bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Tumor-Only Whole Genome Sequencing Pipeline for the Development of Molecular Pathology Assays for AML
Authors: Velazquez-Muriel Javier , Tyndale Selene , D'Angelo Julian , Sanchez Paulina , Shah Presha , Huang Ying , Miller Jeffrey E , Niemeijer Meindert 
Published: December 2024

Introduction
The discovery of the genomic variants that are part of Acute Myeloid Leukemia (AML) is of great importance for its diagnosis, clinical subtype classifications, treatment, and prognosis. The current state of the art for variant detection utilizes next generation sequencing techniques, typically sequencing only selected regions of the genome involving the most-frequently affected genes (targeted gene panels), or all coding regions. With decreasing costs, the use of whole genome sequencing (WGS) is becoming attractive, as it offers the advantage of uncovering variants outside gene panels or coding regions, a feature of key importance for AML, where structural variants, and in particular gene fusions, are known to play a significant role. We present a tumor-only, somatic WGS pipeline for the development of molecular pathology assays for AML, and potentially, other diseases.
Methods
We built a cloud-based WGS pipeline consisting of 1) sequencing WGS libraries prepared from AML samples using the Illumina DNA Prep workflow on an Illumina NovaSeq 6000 sequencer and S4 flow cell, generating 72-108X coverage per sample, 2) demultiplexing on local hardware to generate sample FASTQ read files, and 3) : read-mapping to the reference genome, quality metrics gathering, deduplication of reads, base quality recalibration, variant calling (single nucleotide variants and small indels), and variant filtering.
We compared the results of our WGS pipeline to those obtained with Invivoscribe's gene panel for 10 clinical samples, 2 AML cell lines (OCI-AML3, MV4-11), and a negative control (HG002). We also ran our WGS pipeline with a reference sample (Seracare Myeloid Mutation DNA mix). In all cases, we looked for detection of the Pathogenic/Likely Pathogenic (P/LP) variants and their variant allele fraction (VAF).
Results
Our WGS pipeline was able to from the reference sample. Compared to MyAML, the WGS pipeline achieved 100% (44/44) detection of the P/LP variants present at for the other samples. Of the 15 P/LP variants with VAF &lt; 5% reported by MyAML, only 1 was detected by the WGS pipeline. The average absolute difference for the VAF value between MyAML and the WGS pipeline was 10% or less for . Our cloud WGS pipeline can process an entire sample from NovaSeq run in 4h or less.
Conclusions
Our WGS pipeline for analyzing WGS data from AML samples can be an effective substitute of the current MyAML gene panel for variants detection with VAF &gt; 5%, . We are working on expanding the capabilities of our current WGS pipeline by adding structural variant calling, variant annotation, and optimization of running times. This proof-of-concept WGS work for AML can be leveraged to develop assays for other diseases with minimal changes in the experimental protocol and bioinformatics analyses.
Clinical Evaluation of Fast-in-Time (FIT) Anti-CD19 CAR T-a Non-Viral, 2-Day Rapid Manufacture CAR T-Cell Therapy for B-Cell Malignancies
Authors: Li Ping , Ge Jian , Ye Shiguang , Zhou Lili , Gong Yiming , Ruan Huaying , Kouros-Mehr Hosein , Liang Aibin 
Published: December 2024

Chimeric antigen receptor (CAR) T-cell therapy has shown promise in the treatment of hematologic malignancies, but access barriers exist globally. FIT™, a non-viral, 2-day rapid manufacture autologous CAR T platform, aims to address limitations associated with current CAR T-cell therapies. Here we performed initial clinical evaluation of FIT-CD19-CAR-T, a 2nd generation CD28-CD3ζ CAR T utilizing a humanized anti-CD19 binder.
This investigator-initiated trial evaluated the safety, pharmacokinetics (PK), and preliminary efficacy of FIT-CD19-CAR-T cells in 4 patients (pts) with relapsed or refractory B-cell malignancies, including a B-ALL patient (pt) with 9 prior lines of therapy (LOT) and 50% bone marrow (BM) blasts, a B-ALL pt with 2 LOT and 0.5% BM blasts, an FL pt with 4 LOT and moderate tumor burden (sum of product of diameters [SPD] 3440 mm2) and an FL pt with 2 LOT and 36% BM tumor cells.
CAR T-cells were prepared within 3 days post apheresis. Three pts received 2-3 days of LD chemotherapy (cyclophosphamide 250 mg/m2/day and fludarabine 25 mg/m2/day) begun within 1 day of apheresis at the investigator's discretion and received fresh (non-frozen) FIT-CD19-CAR T-cells with a 5-day vein-to-vein time, while 1 FL is planned to receive cryopreserved CAR T-cells as per his willingness. Two ALL pts received 70k and 100k CAR-T cells/kg, while the FL pt received 600k CAR T-cells/kg. Peak CAR T-cell copy numbers were comparable to approved CD19 CAR T-cell products with Cmax occurring on days 13-14 after CAR T treatment. Overall, the treatment exhibited an acceptable safety profile with manageable cytokine release syndrome (CRS; G3 and G2 in ALL pts; no CRS in FL pt) and immune effector cell-associated neurotoxicity syndrome (ICANS; 1 case of G3 in ALL patient). All three evaluable pts have achieved complete remission as their best objective response, with ongoing MRD-negative CR for over 4 months and 6 months in the two ALL pts. One FL pt experienced disease progression at the 6-month assessment due to newly developed cervical lesions, while the original lesions continued to show ongoing metabolic remission.
In conclusion, FIT-CD19-CAR-T demonstrates a favorable safety profile and encouraging initial efficacy and PK at relative low doses in pts with heavily pretreated B-cell malignancies, which may be attributable to enhanced expression of naïve and stem cell memory markers on rapidly manufactured FIT-CD19-CAR-T cells that were not expanded or activated ex vivo. Phase 1 studies are planned for continued investigation.
Modulating Schlafen 12 Activity Using Velcrins in Acute Myeloid Leukemia Cells
Authors: Guillen Magana Jamie Nelly , Platanias Leonidas C. , Zannikou Markella , Small Sara H. , Baran Aneta H. , Beauchamp Elspeth M. , Eckerdt Frank Dieter 
Published: December 2024

Schlafen 12 (SLFN12) belongs to the Schlafen (SLFN) family of proteins, classified as
interferon-stimulated genes with diverse biological functions. In humans, SLFNs exert a role via
their endonuclease and/or helicase domains in cellular proliferation, differentiation, immune
responses, and chemosensitivity of malignant cells. Accumulating evidence suggests that SLFN
family members could serve as prognostic markers in certain malignancies and may be
potential novel therapeutic targets. Using data from the TCGA database, we found that SLFN12
is notably overexpressed in acute myeloid leukemia (AML). To modulate SLFN12 activity in
AML cell lines, we utilized velcrins. Velcrins are a class of molecular glues that facilitate
heterotetramer formation between SLFN12 and phosphodiesterase 3A (PDE3A). This stabilizes
SLFN12 protein and enhances its RNAse activity, ultimately inducing cancer cell death. Velcrins
effectively reduced cell viability and leukemic progenitor potential in colony forming assays in
AML cell lines, with particular sensitivity observed in HEL cells characterized by elevated
SLFN12 and PDE3A levels. Further investigation revealed that velcrin treatment promoted the
SLFN12-PDE3A interaction and potently induced apoptosis in AML cell lines. In cell lines with
lower PDE3A levels, PDE3B, an isoform of PDE3, seems to be partially mediating velcrin
sensitivity as co-immunoprecipitation analysis confirmed a PDE3B-SLFN12 protein interaction
following velcrin treatment in U937 cells, which do not express PDE3A. Moreover, in vivo
experiments utilizing HEL subcutaneous xenografts, demonstrated significant reduction in tumor
burden and prolonged survival upon velcrin treatment, further supporting its therapeutic efficacy
in AML. We also demonstrated enhanced effects in vitro when combined with azacitidine in the
reduction of leukemic cell viability. Altogether, these findings demonstrate an important role for
SLFN12 in AML and raise the potential of velcrins as agents with unique activity in the
treatment of AML.
Co-Concurrent Protein C Deficiency and Myocardial Infarction: A Case Report and Systematic Review
Authors: Kanitthamniyom Chanakarn , Rungjirajittranon Tarinee , Owattanapanich Weerapat 
Published: December 2024

Introduction:
The association between arterial thrombosis and protein C (PC) deficiency has not been well-studied. Previous Systematic reviews and meta-analyses have shown a two-fold increase in ischemic stroke incidence among PC-deficient patients compared to controls. However, data on myocardial infarction (MI) is limited.
Objective:
This study reports a case of MI in a patient with PC deficiency and performs a systematic review to characterize MI presentations, PC deficiency details, and treatments in affected patients.
Methods:
We conducted a descriptive review of case reports on PC deficiency and MI. Studies published before June 2024 were searched in Ovid MEDLINE and EMBASE by three investigators.
Results:
We included 33 patients, including our case. The median age was 37 years (IQR, 26.5-44 years). Six patients (18.2%) had additional atherosclerotic risk factors. Notably, 57.6% (19 patients) had recurrent thrombotic events, both arterial and venous. Median PC activity was 42.8% (IQR 32.3-50.5%), and median PC antigen level was 44% (IQR 39.7-52.2%). Four genetic mutations in the PROC gene were identified: c.325G&gt;A (p.G109R), c.764T&gt;A (p.M255L), c.577_579delAAG (p.192delK), and c.565C&gt;T (p.R189W). Coronary angiography frequently showed total occlusion by thrombus without obvious atherosclerosis. Most patients were treated with oral anticoagulants and anti-platelet therapies.
Conclusions:
This study suggests a potential association between PC deficiency and MI, with recurrent thrombotic events in some patients. These findings highlight the need to consider PC deficiency in MI diagnosis, especially when coronary angiography shows no atherosclerotic disease. Further research is needed to clarify this association.
Retrospective Analysis of 118 Cases of Primary Central Nervous System Lymphoma
Authors: Wu Shaojie , Deng Yanni , Lai Mingyao , Tu Sanfang , Cai Linbo , Li Yuhua 
Published: December 2024

Purpose: To retrospectively analyze the clinical efficacy of high-dose methotrexate (HD-MTX)-based regimens in treating primary central nervous system lymphoma (PCNSL), and to evaluate the impact of autologous hematopoietic stem cell transplantation (AHSCT) or maintenance therapy on long-term survival of patients.
Methods: A total of 118 PCNSL patients treated between January 2016 and December 2023 were included. They were classified into 5 groups based on treatment regimens: single-agent (HD-MTX), two-drug(HD-MTX and temozolomide), three-drug (rituximab, HD-MTX and temozolomide or radiation), four-drug (rituximab, HD-MTX, temozolomide and BTKi), and radiation alone. The number of cases in each group was as follows:17, 18, 39, 20,and 24,respectively. Clinical efficacy and adverse events among these groups were analyzed.
Results: The median follow-up time for the 118 PCNSL patients was 45 months. The median overall survival (OS) was 25 months, and the median progression-free survival (PFS) was 20 months. Subgroup analysis revealed that patients in the four-drug regimen group had significantly higher OS and PFS compared to the other four groups (P values of 0.045 and 0.036, respectively). Additionally, patients in the four-drug group had a significantly higher objective response rate (ORR) after two cycles compared to the other groups (P=0.026). Further analysis demonstrated a trend towards improved OS (P=0.077) and PFS (P=0.067) in the group receiving BTKi-containing regimens. After induction chemotherapy followed by sequential AHSCT or maintenance therapy, the median OS was 25 months and median PFS was 20 months for both the AHSCT group and the maintenance therapy group. Both OS in the maintenance therapy and AHSCT groups were significantly higher than those in the observation group (P values of 0.037 and 0.039, respectively).Similarly, PFS was superior in both the maintenance therapy group and the AHSCT group compared to the observation group (P values were 0.017 and 0.062, respectively). Hematologic toxicity was observed in 53.4% (63/118) of patients, all graded as CTCAE 1-2. Non-hematologic toxicities, mainly nausea, vomiting, and mucositis, were also graded as 1-2 and did not lead to any toxicity-related death.
Conclusion: The use of four-drug regimens based on HD-MTX shows significant efficacy in the treatment of PCNSL, with a higher ORR after two cycles. Post-induction strategies with AHSCT or maintenance therapy further improve treatment efficacy. In addition, regimens containing BTKi indicate a potential benefit in long-term survival, which warrants further investigation.
Combined Natural Language Processing and Gpt-4 Pathology Report Interpretation Efficiently Identify a Myelodysplastic Syndrome Cohort for Large Scale Clinical Research Applications
Authors: Gracie Thomas J. , Pershad Yash , Bejan Cosmin , Bick Alexander G. , Ferrell Brent , Kishtagari Ashwin 
Published: December 2024

Introduction
Cohort studies provide a unique opportunity to test hypotheses that cannot be evaluated through randomized controlled trials. To be effective, they require a substantial and carefully chosen cohort, which typically necessitates time-consuming doctor chart reviews. Some Electronic Health Record (EHR) compatible automation strategies have been designed to speed up this process. However, these are often ineffective for diseases diagnosed through pathology, such as Myelodysplastic Syndrome (MDS), due to the storage of clinical pathology data in free-text reports. In this study, we used a combination of natural-language processing (NLP), International Classification of Diseases (ICD) coding, and Generative Pre-trained Transformer 4 (GPT-4) free-text analysis to sift through a large clinical database and identify patients with pathology-confirmed MDS that met several additional criteria.
Methods
We used the Research Derivative (RD), a clinically annotated database at VUMC, to screen for patients with MDS-related ICD-10 codes, available sequencing data, and hematopathology keywords identified through NLP. Out of 5 million patients, 724 met these criteria. We then used GPT-4 to analyze the pathology reports from their diagnostic bone marrow biopsies. The model provided a certainty score between 0 and 1 for the usability of each report, with 1 representing 100% certainty. The usability of a report was defined by three criteria: it was a bone marrow biopsy report diagnostic of MDS; it showed no evidence of any other hematologic disease; and it did not mention any prior MDS treatment. We used these scores to generate a Receiver Operating Characteristic (ROC) curve, which helped us determine the best threshold for converting usability scores into a simple ‘yes’ or ‘no’. We then compared these results with manual chart reviews for verification.
Results
The area under the ROC was 0.95, with the optimal threshold for classification at a usability score of 0.5. Using this threshold, the GPT model achieved a recall of 0.981, incorrectly excluding only one case out of the 724 patients that met the NLP and ICD10 criteria. The accuracy was 0.756, with the most common reason for inaccuracy being the absence of pretreatment information in the hematopathology report. This was confirmed through manual chart reviews.
Conclusions
The combination of NLP, ICD coding, and GPT-4 analysis proved highly effective in screening a large clinical database for patients with pathology-confirmed MDS, reducing potential study candidates from five million to several hundred. Manual reviews of separate clinical charts revealed treatment status information not listed in the pathology reports. Future automated phenotyping efforts could benefit from GPT-4 screening of contemporaneous clinic notes to enhance precision.
Ultrasound Exhibited Superior Advantages over 18F-FDG PET/CT in Monitoring Follow-up of DLBCL
Authors: Hanzhen Zhang , Wei Yongqiang , Wei Xiaolei , Feng Ru 
Published: December 2024

Purpose: The purpose of this study was to comparison of Ultrasound and 18F-FDG PET/CT for finding refractory/relapse DLBCL after first-line therapy.
Methods: From January 2012 to September 2023, newly diagnosed DLBCL patients in our center who underwent standard first-line treatment and had complete follow-up records after treatment were enrolled. Data regarding patients' clinical and imaging data, as well as their therapeutic responses were collected.
Results: A total of 597 patients was analyzed, including 146 patients with refractory/relapse DLBCL. Among the 146 cases, there were 49 patients presented with signs and symptoms of relapse. 97 patients showed recurrence on imaging follow-up without abnormal signs or symptoms, 93 of these patients was detected by ultrasound, 52 of these were also confirmed through 18F-FDG PET/CT imaging and 41patients did not undergo 18F-FDG PET/CT due to economic constraints, intolerance, or other factors. 18F-FDG PET/CT indicated recurrence despite normal ultrasound imaging in two patients, one patient had mesenteric lymph node recurrence, another one patient had intravertebral recurrence. CT indicated recurrence despite normal PET/CT imaging in two patients.
Conclusions: Ultrasound identified most of asymptomatic DLBCL patients with relapse. However, the application of PET/CT is limited due to its high cost and radiation characteristics. Therefore, it is recommended that ultrasound be used as a routine follow-up examination for DLBCL.
Protein Energy Malnutrition and in-Hospital Outcomes Among Hospitalized Patients with Immune Thrombocytopenia: A United States Collaborative Network Cohort Study
Authors: Jones Colton Frisco , Obomanu Elvis , Verinumbe Tarfa , Elom Hilary A , Yusuf Hasiya , Byfield Karecia , Ugwe Chidiebube , Arya Yajur , Syal Arshi , Mayo Ryan J 
Published: December 2024

Background
Immune thrombocytopenia (ITP) is an acquired form of thrombocytopenia seen in adults and children. It is characterized by immune-mediated platelet destruction and can lead to life-threatening bleeding in certain patients. Protein-energy malnutrition (PEM) can lead to adverse outcomes in many medical conditions; however, whether its presence leads to adverse outcomes in patients with ITP is yet to be determined.
Methodology
We conducted a secondary analysis of data from the United States Collaborative Network-TriNetX. Our study sample included patients with ITP [defined based on the International Classification of Disease, 10th Revision (ICD-10) code (D69.3)]. PEM was our primary exposure (determined based on the ICD-10 code E46). ITP patients with and without PEM were propensity-matched to ensure both groups had similar sociodemographic characteristics. Clinical outcomes assessed were hospital readmission, intensive care unit (ICU) admission, recurrent bleeding, need for transfusion, risk of myocardial infarction (MI) and pulmonary embolism (PE), and all-cause mortality. Generalized linear models were used to measure the association of PEM and the clinical outcomes of interest. Estimates were presented as risk ratios and 95% confidence intervals, and a p-value of &lt;0.05 was considered statistically significant.
Results
After propensity score matching, 4607 participants were included in each cohort. In the PEM cohort, 46% were male, 64%% were white, and the mean age was 64.8 years (SD +/- 20.2). About 76% had hospital readmission, 30% had an ICU admission, 13% experienced recurrent bleeding, 15% needed transfusion, 6% had MI and PE, and all-cause mortality was 32% in the PEM cohort. Participants admitted with ITP and concurrent PEM had a statistically significant higher risk of hospital readmission (RR 1.329, 95% CI: 1.290-1.369), ICU admission (RR 2.153, 95% CI: 1.980-2.341), recurrent bleeding (RR 1.145, 95% CI: 1.026-1.278), need for transfusion (RR 1.640, 95% CI 1.423-1.889), risk of MI and PE (RR 1.507, 95% CI 1.226-1.852), and risk of all-cause mortality (RR 1.905, 95% CI 1.764-2.056) when compared to those without PEM.
Conclusion
Our study found a considerable proportion of patients with ITP and comorbid PEM. Findings suggest that ITP patients with concurrent PEM are at a higher risk of adverse health outcomes and mortality than ITP patients without PEM. Early recognition and prompt management of PEM among patients with ITP may contribute to improved clinical outcomes.
Gender Influences Epidemiologic Characteristics of Secondary Malignant Neoplasms in Classical Ph Negative Myeloproliferative Neoplasms
Authors: Cai Yanan , Wang Yuebo , Lu Wenyi , Zhang Ping , Zhu Zunmin 
Published: December 2024

Objectives:
To explore the influence of gender on the incidence of secondary malignant neoplasms (SMNs) among patients with polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF), based on The Surveillance, Epidemiology and End Results (SEER).
Methods:
We used the ICD (International Classification of Diseases) for Oncology, third edition (codes 9950, 9961, and 9962) to assemble a retrospective cohort of patients with PV, ET and PMF diagnosed between 2000 and 2018 in SEER 18. SMNs were defined as new cancer diagnoses occurring in patients with diagnosis of PV, ET and PMF at least 6 months prior to the diagnosis of a new malignancy. Other exclusion criteria included unknown age and diagnosis by autopsy or death certificate only.
Results:
The cohorts enrolled 35645 patients with myeloproliferative neoplasms (MPNs), including 17416 male patients (48.9%) and 18229 female patients (51.1%). The incidence of SMNs in male patients was higher than female patients (11.7% versus 9.1%，P＜0.001). This trend was also observed across PV,ET and PMF patients (11.4% versus 9.8%, 12.6% versus 8.7%, 10.9% versus 8.3% respectively，all P value＜0.05). The median time from diagnosis of MPNs to SMNs in male and female patients were similar [48 (6-217) versus 49.5 (6-207) months, P=0.884]. In subgroup analysis, the median time from diagnosis of PV and ET to SMNs in male patients were 54 (6-200) and 50.5 (6-207) months respectively, similar to those in female patients [54 (6-227) and 49 (6-201) months with P=0.994 and 0.645, respectively]. However, the median time from diagnosis of PMF to SMNs in male patients was shortened when compared with female patients [30(6-159) versus 38 (7-186) months, P=0.046]. In terms of the spectrum of SMNs, the most common site of non-hematological solid SMNs in male patients were prostate (2.5%), lung (1.5%), skin (0.7%), bladder (0.5%), gastrointestinal (0.4%) and kidney (0.4%), while breast (1.5%), lung (1.2%), reproductive system (0.5%), skin (0.3%), gastrointestinal (0.3%), kidney (0.3%) and thyroid (0.2%) cancers dominated the top of non-hematological solid SMNs in female patients. Survival analysis showed that the cumulative incidence of SMNs, leukemia, non-leukemic hematological cancers (including myelodysplastic syndromes and lymphoma) and solid SMNs were similar between male and female patients with PV and ET (all P value＞0.05). However, male patients with PMF suffered higher incidence of SMNs and leukemia than female patients with PMF (P=0.002 and 0.005, respectively), but the cumulative incidence of non-leukemic hematological cancers and solid SMNs in male PMF patients did not differ with female PMF patients (P=0.52 and 0.081, respectively).
Conclusion:
Gender influences incidence and spectrum of SMNs in MPNs. Male patients with PMF developed SMNs earlier and suffered higher incidence of SMNs, especially leukemia, over time.