Targeting Thyroid Stimulating Hormone Receptors in Radioiodine Resistant Dedifferentiated Thyroid Cancer

PhDThe most common type of thyroid cancer, differentiated thyroid cancer (DTC), is diagnosed by radioactive iodine whole body scanning (WBS) and treated with radiotherapy using iodine-131 (131I). The success of this diagnosis/treatment approach relies on the relatively selective localisation of the sodium/iodide symporter (NIS) in cells of the thyroid gland. However, in some de-differentiated thyroid cancers, NIS expression is lost. This results in the inability of WBS to stage the disease and it also decreases the effectiveness of treatment with 131I. A number of reports have shown that de-differentiated thyroid carcinomas, however, continue to express thyroid stimulating hormone receptor (TSHR). TSHR is, therefore, a potential target for the diagnosis and treatment of radioiodine resistant de-differentiated thyroid carcinoma. In this study an anti-TSHR monoclonal antibody (mAb9) and human recombinant TSH (rhTSH) were radiolabelled and evaluated for their potential use in the diagnosis and treatment of radioiodine resistant thyroid cancer. A number of radiolabelling methods and quality control experiments were initially carried out to ensure high purity radiolabelled mAb9 and rhTSH were produced. In vitro studies were conducted to assess the binding affinity of 125I-mAb9, 111In-mAb9 and 125I-rhTSH to the TSHR in thyroid cancer cell lines, TPC-1, FTC-133, and FRTL5, and in a TSHR transfected cell line, GPI. SPECT/CT animal studies were performed in mice to investigate whether 125I-mAb9, 111In-mAb9 and 125I-rhTSH bound to TSHR in the thyroid of mice in vivo. 125I-mAb9, 111In-mAb9 and 125I-rhTSH bound to GPI cells but did not bind specifically to the TSHR in FTC-133, TPC-1 and FRTL5 cells as well as to the thyroid of normal mice in vivo. Radiolabelled mAb9 and radiolabelled rhTSH are therefore unlikely to be of use in the diagnosis and treatment of radioiodine resistant de-differentiated thyroid cancer.Cancer Research U

A randomized controlled trial to investigate the use of acute coronary syndrome therapy in patients hospitalized with COVID-19: the COVID-19 Acute Coronary Syndrome trial.

BackgroundPatients hospitalized with COVID-19 suffer thrombotic complications. Risk factors for poor outcomes are shared with coronary artery disease.ObjectivesTo investigate the efficacy of an acute coronary syndrome regimen in patients hospitalized with COVID-19 and coronary disease risk factors.MethodsA randomized controlled, open-label trial across acute hospitals (United Kingdom and Brazil) added aspirin, clopidogrel, low-dose rivaroxaban, atorvastatin, and omeprazole to standard care for 28 days. Primary efficacy and safety outcomes were 30-day mortality and bleeding. The key secondary outcome was a daily clinical status (at home, in hospital, on intensive therapy unit admission, or death).ResultsThree hundred twenty patients from 9 centers were randomized. The trial terminated early due to low recruitment. At 30 days, there was no significant difference in mortality (intervention vs control, 11.5% vs 15%; unadjusted odds ratio [OR], 0.73; 95% CI, 0.38-1.41; p = .355). Significant bleeds were infrequent and were not significantly different between the arms (intervention vs control, 1.9% vs 1.9%; p > .999). Using a Bayesian Markov longitudinal ordinal model, it was 93% probable that intervention arm participants were more likely to transition to a better clinical state each day (OR, 1.46; 95% credible interval [CrI], 0.88-2.37; Pr [beta > 0], 93%; adjusted OR, 1.50; 95% CrI, 0.91-2.45; Pr [beta > 0], 95%) and median time to discharge to home was 2 days shorter (95% CrI, -4 to 0; 2% probability that it was worse).ConclusionAcute coronary syndrome treatment regimen was associated with a reduction in the length of hospital stay without an excess in major bleeding. A larger trial is needed to evaluate mortality

A randomized controlled trial to investigate the use of acute coronary syndrome therapy in patients hospitalized with COVID-19: the COVID-19 Acute Coronary Syndrome trial.

BACKGROUND: Patients hospitalized with COVID-19 suffer thrombotic complications. Risk factors for poor outcomes are shared with coronary artery disease. OBJECTIVES: To investigate the efficacy of an acute coronary syndrome regimen in patients hospitalized with COVID-19 and coronary disease risk factors. METHODS: A randomized controlled, open-label trial across acute hospitals (United Kingdom and Brazil) added aspirin, clopidogrel, low-dose rivaroxaban, atorvastatin, and omeprazole to standard care for 28 days. Primary efficacy and safety outcomes were 30-day mortality and bleeding. The key secondary outcome was a daily clinical status (at home, in hospital, on intensive therapy unit admission, or death). RESULTS: Three hundred twenty patients from 9 centers were randomized. The trial terminated early due to low recruitment. At 30 days, there was no significant difference in mortality (intervention vs control, 11.5% vs 15%; unadjusted odds ratio [OR], 0.73; 95% CI, 0.38-1.41; p = .355). Significant bleeds were infrequent and were not significantly different between the arms (intervention vs control, 1.9% vs 1.9%; p > .999). Using a Bayesian Markov longitudinal ordinal model, it was 93% probable that intervention arm participants were more likely to transition to a better clinical state each day (OR, 1.46; 95% credible interval [CrI], 0.88-2.37; Pr [beta > 0], 93%; adjusted OR, 1.50; 95% CrI, 0.91-2.45; Pr [beta > 0], 95%) and median time to discharge to home was 2 days shorter (95% CrI, -4 to 0; 2% probability that it was worse). CONCLUSION: Acute coronary syndrome treatment regimen was associated with a reduction in the length of hospital stay without an excess in major bleeding. A larger trial is needed to evaluate mortality

Mycophenolate and azathioprine efficacy in interstitial lung disease: a systematic review and meta-analysis

Objectives Mycophenolate mofetil (MMF) and azathioprine (AZA) are immunomodulatory treatments in interstitial lung disease (ILD). This systematic review aimed to evaluate the efficacy of MMF or AZA on pulmonary function in ILD.Design Population included any ILD diagnosis, intervention included MMF or AZA treatment, outcome was delta change from baseline in per cent predicted forced vital capacity (%FVC) and gas transfer (diffusion lung capacity of carbon monoxide, %DLco). The primary endpoint compared outcomes relative to placebo comparator, the secondary endpoint assessed outcomes in treated groups only.Eligibility criteria Randomised controlled trials (RCTs) and prospective observational studies were included. No language restrictions were applied. Retrospective studies and studies with high-dose concomitant steroids were excluded.Data synthesis The systematic search was performed on 9 May. Meta-analyses according to drug and outcome were specified with random effects, I2 evaluated heterogeneity and Grading of Recommendations, Assessment, Development and Evaluation evaluated certainty of evidence. Primary endpoint analysis was restricted to RCT design, secondary endpoint included subgroup analysis according to prospective observational or RCT design.Results A total of 2831 publications were screened, 12 were suitable for quantitative synthesis. Three MMF RCTs were included with no significant effect on the primary endpoints (%FVC 2.94, 95% CI −4.00 to 9.88, I2=79.3%; %DLco −2.03, 95% CI −4.38 to 0.32, I2=0.0%). An overall 2.03% change from baseline in %FVC (95% CI 0.65 to 3.42, I2=0.0%) was observed in MMF, and RCT subgroup summary estimated a 4.42% change from baseline in %DLCO (95% CI 2.05 to 6.79, I2=0.0%). AZA studies were limited. All estimates were considered very low certainty evidence.Conclusions There were limited RCTs of MMF or AZA and their benefit in ILD was of very low certainty. MMF may support preservation of pulmonary function, yet confidence in the effect was weak. To support high certainty evidence, RCTs should be designed to directly assess MMF efficacy in ILD.PROSPERO registration number CRD42023423223