الفهرس 
TitleOnly 14 pages are availabe for public view
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Abstract
Thyroid nodules are common disorder in the adult population. Most of thyroid nodules
are benign and only 5-15% are malignant. Thyroid cancer represents about 2.2% of all
cancers in Egypt. The initial evaluation of patients with thyroid nodules includes full detailed
history, physical examination, assessing risk factors, neck ultrasonography to assess the size
and suspicious characteristics, and fine needle aspiration cytology (FNAC). The gold standard
definitive diagnostic tool is the postoperative histopathological examination.
Fine needle aspiration cytology (FNAC) has proved to be a reliable and cost effective
way to evaluate thyroid nodules. It is a main method used to evaluate and triage thyroid
nodules. However, FNAC still has its technical and diagnostic limitations. Nodules classified
as atypia of undetermined significance or follicular neoplasm and even those suspicious for
malignancy, represent inconclusive diagnoses and may necessitate surgical intervention for
excisional biopsy and postoperative histopathological examination to reach a conclusive
accurate diagnosis, though many of which prove later, by postoperative biopsy, to be of
benign nature. Moreover, part of FNAC limitations is related to aspiration, showing
inadequate cells. In addition, FNAC is an invasive diagnostic method and depends strongly on
the technical performance and competence of the operators. All the previous makes a defect in
the clinical decision pathway and exerts an extra burden on patients with thyroid nodules.
Therefore, more accurate and less invasive methods must be developed to add more reliable
and appropriate diagnostic tools.
Molecular testing platforms have been developed and are used in combination with
FNAC as an essential part of the cytologic evaluation. The definitive goal of thyroid
molecular analysis is to ameliorate the clinical management of patients with thyroid nodules,
by accurately assessing the nature of thyroid nodules and decreasing the diagnostic
uncertainty of cytologically indeterminate thyroid nodules before surgical interferance.
Avoiding unnecessary diagnostic thyroid surgeries has massive implications on overall patient
quality of life and cost of health care.
miRNAs are endogenous small non-coding RNAs of 19 to 25 nucleotides that
negatively regulates gene expression by destroying messenger RNAs (mRNAs) or preventing
their translations. Several miRNAs are known to target mRNAs entangled in cancer,
including those of oncogenes and tumor suppressor genes and therefore have fundamental
roles in cancer establishment, progression in addition to metastasis. miRNA profiles have
emerged as a noninvasive way to classify extensive types of human cancers. Due to the good
stability of miRNAs in peripheral blood, the identification of miRNAs is noninvasive,
sensitive and simple, which has become a hot topic in the molecular biology of tumors in
recent years. Recent studies suggest that circulating miRNAs may be useful as thyroid cancer
marker.
The aim of the present study was to evaluate the expression of circulating miRNA 222
and miRNA 146b as a potential differentiating tool between benign and malignant thyroid
nodules
Summary, Conclusion and Recommendations
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This study was conducted on 46 Egyptian adults. Subjects were categorized into 2
groups, each twenty three patients, based on microscopic pathological examination. group (I)
confirmed to have malignant nodules and group (II) confirmed to have benign nodules.
Both groups were subjected to full detailed medical history, clinical physical
examination and ultrasonography (US) of thyroid gland and neck. Cytopathological
examination of fine needle aspirate (FNA) from thyroid nodule is done for most of the cases.
Plasma miRNA 222 and 146b were measured by Real time quantitative PCR.
We investigated the two miRNAs (146b and 222) as possible circulating biomarkers for
thyroid cancer. We compared their expression levels in plasma samples of cases with thyroid
cancer and cases with benign nodules. We also analyzed the relation of their expression with
thyroid ultrasound findings and the pathologic characteristics of thyroid cancer
Results found a significant upregulation of plasma miRNA 222 and miRNA 146b in
patients with malignant thyroid nodules compared to patients with benign thyroid nodules (p
value = 0.001). This upregulation of both miRNAs showed a good diagnostic performance
represented with high AUC (0.776) of ROC curve, diagnostic sensitivity (60.87%) and
specificity (100 %) for miRNA 222 and, high AUC (0.825), diagnostic sensitivity (78.26%)
and specificity (78.26 %) for miRNA 146b. These results denote a promising diagnostic value
of circulating miRNAs 222 and 146b for identification of thyroid cancer and discriminating
malignant from benign thyroid nodules.
The present study revealed a significant increase of plasma miRNA 222 with vascular
invasion in malignant thyroid nodules (P=0.044) that suggests a correlation between its
upregulation and tumor aggressiveness. However, we found no significant relation between
miRNA 146b and vascular or capsular invasion nor nodal metastasis.
Combined rise of plasma miRNAs 222 and 146b, above Youden identified cutoffs,
revealed a diagnostic sensitivity of 60.87 % , specificity and PPV of 100% to identify thyroid
cancer and to discriminate malignant from benign thyroid nodules.
We discovered also a significant additive role of plasma miRNA 222 and miRNA 146b
with different ultrasound and pathological diagnostic parameters. It was found that by adding
either plasma miRNA 222 or miRNA 146b to microcalcification or TIRAD 4 &5 or Bethesda
class III, & IV, AUC of ROC curves increased significantly. Combining miRNAs 222 and
146b to ultrasound diagnostic parameters significantly increased the diagnostic specificity.
Summary, Conclusion and Recommendations
85
6.2. Conclusion
Our study found that plasma molecular biomarker miRNA 222 and miRNA 146b show
promising diagnostic value for identification of thyroid cancer and discriminating malignant
from benign thyroid nodules.
We discovered also that plasma miRNA 222 was increased in relation to vascular
invasion in malignant thyroid nodules suggesting a possible relation to tumor aggressiveness.
Regarding the diagnostic performance of combined examination of circulating miRNA
222 and miRNA 146b in both studied groups, it showed a significant increase in thyroid
cancer group with high specificity and positive predictive value of 100%.
The present study revealed the additive diagnostic role of plasma miRNA 222 and
miRNA 146b with ultrasound diagnostic parameters, microcalcification or TIRAD IV &V or
Bethesda class III, & IV that could help to distinguish between benign and malignant nodules.
6.3. Recommendations
Considering the evaluation of combined plasma miRNAs 222 and 146b as a potential
diagnostic tool, to distinguish malignant from benign thyroid nodules to improve the accuracy
of diagnosis of thyroid nodule and to reduce the number of unnecessary diagnostic thyroid
surgeries aiming for a better clinical management of patients.
More studies are recommended with increasing number of cases to confirm the relation
between miRNA 146b and vascular or capsular invasion and nodal metastasis in malignant
thyroid nodules.
Evaluation of plasma miRNAs 222 and 146b in patients with recurrent thyroid cancer is
recommended to assess their role in the follow up of thyroid cancer.
Further studies are needed to be performed on the correlation of circulating miRNAs
222 and 146b with other genetic mutations such as, BRAF (V600E) mutation .