RESUMEN

The c-MPL-TPO axis regulates hematopoiesis by activating various signalling cascades, including JAK/STAT, MAPK/ERK, and PIK3/AKT. Here, we have summarized how TPO is regulated by c-MPL and, how mutations in the c-MPL regulate hematopoiesis. We also focus on its non-hematological regulatory role in diseases like Unstable Angina and pathways like DNA damage repair, skeletal homeostasis, & apoptotic regulation of neurons/HSCs at the embryonic state. We discuss the therapeutic efficiency of c-MPL and, its potential to be developed as a bio-marker for detecting metastasis and development of chemo-resistance in various cancers, justifying the multifaceted nature of c-MPL. We have also highlighted the importance of c-MPL isoforms and their stoichiometry in controlling the HSC quiescent and proliferative state. The regulation of the ratio of different isoforms through gene-therapy can open future therapeutic avenues. A systematic understanding of c-MPL-isoforms would undoubtedly take one step closer to facilitating c-MPL from basic-research towards translational medicine.

RESUMEN

Metal-phenolic Networks (MPNs) are a novel class of nanomaterial developed gradually in recent years which are self-assembled by metal ions and polyphenolic ligands. Due to their environmental protection, good adhesion, and biocompatibility with green phenolic ligands, MPNs can be used as a new type of nanomaterial. They show excellent properties such as anti-inflammatory, antioxidant, antibacterial, and anticancer, and have been widely studied in the biomedical field. As one of the most common subclasses of the MPNs family, copper-based MPNs have been widely studied for drug delivery, Photodynamic Therapy (PDT), Chemo dynamic Therapy (CDT), antibacterial and anti-inflammatory, bone tissue regeneration, skin regeneration wound repair, and metal ion imaging. In this paper, the preparation strategies of different types of copper-based MPNs are reviewed. Then, the application status of copper-based MPNs in the biomedical field under different polyphenol ligands is introduced in detail. Finally, the existing problems and challenges of copper-based MPNs are discussed, as well as their future application prospects in the biomedical field.

Asunto(s)

RESUMEN

Dysregulated JAK/STAT hyperactivity is essential to the pathogenesis of myelofibrosis, and JAK inhibitors are the first-line treatment option for many patients. There are four FDA-approved JAK inhibitors for patients with myelofibrosis. Single-agent JAK inhibition can improve splenomegaly, symptom burden, cytopenias, and possibly survival in patients with myelofibrosis. Despite their efficacy, JAK inhibitors produce variable or short-lived responses, in part due to the large network of cooperating signaling pathways and downstream targets of JAK/STAT, which mediates upfront or acquired resistance to JAK inhibitors. Synergistic inhibition of JAK/STAT accessory pathways can increase the rates and duration of response for patients with myelofibrosis. Two recently reported, placebo-controlled phase III trials of novel agents added to JAK inhibition met their primary endpoint, and additional late-stage studies are ongoing. This paper will review role of dysregulated JAK/STAT signaling, biological plausible additional therapeutic targets and the recent advancements in combination strategies with JAK inhibitors for myelofibrosis.

Asunto(s)

RESUMEN

OBJECTIVE: The aim of this study is to gain insight into the physical, psychological and social impact of having a myeloproliferative neoplasm (MPN), a rare type of cancer with an often chronic course. METHODS: An online survey was conducted among 455 Dutch MPN patients (62.7% female, age M 63) to explore the impact of the disease by measuring the MPN symptom burden (MPN-SAF TSS) and quality of life (QoL) (EORTC QLQ-C30) and its subscales within a hierarchical QoL model. We examined differences in MPN symptom burden and QoL in relation to sociodemographic and disease-related factors. Hierarchical regression analysis was used to explain variances in QoL. RESULTS: Most patients (97%) experienced MPN-related health complaints, with a significantly higher MPN symptom burden in women (M 31.50) compared to men (M 24.10). Regarding to fatigue and cognitive functioning MPN patients suffered more compared to a reference group of other cancers. MPN subtype or type of treatment did not show significant differences in MPN symptom burden or QoL. However, experiencing side effects, complications or comorbidities significantly negatively affected MPN symptom burden and QoL. 48.8% of patients reported that MPN affected their ability to work. The explained variance in overall QoL was 58%, most importantly by disease progression, comorbidities, MPN symptom burden and role, emotional and social functioning. CONCLUSION: This study revealed that having an MPN has a negative impact on several domains of QoL. Symptom assessment and support should be included in the healthcare management of MPN patients.

Asunto(s)

RESUMEN

The escalating prevalence of nanoplastics contamination in environmental ecosystems has emerged as a significant health hazard. Conventional analytical methods are suboptimal, hindered by their inefficiency in analyzing nanoplastics at low concentrations and their time-intensive processes. In this context, we have developed an innovative approach that employs luminescent metal-phenolic networks (L-MPNs) coupled with surface-enhanced Raman spectroscopy (SERS) to separate and label nanoplastics, enabling rapid, sensitive and quantitative detection. Our strategy utilizes L-MPNs composed of zirconium ions, tannic acid, and rhodamine B to uniformly label nanoplastics across a spectrum of sizes (50-500 nm) and types (e.g., polystyrene, polymethyl methacrylate, polylactic acid). Rhodamine B (RhB) functions as a Raman reporter within these L-MPNs-based SERS tags, providing the requisite sensitivity for trace measurement of nanoplastics. Moreover, the labeling with L-MPNs aids in the efficient separation of nanoplastics from liquid media. Utilizing a portable Raman instrument, our methodology offers cost-effective, swift, and field-deployable detection capabilities, with excellent sensitivity in nanoplastic analysis and a detection threshold as low as 0.1 µg/mL. Overall, this study proposes a highly promising strategy for the robust and sensitive analysis of a broad spectrum of particle analytes, underscored by the effective labeling performance of L-MPNs when coupled with SERS techniques.

RESUMEN

The limited osteointegration often leads to the failure of implant, which can be improved by fixing bioactive molecules onto the surface, such as arginyl-glycyl-aspartic acid (RGD): a cell adhesion motif. Metal-Phenolic Networks (MPNs) have garnered increasing attention from different disciplines in recent years due to their simple and rapid process for depositing on various substrates or particles with different shapes. However, the lack of cellular binding sites on MPNs greatly blocks its application in tissue engineering. In this study, we present a facile and efficient approach for producing PC/Fe@c(RGDfc) composite coatings through the conjugation of c(RGDfc) peptides onto the surface of PC/Fe-MPNs utilizing thiol-click reaction. By combined various techniques (ellipsometry, X-ray photoelectron spectroscopy, Liquid Chromatography-Mass Spectrometry, water contact angle, scanning electronic microscopy, atomic force microscopy) the physicochemical properties (composition, coating mechanism and process, modulus and hydrophilicity) of PC/Fe@c(RGDfc) surface were characterized in detail. In addition, the PC/Fe@c(RGDfc) coating exhibits the remarkable ability to positively modulate cellular attachment, proliferation, migration and promoted bone-implant integration in vivo, maintaining the inherent features of MPNs: anti-inflammatory, anti-oxidative properties, as well as multiple substrate deposition. This work contributes to engineering MPNs-based coatings with bioactive molecules by a facile and efficient thiol-click reaction, as an innovative perspective for future development of surface modification of implant materials.

RESUMEN

BACKGROUND: Calcium (Ca2+) signaling regulates various vital cellular functions, including integrin activation and cell migration. Store-operated calcium entry (SOCE) via calcium release-activated calcium (CRAC) channels represents a major pathway for Ca2+ influx from the extracellular space in multiple cell types. The impact of JAK2-V617F and CALR mutations which are disease initiating in myeloproliferative neoplasms (MPN) on SOCE, calcium flux from the endoplasmic reticulum (ER) to the cytosol, and related key signaling pathways in the presence or absence of erythropoietin (EPO) or thrombopoietin (TPO) is poorly understood. Thus, this study aimed to elucidate the effects of these mutations on the aforementioned calcium dynamics, in cellular models of MPN. METHODS: Intracellular Ca2+ levels were measured over a time frame of 0-1080 s in Fura-2 AM labeled myeloid progenitor 32D cells expressing various mutations (JAK2-WT/EpoR, JAK2-V617F/EpoR; CALR-WT/MPL, CALR-ins5/MPL, and del52/MPL). Basal Ca2+ concentrations were assessed from 0-108 s. Subsequently, cells were stimulated with EPO/TPO in Ca2+-free Ringer solution, measuring Ca2+ levels from 109-594 s (store depletion). Then, 2 mM of Ca2+ buffer resembling physiological concentrations was added to induce SOCE, and Ca2+ levels were measured from 595-1080 s. Fura-2 AM emission ratios (F340/380) were used to quantify the integrated Ca2+ signal. Statistical significance was assessed by unpaired Student's t-test or Mann-Whitney-U-test, one-way or two-way ANOVA followed by Tukey's multiple comparison test. RESULTS: Following EPO stimulation, the area under the curve (AUC) representing SOCE significantly increased in 32D-JAK2-V617F cells compared to JAK2-WT cells. In TPO-stimulated CALR cells, we observed elevated Ca2+ levels during store depletion and SOCE in CALR-WT cells compared to CALR-ins5 and del52 cells. Notably, upon stimulation, key components of the Ca2+ signaling pathways, including PLCγ-1 and IP3R, were differentially affected in these cell lines. Hyper-activated PLCγ-1 and IP3R were observed in JAK2-V617F but not in CALR mutated cells. Inhibition of calcium regulatory mechanisms suppressed cellular growth and induced apoptosis in JAK2-V617F cells. CONCLUSIONS: This report highlights the impact of JAK2 and CALR mutations on Ca2+ flux (store depletion and SOCE) in response to stimulation with EPO and TPO. The study shows that the JAK2-V617F mutation strongly alters the regulatory mechanism of EpoR/JAK2-dependent intracellular calcium balance, affecting baseline calcium levels, EPO-induced calcium entry, and PLCγ-1 signaling pathways. Our results reveal an important role of calcium flux in the homeostasis of JAK2-V617F positive cells.

Asunto(s)

RESUMEN

Interferon-based therapies, such as ropeginterferon alfa-2b have emerged as promising disease-modifying agents for myeloproliferative neoplasms (MPNs), including essential thrombocythemia (ET). Current ET treatments aim to normalize hematological parameters and reduce the thrombotic risk, but they do not modify the natural history of the disease and hence, have no impact on disease progression. Ropeginterferon alfa-2b (trade name BESREMi®), a novel, monopegylated interferon alfa-2b with an extended administration interval, has demonstrated a robust and sustained efficacy in polycythemia vera (PV) patients. Given the similarities in disease pathophysiology and treatment goals, ropeginterferon alfa-2b holds promise as a treatment option for ET. The ROP-ET trial is a prospective, multicenter, single-arm phase III study that includes patients with ET who are intolerant or resistant to, and/or are ineligible for current therapies, such as hydroxyurea (HU), anagrelide (ANA), busulfan (BUS) and pipobroman, leaving these patients with limited treatment options. The primary endpoint is a composite response of hematologic parameters and disease-related symptoms, according to modified European LeukemiaNet (ELN) criteria. Secondary endpoints include improvements in symptoms and quality of life, molecular response and the safety profile of ropeginterferon alfa-2b. Over a 3-year period the trial assesses longer term outcomes, particularly the effects on allele burden and clinical outcomes, such as disease-related symptoms, vascular events and disease progression. No prospective clinical trial data exist for ropeginterferon alfa-2b in the planned ET study population and this study will provide new findings that may contribute to advancing the treatment landscape for ET patients with limited alternatives. TRIAL REGISTRATION: EU Clinical Trials Register; EudraCT, 2023-505160-12-00; Registered on October 30, 2023.

Asunto(s)

RESUMEN

In response to the escalating issue of antibiotic-resistant bacteria adhering to and thriving on medical equipment, scientists are pioneering innovative "intelligent" materials and coatings. These advancements entail the targeted release of antimicrobial substances, specifically activated when bacteria are detected. The next section discusses three revolutionary substances: hydrogels, nanoparticles, and thin films. Furthermore, intelligent antibacterial materials are divided into 2 groups based on the triggering source: those that react to biological stimuli and those that react to non-biological ones, like temperature and electric cues associated with bacterial presence, such as pH shifts or bacterial enzyme discharge. Moreover, because of their simple construction technique, outstanding biocompatibility, and robust antibacterial characteristics derived from polyphenols and metal ions, metallic-polyphenolic nanoparticles (MPNs) have obtained substantial interest in tackling antimicrobial infections. This article presents an introduction to several MPN-centered biomaterials (like nanoparticles, coatings, capsules, and hydrogels) and highlights the latest advancements in research in its applications for addressing microbial threats in the field of biomedicine. Furthermore, the usage of smart materials is classified based on their application domains, encompassing medical implants, waste reduction, and nano-engineered systems.

RESUMEN

Surface-enhanced Raman scattering (SERS) technology has been widely recognized for its remarkable sensitivity in biochip development. This study presents a novel sandwich immunoassay that synergizes SERS with magnetoplasmonic nanoparticles (MPNs) to improve sensitivity. By taking advantage of the unique magnetism of these nanoparticles, we further enhance the detection sensitivity of SERS biochips through the applied magnetic field. Despite the high sensitivity, practical applications of SERS biochips are often limited by the issues of stability and reproducibility. In this study, we introduced a straightforward statistical method known as "Gaussian binning", which involves initially binning the two-dimensional Raman mapping data and subsequently applying Gaussian fitting. This approach enables a more consistent and reliable interpretation of data by reducing the variability inherent in Raman signal measurements. Based on our method, the biochip, targeting for C-reactive protein (CRP), achieves an impressive detection limit of 5.96 fg/mL, and with the application of a 3700 G magnetic field, it further enhances the detection limit by 5.7 times, reaching 1.05 fg/mL. Furthermore, this highly sensitive and magnetically tunable SERS biochip is easily designed for versatile adaptability, enabling the detection of other proteins. We believe that this innovation holds promise in enhancing the clinical applicability of SERS biochips.

Asunto(s)

RESUMEN

Philadelphia chromosome-negative chronic myeloproliferative neoplasms (MPNs) arise due to acquired somatic driver mutations in stem cells and develop over 10-30 years from the earliest cancer stages (essential thrombocythemia, polycythemia vera) towards the advanced myelofibrosis stage with bone marrow failure. The JAK2V617F mutation is the most prevalent driver mutation. Chronic inflammation is considered to be a major pathogenetic player, both as a trigger of MPN development and as a driver of disease progression. Chronic inflammation in MPNs is characterized by persistent connective tissue remodeling, which leads to organ dysfunction and ultimately, organ failure, due to excessive accumulation of extracellular matrix (ECM). Considering that MPNs are acquired clonal stem cell diseases developing in an inflammatory microenvironment in which the hematopoietic cell populations are progressively replaced by stromal proliferation-"a wound that never heals"-we herein aim to provide a comprehensive review of previous promising research in the field of circulating ECM fragments in the diagnosis, treatment and monitoring of MPNs. We address the rationales and highlight new perspectives for the use of circulating ECM protein fragments as biologically plausible, noninvasive disease markers in the management of MPNs.

RESUMEN

BACKGROUND: The Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) are associated with a huge comorbidity burden, including an increased risk of cardiovascular diseases. Recently, chronic inflammation has been suggested to be the driving force for clonal evolution and disease progression in MPN but also potentially having an impact upon the development of accelerated (premature) atherosclerosis. OBJECTIVES: Since chronic inflammation, atherosclerosis, and atherothrombosis are prevalent in MPNs and we have previously shown oxidative stress genes to be markedly upregulated in MPNs, we hypothesized that genes linked to development of atherosclerosis might be highly deregulated as well. METHODS: Using whole blood gene expression profiling in patients with essential thrombocythemia (ET; n = 19), polycythemia vera (PV; n = 41), or primary myelofibrosis (PMF; n = 9), we herein for the first time report aberrant expression of several atherosclerosis genes. RESULTS: Of 84 atherosclerosis genes, 45, 56, and 46 genes were deregulated in patients with ET, PV, or PMF, respectively. Furthermore, BCL2L1, MMP1, PDGFA, PTGS1, and THBS4 were progressively significantly upregulated and BCL2 progressively significantly downregulated from ET over PV to PMF (all FDR <0.05). CONCLUSIONS: We have for the first time shown massive deregulation of atherosclerosis genes in MPNs, likely reflecting the inflammatory state in MPNs in association with in vivo activation of leukocytes, platelets, and endothelial cells being deeply involved in the atherosclerotic process.

RESUMEN

Essential Thrombocythemia (ET) and Polycythemia Vera (PV) are chronic myeloproliferative neoplasms (MPNs) characterized by thrombotic and hemorrhagic complications, leading to a high risk of disability and mortality. Although arterial hypertension was found to be the most significant modifiable cardiovascular (CV) risk factor in the general population, little is known about its role in MPNs as well as a possible role of renin-angiotensin system inhibitors (RASi) in comparison with other anti-hypertensive treatments. We investigated a large cohort of 404 MPN adult patients, 133 diagnosed with PV and 271 with ET. Over half of the patients (53.7%) reported hypertension at MPN diagnosis. The 15-year cumulative incidence of thrombotic-adverse events (TAEs) was significantly higher in patients with hypertension (66.8 ± 10.3% vs 38.5 ± 8.4%; HR = 1.83; 95%CI 1.08-3.1). Multivariate analysis showed that PV diagnosis and hypertension were independently associated with a higher risk of developing TAEs (HR = 3.5; 95%CI 1.928-6.451, p < 0.001 and HR = 1.8; 95%CI 0.983-3.550, p = 0.05, respectively). In multivariate analysis, the diagnosis of PV confirmed a significant predictive role in developing TAEs (HR = 4.4; 95%CI 1.92-10.09, p < 0.01), also considering only MPN patients with hypertension. In addition, we found that the use of RASi showed a protective effect from TAEs both in the whole cohort of MPN with hypertension (HR = 0.46; 95%CI 0.21-0.98, p = 0.04) and in the subgroup of thrombotic high-risk score patients (HR = 0.49; 95%CI 0.24-1.01, p = 0.04). In particular, patients with ET and a high risk of thrombosis seem to benefit most from RASi treatment (HR = 0.27; 95%CI 0.07-1.01, p = 0.03). Hypertension in MPN patients represents a significant risk factor for TAEs and should be adequately treated.

Asunto(s)

RESUMEN

The Philadelphia-negative myeloproliferative neoplasms (MPNs), defined as clonal disorders of the hematopoietic stem cells, are characterized by the proliferation of mature myeloid cells in the bone marrow and a chronic inflammatory status impacting the initiation, progression, and symptomatology of the malignancies. There are three main entities defined as essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF), and genetically classified by JAK2V617F, CALR, or MPL mutations. In MPNs, due to the overproduction of inflammatory cytokines by the neoplastic cells and non-transformed immune cells, chronic inflammation may provoke the generation and expansion of myeloid-derived suppressors cells (MDSCs) that highly influence the adaptive immune response. Although peripheral blood MDSC levels are elevated, their frequency in the bone marrow of MPNs patients is not well elucidated yet. Our results indicated increased levels of total (T)-MDSCs (CD33+HLA-DR-/low) and polymorphonuclear (PMN)-MDSCs (CD33+/HLA-DRlow/CD15+/CD14-) in the bone marrow and peripheral blood of all three types of MPNs malignancies. However, these bone marrow MDSCs-increased frequencies did not correlate with the clinical parameters, such as hepatomegaly, leukocytes, hemoglobin, or platelet levels, or with JAK2 and CALR mutations. Besides, bone marrow MDSCs, from ET, PV, and PMF patients, exhibited immunosuppressive function, determined as T-cell proliferation inhibition. Notably, the highest T-MDSCs and PMN-MDSC levels were found in PMF samples, and the increased MDSCs frequency strongly correlated with the degree of myelofibrosis. Thus, these data together indicate that the immunosuppressive MDSCs population is increased in the bone marrow of MPNs patients and may be implicated in generating a fibrotic microenvironment.

Asunto(s)

RESUMEN

Development of myelofibrosis (MF) therapeutics has reached fruition as the transformative impact of JAK2 inhibitors in the MPN landscape is complemented/expanded by a profusion of novel monotherapies and rational combinations in the frontline and second line settings. Agents in advanced clinical development span various mechanisms of action (eg, epigenetic or apoptotic regulation), may address urgent unmet clinical needs (cytopenias), increase the depth/duration of spleen and symptom responses elicited by ruxolitinib, improve other aspects of the disease besides splenomegaly/constitutional symptoms (eg, resistance to ruxolitinib, bone marrow fibrosis or disease course), provide personalized strategies, and extend overall survival (OS). Ruxolitinib had a dramatic impact on the quality of life and OS of MF patients. Recently, pacritinib received regulatory approval for severely thrombocytopenic MF patients. Momelotinib is advantageously poised among JAK inhibitors given its differentiated mode of action (suppression of hepcidin expression). Momelotinib demonstrated significant improvements in anemia measures, spleen responses, and MF-associated symptoms in MF patients with anemia; and will likely receive regulatory approval in 2023. An array of other novel agents combined with ruxolitinib, such as pelabresib, navitoclax, parsaclisib, or as monotherapies (navtemadlin) are evaluated in pivotal phase 3 trials. Imetelstat (telomerase inhibitor) is currently evaluated in the second line setting; OS was set as the primary endpoint, marking an unprecedented goal in MF trials, wherein SVR35 and TSS50 at 24 weeks have been typical endpoints heretofore. Transfusion independence may be considered another clinically meaningful endpoint in MF trials given its correlation with OS. Overall, therapeutics are at the cusp of an exponential expansion and advancements that will likely lead to the golden era in treatment of MF.

Asunto(s)

RESUMEN

Polyphenols, commonly found in various plants, have attracted enormous attention due to their potential pharmacological activity, especially antitumor activity dependent on immune function. In recent years, the development of nanomedicine can counteract the low bioavailability of polyphenols and improve the effect of tumor treatment. Among them, metal-phenolic networks (MPNs), which utilize various metal ions and phenolic ligands for coordination binding, have now become candidates for polyphenol-based nanomedicine treatment of tumors. In this mini-review, we described the classification of polyphenols and their mechanisms in antitumor immune responses, and provided suggestions for the next steps of treating tumors with polyphenols.

Asunto(s)

RESUMEN

About 30 years ago, the first clinical trials of the safety and efficacy of recombinant interferon-α2 (rIFN-α2) were performed. Since then, several single-arm studies have shown rIFN-α2 to be a highly potent anticancer agent against several cancer types. Unfortunately, however, a high toxicity profile in early studies with rIFN-α2 -among other reasons likely due to the high dosages being used-disqualified rIFN-α2, which was accordingly replaced with competitive drugs that might at first glance look more attractive to clinicians. Later, pegylated IFN-α2a (Pegasys) and pegylated IFN-α2b (PegIntron) were introduced, which have since been reported to be better tolerated due to reduced toxicity. Today, treatment with rIFN-α2 is virtually outdated in non-hematological cancers, where other immunotherapies-e.g., immune-checkpoint inhibitors-are routinely used in several cancer types and are being intensively investigated in others, either as monotherapy or in combination with immunomodulatory agents, although only rarely in combination with rIFN-α2. Within the hematological malignancies, rIFN-α2 has been used off-label for decades in patients with Philadelphia-negative chronic myeloproliferative neoplasms (MPNs)-i.e., essential thrombocythemia, polycythemia vera, and myelofibrosis-and in recent years rIFN-α2 has been revived with the marketing of ropeginterferon-α2b (Besremi) for the treatment of polycythemia vera patients. Additionally, rIFN-α2 has been revived for the treatment of chronic myelogenous leukemia in combination with tyrosine kinase inhibitors. Another rIFN formulation-recombinant interferon-ß (rIFN-ß)-has been used for decades in the treatment of multiple sclerosis but has never been studied as a potential agent to be used in patients with MPNs, although several studies and reviews have repeatedly described rIFN-ß as an effective anticancer agent as well. In this paper, we describe the rationales and perspectives for launching studies on the safety and efficacy of rIFN-ß in patients with MPNs.

RESUMEN

Polycythemia vera (PV) is a myeloid stem cell disorder characterized by excess red cell mass. The two major complications of PV are thrombosis and bleeding. Atrial fibrillation is a potentially devastating condition that can complicate the course of PV. We describe a case of a 65-year-old woman with PV who presented with new-onset atrial fibrillation. The atrial fibrillation was aborted successfully, and the patient was started on oral anticoagulation with rivaroxaban. PV with atrial fibrillation poses a challenge in management due to the risk of thrombosis and bleeding. Despite the lack of standard recommendations or guidelines, this case highlights that oral anticoagulation therapy can be safe and convenient for such patients.

RESUMEN

Computed tomography (CT), an efficient radiological technology, is used to detect lung cancer in the clinic. Carcinoembryonic antigen (CEA), a common tumor biomarker, is applied in the detection of various tumors. To highlight the advantages of two-dimensional techniques and assist clinicians in optimizing lung cancer diagnostic schemes, we established a favorable model combining CT and CEA. In the study, univariate analysis was performed to screen independent predictors in a training cohort of 271 patients with malignant pulmonary nodules (MPNs) and 92 with benign pulmonary nodules (BPNs). Six machine learning-based models involving five CT predictors (mediastinal lymph node enlargement, lobulation, vascular notch sign, spiculation, and nodule number) and lnCEA were constructed and validated in an independent cohort of 129 participants (92 MPNs and 37 BPNs) by SPSS Modeler. A nomogram and the Delong test were generated by R software. Finally, the model established by logistic regression had highest diagnostic efficiency (area under the curve [AUC] = 0.912). Moreover, the diagnostic ability of the logistic model in the validation cohort (AUC = 0.882, 80.4% sensitivity, 75.7% specificity) was higher than that of the Peking University model (AUC = 0.712, 68.5% sensitivity, 70.3% specificity) and the Mayo model (AUC = 0.745, 62.0% sensitivity, 75.7% specificity). Interestingly, for the participants with intermediate (10-30 mm) and CEA-negative nodule, the model reached an AUC of 0.835 (72.3% sensitivity, 83.3% specificity). The AUC for the early lung cancer was as high as 0.822 with 67.3% sensitivity and 78.9% specificity. As a conclusion, this promising model presents a new diagnostic strategy for the clinic to distinguish MPNs from BPNs.

Asunto(s)

RESUMEN

Background: Philadelphia-negative myeloproliferative neoplasms (Ph-MPNs) are clonal hematopoietic cell malignancy that comprises polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). They prone to develop thrombosis, bleeding, fibrotic progression, and leukemic transformation. We aimed to study clinical characteristics, thrombosis complications, and prognostic risk in Indonesians with Ph-MPNs. Methods: This was a single-center retrospective cross-sectional study, including patients with Ph-MPNs who attended Hematology and Medical Oncology outpatient clinic at Cipto Mangunkusumo General Hospital, Jakarta, between 2016 and 2021. Demographic data, clinical characteristics, previous antiplatelet treatment, baseline laboratory data, JAK2V617F mutation, and treatment were reviewed for analysis. The prognostic risk model was assessed for PV (IPSS), ET (IPSET-thrombosis), and PMF (IPSS and DIPPS) patients. Results: One hundred forty-six patients were classified as PV (31.5%), ET (38.4%), and PMF (30.1%) with median ages of 54, 53.5, and 55 years, respectively. PMF presented with the most diverse clinical presentations. JAK2V617 mutations were detected in 82%, 42.5%, and 76.5% of PV, ET, and PMF patients. PV had the highest thrombosis event pre/at diagnosis (26.1%), with predominantly arterial thrombosis. Bleeding occurred more in PMF (20.5%). Phlebotomy and hydroxyurea are the only treatment available for Ph-MPNs in the government hospital in Indonesia. IPSS intermediate risk in PV (47.8%), IPSET-thrombosis low risk in ET (46.4%), and IPSS and DIPSS intermediate-2 in PMF (38.6% and 50% respectively) were the most common risk groups. Conclusion: Essential thrombocythemia was the most prevalent Ph-MPNs in Indonesia. Arterial thrombosis was the highest thrombosis event pre/at diagnosis in PV despite IPSET-thrombosis low risk being the most common risk group. In JAK2V617 mutation-positive MPN population, thrombosis event was also the highest in PV.