Immune-Related Adverse Events Due to Cancer Immunotherapy: Immune Mechanisms and Clinical Manifestations.

The landscape of cancer treatment has undergone a significant transformation with the introduction of Immune Checkpoint Inhibitors (ICIs). Patients undergoing these treatments often report prolonged clinical and radiological responses, albeit with a potential risk of developing immune-related adverse events (irAEs). Here, we reviewed and discussed the mechanisms of action of ICIs and their pivotal role in regulating the immune system to enhance the anti-tumor immune response. We scrutinized the intricate pathogenic mechanisms responsible for irAEs, arising from the evasion of self-tolerance checkpoints due to drug-induced immune modulation. We also summarized the main clinical manifestations due to irAEs categorized by organ types, detailing their incidence and associated risk factors. The occurrence of irAEs is more frequent when ICIs are combined; with neurological, cardiovascular, hematological, and rheumatic irAEs more commonly linked to PD1/PD-L1 inhibitors and cutaneous and gastrointestinal irAEs more prevalent with CTLA4 inhibitors. Due to the often-nonspecific signs and symptoms, the diagnosis of irAEs (especially for those rare ones) can be challenging. The differential with primary autoimmune disorders becomes sometimes intricate, given the clinical and pathophysiological similarities. In conclusion, considering the escalating use of ICIs, this area of research necessitates additional clinical studies and practical insights, especially the development of biomarkers for predicting immune toxicities. In addition, there is a need for heightened education for both clinicians and patients to enhance understanding and awareness.

Immune escape of multiple myeloma cells results from low miR29b and the ensuing epigenetic silencing of proteasome genes.

BACKGROUND: Activation of CD28 on multiple myeloma (MM) plasma cells, by binding to CD80 and CD86 on dendritic cells, decreases proteasome subunit expression in the tumor cells and thereby helps them evade being killed by CD8+ T cells. Understanding how CD28 activation leads to proteasome subunit downregulation is needed to design new MM therapies. METHODS: This study investigates the molecular pathway downstream of CD28 activation, using an in vitro model consisting of myeloma cell lines stimulated with anti-CD28-coated beads. RESULTS: We show that CD28 engagement on U266 and RPMI 8226 cells activates the PI3K/AKT pathway, reduces miR29b expression, increases the expression of DNA methyltransferase 3B (DNMT3B, a target of miR29b), and decreases immunoproteasome subunit expression. In vitro transfection of U266 and RPMI 8226 cells with a miR29b mimic downregulates the PI3K/AKT pathway and DNMT3B expression, restores proteasome subunit levels, and promotes myeloma cell killing by bone marrow CD8+ T cells from MM patients. Freshly purified bone marrow plasma cells (CD138+) from MM patients have lower miR29b and higher DNMT3B (mRNA and protein) than do cells from patients with monoclonal gammopathy of undetermined significance. Finally, in MM patients, high DNMT3B levels associate with shorter overall survival. CONCLUSIONS: Altogether, this study describes a novel molecular pathway in MM. This pathway starts from CD28 expressed on tumor plasma cells and, through the PI3K-miR29b-DNMT3B axis, leads to epigenetic silencing of immunoproteasome subunits, allowing MM plasma cells to elude immunosurveillance. This discovery has implications for the design of innovative miR29b-based therapies for MM.

Endothelial cells in tumor microenvironment: insights and perspectives.

The tumor microenvironment is a highly complex and dynamic mixture of cell types, including tumor, immune and endothelial cells (ECs), soluble factors (cytokines, chemokines, and growth factors), blood vessels and extracellular matrix. Within this complex network, ECs are not only relevant for controlling blood fluidity and permeability, and orchestrating tumor angiogenesis but also for regulating the antitumor immune response. Lining the luminal side of vessels, ECs check the passage of molecules into the tumor compartment, regulate cellular transmigration, and interact with both circulating pathogens and innate and adaptive immune cells. Thus, they represent a first-line defense system that participates in immune responses. Tumor-associated ECs are involved in T cell priming, activation, and proliferation by acting as semi-professional antigen presenting cells. Thus, targeting ECs may assist in improving antitumor immune cell functions. Moreover, tumor-associated ECs contribute to the development at the tumor site of tertiary lymphoid structures, which have recently been associated with enhanced response to immune checkpoint inhibitors (ICI). When compared to normal ECs, tumor-associated ECs are abnormal in terms of phenotype, genetic expression profile, and functions. They are characterized by high proliferative potential and the ability to activate immunosuppressive mechanisms that support tumor progression and metastatic dissemination. A complete phenotypic and functional characterization of tumor-associated ECs could be helpful to clarify their complex role within the tumor microenvironment and to identify EC specific drug targets to improve cancer therapy. The emerging therapeutic strategies based on the combination of anti-angiogenic treatments with immunotherapy strategies, including ICI, CAR T cells and bispecific antibodies aim to impact both ECs and immune cells to block angiogenesis and at the same time to increase recruitment and activation of effector cells within the tumor.

Classic pyoderma gangrenosum.

Pyoderma gangrenosum is a rare inflammatory ulcerative skin disease of unknown etiology. We report an image of a patient with pyoderma gangrenosum who presented right leg ulcers with violaceous margins, histologically characterized by mono- and polynuclear cell infiltrates. The patient was successfully treated with cyclosporin A.

Deciphering the immune landscape of head and neck squamous cell carcinoma: A single-cell transcriptomic analysis of regulatory T cell responses to PD-1 blockade therapy.

Immunotherapy is changing the Head and Neck Squamous Cell Carcinoma (HNSCC) landscape and improving outcomes for patients with recurrent or metastatic HNSCC. A deeper understanding of the tumor microenvironment (TME) is required in light of the limitations of patients' responses to immunotherapy. Here, we aimed to examine how Nivolumab affects infiltrating Tregs in the HNSCC TME. We used single-cell RNA sequencing data from eight tissues isolated from four HNSCC donors before and after Nivolumab treatment. Interestingly, the study found that Treg counts and suppressive activity increased following Nivolumab therapy. We also discovered that changes in the CD44-SSP1 axis, NKG2C/D-HLA-E axis, and KRAS signaling may have contributed to the increase in Treg numbers. Furthermore, our study suggests that decreasing the activity of the KRAS and Notch signaling pathways, and increasing FOXP3, CTLA-4, LAG-3, and GZMA expression, may be mechanisms that enhance the killing and suppressive capacity of Tregs. Additionally, the result of pseudo-temporal analysis of the HNSCC TME indicated that after Nivolumab therapy, the expression of certain inhibitory immune checkpoints including TIGIT, ENTPD1, and CD276 and LY9, were decreased in Tregs, while LAG-3 showed an increased expression level. The study also found that Tregs had a dense communication network with cluster two, and that certain ligand-receptor pairs, including SPP1/CD44, HLA-E/KLRC2, HLA-E/KLRK1, ANXA1/FPR3, and CXCL9/FCGR2A, had notable changes after the therapy. These changes in gene expression and cell interactions may have implications for the role of Tregs in the TME and in response to Nivolumab therapy.

Cutaneous polyarteritis nodosa and pulmonary arterial hypertension: An unexpected liaison. A case report.

BACKGROUND: Cutaneous polyarteritis nodosa (cPAN) is a form of medium-sized vessel necrotizing vasculitis. It is a rare, skin-limited variant of polyarteritis nodosa, characterized by dermal and subcutaneous tissue involvement. The most common findings in cPAN include digital gangrene, livedo reticularis, and tender subcutaneous nodules. However, while limited to the skin, cPAN results in significant morbidity and mortality due to the accompanying skin ischemia and necrosis, such that patients are vulnerable to superinfection. Here, we describe a unique presentation of cPAN associated with pulmonary arterial hypertension (PAH). METHODS: A 78-year-old female presented with digital ischemia and leg ulcers associated with PAH. Skin biopsy showed necrotizing fibrinoid necrosis of the small- and middle-sized vessels of the dermis. A diagnosis of cPAN and PAH was made. The patient was treated with glucocorticoids, vasodilators, and cyclophosphamide. RESULTS: She died due to severe sepsis complications. CONCLUSION: To date, this is the first case report describing the association between cPAN and PAH. In this case, PAH is a complication of the cutaneous vasculitides suggesting that vasculopathy could play a role in the pathophysiology of PAH. However, the underlying pathophysiological mechanisms still have to be firmly established.

Corrigendum: Cancer survivorship at heart: a multidisciplinary cardio-oncology roadmap for healthcare professionals.

[This corrects the article DOI: 10.3389/fcvm.2023.1223660.].

Cancer survivorship at heart: a multidisciplinary cardio-oncology roadmap for healthcare professionals.

In cancer, a patient is considered a survivor from the time of initial diagnosis until the end of life. With improvements in early diagnosis and treatment, the number of cancer survivors (CS) has grown considerably and includes: (1) Patients cured and free from cancer who may be at risk of late-onset cancer therapy-related cardiovascular toxicity (CTR-CVT); (2) Patients with long-term control of not-curable cancers in whom CTR-CVT may need to be addressed. This paper highlights the importance of the cancer care continuum, of a patient-centered approach and of a prevention-oriented policy. The ultimate goal is a personalized care of CS, achievable only through a multidisciplinary-guided survivorship care plan, one that replaces the fragmented management of current healthcare systems. Collaboration between oncologists and cardiologists is the pillar of a framework in which primary care providers and other specialists must be engaged and in which familial, social and environmental factors are also taken into account.

Lenalidomide arrests cell cycle and modulates PD1-dependent downstream mTOR intracellular signals in melanoma cells.

Despite numerous efforts to define the best therapeutic strategies in advanced melanoma, the response of many patients remains heterogeneous and of short duration. Lenalidomide, an immunomodulating drug, has shown anti-inflammatory, antiangiogenic and anticancer properties in haematological disorders; however, few preclinical data support the rationale for using this drug in melanoma patients. In this study, we investigate lenalidomide's potential role in melanoma by focusing on the in-vitro drug's antiproliferative activity. The antiproliferative action of lenalidomide was evaluated on two melanoma cell lines by MTT assay, cell cycle and apoptosis assay. P21 protein levels were evaluated with droplet digital PCR (ddPCR) and western blot analysis while his interaction with specific cyclin-dependent kinase (CDK) was assessed by immunoprecipitation test. The biological effect and molecular mechanisms of programmed cell death-1 (PD-1) in the regulation of proliferation were evaluated using ddPCR, flow cytometry, western blot and small interfering RNA transfection. We observed that lenalidomide exerts a cytostatic effect in melanoma cell lines by inducing cell cycle arrest in the G0-G1 phase through p21 upregulation and modulation of CDK complexes. Furthermore, we found that lenalidomide has an antiproliferative action through the downregulation of melanoma-PD1 expression and consequently the alteration of intracellular signaling of mammalian target of rapamycin/S6. The present study aims to provide new insights into the role of lenalidomide in melanoma and suggesting to potentially translating these findings into a clinical setting to use immunomodulatory derivatives for blocking the pro-tumorigenic activity of the melanoma through the PD-1/PD-L1 axis.

Non-Classical HLA Class 1b and Hepatocellular Carcinoma.

A number of studies are underway to gain a better understanding of the role of immunity in the pathogenesis of hepatocellular carcinoma and to identify subgroups of individuals who may benefit the most from systemic therapy according to the etiology of their tumor. Human leukocyte antigens play a key role in antigen presentation to T cells. This is fundamental to the host's defense against pathogens and tumor cells. In addition, HLA-specific interactions with innate lymphoid cell receptors, such those present on natural killer cells and innate lymphoid cell type 2, have been shown to be important activators of immune function in the context of several liver diseases. More recent studies have highlighted the key role of members of the non-classical HLA-Ib and the transcript adjacent to the HLA-F locus, FAT10, in hepatocarcinoma. The present review analyzes the major contribution of these molecules to hepatic viral infection and hepatocellular prognosis. Particular attention has been paid to the association of natural killer and Vδ2 T-cell activation, mediated by specific HLA class Ib molecules, with risk assessment and novel treatment strategies to improve immunotherapy in HCC.

Single-cell RNA sequencing uncovers heterogeneous transcriptional signatures in tumor-infiltrated dendritic cells in prostate cancer.

Prostate cancer (PCa) is one of the two solid malignancies in which a higher T cell infiltration in the tumor microenvironment (TME) corresponds with a worse prognosis for the tumor. The inability of T cells to eliminate tumor cells despite an increase in their number reinforces the possibility of impaired antigen presentation. In this study, we investigated the TME at single-cell resolution to understand the molecular function and communication of dendritic cells (DCs) (as professional antigen-presenting cells). According to our data, tumor cells stimulate the migration of immature DCs to the tumor site by inducing inflammatory chemokines. Many signaling pathways such as TNF-α/NF-κB, IL2/STAT5, and E2F up-regulated after DCs enter the tumor location. In addition, some molecules such as GPR34 and SLCO2B1 decreased on the surface of DCs. The analysis of molecular and signaling alterations in DCs revealed some suppression mechanisms of tumors, such as removing mature DCs, reducing the DC's survival, inducing anergy or exhaustion in the effector T cells, and enhancing the differentiation of T cells to Th2 and Tregs. In addition, we investigated the cellular and molecular communication between DCs and macrophages in the tumor site and found three molecular pairs including CCR5/CCL5, CD52/SIGLEC10, and HLA-DPB1/TNFSF13B. These molecular pairs are involved in the migration of immature DCs to the TME and disrupt the antigen-presenting function of DCs. Furthermore, we presented new therapeutic targets by the construction of a gene co-expression network. These data increase our knowledge of the heterogeneity and the role of DCs in PCa TME.

Unraveling the Role of Peroxisome Proliferator-Activated Receptor ß/Δ (PPAR ß/Δ) in Angiogenesis Associated with Multiple Myeloma.

Growing evidence suggests a role for peroxisome proliferator-activated receptor ß/δ (PPAR ß/δ) in the angiogenesis, growth, and metastasis of solid tumors, but little is known about its role in multiple myeloma (MM). Angiogenesis in the bone marrow (BM) is characteristic of disease transition from monoclonal gammopathy of undetermined significance (MGUS) to MM. We examined the expression and function of PPAR ß/δ in endothelial cells (EC) from the BM of MGUS (MGEC) and MM (MMEC) patients and showed that PPAR ß/δ was expressed at higher levels in MMEC than in MGEC and that the overexpression depended on myeloma plasma cells. The interaction between myeloma plasma cells and MMEC promoted the release of the PPAR ß/δ ligand prostaglandin I2 (PGI2) by MMEC, leading to the activation of PPAR ß/δ. We also demonstrated that PPAR ß/δ was a strong stimulator of angiogenesis in vitro and that PPAR ß/δ inhibition by a specific antagonist greatly impaired the angiogenic functions of MMEC. These findings define PGI2-PPAR ß/δ signaling in EC as a potential target of anti-angiogenic therapy. They also sustain the use of PPAR ß/δ inhibitors in association with conventional drugs as a new therapeutic approach in MM.

Cardiotoxicity Induced by Immune Checkpoint Inhibitors: What a Cardio-Oncology Team Should Know and Do.

Immune checkpoint inhibitors (ICIs) have revolutionized the therapeutic scenario for several malignancies. However, they can be responsible for immune-related adverse events (irAEs), involving several organs, with a pooled incidence ranging between 54% and 76%. The frequency of cardiovascular system involvement is <1%. Among the cardiovascular irAEs, myocarditis is the most common and the most dangerous but other, less common manifestations of ICI-related cardiotoxicity include pericardial disease, arrhythmias, Takotsubo-like syndrome, and acute myocardial infarction, all of which remain poorly explored. Both oncologists and cardiologists, as well as the patients, should be aware of the possible occurrence of one or more of these complications, which in some cases are fatal, in order to implement effective strategies of cardiac surveillance. In this review, we summarize the latest studies and recommendations on the pathogenesis, clinical manifestation, diagnosis, and management of ICI-related cardiotoxicity in order to realize a complete and updated overview on the main aspects of ICI-related cardiotoxicity, from surveillance to diagnosis to management, useful for both oncologists and cardiologists in their clinical practice. In particular, in the first part of the review, we realize a description of the pathogenetic mechanisms and risk factors of the main cardiovascular irAEs. Then, we focus on the management of ICI-related cardiotoxicity by analyzing five main points: (1) identifying and evaluating the type and severity of the cardiotoxicity; (2) deciding whether to withhold ICI therapy; (3) initiating steroid and immunosuppressive therapy; (4) starting conventional cardiac treatment; and (5) restarting ICI therapy. Finally, we discuss the existing evidence on surveillance for ICI-related cardiotoxicity and propose a surveillance strategy for both short- and long-term cardiotoxicity, according to the most recent guidelines.

Drug resistance in multiple myeloma: Soldiers and weapons in the bone marrow niche.

Multiple myeloma (MM) is still an incurable disease, despite considerable improvements in treatment strategies, as resistance to most currently available agents is not uncommon. In this study, data on drug resistance in MM were analyzed and led to the following conclusions: resistance occurs via intrinsic and extrinsic mechanisms, including intraclonal heterogeneity, drug efflux pumps, alterations of drug targets, the inhibition of apoptosis, increased DNA repair and interactions with the bone marrow (BM) microenvironment, cell adhesion, and the release of soluble factors. Since MM involves the BM, interactions in the MM-BM microenvironment were examined as well, with a focus on the cross-talk between BM stromal cells (BMSCs), adipocytes, osteoclasts, osteoblasts, endothelial cells, and immune cells. Given the complex mechanisms that drive MM, next-generation treatment strategies that avoid drug resistance must target both the neoplastic clone and its non-malignant environment. Possible approaches based on recent evidence include: (i) proteasome and histone deacetylases inhibitors that not only target MM but also act on BMSCs and osteoclasts; (ii) novel peptide drug conjugates that target both the MM malignant clone and angiogenesis to unleash an effective anti-MM immune response. Finally, the role of cancer stem cells in MM is unknown but given their roles in the development of solid and hematological malignancies, cancer relapse, and drug resistance, their identification and description are of paramount importance for MM management.

The worldwide impact of COVID-19 on cancer care: A meta-analysis of surveys published after the first wave of the pandemic.

Background: The rapid and global spread of COVID-19 posed a massive challenge to healthcare systems, which came across the need to provide high-intensity assistance to thousands of patients suffering from SARS-CoV-2 infection while assuring continuous care for all other diseases. This has been of particular importance in the oncology field. This study explores how oncology centers responded to the pandemic at a single center level by assessing surveys addressing different aspects of cancer care after the pandemic outbreak. Methods: We performed a systematic review and meta-analysis of the cancer care surveys published until December 11th, 2020. Data were analyzed according to three main areas of interest, namely health care organization, including cancellation/delay and/or modification of scheduled treatments, cancellation/delay of outpatient visits, and reduction of overall cancer care activities; routine use of preventive measures, such as personal protective equipment (PPE) by both patients and health care workers, and systematic SARS-CoV-2 screening by nasopharyngeal swabs; and implementation of telemedicine through remote consultations. Findings: Fifty surveys reporting data on 9150 providers from 121 countries on 5 continents were included. Cancellation/delay of treatment occurred in 58% of centers; delay of outpatient visits in 75%; changes in treatment plans in 65%; and a general reduction in clinical activity in 58%. Routine use of PPE by patients and healthcare personnel was reported by 81% and 80% of centers, respectively; systematic SARS-CoV-2 screening by nasopharyngeal swabs was reported by only 41% of centers. Virtual visits were implemented by the majority (72%) of centers. Interpretation: These results describe the negative impact of COVID-19 on cancer care, the rapid response of cancer centers in terms of preventive measures and alternative treatment approaches such as telemedicine, and confirm that surveys can provide the valuable, low-cost and immediate information that critical situations require.

Hepatocellular Carcinoma Intrinsic Cell Death Regulates Immune Response and Prognosis.

Ablative and locoregional treatment options, such as radiofrequency, ethanol injection, microwave, and cryoablation, as well as irreversible electroporation, are effective therapies for early-stage hepatocellular carcinoma (HCC). Hepatocyte death caused by ablative procedures is known to increase the release of tumor-associated antigen, thus enhancing tumor immunogenicity. In addition, the heat ablative resection induces pyroptotic cell death accompanied by the release of several inflammatory factors and immune-related proteins, including damage-associated molecular patterns (DAMPs), heat shock proteins (HSPs), ficolin 3, ATP, and DNA/RNA, which potentiate the antitumoral immune response. Surgical approaches that enhance tumor necrosis and reduce hypoxia in the residual liver parenchyma have been shown to increase the disease-free survival rate by reducing the host's immunosuppressive response. Scalpel devices and targeted surgical approach combined with immune-modulating drugs are an interesting and promising area to maximize therapeutic outcomes after HCC ablation.

Tumor necrosis factor­α in systemic lupus erythematosus: Structure, function and therapeutic implications (Review).

Tumor necrosis factor­α (TNF­α) is a pleiotropic pro­inflammatory cytokine that contributes to the pathophysiology of several autoimmune diseases, such as multiple sclerosis, inflammatory bowel disease, rheumatoid arthritis, psoriatic arthritis and systemic lupus erythematosus (SLE). The specific role of TNF­α in autoimmunity is not yet fully understood however, partially, in a complex disease such as SLE. Through the engagement of the TNF receptor 1 (TNFR1) and TNF receptor 2 (TNFR2), both the two variants, soluble and transmembrane TNF­α, can exert multiple biological effects according to different settings. They can either function as immune regulators, impacting B­, T­ and dendritic cell activity, modulating the autoimmune response, or as pro­inflammatory mediators, regulating the induction and maintenance of inflammatory processes in SLE. The present study reviews the dual role of TNF­α, focusing on the different effects that TNF­α may have on the pathogenesis of SLE. In addition, the efficacy and safety of anti­TNF­α therapies in preclinical and clinical trials SLE are discussed.

Second-line treatments for Advanced Hepatocellular Carcinoma: A Systematic Review and Bayesian Network Meta-analysis.

BACKGROUND & AIMS: A plethora of second-line therapies have been recently introduced for hepatocellular carcinoma (HCC) treatment with promising results. A meta-analysis of second-line treatments for HCC has been performed to better tailor their use based on improved patient stratification and to identify the best available option. METHODS: Pubmed, Scopus, Web of Science, and ClinicalTrials.gov were searched for randomized controlled trials evaluating second-line treatment for advanced HCC in patients already treated with sorafenib. The primary outcome was overall survival (OS). Secondary outcomes were progression-free survival (PFS) and drug withdrawal due to adverse events. Network meta-analyses were performed considering placebo as the basis for comparison in efficacy and safety analyses. Subgroup stratification considered gender, age, sorafenib-responsiveness and drug tolerability, viral infection, macrovascular invasion, HCC extrahepatic spread, performance status, and alpha-fetoprotein levels. RESULTS: Fourteen phase II or III randomized controlled trials, involving 5,488 patients and 12 regimens, were included in the analysis. Regorafenib (hazard ratio (HR) = 0.63, 95% confidence interval (CI) = 0.50-0.79), cabozantinib (HR = 0.76, 95% CI = 0.63-0.92), and ramucirumab (HR = 0.82, 95% CI = 0.70-0.76) significantly prolonged OS compared with placebo. Cabozantinib (HR = 0.44, 95% CI = 0.36-0.52), regorafenib (HR = 0.46, 95% CI = 0.37-0.56), ramucirumab (HR = 0.54, 95% CI = 0.43-0.68), brivanib (HR = 0.56, 95% CI = 0.42-0.76), S-1 (HR = 0.60, 95% CI = 0.46-0.77), axitinib (HR = 0.62, 95% CI = 0.44-0.87), and pembrolizumab (HR = 0.72, 95% CI = 0.57-0.90) significantly improved PFS compared with placebo. None of the compared drugs deemed undoubtedly superior after having performed a patients' stratification. CONCLUSIONS: The results of this network meta-analysis suggest the use of regorafenib and cabozantinib as second-line treatments in HCC.

Exploiting systems biology to investigate the gene modules and drugs in ovarian cancer: A hypothesis based on the weighted gene co-expression network analysis.

BACKGROUND: Ovarian cancer (OC) is one of the worrisome gynecological cancers worldwide. Given its considerable mortality rate, it is necessary to investigate its oncogenesis. METHODS: In this study, we used systems biology approaches to describe the key gene modules, hub genes, and regulatory drugs associated with serous OC as the novel biomarkers using weighted gene co-expression network analysis (WGCNA). FINDINGS: Our findings have demonstrated that the blue module genes (r = 0.8, p-value = 1e-16) are involved in OC progression. Based on gene enrichment analysis, the genes in this module are frequently involved in biological processes such as the Cyclic adenosine monophosphate (cAMP) signaling pathway and the cellular response to transforming growth factor-beta stimulation. The co-expression network has been built using the correlated module's top hub genes, which are ADORA1, ANO9, CD24P4, CLDN3, CLDN7, ELF3, KLHL14, PRSS8, RASAL1, RIPK4, SERINC2, and WNT7A. Finally, a drug-target network has been built to show the interaction of the FDA-approved drugs with hub genes. CONCLUSIONS: Our results have discovered that ADORA1, ANO9, SERINC2, and KLHL14 are hub genes associated with serous OC. These genes can be considered as novel candidate target genes for treating OC.

CT pulmonary angiography appropriateness in a single emergency department: does the use of revised Geneva score matter?

PURPOSE: To assess the percentage of computed tomography pulmonary angiography (CTPA) procedures that could have been avoided by methodical application of the Revised Geneva Score (RGS) coupled with age-adjusted D-dimer cut-offs rather than only clinical judgment in Emergency Department patients with suspected pulmonary embolism (PE). MATERIAL AND METHODS: Between November 2019 and May 2020, 437 patients with suspected PE based on symptoms and D-dimer test were included in this study. All patients underwent to CTPA. For each patient, we retrospectively calculated the age-adjusted D-dimer cut-offs and the RGS in the original version. Finally, CT images were retrospectively reviewed, and the presence of PE was recorded. RESULTS: In total, 43 (9.84%) CTPA could have been avoided by use of RGS coupled with age-adjusted D-dimer cut-offs. Prevalence of PE was 14.87%. From the analysis of 43 inappropriate CTPA, 24 (55.81%) of patients did not show any thoracic signs, two (4.65%) of patients had PE, and the remaining patients had alternative thoracic findings. CONCLUSION: The study showed good prevalence of PE diagnoses in our department using only physician assessment, although 9.84% CTPA could have been avoided by methodical application of RGS coupled with age-adjusted D-dimer cut-offs.