Coverage from the 88th Annual Meeting of the American Thyroid Association®
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ATA 2018 Abstracts Available Online
The American Thyroid Association holds its 88th Annual Meeting at the Marriott Marquis, Washington DC from October 3-7, 2018
Thyroid Cancer Presentations at American Thyroid Association: 88th Annual Meeting
Disorders of Thyroid Function Presentations at American Thyroid Association: 88th Annual Meeting
Thyroid Nodules and Goiters Presentations at American Thyroid Association: 88th Annual Meeting
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Eltrombopag is indicated in patients with severe aplastic anemia (SAA) refractory to prior immunosuppressive therapy. The combination of eltrombopag and immunosuppressive therapy (such as cyclosporine) is currently being evaluated in patients with treatment-naive SAA. Cyclosporine is a human breast cancer resistance protein (BCRP) inhibitor, and can potentially alter plasma exposure to eltrombopag, a BCRP substrate. This phase 1, open-label, randomized, 3-period, crossover study evaluated the effect of cyclosporine on the pharmacokinetics of eltrombopag in healthy adults.
Thirty-nine subjects were randomized to either single dose of eltrombopag 50 mg, cyclosporine 200 mg + eltrombopag 50 mg or cyclosporine 600 mg + eltrombopag 50 mg treatment groups. Eltrombopag pharmacokinetic parameters (Cmax, tmax, AUClast, AUCinf, %AUCex, t1/2, and CL/F) were determined using noncompartmental methods.
Geometric mean AUCinf, AUClast, and Cmax, were decreased by 18, 20, and 25%, respectively, for cyclosporine 200 mg + eltrombopag and by 24, 22, and 39%, respectively, for cyclosporine 600 mg + eltrombopag groups compared to the eltrombopag alone group. The median tmax was prolonged by ~ 1 h in both coadministration treatments. The geometric mean t1/2 was ≈ 21, ≈ 24, and ≈ 26 h, respectively, in cyclosporine 200 mg + eltrombopag, cyclosporine 600 mg + eltrombopag and eltrombopag alone groups. All the treatments were safe and well-tolerated. No serious adverse event or death was reported during the study.
These changes in exposure were not considered clinically meaningful as the dose of eltrombopag is adjusted using within-patient dose titration based on platelet counts.
Efforts are underway in improving the informed consent process. The success of these efforts to improve quality of informed consent forms (ICFs) for phase I oncology trials has not been previously measured.
We reviewed and compared ICFs of all phase I trials for metastatic cancer conducted between 1986 and 1999 and 2000–2015 periods at our institution. Information pertaining to ICF length, study purpose description, research regimen/methods, potential risks and benefits was extracted. The reading level was assessed by Flesch–Kincaid readability tests.
Of 364 ICFs screened, 310 ICFs were included in this analysis. The median length of ICFs from 1986 to 1999 and 2000–2015 was 12 and 23 pages, respectively. Only 42% (1986–1999) and 57% (2000–2015) of ICFs stated that individual participants might not benefit from treatment. Only 21% (1986–1999) and 12% (2000–2015) of all ICFs were written at ≤ 8th grade reading level. The median FRE, FKGL and GFI readability scores of ICFs from 1986 to 1999 were 53.6, 8.8, and 9.5, respectively. The median FRE, FKGL, and GFI scores of studies from 2000 to 2015 were 48.5, 10.7, and 12.4, respectively. These scores indicate that the ICF text was too hard for most people to read. The mechanism of action of the treatment, study schema/calendar, possibility of experiencing unexpected risks or death, and risks to pregnant/lactating women were not reported in a substantial number of forms.
Our results show that ICFs for phase I oncology trials over last 30 years have become longer, more difficult to read but are still lacking some important information.
Optimal salvage chemotherapy for patients with treated advanced/metastatic gastric cancer (AGC) is unknown. Irinotecan is commonly used in Japan. Ramucirumab, a human IgG-1 monoclonal antibody targeting the extracellular domain of VEGF receptor 2, is the first molecularly targeted agent proven to be effective in second-line therapy for AGC in combination with chemotherapy. We sought to determine the maximum tolerated dose (MTD) and recommended dose (RD) of ramucirumab plus irinotecan for AGC previously treated with fluoropyrimidine with/without platinum and taxane.
Patients received systemic chemotherapy with ramucirumab (8 mg/kg) and irinotecan on day 1, repeated every 2 weeks. A decrease in irinotecan dose was planned from start level 1 (irinotecan 150 mg/m2). This trial was registered with the University Hospital Medical Network (UMIN no. 000018606).
Six patients were enrolled from August 2015 to September 2017. No dose-limiting toxicity (DLT) was observed, and the maximum tolerated dose (MTD) was not reached at level 1. Irinotecan 150 mg/m2 in combination with ramucirumab 8 mg/kg was administered with acceptable toxicity, and all patients were treated at these doses. No treatment-related deaths were observed. Adverse events of Grade 3/4 were neutropenia (17%), anemia (17%) and hypertension (17%). Patients were evaluated using the RECIST criteria, and response rate and disease control rate were 17% and 83%, respectively.
Salvage chemotherapy with irinotecan plus ramucirumab was well-tolerated by patients previously treated for AGC. RD was defined as irinotecan 150 mg/m2 in combination with ramucirumab 8 mg/kg.
Pancreatic cancer is a malignant tumor of the digestive system with poor prognosis and high mortality, and the treatment of pancreatic cancer still remains a major challenge. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can induce apoptosis selectively in cancer cells while causing virtually no damage to normal cells, which is promising for cancer therapy. However, many primary tumors and cancer cell lines including various human pancreatic cancer cell lines were found to be resistant to TRAIL-induced apoptosis. Therefore, the purpose of the study was to improve antitumor effect of TRAIL on pancreatic cancer.
The 114–121 amino acid coding sequence "VRERGPQR" of wild type TRAIL protein that was selected changed into "RRRRRRRR", and the novel membrane-penetrating peptide-alike mutant protein was named TRAIL-Mu3. The antitumor effect of TRAIL-Mu3 was analyzed both in vitro and in vivo. Western blotting, immunofluorescence and flow cytometry were used to investigate the underlying mechanisms.
TRAIL-Mu3 could enhance the antitumor effects on pancreatic cancer cell lines, and the antitumor effect of TRAIL-Mu3 was stronger than gemcitabine in vivo. The immunofluorescence results suggested that TRAIL-Mu3 could remarkably enhance the affinity to pancreatic cancer cells. The Western blot results showed that treatment with TRAIL-Mu3 caused a clear cleavage of caspase-3 and caspase-8. In addition, both the Western blot and flow cytometry suggested a significantly up-expression of DR5 in TRAIL-Mu3 group.
Membrane-penetrating peptide-alike mutant-TRAIL-Mu3 induced pancreatic cancer cell death more efficiently than TRAIL, and this effect was supposed to be mediated by the increased affinity to cell membrane, the up-regulation of DR5 and the enhancement of activated caspase.
This study aimed to determine the correlation between DNA repair enzyme O6-methylguanine DNA methyltransferase (MGMT) status and the response to streptozocin in advanced well-differentiated pancreatic neuroendocrine tumors (WD panNETs).
To test the hypothesis that MGMT deficiency was required for an alkylating drug response, we retrospectively reviewed the response of 13 patients with WD panNETs to alkylating agents in relation to MGMT status. We also studied MGMT expression in streptozocin resistance using panNET cell lines.
The cohort included 54% of patients with and 46% without MGMT expression. Among these, 83.3% (5/6) of MGMT-negative cases showed a partial response to streptozocin. In contrast, only 14.2% (1/7) of MGMT-positive cases showed a partial response (P = 0.013). Induced expression of MGMT in BON1 cells (a panNET cell line with undetectable endogenous MGMT) produced streptozocin resistance. Knockdown of MGMT in QGP1 cells, which express MGMT endogenously, did not alter the response to streptozocin.
We observed a relationship between MGMT status and streptozocin response in both patients and cell culture. Despite limited cases examined, high concordance of negative expression of MGMT and response to streptozocin treatment suggest that MGMT expression can be a potential biomarker for this treatment.
Metarrestin is a first-in-class small molecule clinical candidate capable of disrupting the perinucleolar compartment, a subnuclear structure unique to metastatic cancer cells. This study aims to define the pharmacokinetic (PK) profile of metarrestin and the pharmacokinetic/pharmacodynamic relationship of metarrestin-regulated markers.
PK studies included the administration of single or multiple dose of metarrestin at 3, 10, or 25 mg/kg via intravenous (IV) injection, gavage (PO) or with chow to wild-type C57BL/6 mice and KPC mice bearing autochthonous pancreatic tumors. Metarrestin concentrations were analyzed by UPLC–MS/MS. Pharmacodynamic assays included mRNA expression profiling by RNA-seq and qRT-PCR for KPC mice.
Metarrestin had a moderate plasma clearance of 48 mL/min/kg and a large volume of distribution of 17 L/kg at 3 mg/kg IV in C57BL/6 mice. The oral bioavailability after single-dose (SD) treatment was > 80%. In KPC mice treated with SD 25 mg/kg PO, plasma AUC0–∞ of 14400 ng h/mL, Cmax of 810 ng/mL and half-life (t1/2) of 8.5 h were observed. At 24 h after SD of 25 mg/kg PO, the intratumor concentration of metarrestin was high with a mean value of 6.2 µg/g tissue (or 13 µM), well above the cell-based IC50 of 0.4 µM. At multiple dose (MD) 25 mg/kg/day PO in KPC mice, mean tissue/plasma AUC0–24h ratio for tumor, spleen and liver was 37, 30 and 31, respectively. There was a good linear relationship of dosage to AUC0–24h and C24h. AUC0–24h MD to AUC0–24h SD ratios ranged from two for liver to five for tumor indicating additional accumulation in tumors. Dose-dependent normalization of FOXA1 and FOXO6 mRNA expression was observed in KPC tumors.
Metarrestin is an effective therapeutic candidate with a favorable PK profile achieving excellent intratumor tissue levels in a disease with known poor drug delivery.
Publication date: Available online 12 October 2018
Source: Autoimmunity Reviews
Author(s): José Pedro L. Nunes, André C. Cunha, Tiago Meirinhos, Alzira Nunes, Paulo M. Araújo, Ana R. Godinho, Eduardo M. Vilela, Carlos Vaz
The prevalence of auto-antibodies associated to pulmonary arterial hypertension in scleroderma patients was reviewed, based on reports cited in two major scientific databases.
Data was collected on the following types of antibodies: antinuclear, anti-double-stranded DNA, anticentromere, anti-CENP-A, anti-CENP-B, anti-bicaudal D2, anti-nucleolar, anti-Scl-70 (anti-topoisomerase I), anti-topoisomerase II α, anti-RNP, anti-U1RNP, anti-U3RNP, anti-RNA polymerase III, anti-Th/To, anti-histone, antiphospholipid, anti-PmScl, anti-Sm, anti SSA (anti-Ro), anti SSB (La), anti-Ro52 (TRIM 21), anti-Ku, anti-B23, anti-RuvBL1, anti-RuvBL2, anti-fibrin bound tissue plasminogen activator, anti-endothelial cell, anti-phosphatidylserine-prothrombin complex, anti-endothelin-1 type A receptor, anti-angiotensin II type 1 receptor, anti‑carbonic anhydrase II, anti-fibroblast, anti-cyclic citrullinated peptide, anti-4-sulfated N-Acetyl-lactosamine, class I and II anti-human leukocyte antigen.
Auto-antibodies were shown by different authors to be associated to this condition, with different prevalence values for each type of auto-antibody. Antinuclear antibodies, anti-centromere antibodies, antiphospholipid antibodies, anti-U3 RNP antibodies and anti-Th/To antibodies would appear to show a particularly important prevalence in scleroderma patients with pulmonary hypertension, appearing in about 8/10 (antinuclear), 1/ 2 (anti-centromere, anti-phospholipid), and 1/4 (anti-U3RNP, anti-Th/To) of patients.
The available evidence points in the direction of a strong association between auto-immune mechanisms and pulmonary hypertension in the setting of scleroderma.
Publication date: Available online 12 October 2018
Source: Autoimmunity Reviews
Author(s): Cristina Belizna, Francesca Pregnolato, Sebastien Abad, Jaume Alijotas-Reig, Howard Amital, Zahir Amoura, Laura Andreoli, Emmanuel Andres, Achile Aouba, Sule Apras Bilgen, Laurent Arnaud, Boris Bienvenu, Viktoria Bitsadze, Patrick Blanco, Miri Blank, Maria Orietta Borghi, Antonia Caligaro, Elisabeta Candrea, Valentina Canti, Laurent Chiche
The relapse rate in antiphospholipid syndrome (APS) remains high, i.e. around 20%–21% at 5 years in thrombotic APS and 20–28% in obstetrical APS (Cervera et al., 2009, 2015 [2,3]).
Hydroxychloroquine (HCQ) appears as an additional therapy, as it possesses immunomodulatory and anti-thrombotic various effects (Pericleous et al., 2016; Andrade and Tektonidou, 2016; Belizna, 2015; Erkan et al., 2014; Erkan and Lockshin, 2012; De Carolis et al., 2015; Mekinian et al., 2015; Merashli et al., 2015; Galli, 2014; Lopez-Pedrera et al., 2015; Hu et al., 2017; Ben-Zvi et al., 2012; Belizna et al., 2017 [[4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16]]).
Our group recently obtained the orphan designation of HCQ in antiphospholipid syndrome by the European Medicine Agency.
Furthermore, the leaders of the project made the proposal of an international project, HIBISCUS, about the use of Hydroxychloroquine in secondary prevention of obstetrical and thrombotic events in primary APS. This study has been launched in several countries and at now, 53 centers from 16 countries participate to this international trial.
This trial consists in two parts: a retrospective and a prospective study.
The French part of the trial in thrombosis has been granted by the French Minister of Health in December 2015 (the academic trial independent of the pharmaceutical industry PHRC N PAPIRUS) and is coordinated by one of the members of the leading consortium of HIBISCUS.
Publication date: Available online 12 October 2018
Source: Autoimmunity Reviews
Author(s): George J. Kahaly, Lara Frommer, Detlef Schuppan
Celiac disease is a small intestinal inflammatory disease with autoimmune features that is triggered and maintained by the ingestion of the storage proteins (gluten) of wheat, barley and rye. The prevalence of celiac disease is increased in patients with monoglandular and/or polyglandular autoimmunity and their relatives. Between 10 and 30% of patients with celiac disease are thyroid and/or type 1 diabetes antibody positive, while around 5 to 7% of patients with autoimmune thyroid disease and/or type 1 diabetes are IgA anti-tissue transglutaminase antibody positive. The close relationship between celiac disease and endocrine autoimmunity is largely explained by sharing a common genetic background. The HLA antigens DQ2 (DQA1*0501-DQB1*0201) and/or DQ8 (DQA1*0301-DQB1*0302), that are tightly linked to DR3 and DR4, respectively, are the major common genetic predisposition. Moreover, functional single nucleotide polymorphisms of various genes that are involved in immune regulation have been identified as "overlap" susceptibility genes for both celiac disease and monoglandular or polyglandular autoimmunity. While plausible, it remains to be established how far a gluten free diet may prevent or ameliorate glandular autoimmunity. In conclusion, all patients with celiac disease should be screened for type 1 diabetes and/or autoimmune thyroid disease. Conversely, patients with the above autoimmune endocrine disorders should be also screened for celiac disease.
Publication date: Available online 12 October 2018
Source: Autoimmunity Reviews
Author(s): Giovanni Maria Rossi, Alessandro Mannoni, Gerardo Di Scala, Elena Silvestri, Rafaela Diana Cojan, Lorenzo Vannozzi, Alessandra Bettiol, Augusto Vaglio, Giacomo Emmi
Publication date: Available online 12 October 2018
Source: Autoimmunity Reviews
Author(s): Jan Willem Cohen Tervaert
In the present review, recent findings regarding autoimmune/inflammatory syndrome by adjuvants (ASIA) are described. Patients with ASIA present with complaints such as fatigue, cognitive impairment, arthralgias, myalgias, pyrexia, dry eyes and dry mouth. During the last few years, it has been postulated that these symptoms in patients with foreign body implants are due to a chronic inflammatory process and an adjuvant effect of the implanted biomaterial. Ultimately, these inflammatory reactions result in (an increase of) allergies, autoimmune diseases, immune deficiency and/or lymphomas.
Pre-existent allergic disease has been found to be an important risk factor for the development of ASIA after foreign body implantation. Explantation of the foreign body results in the majority of patients in an amelioration of the symptoms. There is an urgent need to start adequately adjusted epidemiological studies to obtain better evidence which percentage of patients does develop symptoms and/or diseases such as ASIA, immune deficiency, and/or autoimmune diseases after implant surgery.
Publication date: Available online 12 October 2018
Source: Autoimmunity Reviews
Author(s): Guillermo Carvajal Alegria, Matthieu Groh, Dewi Guellec, Eric Toussirot, Julien Rigaud, Martin Soubrier, Sébastien Ottaviani, Guillaume Direz, Alain Saraux, Divi Cornec, CRI (Club Rhumatisme et inflammation)
Publication date: Available online 12 October 2018
Source: Autoimmunity Reviews
Author(s): Audrey Beringer, Pierre Miossec
The pro-inflammatory cytokine interleukin(IL)-17 and IL-17-producing cells are important players in the pathogenesis of many autoimmune / inflammatory diseases. More recently, they have been associated with liver diseases. This review first describes the general knowledge on IL-17 and IL-17 producing cells. The second part describes the in vitro and in vivo effects of IL-17 on liver cells and the contribution of IL-17 producing cells to liver diseases. IL-17 induces immune cell infiltration and liver damage driving to hepatic inflammation and fibrosis and contributes to autoimmune liver diseases. The circulating levels of IL-17 and the frequency of IL-17-producing cells are elevated in a variety of acute and chronic liver diseases. The last part focuses on the effects of IL-17 deletion or neutralization in various murine models. Some of these observed beneficial effects suggest that targeting the IL-17 axis could be a new therapeutic strategy to prevent chronicity and progression of various liver diseases.
Publication date: Available online 12 October 2018
Source: Autoimmunity Reviews
Author(s): Xiaoyang Yue, Xinhua Yu, Frank Petersen, Gabriela Riemekasten
SSc is a complex rheumatoid disease characterized by autoimmunity, fibrosis and vasculopathy. Mouse models provide powerful research tools for exploring the pathogenesis of the human diseases. Each mouse model can represent a specific way leading to the development of disease. Moreover, mouse models can be used to investigate the role of candidate molecule in the pathogenesis of disease. So far, more than twenty mouse models for SSc have been established and provide new insights in the understanding of the pathogenesis of SSc. In this review, we provide an overview on recent advances in the field of experimental SSc. We introduce novel mouse models generated in the recent years and discuss their relevance to the SSc pathogenesis. Moreover, we summarize and discuss recent findings in the pathogenesis of classical SSc mouse models.
Publication date: Available online 12 October 2018
Source: Autoimmunity Reviews
Author(s): Gwendoline Montes Diaz, Raymond Hupperts, Judith Fraussen, Veerle Somers
Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system (CNS) in which demyelination and neurodegeneration occurs. The immune system of MS patients is characterized by a dysregulation in the balance between pro- and anti-inflammatory immune cells, whereby both the innate and adaptive immune system are involved. Dimethyl fumarate (DMF) was licensed in 2013 as an oral first-line therapy for relapsing-remitting (RR)MS patients. It has a strong efficacy with neuroprotective and immunomodulatory effects and a favourable benefit-risk profile. However, the effects of DMF on the immune system of MS patients were not clear before entering the market. During the last years, numerous in vitro and ex vivo studies have clarified the working mechanism of DMF in MS. Here, we discuss the pharmacokinetics of DMF and its effect on molecular immune-related pathways, which is further linked to the clinical and immunological effects of DMF treatment. The efficacy and safety of DMF treatment for RRMS is discussed as reported from clinical trials. Further, the immunological effects of DMF treatment in RRMS patients are addressed in more detail, including the distribution and function of immune cells. Taken together, evidence from recent studies points to a multifactorial working mechanism of DMF treatment in MS which leads to a restored immune balance favouring a more tolerogenic or anti-inflammatory immune profile.
Publication date: Available online 11 October 2018
Source: Autoimmunity Reviews
Author(s): Thibaud Chazal, Raphael Lhote, Grégoire Rey, Julien Haroche, Mireille Eb, Zahir Amoura, Fleur Cohen Aubart
Objectives: Giant--cell arteritis (GCA) is a large vessel vasculitis. Data regarding mortality are controversial. We describe the mortality data of the French death certificates for the period of 2005 to 2014.
Methods: Using multiple--cause--of--death (MCOD) analysis, we calculated age--adjusted mortality rates for GCA, examined differences in mortality rates according to age and gender and analyzed the underlying causes of death (UCD).
Results
We analyzed 4628 death certificates listing a diagnosis of GCA as UCD or non-underlying cause of death (NUCD). The mean age of death was 86 (±6.8) years. The overall age--standardized mortality rate among GCA patients was 7.2 per million population. Throughout the study period, the mean age of death was significantly increased (r = 0.17, p < .0001) in both genders. There was no significant difference with age repartition of death in the general population (p = .26). When GCA was listed as the UCD, most frequent associated diseases were cardiovascular (79%) and infectious diseases (35%). When GCA was reported as the NUCD, the listed UCD was a cardiovascular event in 40% of cases, neoplasm in 13%, neurodegenerative disorder in 11% and infectious disease in 10%. When GCA was the UCD or NUCD, an age--adjusted observed/expected ratio > 1 in GCA--associated mortality compared with the general population mortality was observed for tuberculosis, pneumonia and cardiovascular diseases.
Conclusion: In this analysis of French death certificates mentioning GCA, we observed a.
stable standardized mortality rate between 2005 and 2014. The most frequent associated diseases were cardiovascular diseases and infections.
Publication date: Available online 11 October 2018
Source: Autoimmunity Reviews
Author(s): Gustavo Noffs, Thushara Perera, Scott Camaron Kolbe, Camille Jessica Shanahan, Frederique Maria Christina Boonstra, Andrew Evans, Helmut Butzkueven, Anneke van der Walt, Adam Phillip Vogel
IMPORTANCE: Multiple sclerosis produces neurological impairments that are variable in duration, severity and quality. Speech is frequently impaired, resulting in decreased communication skills and quality of life. Advancements in technology now makes it possible to use quantitative acoustic assessment of speech as biomarkers of disease progression.
OBSERVATIONS: Four domains of speech have been identified: articulation (slow articulation and imprecise consonants), voice (pitch and loudness instability), respiration (decreased phonatory time and expiratory pressure) and prosody (longer and frequent pauses, deficient loudness control). Studies also explored I) predictive models for diagnosis of MS and of ataxia using speech variables, II) the relationship of dysarthria with cognition and III) very few studies correlated neuroimaging with dysarthria. We could not identify longitudinal studies of speech or dysarthria in Multiple Sclerosis.
CONCLUSION AND RELEVANCE: Refinement of objective measures of speech has enhanced our understanding of Multiple Sclerosis-related deficits in cross-sectional analysis while both integrative and longitudinal studies are identified as major gaps. This review highlights the potential for using quantitative acoustic assessments as clinical endpoints for diagnosing, monitoring progression and treatment in disease modifying trials.
