bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pulmonary Embolism and the Impact of Concomitant Deep Vein Thrombosis on Outcomes Among Cancer Patients
Authors: Callori Steven , McBane Robert D. , Vlazny Danielle T. , Houghton Damon E. , Froehling David , Hodge David O. , Casanegra Ana I. , Wysokinski Waldemar E. 
Published: December 2023

Intro: Venous thromboembolism (VTE) is a common cause of death among cancer patients, second only to cancer progression. Identifying factors predicting worse outcomes among cancer patients with VTE would be useful clinically. For cancer patients with pulmonary emboli (PE), it remains unclear whether concomitant leg deep vein thrombosis (DVT) as a source for further embolization adversely impacts this risk. The aim of this project was to determine the impact of residual DVT on adverse outcomes among cancer patients suffering acute PE.
Methods: Consecutive patients with confirmed acute PE (March 1, 2013 - June 30, 2021) underwent ultrasound (US) imaging and were divided into two groups depending on the presence or absence of leg DVT. PE severity was classified based on AHA criteria. Patients were followed prospectively for VTE recurrence, major and clinically relevant non-major bleeding (CRNMB) and all-cause mortality.
Results: Over the study interval, 1,035 cancer patients with PE were enrolled (Table 1). Of these, 375 (36.2%) had leg DVT confirmed by US. Patients with leg DVT were older (64.2 vs 61.4 years, p = 0.01), heavier (90.2 vs 85.1 kg, p &lt;0.001), with lower metastatic disease prevalence (49.1% vs 57.1%, p = 0.01) compared to those without leg DVT. Cancer type distribution also differed between groups. PE patients with DVT more often had prostate, genitourinary, and hematologic cancers while those without DVT more often had pancreatic and breast cancers. Patients with DVT more often had symptomatic PE (48.2% vs. 35.9%, p &lt; 0.001), massive (2.9% vs 0.5%, p &lt; 0.001), and submassive (22.0% vs 7.6%, p &lt; 0.001). Patients with DVT more often received unfractionated heparin (39.5% vs 18.7%, p &lt; 0.001) whereas those without DVT were more frequently treated with low molecular weight heparin (57.5% vs. 44.3%, p &lt;0.001), and apixaban (16.4% vs. 11.7%, p &lt; 0.05). Anticoagulant duration, VTE recurrence, major bleeding and CRNMB were similar between groups (Table 2).
Conclusion: Among a large cohort of cancer patients with pulmonary emboli, significant clinical and cancer specific differences exist comparing those with and without leg DVT.While theoretically increasing the risk of recurrent embolization, the presence of residual DVT does not appear to adversely impact important outcomes among cancer patients adequately treated with anticoagulation.
A Pragmatic Approach to Navigating FDA Guidance for Therapeutic Product Development in Malignant Hematological Disease
Authors: Wang Limin , Johnson Angela N 
Published: December 2023

Background: Owing to the unique therapeutic characteristics and diverse etiology of underlying disease, navigating available regulatory guidance can be a challenge for newcomers to therapeutic research and development (R&D). Further, classes of drugs and biologic products are regulated separately by the U.S. Food and Drug Administration (FDA) centers CBER and CDER, respectively.
Methods: We provide background on the FDA guidance structure herein and further examine publicly registered clincialtrials.gov data to provide an overview of development status by phases and novel modality (i.e., CAR-T) in context of the regulatory landscape.
Results: Therapeutic products developed for malignant hematological disease can be regulated by either CDER or CBER depending on the type of drugs, ranging from small molecules to macromolecules, including cellular and gene therapies. In 2019, CDER of Hematology and Oncology Products (OHOP) has been reorganized and renamed the Office of Oncologic Diseases (OOD). The new OOD structure consists of six divisions including Division of Hematologic Malignancies 1 (DHM1) and Division of Hematologic Malignancies 2 (DHM2) for the review of hematologic malignancies. In 2022, CBER of Office of Tissues and Advanced Therapies (OTAT) was transformed into the Office of Therapeutic Products (OTP) to address the exponential growth in cell and gene therapies. PDUFA VII expanded the INTERACT meeting program to include both centers, a major change that may drive early phase development collaboration.
A review on the current state of hematologic malignancies clinical trials in USA shows that, of 301 hematologic malignancies related trails in USA registered to ClinicalTrials.gov (Fig. 1), 4 are in early phase 1(exploratory phase), 126 in phase 1, 120 in phase 2, 18 in phase 3, and 1 in phase 4. Most of the trials are still in early phases 1 or 2. Among the 301 registered clinical trials, 21 of clinical trials (Fig. 2) are CAR-T related, and 10 of the trials are gene modified cell products related.
Conclusions: Compared with traditional treatment on malignant hematological disease, immunotherapy is the upcoming trend in cancer treatment. Chimeric antigen receptor (CAR) therapy is at the forefront of cellular/adoptive immunotherapy for cancer treatment due to its sustained remission and better quality of life. Much research and clinical trials have been undertaken in recent years which led to several successful outcomes in CAR therapy. Despite tremendous progress, CAR-T are still faced with many challenges, including evolving regulatory framework along the road. We summarize the regulatory landscape to assist therapy developers to align with FDA expectations.
A Retrospective Analysis on the Efficacy and Saftey of Obinutuzumab in the Treatment of Non-Hodgkin B Cell Lymphoma
Authors: Zhao Yangzhi , Guo Wei , Li Jia , Wang Xingtong , Wan Xin , Li Junna , Bai Ou 
Published: December 2023

Backgroud: Obinutuzumab was approved by China's Drug Administration in June 2021, and there have been few real-world reports about efficacy and safety.
Objective: Analysis the efficacy and safety of Obinutuzumab in the treatment of non-Hodgkin B cell lymphoma in our center.
Methods ： We analysed the non-Hodgkin B cell lymphoma patients who received Obinutuzumab combined with chemotherapy or maintenance treatment during September 2021 and July 2023, median follow up 9 months（1-20）, to evaluate efficacy and safety.
Results: In all 165 patients, male 88（53%), female 77（47%）, median 56 (26-83) years. FL 80 (48%), MZL 22 (13%), CLL/SLL 13 (8%), DLBCL 42 (25%), others 8 (5%). Newly diagnosed patients 114 (69%), relapsed/refractory 51 (31%). 124 patients received Obinutuzumab combined therapy, and 42 (25%) patients received Obinutuzumab maintenance treatment. Median treatment 4 cycles（1-11）. I/II 33 (20 %), III/IV 131 (79 %). Low-medium group 91（55%）, medium-high group 74（45%）. ORR 66.7%, CRR 40.6%. 3 patients died of progression of disease. 1 elder patient died of pneumonia. Further subgroup analysis revealed, ORR（78% vs 22%, p&lt;0.001）and CRR（81% vs 19%, p=0.02）of newly diagnosed patients were better than relapsed/refractory patients. There was no difference in CRR among different stages patients（I/II vs III/IV, 24% vs 76%, p=0.424）, ORR（58% vs 42%, p=0.373）and CRR (63% vs 37%, p=0.481）between low-medium and medium-high patients. The patients received more than 4 cycles treatment with better ORR and CRR. The intensive treatment of Obinutuzumab in first cycle could improve ORR (87% vs 13%, p=0.036,）and decreased IgM ( p=0.0016）, but didn't not affect CRR （87% vs13%, p=0.343）, IgG ( p=0.13） and IgA ( p=0.41）. Maintenance treatment decreased IgM ( p=0.00064）but not for IgG or IgA. In treatment related side effects, any adverse events were 42（25%）, more than grade III were 18（11%）, tumor lysis syndrome 11 (7%), only one patient need blood purification treatment and recovered. Liver injury 8 (5%) . All the infusion-related response 23（14%）were grade I-II. Only 2 patients delayed treatment because of the side effects.
Conclusion: Obinutuzumab is safe and effective in the treatment of non-Hodgkin B cell lymphoma, even for the III/IV or medium-high group patients will have similar results with I/II or low-medium patients. Further follow-up is still needed to determine the long-time efficacy and safety.
Key words: retrospective analysis,Obinutuzumab, non-Hodgkin lymphoma.
Efficacy and Safety of Polatuzumab Vedotin in Follicular Lymphoma: A Systematic Review of Clinical Trials
Authors: Jumean Samer , Aiman Wajeeha , Qirem Murad , Alkhlaifat Osama , Ali Muhammad Ashar , Shaaban Hamid , Guron Gunwant , Al Omour Bader , Ramahi Amr , Isbeih Nooredeen 
Published: December 2023

Introduction:
Polatuzumab vedotin (Pola) is a humanized anti-CD79b monoclonal antibody linked with antimitotic agent monomethyl auristatin E. On internalization, the linker is cleaved, and antimitotic activity inhibits the cell division and growth of cancer cells. Pola is tested in multiple combinations in relapsed/refractory (RR) follicular lymphoma (FL) in recent years. In this systematic study, we will assess the efficacy and safety of Pola based combinations in RR FL.
Methods:
A literature search was performed on PubMed with keywords, “Polatuzumab vendotin” and “lymphoma” from the inception of data till 07/01/2023. PRISMA guidelines were followed while conducting this systematic review. We reviewed 160 articles and included 1 randomized clinical trial (RCT, N=41), and 4 non-randomized clinical trials (nRCT, N=163) based on inclusion criteria. Data was extracted for complete response (CR), partial response (PR), overall response (ORR), progression free survival (PFS), overall survival (OS) and ≥grade 3 side effects.
Results:
In 5 trials (N=204), 13 patients with Pola + atezolizumab (Ate) + obinutuzumab (Obi), 49 patients with Pola + Obi + venetoclax (Ven), 39 patients with Pola + Obi, 62 with Pola + Obi + lenalidomide (Len), and 20 patients with Pola + rituximab (Rit). In an RCT by Morschhauser et al. (N=41), Pola + Rit was compared with pinatuzumab vedotin (Pina) + Rit. ORR, CR, PR, and mPFS was 70%, 45%, 25%, and 15.3 months, respectively with Pola + Rit, as compared to 62%, 5%, 57%, and 12.7 months, respectively, with Pina + Rit. In a trial by Philips et al. (N=39), ORR, CR, PR, and mPFS were 67%, 36%, 31%, and 11.5 months, respectively. In 3 nRCTs (N=124), three drug regimens were used with Pola and Obi as backbone. ORR, CR, PR were 50%-83%, 20%-61%, and 20%-39%. Table 1. ≥ Grade 3 hematological and non-hematological side effects are given in table 1.
Conclusion:
Pola was well tolerated by most of the patients with FL alone or in combination with Obi, Rit, Len, Ven. Pola had relatively better response and survival rates as compared to Pina in combination with Rit. In early phase clinical trials, three drug regimens of Pola and Obi with Ven, and Len were effective in the treatment of heavily pretreated follicular lymphoma. In an early phase trial, Pola + Obi + Ate had limited efficacy in FL with safety concerns. More randomized double blind multicenter phase III clinical trials are needed to confirm these results.
Interplay between Spatial Confinement of Thrombin Activity and Dense Granule Secretion Regulates Dynamics of Thrombus Formation
Authors: Masaltseva Anastasiia , Panteleev Mikhail A. , Nechipurenko Dmitry 
Published: December 2023

Background
Thrombi formed in healthy murine microvessels have a heterogeneous structure, comprising a thrombin-dependent core and a shell supplied by platelet-derived agonists, such as ADP from dense granules. After the injury is inflicted, the core steadily grows until it reaches a plateau in size, while the shell follows three stage dynamics of rapid growth, shrinkage and stabilization. However, it is not clear how the complex dynamics of the overall thrombus structure is orchestrated by various cues.
Aim
We aimed to analyze whether spatiotemporal kinetics of thrombin-induced dense granule secretion is responsible for the observed dynamics of thrombus formation in microvessels.
Methods
We developed a multiscale computational model of thrombogenesis in response to a vessel wall injury. Platelets were modeled as two-dimensional particles, while platelet agonists were described as virtual particles, which induced platelet activation through affecting mechanical interactions between platelets and triggering platelet degranulation. As a platelet aggregate grew, the blood flow was recalculated. The model was built in a bottom-up manner and its description of single-cell processes was based on the experimental findings.
Results
The model showed that thrombin produced at the injury site was mostly confined to the innermost layers of the thrombus due to competing intrathrombus diffusion and flow-mediated dilution. Such spatial confinement of thombin resulted in the formation of a thrombus with a pronounced thrombin-activated core where platelets were able to secrete their dense granules. Released ADP recruited new platelets and triggered the formation of a thrombin-free thrombus shell. The thrombus grew until it ruptured under the hydrodynamic force and the growth repeated in cycles. However, our results predicted that if the propagation of thrombin along the flow was limited either by volumetric or surface inhibition, the cycles of thrombus formation stopped once the dense granule pool in the core was depleted. Without the supply of newly secreted ADP, the thrombus shell disassembled and the thrombus size was stabilized, in line with experimental findings.
Conclusion
Computational modelling predicts that thrombin-induced dense granule secretion is responsible for the rapid formation of the thrombus shell, which disintegrates once the granule pool is depleted due to intense secretion in the confined thrombus core. We suggest that this mechanism is responsible for the three-stage dynamics of thrombus growth in vivo.
Title: Single-Cell Transcriptome Analyses Further Elucidate the Mechanism of Action of Eed Inhibition on HbF Induction
Authors: Han Summer Xia , Fitz Emily M , Allen Allysa , Choudhuri Avik , Sartain Caroline V , Bruno Paul A , Jacobs Jeffrey W , Stuart Billy 
Published: December 2023

Mutations in the gene encoding the hemoglobin β (HBβ) subunit lead to red blood cell disorders such as Sickle Cell Disease (SCD) and β-thalassemia. Hemoglobin γ subunit, a fetal counterpart of HBβ, can relieve the disease symptoms by forming a functional complex with hemoglobin a subunit, thereby compensating for the mutated HBβ. The expression of β-like hemoglobins is tightly regulated during development, with a switch from the fetal ortholog (γ) to the adult ortholog (β) shortly after birth. Maintenance of HBγ is therapeutically beneficial for SCD patients and is observed clinically in individuals with mutations for both SCD and hereditary persistent fetal hemoglobin (HPFH) who exhibit less severe or even no SCD-related symptoms. Polycomb repressive complex (PRC) proteins have been shown to regulate the expression of β-like hemoglobins. Our previous research has demonstrated inhibitors targeting the PRC2 protein embryonic ectoderm development (EED) upregulate fetal hemoglobin (HbF) expression, leading to the formation of HbF complexes in both human CD34 + HSC-derived erythroid cells and the Townes SCD mouse model. However, the functional mechanisms of PRC complexes in this regulatory process and their target genes remain to be clarified.
In our study, we conducted single-cell transcriptome analyses on erythroid cells derived from CD34 + HSCs collected at various stages of differentiation. We identified several erythroid subpopulations, from early progenitors to maturing cells, within the CD34 + derived erythroid cell cultures. HbF + and HbF - cell populations were also identified using known markers.
To explore the mechanisms underlying HbF upregulation by EED inhibition, we compared single-cell transcriptome profiles of samples treated with and without an EED inhibitor. Our findings reveal that EED inhibitor treatment consistently leads to increased HbF + populations across multiple donors without impacting erythroid cell differentiation.
Differential gene expression analysis revealed sequential changes in the expression of previously identified HbF regulators during differentiation in the presence of EED inhibitor treatment. Through pseudotime analyses, we identified erythroid progenitor cells undergoing fate bifurcation, leading to an increase in the lineage of mature cells that express HBγ. Finally, by comparing the pseudotime trajectories of different samples, we identified genes whose expression changed along the differentiation trajectories in response to EED inhibitor treatment which influence cell fate. Overall, this study provides a deeper understanding of the relevant biological pathways that respond to EED inhibition and potential for the identification of novel molecular targets for HbF induction.
Has the Survival in Patients with Multiple Myeloma Changed with the Advent of Latest Treatments?
Authors: Desai Krishna , Iqbal Sabah , Rather Manzoor , Thirumaran Rajesh 
Published: December 2023

Introduction:
Multiple Myeloma (MM) is a hematologic malignancy of plasma cells. Over the last couple of decades, there have been groundbreaking advances in its treatment, emergence of chimeric antigen receptor T-cell (CAR-T) therapies and bispecific antibodies (bsAbs). As per National Comprehensive Cancer Network's (NCCN) current guidelines, the current standard of treatment is a 3-drug regimen bortezomib/lenalidomide/dexamethasone. The year 2003, marked the beginning of the revolution in the MM biological treatment. The aim of this retrospective study is to analyze the trends of multiple myeloma, particularly to assess the difference in survival, with the innovation in its novel treatment options.
Methods:
The data was collected from Surveillance, Epidemiology and End Result database Research. We extracted Multiple Myeloma cases diagnosed between 01-85+ years of age, using Incidence- SEER Research Date 17 Registries, Nov 2022 Sub (2000-2020), with ICD 0-3 Hist/behavior, malignant, code 9732/3 for plasma cell myeloma. The analysis was stratified based on age, sex, race, & survival curves based were compared, using the Log-rank test (GraphPad Prism).
Results:
A total of 109222 cases of multiple myeloma were identified between 2000-2020. Of these, ~55.18% were males and ~44.81% were females. Median age at the time of diagnosis is 69 years. The incidence rate overall has been increasing and was noted to be 62.38 per 1,000,000 population vs 56.38 in the year 2000. When stratified further on gender, incidence rates for males were noted to be up-trending from 69.32 in 2000 to 75.87 in the year 2020. Whereas for females the incidence rates in females in 2000 was at 47.02 and at 51.51 in 2020. The survival was compared for the general population before and after the emergence of newer treatment in the year 2003. There was a statistical difference found in the median of survival (mOS) before the introduction of the biologicals in 2003, was 25 months, and after the year 2003, was 46 months (P Value &lt;0.0001, Hazard Ratio 1.451 95% Confidence Interval 1.421 to 1.481).
Conclusion:
Multiple Myeloma is a relatively rare malignancy, with a slightly stronger male predilection. Its overall incidence has been noted to be up-trending within the last 20 years, in the United States. The median age for diagnosis is 69 years. In the year 2003, FDA approved Bortezomib for the treatment of MM, which primarily targeted the proteasome and the ubiquitin proteasome system (UPS). This established the role of UPS in MM, and further led to the invention of newer biological treatment options for MM. When survival months were compared in the pre-and-post biological treatment era, it was noted that the mOS was only 25 months, whereas a significant increase in mOS to 46 months was noted, after the introduction of biological therapy in 2003. With newer groundbreaking research and approval of CAR-T therapies, we are on our way to making MM, a curable malignancy.
HbF Inducing Eed Inhibitor Ftx-6058 Selectively and Reversibly Impacts Bone Marrow in Wild-Type Mice
Authors: Fitz Emily M , Allen Allysa , Edwards Lynn , Raghunathan Suchi , Steward Briana , Matson David J , Sartain Caroline V , Bruno Paul A , Jacobs Jeffrey W , Stuart Billy 
Published: December 2023

Sickle cell disease (SCD) is a genetic disorder characterized by red blood cell sickling, hemolysis, vaso-occlusive crises (VOCs), and other complications resulting from a mutation in the HBB gene. Increasing fetal hemoglobin (HbF) levels has shown promise in mitigating disease-related pathophysiology. In individuals with SCD who exhibit hereditary persistence of fetal hemoglobin (HPFH) and have HbF levels ranging from 20% to 30%, a remarkable reduction in symptoms is observed, highlighting the protective effect of increased HbF in SCD.
Preclinical and clinical findings indicate that compounds inhibiting the embryonic ectoderm development (EED) component of polycomb repressive complex 2 (PRC2) leads to elevations in HbF to therapeutic levels. These results suggest the potential for a substantial benefit for individuals living with SCD. To further understand the effects of PRC2 inhibition, this study aims to characterize the onset and reversibility of EED inhibition by FTX-6058.
Results from in vivo studies in wild-type mice demonstrated upregulation of the mouse fetal hemoglobin ortholog mRNA (Hbb-bh1) as well as target engagement in bone marrow though quantification of H3K27 trimethylation during seven days of active dosing of FTX-6058. Target engagement and differential gene expression profiles in the bone marrow subsequently returned to baseline shortly after the dosing period. These findings demonstrate that inhibition of EED through FTX-6058 leads to a minimal, transient impact on the bone marrow in mice, and any transcriptional changes are rapidly reversible following cessation of dosing. A small molecule EED inhibitor has the potential to provide a new treatment for sickle cell disease without irreversibly altering the bone marrow.