FAP is a prognostic marker, but not a viable therapeutic target for clinical translation in HNSCC.

PURPOSE: PD-1 targeted immunotherapy has imparted a survival benefit to advanced head and neck squamous cell carcinoma (HNSCC), but less than 20% patients produce a durable response to this therapy. Here we aimed to investigate the potential biomarkers for predicting the clinical outcome and resistance to PD-1 targeted immunotherapy in HNSCC patients, and to examine the involvement of FAP+ cancer-associated fibroblasts (CAFs). METHODS: Bioinformatics methods were applied to analyze multiple datasets and explore the role of PD-1 and FAP in HNSCC. Immunohistochemistry was used to detect the expression of FAP protein. Fap gene knockout mice (Fap-/-) and L929 cells with different levels of Fap overexpression (L929-Fap-Low/High) were established to demonstrate the role of FAP+ CAFs in tumor development and immune checkpoint blockade (ICB) resistance. RESULTS: The expression level of PD-1 gene was positively correlated with better overall survival and therapeutic response to PD-1 blockade in HNSCC, but not all tumors with high expression of both PD-1 and PD-L1 were responsive. Moreover, FAP gene was overexpressed in pan-cancer tissues, and could serve as a prognostic biomarker for several cancers, including HNSCC. However, FAP protein was undetectable in mouse MTCQ1 tumors and barely expressed in human HNSCC tumors. Furthermore, FAP+ CAFs did not promote tumor growth or enhance the resistance to PD-1 inhibitor treatment. CONCLUSION: Although FAP+ CAFs have attracted increasing attention for their role in cancer, the feasibility and efficacy of FAP-targeting therapies for HNSCC remain doubtful.

Comparative study of optical coherence tomograph and histological images of eustachian tube nasopharyngeal region and adjacent structures in vivo and ex-vivo miniature pigs.

OBJECTIVES: Optical Coherence Tomograph (OCT) imaging technology can be used to examine, in vivo, the human ET. At present, it is impossible to achieve the OCT scanning vivo and ex vivo in the same individual human body, or study the consistency between OCT images and histological images of the eustachian tube nasopharyngeal region and adjacent structures. The aim of this study was to determine the consistency between OCT images and histological sections in vivo and ex vivo in miniature pigs. METHODS: OCT imaging was performed on five adult miniature pigs in vivo and ex vivo. The images of the eustachian tube OCT (ET-OCT), nasopharynx OCT (NP-OCT) and histological cross sections were further studied. RESULTS: All five miniature pigs achieved the OCT scan successfully, acquiring ET-OCT and NP-OCT images in vivo and ex vivo on both sides. The acquired ET OCT images closely matched the histological images, revealing details of the cartilage, submucosa, glands, and mucosa. The lower segment of the ET wall mucosa had an abundance of glands and submucosal tissues, with more low-signal areas appearing in the ex vivo images. The NP-OCT images of the nasopharynx matched the details of the mucosa and submucosal tissues. The ex-vivo OCT images showed thicker mucosa and more scattered slightly lower signal areas compared to the vivo OCT images. CONCLUSIONS: ET-OCT images and NP-OCT images matched the histological structure of eustachian tube nasopharyngeal region structures in miniature pigs both in vivo and ex vivo. OCT images may be sensitive to changes in edema and ischemia status. There is a great potential for morphological assessment of inflammation, edema, injure, mucus gland status.

Tumor size rather than the thyroid invasion affects the prognosis of parathyroid carcinoma without lymph node or distant metastasis.

PURPOSE: This study aimed to explore the prognostic value of thyroid invasion of parathyroid carcinoma without lymph node or distant metastasis. METHODS: Two hundred and nine cases of parathyroid carcinoma from the SEER (1989-2014) were eligible for this study. A Chi-squared test, t test, X-tile, Kaplan-Meier curves, and multivariate Cox proportional hazard regression were used for analysis. RESULTS: Thyroid invasion, sex, race, age, radiation, and surgery were not significantly associated with cancer-specific survival by multivariate analysis. However, tumor size ≥ 4 cm was significantly associated with worse cancer-specific survival (P < 0.001). CONCLUSION: Thyroid invasion, which was the criterion for T1 and T2 staging criteria of parathyroid carcinoma according to the AJCC, did not affect the prognosis of patients with parathyroid carcinoma without local lymph node or distant metastasis. Our study indicates that a tumor size ≥ 4 cm may be an appropriate indicator of T1 and T2 cancer staging.

Autoimmune thyroiditis in patients with sudden sensorineural hearing loss.

Objective: This study aims to evaluate the association between autoimmune thyroiditis and Sudden Sensorineural Hearing Loss (SSNHL). Methods: Hundred and five patients with SSNHL were enrolled. Audiometric tests, serum thyroid autoantibodies (TPOAb, TgAb) were studied. Based on the thyroid autoantibody results, patients were divided into two groups: thyroid autoantibody-positive and negative. The relationship between thyroid autoimmunity and audiological characteristics was analyzed. Results: Twenty-six patients (24.8%) of the SSNHL had thyroid autoantibody elevated. The pure tone average (PTA) of patients with and without thyroid autoantibody is 60 ± 38.51 and 54.99 ± 33.87 dBHL, respectively. The PTA was significantly improved in both groups after treatment (p < 0.001), but the hearing gains were similar in both groups (p = 0.205). Hearing loss of 2000-8000 Hz was worse than 125-1000 Hz among thyroid autoantibody-positive patients (p < 0.05), but the hearing improvement of both groups have no significant difference. The hearing improvement of 125-1000 Hz is significantly better than 2000-8000 Hz among patients with thyroid autoantibody negative (p < 0.05). Conclusions: We speculate that a potential association between thyroid autoimmunity and SSNHL. Thyroid autoimmunity may be a pathogenesis factor of SSNHL and associated with more severe hearing loss of high-frequency hearing.

Pan-cancer analysis of GALNTs expression identifies a prognostic of GALNTs feature in low grade glioma.

Polypeptide N-acetylgalactosaminyltransferases (GalNAc-Ts), a group of isoenzymes that initiate mucin-type O-glycosylation, have been shown to mediate tumor growth and metastasis in various cancer types. However, data on the clinical significance and features of GalNAc-Ts remain scant. Here, we used Oncomine and The Cancer Genome Atlas (TCGA) databases to analyze the transcription and survival effect of GALNTs (N-acetylgalactosaminyltransferase genes) in pan-cancer. The data showed that the GALNTs were aberrantly expressed in various human cancers and significantly associated with patients' clinical outcomes. The expression of 13 GALNTs were correlated with prognosis in brain low grade glioma (LGG) patients. In addition, based on the expression profiles of GALNT family genes in TCGA-LGG dataset, we identified 2 molecular subtypes (cluster1/2) by consensus clustering and analyzed tumor heterogeneity. Our results demonstrated that cluster 2 group was associated with poor prognosis, CD8+ T cells, macrophages and DCs infiltration, up-regulated expression of immune checkpoints, and higher tumor immune dysfunction and exclusion score, indicating that GalNAc-Ts might contribute to tumor immune escape. Furthermore, we employed LASSO regression and time-dependent ROC analysis to construct a GALNTs-related prognostic signature with the TCGA-LGG dataset, and then validated the signature using 2 external cohorts. Taken together, our study successfully developed a novel prognostic biomarker for LGG and provides a basis for personalized immunotherapy in brain cancer.

This study successfully developed a novel prognostic biomarker for LGG and provides a basis for personalized immunotherapy in brain cancer.

Role of primary tumor resection in patients with metastatic medullary thyroid cancer who have unresectable distant metastases.

BACKGROUND: Whether patients with medullary thyroid carcinoma (MTC) who have unresectable synchronous distant metastases should undergo primary surgical resection (PTR) remains controversial. This study aimed to identify predictive factors associated with the survival of such patients. METHODS: We conducted a retrospective study of patients with MTC who were registered in the Surveillance, Epidemiology, and End Results registry. The overall and cancer-specific mortality rates were assessed using risk-adjusted Cox proportional hazards regression modeling and stratified propensity score matching. RESULTS: One hundred and eight matched patients were assessed. Patients in the PTR group had lower overall mortality than did those in the non-PTR group. The 1-, 3-, and 5-year overall and cancer-specific survival rates in the PTR group were significantly higher. CONCLUSIONS: PTR appears to be the most appropriate intervention for patients with good performance status. Such patients are likely to benefit from surgery and to experience long-term stable disease.

Treatment and Prognosis of Anaplastic Thyroid Carcinoma: A Clinical Study of 50 Cases.

INTRODUCTION: Although anaplastic thyroid carcinoma (ATC) is rare, it is one of the most aggressive human cancers. The optimal multimodal therapy policy of ATC is still debated, and a standardized treatment strategy remains to be established. This study aimed to evaluate the management aspect and prognosis of ATC. MATERIALS AND METHODS: The data were analyzed retrospectively for 50 patients with ATC to evaluate the clinical characters, management and factors influencing survival. Survival analysis was performed by Kaplan-Merier method and log-rank test, and multivariate analysis was performed using Cox proportional hazard model. RESULTS: The 1-year and 2-year overall survival rates (OS) were 48.0% and 26.0% respectively in all patients, with the 2-year OS of 40.0% and 31.0% and 6.3% for stage IVA, IVB and IVC respectively (P <0.05). In stage IVA and IVB patients, combined surgery with radiotherapy improved overall survival, and the 2-year OS were 50.0% and 35.7% respectively in the group with combined surgery with radiotherapy and the group with surgery with only (P <0.05). Postoperative radiotherapy improved local control rate in stage IVA and IVB patients (P <0.05). However, surgery, radiotherapy or chemotherapy could not improve the survival of stage IVC patients. Multivariate analysis showed that distant metastases, surgery, radiotherapy and tumor residue could predict the prognosis. CONCLUSION: Combined surgery and radiotherapy could improve overall survival in stage IVA and IVB patients. Patients with ATC have a bad prognosis. Distant metastases, surgery, radiotherapy and tumor residue are the most important factors affecting the prognosis.

Cancer-associated fibroblasts provide a suitable microenvironment for tumor development and progression in oral tongue squamous cancer.

BACKGROUND: Oral tongue squamous cell carcinoma (OTSCC) is still associated with a poor prognosis due to local recurrence and metastasis. Cancer-associated fibroblasts (CAFs) play an important role in the complex processes of cancer stroma interaction and tumorigenesis. This study aims to determine the role of CAFs in the development and progression of OTSCC. METHODS: Immunohistochemistry was performed to evaluate the frequency and distribution of CAFs in 178 paraffin specimens from patients with OTSCC. Immunofluorescence, a cell proliferation assay, flow cytometry, migration and invasion assays and western blot analysis were used to study the effects of CAFs and the corresponding conditioned medium (CM) on the proliferation and invasion of OTSCC cell lines. RESULTS: Statistical analysis showed a strong correlation between the frequency and distribution of CAFs and the clinicopathological characteristics of patients with cN0 OTSCC, including pathological stage (P = 0.001), T classification (P = 0.001), and N classification (P = 0.009). Survival analysis demonstrated a negative correlation of the frequency and distribution of CAFs with the overall survival and disease-free survival of patients with cN0 tongue squamous cell cancer (P = 0.009, 0.002, respectively); Cox regression analysis showed that the presence of CAFs (relative risk: 2.113, CI 1.461-3.015, P = 0.023) is an independent prognostic factor. A functional study demonstrated that CAFs and CM from CAFs could promote the growth, proliferation, mobility, invasion and even Epithelial Mesenchymal Transition (EMT) of OTSCC cells compared with NFs and CM from NFs. CONCLUSIONS: CAFs were an independent prognostic factor for patients with OTSCC. Compared with NFs, CAFs and their CM have the ability to promote the growth, proliferation, metastasis and even EMT of OTSCC cells.

The Role of Tracheostomy in Anaplastic Thyroid Carcinoma.

Even though management of thyroid cancer is generally standardized and has an overall excellent long-term outcome, anaplastic thyroid cancer (ATC) continues to be a major diagnostic and therapeutic challenge. ATC is an uncommon thyroid malignancy with a poor prognosis. American Thyroid Association guidelines acknowledge the complexity of airway management in these patients. We studied the literature with the aim of providing guidance in airway management in ATC. Tracheotomy can facilitate completion of palliative treatment in those patients with ATC and stridor. Given the short life expectancy of these patients, a balanced decision must be made regarding the role and timing of tracheotomy.

Management of lymph node metastases from an unknown primary site to the head and neck (Review).

Cancer of unknown primary site (CUP) is an intriguing clinical phenomenon found in ~3-9% of all head and neck cancers. It has not yet been determined whether CUP forms a distinct biological entity with specific genetic and phenotypic characteristics, or whether it is the clinical presentation of metastasis in patients with an undetected primary tumor and no visible clinical signs. The treatment of patients with cervical lymph node metastases from CUP remains controversial, due to the lack of randomized clinical trials comparing different treatment options. Consequently, treatment is currently based on non-randomized data and institutional policy. In the present review, the range and limitations of diagnostic procedures are summarized and an optimal diagnostic work-up is recommended. The initial preferred diagnostic procedures include fine-needle aspiration biopsy (FNAB) and imaging. Although neck dissection followed by postoperative radiotherapy is the the most generally accepted approach, other curative options may be used in certain patients, such as neck dissection alone, nodal excision followed by postoperative radiotherapy, or radiotherapy alone. There remains controversy regarding target radiation volumes, ranging from ipsilateral neck irradiation to prophylactic irradiation of all the potential mucosal sites and both sides of the neck. When no primary lesion is identified with imaging and endoscopy in patients without history of smoking and alcohol abuse, molecular profiling of an FNAB sample for human papillomavirus and/or Epstein-Barr virus is required.

Prognostic significance of Flotillin1 expression in clinically N0 tongue squamous cell cancer.

PURPOSE: The present study aimed to investigate the clinical and prognostic significance of Flotillin1 (FLOT1) in clinically N0 tongue squamous cell cancer (cN0 TSCC). METHODS: Real-time PCR and Western blotting analyses were carried out to examine FLOT1 expression in four tongue squamous cell cancer cell lines, primary cultured normal tongue epithelial cells, and eight matched pairs of oral tongue cancer samples and adjacent non-cancerous tissue samples from the same patient. Immunohistochemistry was performed to examine FLOT1 protein expression in paraffin-embedded tissues from 181 cN0 TSCC patients. Statistical analyses evaluated the diagnostic value and the associations of FLOT1 expression with clinical parameters. RESULTS: FLOT1 mRNA and protein levels were upregulated in tongue squamous cell cancer cell lines and cancerous tissues compared with that in TEC and adjacent non-cancerous tissue samples. The level of FLOT1 protein was positively correlated with clinical stage (P = 0.001), T classification (P = 0.009), N classification (P = 0.001) and recurrence (P = 0.018). Patients with higher FLOT1 expression had shorter overall survival times. CONCLUSION: Our results suggest that overexpression of FLOT1 can be found in patients with higher pathological stage, T classification, N classification or recurrence. FLOT1 expression is associated with cN0 TSCC progression and may be valuable for the prognostic evaluation of cN0 TSCC.

Galectin-3 accelerates the progression of oral tongue squamous cell carcinoma via a Wnt/ß-catenin-dependent pathway.

The purpose of this study was to elucidate the clinicopathological significance and mechanism of action of galectin-3 in oral tongue squamous cell carcinoma (OTSCC). Here, the expression of galectin-3 was quantified in OTSCC (n = 68) and paired OTSCC and normal surrounding tissues (n = 10) using immunohistochemical staining. Tca8113 OTSCC cells were transfected with a plasmid expressing galectin-3 cDNA or siRNA against galectin-3. Cell proliferation, migration and invasion were measured using the MTT assay, Matrigel-coated Transwell migration assay and wound healing assay. The effect of galectin-3 on the Wnt/ß-catenin signaling pathway and epithelial mesenchymal transition (EMT) were investigated using a plasmid expressing the Wnt antagonist dickkopf 1 (DKK1) and Western blotting. Galectin-3 was expressed at significantly higher levels in OTSCC than the normal adjacent tissues; galectin-3 expression correlated strongly with pathological stage, pathological grade and lymph node invasion in OTSCC. Overexpression of galectin-3 promoted Tca8113 cell proliferation, migration and invasion, upregulated Wnt protein expression, activated ß-catenin and induced the EMT; knockdown of galectin-3 had the opposite effects. Co-transfection of Tca8113 cells overexpressing galectin-3 with the Wnt antagonist DKK1 reduced the ability of galectin-3 to increase cell proliferation, migration and invasion, reduced upregulation of Wnt, inhibited ß-catenin activation and abrogated the EMT, demonstrating that the Wnt/ß-catenin signaling pathway mediated the effects of galectin-3. Galectin-3 plays an important role in the progression of OTSCC via activation of the Wnt/ß-catenin signaling pathway.

Irradiation of the recipient site does not adversely affect successful free flap transfer in the repair of head and neck defects after salvage surgery for recurrent nasopharyngeal carcinoma originally treated with radiotherapy.

Irradiation of the recipient site has been associated with postoperative complications and an increased rate of flap failure in facial reconstruction. The aim of this study was to report the outcomes of our use of four different types of flaps (two free and two pedicled) for the reconstruction of patients with nasopharyngeal carcinoma (NPC) treated with radiotherapy, who subsequently received salvage surgery after the development of recurrence or secondary primary tumours. The records of 12 NPC patients who underwent salvage surgery and reconstruction from 2002-2007 were retrospectively reviewed. There were no intraoperative or significant postoperative complications. All flaps survived. The average cosmetic outcome was 2.7 (1 = poor, 4 = excellent), all patients could tolerate a liquid to normal diet, and nine patients had normal or intelligible speech, while three exhibited slurred speech. These results indicate that the effects of irradiation on the recipient site do not appear to adversely affect successful flap transfer or outcomes.

Survival study and clinicopathological evaluation of trichilemmal carcinoma.

Trichilemmal carcinoma (TC) is a rare malignancy, commonly located on the scalp, forehead and neck, trunk or the upper extremities. The aim of this study was to investigate the clinicopathological characteristics and prognostic factors of TC, and to determine an optimal treatment strategy for these patients. Consecutive patients who were admitted to the Sun Yat-sen University Cancer Center between 1998 and 2012 were included in this retrospective study. The key prognostic factors affecting survival were lymph node metastasis and surgery margin. Multivariate analysis demonstrated that there was no risk factor for patient survival. Surgery margin and lymph node metastasis were the prognostic factors that influenced the treatment outcome. Simple excision with 1 cm margins is safe, cost-effective and effective for the treatment of TC. Additionally, postoperative follow-up of the patient in order to facilitate early diagnosis of recurrence and distant metastasis is necessary. Systemic chemotherapy should be considered in the case of patients with distant metastases.

GOLPH3 overexpression correlates with tumor progression and poor prognosis in patients with clinically N0 oral tongue cancer.

BACKGROUND: Overexpression of GOLPH3 (Golgi phosphoprotein 3, 34 kDa) is associated with the progression of many solid tumor types leading to an unfavorable clinical outcome. We aimed to investigate the clinical significance of GOLPH3 expression in the development and progression of clinically N0 (cN0) oral tongue cancer. METHODS: Real-time PCR and Western blotting analyses were employed to examine GOLPH3 expression in four oral tongue cancer cell lines, primary cultured normal tongue epithelial cells (TEC), eight matched pairs of oral tongue cancer samples and adjacent noncancerous tissue samples from the same patient. Immunohistochemistry (IHC) was performed to examine GOLPH3 protein expression in paraffin-embedded tissues from 179 cN0 oral tongue cancer patients. Statistical analyses were applied to evaluate the diagnostic value and the associations of GOLPH3 expression with clinical parameters. RESULTS: GOLPH3 mRNA and protein was up-regulated in oral tongue cancer cell lines and cancerous tissues compared with that in primary cultured normal tongue epithelial cells (TEC) and adjacent noncancerous tissue samples. GOLPH3 protein level was positively correlated with clinical stage (P = 0.001), T classification (P = 0.001), N classification (P = 0.043) and recurrence (P = 0.009). Patients with higher GOLPH3 expression had shorter overall survival time, whereas those with lower GOLPH3 expression had longer survival time. CONCLUSION: Our results suggest GOLPH3 overexpression is associated with poor prognosis for cN0 oral tongue cancer patients and may represent a novel and useful prognostic indicator for cN0 oral tongue cancer.

Survival study and treatment strategy for second primary tumors in the oral cavity in patients with nasopharyngeal carcinoma after definitive radiation.

BACKGROUND: The purpose of this study was to investigate the clinicopathologic characteristics and prognostic factors of second primary tumors (SPTs) in the oral cavity in patients with nasopharyngeal carcinoma (NPC) after definitive radiation, and to determine an optimal treatment strategy for these patients. METHODS: This retrospective study enrolled consecutive patients who were admitted to the Sun Yat-Sen University Cancer Center between 1990 and 2005. RESULTS: The key prognostic factors influencing the survival were age when NPC was diagnosed, TNM stage, and surgery treatment modality. Multivariate analysis revealed that the clinical TNM stage was an independent risk factor for patient survival. CONCLUSION: Clinical TNM stage was an independent prognostic factor that influenced the treatment outcome. Our data indicate that the survival of patients with SPTs in the oral cavity can be improved by modifying treatment strategy, and that surgery is preferred when SPTs are diagnosed at an earlier stage.

Invasion of the hypoglossal nerve by adenoid cystic carcinoma of the tongue: case report and review of the literature.

Adenoid cystic carcinoma (ACC) is a rare but highly aggressive malignancy mainly originating from the salivary glands. ACC is well known for its propensity toward neural invasion (NI). NI is the process of neoplastic invasion in and along nerves. It is a distinct and well-documented phenomenon in ACC; however, it is an underestimated route of metastatic spread. Multiple distant metastases can be established through NI route, and NI is believed to portend a poor prognosis. Despite increasing recognition of NI in many malignancies, the molecular mechanism behind NI is not well established. We present a unique case of hypoglossal nerve invasion by ACC arising from the minor salivary glands in the tongue of a 34-year-old man. We also review and discuss current theories on the pathogenesis and mechanism of NI.

External monitoring of buried radial forearm free flaps in hypopharyngeal reconstruction.

CONCLUSION: The radial forearm free flap (RFFF) is one of the optimal choices for hypopharyngeal reconstruction. Our series demonstrates that the technique of an indicator flap for the monitoring of the buried flap is simple, reliable, and inexpensive. The condition of the indicator flap can be easily interpreted by the physicians and the nursing staff. Therefore, the success rate of this microsurgical reconstruction may be improved. OBJECTIVES: The RFFF is increasingly applied in reconstruction of the hypopharynx after radical resection for advanced hypopharyngeal cancer. However, postoperative monitoring of the buried free flap is extremely difficult. We designed a small external component as an indicator flap to monitor the perfusion of the buried vascular pedicle. METHODS: Eight consecutive patients with hypopharyngeal cancer underwent radical surgery and hypopharyngeal reconstruction using RFFF at the Sun Yat-sen University Cancer Center between January 2005 and January 2007. The indicator flap was sutured to the surface of the neck for postoperative monitoring. RESULTS: All of the indicator flaps remained viable. One patient experienced vascular compromise and was successfully salvaged. The success rate of the buried flaps was 100%. Pharyngocutaneous fistula occurred in one patient. All patients resumed an oral diet eventually.