Claudin-1 mediates progression by regulating EMT through AMPK/TGF-ß signaling in head and neck squamous cell carcinoma.

Claudin-1 (CLDN1), a major component of tight junction complexes in the epithelium, maintains cellular polarity, and plays a critical role in cell-to-cell communication as well as epithelial cell homeostasis. Although the role of CLDN1 has been widely studied in cancer, its role in the progression and the exact regulatory mechanisms, remain controversial. Using next-generation sequencing, we first analyzed the expression profiles of tumor/non-tumor paired tissue in patients with head and neck squamous cell carcinoma (HNSC) from public and local cohorts and found out that CLDN1 is upregulated in tumors compared to normal tissues. Next, its correlation with lymph node metastasis and poor prognosis was validated in the retrospective cohort, which collectively suggests CLDN1 as an oncogene in HNSC. As expected, the knockdown of CLDN1 inhibited invasive phenotypes by downregulating epithelial-to-mesenchymal transition (EMT) in vitro. To ascertain the regulatory mechanism of CLDN1 in HNSC analysis of GO term enrichment, KEGG pathways, and curated gene sets were used. As a result, CLDN1 was negatively associated with AMP-activated protein kinase (AMPK) and positively associated with transforming growth factor-ß (TGF-ß) signaling. In vitro mechanistic assay showed that CLDN1 inhibited AMPK phosphorylation by regulating AMPK upstream phosphatases, which led to inhibition of Smad2 activity. Intriguingly, the invasive phenotype of cancer cells increased by CLDN1 overexpression was rescued by AMPK activation, indicating a role of the CLDN1/AMPK/TGF-ß/EMT cascade in HNSC. Consistently in vivo, CLDN1 suppression significantly inhibited the tumor growth, with elevated AMPK expression, suggesting the novel observation of oncogenic CLDN1-AMPK signaling in HNSC.

Pediatric aggressive giant cell granuloma of nasal cavity.

INTRODUCTION: Giant cell granuloma (GCG) is a non-neoplastic osseous proliferative lesion of unknown etiology. Although a benign disease process, GCG can be locally destructive. It is extremely rare to have a pediatric case of GCG occurring in the nasal cavity with intracranial invasion. PRESENTATION OF CASE: We report a case of an aggressive and recurrent giant cell granuloma with intracranial invasion in a 10 years old female patient which was completely excised with endoscopic craniofacial resection. DISCUSSION: A literature review on pathogenesis, diagnosis and management is also performed. CONCLUSION: The most common treatment for giant cell granuloma is surgery, ranging from simple curettage to resection. However, it must be completely excised in cases of aggressive and extensive lesion because of the high recurrence rate after incomplete removal.

Transient and permanent hypocalcemia after total thyroidectomy: Early predictive factors and long-term follow-up results.

BACKGROUND: Post-thyroidectomy hypocalcemia is among the most common complications of total thyroidectomy. The purpose of this study was to evaluate early predictive factors and long-term changes in intact parathyroid hormone (iPTH) levels in patients with transient and permanent hypocalcemia after total thyroidectomy. PATIENTS AND METHODS: A total of 349 consecutive patients who underwent total thyroidectomy with or without neck dissection between 2009 and 2011 were reviewed. PTH, total calcium (Ca), and ionized Ca (iCa) levels were evaluated at 1 hour, and 1, 3, 5, and 7 days, and 1, 3, 6, and 12 months postoperatively. Biochemical profiles at 1 hour after total thyroidectomy in patients with transient and permanent hypocalcemia were compared. Patients with postoperative hypocalcemia were followed for 12 months. RESULTS: Lesser preoperative serum levels of Ca and more extensive surgery were significantly associated with postoperative hypocalcemia (P < .05). The absolute level and relative decline (%) in iPTH at 1 hour were the most reliable predictors of postoperative hypocalcemia according to the receiver operating characteristics curve, with a threshold of 10.42 pg/mL and 70%. Sensitivity and specificity of the predictors were 83.4% (95% CI, 76.4-89.1), 100% (95% CI, 84.6-100.0), 84.1 (95% CI, 77.2-89.7), and 95.5% (95% CI, 77.2-99.9), respectively. Parathyroid function recovered in the first month after total thyroidectomy in 78 of 99 patients (79%) with transient hypocalcemia. However, 46 of 61 patients (74%) with a subnormal iPTH level at 3 months after surgery had permanent hypocalcemia. CONCLUSION: Mean postoperative PTH level and the mean relative decline in PTH measured 1 hour postoperatively were the most reliable predictors of postoperative or permanent hypocalcemia.

Sinonasal organized hematoma: Clinical features of seventeen cases and a systematic review.

OBJECTIVES/HYPOTHESIS: Organized hematoma (OH) is a rare non-neoplastic disease. We studied the clinical characteristics of 17 patients with sinonasal OH and those of 75 cases in the English literature. STUDY DESIGN: Retrospective review of medical records and systematic review of the literature on OH. METHODS: Comprehensive review of the English-language literature on OH was performed. We screened all eligible cases based on initial features, and 75 eligible cases found in 15 publications were analyzed. We also retrospectively analyzed and compared medical records of 17 patients diagnosed with pathologically proven sinonasal OH. Data such as demographics, clinical characteristics, pathologic features, radiologic findings, treatment modalities, and follow-up results were compared to the 75 previously mentioned cases. RESULTS: Fifteen cases involved the maxillary sinus, one case involved the frontal sinus, and one case involved the sphenoid sinus. There were six patients over 60 years old, and all were taking an antiplatelet agent. The paranasal sinus computed tomography (CT) of seven patients showed bony destruction of the involved sinus. A review of the available literature revealed mostly similar results with our cases, except for the proportion of patients taking aspirin (5.3%) and sex distribution (male:female = 49:25). CONCLUSIONS: We reported 17 cases of OH, including a case of frontal sinus and a case of sphenoid sinus lesion. A large proportion of OH patients had bony destruction of the affected sinus on CT. In these patients, a careful diagnosis should be made to distinguish them from a malignant tumor or other expansile diseases. LEVEL OF EVIDENCE: 4.

Recurrence in regional lymph nodes after total thyroidectomy and neck dissection in patients with papillary thyroid cancer.

BACKGROUND: We investigated the risk factors of the regional lymph node (LN) recurrence in papillary thyroid cancer (PTC) patients underwent thyroidectomy and neck dissection according to the clinicopathologic features, preoperative clinical nodal status and the recurrence in previously dissected or undissected compartment of the neck. METHODS: A retrospective analysis was performed on 297 patients who underwent total thyroidectomy and LN dissection between 2004 and 2010. Patients with and without regional recurrence were compared by the various clinicopathological factors. Recurrence-free survival rates were estimated by the Kaplan-Meier and Cox regression method. RESULTS: With a median follow-up of 53 months, 22 (7.4%) patients developed regional LN recurrence. Initial LN metastasis and tumor size ⩾1 cm were independent predictive factors for regional recurrence. In patients without preoperative clinical LN, Tumor size ⩾1 cm and extrathyroidal extension were significant risk factors for regional recurrence. In cases with preoperative clinical LN, there was no specific significant factor for recurrence. Tumor size ⩾1 cm, capsular invasion, extrathyroidal extension, and lymphovascular invasion were significant risk factors of regional recurrence in previously dissected compartments. Tumor size ⩾1 cm and extrathyroidal extension were significant predictive factors of regional recurrence in previously undissected compartments. CONCLUSIONS: Tumor size and LN metastasis were independent predictors of regional LN recurrence in PTC patients after total thyroidectomy and central neck dissection. Patients with tumor size >1 cm or extrathyroidal extension were more likely to have tumor recur both within the previously dissected field as well as the un-dissected compartments.

Upregulation of HGF and c-MET is associated with subclinical central lymph node metastasis in papillary thyroid microcarcinoma.

BACKGROUND: Identification of a novel biomarker of subclinical lymph node metastasis (SLNM) in papillary thyroid microcarcinoma (PTMC) could provide important clues regarding SLNM in PTMC. We evaluated the significance of HGF and c-Met expression in surgically removed tumor tissue from PTMC patients as a predictive marker of SLNM. METHODS: We analyzed the immunohistochemical relationship between HGF and c-Met expression and SLNM in 113 surgically treated PTMC patients with clinically negative nodes presurgery. In addition, we explored whether HGF/c-Met pathway activation enhanced the in vitro migration and invasion of PTC cells. RESULTS: Positive immunohistochemical HGF and c-Met staining was found in 107 (95 %) and 103 (91 %) cases, respectively. The HGF staining distribution was as follows: no staining in 6 cases, weak staining in 43, moderate staining in 55, and strong staining in 9. Of the nine cases with strong HGF staining, eight (89 %) had SLNM. The c-Met staining distribution was as follows: no staining in 10 cases, weak staining in 39, moderate staining in 59, and strong staining in 5. Of the five cases with strong c-Met staining, three (60 %) had SLNM. The presence of SLNM was strongly correlated with HGF and c-Met expression in PTMC in a univariate analysis (P < 0.05). HGF overexpression was also associated with SLNM in a multivariate analysis (P < 0.05). Stimulation with exogenous HGF and constitutive activation of c-Met enhanced the migration and invasion of PTC cells in vitro by enhancing VEGF-A expression. CONCLUSIONS: HGF/c-Met pathway activation is associated with SLNM of the central neck in PTMC.

Prophylactic lymphadenectomy of neck level II in clinically node-positive papillary thyroid carcinoma.

BACKGROUND: The purpose of this study was to examine the frequency, pattern, and predictive factors associated with occult level II lymph node (LN) metastases in papillary thyroid carcinoma (PTC) patients with clinically metastatic lymph nodes in the lateral neck (level III, IV, and/or V) by preoperative ultrasonography. METHODS: We retrospectively reviewed the medical records of 52 PTC patients with clinically positive neck lymph nodes in level III, IV, and/or V based on preoperative ultrasonography, who underwent therapeutic lateral neck dissection (ND) (level II-V) between March 2004 and October 2009. All patients had no suspicion of clinically positive neck nodes in level II. Histopathological analysis of neck specimens according to each node level of the neck was performed, with special attention given to level II. RESULTS: Forty-two (81%), 41 (79%), and 6 (12%) patients had histologically positive lymph nodes in level III, IV, and V, respectively. Occult metastases in level II were observed in ten (19%) patients. Patients without suspicious positive LNs in both neck level III and IV by preoperative ultrasonography, and patients without pathologic LN metastases in level III, had no occult LN metastases occurrence to level II. Based on multivariate analysis, presence of more than four metastatic LNs was an independent predictive factor for occult level II metastases [P = 0.022, odds ratio (OR) = 7.738]. CONCLUSIONS: Prophylactic level II LN dissection may be omitted in PTC patients with clinically positive neck nodes if suspicious positive lymph nodes in level III are absent during preoperative ultrasonography.