Radioiodine therapy of thyroid autonomy.

Radioiodine therapy (RIT) of thyroid functional autonomy (TFA) is rapidly evolving, though it has been recognized for decades as a very effective treatment of toxic nodular varieties. Indeed, TFA is a frequent cause of persistent subclinical hyperthyroidism, which should be regarded as a new metabolic syndrome, with well-established adverse cardio-vascular consequences. Sensitive TSH assays and multiparametric ultrasounds are not accurate enough to reliably diagnose TFA and identify its main variants, unifocal, multifocal (UFA/MFA) and disseminated autonomy (DISA). Modern diagnostic tools are extensively presented and rely upon Thyroid Scan imaging and quantification. A new relationship allows predicting at baseline, an excess of 123I uptake as compared to the TSH stimulation in compensated TFA. Suppressed TS are useful with either isotope, otherwise. Diagnosis of the DISA variant is presented as compared to Graves' disease. Dosimetry has some specificity in TFA work-up. Indeed, the spatial distribution of the dose is as important as the mean value itself and can be eventually controlled by adjusting the TSH level with the smart use of LT3 or antithyroid drug therapy (ATD). A review of the different ways to determine the target mass from anatomical to functional approaches is presented. Main clinical and dosimetric published results of RIT are summarized according to clinical goals. Endogenous TSH stimulation using an ATD preparation has promising results in reducing big autonomously functioning goiters. Finally, we report preliminary successful results of preventive RIT using short term LT3 suppression in compensated TFA, with low administered activities and low rate of hypothyroidism.

Prolonged response to 177Lu-DOTATATE therapy of a bone marrow infiltration in a refractory thymic neuro endocrine tumor.

Thymic neuro endocrine tumor (tNET) are extremely rare malignancies with poor prognosis, requiring investigation of novel therapeutic approaches. 177Lu-DOTATATE is a successful systemic treatment modality in patients with metastatic gastroenteropancreatic but it role in tNET is not yet well established. Here we report a case of a 39-year-old man with refractory bone marrow infiltration of a tNET, treated by 4 cycles of peptide receptor radionuclide therapy (PRRT) with 177Lu DOTATATE. Since the first cycle, clinical symptoms were substantially decreased, without any severe subacute haematological toxicity. Three months after the end of PRRT, both 68Ga-DOTATOC and 18F-FDG PET confirmed a partial response, already suggested by 177Lu-DOTATATE treatment scan with a significant decrease of the bone marrow uptake between the first and fourth cycle. This report highlights that PRRT could be an effective therapeutic option for advanced bone metastatic disease tNET, with the significant benefit of alleviation of bone pain and radiologic response, without severe or irreversible haematotoxicity.

Left atrial strain and distensibility in relation to left ventricular dysfunction and prognosis in aortic stenosis.

OBJECTIVE: To test the relationship between left atrial (LA) distensibility (LAD), LA strain (LAS), and left ventricular (LV) dysfunction and prognosis in aortic stenosis (AS). METHODS: Transthoracic Doppler echocardiography was performed prospectively in 102 consecutive patients with AS (77 with severe, 25 with moderate, mean age 77 years). LA volume was calculated by the area-length method in apical four- and two-chamber views, immediately before mitral valve opening (Volmax ) and at mitral valve closure (Volmin ). LAD was defined as (Volmax  - Volmin ) × 100%/Volmin . LAS (mean of maximal strain from the 4-2 chamber views) was conducted using a dedicated software package. The endpoint was hospitalization for heart failure and death from any cause. RESULTS: Left atrial strain, LAD, and LA vol/m² were significantly correlated with LV diastolic parameters, and PASP (all, P < 0.05). However, LAD and LAS but not LA vol/m² were significantly correlated with Charlson score, LV global longitudinal strain, and to transaortic mean gradient (all, P < 0.05). At a median follow-up of 25 months, 53 patients had an event. LAS, LAD, LA vol/m², and Charlson index were associated with events (all, P < 0.05). In multivariate analysis, LAD, LAS, and Charlson index (all, P < 0.01) remained independently associated with events. Using a ROC curve analysis, LAD ≤ 69% and LAS ≤ 17% were the best cutoffs associated with an event. CONCLUSION: In patients with moderate to severe AS, LAD and LAS are associated with LV dysfunction, AS severity, and are independently linked to events.

Cyclosporine before PCI in Patients with Acute Myocardial Infarction.

BACKGROUND: Experimental and clinical evidence suggests that cyclosporine may attenuate reperfusion injury and reduce myocardial infarct size. We aimed to test whether cyclosporine would improve clinical outcomes and prevent adverse left ventricular remodeling. METHODS: In a multicenter, double-blind, randomized trial, we assigned 970 patients with an acute anterior ST-segment elevation myocardial infarction (STEMI) who were undergoing percutaneous coronary intervention (PCI) within 12 hours after symptom onset and who had complete occlusion of the culprit coronary artery to receive a bolus injection of cyclosporine (administered intravenously at a dose of 2.5 mg per kilogram of body weight) or matching placebo before coronary recanalization. The primary outcome was a composite of death from any cause, worsening of heart failure during the initial hospitalization, rehospitalization for heart failure, or adverse left ventricular remodeling at 1 year. Adverse left ventricular remodeling was defined as an increase of 15% or more in the left ventricular end-diastolic volume. RESULTS: A total of 395 patients in the cyclosporine group and 396 in the placebo group received the assigned study drug and had data that could be evaluated for the primary outcome at 1 year. The rate of the primary outcome was 59.0% in the cyclosporine group and 58.1% in the control group (odds ratio, 1.04; 95% confidence interval [CI], 0.78 to 1.39; P=0.77). Cyclosporine did not reduce the incidence of the separate clinical components of the primary outcome or other events, including recurrent infarction, unstable angina, and stroke. No significant difference in the safety profile was observed between the two treatment groups. CONCLUSIONS: In patients with anterior STEMI who had been referred for primary PCI, intravenous cyclosporine did not result in better clinical outcomes than those with placebo and did not prevent adverse left ventricular remodeling at 1 year. (Funded by the French Ministry of Health and NeuroVive Pharmaceutical; CIRCUS ClinicalTrials.gov number, NCT01502774; EudraCT number, 2009-013713-99.).

Rationale and design of the Cyclosporine to ImpRove Clinical oUtcome in ST-elevation myocardial infarction patients (the CIRCUS trial).

BACKGROUND: Both acute myocardial ischemia and reperfusion contribute to cardiomyocyte death in ST-elevation myocardial infarction (STEMI). The final infarct size is the principal determinant of subsequent clinical outcome in STEMI patients. In a proof-of-concept phase II trial, the administration of cyclosporine prior to primary percutaneous coronary intervention (PPCI) has been associated with a reduction of infarct size in STEMI patients. METHODS: CIRCUS is an international, prospective, multicenter, randomized, double-blinded, placebo-controlled trial. The study is designed to compare the efficacy and safety of cyclosporine versus placebo, in addition to revascularization by PPCI, in patients presenting with acute anterior myocardial infarction within 12 hours of symptoms onset and initial TIMI flow ≤1 in the culprit left anterior descending coronary artery. Patients are randomized in a 1:1 fashion to 2.5 mg/kg intravenous infusion of cyclosporine or matching placebo performed in the minutes preceding PCI. The primary efficacy end point of CIRCUS is a composite of 1-year all-cause mortality, rehospitalization for heart failure or heart failure worsening during initial hospitalization, and left ventricular adverse remodeling as determined by sequential transthoracic echochardiography. Secondary outcomes will be tested using a hierarchical sequence of left ventricular (LV) ejection fraction and absolute measurements of LV volumes. The composite of death and rehospitalization for heart failure or heart failure worsening during initial hospitalization will be further assessed at three years after the initial infarction. RESULTS: Recruitment lasted from April 2011 to February 2014. The CIRCUS trial has recruited 975 patients with acute anterior myocardial infarction. The 12-months results are expected to be available in 2015. CONCLUSIONS: The CIRCUS trial is testing the hypothesis that cyclosporine in addition to early revascularization with PPCI compared to placebo in patients with acute anterior myocardial infarction reduces the incidence of death, heart failure and adverse LV remodeling at one-year follow-up.

Critical role of sorafenib exposure over time for its antitumor activity in thyroid cancer.

Sorafenib, a multi-kinase inhibitor that targets the VEGF, PDGF and BRAF pathways, has demonstrated significant clinical activity in metastatic differentiated thyroid cancer. However, all patients eventually experience disease progression with a median progression-free survival close to 10 months. Since sorafenib exposure is known to decrease over time, we hypothesized that dose adjustments aiming to restore adequate exposure could lead to further clinical activity. We report, as a proof of concept on a patient with radio-iodine resistant metastatic thyroid cancer, who experienced disease progression after an initial response to sorafenib (400 mg twice daily). Whereas the thyroglobulin-progression-free survival at standard doses was 6 months, iterative dose optimization led to a prolonged progression-free survival up to 41 months. Sorafenib doses were increased up to 1600 mg bid, in order to maintain clinical activity, and to restore active plasma concentration, since sorafenib exposure had decreased over the time. Toxicity was mild and manageable for more than 2 years. However, the patient eventually experienced grade 3 proteinuria leading to treatment discontinuation. This observation opens up new horizons for daily management of radioactive iodine-refractory differentiated thyroid cancer patients progressing under standard doses of sorafenib, and stress the need to monitor its plasma concentration.

Enantioselective total synthesis of the lignan (+)-linoxepin.

An enantioselective total synthesis of the natural (+)-linoxepin (1) was accomplished in eleven steps from bromovanin (24). Key steps are a domino carbopalladation/ Mizoroki-Heck reaction with the formation of a pentacyclic system, an asymmetric hydroboration as well as an oxidative lactonization.

Judgments of relevance in preschoolers: a study of training and transfer of self-cueing strategies.

Introduction: When facing a task, children must analyze it precisely to fully identify what its goal is. This is particularly difficult for young children, who mainly rely on environmental cues to get there. Research suggests that training children to look for the most relevant perceptual cues is promising. Furthermore, as transferring skills to a new task is difficult, the question of whether young children are able to transfer such training remains open. The aim of this study was to test the extent to which two strategies of goal self-cueing-labeling and pointing-can help 4-year-old children to identify the relevant cues to clearly identify the goal of the task. The effects of explicit strategy training were tested in a near transfer task. Method: Ninety-nine typically developing 4 year olds took part in the study. They were divided into three groups: two were trained collectively in one of the two strategies and the third group as a control group with no strategy training. All children performed a cued card-sorting task four times: Pre-test, Collective training, Post-test, and Transfer with new cards. Results: Results confirmed the beneficial effect of strategy training on goal identification, particularly after training (Post-test). In the transfer phase, all three groups performed equally well. Discussion: This study contributes to our understanding of how young children seek information when they look for the most relevant cues for identifying the goal of a task, and the benefits they may derive in a transfer task. It seems that the use of visual cues and self-cueing strategies helps preschoolers to clearly identify the goal of a task. Results are discussed in the light of the self-regulated learning framework. Some possible classroom applications are suggested.

Tumor Location Relative to the Spleen Is a Prognostic Factor in Lymphoma Patients: A Demonstration from the REMARC Trial.

Baseline [18F]FDG PET/CT radiomic features can improve the survival prediction in patients with diffuse large B-cell lymphoma (DLBCL). The purpose of this study was to investigate whether characterizing tumor locations relative to the spleen location in baseline [18F]FDG PET/CT images predicts survival in patients with DLBCL and improves the predictive value of total metabolic tumor volume (TMTV) and age-adjusted international prognostic index (IPI). Methods: This retrospective study included 301 DLBCL patients from the REMARC (NCT01122472) cohort. Physicians delineated the tumor regions, whereas the spleen was automatically segmented using an open-access artificial intelligence algorithm. We systematically measured the distance between the centroid of the spleen and all other lesions, defining the SD of these distances as the lesion spread (SpreadSpleen). We calculated the maximum distance between the spleen and another lesion (Dspleen) for each patient and normalized it with the body surface area, resulting in standardized Dspleen (sDspleen). The predictive value of each PET/CT feature for progression-free survival (PFS) and overall survival (OS) was evaluated through univariate and multivariate time-dependent Cox models and Kaplan-Meier analysis. Results: In total, 282 patients (mean age, 68.33 ± 5.41 y; 164 men) were evaluated. The artificial intelligence algorithm successfully segmented the spleen in 96% of the patients. SpreadSpleen, Dspleen, and sDspleen were correlated neither with TMTV (Pearson ρ < 0.23) nor with IPI (Pearson ρ < 0.15). When median values were used as the cutoff, SpreadSpleen, Dspleen, and sDspleen all significantly classified patients into 2 risk groups for PFS and OS (P < 0.001). They complemented TMTV and IPI to classify the patients into 3 risk groups for PFS and OS (P < 0.001). Integrating SpreadSpleen, Dspleen, or sDspleen into a Cox model on the basis of TMTV, IPI, and TMTV combined with IPI significantly improved the concordance index for PFS and OS (P < 0.05). Conclusion: Baseline PET/CT features that characterize tumor spread and dissemination relative to the spleen strongly predicted survival in patients with DLBCL. Integrating these features with TMTV and IPI further improved survival prediction.

MAPK Pathway Inhibitors in Thyroid Cancer: Preclinical and Clinical Data.

Thyroid cancer is the most common endocrine cancer, with a good prognosis in most cases. However, some cancers of follicular origin are metastatic or recurrent and eventually become radioiodine refractory thyroid cancers (RAIR-TC). These more aggressive cancers are a clinical concern for which the therapeutic arsenal remains limited. Molecular biology of these tumors has highlighted a hyper-activation of the Mitogen-Activated Protein Kinases (MAPK) pathway (RAS-RAF-MEK-ERK), mostly secondary to the BRAFV600E hotspot mutation occurring in about 60% of papillary cancers and 45% of anaplastic cancers. Therapies targeting the different protagonists of this signaling pathway have been tested in preclinical and clinical models: first and second generation RAF inhibitors and MEK inhibitors. In clinical practice, dual therapies with a BRAF inhibitor and a MEK inhibitor are being recommended in anaplastic cancers with the BRAFV600E mutation. Concerning RAIR-TC, these inhibitors can be used as anti-proliferative drugs, but their efficacy is inconsistent due to primary or secondary resistance. A specific therapeutic approach in thyroid cancers consists of performing a short-term treatment with these MAPK pathway inhibitors to evaluate their capacity to redifferentiate a refractory tumor, with the aim of retreating the patients by radioactive iodine therapy in case of re-expression of the sodium-iodide symporter (NIS). In this work, we report data from recent preclinical and clinical studies on the efficacy of MAPK pathway inhibitors and their resistance mechanisms. We will also report the different preclinical and clinical studies that have investigated the redifferentiation with these therapies.

Automated synthesis and quality control of [68Ga]Ga-PentixaFor using the Gaia/Luna Elysia-Raytest module for CXCR4 PET imaging.

BACKGROUND: [68Ga]Ga-PentixaFor is a promising radiotracer for positron emission tomography imaging of several human tumors overexpressing the chemokine receptor-4 (CXCR4). CXCR4 overexpression has been demonstrated in patients with hematologic malignancies, solid cancers, as well as cardiovascular pathologies of inflammatory origins. However, its radio synthesis is not yet fully developed in France, and existing methods do not use our type of synthesis module. Therefore, we aimed at developing a [68Ga]Ga-PentixaFor synthesis with Gaia/Luna Elysia-Raytest module to use it in clinical purpose. RESULTS: 12 syntheses were carried out by varying the temperature conditions and radiolabeling times, and led to choose specific labelling conditions with the Gaia/Luna Elysia-Raytest module: 97 °C, 4 min. The mean synthesis time of the 3 validation runs under good manufacturing practice (GMP) was 24 min 27 s (± 8 s), and the mean radiochemical yield was 87.0% [standard deviation (SD) 6.67%]. Different quality control parameters were also evaluated in accordance with European Pharmacopeia: radiochemical and radionuclidic purity, pH, sterility, stability and endotoxins levels. The average radiochemical purity was 99.1% (SD 0.25%) assessed by instant thin layer chromatography and 99.8% (SD 0.092%) assessed by high pressure liquid chromatography. average [68Ge] breakthrough was 1.48 × 10-5%, under the recommended level of 0.001%. We assessed the stability of the radiotracer up to 4 h at room temperature (no augmentation of the [68Ga] chloride in the final product, i.e. radiochemical purity (RCP) > 98.5%). The endotoxins levels were < 5 EU/mL, and the pH was 6.5 (same for the three syntheses). CONCLUSION: The [68Ga]Ga-PentixaFor synthesis process developed on the Gaia/Luna Elysia-Raytest module has fulfilled all acceptance criteria for injectable radiopharmaceutical products regarding the European Pharmacopeia. The radiochemical purity, stability, efficacy, as well as the microbiological quality of the three GMP batches were found to be good. The robustness of the synthesis process may be suitable for multi-dose application in clinical settings.

Pharmacokinetics/Pharmacodynamics of Dabrafenib and Trametinib for Redifferentiation and Treatment of Radioactive Iodine-Resistant Mutated Advanced Differentiated Thyroid Cancer.

Background: BRAF and MEK inhibitors are cornerstones of the redifferentiation strategy in metastatic radioactive iodine (RAI)-resistant mutant thyroid cancers. We explored the exposure-toxicity relationship for dose-limiting toxicity (DLT) onset in patients treated with dabrafenib and/or trametinib and investigated whether plasma exposure was associated with RAI reuptake. Methods: We conducted a retrospective monocentric study in which we reviewed the electronic medical records of patients treated in our institution with a tumor redifferentiation strategy, for whom plasma concentration of dabrafenib, its active metabolite hydroxy-dabrafenib, and trametinib was measured. Trough concentrations (Cminpred) and total plasma drug exposure (area under the curve, AUC) of dabrafenib (AUCDAB), hydroxy-dabrafenib (AUCOHD), and trametinib (AUCTRA) were estimated. Results: Of the 22 patients treated in a redifferentiation strategy between March 2014 and December 2021, 15 were included in this study. A dabrafenib- or trametinib-related DLT was experienced by 8 (62%) and 9 (64%) patients, respectively. Patients who experienced a trametinib-related DLT exhibited a significantly higher last AUCTRA than the average AUCTRA of patients who had no DLT (390, IQR: 67 vs. 215, IQR: 91 ng/mL·h-1, respectively; p = 0.008). Patients who experienced a dabrafenib-related DLT had a higher AUCDAB than observed in other patients (9265 ng/mL·h-1 vs. 6953 ng/mL·h-1, respectively; p = 0.09). No clinical and demographical characteristic was associated with the DLT onset. Overall, 9 of 15 (60%) patients demonstrated tumor redifferentiation. Patients in whom RAI reuptake was achieved had significant lower AUCDAB (6990 ng/mL·h-1 vs. 9764 ng/mL·h-1, p = 0.014; respectively) compared with patients who did not. Moreover, the relative exposure ratio of AUCOHD/DAB was significantly higher in patients who achieved RAI reuptake (1.11 vs. 0.71, respectively; p = 0.0047). Conclusions: Our data suggest a relationship between DLT onset and trametinib plasma exposure, as well as an association between achievement of RAI reuptake and dabrafenib plasma exposure (AUC and ratio of AUCOHD/DAB). These data imply that the use of plasma drug monitoring could be helpful in guiding clinical practice in redifferentiation treatment.

FCH-PET/CT in Primary Hyperparathyroidism With Discordant/Negative MIBI Scintigraphy and Ultrasonography.

CONTEXT: The contribution of [18F]F-fluorocholine (FCH)-positron emission tomography (PET)/computed tomography (CT) in normocalcemic primary hyperparathyroidism (nPHPT) remains unknown. OBJECTIVE: To evaluate the sensitivity and specificity of FCH-PET/CT in a cohort of osteoporotic patients with nPHPT and discordant or negative [99mTc]Tc-sestamibi scintigraphy and ultrasonography who all underwent parathyroidectomy (PTX). DESIGN: Longitudinal retrospective cohort study in patients referred for osteoporosis with mild biological primary hyperparathyroidism. SETTING: Tertiary referral center with expertise in bone metabolism and surgical management of hyperparathyroidism. PATIENTS: Among 109 patients with PHPT analyzed, 3 groups were individualized according to total serum calcium (tCa) and ionized calcium (iCa): 32 patients with hypercalcemia (HtCa group), 39 patients with normal tCa and elevated iCa (NtCa group), and 38 patients with both normal tCa and iCa (NiCa). All patients had biochemical follow-up confirming or not the success of PTX. MAIN OUTCOME MEASURES: To evaluate the performance of FCH-PET/CT in terms of sensitivity and specificity, and to compare with first-line imaging procedures in the setting of nPHPT. RESULTS: The sensitivity of FCH-PET/CT was 67% in the hypercalcemic group, 48% in the NtCa group (P = .05 vs HtCa), and 33% in the NiCa group (P = .004 vs HtCa). Specificity ranged from 97% to 99%. FCH-PET/CT was positive in 64.3% of patients with negative conventional imaging, with biochemical resolution after PTX in 77.8% of patients. Triple negative imaging was observed in 20 patients, with PHPT resolution in 85% of these patients. CONCLUSION: This study highlights the contribution of FCH-PET/CT in a well-phenotyped cohort of normocalcemic patients with discordant or negative findings in [99mTc]Tc-sestamibi scintigraphy and ultrasonography. However, negative imaging in nPHPT does not rule out the possibility of surgical cure by an experienced surgeon.

Activity enhancement of the synthetic syrbactin proteasome inhibitor hybrid and biological evaluation in tumor cells.

Syrbactins belong to a recently emergent class of bacterial natural product inhibitors that irreversibly inhibit the proteasome of eukaryotes by a novel mechanism. The total syntheses of the syrbactin molecules syringolin A, syringolin B, and glidobactin A have been achieved, which allowed the preparation of syrbactin-inspired derivatives, such as the syringolin A-glidobactin A hybrid molecule (SylA-GlbA). To determine the potency of SylA-GlbA, we employed both in vitro and cell culture-based proteasome assays that measure the subcatalytic chymotrypsin-like (CT-L), trypsin-like (T-L), and caspase-like (C-L) activities. We further studied the inhibitory effects of SylA-GlbA on tumor cell growth using a panel of multiple myeloma, neuroblastoma, and ovarian cancer cell lines and showed that SylA-GlbA strongly blocks the activity of NF-κB. To gain more insights into the structure-activity relationship, we cocrystallized SylA-GlbA in complex with the proteasome and determined the X-ray structure. The electron density map displays covalent binding of the Thr1O(γ) atoms of all active sites to the macrolactam ring of the ligand via ether bond formation, thus providing insights into the structure-activity relationship for the improved affinity of SylA-GlbA for the CT-L activity compared to those of the natural compounds SylA and GlbA. Our study revealed that the novel synthetic syrbactin compound represents one of the most potent proteasome inhibitors analyzed to date and therefore exhibits promising properties for improved drug development as an anticancer therapeutic.

Proteasome activity imaging and profiling characterizes bacterial effector syringolin A.

Syringolin A (SylA) is a nonribosomal cyclic peptide produced by the bacterial pathogen Pseudomonas syringae pv syringae that can inhibit the eukaryotic proteasome. The proteasome is a multisubunit proteolytic complex that resides in the nucleus and cytoplasm and contains three subunits with different catalytic activities: ß1, ß2, and ß5. Here, we studied how SylA targets the plant proteasome in living cells using activity-based profiling and imaging. We further developed this technology by introducing new, more selective probes and establishing procedures of noninvasive imaging in living Arabidopsis (Arabidopsis thaliana) cells. These studies showed that SylA preferentially targets ß2 and ß5 of the plant proteasome in vitro and in vivo. Structure-activity analysis revealed that the dipeptide tail of SylA contributes to ß2 specificity and identified a nonreactive SylA derivative that proved essential for imaging experiments. Interestingly, subcellular imaging with probes based on epoxomicin and SylA showed that SylA accumulates in the nucleus of the plant cell and suggests that SylA targets the nuclear proteasome. Furthermore, subcellular fractionation studies showed that SylA labels nuclear and cytoplasmic proteasomes. The selectivity of SylA for the catalytic subunits and subcellular compartments is discussed, and the subunit selectivity is explained by crystallographic data.