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1.
Molecular therapies for HCC: Looking outside the box.
Faivre, S, Rimassa, L, Finn, RS
Journal of hepatology. 2020;(2):342-352
Abstract
Over the past decade, sorafenib has been the only systemic agent with proven clinical efficacy for patients with unresectable hepatocellular carcinoma (HCC). Recently, lenvatinib was shown to be non-inferior to sorafenib, while regorafenib, cabozantinib, and ramucirumab were shown to be superior to placebo in patients failing sorafenib. In addition, trials of immune checkpoint inhibitors reported encouraging efficacy signals. However, apart from alpha-fetoprotein, which is used to select patients for ramucirumab, no biomarkers are available to identify patients that may respond to a specific treatment. Different synergisms have been postulated based on the potential interplay between antiangiogenic drugs and immunotherapy, with several clinical trials currently testing this hypothesis. Indeed, encouraging preliminary results of phase I studies of bevacizumab plus atezolizumab and lenvatinib plus pembrolizumab have led to the design of ongoing phase III trials, including both antiangiogenics and immune checkpoint inhibitors in the front-line setting. Other important phase II studies have tested molecular therapies directed against different novel targets, such as transforming growth factor-beta, MET (hepatocyte growth factor receptor), and fibroblast growth factor receptor 4. These studies integrated translational research with the aim of better defining the biological tumour profile and identifying tumour and blood biomarkers that select patients who may really benefit from a specific molecular therapy. Importantly, good safety profiles make these drugs suitable for future combinations. In this review, we discuss the most recent data on novel combination strategies and targets, as well as looking ahead to the future role of molecular therapies in the treatment of patients with advanced HCC.
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2.
PCSK9: from molecular biology to clinical applications.
Malo, J, Parajuli, A, Walker, SW
Annals of clinical biochemistry. 2020;(1):7-25
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3.
Clinical Management and Therapeutic Strategies for the Thyroid-Associated Ophthalmopathy: Current and Future Perspectives.
Mishra, S, Maurya, VK, Kumar, S, Ankita, , Kaur, A, Saxena, SK
Current eye research. 2020;(11):1325-1341
Abstract
PURPOSE TAO is an organ specific autoimmune disease associated with thyroid, and inflammation of the orbit and periorbital tissues, which is different from systemic autoimmune diseases such as SLE. However, Grave's disease is a kind of systemic autoimmune syndrome which might involve the thyroid, the eye ball and the anterior tibial tissue. Considering the inexplicable understanding of TAO pathogenesis, the disease worsens for the patients. Therefore, this manuscript provides insights into the recent advancements of clinical features, epidemiology, pathogenesis with gene-interactions, diagnosis, including available and novel treatment options for TAO, based on available data including RCTs, meta-analyses, and systematic reviews. METHODS Articles with clinical features, epidemiology, pathogenesis, diagnosis, and treatment of the disease were thoroughly studied. To perform the gene expression and pathway analysis, articles were searched on PubMed, MEDLINE Cochrane Library and ClinicalTrial.gov from 1982 to 2020. To predict novel TAO-specific therapeutic molecule, structure-based drug design (SBDD) was performed. RESULTS We observed gene expression and pathway analysis and SBDD approaches might bring new insights in the field of TAO pathogenesis, diagnosis, and treatment. A genome-wide map of human genetic interactions revealed involvement of crucial cell-signalling pathways, such as TNF-mediated signalling pathway, type-I interferon signalling pathway, toll-like receptor signalling pathway, transforming growth factor-beta receptor signalling pathway etc. Recently, FDA-approved teprotumumab a breakthrough, first drug for the treatment of active thyroid eye disease, which reduces proptosis and the need for orbital decompression surgery. Furthermore, our SBDD results revealed that cost-effective Curcumin, Withaferin A, Resveratrol, Scopolamine, Quercetin, and Berberine may have significant binding affinity for hyaluronan protein and may be exploited for therapeutic purposes in TAO. CONCLUSIONS Considering the increasing risk and nature of disease, novel drug therapies and markers for prognosis need to be investigated. Moreover, evidence-based non-invasive/minimal surgical therapies should be developed for the better management of the disease. ABBREVIATIONS ADIPOQ Adiponectin; CAS: Clinical Activity Score; CCL5: C-C Motif Chemokine Ligand 5; CT: Computed Tomography; DON: Dysthyroid Optic Neuropathy; EUGOGO European Group of Graves' Orbitopathy; FDA: U.S. Food and Drug Administration; FOS: Fos Proto-Oncogene, AP-1 Transcription Factor Subunit; HLA: Human Leukocyte Antigen; HLA-DRA: Major Histocompatibility Complex, Class II, DR Alpha; ICAM1: Intercellular Adhesion Molecule 1; IFNG Interferon Gamma; IGF-1: Insulin-like Growth Factor 1; IGF-1R: Insulin-like Growth Factor-1 Receptor; IL12B: Interleukin 12B; IL23R: Interleukin 23 Receptor; IL6: Interleukin 6; IOP: Intraocular Pressure; IRF1: Interferon Regulatory Factor 1; IRF5: Interferon Regulatory Factor 5; IRF7: Interferon Regulatory Factor 7; IRF9: Interferon Regulatory Factor 9; JUN: Jun Proto-Oncogene, AP-1 Transcription Factor Subunit; JUNB JunB Proto-Oncogene, AP-1 Transcription Factor Subunit; MHC: Major Histocompatibility Complex; MRI: Magnetic Resonance Imaging; NFKB1: Nuclear Factor Kappa B Subunit 1; NFKBIA Nuclear Factor Kappa B Inhibitor Alpha; OADSCs: Orbital Adipose Derived Stromal Cells; PDGFB Platelet Derived Growth Factor Subunit B; PPARG Peroxisome Proliferator Activated Receptor Gamma; RANTES Regulated on Activation Normal T cell Expressed and Secreted; RARA Retinoic Acid Receptor Alpha; RCTs (Randomized Controlled Trials; SLE: Systemic lupus erythematosus; SOCS3: Suppressor of Cytokine Signaling 3; STAT1: Signal Transducer and Activator of Transcription 1; TAO: Thyroid-Associated Ophthalmopathy; TED: Thyroid eye disease; TGFB1: Transforming Growth Factor Beta 1; TGFB2: Transforming Growth Factor Beta 2; TGF-β: Transforming Growth Factor-beta; TLR7: Toll like Receptor 7; TLR9: Toll like Receptor 9; TNFRSF18: Tumor Necrosis Factor Receptor Superfamily Member 18; TNFSF11: Tumor Necrosis Factor Receptor Superfamily Member 11; TNF-α: Tumor Necrosis Factor-alpha; TSHR Thyroid Stimulating Hormone Receptor; TSIs: Thyroid Stimulating Immunoglobulin; WNT5A: Wingless-Type MMTV Integration Site Family, Member 5A.
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4.
X-Linked Hypophosphataemic Rickets and Growth.
Santos Rodríguez, F
Advances in therapy. 2020;(Suppl 2):55-61
Abstract
X-linked hypophosphataemia (XLH) is the most prevalent form of hereditary rickets characterized by an alteration of phosphate metabolism which frequently leads to the appearance of fractures, bone deformities and growth delay. Although the mechanism of growth impairment in patients with XLH still needs to be clarified, it is known that this alteration is not due to genetic or endocrine factors. A potential explanation for the impairment of growth in this disease is the alteration of the growth plate, a structure responsible for longitudinal growth of bones. Some of the findings in the growth plate of patients with XLH include atypical organization of chondrocytes due to low rates of proliferation and apoptosis and disturbance of chondrocyte hypertrophy, overactivation of the mitogen-activated protein kinase (MAPK) signalling pathway and upregulation of phosphorylated extracellular signal-regulated kinase (pERK). Conventional treatment of XLH (consisting of oral phosphate supplements and active vitamin D analogues) is often insufficient for the longitudinal growth of bone, but other strategies based on recombinant growth hormone or therapies targeting fibroblast growth factor 23 (FGF23) or its receptor, such as burosumab, have shown promising results. This article briefly describes the relationship between XLH and growth retardation, and how to address this alteration in patients with XLH.
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5.
Coronavirus disease 2019 (COVID-19) in a patient with ankylosing spondylitis treated with secukinumab: a case-based review.
Coskun Benlidayi, I, Kurtaran, B, Tirasci, E, Guzel, R
Rheumatology international. 2020;(10):1707-1716
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Abstract
Severe acute respiratory syndrome coranovirus-2 (SARS-CoV-2) infection has become an important health-care issue worldwide. The coronavirus disease 2019 (COVID-19) has also raised concerns among patients with inflammatory rheumatic conditions and their treating physicians. There are emerging data regarding the potential risks of SARS-CoV-2 for this particular patient group. However, less is known with regard to the course of COVID-19 among patients receiving IL-17 inhibitors. The aim of the current article is to review the growing body of knowledge on the course/management of COVID-19 in patients with inflammatory rheumatic diseases by presenting a SARS-CoV-2 infected case with ankylosing spondylitis under secukinumab therapy. A 61-year old patient with ankylosing spondylitis who was on secukinumab therapy for 5 months admitted with newly onset fever and gastrointestinal complaints. After being hospitalized, she developed respiratory manifestations with focal pulmonary ground-glass opacities and multiple nodular densities in both lungs. The patient was tested positive for SARS-CoV-2 infection. Substantial clinical improvement was obtained following a management plan, which included tocilizumab, hydroxychloroquine, prednisolone and enoxaparin sodium. PubMed/MEDLINE and Scopus databases were searched by using relevant keywords and their combinations. The literature search revealed four articles reporting the clinical course of COVID-19 in seven rheumatic patients on secukinumab. The clinical course of SARS-CoV-2 infection was mild in most of these patients, while one of them experienced severe COVID-19. Interleukin-17 has been related to the hyperinflammatory state in COVID-19 and IL-17 inhibitors were presented as promising targets for the prevention of aberrant inflammation and acute respiratory distress in COVID-19. However, this hypothesis still remains to be proved. Further studies are warranted in order to test the benefits and risks of IL-inhibitors in SARS-CoV-2 infected individuals.
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Early-onset meningitis associated with atezolizumab treatment for non-small cell lung cancer: case report and literature review.
Ogawa, K, Kaneda, H, Kawamoto, T, Tani, Y, Izumi, M, Matsumoto, Y, Sawa, K, Suzumura, T, Watanabe, T, Mitsuoka, S, et al
Investigational new drugs. 2020;(6):1901-1905
Abstract
Immune checkpoint inhibitors (ICIs) have improved the overall survival of many patients with advanced cancers. However, unlike cytotoxic and targeted drugs, ICIs may cause various immune-related adverse events (irAEs). Among these irAEs, autoimmune meningitis is very rare. Here, we report a case of early-onset, atezolizumab-induced meningitis after administration of one dose of atezolizumab. A 56-year-old man with lung adenocarcinoma had received seventh-line treatment with atezolizumab when he experienced dysarthria. Blood examinations, including the measurement of electrolytes, glucose, and organ functions, were unremarkable, but enhanced head magnetic resonance imaging T1-weighted images showed meningeal enhancement. Although cerebral spinal fluid (CSF) examinations revealed elevated lymphocyte and protein levels, no cancer cells were detected in the CSF. CSF cultures and serological tests, including polymerase chain reaction for herpes simplex virus, were negative. The patient was therefore diagnosed with atezolizumab-triggered autoimmune meningitis. With steroid treatment, the patient's clinical and neurological state improved immediately and he recovered to baseline conditions. Prompt diagnosis and therapeutic intervention are essential for the effective treatment of autoimmune meningitis.
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Optimization of biologics to reduce treatment failure in inflammatory bowel diseases.
Bourchany, A, Gilletta De Saint-Joseph, C, Breton, A, Barreau, F, Mas, E
Current opinion in pharmacology. 2020;:51-58
Abstract
Moderate to severe inflammatory bowel disease patients can fail to respond to conventional therapy and/or to biologic treatment. In the era of TNFα antagonists and other non-anti-TNF biologic drugs, it is important to review the literature on biologic treatment failure, which could be defined as primary non-response, secondary loss of response and intolerance. Therapeutic drug monitoring (TDM), that is, drug trough level and antidrug antibodies, should enable to determine the mechanisms of treatment failure and to optimize drug efficacy. There is a consensus on reactive TDM at the time of loss of response. Proactive TDM could be of interest during induction and/or maintenance, but randomized controlled trials are required.
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8.
Predictive role of vitamin A serum concentration in psoriatic patients treated with IL-17 inhibitors to prevent skin and systemic fungal infections.
Campione, E, Cosio, T, Lanna, C, Mazzilli, S, Ventura, A, Dika, E, Gaziano, R, Dattola, A, Candi, E, Bianchi, L
Journal of pharmacological sciences. 2020;(1):52-56
Abstract
The use of biological drugs in psoriasis is replacing traditional therapies due to their specific mechanism and limited side effects. However, the use of Interleukin 17 inhibitors and the modification of its cytokine pathway could favor the risk of fungal infections. All-trans retinoic acid is an active metabolite of vitamin A with anti-inflammatory and immunoregulatory properties through its capacity to stimulate both innate and adaptive immunity and to its effects on proliferation, differentiation and apoptosis in a variety of immune cells. Furthermore, it has been recently discovered that All-trans retinoic acid has a direct fungistatic effect against Candida and Aspergillus Fumigatus. On the basis of these new insights, in the current review, we suggest that the evaluation of serum level of All-trans retinoic acid or vitamin A should be considered as a predictive marker for the development of fungal infections among psoriatic patients treated with Interleukin 17 inhibitors. In clinical practice, vitamin A test could be added in the routine hospital diagnostic management for a better selection of psoriatic patients eligible to Interleukin 17 inhibitors.
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9.
Bullous dermatoses secondary to anti-PD-L1 agents: a case report and review of the literature.
Kosche, C, Owen, JL, Sadowsky, LM, Choi, JN
Dermatology online journal. 2019;(10)
Abstract
Immune checkpoint inhibitors are used to treat numerous malignancies but may be associated with severe adverse events. Bullous dermatoses, chiefly bullous pemphigoid (BP), are potentially progressive adverse events that cause blistering skin lesions and may involve a significant body surface area. Herein, we report an 87-year-old man with urothelial cell carcinoma undergoing atezolizumab treatment who presented with an acute-onset blistering eruption. Biopsy revealed a subepidermal bulla, direct immunofluorescence revealed linear IgG and C3 deposits at the dermal-epidermal junction, and serum studies revealed elevated levels of antibodies to BP180 and BP230. Anti-PD-L1-induced BP was diagnosed, immunotherapy was withheld, and he was treated with oral doxycycline with niacinamide and clobetasol ointment. He restarted atezolizumab and has successfully received four cycles (every 3 weeks) while continuing this BP treatment regimen. A literature review revealed eight other cases of anti-PD-L1-induced bullous disorders. The incidence of bullous dermatoses with anti-PD-1/anti-PD-L1 agents combined is 1%, whereas the reported incidence for anti-PD-L1 agents alone ranges from 1.3-5%, raising concerns for a higher overall risk. In addition to our case, only one other case reported successful resumption of immunotherapy. Early control and management of immunotherapy-induced BP may reduce complications and prevent treatment discontinuation.
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10.
Therapeutic drug monitoring with vedolizumab in inflammatory bowel disease.
Pugliese, D, Privitera, G, Pizzolante, F, Gasbarrini, A, Guidi, L, Armuzzi, A
Minerva gastroenterologica e dietologica. 2019;(4):280-290
Abstract
Therapeutic drug monitoring (TDM) is a useful tool for decision-making process in patients with inflammatory bowel disease (IBD) treated with anti TNF-α drugs, especially when experiencing loss of response. Growing evidences support the existence of exposure-response relationship with vedolizumab, but the utility and the appropriate use of TDM in clinical practice is still under debate. In this review, we summarize all evidences supporting a TDM-guided approach for patients treated with vedolizumab, suggesting three potential scenarios: 1) early prediction of long-term outcomes; 2) verifying the best strategy in case of loss of response; 3) maximizing therapeutic efficacy during maintenance treatment. Vedolizumab through concentrations <20 µg/mL at week 6 and >12 µg/mL seem to be associated with more favorable outcomes. No comparative studies have been conducted so far to demonstrate the advantage of adopting a TDM-guided versus an empirical approach for managing primary or secondary nonresponses. The frequency of antibodies to vedolizumab detection is quite low (up to 4% in pivotal trials), suggesting, unlike of anti TNF-α agents, a low probability of experiencing an immune-mediated pharmacokinetic failure in clinical practice. Future prospective and controlled studies are warranted to establish the guidance on the use of a TDM-guided approach with vedolizumab in clinical practice.