Purpose: Restoration of iodine incorporation (redifferentiation) by MAPK inhibition was achieved in previously radioiodine-refractory, unresectable thyroid carcinoma (RR-TC). However, results were unsatisfactory in BRAFV600E-mutant (BRAF-MUT) RR-TC. Here we assess safety and efficacy of redifferentiation therapy through genotype-guided MAPK-modulation in patients with BRAF-MUT or wildtype (BRAF-WT) RR-TC. Patients and Methods: In this prospective single-center, two-arm phase II study, patients received trametinib (BRAF-WT) or trametinib + dabrafenib (BRAF-MUT) for 21 ± 3 days. Redifferentiation was assessed by 123I-scintigraphy. In case of restored radioiodine uptake, 124I-guided 131I therapy was performed. Primary endpoint was the redifferentiation rate. Secondary endpoints were treatment response (thyroglobulin, RECIST 1.1) and safety. Parameters predicting successful redifferentiation were assessed using a receiver operating characteristic analysis and Youden J statistic. Results: Redifferentiation was achieved in 7 of 20 (35%) patients, 2 of 6 (33%) in the BRAF-MUT and 5 of 14 (36%) in the BRAF-WT arm. Patients received a mean (range) activity of 300.0 (273.0–421.6) mCi for 131I therapy. Any thyroglobulin decline was seen in 57% (4/7) of the patients, RECIST 1.1 stable/partial response/progressive disease in 71% (5/7)/14% (1/7)/14% (1/7). Peak standardized uptake value (SUVpeak) < 10 on 2[18F]fluoro-2-deoxy-D-glucose (FDG)-PET was associated with successful redifferentiation (P = 0.01). Transient pyrexia (grade 3) and rash (grade 4) were noted in one patient each. Conclusions: Genotype-guided MAPK inhibition was safe and resulted in successful redifferentiation in about one third of patients in each arm. Subsequent 131I therapy led to a thyroglobulin (Tg) decline in more than half of the treated patients. Low tumor glycolytic rate as assessed by FDG-PET is predictive of redifferentiation success. See related commentary by Cabanillas et al., p. 4164

Cardiac transthyretin amyloidosis is an infiltrative cardiomyopathy with high mortality. To date, there are no specific biomarkers to directly assess disease activity and response to specific treatments. Our aim was to evaluate scintigraphic changes after treatment with the transthyretin stabilizer tafamidis. Methods: We included patients who had undergone ^99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (^99mTc-DPD) scintigraphy before tafamidis initiation and after at least 9 mo. Tracer activity was assessed visually and quantitatively as SUV_max. Results: The study included 14 patients who were on tafamidis for 44 ± 14 mo. We observed regression of Perugini grade in 5 patients, unchanged grade in 9 patients, and regression of mean heart–to–contralateral-lung ratio (P = 0.015) and SUV_max (P = 0.005). There were no changes in N-terminal pro-B-type natriuretic peptide or echocardiographic measures. Conclusion: Treatment with tafamidis results in regression of myocardial ^99mTc-DPD uptake. ^99mTc-DPD scintigraphy may provide useful imaging biomarkers to assess response to treatment. Visual Abstract

Among various nanoparticles tested for pharmacological applications over the recent years, graphene quantum dots (GQDs) seem to be promising candidates for the construction of drug delivery systems due to their superior biophysical and biochemical properties. The subcellular fate of incorporated nanomaterial is decisive for transporting pharmaceuticals into target cells. Therefore a detailed characterization of the uptake of GQDs into different breast cancer models was performed. The demonstrated accumulation inside the endolysosomal system might be the reason for the particles’ low toxicity, but has to be overcome for cytosolic or nuclear drug delivery. Furthermore, the penetration of GQDs into precision-cut mammary tumor slices was studied. These constitute a far closer to reality model system than monoclonal cell lines. The constant uptake into the depth of the tissue slices underlines the systems’ potential for drug delivery into solid tumors.

Background: The clinical phenotype of poorly differentiated thyroid cancer (PDTC) can vary substantially. We aim to evaluate risk factors for radioiodine refractory (RAI-R) disease and reduced overall survival (OS). Methods: We retrospectively screened our institutional database for PDTC patients. For the assessment of RAI-R disease, we included patients who underwent dual imaging with ¹⁸F-FDG-PET and ¹²⁴I-PET/¹³¹I scintigraphy that met the internal standard of care. We tested primary size, extrathyroidal extension (ETE), and age >55 years as risk factors for RAI-R disease at initial diagnosis and during the disease course using uni- and multivariate analyses. We tested metabolic tumor volume (MTV), total lesion glycolysis (TLG) on ¹⁸F-FDG-PET, and the progression of stimulated thyroglobulin within 4–6 months of initial radioiodine therapy as prognostic markers for OS. Results: Size of primary >40 mm and ETE were significant predictors of RAI-R disease in the course of disease in univariate (81% vs. 27%, p = 0.001; 89% vs. 33%, p < 0.001) and multivariate analyses. Primary tumor size was an excellent predictor of RAI-R disease (AUC = 0.90). TLG/MTV > upper quartile and early thyroglobulin progression were significantly associated with shorter median OS (29.0 months vs. 56.9 months, p < 0.05; 57.8 months vs. not reached p < 0.005, respectively). Discussion: PDTC patients, especially those with additional risk factors, should be assessed for RAI-R disease at initial diagnosis and in the course of disease, allowing for early implementation of multimodal treatment. Primary tumor size >40 mm, ETE, and age >55 are significant risk factors for RAI-R disease. High MTV/TLG is a significant risk factor for premature death and can help identify patients requiring intervention.

Novel therapeutic options have significantly improved survival and long-term outcomes in many cancer entities. Unfortunately, this improvement in outcome is often accompanied by new and increasingly relevant therapy-related cardiovascular toxicity. In this context, cardiooncology has emerged as a new field of interdisciplinary individual patient care. Important tasks are pretherapeutic risk stratification and early detection and treatment of cardiotoxicity, which comprises cardiac damage in relation to cardiovascular comorbidities, the tumor disease, and cancer treatment. Clinical manifestations can cover a broad spectrum, ranging from subtle and usually asymptomatic abnormalities to serious acute or chronic complications. Typical manifestations include acute and chronic heart failure, myo- and pericarditis, arrythmias, ischemia, and endothelial damage. They can be related to almost all current cancer treatments, including cytotoxic chemotherapy, targeted therapy, immunotherapy, hormonal therapy, and radiotherapy. Molecular imaging biomarkers can aid in pretherapeutic cardiooncologic assessment for primary prevention and personalized surveillance, detection, and differential diagnosis of cardiotoxic complications. Potential advantages over conventional diagnostics are the higher detection sensitivity for subtle changes in cardiac homeostasis, higher reproducibility, and better observer independence. Hybrid imaging with highly sensitive PET/MRI may be particularly suited for early diagnosis. Important technologies that are encouraged in current multidisciplinary guidelines are equilibrium radionuclide angiography for evaluation of ventricular function and chamber morphology, as well as myocardial perfusion imaging for additional detection of ischemia. Novel modalities that may detect even earlier signs of cardiotoxicity comprise ¹²³I-metaiodobenzylguanidine SPECT to visualize sympathetic innervation, ¹⁸F-FDG and somatostatin receptor (⁶⁸Ga-DOTATOC/DOTATATE) PET to indicate a metabolic shift and inflammation, and ⁶⁸Ga-fibroblast activation protein inhibitor PET to monitor cardiac remodeling. In addition, PET imaging of mitochondrial function has recently been introduced in preclinical models and will potentially broaden the field of application through higher sensitivity and specificity and by enabling higher individualization of diagnostic concepts.