bluuebunny/crossref_metadata_2025_split huggingface dataset:
Updated Meta-Analysis of Phase III Randomized Controlled Trials (RCTs) to Evaluate the Incidence of Second Primary Malignancies (SPMs) in Patients with Multiple Myeloma (MM) Treated with Isatuximab
Authors: Aboaid Hazem , Nguyen Kevin , Jones Daniel Thomas , Srinivasmurthy Ramaditya , Nanda Rishi Kumar , Thein Kyaw Zin , Htut Thura Win 
Published: December 2024

Introduction:
The management of multiple myeloma has experienced significant advancements in recent years.The isatuximab combination regimens are becoming the standard of care nowadays for both newly diagnosed (ND) and relapsed/refractory (RR) MM. However, it is crucial to consider all potential risks, particularly the risk of second primary malignancies (SPMs). The purpose of this meta-analysis is to further investigate the risk of SPMs in patients with MM treated with isatuximab.
Methods:
We conducted a comprehensive systematic literature search using MEDLINE, EMBASE, and cochrane databases from inception through July 22nd, 2024. Phase III RCTs utilizing isatuximab in patients with either RRMM or NDMM that report SPMs were included in the analysis. We reported the total number of SPMs including both solid and non-solid malignancy. We performed a subgroup analysis regarding the incidence of SPMs in the first-line treatment setting (NDMM) and second-line treatment setting (RRMM). Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR), with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q- statistic. Random effects model was applied.
Results:
A total of 1704 patients from 4 phase III RCTs were eligible (1104 patients with NDMM from GMMG-HD7 and IMROZ trials + 600 patients with RRMM from IKEMA and ICARIA-MM trials). ICARIA-MM and IKEMA compared isatuximab (I) + pomalidomide (P) + dexamethasone (d) vs Pd, and isatuximab (I) + Carfilzomib (K) + dexamethasone (d) vs Kd respectively. IMROZ and GMMG-HD7 both compared isatuximab (I) + bortezomib (V) + lenalidomide (R) + dexamethasone (d) vs VRd. Randomization ratios were 1:1 in ICARIA-MM and GMMG-HD7 studies, and 3:2 in IKEMA and IMROZ studies. Overall, the incidence of SPMs was 6.50% in the isatuximab group vs 4.22% in the control group (RR, 1.39; 95% CI: 0.83-2.33; P=0.21), (risk difference [RD], 0.02; 95% CI: -0.01-0.05; P=0.24). In the subgroup analysis, the results were also not statistically significant. In the NDMM cohort, incidence of SPMs was 5.38% (isatuximab group) vs 3.92% (control group) (RR, 1.16; 95% CI: 0.48-2.80; P=0.74), (RD, 0.01; 95% CI: -0.04-0.06); P=0.67). In the RRMM cohort, incidence of SPMs was 8.51% (isatuximab group) vs 4.79% (control group) (RR, 1.75; 95% CI: 0.70-4.35; P=0.23), (RD, 0.04; 95% CI: -0.00-0.07; P=0.05).
Conclusion:
This meta-analysis shows no increased risk of SPMs overall in patients with NDMM or RRMM treated with isatuximab. Further investigations and long term follow up with close surveillance of those patients on the studies are needed to monitor for any developing malignancies in the future and define the actual relation and definitive incidence.
Enhanced Mitochondrial Priming By Momelotinib Confers Superior In Vivo Efficacy in Combination with Venetoclax Compared to Gilteritinib or Ruxolitinib
Authors: Kincaid Zachary , Ansari Sekhu , Azhar Mohammad , Kesarwani Meenu , Azam Mohammad 
Published: December 2024

Introduction. Acute Myeloid Leukemia (AML) is a complex hematologic malignancy marked by significant genetic heterogeneity, with FLT3 mutations being among the most common and prognostically unfavorable alterations. Despite advancements in targeted therapies, FLT3-mutated AML remains a significant challenge due to frequent relapses and resistance to existing treatments. Targeting mitochondrial apoptosis pathways has emerged as a promising strategy to enhance therapeutic efficacy. Proteomic and signaling studies have revealed that Momelotinib enhances mitochondrial priming in AML cells, irrespective of FLT3 mutational status. Consequently, Momelotinib treatment exhibits superior efficacy when combined with Venetoclax, compared to combinations with Gilteritinib or Ruxolitinib. Preclinical evaluations of Gilteritinib and Ruxolitinib in combination with BCL2 inhibitors have been limited to FLT3 and JAK2 mutant cases, respectively. In contrast, Momelotinib has demonstrated a synergistic response across all AML genotypes.
Result. Mitochondrial priming is a major determinant of therapeutic outcome in FLT3 mutated AML treated with BCL2 inhibitors. BH3 profiling of AML cells with and without FLT3 mutations reveled that momelotinib treatment enhances mitochondrial priming in AML regardless of FLT3 mutational status. In contrast, treatment with Gilteritinib or Ruxolitinib showed minimal change on mitochondrial priming. Our findings indicate that Momelotinib significantly enhances mitochondrial priming, leading to increased apoptosis and reduced leukemic cell viability when used in combination with Venetoclax. In FLT3-mutated AML cell lines and primary patient samples, the Momelotinib+Venetoclax combination exhibited superior response than Gilteritinib+Ventoclax combination. Strikingly, Momelotinib+Venetoclax showed effective suppression of non-FLT3 mutated AML while treatment with Gilteritinib+Ventoclax were ineffective against these cells. In vivo studies utilizing xenograft models of FLT3-mutated AML cells from cell lines and primary patient samples demonstrated that the Momelotinib-Venetoclax combination achieved superior leukemic clearance and prolonged survival.
In conclusion, our study underscores the potent synergistic effect of Momelotinib and Venetoclax in AML regardless of FLT3 mutational status, attributable to enhanced mitochondrial priming. These findings provide a compelling rationale for the clinical evaluation of Momelotinib and Venetoclax combination therapy, highlighting its potential to improve treatment outcomes in patients with high-risk AML.
Epidemiological Analysis of Water Contaminants and Their Correlation with Leukemia and Non-Hodgkin Lymphoma Incidence in Florida
Authors: Nagarajan Samit , Jabbal Iktej , Chaulagain Chakra 
Published: December 2024

Introduction
This study investigates the incidence of leukemia and non-Hodgkin lymphoma (NHL) in relation to various water contaminants, including arsenic, across different counties in Florida. Arsenic, a known carcinogen, and other chemicals, such as haloacetic acid, radium, chromium, and trihalomethanes, have been detected in multiple water sources, prompting public health concerns1-4.
Methods
A meticulous and comprehensive epidemiological analysis was conducted using data from National Institute of Health database and the Environmental Working Group's tap water contaminant database. The study population included individuals residing in areas with documented contamination compared to those in regions with low or non-detectable levels. Correlation coefficients were calculated to assess the relationship between contaminant exposure and cancer incidence, ensuring the thoroughness and reliability of the findings.
Results
Statistical analysis revealed a moderately strong correlation between arsenic exposure and the incidence of leukemia (correlation coefficient = 0.47) and NHL (correlation coefficient = 0.21). Similarly, chromium exposure showed a moderately strong correlation with leukemia (correlation coefficient = 0.42) and a weaker correlation with NHL (correlation coefficient = 0.052). In contrast, haloacetic acid and trihalomethanes were negatively correlated with both leukemia and NHL, while radium showed a minimal correlation with leukemia and a weak positive correlation with NHL.
Conclusion
These results underscore the potential impact of continued water quality monitoring and mitigation strategies in reducing exposure to these contaminants. While the study found weak to moderately strong correlations, it highlights the significant role of environmental factors in cancer prevention efforts. Further research is recommended to explore the biological mechanisms underlying contaminant-induced carcinogenesis and to develop effective public health interventions, emphasizing the potential impact of this research on public health.
Hepatocyte Growth Factor Is Overexpressed in AML and Remodels the Mesenchymal Stromal Cell Niche
Authors: Chura Annika , Li Wantong , Oyman Konur , Wang Victoria , Blaser Bradley Wayne 
Published: December 2024

Acute Myeloid Leukemia (AML) is a highly heterogenous and aggressive cancer characterized by the rapid proliferation of abnormal myeloid cells in the bone marrow and blood. Despite advances in chemotherapy, targeted therapy, and stem cell transplantation, these treatments are often insufficient, resulting in disease relapse and a 5-year survival rate of under 32% (National Cancer Institute, 2021).
Ficlatuzumab is an anti-HGF (hepatocyte growth factor) antibody that has demonstrated effectiveness in relapsed/refractory AML with an overall response rate of 53% observed in a phase 1b clinical trial (Wang et al, 2021). Aberrant expression of HGF and activation of its receptor, c-MET, is frequently observed in cancers, including AML (Fu, et. al 2021; Kentsis et al., 2012). Complete response to ficlatuzumab was associated with suppression of MET signaling while non-response to ficlatuzumab was associated with augmented expression of HGF by a subpopulation of AML blasts (Wang et al., 2021). Effects of HGF signaling on the hematopoietic microenvironment in this context are unknown.
To address this gap in knowledge, we generated a transgenic zebrafish model in which expression of zebrafish HGF (hgfa) is enforced in hematopoietic stem cells (HSCs) using the Runx1 enhancer element. By fluorescent microscopy, there were no significant changes in HSC numbers in 72 hour-post-fertilization (hpf) embryos with hgfa overexpression compared to clutchmate controls. This suggests that overexpression of hgfa alone may not be sufficient to alter HSC numbers in short term assays.
However, single cell RNA-sequencing (scRNA-seq) performed at this timepoint did show a 1.7-fold expansion of lepr+ mesenchymal stromal cells (MSCs) in Runx1:hgfa transgenic animals compared to controls. Gene expression profiling showed nearly exclusive expression of met in the MSC cluster, consistent with this expansion being a direct consequence of hgf signaling. To identify potential downstream effects of MSC expansion, scRNA-seq data from the ficlatuzumab trial was reanalyzed to identify markers specific for treatment-resistant blasts. One such marker, CD44, was expressed specifically in a population of hematopoietic progenitor cells that was overrepresented by 2.1-fold in Runx1:hgfa transgenic animals. CD44 is a receptor for extracellular matrix proteins including collagen, which is abundantly produced by the MSC population in this study. CD44 transcription is controlled in part by WNT signaling (Wielenga, et. al, 1999; Schmitt, et. al 2014); MSCs were the dominant producer of wnt3, 4, 6 and 9.
Together, these in vivo data point to a novel set of complex interactions between hematopoietic cells and MSCs which may have relevance for therapeutic resistance in AML.
Central Nervous System Complications in Different Types of Sickle Cell Disorders: A Nation-Wide Analysis
Authors: Eltaher Basant , Shah Purva , Mahmoud Amir , Singh Harkarandeep , Sanjeevi Aditya , Mostafa Mariam , Abdelhay Ali 
Published: December 2024

Introduction: Sickle cell disorders have long been associated with central nervous system (CNS) complications. Morbidity and outcomes of sickle cell anemia have been extensively studied. However, few studies are available examining CNS complications in adult patients with different types of sickle cell disorders.
Methods: We used the National Inpatient Sample (NIS) ICD-10 codes between 2016 and 2020 in STATA BE software to perform a retrospective study and evaluate CNS complications in adult hospitalized patients with different types of sickle cell disorders. We have applied descriptive statistics to detect baseline characteristics of these patients and logistic regression analysis to assess CNS complications while adjusting for comorbid conditions.
Results: 105,976 patients were hospitalized with sickle cell disorders between 2016 and 2020. The most common sickle cell disorder was sickle cell anemia (SS) (88%), followed by sickle-hemoglobin C disease (SC) (5.8%), sickle-cell thalassemia (ST) (5%), and other unspecified sickle cell disorders (1%). Most patients were women (57%), black (90%), and with a mean age of 34 years. We have analyzed different CNS complications in these patients, including stroke, migraine, and seizures.
All sickle cell disorders were associated with increased association with stroke except for ST, though these findings weren't statistically significant (p =0.92, p=0.71, and P=0.76, respectively). It was observed that African Americans were less likely to have stroke (Odds ratio (OR) 0.7, 95% CI, 0.5-0.97; p =0.03). Hypertension (OR 1.6, 95% CI,1.36-1.8), congestive heart failure (OR 1.4, 95% CI, 1.1-1.7), hyperlipidemia (OR 2.5, 95% CI, 2.1-2.9), and thrombophilia (OR 4.7, 95% CI, 3.5-6.2) had a strong association with stroke in patients with sickle cell disorders. There was no statistically significant difference in the incidence of migraine among sickle cell disorder patients.
Interestingly, the odds of developing seizures were less in SC (OR 0.6, 95% CI, 0.4-0.9; p&lt;0.01) and in ST (OR 0.5, 95% CI, 0.35-0.8; p&lt;0.003). Congestive heart failure (OR 2, 95% CI, 1.7-2.7), chronic kidney disease (OR 1.4, 95% CI, 1.1-1.8), and end-stage renal disease (OR 2.5, 95% CI, 2-3.1) patients with sickle cell disorders had increased likelihood of mortality.
Conclusion: Our analysis didn't show a statistically significant difference in the likelihood of CNS complications in different types of sickle cell disorders, except in less odds of developing seizures in SC and ST. However, multiple comorbidities were associated with worse outcomes. More studies are needed to assess morbidity among different sickle cell disorders in adult patients.
Ketamine for Pain Relief in Sickle Cell Vaso-Occlusive Crises: A Systematic Review
Authors: Martinez Ernesto Calderon , Saji Stephin Zachariah , Carmona Thomas Campos , Abbagoni Vaidarshi , Fernando Druvini , Karnan Nithin , Salman Mohammad , Mylavarapu Suchita , Vargas Mishell Estefania Llerena , Samad Nathalia Schettino , Sheethal Arvapalli Lakshmi , Dost Sara 
Published: December 2024

Introduction: Sickle cell disease (SCD) is the most common genetic disorder that is prevalent in the African American population, and vaso occlusive crisis(VOC) is a hallmark of SCD, characterized by intense pain and tissue ischemia due to occlusion of small blood vessels by sickled cells. The standard treatment for relieving pain is intravenous opioid administration. However, it has been hypothesized that frequent exposure to opioids in these patients could lead to tolerance, which is thought to contribute to opioid refractory pain. This analysis aims to determine if the use of ketamine in this type of patient is safe and effective when compared with opioids.
Objectives/Methods: Adhering to PRISMA guidelines, a systematic search was initially conducted on 05/20/2024 in PubMed, MEDLINE, Cochrane, Scopus, Web of Science, EMBASE, and CINAHL using the following keywords: ‘Ketamine’, “Sickle cell disease”, and “Vaso-occlusive Crisis. We meticulously included randomized controlled trials (RCT), cohort, case-crossover and case-control studies.
Results: Five studies (689 participants) met the inclusion criteria. Four out of five studies qualitatively reported pain reduction with ketamine. The meta-analysis of two studies (518 observations) for the Numerical Rating Scale (NRS) pain score showed a standardized mean difference (SMD) of -0.11 (95% CI: -0.42 to 0.21, p=0.50, I²=69.7%). For Morphine Milligram Equivalent (MME), two studies (344 observations) yielded an SMD of 0.0043 (95% CI: -1.31 to 1.32, p=0.99, I²=98.5%). Side effects analysis of four studies (608 observations) showed a relative risk (RR) of 5.74 (95% CI: 2.80 to 11.79, p&lt;0.0001, I²=0%).Though the qualitative analysis showed an effective pain reduction with ketamine, there was no statistically significant difference in the numerical pain score reduction analysis.
Conclusion: Our qualitative analysis highlights ketamine's efficacy in VOC to improve pain management with an incidence of dose-dependent side effects. There still needs to be studies on the safety profile of ketamine and standardization of the pain scale. To establish ketamine as a safe and effective treatment for patients with sickle cell disease experiencing a VOC, additional studies are required to increase the statistical power of the research and lead to a definitive conclusion.
Association of Palliative Care Involvement and Infectious Complications in Hospitalized Multiple Myeloma Patients - National Inpatient Database Study
Authors: Shah Purva , Eltaher Basant , Mahmoud Amir , Herman Adam 
Published: December 2024

Background
Pain is the most common symptom in multiple myeloma (MM), and palliative care (PC) involvement often focuses on symptom management. Improvement in MM treatment has increased survival rates, consequently increasing symptom burden and comorbidities. Infection is a major concern in hospitalized MM patients due to their immunocompromised state. Evaluating the association between PC involvement and infectious complications in hospitalized MM patients can provide insights into quality of care and patient outcomes.
Methods
A retrospective cohort study using the ICD10 codes from the National Inpatient Database (2016-2020) was performed with STATA BE software. Chi square test was used for crude analysis and logistic regression was used to adjust for confounders for categorical variables. Z score was calculated to assess the difference between the Log Odds Ratios of two separate analyses. Results were adjusted for age, gender, race, insurance, hospital size and location, nicotine and alcohol use, diabetes, heart failure, chronic kidney disease, obesity, bone marrow transplantation (BMT), chemotherapy, immunotherapy, neutropenia, hypogammaglobulinemia, and myeloma type (multiple myeloma, plasma cell leukemia, solitary and extramedullary plasmacytoma).
Results
This study included 118,369 hospitalized MM patients with a mean age of 69.49土11.46 years and 44.31% females. Palliative care involvement was significantly associated with infection [OR 1.15; 95%CI 1.45-1.58] and in-hospital mortality [OR 15.43; 95%CI 14.55-16.36] likely because of the same ICD 10 code used for PC and hospice care. Delayed involvement of PC in patient care primarily for goals of care conversations might also be contributory. Interestingly, the association between infection and mortality was significantly lower [z-score 6.76; p value&lt;0.001] when PC was involved [OR 2.23; 95%CI 2.04-2.44] as compared to when PC was not involved [OR 3.41; 95%CI 3.14-3.71]. When PC was involved for MM patients with infection, BMT [OR 0.87; 95%CI 0.76-0.99] and chemotherapy [OR 0.61; 95%CI 0.53-0.71] were associated with significantly less mortality. When PC was not involved, BMT [OR 1.16; 95%CI 1.00-1.35] was associated with significantly higher and chemotherapy [OR 0.85; 95%CI 0.73-0.98] with significantly lower mortality.
Conclusion
In addition to symptom management and advance care planning, PC involvement in admitted MM patients with an infection might be associated with lower mortality. Longitudinal studies need to be conducted to establish a causal relationship of this hypothesis. Separate ICD10 codes for PC and hospice would result in a more accurate assessment of PC involvement in patient care.
The Financial Burden of Unnecessary MTHFR Gene Testing
Authors: Singh Anaiya , Ghaffar Yahya , Goyal Shriya , Gaddam Shiva Jashwanth , Ramadas Poornima 
Published: December 2024

Introduction:
Polymorphisms of the methylene tetrahydrofolate reductase (MTHFR) gene have controversially been associated with an increased risk of venous thromboembolic event(s) VTEs and cerebrovascular accidents (CVAs). However, as per consensus guidelines and evidence-based recommendations, routine testing of the MTHFR gene has not been recommended for workup of thrombophilia and stroke. Despite these existing guidelines, testing of the MTHFR gene mutation is still frequently performed. We aim to analyze the financial burden of this unnecessary and clinically irrelevant testing.
Methods:
At our institution, we conducted an Institutional Review Board (IRB)-approved retrospective study, collecting data on 196 patients who had undergone testing for MTHFR gene mutations between 12/2019 to 12/2022. We excluded patients with these tests performed for indications other than workup for thrombophilia(s) and cerebrovascular accidents (CVAs). Our data collection included patient demographics, indications for testing, and insurance coverage. We incorporated this data to calculate the financial implication on our institution, associated with unnecessary testing of MTHFR gene mutations in patients with elevated thrombotic risk and stroke(s).
Results:
The median age of testing for the MTHFR gene was 42+/-6 years, with females contributing (58) 64.6% and males (32) constituting 35.5%. Gene testing was done for 24 patients with TIAs and CVAs and in 66 patients with VTEs. Out of all the 90 patients tested for the gene mutations, 16 were covered by Medicare, 27 by Medicaid and 47 benefitted from private-based insurance. MTHFR testing costs approximately $300 to a patient willing to get tested for it at our institution, with prices being higher, around $400, if the testing was done outpatient.
Conclusions:
We found that over three years, an expenditure of $27,000 was spent on testing MTHFR gene mutations. We aim to publish this data within our institution and conduct educational sessions across various departments, and physician education regarding clinical insignificance and excessive costs of this single test. This initiative is focused on minimizing unnecessary testing to decrease patient costs and reduce overall healthcare expenses.
Mapping Path Forward for Using the Generative AI for Comprehension of Prognostic Genesets Implicated in Hematologic Malignancies
Authors: Rech Andrew , Goltsev Yury , Samusik Nikolay , Li Henri , Nolan Garry P. , June Carl H. , Jhala Amol 
Published: December 2024

Recent advancements in generative AI, including models such as GPT-4 and LLAMA2, have been rapidly integrated into cancer research. It is not clear to which extent the AI assisted outputs can be trusted and used to the advancement of biomedical knowledge. We discuss and demonstrate several ways the genAI could be used in hematology and related fields.
We have compared a number of commonly available LLM based tools as well as custom trained AIs to determine their ability to enhance the accuracy of functional and genomic discovery screens by reducing the incidence of false positives and refining the interpretation process.
We demonstrate and discuss how custom training of the off-the-shelf genAI can be used to reduce or eliminate the AI-generated inaccuracies, often referred to as 'hallucinations“ . We further show the capacity of semantic scoring applied to candidates based on three orthogonally-tuned criteria: effectiveness, confidence, and novelty.
We observe that in benchmarking tests, the multi-agent scoring systems can outperform GPT-4 and prove particularly adept at identifying candidate targets that may have been overlooked in previous research.
The versatility of the custom trained genAI pipelines is demonstrated through their application in three distinct areas of cancer research. First - we discuss their applicability for optimization of chimeric antigen receptor (CAR) T-cell therapies. Second, we use them to elucidate the network of chemotactic molecules that orchestrate immune cell infiltration and tissue remodeling in the lungs of patients with COVID-19. Third, we use genAI to spatially define signaling pathways in humanized xenograft murine tumor experiments, for which existing cross-species database knowledge is limited.
These applications underscore the genAI potential to contribute to the understanding and treatment of complex diseases.