bluuebunny/crossref_metadata_2025 huggingface dataset:
Integration of Deep Learning in Baseline PET/CT and Multi-Omics Data for Prognostic Modeling in Diffuse Large B-Cell Lymphoma: The Clinicalpet Lymphplex Model
Authors: Wang Yue , Wang Xue , Huang Xinyun , Qian Ying , Mu Rongji , Shi Qing , Fu Di , Yi Hongmei , Ou-Yang Bin-Shen , Li Zhuo Han , Cheng Shu , Li Wang , Wen Ning , Xu Pengpeng , Zhao Wei Li
Published: December 2024

[18F]-Fluorodeoxyglucose (FDG)-PET/CT is essential for staging and evaluating treatment response in diffuse large B-cell lymphoma (DLBCL). The prognostic potential of PET-derived biomarkers requires efficient extraction and analysis of biological signatures. In this study, 18F-FDG-PET scans of 839 newly diagnosed DLBCL patients were analyzed, with DNA sequencing performed on 710 patients. Using the nnUNet deep learning framework, trained on both AutoPET public and in-house datasets, enabled precise PET scan segmentation and biomarker extraction. Key biomarkers, including total metabolic tumor volume (TMTV), Max MTV (MAX_MTV), standardized maximum tumor dissemination (SDmax_patient), and standardized maximum distance between the largest and another lesion (SDmax_bulk), showed significant prognostic value. Integrating LymphPlex genetic subtypes with PET biomarkers and clinical risk factors, we identified critical prognostic indicators: EZB-like-MYC+, MCD-like, TP53Mut subtypes, high TMTV, and elevated lactate dehydrogenase (LDH). Consequently, the ClinicalPET LymphPlex model was developed, effectively differentiating survival rates across various treatments. Additionally, combined with transcriptomic data, we revealed that risk factors within the ClinicalPET LymphPlex like high TMTV and LDH were notably associated with immune-suppressive tumor microenvironments.
A Case of Proliferative Glomerulonephritis with Monoclonal Kappa-Light Chain Deposits Treated with Daratumumab Combination Therapy
Authors: Du Jun , Wang Jue , Lv JunTing , Xiao Dan , Liu Jia , Zhong Lu
Published: December 2024

Introduction: Proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) is a chronic glomerular disease caused by monoclonal gammopathy. Daratumumab has been proved effective in the treatment of plasma cell myeloma while its effect for PGNMID has rarely been reported.

Methods: A Daratumumab combination therapy (D-VCd regimen, specifically are Daratumumab + Dexamethasone + Bortezomib + Cyclophosphamide) was adopted to treat a patient diagnosed with PGNMID with glomerular deposits mainly composed of κ-light chain ( κ-light chain restricted PGNMID).

Results: The utility of D-VCd regimen showed a favorable effect in this patient. After the fixed course, his clinical symptom, laboratory parameters, neoplastic plasma cells clonity all restored to normal range, and no obvious disease progression was observed throughout the treatment. Following the treatment, 24H microalbuminuria, 24H urine total protein levels restored from 6142.35 and 9114.7mg/24h to 117 and 212mg/24h, respectively. Urinal IgG titers transformed from 129mg/L to 6.3mg/L. Urinary κ and λ -light light-chain decreased from 49.6 and 31.7mg/L to 7 and 3.9mg/L, respectively. All the while serum creatinine fluctuated within the normal range.

Conclusion: This case underscores the utility of Daratumumab in treatment of PGNMID, and it's inferred that Daratumumab has clinical effects in the disease primarily through targeting tumor clonity. However, data on the use of Daratumumab in clinical trials of PGNMIDs is currently so limited that that more experiments are needed to support the inference.
Case Series of Myeloid Sarcoma from a Tertiary Center
Authors: Rahman Iris , Kim Salem , Latif Hira , Smith Hedy
Published: December 2024

Introduction: Myeloid sarcoma (MS) represents a rare neoplasm derived from myeloid precursor cells, typically manifesting as an extramedullary tumor mass. While frequently associated with acute myeloid leukemia (AML), chronic myeloid leukemia (CML), or myelodysplastic syndrome (MDS), it can also manifest independently as a solitary lesion. This phenomenon underscores the heterogeneous clinical presentations of myeloid sarcoma, necessitating thorough diagnostic evaluation and tailored management strategies. Management strategies are primarily guided by protocols established for AML, although MS exhibits considerable clinical variability and is associated with a generally unfavorable prognosis (Aldapt et al., 2022, Blood). Herein, we report six cases of myeloid sarcoma diagnosed at a tertiary care facility over the preceding decade.

Clinical Cases: The average age at presentation was 42 years old with average baseline hemoglobin 8.84, WBC 11.49 (range: 0.2 to 35.5), LDH 445. The average time to treatment was 32 days. 5 cases were associated with a diagnoses of MDS or AML while one case had no associated diagnosis.

Case 1 presented with gingival MS in the context of AML, achieving disease remission after multiple rounds of chemotherapy. Case 2, diagnosed with CML, was found to have a gastric mass on CT, which was later diagnosed as MS with AML transformation. Case 3, known for MDS, presented with bleeding and was diagnosed with MS involving an axillary lymph node. Case 4 presented with finger ulceration, diagnosed with MS and concurrent AML necessitating finger amputation and ongoing treatment. Case 5 presented with a rapidly growing eye mass, diagnosed with MS that metastasized and subsequently developed AML. Case 6 presented with neck and chest pain, diagnosed with solitary mediastinal myeloid sarcoma, experiencing persistent disease activity despite treatment.

The overall prognosis was poor, compounded by treatment complications and mass effect. Treatment approaches varied; two patients underwent surgical interventions due to mass-related complications. Immunohistochemical profiles differed across biopsies, with genetic testing for targeted therapies conducted only in the most recent patient (Case 4).

Conclusion: This case series aims to explore the diverse presentations and progression of myeloid sarcoma (MS). Extramedullary masses can vary in location and may present asymptomatically. MS should be considered in patients with a history of myeloid disorders or new masses. Delays in diagnosis and treatment are common as patients often seek care from multiple providers despite the disease's rapid progression. While management guidelines primarily align with those for AML, integrating surgical oncology guidelines could improve outcomes, especially in cases of isolated MS where mass-related complications and disease progression are concerns.
Efficacy and Safety of Combined Anti-PD-1, Bortezomib and Pegaspargase Regimen for Newly Diagnosed Early Stage Extranodal NK/T-Cell Lymphoma
Authors: Wang Xiangmin , Zhang Qing , Li Yujie , Xie Ruiyang , Zhou Hongyuan , Chen Xicheng , Xu Linyan , Qiao Jianlin , Yan Dongmei , Xu Kailin , Sang Wei
Published: December 2024

Extranodal natural killer/T-cell lymphoma (ENKTL) is an aggressive lymphoma with a poor prognosis. L-asparaginase-based treatment regimens, such as SMILE (dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide), DDGP (dexamethasone, cisplatin, gemcitabine,and pegaspargase) and P-gemox (gemcitabine, oxaliplatin, and pegaspargase), have shown higher response rate and survival outcomes than traditional anthracycline-containing regimen. However, the safety profile did not seem satisfactory. It is imperative to develop novel approach with low toxicity and high efficiency for ENKTL patients. In this single arm, multi-center pilot study (ChiCTR2200066349), we aimed to observe the efficacy and safety of PPB (anti-PD-1, bortezomib and pegaspargase) regimen in newly diagnosed early stage ENKTL patients. Patients were eligible if they were≤70 years old with newly diagnosed ENKTL in stages I/II and had an Eastern Cooperative Oncology Group performance status of 0 to 2. Treatment included 6 cycles of PPB: intravenous tislelizumab (200mg, d1), subcutaneous bortezomib (1.3mg/m2, d1,4,8,11) and intramuscular pegaspargase (2500 IU/m2, d1), and repeated every 3 weeks. Additionally, local radiotherapy was performed after two cycles of PPB regimen. We enrolled 7 patients in the preliminary study, with 3 achieving CR and 4 achieving PR, resulting in a CR rate of 42.9% and an ORR of 100% (7/7). In terms of safety, PPB regimen is well tolerated, and the incidence of hematological toxicity (including neutropenia, anemia and thrombocytopenia) is 71.4% (5/7). Most patients (4/7) have only grade 1-2 hematological toxicity, and only one patient experienced grade 3 neutropenia. Three patients showed mild transaminase abnormalities, with no severe hepatic/renal insufficiency or coagulation disorders. Four patients had mild nausea and vomiting, one patient had mild diarrhea. All patients had no cardiac events. In this single arm clinical trial, the PPB regimen showed promising preliminary results with tolerable side effects. A confirmation trial based on larger population is needed in the future.
Assessing Venous Thromboembolism Risk in Patients with Multiple Myeloma: A Nationwide Population-Based Study in Taiwan
Authors: Liu Chia-Jen , Tsai Chun-Kuang , Hsu Te-Lin , Wang Hao-Yuan
Published: December 2024

Background . Venous thromboembolism (VTE) represents a significant disease- and treatment-related complication in multiple myeloma (MM). The studies of VTE in Asian myeloma patients are limited due to the low incidence of VTE in the Asian population. We conducted a comprehensive nationwide population-based study to elucidate the incidence and risk factors of VTE among MM patients in Taiwan.

Material and methods. We consecutively enrolled all patients newly diagnosed with MM in Taiwan from 2000 to 2021. The patients aged less than 18 or those without baseline data were excluded. The primary endpoint was the occurrence of VTE, including deep venous thrombosis and pulmonary embolism. Hazard ratios (HRs) for VTE risk in MM patients relative to an age- and sex-matched cohort were computed using Cox proportional regression analysis. Therapeutic agents were integrated into the Cox models as time-dependent covariates to mitigate immortal time bias. Multivariable Cox proportional hazards models were employed to identify independent predictors of VTE.

Results. This study encompassed 10,865 patients with MM and the same matched individuals, with a median age of 68 years (interquartile range 60-77). Among the MM patients, 57.0% were male. The most common comorbidities were dyslipidemia (76.3%), hypertension (67.5%), chronic kidney disease (45.2%), coronary artery disease (CAD; 44.0%), and chronic obstructive pulmonary disease (COPD; 39.3%). One hundred sixty-four VTE events developed among the MM patients, with a follow-up of 31,078.0 person-years. The VTE incidence was 14.5 times higher in the MM cohort than in the matched cohort (5.3 vs. 0.4 cases per 1,000 person-years; p < 0.001). Univariate analysis identified several significant predictors of VTE, including CAD (HR 1.81), COPD (HR 1.37), cerebrovascular accident (HR 1.60), heart failure (HF; HR 1.47), hypertension (HR 1.85), prior VTE (HR 24.29), age ≥ 65 years (HR 1.54), male gender (HR 0.75), and immunomodulatory drug (IMiD) therapy (HR 1.70). The multivariable Cox proportional hazards models highlighted CAD (adjusted HR 1.43; 95% CI 1.01-2.01, p = 0.042), prior VTE (adjusted HR 21.12; 95% CI 11.30-39.47, p < 0.001), and IMiD therapy (adjusted HR 1.68; 95% CI 1.19-2.37, p = 0.003) as independent risk factors for VTE in MM patients. Further analysis of IMiD therapy revealed adjusted HRs of 1.53 (95% CI 1.09-2.17; p = 0.015) for thalidomide and 2.05 (95% CI 1.34-3.13; p = 0.001) for lenalidomide.

Conclusion. This study substantiates the elevated risk of VTE in MM patients compared to an age- and sex-matched cohort. CAD, prior VTE, and immunomodulatory drug treatment are linked to an increased VTE risk in this population. These findings underscore the importance of implementing targeted preventive strategies for this high-risk group.
Orally Effective CDK9 Inhibitor YX0798 for Treating Aggressive Lymphoma
Authors: Jiang Vivian , Xue Yu , Kim Hong , Cai Qingsong , Zhang Tianci , Nie Lei , McIntosh Joseph , Liu Yang , Chen Haiyan , Santos David , Thirumurthi Selvi , Zhou Jia , Wang Michael
Published: December 2024

Introduction

Non-genetic transcription evolution has been increasingly recognized as a contributor to tumor cell progression and therapeutic resistance. Transcriptomic reprogramming and tumor cell progression results from cyclin-dependent kinase 9 (CDK9) dysfunction, with CDK9 as the linchpin of transcription machinery through RNA polymerase II (Pol II) transcription. Our laboratory has recently shown that in mantle cell lymphoma (MCL), the HSP90-MYC-CDK9 network drives transcriptomic reprogramming, resulting in therapy resistance. We also showed AZD4573 and enitociclib are safe and effective treatments in preclinical MCL models, and the therapeutics target CDK9. However, current CDK9 therapeutic candidates could be improved by enhancing target selectivity and oral bioavailability.

Methods

In this study, we showcase a novel CDK9 inhibitor, YX0798, evaluating its potency and safety using preclinical MCL platforms and models. Molecular docking with Schrodinger was used to investigate the interaction of YX0798 with the CDK9 crystal structure. Binding assays with scanMAX were used to determine the selectivity of YX0798 across 468 kinases. Cell viability assays were conducted to assess in vitro efficacy. Apoptosis assays, western blots, and bulk RNA sequencing were used to determine the mechanism of action in MCL cells. Pharmacokinetic and pharmacodynamic profiling was conducted to determine the drug-like potential of YX0798. Patient-derived xenograft (PDX) models were used to determine the therapeutic potential of YX0798.

Results

The novel CDK9 inhibitor YX0798 have high target selectivity and good oral bioavailability. YX0798 demonstrated greater selectivity and greater affinity than commercial competitor in binding to CDK9. When administrated orally (5 mg/kg, daily), YX0798 led to even better anti-tumor activity in MCL resistance PDX models than the commercial competitor with intravenous injection at an equivalent dosing. Mechanistically, YX0798 or the commercial competitor led to CDK9 inhibition and primarily resulted in downregulation of short-lived oncoprotein c-MYC and pro-survival protein MCL-1. Ultimately, CDK9 inhibition disrupted the cell cycle and switched cellular metabolism towards oxidative phosphorylation, eventually leading to cell death.

Conclusions

Together, our study demonstrates that YX0798 is an orally bioavailable CDK9 inhibitor with exquisite selectivity and anti-tumor potency that drives transcription reprogramming towards tumor cell killing.
A Longitudinal Examination of the Quality of Life of Persons with Hemophilia a Switching from Intravenous Recombinant Factor VIII Concentrate to Subcutaneous Non-FVIII Replacement Therapy
Authors: O'Rourke Roxy , Bouskill Vanessa , Wakefield Cindy , Carcao Manuel , Abad Audrey , Blanchette Victor , Malcolmson Caroline
Published: December 2024

Background. In Canada, ‘standard of care’ for persons with hemophilia A (PWH-A) has been regular intravenous infusions of factor VIII (FVIII) concentrates started early in life. Recently, novel non FVIII therapies that do not require intravenous infusion, and are administered infrequently and subcutaneously, have become clinically available. These therapies may impact health-related quality of life (HR-QoL) of PWH-A. This patient-reported outcome can be assessed using the Canadian Hemophilia Outcomes-Kids Life Assessment Tool (CHO-KLATv3.0).

Aim. To compare the long-term HR-QoL of PWH-A pre-/post-switch to emicizumab.

Methods. PWH-A on FVIII prophylaxis, and their caregivers, completed questionnaires at baseline (day of switch to emicizumab), 3-, 6-, and 12-months post-switch. This study was approved by the institutional research ethics board. Informed consent was obtained from participants. PWH-A aged 7-18 years completed the self-report CHO-KLAT, and caregivers of PWH-A aged 0-18 years completed the caregiver-report CHO-KLAT. The CHO-KLAT is scored 0- 100, with 100 representing best HR-QoL. The CHO-KLAT is also scored within 7 domains: activities, autonomy, bleeding, emotional health, hemophilia knowledge, social functioning, and treatment.

Results. PWH-A (N=26; Mage=12.4 years, SD=4.2; 100% male; 97% infusing prophylaxis >twice/week pre-switch) and their caregivers (N=34) completed the questionnaires. Mean CHO KLAT scores increased at 3-months and plateaued by 12-months. Child and caregiver CHO-KLAT scores were significantly correlated at baseline (ρ=.53**, CI=.16-.77) and 12-months (ρ=.92**, CI=.66-.98), indicating similar caregiver versus child-perceived HR-QoL longitudinally. There was a significant improvement in caregiver-reported CHO-KLAT scores from baseline to 3- months, by an average of 8.65 (t18=-3.36, CI=-14.05–3.25). There was a significant improvement in caregiver-reported autonomy from baseline to 12-months (Z=-3.26, p<.001).

Conclusion. PWH-A and their caregivers reported greatest HR-QoL at 3- and 6-months post switch. The HR-QoL findings align with the literature on other chronic conditions, where the greatest changes are observed immediately following a treatment switch, followed by a plateau over time.
Evaluation of Prognostic Factors Involved in the Evolution of Secondary Acute Leukemia Patients
Authors: Omer Meilin , Popov Viola Maria , Bumbea Horia , Andreescu Mihaela , Bacanu Maria , Popescu Mihaela , Ofiteru Geanina , Mihai Lidia Felicia , Patrinoiu Oana , Dumitru ION , Soare Dan Sebastian , Arghir Aurora , Vladareanu ANA Maria
Published: December 2024

BACKGROUND

Secondary acute leukemia (sAL) has a worse prognosis, with severe evolution and higher risk of sepsis. Previous chemotherapy could cause genetic mutations that influenced the prognosis of sAL.

OBJECTIVE

To identify prognostic factors in patients with sAL.

METHOD

A retrospective study from 2015-2024 included 109 patients with acute leukemia diagnosed in the Hematology Clinic of the Colentina Clinical Hospital. The study group included 69 patients with secondary acute leukemia: 39 patients with chronic hematologic neoplasms and 30 patients with solid tumors. We enrolled a control group that included 40 patients without neoplasia in their medical history. The analyzed variables were Flow cytometry markers: CD56, CD71, CD 123, CD7, CD9; cytogenetic and molecular markers, hematological and biochemical parameters.

RESULT

Aberrant expression of CD56, CD7, CD9, CD71 and CD123 influenced the survival of patients with sAL, the chi-squared of overall model fit is 13.61, p=0.01. The most important marker is CD71 expression, the median survival in the patient group is 3 months (95% for median-1-9 months) vs 14 months (95%Ci for median-5-60 months) in the control group, p = 0.0006. We obtained no significant differences in cytogenetic or molecular marker for survival analyses. Patients with sAL followed by solid tumor have more blasts in the bone marrow than patients with chronic hematological neoplasms with a median value 43% , average rank =19.63 vs 75% average rank= 28.5, p=0.02. The severity of neutropenia is more important in patients with sAl with solid tumor in their history than in patients with chronic hematologic neoplasia, with a median value 1.15, average rank 28,96 vs 2.72 average rank =37,61, p=0, 05. Probably because of neutropenia, patients with solid tumors have higher values of C-reactive protein (CRP) and fibrinogen and more frequent severe infections that influenced the evolution of patients.

CONCLUSIONS

Patients with solid tumor in the medical history have an aggressive form of acute leukemia at onset represented by severe neutropenia and with higher frequency of inflammatory markers, higher rate of bone marrow blasts. The presence of CD71, CD56, Cd7, CD9 and CD 123 expression could indicate the worst evolution of sAL patients.
Resensitizing the Imatinib-Resistant Chronic Myeloid Leukemia through Reshaping the Glucose Mtabolism By Insulin Sensitizer
Authors: LAI Qian , Duan Hongpeng , Jiang Yuelong , Yang Liuzhen , Deng Manman , Lin Zhijuan , Shan Weihang , Zhong Mengya , Yao Jingwei , Zhang Li , Zha Jie , Xu Bing
Published: December 2024

Tyrosine kinase inhibitor (TKI) such as Imatinib (IM) is the preferred treatment for Chronic Myeloid Leukemia (CML). However, TKIs resistant generate a significant challenge to disease management. Activation of key signaling pathways, cell cycle disruptions, abnormal epigenetic events, aberrant stem cell niche microenvironments, and metabolic shifts had been reported to be associated with TKI resistance. We detected the increased glucose uptake and lactate production in high dose IM-induced CML resistant cells. Chiglitazar (Chi), a novel Insulin Sensitizer, reduced the glucose metabolism in stem-like cell of Acute Myeloid Leumia (AML) according to our previous study. This inspired us to test its therapeutic effect in CML management. Cell proliferation, cell cycle distribution, and apoptosis results showed the cell killing effect when combined with IM but not Chi-only in IM-resistant CML cells. RNA-Seq and western blotting showed the Chi reducing the glucose uptake, reducing lactate production, and resensitizing the IM-resistant CML cells through the PPARγ/mTOR/PKM2 pathway. Further, we introduced shPPARγ to knockdown PPARγ in IM-resistant cells after Chi treatment for 24h. Downregulation of PPARγ significantly redued the apoptosis-induction effect when IM-resistant cells treated with IM and Chi combined treatment. Moreover, mTOR activator (MHY1485) could mimic the the synergistic effect of Chi and IM combination treatment. Finally, in vivo data confirmed the anti-leukemic effect of Chi and IM combination regimen in CDX (cell derived xnograft) models. Thus, we concluded that combining Chi and IM serves as a potential thrapeutic regimen in CML clinical management.
Genome-Wide Association Study of Chronic Pain in Sickle Cell Disease
Authors: Sowa Anna , Hu Yue , Gladwin Mark T. , Gordeuk Victor R. , Nouraie Seyed Mehdi , Zhang Yingze , Pashankar Farzana D. , Krishnamurti Lakshmanan , Gruen Jeffrey
Published: December 2024

Background:

For many patients with sickle cell disease (SCD), episodes of acute pain occur within the context of debilitating persistent or chronic pain. Over half of adult patients report pain on more than half of the days, and almost a third experience pain on 95% of days. No previous GWAS studies have explored the association of genetic polymorphisms with chronic pain in SCD.

Methods:

We conducted a genome-wide association study (GWAS) involving 405 SCD patients using data from the screening phase of the Walk-PHaSST study (NCT00492531). Participants were age 12 years and older, with a median age of 35 years, and 53% were female; 73% had hemoglobin (Hb) SS, 18% had Hb SC, 4.0% had Hb Sβ + thalassemia, and 4.9% had other subtypes of SCD. Genotypic data were filtered to exclude SNPs with a call rate below 95%, deviations from Hardy-Weinberg equilibrium (P < 0.00001), or a minor allele frequency under 0.05, resulting in 9,874,538 SNPs for analysis. We performed a proportional odds logistic regression to evaluate the association between SNPs and self-reported chronic pain levels, rated on a 0 to 10 scale. Adjustments were made for age, sex, SCD subtype, alpha-thalassemia, hemoglobin concentration, hydroxyurea usage, and the first 10 principal components to control for population stratification.

Results:

Chronic pain was reported by 146 patients (36%). Three SNPs reached genome-wide significance: rs8026638 (p = 4.16 × 10^-8), rs7180285 (p = 4.64 × 10^-8), and rs10152723 (p = 4.96 × 10^-8). These SNPs, all in high linkage disequilibrium, are located on chromosome 15 within the intronic region of the CHD2 (Chromodomain Helicase DNA Binding Protein 2) gene.

Conclusions:

To the best of our knowledge, this is the first GWAS to identify a locus for chronic pain in SCD that exceeds genome-wide significance threshold. Analyzing a small but well-phenotyped cohort of individuals with SCD, we found association with three SNPs within the CHD2 gene. The CHD2 gene, part of a family of genes that modify chromatin structure to alter gene expression, has previously been associated with cognitive function, generalized myoclonic and atypical absence seizures, and abnormal pyramidal signs. Further validation in larger cohorts and additional biological studies are needed to confirm these associations and to further explore their potential modulating effects on pain pathophysiology and perception.
Variability in Internal Algorithms for Sickle Cell Disease
Authors: Quraishi Mariam z , Menon Neethu M , Yadav Aravind , Srivaths Lakshmi V , Brown Deborah L , Okeleji Olayinka , Elgehiny Amr
Published: December 2024

Background:

While national guidelines for the management of vaso-occlusive crisis (VOC) and acute chest syndrome (ACS) in sickle cell disease (SCD) exist, institutional algorithms are tailored to their clinical practices. This study aims to compare institutional algorithms to each other and to national recommendations for VOC/ACS in pediatric SCD.

Methods:

Algorithms were collected from children's hospitals across the United States and compared to recommendations made by the National Heart, Lung, and Blood Institute (NHLBI) 2014 and the American Society of Hematology (ASH) 2020 regarding management of VOC/ACS in SCD.

Results:

Review of 37 VOC and 17 ACS algorithms from 40 children's hospitals showed that most followed national guidelines for diagnostic evaluation of VOC/ACS. Parenteral opioids and NSAIDs were recommended by all VOC algorithms, with variations in dosing and administration. Intranasal fentanyl was recommended by 31 algorithms, with individualized pain protocol and non-pharmacological measures mentioned in 19 each. Incentive spirometry was included in 16 of 17 ACS algorithms, but only 11 of 37 VOC algorithms. Antibiotics were recommended by all ACS algorithms, but 4 used regimens different from the NHLBI recommendation. Most ACS algorithms had recommendations regarding transfusion, but with considerable variability. Exchange transfusion guidelines from either NHLBI or ASH were included in 14 of 17 ACS algorithms. Intravenous fluid management strategies were highly variable and hypotonic fluids were recommended in 6 VOC and 4 ACS algorithms.

Discussion:

This study is the first of its kind to review algorithms across the country regarding VOC and ACS management in children. Institutional algorithms generally aligned with national guidelines for management of VOC and ACS, but significant treatment variations were observed. Many algorithms did not include certain recommendations specified in the national guidelines, such as incentive spirometry, despite its widespread availability and effectiveness. Intranasal fentanyl (INF) was commonly recommended in VOC algorithms, aligning with its proven efficacy as an opioid analgesic. Variability in IVF recommendations likely stems from the lack of randomized controlled trials addressing IVF benefits and risks in VOC and ACS. Variations existed in transfusion indications in ACS, possibly due to ambiguity in definitions of severity of ACS in national guidelines. Despite technical challenges, most protocols recommended exchange transfusion for severe ACS, in line with national guidelines.

Conclusion:

Despite the presence of national guidelines, internal algorithms for VOC and ACS in pediatric SCD show great variability, likely due to the lack of robust evidence supporting specific recommendations in national guidelines. Prospective studies are crucial to fill these evidence gaps with the overall goal of improving patient care.
Adaptive, Rapid, Parallel-Phase Implementation of the Chemopad to Combat Substandard/Falsified (SF) Chemotherapy Drugs across Sub-Saharan Africa
Authors: Gomes Suzan , Stillwell Anna , Ippolito Elise , Lieberman Marya , Muluneh Benyam
Published: December 2024

Background: In low- and middle-income countries (LMICs), a significant proportion of medications, including anticancer agents, are substandard or falsified (SF).1 These poor-quality medicines do not meet the necessary specifications for standard, appropriate patient care.1 The prevalence of SF chemotherapy drugs compromises treatment efficacy and patient safety, increasing the risk of morbidity and mortality and loss of rapport in the healthcare system.2 To safeguard public health, the ChemoPAD, a low-cost paper analytical device, was developed to detect the presence of active pharmaceutical ingredients (APIs) and identify potential SF chemotherapy medications in LMICs.3

Methods: This study methodology was guided by implementation mapping and consisted of a parallel, adaptive approach of two phases - pre-implementation and clinical implementation.4 The pre-implementation involved a collaboration with Tikur Anbessa Specialized Hospital (TASH), Moi Teaching and Referral Hospital (MTRH), and Kamuzu Central Hospital (KCH) - National Cancer Center, to conduct an implementation needs assessment through three virtual informal focus groups. The participants (n = 8) were pharmacists, pharmaceutical coordinators, and the heads of the pharmacy department. The discussion was guided by workflow mapping questions using the CFIR framework. A data trend analysis compared current workflow processes, ChemoPAD feasibility, and barriers and facilitators for implementation. In parallel, a nominal group technique was employed to facilitate discussions on exploring and refining program objectives and implementation strategies with the ChemoPAD research team (n = 14) for the clinical implementation phase.5 This iterative approach facilitated consensus and generated ideas, which were further refined through focus groups before reintroduction to the research team for additional feedback and consensus-building.

Results: Both phases discovered ways to promote sustainable workflows. In the pre-implementation phase, participants were receptive to incorporating the ChemoPAD into the workflow, favoring a proactive screening approach for hospital-supplied chemotherapy medicines to ensure drug quality, reduce the risk of adverse events, and prevent supply chain disruptions. Barriers and facilitators have been identified and will be considered for successful ChemoPAD implementation. In the clinical implementation phase, concrete strategies developed include: standard operating procedure, training materials, workflow diagrams, and designating hospital staff and regulatory champions.

Conclusions: This study demonstrated the use of a rapid, adaptive, parallel-phase implementation approach and virtual communication methods to enhance implementation science research in multiple LMIC settings.
Novel Instrument for Measuring Oxygen-Equilibrium Curve
Authors: Aprelev Alex , Pochron Mira , Gaputan Polo , Shestakov Olek
Published: December 2024

Introduction: Hemoglobin plays a crucial role in the delivery of oxygen from the lungs to the body's tissues. The binding function of hemoglobin can be directly measured by simultaneously assessing both the oxygen pressure and saturation level of hemoglobin while changing the oxygen content from zero to a reasonable maximum, then back to zero. The curve describing the dependence of hemoglobin saturation as a function of oxygen pressure is called the Oxygen Equilibrium Curve (OEC). The characteristic point of the OEC curve is the oxygen pressure corresponding to 50% saturation of hemoglobin (P50).

Current instruments capable of measuring OEC have a variety of limitations that have thus far limited the wider applications for OEC measurements in pharmacological and medical applications. This includes large blood sample sizes, complex consumables, and lengthy test procedures.

Aim: The goal of our current development is to suggest a novel method for improved measurement of P50 and the OEC curve.

Methods: OxyDial's OEC measurement methodology prioritizes improvements in four key areas when compared to currently-available instruments: Full spectrum absorption spectroscopy is used to measure hemoglobin saturation. This increases measurement precision and enables the detection of Met-Hemoglobin.Oxygen pressure is measured using the lifetime of phosphorescent dye. This simplifies the instrument and negates the need for calibrations which would otherwise be required.An enzymatic reaction is used to reduce oxygen pressure from atmospheric levels to zero. This decreases the required sample volume to 10uL, and avoids the need for gas cylinders.Samples are contained in a small glass capillary (similar to a micro-hematocrit capillary), ensuring contamination-free cleaning and operation, as the only component in direct contact with blood is the disposable capillary itself. Capillary temperature can be precisely controlled to a level of 10mC.

Results: The suggested method provides significant improvements compared to methods used in the older instruments, which are limited to 2 wavelengths, and necessitates the use of Clark's electrodes, a 1 cm optical cuvette with a stirrer, and a defoaming agent. In contrast, OxyDial's novel OEC method and instrumentation have been proven to provide more reliable and precise operation and require no significant service or deployments. A single OxyDial OEC instrument could conduct 30 full tests in a day, with the simple operation allowing a single operator to run up to 4 instruments simultaneously.

Conclusion(s): We recommend switching from the older OEC testing methods to novel OxyDial OEC testing methods.
Leukemia Associated Macrophages and Neutrophils Contribute to Immune Suppression through PD-L1 and Arginase in BCR-ABL1 Chronic Myeloid Leukemia
Authors: Liu Chang , Lu Xiaocui , Fang Hui , Cowell John Kenneth , Hu Tianxiang
Published: December 2024

The BCR-ABL1 fusion gene is the molecular hallmark of chronic myeloid leukemia (CML). Despite the success of oral tyrosine kinase inhibitors (TKIs), challenges remain in management of CML patients. Emerging immunotherapy provides potential for further improvement of patient outcome. Our current investigation in a transgenic mouse model of BCR-ABL1 CML revealed continuous increases in CD11b+Ly6CInt PMN-MDSC, CD11b+Ly6CHigh M-MDSC and F4/80+ macrophages during CML progression. Concurrently, significant reductions occurred in the levels of immune effector T, B and NK cells. This immune suppression phenomenon was consistent in both primary leukemia induction and following leukemia cell transplantation. PD-L1 was exclusively upregulated in M-MDSCs/macrophages, accompanied by remarkable increases of PD1+ CD4 and CD8 T cells. When co-cultured with CD4+ T cells, PMN-MDSCs significantly inhibited their division. Mechanistically, there is a global activation of the immunosuppressive genes including Arg1, Entpd1 and S100a8/9 in PMN-MDSCs. Importantly, expression correlation assay and pharmacological inhibition indicate a direct regulation of those genes by BCR-ABL1. Furthermore, blocking BCR-ABL1 or arginases activities with inhibitors proved BCR-ABL1 directly regulated targets such as Arg1 in immune suppression. Taken together, our results indicate two different immune suppression mechanisms in a CML mouse model, through the immune suppressive PMN-MDSCs and PD-L1+ M-MDSCs/macrophages. Accordingly, combination treatment with ponatinib and anti-PD1 antibody not only provides rapid remission, but also better disease control after treatment discontinuation. This study, therefore, has revealed the detailed mechanisms underlying immune evasion of BCR-ABL1 CML cells, which justifies exploring combination treatment to improve the success rate of treatment free remission of CML.
Heme Oxygenase-1 Regulates the Hepatic Expression of Hemoglobin Scavenger Receptor CD163 in Sickle Cell Disease
Authors: Mozhenkova Anna , Pradhan-Sundd Tirthadipa
Published: December 2024

Sickle cell disease (SCD) is the result of a genetic mutation in the β-globin gene, where both copies of the gene are affected. This mutation causes red blood cells to change shape into a sickle shape, leading to their premature destruction and the release of hemoglobin. Plasma haptoglobin scavenges cell free hemoglobin (Hb) and escorts it to the liver, where it is cleared by macrophages (specifically hepatic Kupffer cells) through a process that depends on the hemoglobin scavenger receptor CD163. Nevertheless, the persistent breakdown of red blood cells in SCD causes a decrease in plasma haptoglobin levels, which in turn leads to the buildup of hemoglobin, heme, and iron, leading to multi organ damage including liver damage. Past investigations have demonstrated a limited number of instances where there is a positive relationship between CD163 expression and unfavorable clinical outcomes in patients with SCD. However, the precise function and control of CD163 in regulating hepatobiliary damage in SCD have not yet been completely understood.

The objective of this study was to examine the function of CD163 as a potential biomarker for the severity of liver damage associated with SCD. This was done by utilizing a humanized mice model and liver biopsy samples obtained from SCD patients. We found that there is a positive correlation between chronic liver damage in mice and individuals with sickle cell disease (SCD) and increased levels of hepatic membrane bound CD163. Mechanistically we show that heme oxygenase 1 (HO-1) is a positive regulator of CD163 in the liver of SCD mice, independent of the nuclear factor erythroid 2-related factor 2 (NRF2) signaling. Additional investigation revealed that toll-like receptors (TLRs) 4 and 9 interact with both CD163 and HO-1 and control the regulation of membrane bound CD163 in SCD mice liver. Finally, we demonstrate that the reduced activity of CD163 exacerbates liver damage caused by hemolysis in sickle cell disease (SCD) as a result of the accumulation of hemoglobin specifically in the liver.

This study finds CD163 as a possible indicator of liver damage caused by hemolysis in SCD. A comprehensive comprehension of the HO-1 mediated signaling pathways that regulate CD163 expression will prove valuable in the development of innovative treatment strategies for addressing tissue damage caused by hemolysis in SCD and other hemolytic diseases.
Stapled BAD BH3 Helices Effectively Target BCL-2 Mutants That Cause Venetoclax Resistance
Authors: Deangelo Thomas M. , Adhikary Utsarga , Korshavn Kyle J. , Brotzen-Smith Clara R. , Seo Hyuk-Soo , Song Kijun , Sebastian Luke , Dhe-Paganon Sirano , Wales Thomas E. , Bird Gregory H. , Walensky Loren D.
Published: December 2024

Background and Rationale: BCL-2 is the founding member of a family of proteins that regulate apoptosis by controlling the integrity of the mitochondrial outer membrane. BCL-2 intercepts and traps the critical BH3 helices of BAX and BAK in a groove on the protein surface, blocking BAX/BAK-mediated apoptosis. Venetoclax is a selective small molecule inhibitor that binds within the BCL-2 groove and restores the apoptotic pathway by neutralizing the capacity of BCL-2 to inhibit BAX and BAK, effectively “inhibiting an inhibitor” of apoptosis (Souers et al., Nat Med 2013). As the clinical use of venetoclax has expanded, resistance mutations in BCL-2 have arisen that thwart venetoclax binding yet preserve native BH3 interactions, thus re-establishing apoptotic blockade (Blombery et al., Blood 2020). Here, we harnessed the capacity to stabilize the secondary structure of native, bioactive alpha-helices by all-hydrocarbon stapling (Walensky et al., Science 2004) to develop and interrogate BH3 helices that bind venetoclax-resistant mutants of BCL-2 with high affinity and restore BCL-2 inhibition.

Results and Conclusions: We screened a library of “stapled” BH3 peptides modeled after the BAD BH3-only protein, which selectively engages the anti-apoptotic proteins BCL-2, BCL-XL, and BCL-w. We identified lead alpha-helical constructs that retain the ability to potently target and functionally inhibit BCL-2 irrespective of venetoclax resistance mutations. We performed a series of structural analyses that revealed both the conformational consequences of BCL-2 mutagenesis and the mechanistic basis for retention of high-affinity binding by lead stapled BAD BH3 peptides. These compounds provide prototypes for the development of next-generation BCL-2 inhibitors that overcome resistance to small molecule treatment.
Risks and Harms to Physicians Reporting Hematologic Adverse Drug Reactions (ADRs) to Health Authorities
Authors: Bennett Charles , Watson Gretchen , Knopf Kevin , Martin Linda , Gale Robert Peter
Published: December 2024

Background : The Southern Network on Adverse Reports group (SONAR) has previously identified severe risks and harms to physicians who reported serious ADRs to Heath Authorities related to solid-tumor oncology pharmaceuticals. (eClinMed, PLOS One, Journal of Scientific and Professional Integrity) We investigated whether similar risks and harms occurred to clinicians/scientists who reported hematology-associated ADRS.

Methods: Quotes were abstracted from media coverage or Health Authority hearings for individual hematology drugs.

Results : Risks and harms were reported in regulatory agency or government agency meetings by eight clinician/scientists physicians who led phase-3 pharmaceutical-sponsored clinical trials (Olivieri N (U Toronto, NEJM 1996, Singh G, Stanford, unpublished 2004), Buse J (U of North Carolina, unpublished 1999, Henke M (Abteilung Universitatsklinik, Lancet 2003, Mangano D (UCSF, NEJM 2005), Topol E and Nissen S (Cleveland Clinic JAMA 2004), meta-analyses (n = 2) (Bennett C (Northwestern, JAMA 2008, Mangano D (UCSF, NEJM 2006); database analyses (n = 1) (Mangano D (UCSF, NEJM 2004), case-control studies (n = 1) (Brass L, Yale, NEJM 2005) and an independent safety review (n = 1) (Solomon S, Harvard, JAMA 2005) including lawsuits, loss of job, public harassment and loss of grants. Three physicians lost academic positions (Topol, Olivieri, Mangano), two physicians lost federal grants (Olivieri, Bennett), and one FDA scientist (Graham) was demoted. ADR findings resulted in drug removal (n = 7; Vioxx, Avandia, Bextra, Celebrex, Trasylol, Phenyl propanolamine, Hydroxy-ethyl starch), revised indications (n = 2) (Procrit, Aranesp 2007, 2008, 2010)) or 10-year delay in FDA-approval (n = 1) (Fereprox). Median time from FDA approval to ADR identification was 8 years (Range, 4 years (Bextra) to 62 years PPA)). Numbers of persons reportedly seriously injured or dying from 1 ADR was 10,00 (Procrit)- 270,000 (Vioxx) (median 120,000). Manufacturer allegations that resulted in pharmaceutical companies actions included violation of secrecy agreement (n = 2) (Fererpox, PPAs) and public reporting of proprietary data (n = 11). Pharmaceutical companies paid $600,000 (Fereprox) to $5.8 billion (Vioxx) in fines and settlements.

Discussion: Twelve physicians experienced severe threats and/or harms after reporting hematologic-associated ADRs to Health Authorities and/or in major publications. We suggest physicians not sign secrecy agreements that might jeopardize public safety (as currently established by almost all US medical universities) and should partner with independent drug safety monitoring boards (DSMBs) on ADR evaluations to monitor safety concerns of drugs and medical devices.
Correlations between Lesion Avidity, Immune Effector Cell-Associated Neurotoxicity Syndrome Scoring, and Fracture Risk in Patients with Multiple Myeloma Undergoing Chimeric Antigen Receptor T-Cell Therapy
Authors: Clampitt Bryan , Huynh Thien Huong , Chose Chloe Min , Nester Mathew Daniel , Kuruvilla Davis , Joyce David , Binitie Odion , Freeman Ciara Louise , Lazarides Alexander
Published: December 2024

Background :

Patients with refractory multiple myeloma (MM) may be eligible for chimeric antigen receptor T-cell (CAR-T) therapy. Such patients are monitored for treatment toxicities, commonly cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Patients' skeletal disease may also be characterized by lesion avidity and categorized by fracture risk. The purpose of the present study is to evaluate the associations between treatment toxicity, fracture, and pre-CAR-T lesion avidity in MM patients.

Methods :

A prospective, consecutive cohort of (MM) patients undergoing treatment with CAR-T therapy were reviewed retrospectively. The primary outcome measure was fracture risk as characterized by a modified Mirel's criteria. The secondary outcome measure was change in lesion avidity, measured as standardized uptake value (SUV) units, on PET-CT. Correlations were performed using Pearson and Spearman correlations.

Results :

We identified 139 patients who underwent CAR-T for multiple myeloma. The mean age was 64.4 years with 58 female patients (41.7%). There was a negative correlation between ICANS Toxicity Grade and days survived (rs=-0.322, p<0.02) and positive correlation with the lesion SUV measurements prior to CAR-T (rs=0.375, p<0.01). No significant correlations were found with CRS. The SUV of lesions prior to CAR-T had positive correlations with pre-CAR-T Mirel's criteria of size (rs=0.196, p<0.035), nature(rs=0.362, p<0.000), pain(rs=0.303, p<0.001), and overall score (rs=0.327, p<0.000) of the lesions. There were positive correlations between fracture occurrence with pre-CAR-T Mirel's criteria of size (rs=0.362, p<0.000), nature (rs=0.219, p<0.012), pain(rs=0.393, p<0.000), and overall score(rs=0.394, p<0.000) of the lesions. Pre-CAR-T SUV values were positively correlated with fracture occurrence (rp=0.205, p<0.025)

Conclusions:

Our findings suggest that SUV measurements may have some association with fractures and ICANS grade in MM patients undergoing CAR-T. While SUV may correlate with Mirel's criteria, it is not as strongly correlated with fractures.