Background:
The benefits of prophylactic central compartment lymph node dissection (pCCND) in papillary thyroid cancer (PTC) are still under investigation. This treatment seems to reduce PTC ...recurrence/mortality rates but has a higher risk of surgical complications. The lack of prospective randomized trials does not allow definitive recommendations. The aim of this prospective randomized controlled study was to evaluate the clinical advantages and disadvantages of pCCND.
Patients:
A total of 181 patients with PTC without evidence of preoperative/intraoperative lymph node metastases (cN0) were randomly assigned to either Group A (n = 88) and treated with total thyroidectomy (TTx) or Group B (n = 93) and treated with TTx + pCCND.
Results:
After 5 years of followup, no difference was observed in the outcome of the two groups. However, a higher percentage of Group A were treated with a higher number of 131I courses (P = .002), whereas a higher prevalence of permanent hypoparathyroidism was observed in Group B (P = .02). No preoperative predictors of central compartment lymph node metastases (N1a) were identified. Only three patients were upstaged, and the therapeutic strategy changed in only one case.
Conclusions:
cN0 patients with PTC treated either with TTx or TTx + pCCND showed a similar outcome. One advantage of TTx + pCCND was a reduced necessity to repeat 131I treatments, but the disadvantage was a higher prevalence of permanent hypoparathyroidism. Almost 50% of patients with PTC had micrometastatic lymph nodes in the central compartment, but none of the presurgical features analyzed, including BRAF mutation, was able to predict their presence; moreover, to be aware of their presence does not seem to have any effect on the outcome.
Purpose
The SARS-CoV-2 genome has been detected in a variety of human samples including blood, urine, semen, and faeces. However, evidence of virus presence in tissues other than lung are limited.
...Methods
We investigated whether SARS-CoV-2 could be detected in 50 autoptic specimens of endocrine organs from 29 patients who died of COVID-19.
Results
The virus was detected in 25 specimens including ten abdominal subcutaneous adipose tissue samples (62%), six testes (67%), and nine thyroid (36%) samples. The analysis of multiple endocrine organ samples obtained from the same patients showed that, in virus-positive cases, the viral genome was consistently detected in all but two matched specimens.
Conclusion
Our findings show that the virus spread into endocrine organs is a common event in severe cases. Further studies should assess the rate of the phenomenon in clinically mild cases. The potential long-term effects of COVID-19 on endocrine functions should be taken into consideration.
Background
Thyroid nodules are a common clinical problem, and differentiated thyroid cancer is becoming increasingly prevalent.
Methods
Six scientific Italian societies entitled to cure thyroid ...cancer patients (the Italian Thyroid Association, the Medical Endocrinology Association, the Italian Society of Endocrinology, the Italian Association of Nuclear Medicine and Molecular Imaging, the Italian Society of Unified Endocrine Surgery and the Italian Society of Anatomic Pathology and Diagnostic Cytology) felt the need to develop a consensus report based on significant scientific advances occurred in the field.
Objective
The document includes recommendations regarding initial evaluation of thyroid nodules, clinical and ultrasound criteria for fine-needle aspiration biopsy, initial management of thyroid cancer including staging and risk assessment, surgical management, radioiodine remnant ablation, and levothyroxine therapy, short-term and long-term follow-up strategies, and management of recurrent and metastatic disease. The objective of this consensus is to inform clinicians, patients, researchers, and health policy makers about the best strategies (and their limitations) relating to the diagnosis and treatment of differentiated thyroid cancer.
Objective
Obesity is a recognized risk factor for the progression to severe forms of COVID-19, yet the mechanisms of the association are unclear.
Methods
Subcutaneous abdominal adipose tissue ...specimens of subjects deceased from COVID-19 (
n
= 23) were compared to those of controls dying abruptly from causes other than infectious (accidental trauma, sudden cardiac death). Alterations of lung parenchyma consistent with moderate to severe disease were detected in all COVID-19 cases, not in controls. Investigations included: histopathologic features, detection of virus antigens and genome, characterization of infiltrating leukocytes, transcription levels of immune-related genes.
Results
By RT-PCR, the SARS-CoV-2 genome was detected in the adipose tissue of 13/23 (56%) cases of the COVID-19 cohort. The virus nucleocapsid antigen was detected in the cytoplasm of 1–5% adipocytes in 12/12 COVID-19 cases that were virus-positive by PCR in the adipose tissue (one case could not be assessed due insufficient tissue). The adipose tissue of COVID-19 cases showed leukocyte infiltrates and upregulation of the interferon-alpha pathway. After adjusting for age and sex, the activation score of IFN-alpha was directly related with transcription levels of the ACE2 gene, a key entry factor of SARS-CoV-2.
Conclusions
In lethal COVID-19 cases, the SARS-CoV-2 nucleocapsid antigen has been detected in a sizeable proportion of adipocytes, showing that the virus may directly infect the parenchymal cells of subcutaneous fat. Infection appears to activate the IFN alpha pathway and to attract infiltrating leukocytes. Due to the huge numbers of adipocytes in adults, the adipose tissue represents a significant reservoir for SARS-CoV-2 and an important source of inflammatory mediators.
KRAS codons 12 and 13 mutations predict resistance to anti-EGFR monoclonal antibodies (moAbs) in metastatic colorectal cancer. Also, BRAF V600E mutation has been associated with resistance. ...Additional KRAS mutations are described in CRC.
We investigated the role of KRAS codons 61 and 146 and BRAF V600E mutations in predicting resistance to cetuximab plus irinotecan in a cohort of KRAS codons 12 and 13 wild-type patients.
Among 87 KRAS codons 12 and 13 wild-type patients, KRAS codons 61 and 146 were mutated in 7 and 1 case, respectively. None of mutated patients responded vs 22 of 68 wild type (P=0.096). Eleven patients were not evaluable. KRAS mutations were associated with shorter progression-free survival (PFS, HR: 0.46, P=0.028). None of 13 BRAF-mutated patients responded vs 24 of 74 BRAF wild type (P=0.016). BRAF mutation was associated with a trend towards shorter PFS (HR: 0.59, P=0.073). In the subgroup of BRAF wild-type patients, KRAS codons 61/146 mutations determined a lower response rate (0 vs 37%, P=0.047) and worse PFS (HR: 0.45, P=0.023). Patients bearing KRAS or BRAF mutations had poorer response rate (0 vs 37%, P=0.0005) and PFS (HR: 0.51, P=0.006) compared with KRAS and BRAF wild-type patients.
Assessing KRAS codons 61/146 and BRAF V600E mutations might help optimising the selection of the candidate patients to receive anti-EGFR moAbs.
In different human carcinoma types, mast cell infiltrate increases with respect to normal tissue and mast cell density correlates with a bad prognosis. To assess the role of mast cells in human ...thyroid cancer, we compared the density of tryptase-positive mast cells in 96 papillary thyroid carcinomas (PTCs) versus normal thyroid tissue from 14 healthy individuals. Mast cell density was higher in 95% of PTCs (n=91) than in control tissue. Mast cell infiltrate correlated with extrathyroidal extension (P=0.0005) of PTCs. We show that thyroid cancer cell-line-derived soluble factors induce mast cell activation and chemoattraction in vitro. Different mast cell lines (HMC-1 and LAD2) and primary human lung mast cells induced thyroid cancer cell invasive ability, survival and DNA synthesis in vitro. The latter effect was mainly mediated by three mast-cell-derived mediators: histamine, and chemokines CXCL1/GROα and CXCL10/IP10. We show that xenografts of thyroid carcinoma cells (8505-C) could recruit mast cells injected into the tail vein of mice. Co-injection of human mast cells accelerated the growth of thyroid cancer cell (8505-C) xenografts in athymic mice. This effect was mediated by increased tumor vascularization and proliferation, and was reverted by treating mice with sodium cromoglycate (Cromolyn), a specific mast cell inhibitor. In conclusion, our study data suggest that mast cells are recruited into thyroid carcinomas and promote proliferation, survival and invasive ability of cancer cells, thereby contributing to thyroid carcinoma growth and invasiveness.
The possible association between Hashimoto's thyroiditis (HT) and papillary thyroid carcinoma (PTC) is a still debated issue. We analyzed the frequency of PTC, TSH levels and thyroid autoantibodies ...(TAb) in 13 738 patients (9824 untreated and 3914 under l-thyroxine, l-T(4)). Patients with nodular-HT (n=1593) had high titer of TAb and/or hypothyroidism. Patients with nodular goiter (NG) were subdivided in TAb-NG (n=8812) with undetectable TAb and TAb+NG (n=3395) with positive TAb. Among untreated patients, those with nodular-HT showed higher frequency of PTC (9.4%) compared with both TAb-NG (6.4%; P=0.002) and TAb+NG (6.5%; P=0.009) and presented also higher serum TSH (median 1.30 vs 0.71 μU/ml, P<0.001 and 0.70 μU/ml, P<0.001 respectively). Independently of clinical diagnosis, patients with high titer of TAb showed a higher frequency of PTC (9.3%) compared to patients with low titer (6.8%, P<0.001) or negative TAb (6.3%, P<0.001) and presented also higher serum TSH (median 1.16 vs 0.75 μU/ml, P<0.001 and 0.72 μU/ml, P<0.001 respectively). PTC frequency was strongly related with serum TSH (odds ratio (OR)=1.111), slightly related with anti-thyroglobulin antibodies (OR=1.001), and unrelated with anti-thyroperoxidase antibodies. In the l-T(4)-treated group, when only patients with serum TSH levels below the median value (0.90 μU/ml) were considered, no significant difference in PTC frequency was found between nodular-HT, TAb-NG and TAb+NG. In conclusion, the frequency of PTC is significantly higher in nodular-HT than in NG and is associated with increased levels of serum TSH. Treatment with l-T(4) reduces TSH levels and decreases the occurrence of clinically detectable PTC.
Purpose
RAS
mutations represent common driver alterations in thyroid cancer. They can be found in benign, low-risk and malignant thyroid tumors with follicular architecture, which are often diagnosed ...as indeterminate nodules on preoperative cytology. Therefore, the detection of
RAS
mutations in preoperative setting has a suboptimal predictive value for malignancy. In this study, we investigated differentially expressed microRNA (miRNA) in benign and malignant thyroid tumors with follicular architecture carrying mutations in
RAS
genes.
Methods
Total RNA was purified from 60
RAS
-mutant follicular-patterned thyroid tumors, including follicular adenoma (FA), noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), papillary and follicular thyroid carcinoma cases (PTC, FTC); 22
RAS
-negative FAs were used as controls. The expression analysis of 798 miRNAs was performed by digital counting (nCounter nanoString platform).
Results
Comparing
RAS
-mutant and
RAS
-negative FAs, 12 miRNAs showed significant deregulation, which was likely related to the oncogenic effects of
RAS
mutations. Twenty-two miRNAs were differentially expressed in
RAS
-mutant benign versus malignant tumors. Considering the tumor type, 24 miRNAs were deregulated in PTC, 19 in NIFTP, and seven in FTC and compared to FA group; among these,
miR-146b-5p
,
miR-144-3p
, and
miR-451a
showed consistent deregulation in all the comparisons with the highest fold change.
Conclusions
The miRNA expression analysis of follicular-patterned thyroid tumors demonstrated that
RAS
mutations influences miRNA profile in benign tumors. In addition, several miRNAs showed a histotype-specific deregulation and could discriminate between
RAS
-mutant benign and
RAS
-mutant malignant thyroid lesions, thus deserving further investigation as potential diagnostic markers.
Higher TSH values, even within normal ranges, have been associated with a greater risk of thyroid malignancy. The relationship between TSH and papillary thyroid cancer (PTC) has been analyzed in 10 ...178 patients submitted to fine needle aspiration of thyroid nodules with a cytology of PTC (n=497) or benign thyroid nodular disease (BTND, n=9681). In 942 patients, submitted to surgery (521 from BTND and 421 from PTC), the histological diagnosis confirmed an elevated specificity (99.6%) and sensitivity (98.1%) of cytology. TSH levels were significantly higher in PTC than in BTND both in the cytological and histological series and also in patients with a clinical diagnosis of multinodular goiter (MNG) and single/isolate nodule (S/I). A significant age-dependent development of thyroid autonomy (TSH <0.4 microU/ml) was observed in patients with benign thyroid disease, but not in those with PTC, diagnosed both on cytology and histology. In patients with MNG, the frequency of thyroid autonomy was higher and the risk of PTC was lower compared to those with S/I. In all patients, the presence of thyroid auto-antibodies (TAb) was associated with a significant increase of TSH. However, both in TAb positive and TAb negative patients TSH levels were significantly higher in PTC than in BTND. Our data confirm a direct relationship between TSH levels and risk of PTC in patients with nodular thyroid diseases. Thyroid autonomy conceivably protects against the risk of PTC, while thyroid autoimmunity does not play a significant role.
Objective
The extent to which mononuclear cells and TSH-receptor autoantibodies (TRAb) contribute to Graves’ orbitopathy (GO) is not completely defined. Here we investigated the relationship between ...the immunohistochemical phenotype of orbital infiltrating cells and GO features in a large number of patients.
Methods
We conducted an observational cohort study in 76 consecutive patients with GO (16 men and 60 women) who underwent orbital decompression over a period of 18 consecutive months. An ophthalmological evaluation was performed in all patients, as well as immunohistochemistry for CD3, CD4, CD8, CD56 (T-cell markers), CD25 (T and B-cell marker), CD20, CD19 (B-cell markers), and CD138 (plasmacell marker) in specimens collected at decompressive surgery.
Results
Having established cutoff values for each marker, cell infiltrates were found in 60 patients (78.9%; CD3: 39.4%, CD4 55.2%, CD8 50%, CD56: 0%, CD25: 28.9%, CD20: 51.3%, CD19: 25%, CD138: 26.3%). Eleven (14.4%) stained exclusively for CD138 (plasmacells). Patients with CD4-positive mononuclear cells had a significantly greater GO clinical activity score (CAS) (mean difference 1.07, 95% CI − 0.33 to − 1.82,
P
= 0.004 by univariate,
P
= 0.05 by multivariate analysis). CAS as well as the remaining GO features were not affected significantly by the mononuclear cell subpopulations in multivariate analyses.
Conclusions
Mononuclear cell infiltrates are present in the majority of GO patients, with a small percentage represented exclusively by plasmacells. CD4 cells exert a major role on GO activity. These findings may represent a further advancement in the comprehension of GO pathogenesis.
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