Michal Mekel

B-Raf(V600E) and thrombospondin-1 promote thyroid cancer progression.

Although B-RafV600E is the most common somatic mutation in papillary thyroid carcinoma (PTC), how it induces tumor aggressiveness is not fully understood. Using gene set enrichment analysis and in vitro and in vivo functional studies, we identified and validated a B-RafV600E gene set signature associated with tumor progression in PTCs. An independent cohort of B-RafV600E-positive PTCs showed significantly higher expression levels of many extracellular matrix genes compared with controls. We performed extensive in vitro and in vivo validations on thrombospondin-1 (TSP-1), because it has been previously shown to be important in the regulation of tumor angiogenesis and metastasis and is present in abundance in tumor stroma. Knockdown of B-RafV600E resulted in TSP-1 down-regulation and a reduction of adhesion and migration/invasion of human thyroid cancer cells. Knockdown of TSP-1 resulted in a similar phenotype. B-RafV600E cells in which either B-RafV600E or TSP-1 were knocked down were implanted orthotopically into the thyroids of immunocompromised mice, resulting in significant reduction in tumor size and fewer pulmonary metastases from the primary carcinoma as compared with the control cells. Treatment of orthotopic thyroid tumors, initiated 1 week after tumor cell implantation with PLX4720, an orally available selective inhibitor of B-RafV600E, caused a significant tumor growth delay and decreased distant metastases, without evidence of toxicity. In conclusion, B-RafV600E plays an important role in PTC progression through genes (i.e., TSP-1) important in tumor invasion and metastasis. Testing of a patients thyroid cancer for B-RafV600E will yield important information about potential tumor aggressiveness and also allow for future use of targeted therapies with selective B-RafV600E inhibitors, such as PLX4720.

Targeting BRAFV600E with PLX4720 Displays Potent Antimigratory and Anti-invasive Activity in Preclinical Models of Human Thyroid Cancer

The role of the B-RafV600E mutation in aggressive thyroid cancers is examined.

A Novel Orthotopic Mouse Model of Human Anaplastic Thyroid Carcinoma

BACKGROUND Orthotopic mouse models of human cancer represent an important in vivo tool for drug testing and validation. Most of the human thyroid carcinoma cell lines used in orthotopic or subcutaneous models are likely of melanoma and colon cancer. Here, we report and characterize a novel orthotopic model of human thyroid carcinoma using a unique thyroid cancer cell line. METHODS We used the cell line 8505c, originated from a thyroid tumor histologically characterized by anaplastic carcinoma cell features. We injected 8505c cells engineered using a green fluorescent protein-positive lentiviral vector orthotopically into the thyroid of severe combined immunodeficient mice. RESULTS Orthotopic implantation with the 8505c cells produced thyroid tumors after 5 weeks, showing large neck masses, with histopathologic features of a high-grade neoplasm (anaplasia, necrosis, high mitotic and proliferative indexes, p53 positivity, extrathyroidal invasion, lymph node and distant metastases) and immunoprofile of follicular thyroid cell origin with positivity for thyroid transcription factor-1 and PAX8, and for cytokeratins. CONCLUSIONS Here we describe a novel orthotopic thyroid carcinoma model using 8505c cells. This model can prove to be a reliable and useful tool to investigate in vivo biological mechanisms determining thyroid cancer aggressiveness, and to test novel therapeutics for the treatment of refractory or advanced thyroid cancers.

Clinical and Cytological Features Predictive of Malignancy in Thyroid Follicular Neoplasms

BACKGROUND The preoperative diagnosis of malignancy in nodules suspicious for a follicular neoplasm remains challenging. A number of clinical and cytological parameters have been previously studied; however, none have significantly impacted clinical practice. The aim of this study was to determine predictive characteristics of follicular neoplasms useful for clinical application. METHODS Four clinical (age, sex, nodule size, solitary nodule) and 17 cytological variables were retrospectively reviewed for 144 patients with a nodule suspicious for follicular neoplasm, diagnosed preoperatively by fine-needle aspiration (FNA), from a single institution over a 2-year period (January 2006 to December 2007). The FNAs were examined by a single, blinded pathologist and compared with final surgical pathology. Significance of clinical and cytological variables was determined by univariate analysis and backward stepwise logistic regression. Odds ratios (ORs) for malignancy, a receiver operating characteristic curve, and predicted probabilities of combined features were determined. RESULTS There was an 11% incidence of malignancy (16/144). On univariate analysis, nodule size >OR=4.0 cm nears significance (p = 0.054) and 9 of 17 cytological features examined were significantly associated with malignancy. Three variables stay in the final model after performing backward stepwise selection in logistic regression: nodule size (OR = 0.25, p = 0.05), presence of a transgressing vessel (OR = 23, p < 0.0001), and nuclear grooves (OR = 4.3, p = 0.03). The predicted probability of malignancy was 88.4% with the presence of all three variables on preoperative FNA. When the two papillary carcinomas were excluded from the analysis, the presence of nuclear grooves was no longer significant, and anisokaryosis (OR = 12.74, p = 0.005) and presence of nucleolus (OR = 0.11, p = 0.04) were significantly associated with malignancy. Excluding the two papillary thyroid carcinomas, a nodule size >or=4 cm, with a transgressing vessel and anisokaryosis and lacking a nucleolus, has a predicted probability of malignancy of 96.5%. CONCLUSIONS A combination of larger nodule size, transgressing vessels, and specific nuclear features are predictive of malignancy in patients with follicular neoplasms. These findings enhance our current limited predictive armamentarium and can be used to guide surgical decision making. Further study may result in the inclusion of these variables to the systematic evaluation of follicular neoplasms.

Diagnostic Value of Diffusion-Weighted Imaging in Simultaneous 18F-FDG PET/MR Imaging for Whole-Body Staging of Women with Pelvic Malignancies

The aim of this study was to assess the diagnostic benefit of diffusion-weighted imaging (DWI) in an 18F-FDG PET/MR imaging protocol for whole-body staging of women with primary or recurrent malignancies of the pelvis. Methods: Forty-eight patients with a primary pelvic malignancy or suspected recurrence of a pelvic malignancy were included in our study. All patients underwent a whole-body 18F-FDG PET/MR imaging examination that included DWI. Two radiologists separately evaluated the PET/MR imaging datasets without DWI followed by a second interpretation with DWI. First, both readers identified all primary tumors, as well as lymph node and distant metastases. In a second session, PET and DWI data were assessed qualitatively. Image interpretation comprised lesion conspicuity defined as visual lesion-to-background contrast (4-point ordinal scale) and diagnostic confidence (3-point ordinal scale) for all tumors. The results from histopathologic examination and cross-sectional imaging follow-up (≥6 mo) were used as the reference standard. Statistical analysis was performed to assess the significance of differences between obtained values. Results: Among the 122 suspected lesions seen, 98 (80.3%) were considered malignant. PET/MR imaging without DWI had a sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy of 92.9%, 87.5%, 96.8%, 75.0%, and 91.8%, respectively, for the detection of malignant lesions. PET/MR imaging with DWI had slightly higher values (94.9%, 83.3%, 95.9%, 80.0%, and 92.6%, respectively), but the difference was not significant (P > 0.05). In the qualitative assessment of lesion-to-background contrast, PET had significantly (P < 0.05) higher values (3.79 ± 0.58) than DWI (3.63 ± 0.77). Furthermore, significantly (P < 0.05) higher scores were found for diagnostic confidence using PET (2.68 ± 0.64) for the determination of malignant lesions, when compared with DWI (2.53 ± 0.69). Conclusion: DWI in PET/MR imaging has no diagnostic benefit for whole-body staging of women with pelvic malignancies. The omission of DWI for staging or restaging gynecologic cancer may significantly reduce examination times, thus increasing patient comfort without a relevant decrease in diagnostic competence.

Thyroid surgery in octogenarians is associated with higher complication rates

BACKGROUND The incidence of thyroid nodules increases with age and little information is available regarding the risks of thyroid surgery in elderly patients. The aim of this study was to determine whether thyroid surgery in patients > or =80 is associated with higher complication rates. METHODS Out of 3,568 patients undergoing thyroid surgery between July 2001 and October 2007 at a single institution, the records of 90 consecutive patients > or =80 years were reviewed retrospectively and compared with a cohort of 242 randomly selected patients aged 18-79, who underwent thyroid surgery during the same time period. Clinical variables included age, gender, pre-operative diagnosis, substernal component, previous surgery, final pathology, length of stay, comorbidities, American Society of Anesthesiologists (ASA) score, body mass index, postoperative complications, and mortality. RESULTS Preoperative indications for surgery included benign disease in 51% vs 39%, suspected malignancy in 19% vs 26%, and suspected follicular neoplasms in 30% vs 35% in the octogenarian patient group (> or =80 years old) vs the younger patient cohort (P = NS). Octogenarians had 20% significant malignancy on final pathology vs 27% in the younger cohort (P = NS). The overall complication rate in the octogenarian group was 24% vs 9% in the younger cohort (P < .001). Male gender and ASA > or =3 were found to be independent risk factors for perioperative complications after thyroid surgery, while age alone was not. CONCLUSION Age > or =80 is associated with higher morbidity after thyroid surgery, although not independently. Earlier operative intervention may be advised in those at high risk for disease progression, whereas follow-up strategies without operation may be advised for others.

Surgical implications of B-RafV600E mutation in fine-needle aspiration of thyroid nodules

BACKGROUND Management of patients with thyroid nodules is based on establishing an accurate diagnosis; however, differentiating benign from malignant lesions preoperatively is not always possible using current cytological techniques. Novel molecular testing on cytological material could lead to clearer treatment algorithms. B-Raf(V600E) mutation is the most common genetic alteration in thyroid cancer, specifically found in papillary thyroid cancer (PTC), and usually reported to be associated with aggressive disease. DATA SOURCE A literature search using PubMed identified all the pertinent literature on the identification and utilization of the B-Raf(V600E) mutation in thyroid cancer. CONCLUSIONS The utility of using B-Raf mutation testing for nodules with indeterminate cytology is limited since many of those nodules (benign and malignant) do not harbor B-Raf mutations. However, when the pathologist sees cytological features suspicious for PTC, B-Raf(V600E) mutation analysis may enhance the assessment of preoperative risks for PTC, directing a more aggressive initial surgical management when appropriate.

Surgical drains can be safely avoided in lateral neck dissections for papillary thyroid cancer

BACKGROUND Drains are widely used in lateral neck dissections (LNDs). Our objective was to compare outcomes of LNDs for papillary thyroid cancer (PTC) with and without drains. METHODS One hundred sixty-five LNDs in 129 patients operated on from July 2001 to October 2008 were analyzed retrospectively. LNDs were divided according to the number of excised lymph nodes as follows: group A < median and group B > median. Further categorization was based on the use of a drain. Main outcome measures were wound complications requiring intervention. RESULTS One hundred two LNDs were performed with a drain and 63 without. The overall rate of wound complications was 3%. There was no significant difference in complication rate between the drain and the non-drain group (group A: 1.8% vs 0; group B: 2.2% vs 7.9%, respectively). CONCLUSIONS Significant seromas/hematomas are rare complications of LNDs. Patients who undergo LND for PTC without a drain show no significantly increased rate of these complications.

Overcoming obstacles to setting up office-based ultrasound for evaluation of thyroid and parathyroid diseases†

Ultrasound is an integral part of the preoperative workup for patients who are being evaluated for thyroid and parathyroid surgery. It helps improve the accuracy of a fine‐needle aspiration biopsy and complements other imaging modalities used for planning the extent of surgery. It also allows imaging of vital structures in relation to the thyroid and parathyroid. The compact nature and portability of ultrasound machines in recent years has made it easier for motivated surgeons (head and neck, general, and endocrine surgeons) to incorporate them into their practice. However, successfully setting up such a service needs adequate planning and an understanding of the obstacles that are involved. We aim to discuss these obstacles in detail, with practical suggestions on how to overcome them. This review may serve as a resource when dealing with issues such as purchasing equipment, training, credentialing, billing, documentation, and collaboration. Although these are discussed with respect to surgeons with an interest in endocrine disease, with some modifications they may also apply to any surgeon who uses ultrasound frequently. Laryngoscope, 2011

Preoperative localization modalities in primary hyperparathyroidism: Correlation with postoperative cure

Background: Accurate preoperative localization is critical to the success of minimally invasive parathyroidectomy. This investigation aimed to assess the correlation among preoperative imaging results, intraoperative findings, and postoperative cure rates in patients undergoing operation for primary hyperparathyroidism. Methods: A retrospective review of all patients who underwent operation for primary hyperparathyroidism between June 2010 and March 2016 was performed. Results: During the study period, 398 patients underwent parathyroidectomy. The overall cure rate was 97.5%. The ultrasonography performed by the surgeon was superior to the ultrasonography performed by the radiologist and to the sestamibi scan in lateralizing the adenoma correctly (80% vs 62% vs 70%, P < .001, respectively), and had the greatest sensitivity (93%) and accuracy (80%) among all tests (P < .001). Age ≥65 was found to be associated with lesser cure rates (94% vs 99.2%, P = .003). The number of positive preoperative studies correlated with cure rate, ranging from 80% for patients with 0 positive studies, to 100% in those with 4 positive studies (P = .0004). In patients with a negative sestamibi and an ultrasonography performed by the radiologist, there was no significant difference in the cure rates among those with no preoperative computed tomography, a positive preoperative computed tomography, or a negative preoperative computed tomography. Conclusion: An ultrasonography performed by an experienced surgeon is an extremely valuable preoperative localization modality. The cure rate obtained is proportional to the number of positive imaging studies. In patients with negative ultrasonography performed by a nonexperienced radiologist and a negative sestamibi scan, the performance of computed tomography does not seem to increase cure rate. Patients with no positive preoperative scans represent a challenging subgroup, with cure rates of approximately 80%.