ESTIMation of the ABiLity of prophylactic central compartment neck dissection to modify outcomes in low-risk differentiated thyroid cancer: a prospective randomized trial.

BACKGROUND: Prophylactic central neck dissection in clinically low-risk cT1bT2N0 papillary thyroid carcinoma is controversial, due to a large number of conflicting retrospective studies, some showing an advantage in terms of locoregional recurrence, others showing no advantage. These previous studies all show high rates of excellent response. We aim to demonstrate the non-inferiority of thyroidectomy alone as compared to total thyroidectomy with prophylactic central neck dissection in conjunction with adjuvant RAI 30 mCi with rTSH stimulation in terms of excellent response at 1 year. TRIAL DESIGN AND METHODS: Prospective randomized open multicenter phase III trial including patients with 11-40-mm papillary thyroid carcinoma (Bethesda VI) or suspicious cytology (Bethesda V) confirmed malignant on intra-operative frozen section analysis, with no suspicious lymph nodes on a specialized preoperative ultrasound examination. Patients will be randomized 1:1 into two groups: the reference group total thyroidectomy with bilateral prophylactic central neck dissection, and the comparator group total thyroidectomy alone. All patients will receive an ablative dose of 30mCi of radioactive iodine (RAI) within 4 months of surgery. The primary outcome is to compare the rate of excellent response at 1 year after surgery between the groups, as defined by an unstimulated serum thyroglobulin (Tg) level ≤ 0.2 ng/mL with no anti-Tg antibodies, an normal neck ultrasound and no ectopic uptake on the post-RAI scintiscan. Non-inferiority will be demonstrated if the rate of patients with excellent response at 1 year after randomization does not differ by more than 5%. Setting the significance level at 0.025 (one-sided) and a power of 80% requires a sample size of 598 patients (299 per group). Secondary outcomes are to compare Tg levels at 8 +/- 2 postoperative weeks, before RAI ablation, the rate of excellent response at 3 and 5 years, the rate of other responses at 1, 3, and 5 years (biochemical incomplete, indeterminate, and structurally incomplete responses), complications, quality of life, and cost-utility. DISCUSSION (POTENTIAL IMPLICATIONS): If non-inferiority is demonstrated with this high-level evidence, prophylactic neck dissection will have been shown to not be necessary in clinically low-risk papillary thyroid carcinoma. TRIAL REGISTRATION: NCT03570021. June 26,2018.

Thyroidectomy without Radioiodine in Patients with Low-Risk Thyroid Cancer.

BACKGROUND: In patients with low-risk differentiated thyroid cancer undergoing thyroidectomy, the postoperative administration of radioiodine (iodine-131) is controversial in the absence of demonstrated benefits. METHODS: In this prospective, randomized, phase 3 trial, we assigned patients with low-risk differentiated thyroid cancer who were undergoing thyroidectomy to receive ablation with postoperative administration of radioiodine (1.1 GBq) after injections of recombinant human thyrotropin (radioiodine group) or to receive no postoperative radioiodine (no-radioiodine group). The primary objective was to assess whether no radioiodine therapy was noninferior to radioiodine therapy with respect to the absence of a composite end point that included functional, structural, and biologic abnormalities at 3 years. Noninferiority was defined as a between-group difference of less than 5 percentage points in the percentage of patients who did not have events that included the presence of abnormal foci of radioiodine uptake on whole-body scanning that required subsequent treatment (in the radioiodine group only), abnormal findings on neck ultrasonography, or elevated levels of thyroglobulin or thyroglobulin antibodies. Secondary end points included prognostic factors for events and molecular characterization. RESULTS: Among 730 patients who could be evaluated 3 years after randomization, the percentage of patients without an event was 95.6% (95% confidence interval [CI], 93.0 to 97.5) in the no-radioiodine group and 95.9% (95% CI, 93.3 to 97.7) in the radioiodine group, a difference of -0.3 percentage points (two-sided 90% CI, -2.7 to 2.2), a result that met the noninferiority criteria. Events consisted of structural or functional abnormalities in 8 patients and biologic abnormalities in 23 patients with 25 events. Events were more frequent in patients with a postoperative serum thyroglobulin level of more than 1 ng per milliliter during thyroid hormone treatment. Molecular alterations were similar in patients with or without an event. No treatment-related adverse events were reported. CONCLUSIONS: In patients with low-risk thyroid cancer undergoing thyroidectomy, a follow-up strategy that did not involve the use of radioiodine was noninferior to an ablation strategy with radioiodine regarding the occurrence of functional, structural, and biologic events at 3 years. (Funded by the French National Cancer Institute; ESTIMABL2 ClinicalTrials.gov number, NCT01837745.).

Safety and Efficacy of Percutaneous Cryoablation of Extraspinal Thyroid Cancer Bone Metastases with Curative Intent: Single-Center Experience with a Median Follow-up of More than 5 Years.

PURPOSE: To determine the oncologic outcomes and safety profile of image-guided percutaneous cryoablation (PCA) for extraspinal thyroid cancer bone metastases with curative intent. MATERIALS AND METHODS: Between January 2010 and January 2020, 16 consecutive patients (8 men, 8 women; mean age, 61 years ± 19; range, 30-84 years) with 18 bone metastases (median bone tumor size, 19 mm; interquartile range [IQR], 12-29 mm; range, 7-58 mm) underwent PCA of oligometastatic extraspinal bone metastases. Thirteen (81%) patients were radioiodine therapy resistant. Two patients underwent 2 bone tumor ablations in a single session. Procedural data, oncologic outcomes, follow-up (with magnetic resonance imaging and positron emission tomography-computed tomography), and adverse events were retrospectively investigated. Local tumor progression-free survival, disease-free survival, and overall survival were estimated using the Kaplan-Meier method. RESULTS: A median of 2 cryoprobes (IQR, 1.25-3 cryoprobes; range, 1-7 cryoprobes) were used, with 2 freezing cycles; the median length of freezing was 20 minutes (IQR, 17-20 minutes; range, 10-20 minutes). The technical success was 100% (18/18), and the primary technical efficacy was 94.4% (17/18). The median follow-up was 68 months (IQR, 38-93 months). During follow-up, 3 of 17 (17.6%) tumors demonstrated local progression at 7, 13, and 27 months. Consequently, the 1-, 2-, 3-, 4-, and 5-year local tumor progression-free survivals were 93.3%, 84.6%, 76.9%, 75%, and 72.7%, respectively. Two of 16 (12.5%) patients died during follow-up at 43 and 88 months. The major adverse event rate was 5.5% (1/18) with 1 postablative acromion fracture. CONCLUSIONS: PCA for extraspinal thyroid cancer bone metastases demonstrated high local tumor control rates with a safe profile at long-term follow-up.

A New Simple Analytical Method for a Highly Accurate Determination of the Optical Parameters of a Slab from Transmittance Data.

To date, determining with high accuracy the optical parameters (extinction coefficient k and refractive index n) of a slab from the sole transmittance data requires an inverse method based on numerical iteration procedures. In this paper, we propose a new inverse analytical method of extracting (k, n) without numerical iterative processes. The high accuracy of this new inverse method is assessed, and as an application example, the optical parameters of CaF2 and Si substrates are determined in the IR spectral range of 4-8 µm.

A Functional Spiking Neural Network of Ultra Compact Neurons.

We demonstrate that recently introduced ultra-compact neurons (UCN) with a minimal number of components can be interconnected to implement a functional spiking neural network. For concreteness we focus on the Jeffress model, which is a classic neuro-computational model proposed in the 40's to explain the sound directionality detection by animals and humans. In addition, we introduce a long-axon neuron, whose architecture is inspired by the Hodgkin-Huxley axon delay-line and where the UCNs implement the nodes of Ranvier. We then interconnect two of those neurons to an output layer of UCNs, which detect coincidences between spikes propagating down the long-axons. This functional spiking neural neuron circuit with biological relevance is built from identical UCN blocks, which are simple enough to be made with off-the-shelf electronic components. Our work realizes a new, accessible and affordable physical model platform, where neuroscientists can construct arbitrary mid-size spiking neuronal networks in a lego-block like fashion that work in continuous time. This should enable them to address in a novel experimental manner fundamental questions about the nature of the neural code and to test predictions from mathematical models and algorithms of basic neurobiology research. The present work aims at opening a new experimental field of basic research in Spiking Neural Networks to a potentially large community, which is at the crossroads of neurobiology, dynamical systems, theoretical neuroscience, condensed matter physics, neuromorphic engineering, artificial intelligence, and complex systems.

Biologically Relevant Dynamical Behaviors Realized in an Ultra-Compact Neuron Model.

We demonstrate a variety of biologically relevant dynamical behaviors building on a recently introduced ultra-compact neuron (UCN) model. We provide the detailed circuits which all share a common basic block that realizes the leaky-integrate-and-fire (LIF) spiking behavior. All circuits have a small number of active components and the basic block has only three, two transistors and a silicon controlled rectifier (SCR). We also demonstrate that numerical simulations can faithfully represent the variety of spiking behavior and can be used for further exploration of dynamical behaviors. Taking Izhikevich's set of biologically relevant behaviors as a reference, our work demonstrates that a circuit of a LIF neuron model can be used as a basis to implement a large variety of relevant spiking patterns. These behaviors may be useful to construct neural networks that can capture complex brain dynamics or may also be useful for artificial intelligence applications. Our UCN model can therefore be considered the electronic circuit counterpart of Izhikevich's (2003) mathematical neuron model, sharing its two seemingly contradicting features, extreme simplicity and rich dynamical behavior.

Evidence of Biorealistic Synaptic Behavior in Diffusive Li-based Two-terminal Resistive Switching Devices.

Following the recent advances in artificial synaptic devices and the renewed interest regarding artificial intelligence and neuromorphic computing, a new two-terminal resistive switching device, based on mobile Li+ ions is hereby explored. Emulation of neural functionalities in a biorealistic manner has been recently implemented through the use of synaptic devices with diffusive dynamics. Mimicking of the spontaneous synaptic weight relaxation of neuron cells, which is regulated by the concentration kinetics of positively charged ions like Ca2+, is facilitated through the conductance relaxation of such diffusive devices. Adopting a battery-like architecture, using LiCoO2 as a resistive switching cathode layer, SiOx as an electrolyte and TiO2 as an anode, Au/LiCoO2/SiOx/TiO2/p++-Si two-terminal devices have been fabricated. Analog conductance modulation, via voltage-driven regulation of Li+ ion concentration in the cathode and anode layers, along with current rectification and nanobattery effects are reported. Furthermore, evidence is provided for biorealistic synaptic behavior, manifested as paired pulse facilitation based on the summation of excitatory post-synaptic currents and spike-timing-dependent plasticity, which are governed by the Li+ ion concentration and its relaxation dynamics.

Incidental thyroid papillary microcarcinoma: survival and follow-up.

OBJECTIVES/HYPOTHESIS: The aim was to study the survival of incidental thyroid papillary microcarcinoma patients treated with surgery for benign thyroid disease to validate absence of oncological follow-up and reduce unnecessary health expenses. STUDY DESIGN: Retrospective cohort study. METHODS: We analyzed patient's files and interviewed 252 patients by telephone whose cases were submitted to the multidisciplinary meeting of thyroid pathology in Strasbourg, France, for incidental thyroid papillary microcarcinoma without clinical lymph node involvement, between January 1996 and December 2012. RESULTS: Thirteen patients (5.8%) died while the data were being collected; however, none of the deaths were due to the thyroid pathology, and no patients showed signs of relapse of the thyroidectomy or cervical lymph node level. CONCLUSIONS: Our retrospective study shows that patients with incidental localized thyroid papillary microcarcinoma who underwent surgery without radioactive iodine treatment have an identical survival compared to the general population at the same age to validate absence of oncological follow-up and reduce unnecessary health expenses. LEVEL OF EVIDENCE: 3 Laryngoscope, 129:1722-1726, 2019.

Direct Evidence of Lithium Ion Migration in Resistive Switching of Lithium Cobalt Oxide Nanobatteries.

Lithium cobalt oxide nanobatteries offer exciting prospects in the field of nonvolatile memories and neuromorphic circuits. However, the precise underlying resistive switching (RS) mechanism remains a matter of debate in two-terminal cells. Herein, intriguing results, obtained by secondary ion mass spectroscopy (SIMS) 3D imaging, clearly demonstrate that the RS mechanism corresponds to lithium migration toward the outside of the Lix CoO2 layer. These observations are very well correlated with the observed insulator-to-metal transition of the oxide. Besides, smaller device area experimentally yields much faster switching kinetics, which is qualitatively well accounted for by a simple numerical simulation. Write/erase endurance is also highly improved with downscaling - much further than the present cycling life of usual lithium-ion batteries. Hence very attractive possibilities can be envisaged for this class of materials in nanoelectronics.

Value of fine-needle aspiration in evaluating large thyroid nodules.

BACKGROUND: The American Thyroid Association (ATA) recommends using ultrasound-guided fine-needle aspiration (FNA) in order to evaluate supracentimetric and suspect thyroid nodules. The purpose of this study was to evaluate the effective use of FNA before surgery for nodules over 3 cm in diameter. METHODS: In this retrospective study, we analyzed the results of ultrasound-guided FNA and postoperative histological analysis in 843 nodules >3 cm. RESULTS: The FNA was informative in 42.6%. The correlation with the final histological analysis was 94.8% for benign nodules and 71.0% for malignant nodules. The FNA had a positive predictive value of 71%, a specificity of 97%, a sensitivity of 56%, and a 4.7% rate of false-negative results. CONCLUSION: Because there is a nonnegligible FNA risk of error, notably allowing the evolution of a cancer in 1 of 20 cases, the FNA data should not delay surgical intervention for potentially suspect nodules >3 cm in diameter. © 2016 Wiley Periodicals, Inc. Head Neck 39: 32-36, 2017.

(18)F-DOPA PET/CT in the diagnosis and localization of persistent medullary thyroid carcinoma.

PURPOSE: To evaluate the performance of (18)F-L-dihydroxyphenylalanine ((18)F-DOPA) PET/CT in the detection of locoregional and distant medullary thyroid carcinoma (MTC) metastases and to compare imaging findings with histological data. METHODS: We retrospectively evaluated 86 MTC patients with persistently high serum calcitonin levels after initial surgery who had undergone (18)F-DOPA PET/CT between January 2007 and December 2014 in two referral centres. They were followed up for at least 6 months after the PET/CT assessment. The results were compared with histological data or with the findings obtained during follow-up using a complementary imaging modality. RESULTS: (18)F-DOPA PET/CT was positive in 65 of the 86 patients, corresponding to a patient-based sensitivity of 75.6 %. Distant metastatic disease (M1) was seen in 29 patients including 11 with previously unknown metastases revealed only by PET/CT. Among the 36 patients without distant metastatic spread, 25 had nodal involvement limited to the neck, and 10 of these 25 patients underwent reoperation. The lymph node compartment-based sensitivity of (18)F-DOPA PET/CT was 100 % in the two institutions but lesion-based sensitivity was only 24 %. Preoperative and postoperative median calcitonin levels were 405 pg/mL (range 128 - 1,960 pg/mL) and 259 pg/mL (range 33 - 1,516 pg/mL), respectively. None of the patients achieved normalization of serum calcitonin after reoperation. CONCLUSION: (18)F-DOPA PET/CT enables early diagnosis of a significant number of patients with distant metastasis. It has a limited sensitivity in the detection of residual disease but provides high performance for regional analysis. A surgical compartment-oriented approach could be the approach of choice whatever the number of nodes revealed by (18)F-DOPA PET/CT.

Vandetanib for the treatment of advanced medullary thyroid cancer outside a clinical trial: results from a French cohort.

BACKGROUND: A randomized phase III trial demonstrated that vandetanib treatment is effective in patients with metastatic medullary thyroid cancer (MTC), leading to regulatory approval, but its use may be associated with toxicities that require specific monitoring and management. The objective of the present study performed in France was to describe the toxicity profile and efficacy of vandetanib treatment when given outside any trial. METHODS: Sixty-eight patients were treated with vandetanib in the frame of a temporary use authorization (ATU) in France from August 2010 to February 2012, when the drug was available on request for patients with locally advanced or metastatic MTC. Patients were registered by the French health authorities, and characteristics, treatment parameters, toxicity profile, and efficacy were retrospectively reviewed. Eight patients were excluded from the analysis because vandetanib treatment was not administered (n=3), had been given in a trial before ATU (n=3), or was given for a non-MTC cancer (n=2). RESULTS: Data from the 60 MTC patients were analyzed. Mean age was 58 years (range 11-83 years), 39 patients were male, and six had hereditary MTC. Fifty-six (93%) had metastatic disease in the mediastinum (82%), bones (65%), liver (53%), or lung (53%), and four had only locally advanced disease. At the time of study evaluation, with a median follow-up of 20 months and a median duration of treatment of 9.7 months (range 0.3-36 months), 15 patients were continuing vandetanib treatment (range 18-36 months). Median progression-free survival was 16.1 months. Twenty-five patients discontinued treatment for disease progression (range 0.3-29 months). Best tumor response was a complete response in one patient, a partial response in 12 (20%), stable disease in 33 (55%), and progression in seven patients (12%). All patients had at least one adverse event (AE) during treatment. The main AEs were skin toxicity, diarrhea, and asthenia. Sixteen patients (27%) discontinued treatment for toxicity, and one patient died from vandetanib-induced cardiac toxicity. CONCLUSIONS: Vandetanib is an effective option for patients with advanced MTC. AEs should be monitored carefully and should be minimized by educating both patients and care providers and by applying symptomatic treatment and dose reduction.

Terminal ileum neuroendocrine incidentaloma in a patient with sporadic medullary thyroid carcinoma: findings from 18F-FDOPA PET/CT investigation.

An incidentaloma is a mass lesion incidentally found, of uncertain significance, and clinically inert. Although incidentaloma is commonly referred to designate an adrenal lesion, it can denote any incidental lesion of other organs. We describe the unexpected finding of an ileum neuroendocrine incidentaloma detected by 6-L-(18F)-fluorodihydroxyphenylalanine (FDOPA) PET/CT performed in an asymptomatic patient with history of sporadic medullary thyroid carcinoma and biochemical suspicion of recurrent disease. This report underlines the high FDOPA PET/CT sensitivity for neuroendocrine tumor detection and the need of complementary diagnostic investigations elucidating the significance of extraphysiological FDOPA intestinal uptake, even in patients with unrelated primary cancer.

Conducting-probe AFM nanoscale joule heating yields charge-density-wave transition detection.

Several layered transition-metal dichalcogenides are studied using conducting probe AFM aiming to investigate the probe-mediated thermal processes likely to arise in the probe-substrate vicinity due to the high-current densities involved. A signature of local heating is found in the shape of current-potential (i/V) curves. The latter allows straightforward detection of a charge-density-wave (CDW) transition for 1T-TaSe(2) samples exhibiting it above room temperature. This is an illustration of a new use of conducting probe AFM to investigate solid-state bulk characteristics owing to a distinctive nanoscale Joule heating.