of 46 years (range: 18–97) were enrolled in this study. Twenty‐one (12%) of 175 patients were carrying HBV when they were diagnosed with CML. Eight HBV carriers were prophylactically treated using an antiviral agent, and the others were closely followed‐up. At a median follow‐up period of 41 months (range 1–129 months), 6 (28.6%) of the 21 HBV carriers had 7 episodes of HBV reactivation. Two (1.3%) of the 154 negative hepatitis B surface antigen (HBsAg) patients had reverse seroconversion and became positive HBsAg, and both patients had acute blastic transformation and allogeneic transplantation. A univariate analysis revealed positive HBsAg and negative anti‐Hepatitis B surface antibodies (anti‐HBs Ab) significantly correlated with HBV reactivation. In this retrospective cohort study, the incidence of HBV reactivation was 0.5 per 100 person‐years in patients with CML carrying HBV who had been treated with TKIs and 0.076 per 100 person‐years in all patients with CML treated with TKIs.Summary/Conclusion:HBV reactivation could develop in patients with CML treated with TKI, especially in those who are HBV carriers. The incidence is lower than it is in hematological patients with HBV carrier status who have been treated with chemotherapy, immunotherapy and stem cell transplantation. We suggest that all patients with CML with positive HBsAg undergo prophylaxis with an antiviral agent. The cause of HBV reactivation in patients with resolved HBV infection and no allogeneic transplantation is unclear, and although the risk is low, further investigation is required.image

ObjectivesFluconazole non-susceptibility (FNS) rates have increased among C. tropicalis isolates in Asia.We aimed to explore the proportions and risk factors of candidemia caused by FNS C. tropicalis and the impact of FNS on patient outcomes. MethodsThere was a prospective Candida bloodstream infections (BSIs) cohort in a single medical center at Northern Taiwan.We retrospectively analyzed the first episode of C. tropicalis BSIs between 2011 and 2017.Antifungal susceptibility testing of the first isolate of each episode was performed by the microdilution colorimetric Sensititre YeastOne SYO-09 panel, and the results were interpreted according to Clinical and Laboratory Standards Institute (CLSI) species-specific breakpoints. ResultsDuring the study period, three hundred and forty-four episodes of C. tropicalis BSIs were identified.Of them, 58 (16.9%) first blood isolates were non-susceptible to fluconazole, including 10 isolates belonging to susceptible dose-dependent and 48 isolates belonging to resistance.The proportions of C. tropicalis BSIs and fluconazole resistant rates showed an increasing trend by years (both P = 0.07, Figure 1).There were no differences of patient outcomes, including 14-day and 30-day mortality, and persistence, between FNS BSIs and fluconazole susceptible (FS) BSIs (Figure 2).Compared to patients with FS BSIs, those with FNS BSIs were more likely to have moderate to severe liver disease, leukemia, receipt of steroid and antifungal exposure (AE), but less receipt of parental hyperalimentation compared to those infected by FS isolate (all P < 0.05).Of note, around 55% patients with FNS BSIs were azole naïve (Table 1). ConclusionFluconazole resistance increased in C. tropicalis BSIs, but didn't worsen patient outcomes.Immunocompromised hosts and those with azole exposure were risk for FNS C. tropicalis BSIs.Further investigations were warranted for azole naïve patients with FNS C. tropicalis BSIs.# Continuous variables: median (IQR); Categorical variables: numbers (%) $ Univariate analysis, P <0.05 * Multivariate logistic regression: Antifungal exposure (aOR, 6.00; 95% CI, 3.17-11.36);Moderate-to-severe liver diseases (aOR, 3.14; 95% CI, 1.05-9.33)

OBJECTIVE:Anti-interferon- γ (IFN-γ) autoantibodies (anti-IFN-γ Abs) have been increasingly recognized as an important cause of disseminated nontuberculous mycobacterial (DNTM) infection, and identification of this immunodeficiency impacts clinical management. However, the protean disease manifestations and inaccessibility to diagnostic tests in clinical settings hamper its early diagnosis. Here, we sought to determine whether QuantiFERON-TB Gold In-tube (QFT-GIT), a commercialized IFN-γ release assay, could be used to screen for neutralizing anti-IFN-γ Abs among previously healthy adults with DNTM infection. METHODS:Non-HIV patients with DNTM infection were prospectively enrolled for the QFT-GIT assays. We measured their plasma concentration of anti-IFN-γ Abs and their neutralizing capacity through enzyme-linked immunosorbent assay and flow cytometry. We then analysed the correlation between QFT-GIT results and the presence of neutralizing anti-IFN-γ Abs among patients with and without previously recognized immunosuppression, respectively. RESULTS:Irrespective of the autoantibody concentration or disease activity, all patients with neutralizing anti-IFN-γ Abs (100%, 30/30) had indeterminate QFT-GIT results because of extremely low or undetectable IFN-γ levels in the mitogen tubes. None of the four DNTM patients who were previously healthy and tested negative of anti-IFN-γ Abs had an indeterminate QFT-GIT result, and their IFN-γ levels in the mitogen tube were significantly higher than those of the patients with anti-IFN-γ Abs (8.28 IU/mL vs. 0.05 IU/mL, p 0.001). CONCLUSION:An indeterminate QFT-GIT result because of undetectable or extremely low IFN-γ level in the mitogen tube suggests the presence of neutralizing anti-IFN-γ Abs in a previously healthy patient with DNTM infection.

The SOX4 transcription factor is a key regulator of embryonic development, cell-fate decision, cellular differentiation and oncogenesis. Abnormal expression of SOX4 is related to malignant tumor transformation and cancer metastasis. However, no reports are available regarding the clinical significance of SOX4 in acute myeloid leukemia (AML) and the role of SOX4 in leukemogenesis. In the current study, we found that AML patients with low bone marrow (BM) SOX4 expression had higher remission rates and longer overall survival than those with high SOX4 expression, regardless of age, white blood cell count at diagnosis, karyotype profile and NPM1/FLT3-ITD status. To elucidate the role of SOX4 in leukemogenesis, we generated a transgenic zebrafish model that overexpressed human SOX4 in the myeloid lineage Tg(spi1-SOX4-EGFP). These transgenic zebrafish showed, at 5 months of age, increased myelopoiesis with dedifferentiation in kidney marrow. At 9 months of age, their kidney structure was significantly effaced and distorted by increased infiltration of myeloid progenitor cells. These results suggest that SOX4 is not only an independent prognostic factor of AML, but also an important molecular factor in leukemogenesis.

The transcriptional repressor B lymphocyte-induced maturation protein-1 (Blimp-1) has crucial roles in the control of plasma cell differentiation and in maintaining survival of plasma cells. However, how Blimp-1 ensures the survival of plasma cell malignancy, multiple myeloma (MM), has remained elusive. Here we identified Aiolos, an anti-apoptotic transcription factor of MM cells, as a Blimp-1-interacting protein by mass spectrometry. ChIP coupled with DNA microarray was used to profile the global binding of Aiolos and Blimp-1 to endogenous targets in MM cells, which revealed their co-binding to a large number of genes, including apoptosis-related genes. Accordingly, Blimp-1 and Aiolos regulate similar transcriptomes in MM cells. Analysis of the binding motifs for Blimp-1 and Aiolos uncovered a partial motif that was similar across sites for both proteins. Aiolos promotes the binding of Blimp-1 to target genes and thereby enhances Blimp-1-dependent transcriptional repression. Furthermore, treatment with an anti-MM agent, lenalidomide, caused ubiquitination and proteasomal degradation of Blimp-1, leading to the de-repression of a new Blimp-1 direct target, CULLIN 4A (CUL4A), and reduced Aiolos levels. Accordingly, lenalidomide-induced cell death was partially rescued by reintroduction of Blimp-1 or knockdown of CUL4A. Thus, we demonstrated the functional impacts and underlying mechanisms of the interaction between Aiolos and Blimp-1 in maintaining MM cell survival. We also showed that interruption of Blimp-1/Aiolos regulatory pathways contributes to lenalidomide-mediated anti-MM activity.

Postprocedural infections by Mycobacterium abscessus complex are increasing worldwide, and the source and route of transmission are infrequently identified. Here the extension of a previous clustering of paediatric patients with surgical site infections due to a single strain of the subspecies M. massiliense is reported. The investigation was conducted at a 2200-bed teaching hospital in Taiwan and included microbial surveillance of the environment ( water, air, equipment and supplies) and a case-control study. We performed molecular identification and typing of the isolates by a trilocus sequencing scheme, confirmed by multilocus sequencing typing and pulsed-field gel electrophoresis. We investigated 40 patients who developed postprocedure soft tissue or bloodstream infections by M. massiliense (TPE101) during a 3-year period. Thirty-eight patients were identified at hospital A, and one newborn and her mother were identified at hospital B ( 185 km from hospital A). A case-control study identified the association of invasive procedures ( adjusted odds ratio, 9.13) and ultrasonography ( adjusted odds ratio, 2.97) ( both p <0.05) with acquiring the outbreak strain. Isolates from the cases and unopened bottles of ultrasound transmission gel were all of strain ST48 and indistinguishable or closely related by pulsed-field gel electrophoresis. After replacement of contaminated gel, no new cases were detected during 18 months' follow-up. This investigation identified the use of contaminated gel as the common source causing an outbreak on a larger scale than had been recognized. Our findings halted production by the manufacturer and prompted revision of hospital guidelines. (C) 2016 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

A number of patient-specific and leukemia-associated factors are related to the poor outcome in older patients with acute myeloid leukemia (AML). However, comprehensive studies regarding the impact of genetic alterations in this group of patients are limited. In this study, we compared relevant mutations in 21 genes between AML patients aged 60 years or older and those younger and exposed their prognostic implications. Compared with the younger patients, the elderly had significantly higher incidences of PTPN11, NPM1, RUNX1, ASXL1, TET2, DNMT3A and TP53 mutations but a lower frequency of WT1 mutations. The older patients more frequently harbored one or more adverse genetic alterations. Multivariate analysis showed that DNMT3A and TP53 mutations were independent poor prognostic factors among the elderly, while NPM1 mutation in the absence of FLT3/ITD was an independent favorable prognostic factor. Furthermore, the status of mutations could well stratify older patients with intermediate-risk cytogenetics into three risk groups. In conclusion, older AML patients showed distinct genetic alterations from the younger group. Integration of cytogenetics and molecular mutations can better risk-stratify older AML patients. Development of novel therapies is needed to improve the outcome of older patients with poor prognosis under current treatment modalities.