Thyroid disorders induced by checkpoint inhibitors

Immune checkpoint inhibitors are drugs that inhibit the "checkpoint molecules". Different types of cancer immune checkpoint inhibitors have been approved recently: CTLA-4 monoclonal antibodies (as ipilimumab); anti-PD-1 monoclonal antibodies (as pembrolizumab and nivolumab); and anti-PD-L1 monoclonal antibodies (as atezolizumab, avelumab, and durmalumab). The increased immune response induced by these agents leads to immune-related adverse events (irAEs), that can vary from mild to fatal, according to the organ system and severity. Immune-related endocrine toxicities are thyroid dysfunctions, hypophysitis, adrenal insufficiency, and type 1 diabetes mellitus, and are usually irreversible in 50%. In particular, hypophysitis is the most frequent anti-CTLA-4-antibodies-related irAE, while thyroid abnormalities (as hypothyroidism, thyrotoxicosis, painless thyroiditis, or even "thyroid storm") are more frequently associated with anti-PD-1-antibodies. The combination of anti-CTLA-4-antibodies, with anti-PD-1-antibodies, is associated with about 30% of irAEs. Clinical signs and symptoms vary according to the influenced target organ. Endocrinopathies can often be managed by the treating oncologist. However in more severe cases (i.e. in the presence of insulin-dependent diabetes, adrenal insufficiency, or disorders of gonadal hormones, or severe hyperthyroidism, or hypothyroidism, or long-lasting management of hypophysitis) an endocrinological evaluation, and a prompt therapy, are needed

Systematic review of prevalence, risk factors, and management of instability following reverse shoulder arthroplasty

Background Since its approval for use, reverse shoulder arthroplasty (RSA) has become the primary treatment for cuff tear arthropathy, with indications expanding more recently to include revision fracture, osteoarthritis with significant glenoid bone loss, tumor, and chronic instability. Instability is a well-described postoperative complication, occurring in 1to 31% of relatively small cohorts and case series. Given the relative infrequency of instability, there remains a need for a comprehensive review of instability with a focus on risk factors and management. Our goal of this systematic review is to describe the prevalence, risk factors, and management strategies for instability following RSA. Methods A systematic review of the PubMed, EMBASE, MEDLINE, Scopus, and Cochrane Library databases was performed according to PRISMA guidelines. Inclusion criteria included primary RSA cohorts ≥ 100 patients, revision RSA cohorts of any size, and minimum 1-year follow-up. The primary outcome of interest was postoperative instability. MINORS criteria were used to assess study bias. Descriptive statistical analysis was performed with data reported as ranges. Results Seventeen studies that included 7885 cases of RSA were reviewed. The mean follow-up ranged from 12 to 84 months. Mean age ranged from 64 to 77 years old, and males represented 19 to 39% of cohorts. There were 204 (2.5%) dislocations in 7885 cases, accounting for a rate of instability from 0.4 to 49% across all studies. By intervention, instability rates ranged from 1 to 5% (primary RSA cases), 1 to 49% (revision RSA cases only), and 0.4 to 10% (mixed cohorts). Subscapularis insufficiency and proximal humerus fractures, and fracture sequelae (malunion and nonunion) were identified as risk factors for instability. Closed reduction and casting and revision RSA were reported as successful treatment strategies with acceptable rates of stable prostheses (28-100% and 55-100%, respectively, across studies). Hemiarthroplasty or resection arthroplasty due to recurrent instability was not uncommon after 2 or more episodes of instability. Conclusion Instability following RSA occurs infrequently (1-5%) following primary RSA and more commonly following revision RSA (1-49%). RSA for acute proximal humerus fracture and fracture sequelae carries a higher risk of instability. Subscapularis repair appears to be a protective factor. While instability may be successfully treated with closed management or revision RSA, recurrent instability may ultimately require hemiarthroplasty or resection arthroplasty

High circulating N-terminal pro-brain natriuretic peptide and tumor necrosis factor-alpha in mixed cryoglobulinemia

AIM: To evaluate serum levels of N-terminal pro-brain natriuretic peptide (NTproBNP) and tumor necrosis factor alpha (TNF-alpha) in a large series of patients with hepatitis C associated with mixed cryoglobulinemia (MC+HCV).METHODS: Serum NTproBNP and TNF-alpha levels were assayed in 50 patients with MC+HCV, and in 50 sex- and age-matched controls.RESULTS: Cryoglobulinemic patients showed significantly higher mean NTproBNP and TNF-alpha levels than controls (P < 0.001; Mann-Whitney U test). By defining high NTproBNP level as a value higher than 125 pg/mL (the single cut-off point for outpatients under 75 years of age), 30% of MC+HCV and 6% of controls had high NTproBNP (c2, P < 0.01). With a cut-off point of 300 pg/mL (used to rule out heart failure (HF) in patients under 75 years of age), 8% of MC+HCV and 0 controls had high NTproBNP (c2, P < 0.04). With a cut-off point of 900 pg/mL (used for ruling in HF in patients aged 50-75 years; such as the patients of our study), 6% of MC+HCV and 0 controls had high NTproBNP (c2, P = 0.08).CONCLUSION: The study demonstrates high levels of circulating NTproBNP and TNF-alpha in MC+HCV patients. The increase of NTproBNP may indicate the presence of a subclinical cardiac dysfunctio

Resting tachycardia, a warning sign in anorexia nervosa: case report

BACKGROUND: Among psychiatric disorders, anorexia nervosa has the highest mortality rate. During an exacerbation of this illness, patients frequently present with nonspecific symptoms. Upon hospitalization, anorexia nervosa patients are often markedly bradycardic, which may be an adaptive response to progressive weight loss and negative energy balance. When anorexia nervosa patients manifest tachycardia, even heart rates in the 80–90 bpm range, a supervening acute illness should be suspected. CASE PRESENTATION: A 52-year old woman with longstanding anorexia nervosa was hospitalized due to progressive leg pain, weakness, and fatigue accompanied by marked weight loss. On physical examination she was cachectic but in no apparent distress. She had fine lanugo-type hair over her face and arms with an erythematous rash noted on her palms and left lower extremity. Her blood pressure was 96/50 mm Hg and resting heart rate was 106 bpm though she appeared euvolemic. Laboratory tests revealed anemia, mild leukocytosis, and hypoalbuminemia. She was initially treated with enteral feedings for an exacerbation of anorexia nervosa, but increasing leukocytosis without fever and worsening left leg pain prompted the diagnosis of an indolent left lower extremity cellulitis. With antibiotic therapy her heart rate decreased to 45 bpm despite minimal restoration of body weight. CONCLUSIONS: Bradycardia is a characteristic feature of anorexia nervosa particularly with significant weight loss. When anorexia nervosa patients present with nonspecific symptoms, resting tachycardia should prompt a search for potentially life-threatening conditions

Farnesyltransferase inhibitors and human malignant pleural mesothelioma: a first-step comparative translational study.

It is known that the potential clinical use of farnesyltransferase inhibitors (FTI) could be expanded to include cancers harboring activated receptor tyrosine kinases. Approximately 70% of malignant pleural mesotheliomas (MPM) overexpress epidermal growth factor receptors (EGFR) and a subset express both EGFR and transforming growth factor A (TGF-A), suggesting an autocrine role for EGFR in MPM. We checked on MPM cells (10 human cell lines, 11 primary cultures obtained by human biopsies, and 7 short-term normal mesothelial cell cultures) concerning the following: (a) the relative overexpression of EGFR (Western blotting, flow cytometry, immunohistochemistry), (b) the relative expression of EGFR ligands (EGF, amphiregulin, TGF-A, ELISA), (c) the relative increase of the activated form of Ras (Ras-bound GTP) after EGF stimulation (Ras activation assay), (d) the efficacy of five different FTIs (HDJ2 prenylation, cell cytotoxicity, and apoptosis using ApopTag and gel ladder). EGFR was overexpressed in MPM cells compared with normal pleural mesothelial cells in equivalent levels as in non\u2013small cell lung cancer cells A549. MPM cells constitutively expressed EGFR ligands; however, Ras activation was attenuated at high EGF concentrations (100 ng/mL). Growth of MPM cells was substantially not affected by treatment with different FTIs (SCH66336, BMS- 214662, R115777, RPR-115135, and Manumycin). Among these, BMS-214662 was the only one moderately active. BMS-214662 triggered apoptosis in a small fraction of cells (not higher than 30%) that was paralleled by a slight decrease in the levels of TGF-A secreted by treated MPM cells. Our data highlighted the concept that the same signaling pathway can be regulated in different ways and these regulations can differ between different cells of different origin

Breath analysis for early detection of malignant pleural mesothelioma: Volatile organic compounds (VOCs) determination and possible biochemical pathways

Malignant pleural mesothelioma (MPM) is a rare neoplasm, mainly caused by asbestos exposure, with a high mortality rate. The management of patients with MPM is controversial due to a long latency period between exposure and diagnosis and because of non-specific symptoms generally appearing at advanced stage of the disease. Breath analysis, aimed at the identification of diagnostic Volatile Organic Compounds (VOCs) pattern in exhaled breath, is believed to improve early detection of MPM. Therefore, in this study, breath samples from 14 MPM patients and 20 healthy controls (HC) were collected and analyzed by Thermal Desorption-Gas Chromatography-Mass Spectrometry (TD-GC/MS). Nonparametric test allowed to identify the most weighting variables to discriminate between MPM and HC breath samples and multivariate statistics were applied. Considering that MPM is an aggressive neoplasm leading to a late diagnosis and thus the recruitment of patients is very difficult, a promising data mining approach was developed and validated in order to discriminate between MPM patients and healthy controls, even if no large population data are available. Three different machine learning algorithms were applied to perform the classification task with a leave-one-out cross-validation approach, leading to remarkable results (Area Under Curve AUC = 93%). Ten VOCs, such as ketones, alkanes and methylate derivates, as well as hydrocarbons, were able to discriminate between MPM patients and healthy controls and for each compound which resulted diagnostic for MPM, the metabolic pathway was studied in order to identify the link between VOC and the neoplasm. Moreover, five breath samples from asymptomatic asbestos-exposed persons (AEx) were exploratively analyzed, processed and tested by the validated statistical method as blinded samples in order to evaluate the performance for the early recognition of patients affected by MPM among asbestos-exposed persons. Good agreement was found between the information obtained by gold-standard diagnostic methods such as computed tomography CT and model output

The new Mobile Universal Lexicon Evaluation System (MULES): A test of rapid picture naming for concussion sized for the sidelines

© 2018 Objective: Measures of rapid automatized naming (RAN) have been used for over 50 years to capture vision-based aspects of cognition. The Mobile Universal Lexicon Evaluation System (MULES) is a test of rapid picture naming under investigation for detection of concussion and other neurological disorders. MULES was designed as a series of 54 grouped color photographs (fruits, random objects, animals) that integrates saccades, color perception and contextual object identification. Recent changes to the MULES test have been made to improve ease of use on the athletic sidelines. Originally an 11 × 17-inch single-sided paper, the test has been reduced to a laminated 8.5 × 11-inch double-sided version. We identified performance changes associated with transition to the new, MULES, now sized for the sidelines, and examined MULES on the sideline for sports-related concussion. Methods: We administered the new laminated MULES to a group of adult office volunteers as well as youth and collegiate athletes during pre-season baseline testing. Athletes with concussion underwent sideline testing after injury. Time scores for the new laminated MULES were compared to those for the larger version (big MULES). Results: Among 501 athletes and office volunteers (age 16 ± 7 years, range 6–59, 29% female), average test times at baseline were 44.4 ± 14.4 s for the new laminated MULES (n = 196) and 46.5 ± 16.3 s for big MULES (n = 248). Both versions were completed by 57 participants, with excellent agreement (p \u3c 0.001, linear regression, accounting for age). Age was a predictor of test times for both MULES versions, with longer times noted for younger participants (p \u3c 0.001). Among 6 athletes with concussion thus far during the fall sports season (median age 15 years, range 11–21) all showed worsening of MULES scores from pre-season baseline (median 4.0 s, range 2.1–16.4). Conclusion: The MULES test has been converted to an 11 × 8.5-inch laminated version, with excellent agreement between versions across age groups. Feasibly administered at pre-season and in an office setting, the MULES test shows preliminary evidence of capacity to identify athletes with sports-related concussion

Neuroprotection in a Novel Mouse Model of Multiple Sclerosis

The authors acknowledge the support of the Barts and the London Charity, the Multiple Sclerosis Society of Great Britain and Northern Ireland, the National Multiple Sclerosis Society, USA, notably the National Centre for the Replacement, Refinement & Reduction of Animals in Research, and the Wellcome Trust (grant no. 092539 to ZA). The siRNA was provided by Quark Pharmaceuticals. The funders and Quark Pharmaceuticals had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript