Anaplastic thyroid carcinoma (ATC) is a rare tumor, with poorly defined oncogenic molecular mechanisms and limited therapeutic options contributing to its poor prognosis. The aims of this ...retrospective study were to determine the frequency of anaplastic lymphoma kinase (ALK) translocations and to identify the mutational profile of ATC including TERT promoter mutations.
One hundred and forty-four ATC cases were collected from 10 centers that are a part of the national French network for management of refractory thyroid tumors. Fluorescence in situ hybridization analysis for ALK rearrangement was performed on tissue microarrays. A panel of 50 genes using next-generation sequencing and TERT promoter mutations using Sanger sequencing were also screened.
Fluorescence in situ hybridization was interpretable for 90 (62.5%) cases. One (1.1%) case was positive for an ALK rearrangement with a borderline threshold (15% positive cells). Next-generation sequencing results were interpretable for 94 (65.3%) cases, and Sanger sequencing (TERT) for 98 (68.1%) cases. A total of 210 mutations (intronic and exonic) were identified. TP53 alterations were the most frequent (54.4%). Forty-three percent harbored a mutation in the (H-K-N)RAS genes, 13.8% a mutation in the BRAF gene (essentially p.V600E), 17% a PI3K-AKT pathway mutation, 6.4% both RAS and PI3K pathway mutations, and 4.3% both TP53 and PTEN mutations. Nearly 10% of the cases showed no mutations of the RAS, PI3K-AKT pathways, or TP53, with mutations of ALK, ATM, APC, CDKN2A, ERBB2, RET, or SMAD4, including mutations not yet described in thyroid tumors. Genes encoding potentially druggable targets included: mutations in the ATM gene in four (4.3%) cases, in ERBB2 in one (1.1%) case, in MET in one (1.1%) case, and in ALK in one (1.1%) case. A TERT promoter alteration was found in 53 (54.0%) cases, including 43 C228T and 10 C250T mutations. Three out of our cases did not harbor mutations in the panel of genes with therapeutic interest.
This study confirms that ALK rearrangements in ATC are rare and that the mutational landscape of ATC is heterogeneous, with many genes implicated in the follicular epithelial cell dedifferentiation process. This may explain the limited effectiveness of targeted therapeutic options tested so far.
Differentiated thyroid cancer (DTC) is the most common of endocrine cancers. Many studies have focused on recurrence-free survival of DTC patients, however, few studies have addressed overall ...survival rates. Given its very good prognosis, estimating overall or long-term survival in patients with DTC seems rational. So far, neither the impact of pre- and post-ablation thyroglobulin, nor that of initial American Thyroid Association (ATA) risk stratification on long-term disease-specific survival, have been sufficiently studied.
The aim of this study was to determine the factors that influence long-term disease-specific survival and thyroglobulin levels in patients with DTC who have been previously treated with thyroidectomy and radioactive iodine (RAI) remnant ablation.
This observational retrospective study included 1093 patients who were treated for DTC between 1995 and 2010 and are still monitored in our tertiary center. Only patients who needed RAI ablation after thyroidectomy were included in this study. Patients who were treated with RAI following rhTSH stimulation, patients who presented positive anti-thyroglobulin antibodies, and patients who had micro-cancers were excluded. Pre-ablation stimulated thyroglobulin (Pre-ablation sTg) was measured after thyroid hormone withdrawal (THW), just before RAI.
According to ATA standards, 29 patients (2.7%) were classified as high-risk patients. Initial ATA high-recurrence risk rating (HR 21.9; 95% CI: 8.5-56.3), age>55 years (HR 23.8; 95%-CI: 7.5-75.3) and pre-ablation sTg≥30 μg/l (HR 8.4; 95% CI: 4.6-15.3) significantly impacted ten-year survival. Moreover, age over 45 years, ATA moderate-risk and follicular DTC were also significant. Ten-year survival was lower in ATA high-risk patients (51% vs 95% and 93% for the low and intermediate risk; p<10-7), patients older than 55 years (82% vs 98%; p<10-7), and in patients with pre-ablation sTg≥30 (78% vs 95%; p<10-7). Three rates of long-term survival were distinguished: excellent (survival rate of 99% in patients<55 years with pre-ablation sTg <30μg/l) representing 59% of the cohort, moderate (survival rate of 94.5% in patients <55 years with pre-ablation sTg ≥30μg/l or ≥55 years with pre-ablation sTg <30 μg/l) representing 38% of the cohort, and low (survival rate of 49% in patients ≥55 years with pre-ablation sTg ≥30μg/l) representing 3% of the cohort.
Initial ATA high-risk classification, age over 55 years old and pre-ablation sTg ≥30 μg/l are the main negative factors that influence the ten-year survival in DTC. We suggest three categories of overall survival rates. Patients older than 55 years with pre-ablation sTg ≥30 μg/l have the worst survival rate.
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.
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.
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.
NCT03570021. June 26,2018.
Purpose
To determine efficacy and safety of thermal ablation (TA) for the local treatment of lung metastases of thyroid cancer.
Methods
We retrospectively studied 47 patients from 10 centers treated ...by TA (radiofrequency, microwaves, and cryoablation) over 10 years. The endpoints were overall survival (OS), local efficacy, complications (CTCAE classification), and factors associated with survival. OS curves after first TA were built using the Kaplan–Meier method and compared with the log-rank test.
Results
A total of 107 lung metastases during 75 sessions were treated by radiofrequency (
n
= 56), microwaves (
n
= 9), and cryoablation (
n
= 10). Median follow-up time after TA was 5.2 years (0.2–13.3). OS was 93% at 2 years (95% confidence interval (CI): 86–94) and 79% at 3 years (95% CI: 66–91). On univariate and multivariate analysis with a Cox model, histology was the only significant factor for OS. OS at 3 years was 94% for follicular, oncocytic, or papillary follicular variant carcinomas, compared to 59% for papillary, medullary, insular or anaplastic carcinomas (
P
= 0.0001). The local control rate was 98.1% at 1 year and 94.8% at 2, 3, 4, and 5 years. Morbidity was low with no major complications (grade 4 and 5 CTCAE) and no complications in 29 of 75 sessions (38.7%).
Conclusions
TA is a useful, safe and effective option for local treatment of lung metastases from thyroid carcinoma. Prolonged OS was obtained, especially for lung metastases from follicular, oncocytic, or papillary follicular variant carcinomas. Achieving disease control with TA delays the need for systemic treatment.
The aim of this study was to find the best ordered combination of two FDG positive musculoskeletal sites with a machine learning algorithm to diagnose polymyalgia rheumatica (PMR) vs. other ...rheumatisms in a cohort of patients with inflammatory rheumatisms.
This retrospective study included 140 patients who underwent
FFDG PET-CT and whose final diagnosis was inflammatory rheumatism. The cohort was randomized, stratified on the final diagnosis into a training and a validation cohort. FDG uptake of 17 musculoskeletal sites was evaluated visually and set positive if uptake was at least equal to that of the liver. A decision tree classifier was trained and validated to find the best combination of two positives sites to diagnose PMR. Diagnosis performances were measured first, for each musculoskeletal site, secondly for combination of two positive sites and thirdly using the decision tree created with machine learning.
55 patients with PMR and 85 patients with other inflammatory rheumatisms were included. Musculoskeletal sites, used either individually or in combination of two, were highly imbalanced to diagnose PMR with a high specificity and a low sensitivity. The machine learning algorithm identified an optimal ordered combination of two sites to diagnose PMR. This required a positive interspinous bursa or, if negative, a positive trochanteric bursa. Following the decision tree, sensitivity and specificity to diagnose PMR were respectively 73.2 and 87.5% in the training cohort and 78.6 and 80.1% in the validation cohort.
Ordered combination of two visually positive sites leads to PMR diagnosis with an accurate sensitivity and specificity vs. other rheumatisms in a large cohort of patients with inflammatory rheumatisms.
Introduction: Loco regional persistence or recurrence of differentiated thyroid cancer (DTC) is frequent despite initial thyroidectomy and radioactive iodine therapy (RAI). The aim of this study was ...to analyze the impact of a complementary adjuvant RAI (Ad-RAI) on disease recurrence following re-operation on patients with locally persistent or recurrent DTC. Patients and Methods: A retrospective study of 85 patients with DTC was conducted. All patients were initially treated with total thyroidectomy and RAI, and re-operated for a locally persistent or recurrent disease. Propensity score was calculated to predict the impact of Ad-RAI on survival after reoperation, and to reduce the bias of the limited sample size and the prognostic tests. Results: 49 (58%) patients were re-treated with Ad-RAI after re-operation while 36 (42%) were only followed up. Disease recurrence after re-treatment (re-operation ± Ad-RAI) was detected in 31 patients (36.5%). In multivariate analysis, age >55 years (HR: 3.9 1.6; 9.5; p < 0.00001) was the main poor prognostic factor for recurrence-free survival. Three parameters independently influenced the decision to administer ad-RAI: low number of previous RAI administrations, Nx before re-operation, and pTg > 30 μg/l. These parameters were incorporated in the Propensity score calculation. If ad-RAI tended to improve recurrence-free survival (median survival 17.4 vs. 10.9 months), adjustment using the Propensity score removed any difference between the groups (p = 0.54), confirming the limited value of ad-RAI. Conclusion: In patients with locally persistent or recurrent DTC, age is the main independent prognostic factor. Adjuvant RAI does not improve recurrence-free survival of DTC patients.
Background
Hyperparathyroidism jaw‐tumor syndrome (HPT‐JT) is the rarest familial cause of primary hyperparathyroidism, with an incidence <1/1000000, caused by a pathogenic variant in the CDC73 (or ...HRPT2) gene that encodes parafibromin, a protein involved in many cellular mechanisms. Patients with HPT‐JT have a 15–20% of risk of developing parathyroid carcinoma, whereas it accounts for only 1% of all cases of primary hyperparathyroidism. Patients also develop jaw tumors in 30% of cases, kidney abnormalities in 15% of cases, and uterine tumors in 50% of patients.
Case Report
Here are report two atypical cases of HPT‐JT with variable expressivity in the same family. In front of an isolated primary hyperparathyroidism at 28 years of age of incidental discovery following a weight gain, the propositus benefited a first‐line panel by Next‐Generation Sequencing of the genes involved in familial hyperparathyroidism: CaSR, CDC73, MEN1, and RET. Genetic testing revealed the presence of a pathogenic germline variation CDC73: c.687_688dup; p.Val230Glufs*28, found only in nine families in the literature and allowing the diagnosis of HPT‐JT. Given a history of primary hyperparathyroidism at 52 years and adenomyosis, the patient's mother also underwent a genetic analysis that found her daughter's variation and established her inherited trait.
Conclusion
In view of the clinical and genotypic heterogeneity, we confirm the interest of using an extended gene panel for the diagnosis of familial primary hyperparathyroidism. CDC73 variations could be more frequent than described in the literature. The association of primary hyperparathyroidism with uterine involvement could be a new indication for analysis.
We report two atypical cases of hyperparathyroidism jaw‐tumor syndrome with variable expressivity within the same family. The index case, a young woman with isolated primary hyperparathyroidism, underwent panel sequencing of genes involved in familial primary hyperparathyroidism. A variation of the CDC73 gene was found. The segregation study identified the variation in his mother who had a history of hyperparathyroidism associated with adenomyosis.
Purpose:
The objective of this study was to evaluate periarticular FDG uptake scores from
18
F-FDG-PET/CT to identify polymyalgia rheumatica (PMR) within a population presenting rheumatic diseases.
...Methods:
A French retrospective study from 2011 to 2015 was conducted. Patients who underwent
18
F-FDG-PET/CT for diagnosis or follow-up of a rheumatism or an unexplained biological inflammatory syndrome were included. Clinical data and final diagnosis were reviewed. Seventeen periarticular sites were sorted by a visual reading enabling us to calculate two scores: mean FDG visual uptake score, number of sites with significant uptake same as that or higher than liver uptake intensity and by a semi-quantitative analysis using mean maximum standardized uptake value (SUVmax). Optimal cutoffs of visual score and SUVmax to diagnose PMR were determined using receiver operating characteristics curves.
Results:
Among 222
18
F-FDG PET/CT selected for 215 patients, 161
18
F-FDG PET/CT were performed in patients who presented inflammatory rheumatism as a final diagnosis (of whom 57 PMR). The presence of at least three sites with significant uptake identified PMR with a sensitivity of 86% and a specificity of 85.5% (AUC 0.872, 95% CI 0.81–0.93). The mean FDG visual score cutoff to diagnose a PMR was 0.765 with a sensitivity of 82.5% and a specificity of 75.8% (AUC 0.854; 95% CI 0.80–0.91). The mean SUVmax cutoff to diagnose PMR was 2.168 with a sensitivity of 77.2% and a specificity of 77.6% (AUC 0.842; 95% CI 0.79–0.89).
Conclusions:
This study suggests that
18
F-FDG PET/CT had good performances to identify PMR within a population presenting rheumatic diseases.
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