bluuebunny/crossref_metadata_2025 huggingface dataset:
Langerhans Cell Histiocytosis: A Rare Case of Unifocal Gastrointestinal Tract Involvement
Authors: Perumal Karthic Drishna , Patel Taral , Brijawi Omar
Published: December 2024

Langerhans cell histiocytosis (LCH) is a rare condition caused by the clonal proliferation of bone-marrow-derived antigen-presenting Langerhans cells. Its incidence is prevalent in the pediatric population with 4-5 million cases per year and in adults the incidence is even more rare with approximately 1-2 million cases per year. It can manifest as a unifocal, multifocal single-system, or even multi-system disease, which creates a true medical challenge in its diagnosis and management. LCH most commonly presents with osseous lesions, but is exceedingly rare in the GI tract with the prevalence limited to only a handful of cases–approximately less than 30 in the English literature to date to the best of our knowledge. We present a 44-year-old Caucasian female with a past medical history significant for GERD, type 2 diabetes mellitus, gastroparesis, essential hypertension, and a family history of colon cancer in the patient's maternal and paternal uncles was referred for evaluation of chronic abdominal pain and diarrhea via colonoscopy. Before the procedure, the patient admitted to chronic diarrhea and intermittent but self-resolving left lower quadrant abdominal pain, but otherwise denied any hematochezia, constipation, tenesmus, nausea or vomiting with oral intake, unintentional weight loss, fevers, chills, or recent illnesses. Colonoscopy showed erythema throughout the sigmoid colon, ulceration in the transverse colon, and a single sessile 2 mm polyp was found in the rectum. Transverse colon biopsy revealed a submucosal infiltrate of Langerhans cells with indented nuclei and pale eosinophilic cytoplasm and admixed inflammatory cells. Furthermore, immunohistochemical staining revealed cells strongly positive for S-100 protein, CD-1a, and CD56-confirming Langerhans cell histiocytosis. Due to the scarcity of studies and trials available for both GI and non-GI LCH cases, it is still difficult to arrive at a definitive standardized treatment protocol. In addition, the number of adult cases compared to the pediatric population is sparse and limits the application of novel treatment strategies to more than just the pediatric population. Although our patient had favorable outcomes without florid systemic involvement and continues to do well, follow-up with patients is crucial to rule out progression to systemic disease. Furthermore, future studies and trials will also be paramount in narrowing down the disease pattern of LCH and its predilection for certain presentations such as the GI tract in order to develop targeted and effective treatment strategies in patients with LCH. Our case is another rare presentation that contributes to the understanding of this highly variable disease and possible treatment with further clinical studies and trials.
Age, Gender and Temporal Trends in Solid Tumor As Second Primary Malignancy Risk after De Novo Myelodysplastic Syndrome: A SEER Database Analysis
Authors: Singh Sneha , Khadka Sushmita
Published: December 2024

Introduction: Myelodysplastic syndromes (MDS), a group of blood disorders characterized by abnormal development of blood cells, are associated with an increased risk of second primary malignancy (SPM), primarily secondary hematological malignancy. Various studies have also established an increased incidence of secondary solid tumors after de novo MDS, a term used to describe MDS that occurs without a known cause. In this population-based cohort study, we aim to understand the influence of age, temporal trends, and gender on solid tumor SPM development in patients with de novo MDS.

Methods: Using the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) 17 database registry, a comprehensive source of cancer incidence and survival data in the United States, we identified a cohort of patients diagnosed with de novo MDS (Site and Morphology Site recode ICD-O-3 2023 Revision Expanded) between 2000 and 2021. We analyzed the incidence of solid tumor SPM using SEER*Stat Multiple Primary- Standardized Incidence Ratio (MP-SIR) session stratified by age group at MDS diagnosis (<60, 60-69, >70), gender (male, female) and year of diagnosis of MDS (2000-2005, 2006-2010, 2011-2015 and 2016-2020). Standardized incidence ratios (SIRs) were calculated to compare observed and expected development rates of solid tumor SPM development.

Results: Among 52,686 de novo MDS patients, 7,423 patients developed SPM. Of 7,423 patients, 3,272 patients developed solid tumors as SPM. There is a significant difference in the overall risk of these solid tumor SPMs among MDS patients compared with the United States general population (SIR: 1.05, 95 % CI [1.01-1.09]). SIRs for these solid tumor SPMs decreased with increasing age of MDS diagnosis (SIRs: <60 years: 1.39, 95% CI [1.25-1.53]; 60-69 years: 1.12, 95% CI [1.04-1.20]; ≥70 years: 0.98, 95% CI [0.94-1.03]). A modest increase in these solid tumor SPMs SIRs was observed over time, with the highest rates in the most recent diagnostic period (SIRs: 2000-2005: 0.95, 95% CI [0.88-1.10]; 2006-2010: 1.02, 95% CI [0.96-1.08]; 2011-2015: 1.12, 95% CI [1.05-1.2]; 2016-2020: 1.16, 95% CI [1.06-1.27]). A slightly higher SIR of these solid tumor SPMs was seen in females compared to males (SIRs: male: 1.04, 95% CI [1.00-1.09]; female: 1.06, 95% CI [1.01-1.12]).

Conclusion: Our study found that younger age at MDS diagnosis, female gender, and more recent diagnosis year is associated with a greater incidence of solid tumor SPM in patients with de novo MDS. These insights can inspire the development of personalized surveillance protocols, facilitating early detection and intervention for SPM. There is a need for further research to understand the underlying mechanism for up-trending SIR for secondary solid tumors SPM in patients with de novo MDS.
Association between Chemotherapy for Nonmetastatic Breast Cancer and Risk of Secondary Hematologic Malignancies
Authors: Lang Wenjing , Han Xiaofeng , Hou Jian
Published: December 2024

Hematologic malignancies, such as leukemia, were serious side-effects of chemotherapy to treat breast cancer. We sought to quantify the risks of developing secondary hematologic malignancies (SHMs) associated with chemotherapy and radiotherapy, respectively, among nonmetastatic breast cancer (BC) survivors. Using the Surveillance, Epidemiology, and End Results (SEER) 12 database, we estimated the adjusted relative risks (RRs) for developing SHMs associated with chemotherapy and radiotherapy (yes vs no/unknown), respectively, among 2-year survivors of nonmetastatic BC diagnosed at age 20-84 years who diagnosed during 1992-2017. Risks were assessed using multivariable Poisson regression models and adjusted for age, latency, and the log of expected number of SHMs as an offset. Among 432,073 nonmetastatic breast cancer (BC) survivors diagnosed between 1992-2017, 169,050 (39.1%) and 231,148 (53.5%) received chemotherapy and radiotherapy, respectively. Chemotherapy was significantly associated with an increased risk of SHMs (RR, 1.19 [95% CI, 1.11 to 1.27]), the elevated risk primarily driven by acute lymphocytic leukemia (ALL) and acute non-lymphocytic leukemia (ANLL) (RR, 1.72 95% [95% CI, 1.09 to 2.77] and 2.31 [95% CI, 1.77 to 3.01], respectively). Younger survivors and triple negative BC were at higher SHM risk post-chemotherapy (both P for interaction < 0.05). Similarly, radiotherapy was significantly associated with heightened risks of SHMs (RR, 1.11 [95% CI, 1.04 to 1.08]), which largely related subsequent ALL and chronic myeloid leukemia (RR, 1.76 [95% CI, 1.09 to 2.86] and 1.49 [95% CI, 1.09 to 2.02], respectively). Racial and ethnic disparities were observed for different SHM risk post-radiotherapy, with Non-Hispanic Whites had increased ALL risk (RR 1.97 [95% CI, 1.08 to 3.57]), while Hispanics showed elevated ANLL risk (RR 1.97 [95% CI, 1.25 to 3.10]). In conclusion, non-metastatic BC survivors exhibited an elevated SHM risk post-chemotherapy and radiotherapy. This finding necessitates rigorous post-treatment monitoring and prompts further exploration of treatment specifics to optimize survivor care.
Provisional Prognostic Score for Hemophagocytic Lymphohistiocytosis
Authors: Haddad Philip A , Chennapragada Suma Sri , Kantamani Deepti , Gaddam Shiva Jashwanth , Gupta Ankita
Published: December 2024

Background

Hemophagocytic Lymphohistiocytosis (HLH) is a severe and potentially life-threatening syndrome characterized by uncontrolled activation of lymphocytes and macrophages, leading to excessive cytokine production, hyperinflammation, and tissue damage. HLH can be broadly classified into two forms: primary (familial) HLH, which is an autosomal recessive disorder often associated with genetic mutations affecting cytotoxic function, and secondary (acquired) HLH, which is triggered by infections, malignancies, autoimmune diseases, or other underlying conditions. HLH outcomes vary considerably. We conducted this study to develop a provisional HLH prognostic score (HLHPS).

Methods

We used our HLH real-world database, which contains retrospective data on 255 cases. Such data included demographics such as sex, age, and race. It also included blood counts, coexisting comorbidities, disease immunohistochemical and molecular phenotype, types of treatment, and survival outcomes. Of the 255 cases, only 219 had complete survival and outcomes data, which is the sample chosen for this study. Cox proportional-hazards model and Log-rank tests were used to assess the influence of clinicopathologic factors on overall survival (OS). We included factors that statistically impacted OS and scored them by the impact of their hazard ratios.

Results

The median OS of the cohort was 24 months. The following dichotomous variables were identified as impactful prognostic factors in this cohort: Age>50 (9 vs. 60 months; p=0.003), underlying malignant etiology (2 vs. 60 months; p=0.0004), splenomegaly (22 vs. NR months; p=0.02), LDH>1000 U/L (24 vs. NR months; p=0.003), and sIL2R>5000 U/ml (6 vs. NR months; p=0.03). A prognostic model was devised using these variables to identify different levels of risk. Each variable was assigned 1 point when present for a maximum possible score of 5. In this exploratory cohort, low risk was assigned a score of 0-1, intermediate risk a score of 2, and high risk a score of 3-5. This prognostic score system led to our cohort's most optimal risk discriminatory model, where low, intermediate, and high risk had a median OS of NR, 22, and 1.8 months, respectively (p<0.0001).

Conclusion

This HLHPS is a promising new tool for risk stratification in patients with HLH. However, it still requires prospective validation.
Addressing Distance As a Barrier to Sickle Cell Care in South Carolina
Authors: Landau Daniel
Published: December 2024

Introduction:

Adult sickle cell care is often centralized in larger hospital systems, which poses a significant challenge for states with extensive rural areas, such as South Carolina. Limited access to these centralized systems due to distance can be a major barrier to care. Data indicates that many patients are unwilling to travel more than 28 minutes or 20 miles for non-emergency care. We hypothesize that this reluctance contributes to the low percentage of sickle cell patients maintaining relationships with hematologists. To address this issue, the Medical University of South Carolina (MUSC) has initiated a dedicated telehealth program for sickle cell patients. This study aims to evaluate the distances patients would need to travel for traditional in-person hematology care compared to the telehealth option.

Methods:

A previous analysis of our patient population revealed that only 18% of sickle cell patients had consulted a hematologist in the prior year. To assess whether distance acts as a barrier to care, we randomly sampled 25 patient charts of patients who have completed a sickle cell telehealth visit with a hematologist. The 25 patients were sampled at random but the sampling confirmed prior analysis showing a paucity of prior hematologic care for these patients. We used Google Maps® to determine the distance and travel time from each patient's home to MUSC, conducting the search at 8 AM on a weekday to account for peak traffic conditions.

Results:

Our findings indicate that patients generally reside at considerable distances from MUSC. The average distance was 27.8 miles (range: 1.2-96.5 miles), with 56% (14/25) of patients living 20 miles or more from MUSC. At 8 AM, the average travel time was 42 minutes (range: 6-119 minutes), and 68% (17/25) of patients would need at least 30 minutes to reach MUSC.

Discussion:

The low percentage of sickle cell patients in South Carolina with an established relationship with a hematologist is concerning. Our results suggest that distance to care is a significant barrier. The implementation of a telehealth program has effectively mitigated this barrier, facilitating better access to hematology care for sickle cell patients.
SLC25A21 Correlates with the Prognosis of Adult Acute Myeloid Leukemia through Inhibiting the Growth of Leukemia Cells Via Downregulating CXCL8
Authors: Wang Shujuan , Liu Yu , Xu Yan , Hao Qianqian , Shi Luyao , Chen Yufei , Liu Yajun , Li Mengya , Zhang Yu , Li Tao , Li Yafei , Jiang Zhongxing , Liu Yanfang , Wang Chong , Zhilei Bian , Yang Lu , Lu Wenyi
Published: December 2024

Background

In recent years, targeting mitochondrial apoptosis has emerged as a promising therapeutic strategy for Acute Myeloid Leukemia (AML). The SLC25 family of mitochondrial carriers plays a critical role in maintaining mitochondrial function and regulating apoptosis. However, the role of SLC25A21, an oxodicarboxylate carrier, in AML progression and its potential as a prognostic biomarker remain underexplored. The aim of this study was to further investigate the role, molecular mechanism, and potential clinical value of SLC25A21 in AML progression.

Methods

The transcript levels of SLC25A21 in bone marrow specimens were analyzed using real-time quantitative polymerase chain reaction. The survival analysis was applied to explore the association between SLC25A21 expression and the prognosis of AML.The target genes were detected by RNA sequencing. Functional studies were detected by CCK8, colony formation, cell cycle, apoptosis, reactive oxygen species, and xenograft tumor mouse model.

Results

The results showed that SLC25A21 was downregulated in adult AML, and the low expression of SLC25A21 was correlated with worse prognosis for AML patients. Furthermore, overexpression of SLC25A21 inhibited cell proliferation and cell cycle progression, and was correlated with apoptosis through mitochondrial apoptosis signaling pathway. C-X-C motif chemokine ligand 8 (CXCL8) was identified as a downstream target of SLC25A21. These functions of SLC25A21 could be rescued by the overexpression of CXCL8. Moreover, SLC25A21 overexpression significantly suppressed the growth of xenograft tumors.

Conclusions

SLC25A21 was lowly expressed in adult AML, and the low SLC25A21 expression correlated with poor clinical outcome. The overexpression of SLC25A21 inhibited the AML cell survival and proliferation by dysregulating the expression of CXCL8. SLC25A21 might be a potential prognostic marker and a treatment target for AML.
Efficacies of Protein S, Pan-Notch Inhibitor CB-103, and Gemcitabine in Decreasing Cancer Cell Spheroid Growth
Authors: Majumder Rinku , Prouse Teagan , Majumder Samarpan
Published: December 2024

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer with limited treatment options. Patients with PDAC experience a hypercoagulable state and 7.4% experience a form of venous thromboembolism (VTE) within 1 year of diagnosis, compared with other cancer patients who have a risk of 3.1%. The elevated risk of VTE in PDAC patients is likely associated with dysregulation of anticoagulation proteins, such as Protein S (PS). The Majumder laboratory showed that an exogenous increase in PS inhibited growth of PDAC cell lines PANC-1, BxPC-3, and MiaPACA-1. Furthermore, we have shown that high concentrations of free PS, particularly 150 nM, significantly decreased PANC-1 spheroid formation.

Notch, a key regulator of metabolism, displays aberrant signaling in several cancers, including pancreatic cancer. The pan-Notch inhibitor CB103 promotes apoptosis in pancreatic cancer.

In this study, we measured alone and in combination the efficacy of PS, CB103, and gemcitabine, the standard treatment for PDAC, in inhibiting PDAC spheroid formation.

Methods

Primary PANC-1 spheroids were induced from 3.7x106 PANC-1 cells in 0.24% methylcellulose DMEM media on an ultra-low attachment 6-well plate. After incubation for 7 days, PANC-1 spheroids were harvested, and secondary spheroids were placed on a fresh ultra-low attachment 6-well plate with the following additions: 5% DMSO (vehicle control, no treatment),150 nM PS, 250 nM gemcitabine, 5 uM CB103. Combination treatments at the aforesaid concentrations were PS + gemcitabine, CB103 + PS, CB103 + gemcitabine, and all three combined. A representative number of spheroids from each well was washed with PBS and placed in triplicate in an ultra-low attachment 96-well plate. One day after, the cells were imaged, and cell count was determined with ImageJ.

Results

For all treatments, we measured a statistically significant (p <0.0001) reduction in spheroid formation. Individually, PS was the most effective in decreasing spheroid count, and the combination treatment of all three was the most effective overall in decreasing spheroid count.

Conclusions

We found that PS, a natural anticoagulant, had greater efficacy in decreasing PANC-1 spheroid growth compared with the efficacy of either CB103 or gemcitabine, the latter being the standard of care for patients with PDAC. Furthermore, combined treatments synergistically decreased PANC-1 spheroid growth. To proceed with clinical translation of these treatments, we need additional research to fully explain the activities of the three agents toward expression of cancer stem cell markers on PANC-1 and other PDAC cell line spheroids.
Comparison of Weekend and Weekday Admissions for Sickle Cell Disease: Characteristics and Outcomes Using the 2021 Database
Authors: Rajarajan Srinishant , Babu Kalaivani , Correa Amit , Chattaraj Asmi , Abioye Oyepeju , Ramanan Sruthi P , Ramesh Nithya , Nusrat Sanober , Ayanambakkam Attanathi Adanma Anji , Bhanushali Charmi , Roy Arya Mariam
Published: December 2024

Background: Sickle cell disease frequently necessitates hospital admissions due to its complications. This study examines the disparities in treatment outcomes for sickle cell disease between weekend and weekday admissions. Given the acute and unpredictable nature of the disease's exacerbations, as well as the potential for variability and limitations in healthcare staffing and resource availability on weekends, it is crucial to understand how these factors may affect patient care and outcomes.

Methods: The 2021 NIS database was analysed to identify 177,604 admissions with sickle cell disease and associated complications, such as acute chest syndrome, splenic sequestration, cerebral vascular involvement, and dactylitis, using appropriate ICD-10 codes. The study examined demographic characteristics, comorbidities, socioeconomic status, insurance types, hospital characteristics, and mortality outcomes. Chi-square tests and logistic regression models were used to determine statistical significance.

Results: Out of all the SCD admissions, 24.5% occurred on weekends. The overall in-hospital mortality rate was 0.91% (95% CI: 0.81% - 1.02%). Mortality was significantly higher for weekend admissions compared to weekdays (1.10% vs. 0.85%, p=0.0337), with an adjusted odds ratio (OR) of 1.37 (95% CI: 1.06 - 1.78, p=0.016). This indicates that SCD patients admitted on weekends have a higher odds of dying in the hospital compared to those admitted on weekdays, even after adjusting for various demographic and clinical factors.

The mean LOS was 5.48 days (95% CI: 5.36 - 5.59 days), with no significant difference between weekend (5.56 days) and weekday (5.45 days) admissions after adjustment (p=0.356). The mean TOTCHG was $57,061.37 (95% CI: $54,475.07 - $59,647.68), with no significant difference between weekend and weekday admissions after adjustment (p=0.786).

Demographic analysis revealed significant differences in sex and insurance status between weekend and weekday admissions. A higher proportion of male patients were admitted on weekends compared to weekdays (36.57% vs. 34.79%, p=0.0032). Additionally, a higher proportion of Medicaid patients were admitted on weekends (25.08%) compared to weekdays (23.41%, p=0.0001).

Conclusion: SCD patients admitted on weekends exhibit a significantly higher risk of in-hospital mortality compared to those admitted on weekdays, even after adjusting for confounders. However, weekend admissions did not significantly impact LOS or hospital charges. These findings highlight the need for further investigation into the factors contributing to the increased mortality risk for weekend admissions and the development of strategies to improve outcomes for SCD patients.
Factors Associated with in-Hospital Mortality from Gastrointestinal Bleeding in Patients with Hemophilia
Authors: Uche Ifeanyi Nnamdi , Gold-Olufadi Shakirat , Becerra Henry , Wasifuddin Mustafa , Saparov Dosbai , Hehr Rohan , Oluwadeyi Esther Yemisi
Published: December 2024

Introduction

Gastrointestinal bleeding (GIB) is a common complication and potential cause of mortality in hospitalized patients. Patients with hemophilia (PWH) have an increased risk of developing GIB compared to patients without hemophilia. There is a paucity of literature addressing factors that could predict GIB mortality in PWH. Our study aims to identify these factors and other clinical characteristics of GIB in PWH.

Method

Data for this study were obtained from the National Inpatient Sample (NIS) database. We identified PWH aged 18 years and older who had GIB between 2016 and 2020. Patients were categorized into hemophilia A and B. The primary outcome was in-hospital mortality. Patient demographics, clinical and hospital characteristics were compared using x2 test. The association between hemophilia type and in-hospital mortality was assessed using logistic regression controlling for other covariate. A two-sided p≤0.05 was considered statistically significant.

Results

We identified 638 PWH who had GIB, 22.1% (n=141) had Hemophilia A and 77.9% (n=497) had Hemophilia B. 77.12% (n=492) were male, and 22.88% (n=146) were female. 78.06% (n=498) were ≥40 years old and 21.94% (n=140) were <40 years old. Non-Hispanic Whites (NHWs) had less patients with Hemophilia A than B (59.56% vs 74.47%) compared to non-Hispanic Blacks (NHBs) (19.12% vs 13.47%), Hispanics (12.27% vs 3.55%) and Non-Hispanic Others (6.64% vs 4.96%) who had more patients with Hemophilia A than B (p=0.003). The in-hospital mortality of GIB in PWH was 5% (n=32). More patients with Hemophilia A died from GI bleed compared to Hemophilia B (5.9% vs 2.1%), this finding was however not statistically significant. Patients with a higher comorbidity index had higher inpatient mortality than those with co-morbidity index of 0(aOR:5.26, CI95%:1.94-14.23, p=0.001). There was no association between type of Hemophilia, race, gender, income, insurance, or location of GI bleed with inpatient mortality.

Conclusion

Our study demonstrates that the presence of co-morbidities increases in-hospital mortality from GIB in patients with Hemophilia. We also observed that NHWs with Hemophilia B had more episodes of GIB than those with Hemophilia A, while the reverse was true in other racial groups. Our study was limited by a small sample size. More research is needed to identify factors that could improve survival of GIB in PWH.
Zinc Oxide Nanoparticles Induce Diffuse Large B-Cell Lymphoma Cell Apoptosis Via Regulating Mitochondrial Dynamics
Authors: Li Zonghong , Feng Lili , Ji Chunyan , Xu Ruirong
Published: December 2024

Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma. Mitochondrial dynamics refers to the changing process of fission and fusion. An imbalance in mitochondrial dynamics can disrupt mitochondrial function, leading to DLBCL cells abnormal fate. Zinc oxide (ZnO) nanoparticles have excellent anti-tumor properties in the biomedical field. The present study aimed to explore the underlying mechanism by which ZnO nanoparticles induce apoptosis in DLBCL cells (U2932) via regulating mitochondrial dynamics. First, a series of characterizations of ZnO nanoparticles were performed. Next, after U2932 cells were exposed to various concentrations of ZnO nanoparticles, the cell survival rate, morphological changes, apoptosis, ATP generation, mitochondrial membrane potential (Δψm), and lactate dehydrogenase (LDH) levels were measured. Moreover, the expression of mitochondrial fusion 1 (Mfn-1), mitochondrial fusion 2 (Mfn-2), dynamin-related 1 (Drp-1), mitochondrial fission 1 (Fis-1), B-cell lymphoma-2 (Bcl-2), and Bcl-2 associated X (Bax) at mRNA and protein levels was further determined by using quantitative PCR (Q-PCR) and western blotting. The results showed that ZnO nanoparticles could effectively inhibit the proliferation and promote the death of U2932 cells in vitro in a dose- and time-dependent manner. Meanwhile, ZnO nanoparticles could significantly increase the levels of apoptosis and LDH, and decrease the levels of cell Δψm and ATP. Moreover, ZnO nanoparticles significantly increased the expression of Mfn-1, Mfn-2, and Bax, and decreased the expression of Drp-1, Fis-1, and Bcl-2 in U2932 cells, suggesting that ZnO nanoparticles can induce the apoptosis of DLBCL cells by regulating mitochondrial dynamics. Overall, ZnO NPs may provide a new basis and idea for treating DLBCL in clinical practice.
Cerebral Infarction As a Complication of a Hypercoagulable State in the Setting of Hyperthyroidism: A Case Presentation
Authors: Condon Samuel
Published: December 2024

Introduction

Studies have demonstrated a significant association between hyperthyroidism and a hypercoagulable state. Hyperthyroidism, characterized by the excessive production of thyroid hormones, can influence the hemostatic balance, leading to an increased risk of thrombosis. Additionally, hyperthyroidism is a well-known risk factor for atrial fibrillation and cardiomyopathy, both of which can contribute to the development of thromboembolic events. Although rare, cerebral infarction has been reported in patients with hyperthyroidism, particularly due to the hypercoagulable state induced by the excessive thyroid hormones. This case presentation illustrates such an instance, highlighting the complex interplay between thyroid dysfunction and coagulation abnormalities.

Case presentation

A 23-year-old male with a history of Type 1 Diabetes Mellitus, uncontrolled hyperthyroidism due to Graves' disease, and asthma presented with decreased consciousness and possible seizure activity. He was diagnosed with diabetic ketoacidosis (DKA), thyrotoxicosis, cardiogenic shock, a large middle cerebral artery (MCA) infarction, and pulmonary infarction. Transesophageal echocardiogram showed no vegetations. He was initiated on propranolol, methimazole, and hydrocortisone. Hypercoagulable panel, including PT/INR, aPTT, antithrombin III activity, protein C/S, factor V Leiden, G20210A, lupus anticoagulant, homocysteine, and anticardiolipin, was unremarkable. With normalization of thyroid function, cardiac function steadily improved, and no further progression of pulmonary embolism or cerebral infarction was observed. Due to the significant MCA infarction, long-term rehabilitation was required.

Discussion

A hypercoagulable state associated with hyperthyroidism is not commonly recognized but has been documented in several cases. The proposed mechanisms include the upregulation of clotting factors, increased platelet activation, endothelial dysfunction, a hyperadrenergic state, and reduced fibrinolysis. Clinicians should maintain a high index of suspicion for hyperthyroidism as a potential cause of thromboembolic events. Prompt treatment of hyperthyroidism is essential to prevent complications.
No Sickle Cells in Sickle Cell Disease: Possible Effect of Hydroxyurea
Authors: Kim Stanley
Published: December 2024

Peripheral blood smears of 7 adult patients with sickle cell disease who were admitted to Kern Medical Hospital during the period of March 2024 to July 2024 were examined. Six patients had sickle cell SS disease and 1 patient hemoglobin SC disease. All had acute vasoocclusive painful episodes. All patients have been taking hydroxyurea except one patient who was nursing her baby after recent delivery by cesarean section. She did not take the hydroxyurea for prior 10 months.

Total 14 slides of the 7 patients were examined under the high power field and their pictures photographed. About 5% of all red blood cells (RBCs) had abnormal morphologies. None of the patients who were taking hydroxyurea had the typical elongated crescent-shaped sickle cells. The abnormal RBCs seen in the blood smears have the shapes of canoe or spindle (20%), thick lips (20%), coffee bean (20%), pea pod (20%), rod (10%), and others such as fragmented helmets or teardrops (10%). However, the patient who had not been taking hydroxyurea had a few atypical sickle cells. The disappearance of the typical sickle cells and appearance of various abnormal shapes of RBCs may be the effect of hydroxyurea which increases the level of the hemoglobin F and subsequently reduced degree of polymerization. Conclusion: The peripheral blood smears of patients with sickle cell disease who were taking hydroxyurea showed various shapes of RBCs, but not the typical elongated crescent-shaped sickle cells. However, one patient who was off hydroxyurea for prior 10 months had a few atypical sickle cells. The disappearance of the typical sickle cells and appearance of RBCs of various abnormal morphologies may be due to hydroxyurea therapy.
Screening and Validation of Natural Product with Anti ETP-ALL Activity Using a Novel ETP-ALL Cell Line
Authors: Li Fenglin , Zhuang Haihui , Pei Renzhi , Jin Jie , Lu Ying
Published: December 2024

Background: Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) was first identified in 2009 and was classified as a distinct subtype of T-cell acute lymphoblastic leukemia (T-ALL) by the WHO in 2016. Patients with ETP-ALL frequently face higher rates of relapse and treatment resistance, leading to poorer outcomes compared to individuals with other forms of T-ALL. As of now, there are no established treatment guidelines specifically for ETP-ALL.

Method: The ETP-ALL cell line was established by using continuous culture methods. Cell proliferation inhibition experiments were applied to screen the inhibitory effects of 2541 natural products from the Selleck natural product library on ETP-ALL cells. This screening occurred in three rounds with concentrations set at 1,000 nM, 100 nM, and 10 nM. Natural products that achieved an inhibitory concentration of ≥50% were advanced through subsequent rounds. Finally, natural products with an inhibition rate of ≥ 50% at a concentration of 10nM were selected for validation. In the final validation stage, we focused on products that demonstrated an inhibition rate of ≥50% at a concentration of 10 nM to confirm their efficacy against ETP-ALL.

Results: The novel ETP-ALL cell line, named ZYXY-T1, was successfully established from an ETP-ALL patient. ZYXY-T1 exhibited robust proliferation both in vitro and in vivo. The results from Flow cytometry analysis confirmed that ZYXY-T1 presents the typical characteristics of ETP-ALL, showing negative expression for CD1a, CD8, and CD5, along with positive expression for CD34, CD13, and CD33. Based on multiple diagnostic scoring systems, ZYXY-T1 met the criteria for ETP-ALL diagnosis, achieving maximum scores in four out of six scoring systems. In contrast, the Loucy cell line failed to meet ETP-ALL diagnostic criteria. RNA sequencing analyses identified six fusion genes in ZYXY-T1, including MLLT10::PICALM, AC068756.1::AC108690.1, PICALM::MLLT10, PCAT18::KCTD1, LINC02284::TMEM260, AC123912.1::ZNF493.

In the initial screening, 76 natural products demonstrated a half-maximal inhibitory concentration (IC50) of ≤1,000 nM against ETP-ALL. Following a second round of screening, 38 products exhibited IC 50 values below 100 nM. After the third round, 13 natural products were identified with IC50 values under 10 nM. Among these, natural product #1823 exhibited exceptional efficacy against ETP-ALL, with an IC50 of 0.2 nM-at least ten times lower than the other 12 compounds tested .

Conclusions: We successfully established a novel ETP-ALL cell line that reflects the typical ETP-ALL phenotype. Leveraging this cell line, we identified a potent natural product with significant anti-ETP-ALL activity through systematic screening of a natural product library.
Overcoming Barriers to Novel Combination Therapy in Multiple Myeloma (MM): Oncocollective Insights into Improving Patient Outcomes in Europe
Authors: Shih Ya-Chen Tina , Morgan Gilberto , Biru Yelak , Dietrich Eva Susanne , Ehlers Lars Holger , Eriksson Lise-Lott , -Goñi Manuel García , Greiner Wolfgang , Levin Lars-Ake , Postma Maarten , Fernandez Celine , Paranjpe Krupa , Hansen Hilary , Galnares Alvaro Lopez , Caschetta M. B. , Goeckeler Randi , Lee Edwin
Published: December 2024

Background

Access to novel combination therapies for multiple myeloma (MM) remains limited in Europe partly due to health technology assessment (HTA) processes and formal reimbursement mechanisms.1,2 To address issues of access barriers, Sanofi convened OncoCollective (OC), a multi-disciplinary stakeholder collaborative of global experts, to explore solutions.

Methodology

The OC Novel Combination Therapy Working Group developed an illustrative case study to map two hypothetical patient journeys in a specific European country (Sweden), a journey that faces barriers to receiving novel combination treatment for MM versus one with fewer barriers.3−5 The group reviewed existing outcomes data to estimate the potential impact on progression-free survival (PFS) to explore if improved access to novel combination therapies could significantly improve patient outcomes and quality of life.3−5

Results

The illustrative patient journeys demonstrated that an optimized therapeutic course with few barriers to combination therapy enabled more advanced care and extended PFS across multiple lines of therapy. In contrast, a journey facing limited access to combination therapy could result in suboptimal treatment sequencing and shorter PFS.

Conclusion

These findings highlight that current healthcare systems may not be equipped to adequately handle the value of combination therapies, and different reimbursement requirements may create inequalities in MM across countries or regions within the same country. Solutions proposed by the OC include a) advocating for mandatory national guidelines, b) encouraging real-world evidence collection and methodologically sound modelling studies, c) appealing for healthcare funding as an investment, and d) working towards a holistic vision of clinical benefit leading to meaningful improvements in outcomes for all patients with MM.

References EFPIA Report on Access to Oncology Combination Therapy in Europe, April 2023. OECD. Analytical Report, 2020. Latimer N, et al. BMC Health Serv Res. 2021;21(1):412. Moreau P, et al. Ann Oncol. 2017;28(suppl 4):iv52−61. Wålinder G, et al. CancerReports.2022;5:e1614.
Global Burden of Disease of Multiple Myeloma in China from 1990 to 2021
Authors: Duan Guixiang , Dou Xuelin , Zhong Yanting , Liu Kai-Yan , Qi Jinlei , Lu Jin , Zhou Maigeng
Published: December 2024

This study aims to provide an updated disease burden of multiple myeloma in China from 1990 to 2021. We used data from Global Burden of Disease Database (GBD) 2021 to estimate age-, sex-, and province-specific incidence, mortality, prevalence, disability-adjusted life-years (DALYs), years of life lost (YLLs), years lived with disability (YLDs) of 34 provincial administrative units in China. There were estimated 17250 new cases and 12984 cases of death of MM in China in 2021. The age-standardized incidence, mortality and prevalence rate per 100,000 population were 0.8, 0.6 and 2.2, respectively. The highest disease burden were observed in provinces with top per capita GDP. From 1990 to 2021, the estimated age-standardized incidence and mortality increased by 3.1% and 2.2%, in parallel with an unproportioned increase of age-standardized prevalence rate of MM by 5.8%, indicating improved treatment efficacy and extended patient survival in MM. The age-standardized DALY rate increased by 2.2%. There had seen a more rapid increase in incidence among younger populations compare to the eldly. It was estimated that 5.47% of all death MM cases in 2021 were attributable to high BMI. During the past three decades, the disease burden of MM in China continued to increase. This study provided comprehensive estimates that can potentially inform efforts toward management of MM in China.
Arginine Deprivation Induces a Dormient Phenotype in Neoplastic Plasma Cells: The Seed and Soil in Multiple Myeloma
Authors: Scandura Grazia , Dulcamare Ilaria , La Spina Enrico , Dieni Caterina , Cambria Daniela , Giallongo Cesarina , Tibullo Daniele , Di Raimondo Francesco , Romano Alessandra
Published: December 2024

Our previous research has demonstrated that a reduction in arginine (Arg) concentration within the bone marrow microenvironment BMME induces metabolic reprogramming in multiple myeloma (MM) plasma cells (PCs), enhancing their survival both in vitro (Romano, 2020) and in vivo (Trudu, 2022).

To explore how PCs adapt to both acute and chronic arginine deprivation, we employed a combination of mRNA-sequencing (RNA-seq), ribosome profiling (Ribo-seq), in vitro assays, and FACS analysis to evaluate two human myeloma cell lines, U266 and NCI-H929, cultured under arg-deprived conditions to mimic BMME.

Arg deprivation induced oxidative stress as confirmed by the expression and nuclear translocation of HO-1 protein in U266 cell line but not in NCI-H929 cell line. The antioxidant system upregulation reflects a lower sensitivity to treatment with proteasome inhibitors, Bortezomib and Carlfizomib in U266 cell line. Integrative amino acid profiling revealed that, while the H929 cell line maintained intracellular arginine levels after 10 days of arginine deprivation, the U266 cell line exhibited arginine auxotrophy under the same conditions.

The direct pairwise comparison of RNA-seq data revealed 888 differentially expressed genes in both cell lines, disclosing a dormant phenotype for NCI-H929 cell line, confirmed by the up-regulation of Axl gene important for the retention of MM cells in the dormant state (Khoo et al. 2019), and in the autotrophic cell line U266 the acquisition of a senescence-associated secretory phenotype, associated to accumulation of DNA damage, micronuclei and heterochromatin.

Ribosome profiling provided that U266 cells, but not NCI-H929 cells, preferentially translated shorter mRNA fragments, with ribosome footprint lengths centered around 27 nt and 28 nt after 48h of arg deprivation. The ribosome translation frame analysis revealed a preference for the first codon in 28 nt fragments and the second codon in 27 nt fragments, confirming alterations in translation. Applying AS-Quant we identified novel alternative splicing events, common in both cell lines, occurring in the skipped exons (leading to a significant increase in the expression of ASNS, ATF5, Caspase 4-6-8) and in mutually exclusive exons (leading to increased translation of CD74, a transmembrane glycoprotein involved in MHC II protein formation and transport, responsible of downstream translation of genes involved in apoptosis, immune response, and cell migration).

Taken together, our findings suggest that arg deprivation in TME conveys a complex transcriptional and translational response, leading to peptides translated from short-coding or noncoding regions of the genome, providing a basis for subsequent further functional studies, including the evaluation of potential new ne-antigens for further immunotherapy development.
Thirdhand Smoke As a Risk Factor for Pediatric Lymphoblastic Leukemia: Accelerated Leukemia in Female Pax5-P80R Mice
Authors: Zhou Mi , Snijders Antoine M , Mao Jian-Hua , Wiemels Joseph L. , Kogan Scott C
Published: December 2024

Acute lymphoblastic leukemia (ALL) is the most common cancer of childhood. The development of ALL involves genetic and epigenetic processes, but how these factors are influenced by prenatal and early life exposures is poorly understood.

Epidemiologic studies of tobacco smoke and childhood leukemia have suggested that smoking may increase risk for some children. Thirdhand smoke (THS) has gained wide attention in recent years as a newly described health risk. THS includes tobacco smoke residues in indoor environments that remain long after smoking has ended, and which then react and/or re-emit from materials and/or from surfaces. Infants can be exposed to THS through directly contacting these surfaces as well as exposure to house dust and indoor air. We hypothesize that THS exposure interacts with underlying genetics to place children at risk for the development of ALL.

We performed a pilot study to assess whether THS exposure can accelerate the development of ALL in C57BL/6J mice expressing a Pax5P80R allele, a genetic change that efficiently initiates leukemia. Mutations to the PAX5 locus are common abnormalities in human pediatric ALL. These mice therefore provide a model of the situation in humans in which a child acquires a mutation that, in combination with additional lesions, leads to leukemia. A cohort of Pax5WT/P80R animals was established that resulted from exposure of sires to THS for at least 6 weeks, mated with dams exposed at the onset of mating, and with exposure of pups continued until weaning at 3 weeks of age.

Results: In our experimental design, we pre-planned to analyze survival in all pups, in female pups, and in male pups. Pooled analysis with all female and male mice showed the median time to leukemia/lymphoma in Sham-exposed mice was 151 d. vs.140.5 d. for THS-exposed mice (p>0.1). Analysis of females showed the median time to leukemia/lymphoma in Sham-exposed mice was 156 d. vs. 134 d. for THS-exposed mice (p=0.02 by log-rank test). Analysis of males showed the median time to leukemia lymphoma in Sham-exposed mice was 143.5 d. vs. 151 d. for THS-exposed mice (p>0.1 by log-rank test). The results described above indicate that THS can influence the initiation of leukemia in Pax5P80R mice and can promote leukemia, which is remarkably specific for female mice.

Conclusion: Our results unexpectedly showed a sex-bias in the leukemia-promoting effect of THS. Exposure of Pax5WT/P80R animals to THS provides a model for testing hypotheses regarding how THS and sex may interact in leukemogenesis.
Targeted Treatment Additions Ibrutinib + Bortezomib + R-CHOP for Higher-Risk DLBCL: Efficacy, Feasibility and Molecular Signatures for Future Treatment Decisions
Authors: Denker Sophy , Bittner Aitomi , Kase Julia , Frick Mareike , Hoffmann Jörg , Trenker Corinna , Keller Ulrich , Bogner Christian , Hüttmann Andreas , Dürig Jan , Janz Martin , Mathas Stephan , Marks Reinhard , Krohn Ulrike , Na Il-Kang , Richter-Pechanska Paulina , Bhattacharya Animesh , Gebauer Bernhard , Savic Lynn , Hübner Norbert , Akalin Altuna , Eils Roland , Bullinger Lars , Schmitt Clemens
Published: December 2024

Introduction

Targeted treatment additions to R-CHOP for patients with diffuse large B-cell lymphoma (DLBCL) did fail to improve outcome in recent phase III trials. However, there are molecular subgroups that benefit, in retrospect. We have conducted an explorative single-arm open-label phase I/II study from 2017-2024, investigating ibrutinib + bortezomib + R-CHOP as proximal and distal BCR/NF-κB double-targeting strategy for higher-risk DLBCL patients with no molecular pre-selection and collected repeated lymphoma biopsies for multi-omics profiling in the course of therapy to identify molecular signatures indicative of lasting responsiveness.

Methods

Within the investigator-initiated trial (IIT) ImbruVeRCHOP, 38 newly diagnosed DLBCL patients with IPI ≥ 2 and 61-80 years of age were treated with six 21d-cycles of R-CHOP plus ibrutinib (420 mg/d p.o.) and bortezomib (1.3 mg/m2 s.c. d1 + 8) followed by two subsequent applications of single-agent rituximab (ClinicalTrials.gov identifier NCT03129828, EudraCT number 2015-003429-32). Lymphoma and liquid biopsies were obstained pre treatment, once during cycle 1 and, in case of a residual and reasonably accessible tumor manifestation, once again at interim CT imaging prior to cycle 3.

Results

The follow-up phase of the study ends in 2024. Some multi-omics results such as WES and RNA seq are already available; liquid biopsy for detection of minimal residual disease as well as spatial transcriptomics and spatial proteomics are currently being processed. The study cohort with patients from Germany and Austria has a median age of 71 and reached a high R-CHOP dose adherence of 91% (compared to 73% in patients over 60 years in the PHOENIX trial, RCHOP + ibrutinib) under strongly recommended quadruple prophylaxis (G-CSF, ciprofloxacine, acyclovir, cotrimoxazole). The median follow-up is currently 18 months and the CT-based overall response rate is 73%. The primary endpoint is 2-year progression-free-survival. The toxicity profile is moderate with mostly grade 1-3 adverse events, 53% of the patients had grade 4 toxicities. 6 fatal events were observed during follow-up due to infections, secondary malignancy and lymphoma relapse.

Conclusions

The targeted treatment addition of R-CHOP with ibrutinib + bortezomib for elderly high-risk patients with DLBCL is effective and feasible. Our study will give an updated analysis of treatment outcome and insights into candidate molecular response signatures identifying patients benefiting from this therapy optimization.