ABSTRACT
BACKGROUND: Osimertinib represents the standard of care for the treatment of advanced non-small-cell lung cancer (NSCLC) harboring classical epidermal growth factor receptor (EGFR) mutations, constituting 80%-90% of all EGFR alterations. In the remaining cases, an assorted group of uncommon alterations of EGFR (uEGFR) can be detected, which confer variable sensitivity to previous generations of EGFR inhibitors, overall with lower therapeutic activity. Data on osimertinib in this setting are limited and strongly warranted. PATIENTS AND METHODS: The ARTICUNO study retrospectively evaluated data on osimertinib activity from patients with advanced NSCLC harboring uEGFR treated in 21 clinical centers between August 2017 and March 2023. Data analysis was carried out with a descriptive aim. Investigators collected response data according to RECIST version 1.1 criteria. The median duration of response, progression-free survival (mPFS), and overall survival were estimated by the Kaplan-Meier method. RESULTS: Eighty-six patients harboring uEGFR and treated with osimertinib were identified. Patients with 'major' uEGFR, that is, G719X, L861X, and S768I mutations (n = 51), had an overall response rate (ORR) and mPFS of 50% and 9 months, respectively. Variable outcomes were registered in cases with rarer 'minor' mutations (n = 27), with ORR and mPFS of 31% and 4 months, respectively. Among seven patients with exon 20 insertions, ORR was 14%, while the best outcome was registered among patients with compound mutations including at least one classical EGFR mutation (n = 13). Thirty patients presented brain metastases (BMs) and intracranial ORR and mPFS were 58% and 9 months, respectively. Amplification of EGFR or MET, TP53 mutations, and EGFR E709K emerged after osimertinib failure in a dataset of 18 patients with available rebiopsy. CONCLUSION: The ARTICUNO study confirms the activity of osimertinib in patients with uEGFR, especially in those with compound uncommon-common mutations, or major uEGFR, even in the presence of BMs. Alterations at the E709 residue of EGFR are associated with resistance to osimertinib.
Subject(s)
Acrylamides , Aniline Compounds , Carcinoma, Non-Small-Cell Lung , ErbB Receptors , Lung Neoplasms , Mutation , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Retrospective Studies , Acrylamides/therapeutic use , Acrylamides/pharmacology , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , ErbB Receptors/genetics , Aniline Compounds/therapeutic use , Aniline Compounds/pharmacology , Male , Female , Middle Aged , Aged , Adult , Aged, 80 and over , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/pharmacology , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/pharmacology , Indoles , PyrimidinesABSTRACT
PURPOSE: Immune checkpoint inhibitors (ICPIs) disrupting PD-1/PD-L1 axis have revolutionized the management of advanced non-small cell lung cancer (NSCLC). Some studies identified the development of endocrine toxicity as predictor of better survival in cancer patients treated with ICPIs. The aim of study was to evaluate survival and new onset of immune-related endocrine adverse events (irAEs) in patients treated with nivolumab for advanced NSCLC. METHODS: In a prospective study, 73 patients with previously treated advanced NSCLC received nivolumab in monotherapy. Blood samples were collected at each cycle to monitor thyroid autoimmunity, thyroid, adrenal and somatotroph axes, while thyroid morphology was evaluated by ultrasonography. RESULTS: An impaired thyroid function was recorded in 23.4% of patients (n = 15). Eight patients developed asymptomatic transient thyrotoxicosis (ATT) evolving to hypothyroidism in 50% of cases. In addition, seven patients developed overt hypothyroidism without ATT and with negative autoantibodies. Patients who developed hypothyroidism proved to have better overall survival (OS) as compared with non-developers at both univariate (p = 0.021) and multivariate analyses (p = 0.023). The survival curve of patients with reduced IGF-I at baseline, or displaying its reduction during the follow-up, showed significantly reduced median survival compared to patients with normal/high IGF-I levels (p = 0.031). CONCLUSIONS: Thyroid function abnormalities are the major irAEs in patients treated with nivolumab, and hypothyroidism onset is associated with prolonged survival. Our findings indicate that the development of hypothyroidism is a positive predictive biomarker of nivolumab antitumor efficacy in patients with NSCLC. Low IGF-I levels could represent a negative prognostic factor during nivolumab therapy.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Nivolumab , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/mortality , Carcinoma, Non-Small-Cell Lung/pathology , Nivolumab/adverse effects , Male , Female , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Lung Neoplasms/mortality , Prospective Studies , Aged , Middle Aged , Immune Checkpoint Inhibitors/adverse effects , Antineoplastic Agents, Immunological/adverse effects , Antineoplastic Agents, Immunological/therapeutic use , Adult , Prognosis , Survival Rate , Aged, 80 and over , Endocrine System Diseases/chemically induced , Endocrine System Diseases/epidemiology , Follow-Up Studies , Hypothyroidism/chemically inducedABSTRACT
BACKGROUND: Immune checkpoint inhibitors (ICIs) have revolutionized the management of multiple tumors, due to improved efficacy, quality of life, and safety. While most immune-related adverse events (irAEs) are mild and easily managed, in rare cases such events may be life-threatening, especially those affecting the neuromuscular and cardiac system. The management of neuromuscular/cardiac irAEs is not clear due to the lack of consistent data. Therefore, we carried out a pooled analysis of collected cases from selected Italian centers and individual data from published case reports and case series, in order to improve our understanding of these irAEs. PATIENTS AND METHODS: We collected retrospective data from patients treated in six Italian centers with ICIs (programmed cell death protein 1 or programmed death-ligand 1 and/or cytotoxic T-lymphocyte antigen 4 inhibitor) for any solid tumor who experienced neuromuscular and/or cardiovascular toxicity. Then, we carried out a search of case reports and series of neuromuscular/cardiac irAEs from ICIs with any solid tumor. RESULTS: This analysis includes cases from Italian institutions (n = 18) and the case reports identified in our systematic literature search (n = 120), for a total of 138 patients. Among these patients, 50 (36.2%) had complete resolution of their neuromuscular/cardiac irAEs, in 21 (15.2%) cases there was a clinical improvement with mild sequelae, and 53 (38.4%) patients died as a result of the irAEs. Factors significantly associated with worse outcomes were early irAE onset, within the first two cycles of ICI (Fisher P < 0.0001), clinical manifestation of both myositis and myocarditis when compared with patients who developed only myositis or myocarditis (chi-square P = 0.0045), and the development of arrhythmia (Fisher P = 0.0070). CONCLUSIONS: To the best of our knowledge, this is the largest collection of individual cases of immune-related myocarditis/myositis. Early irAE onset, concurrent development of myositis and myocarditis, as well as occurrence of arrhythmias are associated with worse outcomes and should encourage an aggressive immunomodulatory treatment.
Subject(s)
Antineoplastic Agents, Immunological , Myocarditis , Myositis , Neoplasms , Humans , Immune Checkpoint Inhibitors/therapeutic use , Antineoplastic Agents, Immunological/therapeutic use , Retrospective Studies , Myocarditis/chemically induced , Myocarditis/drug therapy , Quality of Life , Neoplasms/drug therapy , Myositis/chemically induced , Myositis/drug therapyABSTRACT
PURPOSE: Autonomic dysfunction is a distinctive but undervalued feature of hereditary transthyretin amyloidosis (ATTRv). It may predate the onset of polyneuropathy and cardiomyopathy, thereby providing crucial prognostic and therapeutic information. The objective of this study was to assess autonomic function by means of the standardized cardiovascular autonomic reflex tests (CRTs) in a cohort of subjects with genetically proven ATTRv from non-endemic areas who were in the symptomatic and pre-symptomatic stages. METHODS: All subjects enrolled in this cross-sectional study had genetically proven ATTRv. They underwent the head-up tilt test, Valsalva manoeuvre, deep breathing test, cold face test and handgrip test while under continuous blood pressure and heart rate monitoring. Based on the results of the nerve conduction study, the subjects were divided into two groups: those with polyneuropathy (ATTRv-wPN) and those without polyneuropathy (ATTRv-woPN). Age- and sex-matched healthy controls (HC) were used for comparison. RESULTS: Thirty-seven ATTRv subjects (19 with ATTRv-wPN, 18 with ATTRv-woPN) and 41 HC performed the CRTs. Of these 37 subjects with ATTRv, four (11%) presented neurogenic orthostatic hypotension the during head-up tilt test. Based on the results of the CRTs, autonomic dysfunction characterized by either sympathetic or parasympathetic impairment was detected in 37% and 63% of ATTRv-wPN subjects, respectively. Subjects with ATTRv-woPN presented a significant impairment of autonomic responses to the Valsalva manoeuvre compared to the HC (overshoot p = 0.004; Valsalva ratio p = 0.001). CONCLUSION: Autonomic dysfunctions are frequent in subjects with ATTRv when investigated by means of standardized CRTs, and are also relevant in the pre-symptomatic stage. Cardiovagal functions are the primary functions affected, among others. This may be crucial in defining the proper diagnostic workout for early diagnosis and improving the likelihood of providing the patient with prompt administration of disease-modifying treatments.
Subject(s)
Autonomic Nervous System Diseases , Polyneuropathies , Humans , Cross-Sectional Studies , Hand Strength , Reflex/physiologyABSTRACT
Glutaredoxins are small proteins that share a common well-conserved thioredoxin-fold and participate in a wide variety of biological processes. Among them, class II Grx are redox-inactive proteins involved in iron-sulfur (Fe-S) metabolism. In the present work, we report different structural and dynamics aspects of 1CGrx1 from the pathogenic parasite Trypanosoma brucei that differentiate it from other orthologues by the presence of a parasite-specific unstructured N-terminal extension whose role has not been fully elucidated yet. Previous nuclear magnetic resonance (NMR) studies revealed significant differences with respect to the mutant lacking the disordered tail. Herein, we have performed atomistic molecular dynamics simulations that, complementary to NMR studies, confirm the intrinsically disordered nature of the N-terminal extension. Moreover, we confirm the main role of these residues in modulating the conformational dynamics of the glutathione-binding pocket. We observe that the N-terminal extension modifies the ligand cavity stiffening it by specific interactions that ultimately modulate its intrinsic flexibility, which may modify its role in the storage and/or transfer of preformed iron-sulfur clusters. These unique structural and dynamics aspects of Trypanosoma brucei 1CGrx1 differentiate it from other orthologues and could have functional relevance. In this way, our results encourage the study of other similar protein folding families with intrinsically disordered regions whose functional roles are still unrevealed and the screening of potential 1CGrx1 inhibitors as antitrypanosomal drug candidates.
Subject(s)
Intrinsically Disordered Proteins , Iron-Sulfur Proteins , Trypanosoma brucei brucei , Glutaredoxins/genetics , Glutaredoxins/metabolism , Humans , Ligands , Protein Binding , Protein Folding , Trypanosoma brucei brucei/metabolismABSTRACT
Lipid-binding proteins (LBPs) are soluble proteins responsible for the uptake, transport, and storage of a large variety of hydrophobic lipophilic molecules including fatty acids, steroids, and other lipids in the cellular environment. Among the LBPs, fatty acid binding proteins (FABPs) present preferential binding affinities for long-chain fatty acids. While most of FABPs in vertebrates and invertebrates present similar ß-barrel structures with ligands accommodated in their central cavity, parasitic nematode worms exhibit additional unusual α-helix rich fatty acid- and retinol-binding proteins (FAR). Herein, we report the comparison of extended molecular dynamics (MD) simulations performed on the ligand-free and palmitic acid-bond states of the Necator americanus FAR-1 (Na-FAR-1) with respect to other classical ß-barrel FABPs. Principal component analysis (PCA) has been used to identify the different conformations adopted by each system during MD simulations. The α-helix fold encompasses a complex internal ligand-binding cavity with a remarkable conformational plasticity that allows reversible switching between distinct states in the holo-Na-FAR-1. The cavity can change up to one-third of its size affected by conformational changes of the protein-ligand complex. Besides, the ligand inside the cavity is not fixed but experiences large conformational changes between bent and stretched conformations. These changes in the ligand conformation follow changes in the cavity size dictated by the transient protein conformation. On the contrary, protein-ligand complex in ß-barrel FABPs fluctuates around a unique conformation. The significantly more flexible holo-Na-FAR-1 ligand-cavity explains its larger ligand multiplicity respect to ß-barrel FABPs.
Subject(s)
Fatty Acid-Binding Proteins/chemistry , Fatty Acid-Binding Proteins/metabolism , Molecular Dynamics Simulation , Retinol-Binding Proteins/chemistry , Retinol-Binding Proteins/metabolism , Ligands , Protein ConformationABSTRACT
BACKGROUND: CEA, CYFRA21-1 and NSE are tumor markers used for monitoring the response to chemotherapy in advanced adenocarcinoma, squamous cell carcinoma and small-cell lung cancer, respectively. Their role in cancer immunotherapy needs to be elucidated. METHODS: Patients with advanced non-small cell lung cancer (NSCLC) were treated with nivolumab 3 mg/kg every 2 weeks within the Italian Nivolumab Expanded Access Program. Blood samples were collected at baseline, at each cycle up to cycle 5 and then every two cycles until patient's withdrawn from the study. All patients underwent a CT-scan after every 4 cycles of treatment and responses were classified according to RECIST 1.1. The biomarkers serum levels were measured with a chemiluminescent microparticle immunoassay for CEA and with an immuno radiometric assay for CYFRA21-1 and NSE. The markers values at baseline and after 4 cycles were used to analyze the relationship between their variation over baseline and the tumor response, evaluated as disease control rate (DCR: CR + PR + SD), and survival (PFS and OS). RESULTS: A total of 70 patients were evaluable for the analysis. Overall, a disease control was obtained in 24 patients (35.8%, 4 PR + 20 SD). After 4 cycles of nivolumab a CEA or CYFRA21-1 reduction ≥ 20% over the baseline was significantly associated with DCR (CEA, p = 0.021; CYFRA21-1, p < 0.001), PFS (CEA, p = 0.028; CYFRA21-1, p < 0.001) and OS (CEA, p = 0.026; CYFRA21-1, p = 0.019). Multivariate analysis confirmed the ability of CYFRA21-1 reduction ≥ 20% to predict DCR (p = 0.002) and PFS (p < 0.001). CONCLUSION: The reduction in serum level of CYFRA21-1 or CEA might be a reliable biomarker to predict immunotherapy efficacy in NSCLC patients. NSE was not significant for monitoring the efficacy of nivolumab.
Subject(s)
Antigens, Neoplasm/blood , Carcinoembryonic Antigen/blood , Carcinoma, Non-Small-Cell Lung/blood , Carcinoma, Non-Small-Cell Lung/drug therapy , Keratin-19/blood , Lung Neoplasms/blood , Lung Neoplasms/drug therapy , Nivolumab/therapeutic use , Phosphopyruvate Hydratase/blood , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/blood , Carcinoma, Non-Small-Cell Lung/pathology , Disease-Free Survival , Female , Humans , Lung Neoplasms/pathology , Male , Middle Aged , Neoplasm StagingABSTRACT
INTRODUCTION: Bowel wall thickening is not an uncommon finding among patient undergoing abdomen CT scan. It may be caused by neoplastic, inflammatory, infectious or ischaemic conditions but also be a normal variant. Although specific radiologic patterns may direct to a precise diagnosis, occasionally misidentification may occur. Thus, in the absence of guidelines, further and not always needed diagnostic procedures (colonoscopy, esophagogastroduodenoscopy or capsule endoscopy) are performed. PATIENTS AND METHODS: We conducted a retrospective study on data collected from May 2016 to June 2017. We selected 40 adult patients, admitted in Emergency Department with "abdominal pain" and undergone an abdomen CT scan, in which bowel wall abnormalities were founded. RESULTS: 75% patients were found to have a benign condition vs 25% a malignant condition. In the stomach group, 50% were found to have a neoplasm, whilst 33.3% presented an aspecific pattern and 16.7% had an inflammatory disease. In the small bowel cluster, 33.3% patients had an ischaemic disease, 33.3% an aspecific pattern, 22.2% an inflammatory disease and 11.1% was diagnosed with cancer. In the colon group, 36% had an inflammatory disease, 24% a colon cancer, 24% an aspecific pattern and 16% an ischaemic condition. CONCLUSIONS: We recommend to perform a further endoscopic procedure to all patients with gastric or colonic wall abnormalities on CT scan, on the basis of growing rate of cancer and IBD. Capsule endoscopy should be taken into account in patients with severe symptoms and after a previous negative endoscopic examination.
Subject(s)
Abdominal Pain/etiology , Gastrointestinal Neoplasms/diagnostic imaging , Intestines/diagnostic imaging , Stomach/diagnostic imaging , Tomography, X-Ray Computed , Abdominal Pain/diagnostic imaging , Adult , Aged , Aged, 80 and over , Colitis/diagnostic imaging , Colitis/pathology , Diverticulitis, Colonic/diagnostic imaging , Diverticulitis, Colonic/pathology , Emergencies , Endoscopy, Gastrointestinal , Enteritis/diagnostic imaging , Enteritis/pathology , Female , Gastritis/diagnostic imaging , Gastritis/pathology , Gastrointestinal Neoplasms/pathology , Humans , Intestines/blood supply , Intestines/pathology , Ischemia/diagnostic imaging , Ischemia/pathology , Male , Middle Aged , Muscle, Smooth/diagnostic imaging , Muscle, Smooth/pathology , Retrospective Studies , Stomach/pathology , Young AdultABSTRACT
This study aimed to quantify 24h body core temperature (BcT°) and sleep-wake cycle rhythm alterations in craniopharyngioma (CP) patients and to identify markers related to the postsurgical outcomes. Ten consecutive CP patients underwent neuroradiological, endocrinological and ophthalmological evaluations, 24h BcT° and sleep-wake cycle recordings before and after endoscopic endonasal surgery. The sample included four women and six men. Nocturnal sleep efficiency was pathologically reduced in eight patients before surgery. Seven out of ten patients presented one to three daytime naps. 24h BcT° rhythm was pathological in six out of ten cases. Post-surgery sleep efficiency normalized in four out of eight patients, whereas nine out of ten patients presented with two to six longer daytime naps. Diurnal naps were mainly present in patients showing pre-operative involvement of the third ventricle floor. 24h BcT° remained pathological in only one out of six cases, returned to normal in two and improved in three. 24h BcT° rhythm improved more in papillary CPs than in adamantomatous CPs. Our data confirmed that both CP and surgery frequently disrupt the sleep-wake cycle and BcT° rhythms. Tumour location and histotype may be related to a worse postsurgical outcome. Therefore, in-depth investigation including circadian monitoring is crucial for surgical outcome.
Subject(s)
Body Temperature/physiology , Circadian Rhythm/physiology , Craniopharyngioma/physiopathology , Craniopharyngioma/surgery , Pituitary Neoplasms/physiopathology , Pituitary Neoplasms/surgery , Female , Humans , Hypothalamus/physiopathology , Hypothalamus/surgery , Male , Middle Aged , Neuroendoscopy , Sleep/physiology , Third Ventricle , Transanal Endoscopic Surgery , Treatment Outcome , Wakefulness/physiologyABSTRACT
BACKGROUND: VeriStrat is a blood-based proteomic test with predictive and prognostic significance in second-line treatments for non-small cell lung cancer (NSCLC). This trial was designed to investigate the role of VeriStrat in first-line treatment of advanced NSCLC with standard chemotherapy. Here we present the results for 76 non-squamous patients treated with a combination of carboplatin or cisplatin with pemetrexed. METHODS: The test-assigned classifications of VeriStrat Good or VeriStrat Poor to samples collected at baseline. The primary end point was progression-free survival (PFS); secondary end points included overall survival (OS) and objective response. Exploratory analyses of end points separately in carboplatin/pemetrexed and cisplatin/pemetrexed subgroups were also conducted. RESULTS: Patients classified as VeriStrat Good had longer PFS and OS than VeriStrat Poor: 6.5 vs 1.6 months and 10.8 vs 3.4 months, respectively; the corresponding hazard ratios (HRs) were 0.36 (P<0.0001) and 0.26 (P<0.0001); they were also more likely to achieve objective response. Prognostic significance of VeriStrat was confirmed in multivariate analysis. Significant differences in OS and PFS between Veristrat classifications were also found when treatment subgroups were analysed separately. CONCLUSIONS: The trial demonstrated clinical utility of VeriStrat as a prognostic test for standard first-line chemotherapy of non-squamous advanced NSCLC.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Blood Chemical Analysis/methods , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Proteomics , Adult , Aged , Aged, 80 and over , Carboplatin/administration & dosage , Carboplatin/adverse effects , Carcinoma, Non-Small-Cell Lung/blood , Carcinoma, Non-Small-Cell Lung/diagnosis , Carcinoma, Non-Small-Cell Lung/mortality , Cisplatin/administration & dosage , Cisplatin/adverse effects , Female , Humans , Lung Neoplasms/blood , Lung Neoplasms/diagnosis , Lung Neoplasms/mortality , Male , Middle Aged , Neoadjuvant Therapy , Pemetrexed/administration & dosage , Pemetrexed/adverse effects , Predictive Value of Tests , Prognosis , Standard of Care , Survival AnalysisABSTRACT
INTRODUCTION: Vinflunine belongs to the class of vinca alkaloids and acts by disrupting the microtubule dynamics during cell cycle; this agent is currently available for previously treated advanced transitional cell carcinoma in Europe. The aim of this invited review is to evaluate the potential role of vinflunine for the treatment of non-small cell lung cancer (NSCLC). Areas covered: The potential role of vinflunine in NSCLC is discussed on the basis of the available data, including full papers and meeting abstracts. Relevant preclinical studies describing the pharmacological properties of vinflunine are also included. The review also summarizes clinical studies, including phase I trials involving NSCLC among other tumors as well as phase II/III trials specifically addressing this malignancy. Additionally, the safety profile and the current regulatory status of vinflunine is discussed. Expert opinion: Vinflunine is active as single agent and as part of platinum-based combinations in NSCLC. It results non-inferior to docetaxel in a randomized phase III trial including previously treated NSCLC patients; additionally, its safety profile is generally considered manageable. Ultimately, further studies are needed to confirm the role of vinflunine in NSCLC, in consideration of the evolving evidence regarding targeted therapies and immune check-point inhibitors.
Subject(s)
Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Vinblastine/analogs & derivatives , Animals , Antineoplastic Agents, Phytogenic/administration & dosage , Antineoplastic Agents, Phytogenic/pharmacology , Carcinoma, Non-Small-Cell Lung/pathology , Humans , Lung Neoplasms/pathology , Randomized Controlled Trials as Topic , Vinblastine/administration & dosage , Vinblastine/adverse effects , Vinblastine/pharmacologyABSTRACT
INTRODUCTION: Malignant pleural mesothelioma (MPM) is an uncommon, aggressive cancer, derived from pleural mesothelial cells, that has a close relationship to asbestos exposure. To date, MPM prognosis is poor and very few treatment options are available for both localized and advanced MPM. AREAS COVERED: The standard of care is still chemotherapy with platinum derivates and antifolate agents. In the last few years, several new agents have been studied on the basis of mesothelioma carcinogenesis and invasiveness mechanisms; however, the recent results are poor and few drugs have been tested in phase III trials because of toxicity or because they did not improve patient outcomes. The aim of this review is to focus on the current available treatment for MPM through the analysis of the results comes from the phase III trials and to discuss the future perspectives in the pathogenesis, diagnosis and treatment. EXPERT OPINION: Many compounds are currently under investigation in different subsets of patients. Interesting data have come from preliminary studies on immunotherapy, but randomized studies are needed to confirm the preliminary positive results of this new strategy. A better comprehension of MPM pathogenesis should be obtained to improve and develop new diagnostic tools and target therapies.
Subject(s)
Lung Neoplasms/therapy , Mesothelioma/therapy , Pleural Neoplasms/therapy , Therapies, Investigational , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Combined Modality Therapy/trends , Humans , Immunotherapy/adverse effects , Immunotherapy/trends , Lung Neoplasms/diagnosis , Mesothelioma/diagnosis , Mesothelioma, Malignant , Pleural Neoplasms/diagnosis , Prognosis , Therapies, Investigational/methods , Therapies, Investigational/trendsSubject(s)
Feeding and Eating Disorders/diagnostic imaging , Adolescent , Adult , Anorexia/diagnostic imaging , Binge-Eating Disorder/diagnostic imaging , Bulimia/diagnostic imaging , Cardiovascular Diseases/diagnostic imaging , Cardiovascular Diseases/epidemiology , Case-Control Studies , Echocardiography , Female , Humans , Middle Aged , Young AdultABSTRACT
Preclinical studies have suggested that combining cytotoxic agents with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) to treat EGFR-mutated tumors may increase their inhibitory effect depending on the order of drug administration. The antitumor efficacy of different treatment sequences using vinorelbine (VNB) and gefitinib (GEF) was investigated both in vitro and in vivo in non-small cell lung cancer (NSCLC) cell lines with the rationale of potentially translating these findings into the clinical setting. The EGFR-wild-type A549 and the EGFR-mutated (exon 21 L858R/exon 20 T790M) H1975 cell lines were treated as follows: GEF followed by VNB, VNB followed by GEF and the two drugs applied individually or concurrently. Results in vitro demonstrated that the sequence of VNB followed by GEF was significantly more active than single-agent treatments. The expression of activated EGFR and its downstream pathway genes indicated that the increased cytotoxic effect of the VNB and GEF treatment sequence was accompanied by inhibition of EGFR, AKT and ERK1/2. Moreover, the increased inhibition of tumor growth after treatment with VNB followed by GEF was also confirmed in CD1-nude mice that were xenotransplanted with H1975 cells (p < 0.0001). This effect was paralleled by a corresponding decrease in cancer glucose consumption, as assessed by micro-positron emission tomography scans (p < 0.05). These preclinical findings in NSCLC cell lines, which are poorly responsive to EGFR-TKIs, demonstrated that the sequential treatment of VNB followed by GEF induced a significant antitumor effect, which supports the translation of this treatment schedule into a clinical setting.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Animals , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/diagnostic imaging , Cell Line, Tumor , Drug Administration Schedule , Drug Resistance, Neoplasm , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/metabolism , Female , Fluorodeoxyglucose F18/pharmacokinetics , Gefitinib , Humans , Lung Neoplasms/diagnostic imaging , Mice, Nude , Protein Kinase Inhibitors/pharmacology , Quinazolines/administration & dosage , Radionuclide Imaging , Radiopharmaceuticals/pharmacokinetics , Signal Transduction , Vinblastine/administration & dosage , Vinblastine/analogs & derivatives , Vinorelbine , Xenograft Model Antitumor AssaysABSTRACT
BACKGROUND AND OBJECTIVES: The autonomic nervous system (ANS) regulates involuntary body functions and is commonly evaluated by measuring reflex responses of systolic and diastolic blood pressure (BP) and heart rate (HR) to physiological and pharmacological stimuli. However, BP and HR values may not sufficient be to explain specific ANS events and other parameters like the electrocardiogram (ECG), BP waves, the respiratory rate and the electroencephalogram (EEG) are mandatory. Although ANS behaviour and its response to stimuli are well-known, their clinical evaluation is often based on individual medical training and experience. As a result, ANS laboratories have been customized, making it impossible to standardize procedures and share results with colleagues. The aim of our study was to build a powerful versatile instrument easy-to-use in clinical practice to standardize procedures and allow a cross-analysis of all the parameters of interest for ANS evaluation. METHODS: The new ANScovery System developed by neurologists and technicians is a two-step device: (1) integrating physiological information from different already existing commercial modules, making it possible to cross-analyse, store and share data; (2) standardizing procedures by an innovative tutor monitor able to guide the patient throughout ANS testing. RESULTS AND CONCLUSIONS: The daily use of the new ANScovery System in clinical practice has proved it is a versatile easy to use instrument. Standardization of the manoeuvres and step-by-step guidance throughout the procedure avoid repetitions and allow intra and inter-patient data comparison.
Subject(s)
Autonomic Nervous System Diseases/diagnosis , Autonomic Nervous System Diseases/physiopathology , Autonomic Nervous System/physiopathology , Baroreflex , Diagnosis, Computer-Assisted/instrumentation , Diagnostic Techniques, Neurological/instrumentation , Heart Function Tests/instrumentation , Diagnosis, Computer-Assisted/methods , Equipment Design , Equipment Failure Analysis , Humans , Reproducibility of Results , Sensitivity and Specificity , Systems Integration , User-Computer InterfaceABSTRACT
Malignant mesothelioma (MM) is an aggressive tumor, mainly derived from the pleura, which is predominantly associated with exposure to asbestos fibers. The prognosis of MM patients is particularly severe, with a median survival of approximately 9-12 months and latency between exposure and diagnosis ranging from 20-50 years (median 30 years). Emerging evidence has demonstrated that tumor aggressiveness is associated with genome and gene expression abnormalities; therefore, several studies have recently focused on the role of microRNAs (miRNAs) in MM tumorigenesis. miRNAs are small non-protein coding single-stranded RNAs (17-22 nucleotides) involved in numerous cellular processes that negatively regulate gene expression by modulating the expression of downstream target genes. miRNAs are often deregulated in cancer; in particular, the differential miRNA expression profiles of MM cells compared to unaffected mesothelial cells have suggested potential roles of miRNAs as either oncogenes or tumor suppressor genes in MM oncogenesis. In this review, the mechanism of MM carcinogenesis was evaluated through the analysis of the published miRNA expression data. The roles of miRNAs as diagnostic biomarkers and prognostic factors for potential therapeutic strategies will be presented and discussed.
Subject(s)
Gene Expression Regulation, Neoplastic , Lung Neoplasms/genetics , Mesothelioma/genetics , MicroRNAs/genetics , Animals , Biomarkers, Tumor/genetics , Humans , Lung/metabolism , Lung/pathology , Lung Neoplasms/diagnosis , Lung Neoplasms/therapy , Mesothelioma/diagnosis , Mesothelioma/therapy , Mesothelioma, Malignant , Oncogenes , PrognosisABSTRACT
BACKGROUND: Objective of this study was to evaluate the acute cardiovascular and respiratory effects of switching on the deep brain stimulation in the follow up of nine Parkinson's disease patients with subthalamic nucleus stimulation and six cluster headache patients with posterior hypothalamic area stimulation. METHODS: Systolic and diastolic blood pressure, heart rate, and respiratory rate were monitored continuously during supine rest in both groups. Each patient was assessed in two conditions: resting supine with stimulator off and with stimulator on. RESULTS: In supine resting condition switching on the DBS induced no significant changes (p>0.05) in systolic and diastolic blood pressure as well as in heart rate and respiratory rate, in both groups of patients, either taking 1 min or 10 heartbeats as a sample for analysis. CONCLUSIONS: Switching on the DBS does not modify heart rate, blood pressure nor respiratory rate in both Parkinson and cluster headache patients under resting conditions.
Subject(s)
Cardiovascular Physiological Phenomena , Cluster Headache/therapy , Deep Brain Stimulation/adverse effects , Parkinson Disease/therapy , Respiratory Physiological Phenomena , Adult , Aged , Cluster Headache/physiopathology , Deep Brain Stimulation/methods , Electrodes, Implanted/adverse effects , Electrodes, Implanted/standards , Female , Follow-Up Studies , Humans , Male , Middle Aged , Parkinson Disease/physiopathologyABSTRACT
OBJECTIVE: To test the autonomic control of cardiovascular reflexes and heart rate variability (HRV) at rest and during orthostatic stress in narcolepsy with cataplexy (NC). METHODS: Ten NC patients with a hypocretin deficit and 18 control subjects underwent head-up tilt test (HUTT), Valsalva manoeuvre, deep breathing and cold face under controlled laboratory conditions. Heart rate variability (HRV) was analysed during supine rest and HUTT considering the normalized unit of LF and HF power (LFnu; HFnu), using autoregressive (AR) and fast Fourier transform (FFT) algorithms. RESULTS: Cardiovascular changes during HUTT, Valsalva manoeuvre, deep breathing, isometric handgrip and cold face were normal and comparable in the two groups. AR and FFT analysis showed an increased LF/HF ratio in NC patients during supine rest. As expected, LFnu increased and HFnu decreased in the control group during HUTT, but did not change in narcoleptics being comparable to values in the supine condition. CONCLUSIONS: NC patients showed an increased sympathetic drive on heart rate (HR) in the supine condition that did not further increase during HUTT. SIGNIFICANCE: These results suggest the proper functioning of cardiovascular reflexes in NC but support an impairment of HR modulation at rest in favour of an enhanced sympathetic activity.
Subject(s)
Fourier Analysis , Heart Rate/physiology , Narcolepsy/diagnosis , Narcolepsy/physiopathology , Sympathetic Nervous System/physiology , Adult , Cataplexy/diagnosis , Cataplexy/physiopathology , Electrocardiography/methods , Female , Humans , Male , Middle Aged , Tilt-Table Test/methods , Valsalva Maneuver/physiologyABSTRACT
OBJECTIVE: To test for the autonomic neuropathy in systemic sclerosis (SSc) using cardiovascular reflex evaluation including the "cold face test", which elicits forehead cold receptors (C-fibres). These tests examine the induced bradycardia-hypertensive response and the integrity of nociceptive afferent and parasympathetic-sympathetic efferent pathways. METHODS: Twelve SSc patients were studied; including 5 with the limited cutaneous (lcSSc) involvement, and 7 with diffuse cutaneous involvement (dcSSc). All patients were matched with healthy controls. We performed cardiovascular autonomic tests (tilt-test, Valsalva manoeuver, deep breathing, sustained handgrip and cold face) with continuous monitoring of beat-to-beat blood pressure (BP) and heart rate (HR). Baroreceptor sensitivity index (BRSI) and power spectral analysis (PSA) of heart rate variability (HRV) were also evaluated. RESULTS: SSc patients showed a statistically significant higher HR at rest (p<0.01), a lower increase of diastolic BP during tilt test (p<0.01). They had suboptimal hypertensive and bradycardic response to the cold face test (Systolic BP: p<0.05; Diastolic BP: p<0.01; HR: p=0.08). The Valsalva manoeuver, deep breathing, isometric handgrip, BRSI and PSA of HRV results were within normal limits in the majority of SSc patients. CONCLUSION: In this group of SSc patients cardiovascular reflexes were normal, whereas the cold face test which acts through cutaneous nociceptive sensory fibres was abnormal in almost all patients. These results suggest that insufficiency of epidermal small fibres (C-fibres) is involved in SSc.
Subject(s)
Autonomic Nervous System Diseases/physiopathology , Cardiovascular System/innervation , Scleroderma, Systemic/physiopathology , Adult , Aged , Autonomic Nervous System Diseases/complications , Blood Pressure , Cardiovascular System/physiopathology , Cold Temperature , Face/physiology , Female , Heart Rate , Humans , Male , Middle Aged , Pain Measurement , Parasympathetic Nervous System/physiopathology , Raynaud Disease , Reflex, Abnormal , Scleroderma, Systemic/complications , Scleroderma, Systemic/diagnosis , Sympathetic Nervous System/physiopathology , Valsalva ManeuverABSTRACT
Sarcoidosis is a multisystem disease of unknown etiology primarily affecting the lungs, skin, and lymph nodes. The disease usually manifests in young adults and is uncommon in childhood. Renal involvement, including granulomatous interstitial nephritis (GIN), is rare, and few cases of isolated sarcoid GIN have been reported in pediatrics. We report a case and review the literature.