Successful Treatment of an AML Patient Infected with Hypervirulent ST463 Pseudomonas Aeruginosa Harboring Rare Carbapenem-Resistant Genes blaAFM-1 and blaKPC-2 Following Allogeneic Hematopoietic Stem Cell Transplantation.

Background: Carbapenem-resistant P. aeruginosa (CRPA) is a common hospital-acquired bacterium. It exhibits high resistance to many antibiotics, including ceftazidime/avibactam and cefteolozane/tazobactam. The presence of carbapenem-resistant genes and co-existence Klebsiella pneumoniae carbapenemase (KPC) and metallo-ß-lactamases (MBLs) further inactivated all ß-lactams. Understanding the resistance genes of CRPA can help in uncovering the resistance mechanism and guiding anti-infective treatment. Herein, we reported a case of perianal infection with hypervirulent ST463 Pseudomonas aeruginosa. Case Presentation: The case is a 32-year-old acute myeloid leukemia (AML) patient with fever and septic shock during hematopoietic stem cell transplantation (HSCT), and the pathogen was finally identified as a highly virulent sequence type 463 (ST463) P. aeruginosa harboring carbapenem-resistant genes blaAFM-1 and blaKPC-2, which was detected in the bloodstream and originated from a perianal infection. The strain was resistant to ceftazidime/avibactam but successfully treated with polymyxin B, surgical debridement, and granulocyte engraftment after HSCT. The AML was cured during the 19-month follow-up. Conclusion: This case emphasizes the importance of metagenomic next-generation sequencing (mNGS) and whole-genome sequencing (WGS) in identifying microbes with rare resistant genes, and managing CRPA, especially in immunocompromised patients. Polymyxin B may be the least resistant option.

Genotype-degree of hemolysis correlation in hereditary spherocytosis.

BACKGROUND: Hereditary spherocytosis (HS) is a common inherited hemolytic anemia, caused by mutations in five genes that encode erythrocyte membrane skeleton proteins. The red blood cell (RBC) lifespan could directly reflect the degree of hemolysis. In the present cohort of 23 patients with HS, we performed next-generation sequencing (NGS) and Levitt's carbon monoxide (CO) breath test to investigate the potential genotype-degree of hemolysis correlation. RESULTS: In the present cohort, we identified 8 ANK1,9 SPTB,5 SLC4A1 and 1 SPTA1 mutations in 23 patients with HS, and the median RBC lifespan was 14(8-48) days. The median RBC lifespan of patients with ANK1, SPTB and SLC4A1 mutations was 13 (8-23), 13 (8-48) and 14 (12-39) days, respectively, with no statistically significant difference (P = 0.618). The median RBC lifespan of patients with missense, splice and nonsense/insertion/deletion mutations was 16.5 (8-48), 14 (11-40) and 13 (8-20) days, respectively, with no significant difference (P = 0.514). Similarly, we found no significant difference in the RBC lifespan of patients with mutations located in the spectrin-binding domain and the nonspectrin-binding domain [14 (8-18) vs. 12.5 (8-48) days, P = 0.959]. In terms of the composition of mutated genes, 25% of patients with mild hemolysis carried ANK1 or SPTA1 mutations, while 75% of patients with mild hemolysis carried SPTB or SLC4A1 mutations. In contrast, 46.7% of patients with severe hemolysis had ANK1 or SPTA1 mutations and 53.3% of patients with severe hemolysis had SPTB or SLC4A1 mutations. However, there was no statistically significant difference in the distribution of mutated genes between the two groups (P = 0.400). CONCLUSION: The present study is the first to investigate the potential association between genotype and degree of hemolysis in HS. The present findings indicated that there is no significant correlation between genotype and degree of hemolysis in HS.

Efficacy of eltrombopag with immunosuppressive therapy for children with acquired aplastic anemia.

Background: Eltrombopag (EPAG), an oral thrombopoietin receptor agonist (TPO-RA), has been proven to improve the hematologic response without increasing toxic effects as a first-line therapy combined with standard immunosuppressive treatment (IST) in adults with severe aplastic anemia (SAA). Nevertheless, the clinical evidence on the efficacy of EPAG in children with acquired aplastic anemia is limited and controversial. Methods: We performed a single-center, retrospective study to analyze the clinical outcomes of fifteen patients aged ≤18 years with newly diagnosed acquired SAA who received first-line IST and EPAG (EPAG group) compared with those of forty-five patients who received IST alone (IST group) by propensity score matching (PSM). Results: There was no difference in the overall response (OR) rate between the EPAG group and IST group (53.3% vs. 46.7% at 3 months, P = 0.655; 66.7% vs. 57.8% at 6 months, P = 0.543), but the complete response (CR) rate was statistically significant (20.0% vs. 4.4% at 3 months, P = 0.094; 46.7% vs. 13.3% at 6 months, P = 0.012). The median time to achieve a hematological response in the EPAG and IST groups was 105 days and 184 days, respectively. No difference was observed in the event-free survival (EFS) or overall survival (OS) rates. Conclusion: Adding EPAG to standard IST as the first-line treatment for children with acquired SAA improved the rapidity of hematological response and the CR rate but did not improve the OR or EFS rates.

The Synergistic Antitumor Activity of Chidamide in Combination with Bortezomib on Gastric Cancer.

PURPOSE: The aim of this study was to investigate the antitumor effect of chidamide in combination with bortezomib on gastric cancer cell lines. MATERIALS AND METHODS: First, the sensitivity and IC50 values of chidamide and bortezomib in several gastric cancer cell lines (MGC-803, BGC-823, SGC-7901, and MKN45) were measured using the CCK-8 assay. Then, the relatively insensitive gastric cancer cell lines (MGC-803 and BGC-823) were treated with low concentrations of chidamide alone, bortezomib alone, or chidamide and bortezomib combination to detect the effects on cell proliferation, apoptosis, migration, and invasion. Finally, the inhibitory effect of the combined chidamide and bortezomib treatment on MGC-803 cells was verified in vivo through tumor formation experiments in nude mice. RESULTS: Compared with low-dose chidamide or bortezomib alone, the low-dose drug combination significantly inhibited the proliferation, migration, and invasion of MGC-803 and BGC-823 cells and induced apoptosis of the cells. The effects of the low-dose chidamide and bortezomib combination reduced the growth on gastric cancer in vivo were investigated by using a subcutaneous tumor mouse model. CONCLUSION: Our results suggest that the combination of chidamide and bortezomib can significantly reduce the proliferation, invasion, and migration of MGC-803 and BGC-823 cells, providing a framework for the clinical evaluation of combined therapies for gastric cancers.

Validation of the EUTOS Long-Term Survival Score in Chinese Chronic Myeloid Leukemia Patients Treated with Imatinib: A Multicenter Real-World Study.

PURPOSE: To validate the clinical efficacy of the recently developed EUTOS long-term survival (ELTS) score in a real-world setting. PATIENTS AND METHODS: A total of 479 chronic myeloid leukemia (CML) patients treated with frontline imatinib between January 2010 and December 2017 were enrolled in this retrospective study. The ELTS score was evaluated on the end-points including complete cytogenetic response (CCyR), progression-free survival (PFS), overall survival (OS) and CML-related death, and the efficiency of the ELTS score was further compared with the historical Sokal, Hasford, EUTOS scores. RESULTS: With a median follow-up of 69 months (range, 9-112 months), 462 evaluable patients were stratified into the ELTS low-risk (n = 230), ELTS intermediate-risk (n = 168) and ELTS high-risk (n = 64) groups. For the regular assessment indicators like CCyR, PFS and OS, the ELTS scoring system could effectively identify the corresponding risk groups, similarly with the results provided by previous scoring systems. With respect to the CML-related death, the ELTS score could accurately identify a high-risk group with a significantly higher risk of dying of CML, and the 5-year cumulative incidence occurred in the ELTS high-, intermediate-, and low-risk groups was 11% (95% CI: 3-19%), 5% (95% CI: 1-9%) and 2% (95% CI: 0-4%), respectively. Most notably, the ELTS score outperformed the Sokal, Hasford and EUTOS scores without statistical difference among different risk groups. CONCLUSION: The ELTS score could effectively predict the prognosis of imatinib-treated CML patients in real-life settings.

Evaluating and monitoring bone marrow hypoplasia in adults with aplastic anemia via high-resolution iliac magnetic resonance imaging in the current era.

The diagnosis and monitoring of aplastic anemia (AA) rely heavily on a complete blood count (CBC), and multiple-site bone marrow (BM) aspirations and biopsies. However, these approaches have certain limitations. We aimed to assess high-resolution magnetic resonance imaging (MRI) as a complementary approach for evaluating BM hypoplasia and monitoring treatment response in adults with AA in the current era.Twelve newly diagnosed AA patients and 12 sex- and age-matched healthy controls were enrolled in this study from January 2017 to August 2018. A bilateral iliac 3.0T MRI was used to collect data for each subject, and the signal intensity on the T1-weighted images (T1WIs) were expressed as a contrast-to-noise ratio (CNR). The MRI, CBC, and BM biopsy data were analyzed and compared.A qualitative analysis identified a significant difference in MRI signal characteristics between the AA group and the healthy control group. The clinical classifications of very severe aplastic anemia (VSAA) and severe aplastic anemia (SAA) corresponded to pattern I and pattern II on the MR images, respectively. However, this imaging classification did not correlate with the biopsy-based BM cellularity measure. A quantitative analysis showed a significantly higher signal intensity in AA patients than in controls. A within-group comparison revealed that more severe types of AA, based on the clinical classification, corresponded to stronger signals. Notably, MRI could detect treatment response earlier than CBC, regardless of whether there were improvements in hematopoiesis.MRI can be used to predict the therapeutic effects in patients with AA and is an important complementary tool for evaluating and monitoring BM hypoplasia.

The synergistic antileukemic effects of eltrombopag and decitabine in myeloid leukemia cells.

BACKGROUND: Hypomethylating agents (HMAs), such as decitabine (DAC), are currently used as first-line therapy for patients with high-risk myelodysplastic syndromes (MDS) and acute myelogenous leukemia (AML) not eligible for standard chemotherapies. Exacerbation of thrombocytopenia is one of the prevalent complications after HMA treatment. Eltrombopag (EP), an oral thrombopoietin receptor agonist, can efficiently stimulate megakaryopoiesis and elevate platelet counts in MDS/AML patients. However, the significance of combining EP with HMAs in patients with high-risk MDS/AML has not been determined. PURPOSE: To explore the impacts and mechanisms of EP and/or DAC on leukemia cell growth and to explore whether EP exhibits antileukemic effects in the context of DAC treatment in human myeloid leukemia cell lines. METHODS: In our study, we assessed the anti-leukemic effect of EP in the context of DAC treatment by measuring cell proliferation, apoptosis, cell-cycle distribution, and intracellular reactive oxygen species (ROS) levels. RESULTS: Our results showed that the combination of EP and DAC had a more obvious antiproliferative effect than that of DAC as a single agent. EP mainly induced S or G0/G1 phase cell cycle arrest, and DAC arrested the cell cycle in the S or G2/M phase. The combination of EP and DAC had a synergistic effect on cell cycle arrest. Furthermore, single-agent treatment with EP or DAC induced a change in intracellular ROS levels, and the combination of EP and DAC had a synergistic effect on ROS levels, exacerbating leukemia cell death. CONCLUSION: Our study provides in vitro evidence of the synergistic antileukemic effect and potential mechanisms of the combination of DAC and EP on myeloid leukemia cells.

The value of FDP/FIB and D-dimer/FIB ratios in predicting high-risk APL-related thrombosis.

Hemorrhage is the typical manifestation of APL-related coagulopathy while thrombosis is infrequently reported. In a retrospective analysis with 33 patients with hyperleukocytic APL, we found 6 out of 33 hyperleukocytic APL patients presented with thrombosis rather than hemorrhage. A notable feature in these high-risk APL patients with thrombosis is that there were no significant abnormalities in fibrinogen (FIB), prothrombin time (PT) and activated partial thromboplastin time (APTT). Compared with the normal ranges, both the high-risk APL patients with thrombosis and the high-risk APL patients with hemorrhage had a significant increase in fibrinogen degradation product (FDP) and d-dimer levels. However, the group with hemorrhage had noticeably higher plasma levels of FDP and d-dimer than the group with thrombosis. To find a close relationship between coagulation markers and the onset of thrombotic events in patients with high-risk APL, the potential effects of FDP/FIB and d-dimer/FIB ratios as risk markers were investigated. We demonstrated that FDP/FIB and d-dimer/FIB ratios in the patients with high-risk APL with thrombosis showed higher ratios than the normal range but significantly lower ratios than the patients with high-risk APL-related hemorrhage. Our data demonstrated that the alteration in FDP/FIB and d-dimer/FIB ratios have more significant relevance than the levels of FIB, FDP or d-dimer as potential factors for predicting thrombosis and may help with designing more appropriately risk-adapted treatment protocols or personalized therapy.