To investigate the prognostic value of BRAF V600E mutation for the recurrence of papillary thyroid cancer (PTC).
This was a retrospective multicenter study of the relationship between BRAF V600E ...mutation and recurrence of PTC in 2,099 patients (1,615 women and 484 men), with a median age of 45 years (interquartile range IQR, 34 to 58 years) and a median follow-up time of 36 months (IQR, 14 to 75 months).
The overall BRAF V600E mutation prevalence was 48.5% (1,017 of 2,099). PTC recurrence occurred in 20.9% (213 of 1,017) of BRAF V600E mutation-positive and 11.6% (125 of 1,082) of BRAF V600E mutation-negative patients. Recurrence rates were 47.71 (95% CI, 41.72 to 54.57) versus 26.03 (95% CI, 21.85 to 31.02) per 1,000 person-years in BRAF mutation-positive versus -negative patients (P < .001), with a hazard ratio (HR) of 1.82 (95% CI, 1.46 to 2.28), which remained significant in a multivariable model adjusting for patient sex and age at diagnosis, medical center, and various conventional pathologic factors. Significant association between BRAF mutation and PTC recurrence was also found in patients with conventionally low-risk disease stage I or II and micro-PTC and within various subtypes of PTC. For example, in BRAF mutation-positive versus -negative follicular-variant PTC, recurrence occurred in 21.3% (19 of 89) and 7.0% (24 of 342) of patients, respectively, with recurrence rates of 53.84 (95% CI, 34.34 to 84.40) versus 19.47 (95% CI, 13.05 to 29.04) per 1,000 person-years (P < .001) and an HR of 3.20 (95% CI, 1.46 to 7.02) after adjustment for clinicopathologic factors. BRAF mutation was associated with poorer recurrence-free probability in Kaplan-Meier survival analyses in various clinicopathologic categories.
This large multicenter study demonstrates an independent prognostic value of BRAF V600E mutation for PTC recurrence in various clinicopathologic categories.
With the widespread use of sensitive imaging techniques, which include neck visualization, a conspicuous number of thyroid nodules emerge and demand attention. Most lesions are benign, asymptomatic, ...and do not warrant treatment. In the case of cancer diagnosis, most are small, intrathyroidal and indolent neoplasms that can safely be managed conservatively. There is a pronounced need for more cost-effective, risk-adapted approaches to the management of this highly prevalent condition, taking the wishes of the patient into consideration. Thus, the present guidelines aim at providing a clinical practice guide for the initial workup and the subsequent management of adult individuals harboring thyroid nodules. Importantly, these guidelines are not intended to cover the management of thyroid malignancy. The manuscript and the specific recommendations were developed by reconciling the best available research evidence with the knowledge and clinical experience of the panelists and updating aspects of a number of previous European Thyroid Association guidelines.
Purpose For the past 65 years, patient age at diagnosis has been widely used as a major mortality risk factor in the risk stratification of papillary thyroid cancer (PTC), but whether this is ...generally applicable, particularly in patients with different BRAF genetic backgrounds, is unclear. The current study was designed to test whether patient age at diagnosis is a major mortality risk factor. Patients and Methods We conducted a comparative study of the relationship between patient age at diagnosis and PTC-specific mortality with respect to BRAF status in 2,638 patients (623 men and 2,015 women) with a median age of 46 years (interquartile range, 35 to 58 years) at diagnosis and a median follow-up time of 58 months (interquartile range, 26 to 107 months). Eleven medical centers from six countries participated in this study. Results There was a linear association between patient age and mortality in patients with BRAF V600E mutation, but not in patients with wild-type BRAF, in whom the mortality rate remained low and flat with increasing age. Kaplan-Meier survival curves rapidly declined with increasing age in patients with BRAF V600E mutation but did not decline in patients with wild-type BRAF, even beyond age 75 years. The association between mortality and age in patients with BRAF V600E was independent of clinicopathologic risk factors. Similar results were observed when only patients with the conventional variant of PTC were analyzed. Conclusion The long-observed age-associated mortality risk in PTC is dependent on BRAF status; age is a strong, continuous, and independent mortality risk factor in patients with BRAF V600E mutation but not in patients with wild-type BRAF. These results question the conventional general use of patient age as a high-risk factor in PTC and call for differentiation between patients with BRAF V600E and wild-type BRAF when applying age to risk stratification and management of PTC.
Gene expression profiling shows that, by gene signature, the difference between
BRAF-positive and
BRAF-negative PTC is so distinct that
BRAF-positive cancer may be regarded as a molecular subtype of ...papillary thyroid cancer (PTC). Since much enthusiasm surrounds the
BRAF-oncogene as a molecular prognostic factor, a central focus of our consideration is to weigh the current arguments for and against applying
BRAF mutation status of the tumor in clinical practice. The frequency of BRAF mutation in PTC is high—45% on average, with values over 70–80% in some populations. This will mean that implementing BRAF mutation as a factor of poor prognosis will shift many PTC patients, considered up to now as low risk ones, to the more extensive treatment. We estimate that 31% of all PTC patients and 39% of those diagnosed with stage I–II disease will face the risk of overtreatment if the decision will be based on the
BRAF-positivity of their tumors. Also, the risk of undertreatment in the young patients with BRAF-negative tumors is evaluated with 26%. We think that, as of now, the evidence-based support for such consequences is still weak. Thus, there is urgent need to look for genes or gene signatures which will be helpful in the stratification of BRAF-positive tumors to specify these with poor prognosis with higher accuracy, needed for clinical decisions. Considering this, in the review we summarize the present status of knowledge on other prognosis-related gene expression changes in papillary and follicular cancer and relate them to he tumor's biology.
Abstract
The purpose of this work was to investigate the distinct and common metabolic features of the malignant and benign thyroid lesions in reference to the non-transformed tissue from the ...contralateral gland (chronic thyroiditis and colloid goiter).
1
H HR MAS NMR spectra of 38 malignant lesions, 32 benign lesions and 112 samples from the non-tumoral tissue (32 from chronic thyroiditis and 80 samples from colloid goiter) were subjected both to multivariate and univariate analysis. The increased succinate, glutamine, glutathione, serine/cysteine, ascorbate, lactate, taurine, threonine, glycine, phosphocholine/glycerophosphocholine and decreased lipids were found in both lesion types in comparison to either colloid goiter or chronic thyroiditis. The elevated glutamate and choline, and reduced citrate and glucose were additionally evident in these lesions in reference to goiter, while the increased myo-inositol—in comparison to thyroiditis. The malignant lesions were characterized by the higher alanine and lysine levels than colloid goiter and thyroiditis, while scyllo-inositol was uniquely increased in the benign lesions (not in cancer) in comparison to both non-tumoral tissue types. Moreover, the benign lesions presented with the unique increase of choline in reference to thyroiditis (not observed in the cancerous tissue). The metabolic heterogeneity of the non-tumoral tissue should be considered in the analysis of metabolic reprogramming in the thyroid lesions.
How lymph node metastasis (LNM)-associated mortality risk is affected by BRAF V600E in papillary thyroid cancer (PTC) remains undefined.
To study whether BRAF V600E affected LNM-associated mortality ...in PTC.
We retrospectively analyzed the effect of LNM on PTC-specific mortality with respect to BRAF status in 2638 patients (2015 females and 623 males) from 11 centers in 6 countries, with median age of 46 interquartile range (IQR) 35-58 years and median follow-up time of 58 (IQR 26-107) months.
Overall, LNM showed a modest mortality risk in wild-type BRAF patients but a strong one in BRAF V600E patients. In conventional PTC (CPTC), LNM showed no increased mortality risk in wild-type BRAF patients but a robustly increased one in BRAF V600E patients; mortality rates were 2/659 (0.3%) vs 4/321 (1.2%) in non-LNM vs LNM patients (P = 0.094) with wild-type BRAF, corresponding to a hazard ratio (HR) (95% CI) of 4.37 (0.80-23.89), which remained insignificant at 3.32 (0.52-21.14) after multivariate adjustment. In BRAF V600E CPTC, morality rates were 7/515 (1.4%) vs 28/363 (7.7%) in non-LNM vs LNM patients (P < 0.001), corresponding to an HR of 4.90 (2.12-11.29) or, after multivariate adjustment, 5.76 (2.19-15.11). Adjusted mortality HR of coexisting LNM and BRAF V600E vs absence of both was 27.39 (5.15-145.80), with Kaplan-Meier analyses showing a similar synergism.
LNM-associated mortality risk is sharply differentiated by the BRAF status in PTC; in CPTC, LNM showed no increased mortality risk with wild-type BRAF but a robust one with BRAF mutation. These results have strong clinical relevance.
Abstract
Context
Multifocality is often treated as a risk factor for papillary thyroid cancer (PTC), prompting aggressive treatments, but its prognostic value remains unestablished.
Objective
To ...investigate the role of tumor multifocality in clinical outcomes of PTC.
Methods
Multicenter study of the relationship between multifocality and clinical outcomes of PTC in 2638 patients (623 men and 2015 women) with median interquartile range (IQR) age of 46 (35 to 58) years and median (IQR) follow-up time of 58 (26 to 107) months at 11 medical centers in six countries. Surveillance, Epidemiology and End Results (SEER) data were used for validation.
Results
Disease recurrence in multifocal and unifocal PTC was 198 of 1000 (19.8%) and 221 of 1624 (13.6%) (P < 0.001), with a hazard ratio of 1.55 95% confidence interval (CI), 1.28 to 1.88, which became insignificant at 1.13 (95% CI, 0.93 to 1.37) on multivariate adjustment. Similar results were obtained in PTC variants: conventional PTC, follicular-variant PTC, tall-cell PTC, and papillary thyroid microcarcinoma. There was no association between multifocality and mortality in any of these PTC settings, whereas there was a strong association between classic risk factors and cancer recurrence or mortality, which remained significant after multivariate adjustment. In 1423 patients with intrathyroidal PTC, disease recurrence was 20 of 455 (4.4%) and 41 of 967 (4.2%) (P = 0.892) and mortality was 0 of 455 (0.0%) and 3 of 967 (0.3%) (P = 0.556) in multifocal and unifocal PTC, respectively. The results were reproduced in 89,680 patients with PTC in the SEER database.
Conclusions
Tumor multifocality has no independent risk prognostic value in clinical outcomes of PTC; its indiscriminate use as an independent risk factor, prompting overtreatments of patients, should be avoided.
Despite common belief, this study shows no independent role of multifocality in clinical outcomes of PTC; its indiscriminate use as a risk factor, prompting overtreatment, should be avoided.
Background Renin-angiotensin system inhibitors (RASIs) are widely used in the treatment of hypertension. However, their impact on the outcome of the combined treatment of rectal cancer is poorly ...understood. The aim of this study was to assess the effect of RASIs on the survival of rectal cancer patients with associated hypertension after neoadjuvant treatment and radical resection. Methods Between 2008 and 2016, 242 radical (R0) rectal resections for cancer were performed after neoadjuvant treatment in patients with associated hypertension. At the time of treatment, 158 patients were on RASIs, including 35 angiotensin-receptor antagonists (ARB) users and 123 angiotensin-converting enzyme inhibitors (ACEI) users. Eighty-four patients were on drugs other than RASIs (non-RASI users). The survival analysis was performed using the Kaplan-Meier estimator with the log-rank test and the Cox proportional hazards model. Results The log-rank test showed a significantly worse overall survival (OS) in the group of ACEI users compared to ARB users (p = 0.009) and non-RASI users (p = 0.013). Disease-free survival (DFS) was better in the group of ARB users compared to ACEI users. However, the difference was not statistically significant (p = 0.064). The Multivariate Cox analysis showed a significant beneficial effect of ARBs on OS (HR: 0.326, 95% CI: 0.147-0.724, p = 0.006) and ARBs on DFS (HR: 0.339, 95% CI: 0.135-0.850, p = 0.021) compared to ACEIs. Other factors affecting OS included age (HR: 1.044, 95% CI: 1.016-1.073, p = 0.002), regional lymph node metastasis (ypN +) (HR: 2.157, 95% CI: 1.395-3.334, p = 0.001) and perineural invasion (PNI) (HR: 3.864, 95% CI: 1.799-8.301, p = 0.001). Additional factors affecting DFS included ypN + (HR: 2.310, 95% CI: 1.374-3.883, p = 0.002) and PNI (HR: 4.351, 95% CI: 1.584-11.954, p = 0.004). Conclusions The use of ARBs instead of ACEIs may improve the outcome of the combined therapy for rectal cancer patients with associated hypertension. Keywords: Rectal cancer, Renin-angiotensin system inhibitors, Angiotensin-converting enzyme inhibitors, ACEI, Angiotensin receptor blockers, ARB, Arterial hypertension
A rising incidence of thyroid cancers (TCs) mainly small tumors, observed during recent years, lead to many controversies regarding treatment strategies. TCs represent a distinct molecular background ...and clinical outcome. Although in most cases TCs are characterized by a good prognosis, there are some aggressive forms, which do not respond to standard treatment. There are still some questions, which have to be resolved to avoid dangerous simplifications in the clinical management. In this article, we focused on the current advantages in preoperative molecular diagnostic tests and histopathological examination including noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). We discussed the controversies regarding the extent of thyroid surgery and adjuvant radioiodine therapy, as well as new treatment modalities for radioiodine-refractory differentiated thyroid cancer (RR-DTC). Considering medullary thyroid cancer (MTC), we analyzed a clinical management based on histopathology and
(ret proto-oncogene) mutation genotype, disease follow-up with a special attention to serum calcitonin doubling time as an important prognostic marker, and targeted therapy applied in advanced MTC. In addition, we provided some data regarding anaplastic thyroid cancer (ATC), a highly lethal neoplasm, which lead to death in nearly 100% of patients due to the lack of effective treatment options.
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