M1-like tumor-associated macrophages cascade a mesenchymal/stem-like phenotype of oral squamous cell carcinoma via the IL6/Stat3/THBS1 feedback loop.

BACKGROUND: Tumor-associated macrophages (TAMs) have a leading position in the tumor microenvironment. Previously, we have demonstrated that M1-like TAMs activated by exosome-transferred THBS1 promote malignant migration in oral squamous cell carcinoma (OSCC). However, the functional roles and associated molecular mechanisms of the activated M1-like TAMs need to be further clarified in OSCC. METHODS: Conditioned Media (CM) were harvested from the exosome activated M1-like TAMs. We measured the malignant behaviors of OSCC under the treatment of CM from M1-like TAMs by performing colony forming assays, invasion assays, wound-healing assays, spheroid forming assays and in vivo xenograft experiments. The underlying mechanisms were investigated by RNA-seq, cytokines analysis, intracellular signaling pathway analysis, ChIP assays, bioinformatics analysis and validation. RESULTS: M1-like TAMs significantly promoted the epithelial-mesenchymal transition (EMT) process, and induced the cancer-stem like cells (CSCs) by upregulating the expression of MME and MMP14 in OSCC cells. Cytokine analysis revealed a shark increase of IL6 secretion from M1-like TAMs. Blocking IL6 in the CM from M1-like TAMs could significantly weaken its effects on the colony forming, invasion, migration, microsphere forming and xenograft forming abilities of OSCC cells. Cellular signaling assays indicated the activation of Jak/Stat3 pathway in the OSCC cells treated by the CM from M1-like TAMs. Blocking the activation of the Jak/Stat3 pathway could significantly weaken the effects of M1-like TAMs on the colony forming, invasion, migration, microsphere forming and xenograft forming abilities of OSCC cells. Further RNA-seq analysis and bioinformatics analysis revealed an increased expression of THBS1 in the OSCC cells treated by M1-like TAMs. Bioinformatics prediction and ChIP assays revealed the activation of Stat3 by CM from M1-like TAMs could directly promote the transcription of THBS1 in OSCC cells. CONCLUSIONS: We proposed that M1-like TAMs could cascade a mesenchymal/stem-like phenotype of OSCC via the IL6/Stat3/THBS1 feedback loop. A better understanding on the functional roles and associated molecular mechanisms of M1-like TAMs might facilitate the development of novel therapies for supplementing the current treatment strategies for OSCC patients.

Prevalence and associated factors of anxiety and depression among patients with oromaxillofacial venous malformations.

BACKGROUND: This study evaluated the levels, prevalence of anxiety and depression among patients with oral and maxillofacial venous malformations, along with associated factors. METHODS: Anxiety and depression, illness perceptions, and social support status of 69 patients with oral and maxillofacial venous malformations were analyzed using the Hospital Anxiety and Depression Scale, Brief Illness Perception Questionnaire, and Social Support Rating Scale, respectively. Eighty healthy controls were matched to the patients by sex, age, monthly income, education level, marital status, and employment status. RESULTS: Patients exhibited significantly higher levels of anxiety (3.41±3.01 vs. 1.03±1.66; P<0.001) and depression (7.14±2.47 vs. 2.19±2.12; P<0.001) compared to controls. Eleven (15.9%) and 30 (43.5%) patients had clinical symptoms of anxiety and depression respectively, compared to 3.8% and 6.3% of the healthy controls, respectively. Thirty-three patients (47.8%) had clinical symptoms of anxiety and/or depression, compared to 7.5% of the healthy controls. Multivariate analyses identified that facial lesions (odds ratio: 17.79, 95% confidence interval: 1.22-259.66; P=0.035), poor utility of social support (odds ratio: 0.02, 95% confidence interval: 0.01-0.31; P=0.006), and poor emotional illness perception (odds ratio: 27.39, 95% confidence interval: 5.01-149.89; P<0.001) were significantly associated with anxiety and depression in patients. CONCLUSIONS: Patients with oral and maxillofacial venous malformations displayed significantly increased levels and prevalence of anxiety and depression. These findings suggest the need for a standardized treatment for such patients, including appropriate medical intervention, psychological consultation, and social support.

Primary undifferentiated pleomorphic sarcoma in oral-maxillary area: retrospective study and molecular analysis.

Undifferentiated pleomorphic sarcoma (UPS) in oral-maxillary area is rarely reported. Herein, we aimed to investigate the clinical characteristics, treatment strategies, prognosis, and molecular features of the oral-maxillary UPS. In total, 10 cases with primary oral-maxillary UPS were included. The rapidly progressive UPS can easily develop to an advanced and life-threatening stage, especially concerning the complex anatomical structures and spaces in the oral-maxillary area. The final diagnosis for UPS greatly depended on histological findings and immunohistochemistry staining after the exclusion of all possible differential diagnoses. Retrospectively, the treatment strategies for the included cases still referred to those of oral squamous cell carcinoma (OSCC). Statistically, the median overall survival (OS) for all the included cases was 7.75 months (range: 5-17 months). Comparatively, 3 cases had improved OS (median survival: 17 months, range: 17-18 months) and experienced PR/SD with neoadjuvant chemotherapy (anlotinib). The molecular features were demonstrated by using whole exonic sequencing for 1 included case. Cancer driver gene detection revealed GBP4 as a candidate driver gene for the primary oral-maxillary UPS. Additionally, a missense mutation in gene PIK3CA (p.E545K) was also identified. Our findings could greatly expand the knowledge about primary oral-maxillary UPS, and provide molecular evidences to improve the therapeutic options for primary oral-maxillary UPS.

Increased nuclear translation of YAP might act as a potential therapeutic target for NF1-related plexiform neurofibroma.

Plexiform neurofibroma (pNF) in the head and neck is a characteristic feature in patients with neurofibromatosis type 1 (NF1) and is associated with significant disfigurement and psychological distress. Yes-associated protein (YAP), the key molecule involved in the Hippo pathway, is a vital transductor that regulates the proliferation and remyelinating of Schwann cells. The functional status of YAP and its feasibility as a potential target are still unknown in pNF. A total of 17 pNF tumor tissue specimens from the head and neck were collected at the Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine. Histologically, diagnosis of the Schwann cell region in pNF was achieved with hematoxylin-eosin staining, positive reactions for S100, SOX10, ERK and p-ERK, and low identification of Ki67 and SMA. Compared with normal nerve tissue, obviously increased nuclear YAP was detected in the Schwann cell region of pNF, with a mean nuclear staining rate of 67.11%. Based on the shNF1 Schwann cell model (the RSC96 cell line), with upregulated expression of RAS, ERK and p-ERK, p-YAP (Ser127) and p-YAP (Ser397) were significantly decreased and total YAP and nuclear YAP were increased. According to a confocal assay, the interference of shNF1 substantially promoted YAP nuclear translocation. Compared with control Schwann cells, the YAP inhibitor CA3 might have a more sensitive effect (IC50: NC=0.96±0.04, shNF1=0.71±0.02, P<0.05) on the shNF1 Schwann cell model than the classic MEK1/2 inhibitor selumetinib (IC50: NC=14.36±0.95, shNF1=24.83±0.98, P>0.05). For in vivo inhibition, the CA3 group and the selumetinib group displayed a similar inhibition effect with no significant difference. Increased nuclear translation and the functional state of YAP implies that the YAP-Hippo pathway might play an important role in the formation and remyelination of pNF. Compared with selumetinib, the YAP inhibitor can exhibit a similar but more sensitive effect on NF1-/- Schwann cells. These observations imply that YAP as a novel or adjuvant therapy target in the treatment of pNF.

Genetic landscape of common venous malformations in the head and neck.

OBJECTIVE: Common venous malformations (VMs) are a frequent sporadic subtype of vascular malformations. Given the TEK and PIK3CA mutations identified, this study aims to investigate the genetic landscape of VMs in the head and neck. METHODS: Patients from published sequencing studies related to common VMs were reviewed. Detailed data regarding clinical characteristics, sequencing strategies, and mutation frequency were synthesized. Lesion distribution of common VMs in the head and neck were further retrospectively analyzed by the pathologic database of the Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital. For the frequently affected sites in the head and neck, patients were selected for targeted sequencing with a designed vascular malformation-related gene panel or whole exome sequencing. Detected variants were analyzed by classical bioinformatic algorithms (SIFT23, PolyPhen-2 HDIV, LRT, MutationTaster, Mutation Assessor, and GERP++). To confirm the expression pattern of particular candidate gene, specimens were examined histochemically. Gene ontology enrichment analysis and a protein-protein interaction network were also constructed. RESULTS: Three hundred patients from eight sequencing studies related to common VMs were reviewed. The total prevalence rates of TEK and PIK3CA mutations were 41.3% and 26.7%, respectively. The most frequent TEK/PIK3CA mutations were TEK-L914F/PIK3CA-H1047R. TEK/PIK3CA mutations existed in 70.3% and 2.7% of VMs in the head and neck. In retrospective data from 649 patients carrying cervicofacial VMs at Shanghai Ninth Hospital, the most frequent sites were the maxillofacial region (lips, cheek, parotid-masseteric region, submandibular region) and the oral and oropharyngeal region (buccal mucosa, tongue). Targeted sequencing for 14 frequent lesions detected TEK variants in three patients (21.4%), but no PIK3CA mutations. On whole exome sequencing of two patients without TEK/PIK3CA mutations, CDH11 was the only shared deleteriously mutated gene. Bioinformatic analyses of CDH11 implied that genes involved in cellular adhesion and junctions formed a significant portion. CONCLUSIONS: Common VMs of the head and neck have a unique genetic landscape. Novel CDH11 and TEK variants imply that pathogenesis is mediated by the regulatory relationship between endothelial cells and extracellular components.

A Novel Laryngoscope-assisted Method for Sealing Pharyngocutaneous Fistula.

ABSTRACT: Pharyngocutaneous fistula (PCF) is one of the most common but stranded complications for salvage laryngectomy. As for localized fistula, there is no convincing standard and method to cure. This paper described a patient who was submitted to extensive resection of mass in right lingual root, total laryngectomy, and pharyngoesophageal reconstruction with an anterolateral thigh flap (ALTF), because of recurred carcinoma of right lingual root which invaded bilateral epiglottis. 2 weeks after surgery, subsequent pharyngocutaneous fistula developed at the junction of the tracheostomy, and maintained over 2 months under conservative treatment. With the assistance of laryngoscope, inner and outer orificiums of fistula were found and sealed by bundled iodoform strip. 9 days after sealing, fistula had been already filled with fresh granulation tissue. During 2 years after surgery, the fistula area dose not recur. This technique provides a safe and effective way for sealing the inner and outer orificiums of fistula.

Oral sarcomatoid squamous cell carcinoma: a retrospective study based on 14 cases.

The treatment outcomes for oral sarcomatoid squamous cell carcinoma (OSSCC) are far from satisfactory in our hospital. The aim of this study was to retrospectively summarize the OSSCC cases admitted to our department. From 2003 to 2017, 14 patients were hospitalized and diagnosed with OSSCC. We summarized and analysed the medical histories, diagnostic examinations, treatment strategies, and clinical outcomes of the involved cases. Of the 14 cases, 8 were located in the gingiva. The imageological diagnosis identified the existence of a mass with an infiltrative morphology pre-operatively. The cytopathologic features revealed a malignant neoplasm with a mixture of squamous cell carcinoma (SCC) components and spindle cell neoplastic components. To confirm the diagnosis of OSSCC, the use of the immunohistochemical markers AE1/AE3 and Vimentin were more indicative. Complete follow-up data were available for 12 patients, and at the last follow-up, all 12 of the patients had died. The median overall survival for these patients was 11.67 months (range: 3-24 months). OSSCC patients respond poorly to the strategies solely referring to experiences from oral squamous cell carcinoma (OSCC) treatment. The effective diagnosis and treatment of OSSCC at an early stage is necessary. The treatment for OSSCC still poses a great challenge for clinical oncologists.

Effect of combined low-dose oral prednisone with beta-adrenergic receptor antagonists for refractory infantile hemangiomas: retrospective cohort study in 76 patients.

BACKGROUND: Beta-adrenergic receptor antagonists have been the first-line treatment for infantile hemangiomas (IHs); however, monotherapy may fail to achieve sufficient efficacy for certain patients, especially for refractory IHs. The aim of this study was to evaluate the efficacy and safety of the combination of prednisone and beta-adrenergic receptor antagonists for refractory IHs. METHODS: We studied 76 patients with refractory IHs. After more than one month of insufficient oral propranolol therapy, forty-four patients received additional treatment of prednisone, while thirty-two patients continued to receive beta-adrenergic receptor antagonists monotherapy. The response to treatment was assessed according to hemangioma score values. RESULTS: The outcomes of patients after combined treatment were significantly better than those with monotherapy of beta-adrenergic receptor antagonists. The age to initiate prednisone was significantly negatively correlated with the improvement in the combination treatment group. The age at initiate treatment showed significant correlation with score variation percentage in both groups. There was no significant difference in the treatment duration observed between the two groups. Multivariable logistic regression analysis for all patients showed prednisone administration was the most important factor to better overall outcomes. CONCLUSIONS: Short-term addition of low-dose oral prednisone is an effective and safe adjunctive treatment for oral propranolol in contributing to refractory IH. Both early administration and long enough duration would be necessary.

Cancer stem cell biomarkers for head and neck squamous cell carcinoma: A bioinformatic analysis.

Several putative biomarkers have been reported to identify cancer stem cells (CSCs) in head and neck squamous cell carcinoma (HNSCC). Herein, we aimed to demonstrate the validity and the underlying relationship for these biomarkers in HNSCC. Bioinformatic analyses for the reported CSC biomarkers of HNSCC were performed based on the TCGA primary HNSCC cohort using the UCSC Xena browser. Targeted strategies for the validated biomarkers were searched and summarized. A total of 27 reported CSC biomarkers for HNSCC were identified and comprehensively evaluated. In regards to the expression pattern of CD44 in HNSCC, the expression patterns for the remaining 26 biomarkers presented 3 different tendencies. We managed to include all the 27 CSC biomarkers for HNSCC into 3 groups. Moreover, the biomarkers in each group indicated distinct clinicopathological features and a different overall survival status for HNSCC patients. The above information suggested the existence of CSC subpopulations in HNSCC. Accordingly, we demonstrated that precisely targeted strategies based on the CSC subgrouping clusters might effectively supplement conventional therapies, and benefit HNSCC patients. Further relevant studies are still necessary to improve treatment strategies for HNSCC based on the CSC area.

EGFR activation induced Snail-dependent EMT and myc-dependent PD-L1 in human salivary adenoid cystic carcinoma cells.

Epithelial-to-mesenchymal transition (EMT) confers cancer cells the ability of invasion and metastasis. However, how does EMT contribute to evasion of immune surveillance is unclear, especially in salivary adenoid cystic carcinoma (SACC). In this study, we investigated the molecular link between EGF-induced EMT and the immune checkpoint ligand programmed death-ligand 1 (PD-L1) by immunoprecipitation (IP) and Westernblot analysis. Cell migration and invasion activity was assayed by transwell assay. Immunohistochemical (IHC) staining analysis was performed for measurement of EMT markers and PD-L1 expression levels in tumor tissues. We found that EGF-induced EGFR activation stabilized Snail expression and induced EMT in SACC. Interestingly, EGFR activation induced simultaneously both EMT and PD-L1 in SACC. Importantly, knockdown of Snail greatly suppressed EGF-induced EMT, but not EGF-induced PD-L1 expression; whereas knockdown of c-Myc strongly repressed PD-L1 expression, but not snail expression and EMT. The molecular link is strongly supported by robust correlations between the EMT markers and PD-L1 expression in human cancer samples.These results suggest that EGFR activated EMT and PD-L1 via two distinct mechanisms. EGFR activation induced EMT and PD-L1 expression in SACC. Snail is required for EGF-induced EMT, but not PD-L1 expression; whereas c-Myc is required for EGFR-mediated PD-L1 upregulation but not EMT. Thus, targeting activated EGFR may inhibit both EMT and PD-L1, which may potentiate the therapeutic effect of PD-L1-based immunotherapy, especially in the malignant subgroups of SACC patients with activated EGFR.

Transgenic Expression of A Venous Malformation Related Mutation, TIE2-R849W, Significantly Induces Multiple Malformations of Zebrafish.

A TIE2 mutation causing arginine-to-tryptophan substitution at residue 849 (TIE2-R849W) is commonly identified in heredofamilial venous malformation. However, there is no in vivo model to confirm the pathogenic role of TIE2-R849W. Humanized TIE2-R849W plasmid was constructed via PCR-mediated site-directed mutagenesis. After transcription and micro-injection, TIE2-R849W significantly induces multiple malformations in zebrafish: caudal vein plexus (CVP) defect, eye abnormalities, forebrain formation perturbations, and mandibular malformation. Histologically, these phenotypes accompany aphakia, confused retina plexiform layer, abnormal mandibular cartilage, ectopic myelencephalon proliferation and aberrant location of neurogliocytes. According to qRT-PCR, except for high expression of egfl7, the other CVP-related genes cd146, nr2f1a, and s1pr1 are not significantly different from control. TIE2-R849W also induced upregulation of the wnt signaling pathway. Gene array in vitro shows that under the effect of TIE2-R849W, consistent with high expression of pik3 and foxo1, high levels of egfl7, wnt9a, lrp5 and dkk1 were partly confirmed. This in vivo model directly identifies the venous-related pathogenic role of TIE2-R849W. Under up-regulation of TIE2-R849W, egfl7 could be considered a potential reason for venous defects. Moreover, the wnt pathway may perform an important role as a key trigger for head multi-malformations.

Dose reduction of bone morphogenetic protein-2 for bone regeneration using a delivery system based on lyophilization with trehalose.

INTRODUCTION: To induce sufficient new bone formation, high doses of bone morphogenetic protein-2 (BMP-2) are applied in regenerative medicine that often induce serious side effects. Therefore, improved treatment strategies are required. Here, we investigate whether the delivery of BMP-2 lyophilized in the presence of trehalose reduced the dose of BMP-2 required for bone regeneration. MATERIALS AND METHODS: A new growth factor delivery system was fabricated using BMP-2-loaded TiO2 nanotubes by lyophilization with trehalose (TiO2-Lyo-Tre-BMP-2). We measured BMP-2 release characteristics, bioactivity, and stability, and determined the effects on the osteogenic differentiation of bone marrow stromal cells in vitro. Additionally, we evaluated the ability of this formulation to regenerate new bone around implants in rat femur defects by micro-computed tomography (micro-CT), sequential fluorescent labelling, and histological analysis. RESULTS: Compared with absorbed BMP-2-loaded TiO2 nanotubes (TiO2-BMP-2), TiO2-Lyo-Tre-BMP-2 exhibited sustained release, consistent bioactivity, and higher stability of BMP-2, and resulted in greater osteogenic differentiation of BMSCs. Eight weeks post-operation, TiO2-Lyo-Tre-BMP-2 nanotubes, with various dosages of BMP-2, regenerated larger amounts of new bone than TiO2-BMP-2 nanotubes. CONCLUSION: Our findings indicate that delivery of BMP-2 lyophilized with trehalose may be a promising method to reduce the dose of BMP-2 and avoid the associated side effects.

Topical Timolol Vs. Oral Propranolol for the Treatment of Superficial Infantile Hemangiomas.

Objective: Infantile hemangiomas (IHs) are the most common vascular tumors of infancy. Oral propranolol has achieved great success in treating IHs since 2008. To minimize the systemic side events caused by oral administration of propranolol, topical timolol started to be applied in the treatment of IHs, especially for superficial lesions. Methods: We treated 724 children with superficial IHs using oral propranolol or topical timolol, and investigated the efficacy and safety of the two treatment patterns. Results: Both oral propranolol and topical timolol achieved a satisfactory therapeutic outcome, with an effective response rate of 97 and 96.4%, respectively. No significant differences in visual analog scale (VAS) improvement between the two groups were observed. Occurrence rate of systemic adverse events for patients treated with oral propranolol (3.9%) was significantly higher than that for patients treated with topical timolol (0%). Clinical response was not associated with gender, duration of treatment, lesion location, lesion size, gestational age, and progesterone use during pregnancy, but closely associated with age at treatment initiation, which indicated that younger age at treatment initiation predicted for a better regression rate. Conclusions: We recommend that topical timolol instead of oral propranolol could be the first-line therapy for superficial IHs because of its good efficacy and improved safety.

Pathology and management of masses in the accessory parotid gland region: 24-year experience at a single institution.

PURPOSE: Masses in the accessory parotid gland (APG) region are clinically rare and their management can lead to conflicts between the need for tumor resection and facial cosmesis. The aim of this study was to analyze the pathological classifications and management of APG lesions in our hospital. MATERIALS AND METHODS: From January 1993 to March 2017, 130 patients with primary tumors in the APG region who underwent surgical treatment were enrolled. Follow-up surveys after surgery were then carried out. RESULTS: Among the 130 patients, 53.8% of lesions were benign (n = 70), 23.8% were malignant (n = 31), 14.6% were vascular malformations (n = 19), 6.15% were sialadenitis (n = 8), and 1.65% were cysts (n = 2). Pleomorphic adenoma accounted for 67.1% of the benign tumors (n = 47). Lymphoma, lymphoepithelial carcinoma, and acinar cell carcinoma topped the list of malignant tumors (5 cases in each group). Surgery and surgery plus radio-chemotherapy were performed for benign and aggressive malignant lesions, respectively. At the time of follow-up, 5-year overall survival was 88.1%; mean follow-up was 139 months (range 3-281 months). CONCLUSIONS: Masses in the APG region have complicated pathological types. Perfect preoperative preparation, with fine-needle aspiration biopsy and imaging examinations, would contribute to identifying characteristics. Treatment schedules and surgical approaches should be determined according to the cytology reports and frozen-section examinations before and during operation.

Interferon-alpha therapy for refractory kaposiform hemangioendothelioma: a single-center experience.

Kaposiform hemangioendothelioma (KHE) is a relatively rare vascular tumor with an aggressive and infiltrating nature. Previous studies have revealed an exclusive relationship between KHE and Kasabach-Merritt Phenomenon (KMP), which is associated with high morbidity and mortality. No universally accepted treatment modality exists for refractory KHE with or without KMP. The aim of this study was to evaluate the safety and efficacy of interferon-alpha (IFN-α) therapy for treatment of refractory KHE. Twelve consecutive patients with KHE were treated with subcutaneous injections of IFN-α after other treatments had failed. Eleven patients exhibited a reduction in tumor size of more than 50%, and the platelet count for all five patients with KMP returned to normal level after IFN-α therapy. The duration of IFN-α treatment ranged from 3 months to 9 months (mean: 6.3 months). The response time for IFN-α treatment ranged from 10 days to 5 weeks (mean: 3.6 weeks). Additionally, no severe complications, such as neurological damage or spastic diplegia, were observed in these patients. In conclusion, our study suggested that IFN-α therapy is effective and safe for refractory KHE, and IFN-α may be used as an alternative after other treatments have failed.

Treatment of deep-seated facial microcystic lymphatic malformations with intralesional injection of pingyangmycin.

Treatment of microcystic lymphatic malformations (LMs) is still a great challenge to physicians in the field of managing vascular anomalies. Several kinds of treatment have been proposed for microcystic LMs, but the responses to these treatment modalities vary considerably among individuals. The aim of the study was to investigate the safety and efficacy of intralesional injection of pingyangmycin for microcystic LMs located in the deep facial region.Twenty-one consecutive patients with deep-seated facial microcystic LMs were treated with intralesional injection of pingyangmycin between March 2010 and April 2015. The patients received 2 to 8 injections, and the average session was 3.7. The therapeutic efficacy was accessed on the basis of the imaging findings and clinical measurements.Among the 21 patients, the clinical responses were excellent in 7 patients (33.33%), good in 9 patients (42.86%), fair in 3 patients (14.29%), and poor in 2 patients (9.52%). No severe side effects were encountered. Furthermore, therapeutic outcomes were significantly associated with lesion location (P = 0.006) and number of injections (P = 0.003).Our study supports that sclerotherapy with pingyangmycin is safe and effective for the treatment of deep-seated facial microcystic LMs.

A retrospective study of six patients with mandibular metastatic carcinoma.

Mandibular metastatic carcinoma is a rare lesion that accounts for <1% of all oral malignancies. To provide greater experience in this field, the present study was conducted in which 6 cases of mandibular metastatic carcinoma were retrospectively reviewed. The origin of the lesions was the prostate in 2 cases, the lungs in 2 cases, the breast in 1 case and the thyroid gland in 1 case. The clinical and computed tomography features, surgical management and follow-up outcomes were investigated. The study indicated that surgeons should include the suspicion of metastasis in the differential diagnosis for mandibular tumor, particularly in patients who have a history of malignancy. A poor prognosis was associated with the examined patients. To extend the survival time as long as possible, a treatment strategy using multiple therapies, including segmental mandibulectomy, radiotherapy and chemotherapy, is recommended.

Long-term results of a randomized phase III trial of TPF induction chemotherapy followed by surgery and radiation in locally advanced oral squamous cell carcinoma.

Previously, we conducted a randomized phase III trial of TPF (docetaxel, cisplatin, and 5-fluorouracil) induction chemotherapy in surgically managed locally advanced oral squamous cell carcinoma (OSCC) and found no improvement in overall survival. This study reports long-term follow-up results from our initial trial. All patients had clinical stage III or IVA locally advanced OSCC. In the experimental group, patients received two cycles of TPF induction chemotherapy (75mg/m2 docetaxel d1, 75mg/m2 cisplatin d1, and 750mg/m2/day 5-fluorouracil d1-5) followed by radical surgery and post-operative radiotherapy; in the control group, patients received upfront radical surgery and post-operative radiotherapy. The primary endpoint was overall survival. Among 256 enrolled patients with a median follow-up of 70 months, estimated 5-year overall survival, disease-free survival, locoregional recurrence-free survival, and distant metastasis-free survival rates were 61.1%, 52.7%, 55.2%, and 60.4%, respectively. There were no significant differences in survival rates between experimental and control groups. However, patients with favorable pathologic responses had improved outcomes compared to those with unfavorable pathologic responses and to those in the control group. Although TPF induction chemotherapy did not improve long-term survival compared to surgery upfront in patients with stage III and IVA OSCC, a favorable pathologic response after induction chemotherapy may be used as a major endpoint and prognosticator in future studies. Furthermore, the negative results observed in this trial may be represent type II error from an underpowered study. Future larger scale phase III trials are warranted to investigate whether a significant benefit exists for TPF induction chemotherapy in surgically managed OSCC.

A survey on clinical use of propranolol for infantile hemangiomas in mainland China.

OBJECTIVE: To provide a guideline for Chinese clinicians regarding oral propranolol treatment on infantile hemangioma (IH). METHODS: A survey for management of propranolol therapy (clinical consultation, dosage initiation, dosage changing, monitoring of complications and effectiveness evaluation) was performed and was delivered to the Division of Vascular Anomalies (DVA), Chinese Stomatological Association (CSA), and to the Division of Hemangioma and Vascular Malformations (DHVM), Chinese Society of Plastic and Reconstructive Surgery. RESULTS: Data from 31 hospitals were collected and analyzed. In all hospitals, IH patients were treated with oral propranolol as a routine. Twenty-two (71%) of the 31 hospitals treated patients with IH as part of a multidisciplinary strategy. Cardiology consultation was routinely sought in 21 (95%) of these 22 hospitals before initiation of propranolol therapy. Sixteen hospitals (52%) recommend an initial propranolol dose of 1 to 1.5 mg/kg/day, in most cases 1.0 mg/kg/day. The dosage frequency of once a day was recommended in 18 (58%) of the surveyed hospitals. The maximum dose of 1.5 mg/kg/day or 2.0 mg/kg/day was suggested in 10 (32%) and 13 (42%) hospitals, respectively. Similarly, the optimal dose of 1.5 mg/kg/day or 2.0 mg/kg/day was recommended in 11 (37%) and 9 (30%) hospitals, respectively. The duration of therapy varied from 1 to 24 months. Tapering was advised by 10 (40%) hospitals and immediate discontinuation was applied in 13 (52%) hospitals. Complications were emphasized by all hospitals. The most common complications were gastrointestinal symptoms (17 of 31 hospitals), whereas the complication most commonly monitored for was changes in heart rate. No rebound effects were reported. CONCLUSIONS: Propranolol has become the first-line agent for IH in mainland China. This is a practical survey which is helpful to standardize and develop a guideline for propranolol therapy.