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Purpose: To evaluate the efficacy and safety of dabrafenib-trametinib-131I for the treatment of radioactive iodine refractory metastatic differentiated thyroid cancer (DTC) with a BRAF p.V600E mutation. Patients and Methods: A prospective phase II trial including patients with RECIST progression within 18 months and no lesion > 3 cm. Following a baseline recombinant human (rh)TSH-stimulated diagnostic whole-body scan (dc1-WBS), dabrafenib and trametinib were given for 42 days. A second rhTSH-stimulated dc WBS (dc2-WBS) was done at day 28 and 131I (5.5 GBq–150 mCi after rhTSH) was administered at day 35. Primary endpoint was the 6-month RECIST objective response rate. In case of partial response (PR) at 6 or 12 months, a second treatment course could be given. Among 24 enrolled patients, 21 were evaluable at 6 months. Results: Abnormal 131I uptake was present on 5%, 65%, and 95% of the dc1-WBS, dc2-WBS, and post-therapy scans, respectively. At 6 months, PR was achieved in 38%, stable disease in 52%, and progressive disease (PD) in 10%. Ten patients received a second treatment course: one complete response and 6 PRs were observed at 6 months. The median progression-free survival (PFS) was not reached. The 12- and 24-month PFS were 82% and 68%, respectively. One death due to PD occurred at 24 months. Adverse events (AE) occurred in 96% of the patients, with 10 grade 3–4 AEs in 7 patients. Conclusions: Dabrafenib-trametinib is effective in BRAF p.V600E-mutated DTC patients for restoring 131I uptake with PR observed 6 months after 131I administration in 38% of the patients.

Female thyroid cancer survivors are more likely to have a higher risk of breast cancer compared to the general population, and the underlying causes are yet to be understood. The potential role of I-131 treatment on this association remains controversial.We pooled individual data of women who were treated for differentiated thyroid cancer from 1934 to 2005 in France, Italy and Sweden. Standardized incidence ratios (SIRs) for breast cancer were estimated by comparison with age, sex and calendar-year expected values of the general population in each country. We estimated breast cancer risk in relation to I-131 treatment using time-dependent Poisson models.Of 8475 women (mean age at diagnosis: 45 years, range 2-90 years), 335 were diagnosed with breast cancer [SIR = 1.52, 95% confidence interval (CI): 1.36-1.69] during a median follow-up time of 12.7 years since diagnosis. Overall, breast cancer risk did not differ between women treated or not with I-131 (relative risk=1.07, 95% CI 0.84-1.35). However, breast cancer risk increased with increasing cumulative I-131 activity, without significant departure from linearity (excess relative risk per 100 mCi=17%, 95% CI: 2% to 38%). The higher risk associated with a cumulative I-131 activity of ≥100 mCi and ≥400 mCi was translated into 4 (95% CI -4 to 13) and 42 (95% CI -8 to 93) excess breast cancer cases per 10,000 person-years, respectively.An elevated risk was observed for the highest cumulative administered activity (=400 mCi), and a significant dose-dependent association was observed among thyroid cancer survivors who were treated with I-131. However, overall, I-131 treatment might only explain partly the increase in breast cancer risk among female thyroid cancer survivors.

Waterfall plot of the RECIST response

Quality of Life scores

Purpose:To evaluate the efficacy and safety of dabrafenib-trametinib-131I for the treatment of radioactive iodine refractory metastatic differentiated thyroid cancer (DTC) with a BRAF p.V600E mutation.Patients and Methods:A prospective phase II trial including patients with RECIST progression within 18 months and no lesion > 3 cm. Following a baseline recombinant human (rh)TSH-stimulated diagnostic whole-body scan (dc1-WBS), dabrafenib and trametinib were given for 42 days. A second rhTSH-stimulated dc WBS (dc2-WBS) was done at day 28 and 131I (5.5 GBq–150 mCi after rhTSH) was administered at day 35. Primary endpoint was the 6-month RECIST objective response rate. In case of partial response (PR) at 6 or 12 months, a second treatment course could be given. Among 24 enrolled patients, 21 were evaluable at 6 months.Results:Abnormal 131I uptake was present on 5%, 65%, and 95% of the dc1-WBS, dc2-WBS, and post-therapy scans, respectively. At 6 months, PR was achieved in 38%, stable disease in 52%, and progressive disease (PD) in 10%. Ten patients received a second treatment course: one complete response and 6 PRs were observed at 6 months. The median progression-free survival (PFS) was not reached. The 12- and 24-month PFS were 82% and 68%, respectively. One death due to PD occurred at 24 months. Adverse events (AE) occurred in 96% of the patients, with 10 grade 3–4 AEs in 7 patients.Conclusions:Dabrafenib-trametinib is effective in BRAF p.V600E-mutated DTC patients for restoring 131I uptake with PR observed 6 months after 131I administration in 38% of the patients.

Purpose We investigated whether artificial intelligence (AI)-based denoising halves PET acquisition time in digital PET/CT. Methods One hundred ninety-five patients referred for [18F]FDG PET/CT were prospectively included. Body PET acquisitions were performed in list mode. Original “PET90” (90 s/bed position) was compared to reconstructed ½-duration PET (45 s/bed position) with and without AI-denoising, “PET45AI and PET45”. Denoising was performed by SubtlePET™ using deep convolutional neural networks. Visual global image quality (IQ) 3-point scores and lesion detectability were evaluated. Lesion maximal and peak standardized uptake values using lean body mass (SULmax and SULpeak), metabolic volumes (MV), and liver SULmean were measured, including both standard and EARL1 (European Association of Nuclear Medicine Research Ltd) compliant SUL. Lesion-to-liver SUL ratios (LLR) and liver coefficients of variation (CVliv) were calculated. Results PET45 showed mediocre IQ (scored poor in 8% and moderate in 68%) and lesion concordance rate with PET90 (88.7%). In PET45AI, IQ scores were similar to PET90 (P = 0.80), good in 92% and moderate in 8% for both. The lesion concordance rate between PET90 and PET45AI was 836/856 (97.7%), with 7 lesions (0.8%) only detected in PET90 and 13 (1.5%) exclusively in PET45AI. Lesion EARL1 SULpeak was not significantly different between both PET (P = 0.09). Lesion standard SULpeak, standard and EARL1 SULmax, LLR and CVliv were lower in PET45AI than in PET90 (P mean were higher (P mean (ICC ≥ 0.87). Conclusion AI allows [18F]FDG PET duration in digital PET/CT to be halved, while restoring degraded ½-duration PET image quality. Future multicentric studies, including other PET radiopharmaceuticals, are warranted.

Introduction Multikinase inhibitor (MKI) treatments have shown efficacy in progressive radioiodine refractory thyroid cancers (RAIR-TC), but most patients experienced substantial adverse effects. This randomised multicentric study investigated intermittent versus continuous pazopanib administration. Patients and methods The PAZOTHYR study included RAIR-TC patients with progressive disease in the last 12 months, who may have received one prior MKI. RAIR-TC patients received pazopanib for 6 months, and patients with stable disease or tumour response were randomly assigned (1:1) to receive continuous (CP) or intermittent (IP) pazopanib until progression. The primary end-point was time to treatment failure (TTF) defined as the time from randomisation to permanent discontinuation of pazopanib, due to any cause. One hundred randomised patients were needed to demonstrate an increase from 50% (CP) to 70% (IP) (hazard ratio (HR) 0.515, 80% power) in the rate of patients still under treatment 6 months (6m-SuT) post-randomisation. Secondary end-points included the overall response rate (ORR), progression-free survival (PFS) under pazopanib and safety. Results RAIR-TC patients (168) enrolled from June 18, 2013 to January 16, 2018, received 6-month pazopanib treatment and showed 35.6% (95% CI 28.2–43.6) best response rate and 89.4% (83.5–93.7) disease control rate. One hundred patients were randomised (IP:50; CP:50). With a median follow-up of 31.3 months, median TTF was not statistically different between arms (IP:14.7, 95% confidence interval (CI) 9.3–17.4; CP:11.9, 95% CI 7.5–15.6) months (HR 0.79, 0.49–1.27). 6m-SuT rates were similar (IP:80% 66.0–88.7%; CP:78% 63.8–87.2%). Median PFS under pazopanib were not statistically different (IP:5.7 4.8–7.8; CP: 9.2 7.3–11.1) months (HR 1.36, 0.88–2.12). Pazopanib-related adverse events grade 3–4 occurred in 36 (IP: 19, 38%; CP: 17, 34%) randomised patients. Seven pazopanib-related deaths occurred. Conclusions Intermittent administration of pazopanib did not demonstrate significant superiority in efficacy or tolerance compared with continuous treatment. An intermittent administration scheme cannot be recommended outside clinical trials. This study was registered with ClinicalTrial.gov , number NCT01813136 .

Background: Refining the risk of malignancy in patients presenting with thyroid nodules with indeterminate cytology (IC) is a critical challenge. We investigated the performances of 18F-fluorocholine (FCH) positron emission tomography/computed tomography (PET/CT) to predict malignancy. Methods: Between May 2016 and March 2019, 107 patients presenting with a thyroid nodule ≥15 mm with IC and eligible for surgery were included in this prospective study. Head-and-neck PET/CT acquisitions were performed 20 and 60 minutes after injection of 1.5 MBq/kg of FCH. PET/CT acquisition was scored positive when maximal standardized uptake value in the IC nodule was higher than in the thyroid background. Pathology was the gold standard for diagnosis. Results: At pathology, 19 (18%) nodules were malignant, 87 were benign, and one was a noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). Sensitivity, specificity, accuracy, positive-predictive value (PPV), and negative-predictive value (NPV) of FCH PET/CT in detecting cancer or NIFTP were 90%, 50%, 55%, 29%, and 96% at 20 minutes and 85%, 49%, 67%, 28%, and 94% at 60 minutes, respectively. Higher specificity (58% vs. 33%, p = 0.01) was observed in nononcocytic (n = 72) than in oncocytic IC nodules (n = 35). The pre-PET/CT probability of cancer or NIFTP in Bethesda III–IV nodules was 11% and the post-PET/CT probability was 19% in PET-positives and 0% in PET-negatives. In retrospective analysis, 42% of surgeries would have been unnecessary after PET/CT and 81% before (p

Introduction Serum calcitonin (CT) and carcinoembryonic antigen (CEA) are valuable tumour markers in patients with medullary thyroid carcinoma (MTC). Both markers most often evolve in parallel after treatment. Selpercatinib (LOXO-292) is a highly selective RET kinase inhibitor indicated in advanced RET-mutant MTC patients. Cases presentation In this study, we report two observations of RET-mutant progressive metastatic and symptomatic MTC patients who were treated with selpercatinib. Patient 1, a 61-year-old man, presented dyspnoea and diarrhoea at selpercatinib initiation with large neck lymph nodes and lung metastases. Patient 2, a 76-year-old man, had acute discomfort with flush and diarrhoea, with small but diffuse bone and liver disease. Both patients had an objective tumour response with rapid clinical improvement and RECIST 1.1 response (−90%) in patient 1. A rapid dramatic decrease in CT level was observed in both patients (−99% in both patients), while CEA levels gradually and sustainably increased after selpercatinib initiation (+207% at cycle 15 in patient 1 and + 835% at cycle 14 in patient 2). In both patients, 18FDG PET/CT did not show any abnormal uptake that could explain the CEA increase. Colonoscopy and oesogastric fibroscopy showed colonic polyposis with mild oesophagitis and gastritis in patient 1 and were normal in patient 2. Conclusion These observations show an unusual and lasting increase in serum CEA in two MTC patients who exhibited an objective tumour response to selpercatinib. The mechanism behind this unexpected rise in CEA level remains unknown. The frequency of this evolving profile will be determined in further phase III studies.

BackgroundIn patients with differentiated thyroid cancer (DTC), tumor burden of persistent disease (PD) is a variable that could affect therapy efficiency. Our aim was to assess its correlation with the 2015 American Thyroid Association (ATA) risk-stratification system, and its impact on response to initial therapy and outcome.MethodsThis retrospective cohort study included 618 consecutive DTC patients referred for postoperative radioiodine (RAI) treatment. Patients were risk-stratified using the 2015 ATA guidelines according to postoperative data, before RAI treatment. Tumor burden of PD was classified into three categories, i.e. very small-, small- and large-volume PD. Very small-volume PD was defined by the presence of abnormal foci on post-RAI scintigraphy with SPECT/CT or18FDG PET/CT without identifiable lesions on anatomic imaging. Small- and large-volume PD were defined by lesions with a largest size ResultsPD was evidenced in 107 patients (17%). Mean follow-up for patients with PD was 7 ± 3 years. The percentage of large-volume PD increased with the ATA risk (18, 56 and 89% in low-, intermediate- and high-risk patients, respectively,p p = 0.01) and at last follow-up visit (75, 28 and 16%, respectively;p = 0.04). On multivariate analysis, age ≥ 45 years, distant and/or thyroid bed disease, small-volume or large-volume tumor burden and18FDG-positive PD were independent risk factors for indeterminate or incomplete response at last follow-up visit.ConclusionsThe tumor burden of PD correlates with the ATA risk-stratification, affects the response to initial therapy and is an independent predictor of residual disease after a mean 7-yr follow-up. This variable might be taken into account in addition to the postoperative ATA risk-stratification to refine outcome prognostication after initial treatment.

18F-FDG PET is recommended for the initial staging of locally advanced breast cancer. Studies have shown the prognostic value of 18F-FDG PET for staging, but its ability to predict pathological complete response remains uncertain. Our objective was to determine the predictive value of early therapeutic evaluation by 18F-FDG PET for HER2-positive breast cancer patients. We studied a subpopulation of the prospective and multicentric French NeoTOP trial, at interim analysis. All patients were eligible for neoadjuvant chemotherapy. A 18F-FDG PET was performed at baseline and then after one cycle of neoadjuvant treatment. 18F-FDG PET were studied by three conventional methods (two visuals and one quantitative) and by textural analysis. Complete pathological response on surgical samples corresponded to grades 1/2 of Chevallier's classification and no responders corresponded to grades 3/4 of Chevallier. Pathological results were available for 21 patients. SUVmax decreased by 55% after one cycle of chemotherapy. No difference between groups was found with visuals, conventional quantitative and textural analysis of tumour uptake evaluations. Early therapeutic evaluation by 18F-FDG PET for HER2-positive breast cancer was not predictive of pathological therapeutic response after neoadjuvant treatment, with conventional study or textural analyses in this interim analysis.

We investigated whether artificial intelligence (AI)-based denoising halves PET acquisition time in digital PET/CT.One hundred ninety-five patients referred for [PET45 showed mediocre IQ (scored poor in 8% and moderate in 68%) and lesion concordance rate with PET90 (88.7%). In PET45AI, IQ scores were similar to PET90 (P = 0.80), good in 92% and moderate in 8% for both. The lesion concordance rate between PET90 and PET45AI was 836/856 (97.7%), with 7 lesions (0.8%) only detected in PET90 and 13 (1.5%) exclusively in PET45AI. Lesion EARLAI allows [

Refractory thyroid cancers include radio-iodine-refractory cancers, metastatic or locally advanced unresectable medullary and anaplastic thyroid cancers. Their management has been based for several years on the use of multi-target kinase inhibitors, with anti-angiogenic action, with the exception of anaplastic cancers usually treated with chemo- and radiotherapy. The situation has recently evolved due to the availability of molecular genotyping techniques allowing the discovery of rare but targetable molecular abnormalities. New treatment options have become available, more effective and less toxic than the previously available multi-target kinase inhibitors. The management of refractory thyroid cancers is therefore becoming more complex both at a diagnosis level with the need to know when, how and why to look for these molecular abnormalities but also at a therapeutic level, innovative treatments being hardly accessible. The cost of molecular analyzes and the access to treatments need also to be homogenized because disparities could lead to inequality of care at a national or international level. Finally, the strategy of identifying molecular alterations and treating these rare tumors reinforces the importance of a discussion in a multidisciplinary consultation meeting., Les cancers thyroïdiens réfractaires regroupent les cancers de souche folliculaire réfractaires à l’iode, les cancers médullaires métastatiques ou localement avancés non résécables et les cancers anaplasiques. Leur prise en charge est basée depuis quelques années sur l’utilisation d’inhibiteurs de kinase multicibles, à action principalement anti-angiogénique, exception faite des cancers anaplasiques habituellement traités par chimio- et radiothérapie. La situation a récemment évolué en raison de la mise à disposition de techniques de génotypage moléculaire permettant la découverte d’anomalies moléculaires rares mais ciblables, et de nouveaux traitements, possiblement plus efficaces et moins toxiques que les inhibiteurs de kinase multicibles préalablement disponibles. La prise en charge de ces cancers se complexifie donc à la fois au niveau diagnostique avec la nécessité de savoir quand, comment et pourquoi rechercher ces anomalies moléculaires mais également au niveau thérapeutique, avec la question de la disponibilité des traitements innovants et de l’accès aux essais cliniques. Le coût des analyses moléculaires et l’accès aux médicaments sont à harmoniser car des disparités pourraient conduire à une inégalité des soins au niveau national ou international. Enfin, la stratégie d’identification des altérations moléculaires et de traitement pour ces tumeurs rares renforce l’importance d’une discussion en réunion de concertation pluridisciplinaire.

Context Little is known about prostate-specific membrane antigen (PSMA) expression in patients with cervical involvement of differentiated thyroid cancer (DTC). Objective We investigated PSMA expression in neck persistent/recurrent disease (PRD) using immunohistochemistry and the association with radioiodine (RAI) or 18-fluorodeoxyglucose (18FDG) uptake, and patient outcome. Design, Setting, and Patients Data from 44 consecutive DTC patients who underwent neck reoperation from 2006 to 2018 in a comprehensive cancer center. Main Outcome Measure(s) Immunostaining was performed with vascular endothelial marker CD31 and PSMA. PSMA expression was quantified using the immunoreactive score (IRS). RAI and 18FDG uptake were assessed before surgery using posttherapeutic RAI scintigraphy and 18FDG positron emission tomography with computed tomography. Mean follow-up after reintervention was 6.5 ± 3.7 years. Results Thirty patients (68%) showed at least 1 PSMA-positive lesion (IRS ≥ 2) with similar proportions in RAI-positive and RAI-negative patients (75% vs 66%). In RAI-negative patients, however, the proportion of PSMA-positive disease (79% vs 25%, P 40 mm) or aggressive subtypes, and was correlated with structural disease at last follow-up. Strong PSMA expression (IRS ≥ 9) was associated with shorter progression-free survival (PFS). Conclusions Our findings show that PSMA expression was present in two-thirds of patients with neck PRD, that it was related to poor prognostic factors and that very high expression was associated with poorer PFS. This preliminary study may offer new perspectives for the management of RAI-refractory DTC.

Patients with radioiodine-refractory (RAIR) differentiated thyroid carcinoma (DTC) represent a challenging subgroup of DTC because they are at higher risk of cancer-related death. Multidisciplinary discussions can assess the role and the nature of local treatments, but also determine the optimal timing for first-line antiangiogenic therapy as some of these patients can be followed for several months or years without any treatment. In this review, we will examine the definition of RAIR-DTC, the different treatment options and finally some of the most recent cancer research breakthroughs for RAIR-DTC.

Refractory thyroid cancers include radio-iodine-refractory cancers, metastatic or locally advanced unresectable medullary and anaplastic thyroid cancers. Their management has been based for several years on the use of multi-target kinase inhibitors, with anti-angiogenic action, with the exception of anaplastic cancers usually treated with chemo- and radiotherapy. The situation has recently evolved due to the availability of molecular genotyping techniques allowing the discovery of rare but targetable molecular abnormalities. New treatment options have become available, more effective and less toxic than the previously available multi-target kinase inhibitors. The management of refractory thyroid cancers is therefore becoming more complex both at a diagnosis level with the need to know when, how and why to look for these molecular abnormalities but also at a therapeutic level, innovative treatments being hardly accessible. The cost of molecular analyzes and the access to treatments need also to be homogenized because disparities could lead to inequality of care at a national or international level. Finally, the strategy of identifying molecular alterations and treating these rare tumors reinforces the importance of a discussion in a multidisciplinary consultation meeting.

Background The common endocrine disorder primary hyperparathyroidism (PHPT) can be cured by surgery. Preoperative localization of parathyroid adenoma (PTA) by imaging is a prerequisite for outpatient minimally invasive parathyroidectomy (MIP). Compared to inpatient bilateral cervical exploration (BCE) which is performed if imaging is inconclusive, MIP is superior in terms of cure and complication rates and less costly. The imaging procedure F18-choline (FCH) PET/CT outperforms Tc99m-sestaMIBI (MIBI) SPECT/CT for PTA localization, but it is much costlier. The aim of this study is to identify the most efficient first-line imaging modality for optimal patient care in PHPT without added cost to society. Methods We will conduct a multicenter open diagnostic intervention randomized phase III trial comparing two diagnostic strategies in patients with PHPT: upfront FCH PET/CT versus MIBI SPECT/CT. The primary endpoint is the proportion of patients in whom the first-line imaging method results in successful MIP and cure. Follow-up including biological tests will be performed 1 and 6 months after surgery. The main secondary endpoint is the social cost of both strategies. Other secondary endpoints are as follows: FCH PET/CT and MIBI SPECT/CT diagnostic performance, performance of surgical procedure and complication rate, FCH PET/CT inter- and intra-observer variability and optimization of FCH PET/CT procedure. Fifty-eight patients will be enrolled and randomized 1:1. Discussion FCH PET/CT is a highly efficient but expensive imaging test for preoperative PTA localization and costs three to four times more than MIBI SPECT/CT. Whether FCH PET/CT improves patient outcomes compared to the reference standard MIBI SPECT/CT is unknown. To justify its added cost, FCH PET/CT-guided parathyroid surgery should lead to improved patient management, resulting in higher cure rates and fewer BCEs and surgical complications. In the previous phase II APACH1 study, we showed that second-line FCH PET/CT led to a cure in 88% of patients with negative or inconclusive MIBI SPECT/CT. BCE could be avoided in 75% of patients and surgical complication rates were low. We therefore hypothesize that upfront FCH PET/CT would improve patient care in PHPT and that the reduction in clinical costs would offset the increase in imaging costs. Trial registration NCT04040946, registered August 1, 2019. Protocol version Version 2.1 dated from 2020/04/23.

Background: New digital versus analogic PET has higher temporal resolution and more stable count rate, potentially limiting the degradation of PET image quality in larger patients. We wanted to describe the influence of patient’s body habitus on [18F]FDG PET image quality primary in digital PET/CT and analogic PET/CT.Results:We studied retrospectively the relation between patient’s weight, BMI, fatty massand PET image quality, described by the coefficient of variance in the liver (CVliv) and visually.177 unique patient exams on digital PET/CT (weight 35-127 kg; BMI 15-44 kg/m2) were performed with 2 protocols (protocol 1: N=52: 3MBq (0,08mCi)/kg [18F]FDG; 2minutes/bed position; 2iterations10subsets; 2mm diameter voxels and protocol 2: N=125: 4MBq (0,11mCi) /kg [18F]FDG; 1min/bed position; 4iterations4subsets; 2mm voxels).74 unique patient exams were analyzed on analogic PET/CT (weight 38-130 kg; BMI 14-52 kg/m2; with one protocol: 4MBq (0,11mCi)/kg [18F]FDG; 2min40sec/bedposition for BMIliv with weight, BMI, fatty mass (p£0.009) and male sex (p£0,03) for both camera’s, with good fit in CVliv versus weight model on digital PET/CT (R2 up to 0.62). 4MBq (0,11mCi) protocol on digital PET/CT versus analogic PET/CT obtained lower CVliv on digital PET/CT in patients liv increased similarly with weight for both protocols, up to 26% [95% Confidence Interval 2-56%] for ³90 kg versus liv values were lower in 4MBq (0,11mCi) protocol 2.Also visually PET image quality decreased with habitus on each camera (p£0.001) and was lower in females on digital PET/CT only (p=0,04).Conclusions:[18F]FDG PET image quality decreases with weight and enlarging body habitus on digital and analogic PET/CT imposing further optimization and harmonization also in digital PET/CT. This is important for clinical routine, but also (multicentric) research and development of artificial intelligence software.

Purpose The aim of this prospective study (ClinicalTrials.gov: NCT01880203) was to evaluate the diagnostic and prognostic value of a 7-panel mutation testing in the aspirates of thyroid nodules with indeterminate cytology (IC). Methods Eligible patients had a thyroid nodule ≥15 mm with IC (Bethesda III–V) for which surgery had been recommended. Detection of BRAF and RAS mutations was performed using pyrosequencing and RET/PTC and PAX8/PPARγ rearrangements using Real-Time quantitative reverse transcription‐polymerase chain reaction (RT-PCR). Results Among 131 nodules with IC, 21 (16%) were malignant including 20 differentiated cancers and one thyroid lymphoma. Molecular abnormalities were identified in 15 nodules with IC corresponding to 10 malignant and 5 benign tumours. BRAF mutation was detected in 4 nodules all corresponding to classic PTC, and PAX8/PPARγ rearrangement in 2 HCC. In contrast, RAS mutation was identified in eight nodules, of which four were malignant, and one RET/PTC3 rearrangement in a follicular adenoma. This data resulted in an accuracy of 88%, sensitivity of 48%, specificity of 95%, positive-predictive value of 67%, and negative-predictive value of 91%. After a 56 month’s follow-up, the proportion of excellent response was similar in patients with molecular alterations (67%) and those without (60%). Conclusions By increasing the overall risk of cancer from 16 to 67% in mutated nodules and by diminishing it to 9% in wild-type, this study confirms the relevance of the 7-panel mutation testing in the diagnostic of nodules with IC. Genetic testing, however, did not predict outcome in the cancer patient subgroup.

Introduction Du debruitage par de l’intelligence artificielle (IA) pourrait ameliorer la qualite d’image TEP et permettre de reduire le temps d’acquisition et/ou l’activite injectee. Nous avons voulu tester la performance diagnostique d’un logiciel de debruitage TEP approuve par le FDA (Subtle PET de Subtle Medical®) en simulant une reduction de temps TEP par 50 %, confrontes a une demande croissante d’examens. Methodes Cent quatre-vingt-dix examens TEP FDG realises sur une camera digitale TEP/TDM VEREOS (4 MBq/kg, 90 s/pas, 4i4s + PSF), de patients inclus en janvier et fevrier 2021 de maniere prospective et consecutive, ont ete reconstruits sur 50 % du temps acquis et ensuite debruites par le logiciel. Cinq medecins nucleaires ont evalue sur la serie 50 % debruitee versus l’originale (standard de reference), la detectabilite lesionnelle et la qualite d’image globale visuelle dans une analyse masquee, cote a cote. Ils ont egalement mesure les valeurs semi-quantitatives standard et EARL1 compatibles suivantes : SUVmax, SULpeak, MTV ainsi que la taille (2D) au scanner de reperage de l’ensemble des lesions, le SULmean hepatique et le CVliv (coefficient de variation dans le foie comme indicateur de bruit). Resultats Au total, 822 lesions ont ete analysees chez 166 patients (avec 24 patients sans lesions hyperfixantes). La sensibilite pour la detection visuelle lesionnelle de la serie 50 % debruitee etait de 99,7 % (sans difference absolue chez 99 % des patients), avec un taux de faux-positifs douteux a 0,4 % (1,5 % des patients). La qualite d’image globale n’etait pas differente (2,72 ± 0,21 versus 2,69 ± 0,22 ; p = 0,2). Les valeurs semi-quantitatives lesionnelles SUL-SUV etait bien correlees (R2 ≥ 0,93), avec un Δmoyen pour la serie debruitee jusque −9 % pour les valeurs standard (range : 0–36 %), −5 % (range : 0–21 %) pour les valeurs EARL1, avec un ΔMTV moyen a +17 %. Le SUL mean hepatique etait de 1,78 ± 0,21 pour la 50 % debruitee versus 1,70 ± 0,23 pour l’originale (p = 0,0003), avec un CVliv a 11,3 ± 2 % versus 13,6 ± 2 % (p Conclusion Un logiciel de debruitage base sur de l’IA peut permettre une reduction par 50 % du temps d’acquisition TEP FDG ou a priori du produit activite* temps avec une tres discrete perte de la performance diagnostique qui parait cliniquement acceptable.

Dose-dense induction and up-front consolidation with autologous stem cell transplantation (ASCT) remain controversial issues when treating patients with high-risk diffuse large B-cell lymphoma. GELA designed a randomized phase 2 trial evaluating the efficacy of either rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone (R-ACVBP) or rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP14) induction and a positron emission tomography (PET)-driven ASCT or standard immunochemotherapy (SIC) consolidation in age-adjusted international prognosis index 2 (aaIPI2)-aaIPI3 patients. PET was performed at baseline, after 2 (PET2) and 4 (PET4) induction cycles, and centrally assessed using international harmonization project (IHP) criteria. PET2-/PET4- patients were assigned SIC, PET2+/PET4- patients were assigned ASCT, and PET4+ patients were treated with the investigator's choice. The primary end-point was the 2007 international working group complete response (CR) rate after induction. Change in maximum standard uptake value (ΔSUVmax) after PET assessment was explored. Two hundred eleven patients were randomly assigned to R-ACVBP (n = 109) or R-CHOP14 (n = 102). PET4-/CR rates were 53%/47% with R-ACVBP and 41%/39% with R-CHOP14 (CR 95% confidence interval [CI], 38%-67% and 28%-54%, respectively; P = .076). Consolidation in the R-ACVBP and R-CHOP14 groups was SIC in 26% and 23% of patients and ASCT in 28% and 18% of patients, respectively. PET4 positivity was higher with R-CHOP14 vs R-ACVBP (54% vs 41%; P = .08), leading to more salvage therapy (37% vs 26%; P = .07) and lower event-free survival (EFS; 4-year EFS, 31% vs 43%; P 70% was associated with better outcome (4-year PFS, 84% vs 35%; 4-year OS, 91% vs 57%; P < .0001), whatever the consolidation. Superiority of R-ACVBP over R-CHOP14 was not established, as IHP criteria did not properly reflect disease control. ΔSUVmax may help better select patients needing an alternative to SIC, including ASCT.

Introduction Les inhibiteurs de tyrosine kinases (ITK) ont montre leur efficacite dans le cancer thyroidien refractaire. Cependant, ces therapies sont associees a une perte de poids. Des etudes ont montre que le niveau de PTHrp etait associe a une perte de poids dans differents cancers. L’hypoparathyroidie post-thyroidectomie et les ITK peuvent modifier le niveau de PTH. Dans cette etude, nous avons evalue si le niveau de PTH serique pouvait influencer la perte de poids sous ITK chez les patients ayant un cancer thyroidien. Methodologie Il s’agissait d’une etude multicentrique retrospective chez des patients atteints d’un cancer thyroidien traite par ITK. Nous avons evalue la correlation entre le niveau de PTH et la perte de poids sous traitement et compare la variation des parametres nutritionnels sous ITK selon la presence ou non d’une hypoparathyroidie post-thyroidectomie. Resultats 159 patients ont ete inclus avec un suivi median de 12 ± 16 mois. 17,6 % des patients presentaient une hypoparathyroidie. Une correlation positive entre le niveau de PTH serique et le pourcentage de perte de poids a ete trouvee apres 6 mois de traitement (r = 0,48, p = 0,02). L’albumine serique et l’indice nutritionnel PNI etaient egalement diminues a la fin du suivi chez les sujets avec un niveau detectable de PTH uniquement (p Conclusion Dans notre etude, la perte de poids pendant le traitement d’un cancer thyroidien par ITK pourrait etre liee, en partie, au niveau de PTH. La correction des facteurs augmentant la PTH tels que la carence en vitamine D devrait etre envisagee.

International audience; A 66-year-old man with prostate cancer underwent F-fluorocholine PET/CT and thereafter Ga-labeled prostate-specific membrane antigen PET/CT to explore a rising prostate-specific antigen level. Both PET/CT studies showed a thyroid incidentaloma of the right lobe. Neck ultrasound confirmed the presence of a 16-mm right thyroid nodule. The serum calcitonin level was moderately increased at 25 ng/mL (

Patients with radioiodine-refractory (RAIR) differentiated thyroid carcinoma (DTC) represent a challenging subgroup of DTC because they are at higher risk of cancer-related death. Multidisciplinary discussions can assess the role and the nature of local treatments, but also determine the optimal timing for first-line antiangiogenic therapy as some of these patients can be followed for several months or years without any treatment. In this review, we will examine the definition of RAIR-DTC, the different treatment options and finally some of the most recent cancer research breakthroughs for RAIR-DTC.

Background: The benefits of post-operative radioactive iodine (RAI) administration have not been demonstrated in patients with low risk differentiated thyroid cancer (DTC). The objective of this randomized phase III trial is to assess in low risk DTC patients the non-inferiority of a follow-up strategy as compared to a systematic adjuvant post-operative RAI administration. Methods: ESTIMABL2 is a French multicentric randomized phase III trial in patients with low-risk DTC treated with total thyroidectomy with or without prophylactic neck lymph node dissection (pT1am N0 or Nx with a sum of the diameters of tumor lesions ≥ 10mm, pT1b N0 or Nx). Two to five months after surgery, in the absence of suspicious lateral neck lymph node on ultrasonography (US), patients were randomized either to the follow-up group (FU, no RAI administration) or to the ablation group and received post-operative RAI (1.1 GBq following rhTSH stimulation). Yearly controls under levothyroxine treatment consisted in thyroglobulin (Tg) and Tg antibodies (TgAb) determinations and neck-US. The primary objective was to assess at 3 years after randomization the non-inferiority of the proportion of patients without tumor-related event in the FU group as compared to the ablation group. Non-inferiority is demonstrated if the rate of patients without event at 3 years does not differ by more than ΔL=-5%. A tumor-related event was defined by the occurrence of subsequent treatment (RAI administration or surgery) for abnormal RAI uptake on the post-therapeutic WBS or by elevated Tg or TgAb levels and/or abnormal neck US during controls. Tg levels on levothyroxine treatment were considered elevated if > 2ng/mL in the FU group and > 1ng/mL in the ablation group. TgAb were considered elevated if > the upper limit range with an increase above 50% on 2 consecutive determinations performed 6 months apart. Results: 776 low-risk DTC patients were included between 2013 and 2017 in 35 French centers within the TUTHYREF network; 83% females, mean age: 52 years, papillary TC: 96%, pT1bNx: 43.6%, pT1bN0: 37.5%, pT1amNx: 12.6%, pT1amN0: 6.3%. Among the 729 patients evaluable at 3 years after randomization, tumor-related events occurred in 18/367 patients (4.9% IC95%=[2.9; 7.6]) in the FU group and in 15/362 patients (4.1% IC95%=[2.3; 6.7]) in the ablation group. Thus, 95.1% of patients in the FU group had no event at 3 years and this percentage is not inferior from the 95.9% of patients observed in the ablation group (difference = -0.8% [95% CI:-3.3%; 1.8%]. The number of subsequent surgery and/or RAI administration was 6 (1.6% IC95%=[0.6; 3.5]) in the FU group and 9 (2.5% IC95%=[1.1; 4.7]) in the ablation group. Conclusion: this phase III trial demonstrates the non-inferiority of a follow-up strategy compared to a systematic adjuvant post-operative administration of RAI (1.1GBq following rhTSH) in low risk DTC patients (PHRC 2012; NCT01837745).

6540 Background: Multikinase inhibitors (MKI) targeting angiogenesis, including pazopanib (P), have shown efficacy in progressive radioiodine refractory thyroid cancers (RAIR-TC) but are accompanied by adverse effects, leading to dose adjustments/interruptions. We aimed to investigate the efficacy and tolerance of a discontinuous scheme of pazopanib administration in this situation. Methods: This randomized phase II study enrolled RAIR-TC patients (pts) in first or second-line of MKI with documented disease progression within 12 months (m). After a 6-m pazopanib continuous induction phase, pts with stable disease (SD) or tumor response were randomly assigned in a 1:1 ratio to receive continuous pazopanib (CP) or intermittent pazopanib (IP) until progression and restart. They were stratified by best tumor response [stable disease vs. objective response] and prior MKI treatment [yes vs. no]). Primary endpoint was time to treatment failure (TTF) defined as time between randomization and permanent discontinuation of pazopanib (either for disease progression or intolerance); secondary endpoints included overall response rate (ORR), progression-free survival (PFS) and safety. Results: 168 pts (66.5 years median age; 51.8% female) were included and 100 pts randomized (CP: 50, IP: 50). The median number of metastatic sites was 2.0 (1-7) and 50 pts (29.8%) were pretreated with MKI. With a median follow-up of 31.3 m, we did not show any statistically significant difference in the TTF, 80% (66.0-88.7%)] of the pts being under P at 6 m after randomization in the IP arm versus 78% (63.8-87.2%) in the CP arm. Median TTF was 14.7 m 95% CI [9.3; 17.4] and 11.9 m 95% CI [7.5; 15.6] respectively (HR 0.79 [0.49-1.27]). The best response with P was 35.6% (95% CI [28.2; 43.6]) and the disease control rate was 89.4% 95% CI [83.5; 93.7]. Median time to progression under P was not statistically different between 2 arms (5.7m 95% CI [4.8;7.8] in the IP arm vs. 9.2m 95% CI [7.3;11.1] in the CP arm (HR 1.36 [0.88; 2.12]). 36/100 pts (36%) experienced pazopanib-related grade 3/4 AEs (CP:17; IP: 19) mainly represented by gastrointestinal disorders, hypertension, cardiac disorders and asthenia. Five pazopanib-related deaths were reported (CP:1;IP: 4). Conclusions: The intermittent administration of pazopanib study did not significantly demonstrate superiority in efficacy or tolerance over continuous treatment. Continuous administration of MKI remains the standard in RAIR-TC. Clinical trial information: NCT01813136 .

International audience; BACKGROUND:18FDG PET/CT is crucial before neck surgery for nodal recurrence localization in iodine-refractory differentiated or poorly differentiated thyroid cancer (DTC/PDTC). A dedicated head-and-neck (HN) acquisition performed with a thin matrix and point-spread-function (PSF) modelling in addition to the whole-body PET study has been shown to improve the detection of small cancer deposits. Different protocols have been reported with various acquisition times of HN PET/CT. We aimed to compare two reconstruction algorithms for disease detection and to determine the optimal acquisition time per bed position using the Siemens Biograph6 with extended field-of-view.METHODS:Twenty-one consecutive and unselected patients with DTC/PDTC underwent HN PET/CT acquisition using list-mode. PET data were reconstructed, mimicking five different acquisition times per bed position from 2 to 10 min. Each PET data set was reconstructed using 3D-ordered subset expectation maximisation (3D-OSEM) or iterative reconstruction with PSF modelling with no post filtering (PSFallpass). These reconstructions resulted in 210 anonymized datasets that were randomly reviewed to assess 18FDG uptake in cervical lymph nodes or in the thyroid bed using a 5-point scale. Noise level, maximal standard uptake values (SUVmax), tumour/background ratios (TBRs) and dimensions of the corresponding lesion on the CT scan were recorded. In surgical patients, the largest tumoral size of each lymph node metastasis was measured by a pathologist.RESULTS:The 120 HN PET studies of the 12 patients with at least 1 18FDG focus scored malignant formed the study group. Noise level significantly decreased between 2 and 4 min for both 3D-OSEM and PSFallpass reconstructions (p

International audience

Summary Background In ESTIMABL1, a randomised phase 3 trial of radioactive iodine ( 131 I) administration after complete surgical resection in patients with low-risk thyroid cancer, 92% of patients had complete thyroid ablation at 6–10 months, defined as a recombinant human thyroid-stimulating hormone (rhTSH)-stimulated serum thyroglobulin concentration of 1 ng/mL or less and normal findings on neck ultrasonography. Equivalence was shown between low-activity (1·1 GBq) and high-activity (3·7 GBq) radioactive iodine and also between the use of rhTSH injections and thyroid hormone withdrawal. Here, we report outcomes after 5 years of follow-up. Methods This multicentre, randomised, open-label, equivalence trial was done at 24 centres in France. Between March 28, 2007, and Feb 25, 2010, we randomly assigned (1:1:1:1) adults with low-risk differentiated thyroid carcinoma who had undergone total thyroidectomy to one of four strategies, each combining one of two methods of thyrotropin stimulation (rhTSH or thyroid hormone withdrawal) and one of two radioactive iodine activities (1·1 GBq or 3·7 GBq). Randomisation was by computer-generated sequence, with variable block size. Follow-up consisted of a yearly serum thyroglobulin measurement on levothyroxine treatment. Measurement of rhTSH-stimulated thyroglobulin and neck ultrasonography were done at the discretion of the treating physician. No evidence of disease was defined as serum thyroglobulin of 1 ng/mL or less on levothyroxine treatment and normal results on neck ultrasonography, when performed. This study was registered with ClinicalTrials.gov, number NCT00435851. Findings 726 patients (97% of the 752 patients originally randomised) were followed up. At a median follow-up since randomisation of 5·4 years (range 0·5–9·2), 715 (98%) had no evidence of disease. The other 11 had either structural disease (n=4), raised serum thyroglobulin concentration (n=5), or indeterminate findings on neck ultrasonography (n=2). At ablation, six of these patients had received 1·1 GBq radioactive iodine (five after rhTSH and one after withdrawal) and five had received 3·7 GBq (two after rhTSH and three after withdrawal). TSH-stimulated (either after rhTSH injections or thyroid hormone withdrawal according to the treatment group) thyroglobulin concentration measured at the time of ablation was prognostic for structural disease status at ablation, ablation status at 6–10 months, and the final outcome. Interpretation Our findings suggest that disease recurrence was not related to the strategy used for ablation. These data validate the use of 1·1 GBq radioactive iodine after rhTSH for postoperative ablation in patients with low-risk thyroid cancer. Funding French National Cancer Institute (INCa), French Ministry of Health, and Sanofi Genzyme.

Item does not contain fulltext We tested baseline positron emission tomography (PET)/computed tomography (CT) as a measure of total tumor burden to better identify high-risk patients with early-stage Hodgkin lymphoma (HL). Patients with stage I-II HL enrolled in the standard arm (combined modality treatment) of the H10 trial (NCT00433433) with available baseline PET and interim PET (iPET2) after 2 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine were included. Total metabolic tumor volume (TMTV) was measured on baseline PET. iPET2 findings were reported negative (DS1-3) or positive (DS4-5) with the Deauville scale (DS). The prognostic value of TMTV was evaluated and compared with baseline characteristics, staging classifications, and iPET2. A total of 258 patients were eligible: 101 favorable and 157 unfavorable. The median follow-up was 55 months, with 27 progression-free survival (PFS) and 12 overall survival (OS) events. TMTV was a prognosticator of PFS (P < .0001) and OS (P = .0001), with 86% and 84% specificity, respectively. Five-year PFS and OS were 71% and 83% in the high-TMTV (>147 cm(3)) group (n = 46), respectively, vs 92% and 98% in the low-TMTV group (147+DS1-3; 5-year PFS, 81.6%), high-intermediate (TMTV147+DS4-5; 5-year PFS, 25%). TMTV improves baseline risk stratification of patients with early-stage HL compared with current staging systems and the predictive value of early PET response as well.

International audience; 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.

Context: The impact of microscopic nodal involvement on the risk of persistent/recurrent disease (PRD) remains controversial in patients with papillary thyroid carcinoma (PTC). Objective: The goal of the study was to assess the risk of PRD and the 4-year outcome in PTC patients according to their initial nodal status [pNx, pN0, pN1 microscopic (cN0/pN1) or pN1 macroscopic (cN1/pN1)]. Design: We conducted a retrospective cohort study. Patients: The study included 305 consecutive PTC patients referred for radioiodine ablation from 2006 to 2011. Main Outcome Measure: We evaluated the risk of structural PRD and the disease status at the last follow-up. At ablation, persistent disease was consistently assessed by using post-radioiodine ablation scintigraphy combining total body scan and neck and thorax single-photon computed tomography-computed tomography (SPECT-CT) acquisition. Results: Of 305 patients, 128 (42%) were pNx, 84 (28%) pN0, 44 (14%) pN1 microscopic, and 49 (16%) pN1 macroscopic. The 4-year cumulative risk of PRD was higher in pN1 macroscopic than in pN1 microscopic patients (49% vs 24%, P = .03), and higher in pN1 microscopic than in pN0 (12%, P = .01) or pNx patients (6%, P < .001). On multivariate analysis, tumor size of 20 mm or greater [relative risk (RR) 3.4; P = .0001], extrathyroid extension (RR 2.6; P < .003), pN1 macroscopic (RR 4.5; P < .0001), and pN1 microscopic (RR 2.5; P < .02) were independent risk factors for PRD. At the last visit, the proportion of patients with no evidence of disease decreased from pNx (98%), pN0 (93%), and pN1 microscopic (89%) to pN1 macroscopic patients (70%) (P < .0001, Cochran-Armitage trend test). Extrathyroid extension (odds ratio 9.7; P < .0001) and N1 macroscopic (OR 4.9; P < .001) independently predicted persistent disease at the last visit, but N1 microscopic did not. Conclusions: Patients with microscopic lymph node involvement present an intermediate outcome between that observed in pN0-pNx patients and pN1 macroscopic patients. These data may justify modifications to the risk recurrence staging systems.