bluuebunny/crossref_metadata_2025 huggingface dataset:
Real-World Safety and Clinical Response of Flumatinib in the Treatment of Chronic Myeloid Leukemia: A Retrospective Study
Authors: Chunyan Chen
Published: December 2023

Objective: The objective of this retrospective study was to assess the effectiveness and safety of flumatinib in the treatment of chronic phase chronic myeloid leukemia (CML) in real-world settings.

Methods: A total of 61 patients who received flumatinib as first-line therapy were compared with 92 patients who received first-line imatinib therapy. Furthermore, the 58 patients who received flumatinib as post-line therapy were divided into two groups based on the timing of switching to flumatinib: an early conversion group (n=18) and a late conversion group (n=40). The molecular responses and outcomes were assessed at multiple time points (3, 6, 9, and 12 months) during the treatment of flumatinib, along with the observation of adverse reactions.

Results: In comparison to imatinib, the use of flumatinib as a first-line therapy demonstrated statistically significant increases in early molecular response (EMR), major molecular response (MMR), and deep molecular response (DMR) at various milestones (p<0.05). Additionally, the incidence of adverse events was lower in the flumatinib group, as evidenced by higher event-free survival (EFS) rates (83.6% vs. 39.1%, P=0.01) and a lower medication switching rate (90.2% vs. 31.5%, P<0.001). However, there were no significant differences observed in overall survival (OS) and progression-free survival (PFS) rates between the two groups (P>0.05). In the context of post-line therapy, a significant proportion of patients (72.2%) achieved EMR at 3 months, while 71.9% achieved MMR at 12 months when treated with flumatinib. Notably, the early conversion group exhibited higher rates of molecular response and demonstrated superior OS, PFS, and EFS at the 12-month mark compared to the late conversion group (P>0.05). Adverse events (AEs) commonly associated with flumatinib encompassed limb discomfort, gastrointestinal reactions, and elevated transaminase levels, with thrombocytopenia being the most frequently observed hematologic AE.

Conclusion: Flumatinib exhibited notable efficacy and safety as a therapeutic option for patients with chronic phase CML, whether utilized as a first-line or post-line treatment. In comparison to imatinib, initial administration of flumatinib resulted in more profound and expeditious molecular responses. The utilization of flumatinib as a post-line therapeutic approach during the early stage of treatment exhibits a favorable influence on patient prognosis. However, no statistically significant disparity was noted when compared to the group receiving switch therapy during the late stage.
Clinical Characterization of Hepatic Light Chain Amyloidosis in the Chinese Population: A Single-Center Retrospective Analysis
Authors: Chen Chen , Yu Chenqi , Li Jing , Wang Weiguang , Wang Zhimei , Cheng Lu-Ya , Chen Fei-fei , Xu Jiadai , Xu Tianhong , Yang Yang , Wang Wenjing , Wang Pu , Liu Peng
Published: December 2023

CONCLUSION

Hepatic light chain amyloidosis is caused by malignant plasma cells that abnormally secrete immunoglobulin light chains, which undergo a conformational change to a β-pleated sheet configuration and are deposited in the liver. The amyloid fibrils are deposited mainly in the hepatic sinusoids, the space of Disse and the walls of blood vessels. Previous autopsy studies have shown that the proportion of systemic light chain amyloidosis with liver involvement is extremely high; however, there are fewer systematic analyses of the clinical features in the Chinese population. Therefore, this study retrospectively analysed the clinical data of patients with hepatic lightchain amyloidosis in our center to further explore the clinical characteristics of this disease.

A total of 40 patients with hepatic light chain amyloidosis were included in the analysis from 2007 to 2022. Inclusion criteria were positive liver tissue biopsy or positive biopsy of other organs with alkaline phosphatase (AKP) greater than 1.5 times the upper limit of normal or total liver span >15 cm in the absence of heart failure.

The median age of these patients was 58±10 years and 80% were male. Of these 40 patients, 66% had light-chain amyloidosis secondary to myeloma and the remainder had primary amyloidosis. The proportion of patients with symptoms related to liver injury as the initial clinical presentation was 33%. Symptoms included malaise, abdominal distention, or jaundice. 40% of patients with symptoms related to abnormal heart function, such as chest tightness, severe shortness of breath, and dizziness. 25% of the patients were first seen for symptoms related to impaired renal function, such as proteinuria with lower limb edema or hypourocrinia. κ-type was found in 28% of the patients and λ-type in 73%. All patients had other sites of involvement, 95% with cardiac involvement (72.9%, Mayo 2004 stage III) and 48% with renal involvement. AKP was elevated in 100% of patients, r-GT in 95%, liver enzymes in 33%, total bilirubin in 44%, and the maximum anteroposterior diameter of the right lobe of the liver was 16.6±1.7 cm (upper limit of normal was 10 cm). In this cohort of patients, 80% received a 2- to 3-drug combination regimen based on proteasome inhibitors and 5% received a 2-drug combination regimen based on melphalan, with a median survival time of 6.5±31.3 months, and patients with a normal total bilirubin level had an overall survival time 2.4 times longer than those with an elevated level (p< 0.05,Figure 1).

Contrary to previous reports of hepatic light chain amyloidosis, λ light chain amyloidosis was predominant in our center; elevated total bilirubin was an independent risk factor for survival.
Aberrant Translation Regulated By METTL1/WDR4-Mediated tRNA N 7-Methylguanosine Modification Drives DLBCL Progression
Authors: Ji Chunyan , Liu Xiaomin
Published: December 2023

Cancer cells selectively promote translation of specific oncogenic transcripts to facilitate cancer survival and progression, but the underlying mechanisms are poorly understood. Here, we find that N 7 - methylguanosine (m 7G) tRNA modification and its methyltransferase complex components, METTL1 and WDR4, are significantly upregulated in diffuse large B-cell lymphoma (DLBCL) and associated with poor prognosis. We further reveal the critical role of METTL1/WDR4 in promoting DLBCL cell survival and progression using loss- and gain-of-function assays in vivo. Mechanistically, m 7G tRNA modification selectively regulates the translation of oncogenic transcripts, in m 7G-tRNA-decoded codon-frequency-dependent mechanisms. Moreover, using overexpression and knockout mouse models, we demonstrate the crucial oncogenic function of Mettl1-mediated m 7G tRNA modification in promoting DLBCL tumorigenesis and progression in vivo. Our study uncovers the important physiological function and mechanism of METTL1-mediated m 7G tRNA modification in the regulation of oncogenic mRNA translation and cancer progression.
Adhesion of Immunoglobulins to Band3 Promotes Increased Erythrocyte Sedimentation Rate in Multiple Myeloma
Authors: Zhang Xialin , Cui Jiangxia , Bian Sicheng , Zhang Ruijuan , Li Yinghua , Chen Xiuhua , Chang Jianmei , Tan Yanhong
Published: December 2023

An increase in ESR can be seen in approximately 85% of patients with MM [1]. Therefore, ESR is often used as one of the sensitive indicators of active MM [1]. It is now widely accepted that the increase in ESR is related to the adhesion of immunoglobulins secreted by myeloma cells to erythrocytes [2, 3]. However, this explanation is descriptive and speculative and has not been confirmed by experimental data [3].

We applied peripheral blood erythrocyte samples from MM patients and used immunofluorescence/immunoprecipitation tandem protein analysis/molecular docking to determine the molecular mechanism by which all types of MM immunoglobulins can target and adhere to erythrocyte membrane Band3.

This result, not only helps to explain the molecular mechanism of ESR acceleration in MM, but will also advance our understanding of the pathophysiologic changes that occur in ESR. At the same time, it may provide a new way to target protection of normal erythrocytes and targeted removal of erythrocyte-bound immunoglobulins.
Circulating NETs Promote Platelet-TLR9 Dependent Acute Chest Syndrome in Sickle Cell Disease
Authors: Dubey Rikesh K , Katoch Omika , Novelli Enrico M , Sundd Prithu
Published: December 2023

Acute chest syndrome (ACS), a type of acute lung injury is one of the primary reasons for mortality among Sickle Cell Disease (SCD) patients. Although new evidence suggests that circulating neutrophil extracellular traps (cNETs) promote lung injury in SCD by triggering occlusion of pulmonary arterioles by neutrophil-platelet-erythrocyte thrombo-inflammatory aggregates, the molecular mechanism underlying cNETs-dependent lung vaso-occlusion remains unknown. Surprisingly, platelets are one of the few cell types that express Toll-like receptor 9 (TLR9), a receptor for double-stranded DNA on the surface (rather than in endosomes), however, the role of platelet-TLR9 in promoting pulmonary thrombo-inflammation in SCD has never been studied. Using intravital (in vivo) lung microscopy in live SCD mice and imaging flow cytometry (in vitro) of SCD mice plasma, we show for the first time that lung vaso-occlusion and elevated levels of cNETs in knock-in humanized SCD mice challenged with 10 μmol/kg oxy-hemoglobin (oxy-Hb) is associated with significant upregulation of TLR9 surface expression in platelets. Importantly, TLR9 inhibition using a function blocking Ab led to significant reduction by ~6 and ~4 fold in the frequency and size of lung vaso-occlusions in SCD mice challenged with IV oxy-Hb. Identical to SCD mice, TLR9 surface expression was also significantly higher in SCD than control human platelets, and the expression was further upregulated following treatment of SCD patient platelet-rich-plasma (PRP) with oxy-Hb. Remarkably, elevated TLR9 expression in SCD patient platelets was concomitant to increased phosphorylation of both downstream TLR9 pathway effector tank-binding-kinase-1 (TBK-1) and the TBK-1 substrate interferon regulatory factor-3 (IRF3), which is the major transcription factor driving IFN-1 response. Taken together, our current findings suggest for the first time that activation of nucleic acid receptor TLR9 on the surface of platelets by cNETs contributes to lung vaso-occlusion and acute chest syndrome in SCD.
Outcomes Among Hospitalized Patients with Relapsing Multiple Myeloma Utilizing Palliative Care: A United States Population-Based Cohort Study
Authors: Arya Yajur , Syal Arshi , Casipit Bruce Adrian , Dourado Claudia , Mayo Ryan J , Heller Gordon
Published: December 2023

Background

Multiple myeloma has a limiting effect on quality of life, with pain being a commonly reported symptom secondary to lytic lesions. Palliative care plays an important role in both pain management as well as addressing individualized goals of care. Newer treatment options are often implemented in patients with relapsing multiple myeloma, and have the potential to cause further treatment related adverse effects. The role of palliative care in this subgroup needs further exploration.

Methods

We utilized the 2018-2020 National Inpatient Sample (NIS) Database in conducting a retrospective cohort study. We identified hospitalized patients who have relapsing multiple myeloma and subsequently had a palliative care encounter using appropriate ICD-10 CM codes. We stratified patients based on whether they had a palliative care encounter during the hospitalization or not. A survey multivariable logistic and linear regression analysis was used to calculate adjusted odds ratios (ORs) for the primary and secondary outcomes. A p value of <0.05 was considered statistically significant. The aim of this study is to investigate the outcomes among hospitalized patients with relapsing multiple myeloma with an in-patient palliative care encounter looking primarily at the in-hospital mortality, hospital LOS as well as total hospital charges.

Results

We identified a total of 16,726 hospitalized patients with relapsing multiple myeloma, of which 11.30% (1890/16,726) had an in-patient palliative care encounter. The overall in-hospital mortality among those with multiple myeloma was 9.86% (1040/16,726). Among those who had a palliative care encounter, the overall in-hospital mortality rate was significantly higher at 29.97% (566/1890) (p=<0.001). Utilizing a stepwise survey multivariable logistic regression model that adjusted for patient and hospital level confounders, the inpatient palliative care encounter among hospitalized multiple myeloma patients significantly increased the risk for in-hospital mortality (adjusted OR 11.99, 95% confidence interval [CI], 8.03-17.92; p=<0.001), longer hospital LOS (median LOS 7 days versus 5 days, p=<0.001) and higher total hospital charges (median total hospital charge 76131 vs 48855, p=0.002)

Conclusion

Our analysis revealed a statistically significant increased risk of in-hospital mortality, hospital LOS, and total hospital charges in hospitalized patients with relapsing multiple myeloma who had a palliative care encounter. Caution should be exercised in interpreting these results as they may reflect uncontrolled and more advanced disease in patients utilizing palliative care. Further prospective studies are needed to better understand short and long-term outcomes in this patient population.
Hemolysis Induced Induction of Matrix Metalloproteinases in Sickle Cell Disease
Authors: Leslie Taylor Michelle , Pradhan-Sundd Tirthadipa
Published: December 2023

Sickle Cell Disease (SCD) is a monogenic disorder that impacts around 100,000 people in the United

States and 20 million people worldwide. SCD is caused by a point mutation in the β-globin gene. SCD

can lead to complications, such as hemolysis, vaso-occlusion, oxidative stress, organ injury, and

erythrocyte sickling. Organ injury, specifically liver injury, is one of the main causes of mortality in SCD

patients. Hemolysis induced accumulation of hemoglobin, heme and iron acts as potent damage

associated molecular pattern (DAMP) and can cause chronic liver injury and inflammation. Previous

studies in the lab have demonstrated exacerbated injury and inflammation in SCD liver.

Chronic inflammation is known to activate matrix metalloproteinases (MMPs) which can then induce the

expression of cytokines and chemokines. In this study, we examined the role of hemolysis-induced

induction of MMPs using blood and liver samples from humanized townes SCD mouse model.

Proteomic analysis using SCD mouse blood sample revealed increased expression of 8 MMPs in

SCD mice following oxyhemoglobin treatment compared to their baseline expression. We next examined

the mRNA expression of these MMPs in the liver by doing qRT-PCR. Interestingly, two MMPs- Steap3

and Timp3, showed significant upregulation in SCD mice liver compared to the littermate control, which

positively correlated with hemolysis and the age of the mouse. Studies are currently underway to

understand the role of Steap3 and Timp3 in hemolysis-induced chronic liver injury and their potential

usage as novel biomarkers of hemolysis-induced chronic organ injury in SCD
Drug Resistance Can be Overcome in Multiple Myeloma and Acute Myeloid Leukemia By Targeting Mcl-1 with the Small Chemical KS18
Authors: Al-Odat Omar S. , Chitren Robert , Von Suskil Max , Aloudat Osama , Gowda Krishne , Budak- Alpddogan Tulin , Jonnalagadda Subash , Pandey Manoj Kumar
Published: December 2023

Drug resistance and patient recurrence are still key clinical difficulties in multiple myeloma (MM) treatment, despite the tremendous improvements provided by bortezomib therapy. In many cancers, Mcl-1, a member of the Bcl-2 protein family, helps keep cells alive by preventing their natural death process, apoptosis. The anti-cancer therapeutic promise of Mcl-1 inhibitors is highlighted by the fact that Mcl-1 overexpression increases carcinogenesis and medication resistance. Here, we provide KS18, a powerful pyoluteorin derivative with excellent effectiveness towards Mcl-1-dependent cancer cells, to address this unmet therapeutic need. Based on our results, we conclude that KS18 causes apoptosis in cancer cells through activating the mitochondrial outer membrane permeabilization (MOMP) pathway, with the participation of Bak and Bax, in particular in MM and acute myeloid leukemia (AML). With IC 50 values below 1.5µM, KS18 demonstrated efficacy against bortezomib-resistant MM cells, outperforming other Mcl-1 inhibitors in clinical trials such as S63845, VU661013, and AZD5991. Total apoptosis in MM patient samples treated with KS18 was an impressive 88.8 percent. After four weeks of treatment with a single tolerable dose each week, a model of bortezomib-resistant MM showed considerable tumor shrinkage, demonstrating the powerful anti-tumor efficacy of KS18. According to these results, KS18 may be able to overcome resistance by concentrating on Mcl-1. These encouraging findings have prompted the development of many models of drug-resistant MM and AML for in vivo evaluation of this potential chemical.
The Kinetics of FLT3L during Induction Chemotherapy for Pediatric Acute Lymphoblastic Leukemia Suggests a Novel Clinical Diagnostic and Treatment Strategy
Authors: Wang Wenqing , Tang Yan-lai , Li Zhen , Jiang Hao , Li Chi-Kong , Chen Chun , Chen Yun , Xue Hongman
Published: December 2023

Acute lymphoblastic leukemia (ALL), one of the most common malignancies, has been reported to account for nearly one-third of all pediatric cancers. Failure of induction chemotherapy is the leading cause of relapse and mortality in pediatric patients treated for ALL. Monitoring the therapeutic efficacy of induction chemotherapy and improving its success rate are critical to the clinical management of ALL. FMS-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase that is expressed on progenitor cells and ALL blasts. FLT3 ligand (FLT3L) is detectable during homeostasis and increases in hypoplasia due to genetic defects or treatment with cytoreductive agents. Here, we continuously monitored changes in FLT3L levels during induction chemotherapy in children with ALL to provide a more sensitive assessment of MRD, similar to NGS. The study included 54 children with ALL whose peripheral blood FLT3L levels were measured by ELISA weekly during induction chemotherapy. Weekly sampling revealed a significant difference in the kinetics of FLT3L response between children in complete remission (CR) and partial remission (PR), at day 14 of treatment (CR:519±10pg/ml vs PR:54±10pg/ml, P＜0.001). Furthermore, the achievement of CR in these patients was associated with higher FLT3L (150±10pg/ml vs 32±10pg/ml, P＜0.05) at day 28. Clinical prediction models show that combining minimal residual disease (MRD) status with FLT3L measurements better predicts whether patients will achieve CR after induction chemotherapy. Moreover, FLT3L levels were positively correlated with DC and T cells and negatively correlated with WBC, PLT and LDH during induction chemotherapy in children with ALL. Therefore, we hypothesized that higher levels of FLT3L might improve antitumor immunity by activating DC and T cells. However, further research is needed. In conclusion, measurement of FLT3L in children with ALL during induction may provide added value in assessing early treatment response to chemotherapy, the impact on long term outcome needs further study.
Mortality and Prognostic Factors of Adult Patients with Acute Leukemia Admitted to the ICU: A Systematic Review
Authors: Cabral Paloma L , Sandoval-Sus Jose , Zang Zhenmei , Gallo de Moraes Alice
Published: December 2023

Introduction: Acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) are the most aggressive group of hematologic malignancies (Pulte et al, 2020) and will be responsible for approximately 12,700 deaths in the U.S. during 2023(Seiger et al,2023). Improved overall survival (OS) has been observed in the past decades in both diseases, but high mortality in the Intensive Care Unit (ICU) persists, which may prevent ICU admission of those patients. We aimed to review the literature on mortality data and survival predictors of patients with acute leukemia (AL) admitted to the ICU.

Methods: Embase, Pubmed and Cochrane databases were searched for articles published from January of 2005 to December of 2020. Due to OS improvement of patients with AML, we only included studies published as of 2005 (Percival et al, 2015). Editorials, case reports and small case series were excluded.

Results: Initial search revealed 1,015 manuscripts from database and references, 650 were screened and 115 were fully assessed, for which 24 met eligibility criteria (Figure 1). A total of 13,350 patients were included in the review. Median age was 54.8 years and 57.3% of patients were male. AML represented the majority of diagnoses (98.2%).Two studies included only newly diagnosed patients, 1 study only included patients with relapsed disease and the rest (N=21) included subjects regardless of the AL status. Only 0.7% of patients had a history of hematopoietic stem cell transplantation . 81.9% of patients required mechanical ventilation, 25.3% needed renal replacement therapy, and 65.9% used vasopressors in studies data was available. Median SOFA score in the first 24h of ICU admission was 10.85 . Pooled ICU mortality and hospital mortality were 45.0% and 43.1%, respectively; 58.2% of patients were deceased at 90-day mark (Table 1). The 12 months OS was 37.3%. Higher SOFA score, need for mechanical ventilation, sepsis, vasopressor use, and age greater than 60 years were the most common predictors of ICU, hospital and 90-day mortality. Relapsed or refractory status of underlying AL was the most significant risk factor for long-term mortality.

Conclusions: Our systemic review showed that ICU mortality in patients with AL was 45.0%, which represents a survival improvement compared to prior studies on patients with hematological malignancies, where ICU mortality could be as high as 69% (Ashkenazi et al, 1986). Predictors of ICU mortality were closely related to the severity of acute illness rather than malignancy status. We acknowledge that our patient population was mostly comprised of AML cases and the majority of the original studies included a small number of patients with AL with exception of one large study (Halpern et al, 2017).
Sickle Cell Trait Is Associated with Adverse Clinical Outcomes in a Matched Case-Control Study at a Tertiary Care Center
Authors: Stafford Katherine , Osataphan Soravis , George Gemlyn , Patell Rushad
Published: December 2023

Background:

Sickle cell trait (SCT) is a common condition affecting more than 300 million individuals worldwide and 3 million in the United States. Although generally believed to be an asymptomatic condition, there is growing data to suggest potential associations with morbidity, including risk for venous-thromboembolic events and chronic kidney disease.

Methods:

We conducted this retrospective cohort study using electronic health record data from the University of Colorado Health Data Compass data warehouse. Patients with a coded diagnosis of SCT were analyzed for SCT-related clinical outcomes compared against a 1:1 randomized matched sample of controls without a history of SCT (matched on age, race, sex). Individuals with sickle cell disease, Sickle-cell/Hb-C disease, sickle-thalassemia, other sickle cell disorders, and hemolytic anemias were excluded from both case and control groups. Outcomes included chronic kidney disease (CKD), deep vein thrombosis (DVT), pulmonary embolism (PE), hematuria, rhabdomyolysis, and splenic infarction. Multivariate logistic regression was used to examine the association of each condition based on SCT carrier status, adjusting for age, sex, and race.

Results:

We included 1447 SCT patients with complete demographic data, along with 1447 matched controls (n = 2894). There were 1019 (70.4%) women and 428 (29.6%) men in each case and control group. A majority (72.7%) were black or African American. The median age of the cohort was 36 years (IQR = 28 - 47). We found significant associations for CKD (OR = 2.95, 95% CI: 2.03 - 4.30), DVT (2.54, 95% CI: 1.42 - 4.54), PE (OR=4.25, 95% CI: 2.43 - 7.45), and hematuria (OR= 2.28, 95% CI: 1.57 - 3.31). (Table) Despite few overall events and wide confidence intervals, association remained significant for rhabdomyolysis (OR=3.32, 95% CI 1.07 - 10.24) and splenic infarction (OR=44.9, 95% CI 6.15 - 328.00). Male sex was strongly associated with splenic infarction (OR = 8.70, 95% CI 4.11 - 18.41) and rhabdomyolysis (OR = 19.14, 95% CI 4.35 - 84.18).

Conclusion:

In this case-control cohort study we found significantly increased risk for CKD, DVT, PE, hematuria, rhabdomyolysis, and splenic infarction for patients with sickle cell trait with odds ratios similar to those seen in other study cohorts. The significant morbidity associated with this common genotype warrants further research into primary prevention of SCT associated adverse outcomes.
Changes in Cardiovascular Magnetic Resonanse T1 and T2 Mapping in Patients Undergoing Autologous Hematopoietic Stem Cell Transplantation
Authors: Vaitiekiene Audrone , Kulboke Migle , Bieseviciene Monika , Jankauskas Antanas , Strazdiene Igne , Lidziute Emilija , Jankauskaite Darija , Gaidamavicius Ignas , Gerbutavicius Rolandas , Vaskelyte Jolanta Justina , Vaitiekus Domas , Sakalyte Gintare , Niederwieser Dietger W.
Published: December 2023

Introduction

Despite the significant improvement in survival afforded by hematopoietic stem cell transplantation (HSCT), the therapy is associated with many complications, cardiovascular being one of them. Cardiovascular magnetic resonance (CMR) can depict changes at the tissue level, which could be a reflection of physiology and pathophysiology. In our study we aimed to evaluate the level and progress of diffuse myocardial fibrosis and edema in the heart using T1 and T2 mapping in patients one year after autologous HSCT.

Methods

Data of 26 patients undergoing autologous HSCT at the Department of Oncology and Hematology in the Hospital of Lithuanian University of Health Sciences Kaunas Clinics between 2021 October and 2022 July was evaluated. Bioethics approvement for prospective study was obtained (No BE-2-96). Cardiac evaluation including cardiovascular magnetic resonance (CMR) was performed before stem cell mobilization and 12 ± 1 months after HSCT. CMR was performed using 3T MRI Siemens Magnetom Skyra, T1 and T2 mapping MOLLI (modified Look-Locker Inversion Recovery) sequences with motion correction (MOCO) were analysed using Syngo.via. Baseline mapping values were compered to values one year after transplantation. SPSS statistics 20 was used for statistical analysis (paired samples T test). Qualitative data is presented as absolute value (N) and percentage (%), quantitative parameters are given as average (m ± standard deviation).

Results

The mean age of patients was 56,7 ± 13,7 years (ranging from 18 to 74). Out of 26 patients there were 14 men (53,8%) and 12 women (46,2%). Mean T1 mapping value representing diffuse fibrosis significantly increased 12 months after transplantation. Mean T1 mapping value before HSCT was 1215,02 ± 35,2 ms and after 1243,07 ± 46,2 ms (p=0,014). Mean T2 mapping value representing edema did not change significantly. Mean T2 mapping value before HSCT was 38,28 ± 2,1 ms and 39,05 ± 1,8 ms after HSCT. (p=0,059).

Conclusions

The extent of diffuse fibrosis in the heart represented by elevation of T1 mapping value tend to increase one year after autologous HSCT. This may lead to further remodelling of the heart.
Hemoglobin Receptor CD163 As a Potential Biomarker of Hemolysis Induced Hepatobiliary Injury in Sickle Cell Disease
Authors: Ungalara Ramakrishna , Katoch Omika , Kaminski Tomasz Waldemar , Pradhan-Sundd Tirthadipa
Published: December 2023

Sickle cell disease (SCD) associated chronic hemolysis promotes oxidative stress, inflammation and thrombosis leading to organ damage, including liver damage. Hemoglobin scavenger receptor CD163 plays a protective role in SCD by scavenging both hemoglobin-haptoglobin complexes and cell free hemoglobin. A limited number of studies in the past have shown a positive correlation of CD163 expression with poor disease outcomes in patients with SCD. However, the role and regulation of CD163 in SCD related hepatobiliary injury has not been fully elucidated yet. Here, we show that chronic liver injury in SCD mice and patients is associated with elevated levels of hepatic CD163. Hemolysis and increase in hepatic heme, hemoglobin, iron and haptoglobin levels elevate CD163 expression in the SCD mouse liver. Mechanistically we show that HO-1 positively regulates CD163 expression and that HO-1 and NRF2 form a complex with CD163 in the SCD liver. Finally, we demonstrate that blocking CD163 activity promotes hemolysis induced liver injury in SCD. These findings indicate that CD163 is a mediator and a potential biomarker of SCD associated hepatobiliary injury. Understanding the role of HO-1 in CD163 regulation may help identify novel therapeutic targets for hemolysis induced chronic liver injury.
Response to Dabrafenib and Tramatenib in an Extra-Cranial Avm with BRAF V600E Mutation
Authors: Fraustro Milena , Olsen Braden , Khatib Ziad
Published: December 2023

Background:

Arteriovenous malformations (AVMs) are blood vessel malformations characterized by shunting of blood through dilated veins and arteries. KRAS is an effector molecule in a MAPK pathway that mediates activation of downstream processes such as BRAF production related to known proliferative disorders such as AVMs. Similarly MAP2K1 mutations that encodes for MEK have recently been implicated in sporadic intracranial and extracranial AVMs. Inhibition of the RAS/MAPK pathway is of interest in treatment of vascular malformations.

Objective: We report a case of treatment response of a BRAF mutated arteriovenous malformation with MEK and RAF inhibitors.

Description of the case:

A 22 year old male presented initially at 6 years of age with swelling of the left face involving the cheek and mandible area, the area continued to grow in size with associated pain and rarely intermittent bleeding from the left buccal mucosa. US and MRI showed evidence of an AVM. He underwent 2 embolizations followed by debulking with some improvement of the swelling. Pathology revealed a BRAF V600 mutation by molecular testing. He was treated with oral Dafrafenib 150 mg twice daily and Trametinib 2 mg daily, showing improvement of the swelling with a 3 month old follow up.

Conclusion:

AVMs continue to present treatment challenges for hematologists, surgeons and other care providers. Treatment with target directed therapies with inhibitors of the RAS-RAF-MEK-ERK pathway such as Trametinib and Dafrafenib have the potential to make a positive impact in the current management of these entities. Further studies are required to explore safety and impact of long term effects of these drugs in pediatric patients.
As Fast As We Can: Rational Design of Rapid Chimeric Antigen Receptor T Cell Manufacturing
Authors: Jiang Pengfei , Cao Shih-Ting , Wang Haiying , Xiong Qinghui , Gu Mingyuan , Fu Chengbing , Li Xiu , Zhang Mian , Li Na , Li Jing , Xu Xin , Gong Yiwei
Published: December 2023

Background

Chimeric antigen receptor T cell proved to be a promising approach to treat hematological malignancies. There are six autologous CAR-T drugs approved by FDA in US. The production of autologous CAR-T cells is carried out by a time-consuming manufacture process typically need 2-3 weeks. Unfortunately, about 25% patients died while awaiting their CAR-T product. Rapid manufacturing CAR-T cells still is an unmet clinical need for fast processing diseases. We developed the “DASH CAR-T” manufacturing platform which harvested CAR-T cell in two-three days. Our first product, autologous DASH CD19 CAR-T demonstrated greater anti-tumor efficacy in murine study correlated with higher T cell expansion compared with conventional CAR-T. In this study, we designed a simplified novel CAR-T manufacturing process with optimized culture and harvest time between 48 hours to 72 hours.

Methods

Rapid manufacturing CAR-T cells comprising common key steps as the conventional CAR-T product : select T cells from PBMC, activated T cells by CD3/28 Dynabeads, transduced with retroviral vector expressed CD19-28z CAR construct, and then the CAR-T cells harvested and cryopreserved for clinical use. We investigated the shortest time for each steps by various reagents, medium and process. Then we compressed the whole process and our novel approaches completed all manufacturing process less than 72 hours.

Results

First, we compared the harvest timing based 3 batches CAR-T cells from health donors. A various factors, such as cell viability, CD3+%, Annexin V-/PI- population, percentage of residual CD19+ cells, and naïve T cell proportion were very similarly between 48 hours CAR-T cells and 72 hours CAR-T cells, indicated comparable harvest timing for manufacture. Second, we investigated 3 batches of CAR-T cells manufactured from B cell malignancy patients. In this scenario, 72 hours CAR-T exhibited better cell viability, increased naïve T cell population, and more Annexin V-/PI- cells in the culture compared to 48 hours CAR-T. The different performance of patient cells and healthy donor cells suggested the importance of the choice of starting material for process development of cell therapy. All batches successfully manufactured in 72 hours. Tumor cell-xenograft NOG mice models were confirmed the anti-tumor activity of DASH CD19 CAR-T cells in vivo.

Conclusions

This study reported an optimized DASH CAR-T process with 48 hours and 72 hours manufacturing. Cell viability, stemness of T cells, CAR expression, and removal of impurity were improved in the CAR-T product manufactured by this novel process. Based on the preclinical study results, an investigator-initiated trial (IIT) has launched to explore the safety, efficacy, pharmacokinetic/pharmacodynamics characteristics in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL).
Accuracy of the Diagnosis of Subsegmental Pulmonary Embolism Among General Radiologists
Authors: Batayneh Osama , Ijaz Ambreen , Toumar Ahmad , Meek Jessica , Abdelrahman Houda , Haddad Stephanie , Minami Taro
Published: December 2023

Background:

Diagnosis and treatment of subsegmental pulmonary embolism (SSPE) are challenging. Contrary to segmental PE, little is known about the accuracy of the diagnosis of SSPE

Methods

A retrospective matched cohort study was conducted at a university-affiliated community hospital. Computed tomographic angiography (CTAs) were reviewed from August 2018 to December 2021. Patients who were 18-year-old or older with the diagnosis of SSPE were included. Patients with a concurrent segmental PE or deep venous thrombosis (DVT) were excluded. Another radiologist reviewed each CTA.

Results

Total of 43 patients with SSPE without segmental PE were identified. The mean age of subjects was 67 years. 24 (56%) patients were males, and 41 (95%) were white. 42 (97%) of CTAs were performed for suspected PE. One case was found incidentally. Forty patients (93%) received therapeutic anticoagulation. Three patients (7%) were discharged from the Emergency Department (ED) without therapeutic anticoagulation. The average duration of anticoagulation therapy was four-months. Another radiologist's review of the CTA on admission revealed a discordant diagnosis: 13 out of 43 (30%) cases were reported negative for SSPE. One case was reported for segmental PE

Conclusion

The accuracy of the diagnosis of SSPE is low as the discordance rate by different radiologists is high.More studies are needed to establish the diagnosis and guide treatment of SSPE.
Frailty Predicts Worse Outcomes in Tumor Lysis Syndrome
Authors: Kamal Ashna , Vikash Sindhu , Vikash Fnu
Published: December 2023

DISCUSSION

Tumor lysis syndrome (TLS) is a potentially life-threatening complication that occurs in the setting of rapid tumor cell destruction. The Hospital Frailty Risk Score (HFRS) is a valuable tool to identify frailty in older individuals, signifying a decline in physiological reserves and coping ability due to age-related deterioration, and it has gained recognition as a crucial factor linked to adverse events, including mortality, hospitalization, and diminished functional outcomes. We aimed to assess the impact of HFRS on individuals admitted with a primary diagnosis of TLS.

Using weighted data from the Nationwide Inpatient Sample (NIS) database from 2016 to 2020, we assessed the outcomes (mortality, hospital utilization, total healthcare charges, complications) of individuals admitted with a primary diagnosis of TLS stratified by the presence and absence of Frailty (determined by the combination of 109 ICD-10 codes each with a different score) (table 1). Baseline characteristics were analyzed using T-test and Chi-Square, and a multivariate regression analysis was used to estimate outcomes between races, adjusted for patient and hospital confounders. Data analysis was performed using STATA® Version 17.0/SE Software, with statistical significance set at p < 0.05.

A total of 4,340 were admitted with a primary diagnosis of TLS from 2016 to 2020, among these, we selected 1,330 admissions aged 75 years or older; these admissions included 59% (N=785) with frailty, and 41% (N=545) without frailty. Frailty was associated with increased length of stay (adjusted mean difference (aMD) = 2.5 days, 95%CI: 1.2 - 3.8 days), and total healthcare expenditures (aMD = 22,541 U.S. dollars (USD), 95%CI: 2,175 - 42,908 USD). Pertaining to the outcomes, a 9- fold increase in the odds of mortality were noted among individuals with frailty, as opposed to those without frailty (adjusted Odds Ratio (aOR) = 8.93, 95%CI: 1.79 - 44.74).

Our study depicts the significant impact of frailty on individuals hospitalized with TLS, revealing associations with elevated mortality rates, prolonged length of hospital stay, and increased healthcare costs. Considering a considerable portion of cancer patients fall within the elderly demographic and often present with multiple comorbidities, the Hospital Frailty Risk Score (HFRS) is a potential valuable tool for assessing the appropriateness of chemotherapy in conjunction with other scores like the Eastern Cooperative Oncology Group (ECOG). Moreover, the HFRS may aid in prognosticating disease outcomes, offering clinicians valuable insights to inform treatment decisions and improve patient care.
Clinical Characteristics of Shwachman-Diamond Syndrome in China - Result from Childhood Bone Marrow Failure Diseases Register of China Alliance for Blood Diseases(cBMFR-CABD)
Authors: Wan Yang , Qin Xia , Tan Shengjiang , Liu Jianping , He Hailong , Ju Xiuli , Liu Yufeng , Jie Yu , Yuan Sun , Hu Qun , Wu Xiaoyan , Liu Rong , Ma Jie , Chen Jing , Warren Alan , Zhu Xiaofan , Tang Xiangfeng
Published: December 2023

OBJECTIVE

This study aimed to identify the clinical features of 73 children diagnosed with SDS from 22 centres in China.

METHODS

Childhood Bone Marrow Failure Diseases Register of China Alliance for Blood Diseases (cBMFR-CABD) was a bidirectional multicenter cohort study that collected data from 22 paediatric blood disease treatment centres from all over China. Patients were enrolled in the sub-centres from 1.1.2011 that were aged < 18 years at diagnosis and met the diagnostic criteria for an inherited bone marrow failure disorder. The clinical data for the 73 SDS patients analyzed in this study were collected between 1.1.2011 and 31.12.2022.

RESULTS

Among the 73 SDS children, 38 were male and 35 were female. Short stature (height<-2SD) was found in 53.4 % (39/73) patients. Chronic diarrhea was observed in 24.7 % (18/73) patients. In children evaluated for intellectual and physical malformations, 7 patients (17.3 %,6/52) had mental retardation and 14 (20.5 %, 15/73) patients had physical deformities.

Genetic testing was available in 63 patients. seventeen (27.0 %) patients carry bi-allelic c.258+2T>C and c.183-184TA>CT SBDS mutations. Eleven patients (17.5%) are homozygous for the c.258+2T>C mutation. Four patients (6.3%) were compound heterozygous for c.258+2T>C and exon 2 deletions. One patient carries bi-allelic mutation of DNAJC21. This patient had a history of repeated infections and pancytopenia.Bone marrow smear shows multilineage dysplasia.

Bone marrow results were available for evaluation in 54 patients including 67 % (36/54) BMF, 30 %(16/54) MDS, 4 % (2/54) AML.TP53 mutation testing was available in 15 patinets with eight (53.3%) patients carry TP53 mutation.Karyotype analysis was available in 36 patinets with 5 patients were complex karyotype.

Among the 56 patients available for follow-up, 17 patients underwent haematopoietic stem cell transplantation, 5 patients died (one infection,three transplant-related death and one relapse). Among the 39 non-HSCT patients, 3 patients died of AML transformation.

Three-year overall survival of all patients were 91.7%(95%CI 99.5 %~ 83.9% ), BMF patients were 100.0%(95%CI 100.0%~100.0% ), MDS/AML patients were 67.7%(95%CI 94.0%~ 41.4% ).

CONCLUSION

Our results provide the clinical features of the largest SDS cohort in China. A high incidence of short stature was observed. Bi-allelic c.258+2T>C with c. 183-184 TA > CT SBDS mutations were the most common mutation type. HSCT is an effective treatment modality in SDS. However, AML transformation is still a major risk factor for children with SDS.
Hemophagocytic Lymphohistiocytosis As an Immune-Related Adverse Events in a Patient with Advanced Lung Adenocarcinoma
Authors: Lu Kai , Polly Oshuare , Achhal El Kadmiri Mohammed Amine
Published: December 2023

I ntroduction: Immune checkpoint inhibitors (ICIs) have been approved as single agents or in combination with cytotoxic chemotherapy for use in the treatment of different tumor types including skin, lung, kidney, endometrium, bladder..., especially in advanced stages. ICIs are usually well tolerated and despite their demonstrated clinical benefit, severe immune-related adverse events (irAEs) can sometimes occur, including colitis, hepatitis, myocarditis, glomerulonephritis, pneumonitis, hypophysitis... Here we are reporting a case of hemophagocytic lymphohistiocytosis (HLH), a rare but potentially life-threatening complication of ICI therapy.

Case presentation: We present the case of a 60-year-old female with metastatic adenocarcinoma of left lung who presented to the emergency room with a week history of generalized weakness, worsening dyspnea on exertion and decreased appetite while on maintenance ICI with pembrolizumab for approximately 1 year.

On admission vital signs were a blood pressure of 88/70mmhg, pulse rate of 139 beats per minute, respiratory rate of 20 cycles per minute, temperature of 98.3°F and oxygen saturation of 98% on room air. Physical exam was unremarkable. A complete blood count revealed leukopenia of 2.7k/uL, hemoglobin of 11.8 g/dL, and mild thrombocytopenia of 131k/uL. A basic metabolic panel was significant for hyponatremia of 133 mmol/L, blood urea nitrogen of 43mg/dL, and creatinine of 1.71mg/dL. She was started on empiric broad-spectrum antibiotics with IV vancomycin and cefepime due to concern for infection in the setting of recurrent febrile episodes and neutropenia. Worsening pancytopenia prompted further work-up and showed elevated ferritin of 19581, lactate dehydrogenase of 2380, folate > 20, vitamin B 12 of 1645, iron level of 62, elevated total and direct bilirubin of 6.3 and 2.9 mg/dL, haptoglobin < 10 mg/dL, fibrinogen level of 174, C- reactive protein of 73.9. Elevated soluble IL2- receptor elevated at 10336.7, d-dimer > 20, elevated partial thromboplastin time of 51.1, Prothrombin Time of 20.5, INR of 1.7. Peripheral blood smear was unremarkable.

Hemophagocytic lymphohistiocytosis was suspected and a bone marrow was performed prior to initiation of intravenous steroids. Bone marrow showed evidence of abundant histiocytes with hemophagocytosis of nucleated cells. She was discharged on an oral steroid taper. She has since been well without evidence of tumor progression off therapy for over 2 years now.

Discussion: HLH is a rare but potentially life-threatening complication of ICI therapy that requires prompt recognition and management. Our patient responded well to steroids and did not require cytotoxic chemotherapy with etoposide.
Treatment of Acute Lymphoblastic Leukemia with PDT Regimen Improves the Prognosis of Newly Diagnosed Central Nervous System Leukemia
Authors: Liang Haimei , Liu Qifa , Zhou Hongsheng
Published: December 2023

Objective

To investigate whether pediatric-like regimen can improve the prognosis of newly diagnosed acute lymphoblastic leukemia (ALL) complicated with central nervous system leukemia (CNSL) and reduce the occurrence of CNSL during treatment compared with the adult regimen.

Methods

We collected the clinical data and survival data of 1023 patients with newly diagnosed ALL in the hematology department of Nanfang Hospital from January 2006 to December 2021. The adult regimen cohort included 612 patients (age≥14 years) diagnosed between January 2006 and December 2015, all of whom were treated with the Hyper-CVAD regimen. The pediatric-like regimen cohort included 411 patients diagnosed between January 2016 and December 2021, all of whom were treated with the PDT-ALL-2016 regimen (a GRAALL2003 backbone, pediatric-inspired regimen therapy). Newly dignosed central nervous system leukemia(Ndx CNSL) is defined as the presence of leukemia cells on cytological examination of the cerebrospinal fluid or significant neurological signs. Differences between OS and EFS in Kaplan-Meier curves were determined using the log-rank test in the R package “survival”.

Results

Among 1023 patients, a total of 59 patients had Ndx CNSL, including 35 patients (5.72%) in the adult regimen cohort and 24 patients (5.84%) in the PDT-ALL-2016 cohort. There were no statistically significant differences in baseline characteristics between the two groups. In the cohort of Ndx CNSL, after a median follow-up of 42.48 months, overall survival (OS) and event-free survival (EFS) of the adult cohort were significantly inferior than the PDT-ALL-2016 cohort (3-year OS, 14.26%vs38.2%, P=0.044; 3-year EFS, 12.42%vs37.1%, P=0.039). During the chemotherapy treatment, CNSL occurred in 69 patients (11.27%) in the adult regimen cohort and 29 patients (7.06%) in the PDT-ALL-2016 cohort, with a significant difference (P=0.032).

Conclusion

Compared with the adult regimen, the pediatric-like regimen PDT-ALL-2016 improves the prognosis of ALL patients with newly diagnosed CNSL and reduces the occurrence of CNSL during the chemotherapy treatment.

This research was supported by the National Natural Science Foundation of China(NFSC82170163, 81970147), Clinical Study of Nanfang Hospital(LC2016ZD009/2019CR012).