Expression of ß1- and ß2-adrenergic receptors in oral squamous cell carcinoma and their association with psychological and clinical factors.

BACKGROUND: Psychological stressors have been related to tumor progression through the activation of beta-adrenergic receptors (ß-AR) in several types of cancer. PURPOSE: This study aimed to investigate the expressions of ß1- and ß2-AR and their association with psychological and clinicopathological variables in patients with oral squamous cell carcinoma. METHODS: Tumor samples from 99 patients diagnosed with OSCC were subjected to immunohistochemical reaction to detect the expression of ß1-AR and ß2-AR. Anxiety and depression symptoms were assessed using the Beck Anxiety Inventory and Beck Depression Inventory (BDI), respectively. The Brunel Mood Scale was used for measuring affective mood states. RESULTS: Univariate analyzes revealed that higher expression of ß1-AR was associated with increased alcohol consumption (p = 0.032), higher education (p = 0.042), worse sleep quality (p = 0.044) and increased levels of pain related to the primary tumor (p < 0.001). Higher expression of ß2-AR was related with regional metastasis (p = 0.014), increased levels of pain related to the primary tumor (p = 0.044), anxiety (p < 0.001) and depressive (p = 0.010) symptoms and higher mood scores of angry (p = 0.010) and fatigue (p = 0.010). Multivariate analysis identified that patients with advanced clinical stage had lower ß1-AR expression (OR=0.145, 95% CI=0.025-0.828, p = 0.003). Higher anxiety symptoms and higher mood fatigue are independent factors for increased ß2-AR expression (OR=4256, 95% CI=1439-12606, p = 0.009; OR=3816, 95% CI=1258-11,573, p = 0.018, respectively). CONCLUSION: This study reveal that anxiety, fatigue symptoms, and clinical staging are associated with tumor expression of beta-adrenergic receptors in patients with oral cancer.

Primary manifestation of HIV-related Burkitt lymphoma in the oral and maxillofacial regions.

BACKGROUND: Burkitt lymphoma (BL) is a subtype of non-Hodgkin lymphoma. It is strongly associated with HIV infection and has a highly aggressive clinical course. The involvement of the maxillofacial region in BL has rarely been reported. CASE DESCRIPTION: A 36-year-old woman with HIV-positive status had painless bilateral swelling of the oral mucosa and middle and lower thirds of the face. Microscopic analysis of the oral lesion revealed an atypical lymphoid infiltrate with a starry sky pattern. The lymphoid cells expressed cluster of differentiation 20, cluster of differentiation 10, B-cell lymphoma 6, and c-Myc; the Ki-67 proliferative index was high. The tumor cells were positive for Epstein-Barr virus. These results led to the diagnosis of HIV-related BL. PRACTICAL IMPLICATIONS: BL and other immunodeficiency-related lymphoproliferative malignancies may affect the oral and maxillofacial regions and should be included in the differential diagnosis of rapidly expanding swelling in young patients.

Bilateral intra-lymph node Warthin's tumor as a potential diagnostic pitfall mimicking metastatic carcinoma.

Warthin's tumor (WT) is a benign and frequent salivary gland tumor primarily affecting the parotid gland. In some cases, this tumor can involve the extra parotid region and affect cervical lymph nodes. Fine-needle aspiration can be the first step in the diagnostic approach to lymphadenopathy; however, specimens from intra-nodal WT can present a potential pitfall, leading to a misdiagnosis of metastasis. Here, we report an unusual case of a patient with bilateral WT in parotid lymph nodes misdiagnosed as metastases. In addition, we highlight the cytopathological aspects of WT to alert cytopathologists about this challenging diagnosis.

A pilot study to improve pain phenotyping in head and neck cancer patients.

Pain associated with head and neck cancer (HNC) is difficult to manage and reduces quality of life. It has been increasingly recognized that HNC patients exhibit a wide range of pain symptoms. Here we developed an orofacial pain assessment questionnaire and conducted a pilot study to improve pain phenotyping in HNC patients at the diagnosis. The questionnaire captures the following pain characteristics: pain intensity, location, quality, duration, and frequency; the impact of pain on daily activities; changes in smell and food sensitivities. Twenty-five HNC patients completed the questionnaire. 88% patients reported pain at the site of tumor; 36% reported multiple pain sites. All patients with pain reported at least one neuropathic pain (NP) descriptor, 54.5% reported at least two NP descriptors. The most common descriptors were "burning" and "pins and needles". Most patients reported increased pain to sour or hot/spicy food/drinks, and to food with coarse/hard textures. Patients exhibited impaired oral function, especially chewing, talking, mouth/jaw opening, and eating. Tumor progression has a significant impact on pain. Nodal metastasis is linked to pain at multiple body sites. Patients with advanced tumor staging experience greater pain at the primary tumor site, when exposed to hot or spicy food/drinks or food with hard/coarse texture, or when eating or chewing. We conclude that HNC patients experience a wide range of pain symptoms with altered mechanical, chemical, and temperature sensation. Improved phenotyping and stratification of pain in HNC patients will help address the underlying etiology, which may enable personalized therapeutic approaches in the future.

Influence of different methods for classification of lymph node metastases on the survival of patients with oral squamous cell carcinoma.

BACKGROUND: Despite the advances in the classification of oral squamous cell carcinoma (OSCC) based on its extension by the TNM system, there is still a need for methods to better classify the patients to predict prognosis and indicate adjuvant therapy. OBJECTIVES: To analyze the influence of the number of positive lymph nodes (PN), lymph node ratio (LNR), and log odds of positive lymph nodes (LODDS) in survival of patients with OSCC. METHODS: Clinicopathologic data from patients with OSCC who were treated with curative purposes by surgery and neck dissection (ND) with or without subsequent adjuvant therapies from 1991 to 2015 was retrospectively assessed. The impact of the PN, LNR, LODDS, and other variables on overall survival (OS) and disease-free survival (DFS) was analyzed in univariate and multivariate analyses. RESULTS: One hundred nineteen patients were included in this study. In the univariate analysis the PN had a significant impact on OS (p = 0.001) and DFS (p = 0.020), and the LNR had a significant impact on the OS (p = 0.042). In the multivariate analysis with other relevant clinicopathologic variables, the PN was the only significantly independent factor influencing in the OS (p = 0.017) but not in DFS (p = 0.096). CONCLUSIONS: The PN is an independent prognostic indicator for OS and DFS in patients with OSCC and has the potential to aggregate the current AJCC classification. The LNR has potential to be an important prognostic indicator, but the methods for this classification require lapidation. The LODDS did not demonstrate prognostic potential.

Early life stress exacerbates bone resorption and inhibits anxiety-like behaviour induced by apical periodontitis in rats.

AIM: To evaluate the influence of the early life stress (ELS) on the severity of the apical periodontitis (AP) in Wistar rats. METHODOLOGY: Forty male Wistar rats were divided into four groups (n = 10): Control rats; AP-rats with AP; ELS-rats subject to ELS; AP + ELS-rats exposed to ELS and subject to AP. ELS was induced by maternal separation (MS) for a period of 3 h for 21 consecutive days. AP was induced via pulp exposure of the first and second right maxillary molars to the oral environment for 40 days. Three days before euthanasia, all rats underwent behavioural analysis to measure anxiety levels by elevated zero maze. Then, the rats were euthanized and the maxillas were removed to assess the occurrence and severity of AP. The periapical region was evaluated for the intensity of the inflammatory infiltrate and the extent of bone loss. The Mann-Whitney test was performed for nonparametric data, and the Tukey's or Student's t-test was performed for parametric data (p < .05). RESULTS: The intensity of the inflammatory infiltrate was significantly larger in the AP + ELS group when compared with AP group (p < .05). The AP + ELS group exhibited significantly greater alveolar bone loss, with a periapical lesion size of 103.5 ± 29.88, compared with 72.3 ± 22.28 in the AP group (p < .05). Rats with AP displayed higher anxiety-like behaviour in relation to the control group (p < .05). However, exposure to ELS abolished the AP-induced increased anxiety-like 'behaviour' throughout, since that rats from AP + ELS group attended more the open arms than non-stressed rats with AP (p < .05). CONCLUSION: Early life stress is predictive of the severity of AP exacerbating the inflammatory process and increasing periapical bone resorption.

Mantle cell lymphoma involving the oral and maxillofacial region: a study of 20 cases.

OBJECTIVE: To investigate the clinicopathologic features of mantle cell lymphoma (MCL) involving the oral and maxillofacial region. METHODS: The MCL cases were retrieved from the pathosis database of 6 pathology laboratories. Original hematoxylin and eosin slides and immunohistochemical reactions were reviewed for confirmation of the initial diagnosis. Clinical data of the cases were obtained from the patients' pathosis and/or medical charts. RESULTS: Twenty cases were included in the study, showing a male predominance and a mean age of 66 years. The oral cavity (12 cases) and the oropharynx (5 cases) were the most commonly involved subsites. Most cases presented as asymptomatic swellings, with 2 cases showing bilateral involvement of the palate. The classic histologic variant predominated (12/20 cases). All cases expressed CD20 with nuclear cyclin D1 positivity. SOX11 was seen in 9/13 cases, CD5 in 6/16 cases, Bcl2 in 16/19 cases, CD10 in 2/20 cases, and Bcl6 in 4/16 cases. Ki67 showed a mean proliferation index of 40.6%. The Epstein-Barr virus (EBV) was negative in all cases investigated. Follow-up data was available for 7 patients, with 5 currently alive and 2 deceased. CONCLUSION: Mantle cell lymphoma, albeit rare, may manifest in the oral and maxillofacial region. Its histologic heterogeneity demands a high degree of diagnostic skill from pathologists.

Potential of lymph-node ratio as a prognostic factor for patients with oral squamous cell carcinoma.

BACKGROUND: To analyze the influence of the lymph node ratio (LNR) in survival of patients with OSCC METHODS: Clinicopathologic data from patients with OSCC who were treated with curative surgery and neck dissection (ND) with or without adjuvant therapies from 1991 to 2015 was retrospectively assessed. The impact of LNR and other variables on overall survival (OS) and disease-free survival (DFS) was analyzed in univariate and multivariate analyses. RESULTS: One hundred nineteen patients were included. In the univariate analysis the LNR had a significant impact on OS (p = 0.01) and DFS (p = 0.01). In the multivariate analysis, the LNR was the only significantly independent factor influencing in the OS (p = 0.03). The adjuvant therapies did not influence on the OS (p = 0.42) and DFS (p = 0.10). CONCLUSIONS: The LNR is an independent prognostic factor in patients with OSCC. The LNR alone is not recommended to indicate the performance of adjuvant therapies.

Predisposing factors for increased cortisol levels in oral cancer patients.

Cancer patients may have a dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and abnormal secretion of cortisol. Increased cortisol levels have been associated with worse prognosis in patients with different types of tumors. Although anxiety and depression can trigger an abnormal cortisol secretion, little is known regarding the influence of these emotional disorders on HPA axis dysregulation in cancer patients when evaluating together with demographic, clinicopathological and biobehavioral variables. This cross-sectional study analyzed the pre-treatment plasma cortisol levels of 133 patients with oral squamous cell carcinoma (OSCC) and its association with demographic, clinicopathological, biobehavioral and psychological variables. Plasma cortisol levels were measured by electrochemiluminescence, and anxiety and depression symptoms were assessed using Beck Anxiety Inventory (BAI) and Depression (BDI), respectively. Demographic, clinicopathological and biobehavioral data were collected from patients' medical records. Results from multivariate analysis showed that the occurrence of cancer-induced pain was predictive for higher cortisol levels (OR = 5.388, p = 0.003). Men with OSCC were 4.5 times more likely to have higher plasma cortisol levels than women (OR = 4.472, p = 0.018). The effect of sex on cortisol concentrations was lost in the adjusted model for clinical staging (OR = 2.945, p = 0.116). The absence of chronic alcohol consumption history was a protective factor for highest hormone concentrations in oral cancer patients (OR = 0.104, p = 0.004). Anxiety symptoms measured by BAI as "hands trembling" (OR = 0.192, p = 0.016) and being "nervous" (OR = 0.207, p = 0.0004) were associated with lower cortisol levels. In contrast, the feeling of "fear of losing control" was a risk factor for highest hormone concentrations (OR = 6.508, p = 0.0004). The global score and specific symptoms of depression measured by the BDI were not predictive for plasma hormone levels (p > 0.05). Together, our results show that pain, alcohol consumption and feeling fear are independent factors for increased systemic cortisol levels in patients with oral cancer. Therefore, psychological intervention, as well as control of pain and alcohol consumption, should be considered to prevent the negative effects of cortisol secretion dysregulation in cancer patients.

Interventions for Radiation-Induced Fibrosis in Patients With Breast Cancer: Systematic Review and Meta-analyses.

Purpose: Radiation therapy can affect normal tissues in patients with breast cancer, causing adverse effects such as fibrosis. Although there are several interventions for radiation-induced fibrosis, the efficacy of these procedures is still unclear. The purpose of this review is to evaluate the efficacy of interventions for radiation-induced fibrosis in patients with breast cancer. Methods and Materials: This is a systematic review of randomized clinical trials. Studies that compared any intervention for fibrosis to another intervention, placebo, or no intervention were included. Outcomes assessed were fibrosis, adverse events, quality of life, treatment adherence, pain, and functionality. Results: A total of 2501 publications were found, and 7 studies were selected because they met the inclusion criteria. The interventions for fibrosis were pentoxifylline and vitamin E, grape seed extract, kinesiotherapy, and endermotherapy. The results showed great heterogeneity in the treatment protocols for radiation-induced fibrosis in patients with breast cancer and in their evaluation metrics. The meta-analyses showed no benefit in using pentoxifylline and vitamin E compared with placebo or no intervention (standardized mean difference: -0.30; 95% confidence interval, -0.79 to 0.20; P = .24 [very low evidence]) compared with placebo and vitamin E (standardized mean difference: -0.09; 95% confidence interval, -0.66 to 0.49; P = .77 [moderate evidence]), respectively, assessed by the Late Effects Normal Tissue Task Force-Subjective, Objective, Management, and Analytic (LENT-SOMA) scoring scale. Conclusions: The effectiveness of these interventions for the treatment of radiation-induced fibrosis in patients with breast cancer could not be determined. Although isolated studies show significant results favorable to the experimental groups, caution should be exercised in these findings because of the small number, small sample size, and high risk of bias presented by some of the included studies, which makes the recommendation for clinical practice still weak.

Propranolol inhibits cell viability and expression of the pro-tumorigenic proteins Akt, NF-ĸB, and VEGF in oral squamous cell carcinoma.

BACKGROUND: Propranolol (PPL) has been suggested as an option for the treatment of various types of cancer. However, data regarding its effectiveness against oral cancer are scarce. Thus, we aimed to evaluate the antitumor potential of PPL in oral squamous cell carcinoma (OSCC) in vitro. METHODS: OSCC cell lines, SCC-9, SCC-25, and Cal27, were treated with PPL at different times and concentrations. OSCC cells were treated with PPL alone or in combination with cisplatin (CDDP) or 5-fluorouracil (5-FU). Cell viability was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The expression of phosphorylated (p)-Akt, p-S6, p-PTEN, p-P65, and VEGF was verified by immunofluorescence. The migratory activity of OSCC cells was evaluated using a wound-healing assay. RESULTS: PPL reduced OSCC cell viability in a dose- and time-dependent manner. Concentrations above 300 µM, 110 µM, and 100 µM for SCC-9, Cal27, and SCC-25, respectively, significantly eliminated tumor cells. The combination of PPL with CDDP and 5-FU enhanced their antitumor effects. There was a modest difference between the use of the IC30 and IC50 of PPL in the combinatory options. PPL downregulated p-P65 NF-ĸB and VEGF expression in SCC-9 and Cal27 cells but not in SCC-25 cells. PPL inhibited the phosphorylation of Akt and s6 and increased the phosphorylation of PTEN in all OSCC cell lines studied. PPL inhibited OSCC cell migration after 24 h of treatment. CONCLUSION: PPL was effective against oral cancer cells and enhanced standard-of-care. PPL inhibited cell viability and the expression of pAkt, NF-ĸB, and VEGF.

HIV-related plasmablastic lymphoma causing extensive bone destruction in the mandible.

Plasmablastic lymphoma (PBL) is a rare subtype of large B-cell lymphoma commonly associated with HIV infection. HIV-related PBL has a dismal prognosis. The aggressive clinical course of the disease may lead to the development of rapid-growing swellings, like several benign and malignant conditions. Herein, we reported the case of a 38-year-old woman with a painful swelling in the mandible initially diagnosed as an abscess derived from a tooth extraction. Intraoral examination revealed a painful swelling with reddish, white and purplish areas in the posterior region of the mandible without signs of infection. Imaging exams showed an extensive bone destruction in the left mandibular body. Histopathological examination revealed a high proliferation of plasmacytoid cells with nuclear hyperchromatism. Tumor cells were negative for CD20, and positive for Ki-67, CD138, IgG and lambda chain. The diagnosis of oral PBL was defined and serological test showed positivity for HIV. Eight months after starting treatment, the patient died due to complications of cancer treatment. Lymphoproliferative malignancies related to HIV infection should be included in the differential diagnosis of rapid-growing swellings in the oral cavity.

Stress hormone norepinephrine incites resistance of oral cancer cells to chemotherapy.

This study investigated whether norepinephrine (NE) and epinephrine (E) interfere in the response of head and neck squamous cell carcinoma (SCC) cell lines to cisplatin and explored the mechanisms of chemoresistance. Head and neck SCC-derived cell lines SCC-9, Cal27, SCC-25, and FaDu were stimulated with NE or E and treated with the inhibitory concentration of cisplatin for 24 h. As for adrenergic receptors (ADRB) inhibition, cells were treated with propranolol. The results showed that, when combined with NE, cisplatin effectiveness against SCC-9 and Cal27 but not SCC-25 and FaDu cells were notably reduced. E did not affect the response of the cells to cisplatin. Further experiments were performed with the responsive SCC-9 and SCC-25 cell lines and the hormone NE. The time course assay showed that stimulation of oral SCC cells with NE decreased the cleavage of caspase-3 and expression of multidrug resistance protein 1 (MDR-1) but only transiently affected ATP-binding cassette (ABC) subfamily G, isoform 2 protein (ABCG2) expression. The expression of cleaved caspase-3 and Bcl-2 were, respectively, decreased and increased by the combination of NE and cisplatin in SCC-9 and Cal27 cells. NE-induced resistance was reverted by previous treatment with propranolol. Expressions of ABCG2, and p-Akt but not of MDR-1, were enhanced by NE plus cisplatin when compared to cisplatin only in both cell lines. Migratory activity of oral SCC cells challenged with cisplatin was not affected by NE. These findings reveal for the first time that stress hormone NE induces resistance of oral cancer cells to cisplatin in vitro through the ADRB/Akt/ABCG2 pathway, pumping the drug out of the cell and inhibiting apoptosis.

The 'AEIOU' system to identify primary oral melanoma.

Primary oral melanoma (POM) is a rare entity that is often asymptomatic and is associated with a poor prognosis. Following the example of the ABCDE acronym for the clinical diagnosis of early cutaneous melanoma, we would like to introduce another acronym, AEIOU, to identify lesions that are clinically suspicious for POM. The letter "A" means age older than 50; "E" means ethnicity in reference to the higher occurrence among Asians, Hispanics, and Africans; "I" means irregularity in reference to irregular borders or color; "O" means oral palate, the most frequent site of POM; and "U" means ulceration. To the best of our knowledge, this paper is the first to describe an acronym AEIOU as a diagnostic aid for POM among health practitioners and the general population. Future studies should test the acronym's sensitivity and specificity for POM diagnosis in clinical practice.

Assessment of the knowledge of canalis sinuosus amongst dentists and dental students: An online-based cross-sectional study.

INTRODUCTION: Canalis sinuosus (CS) is a neurovascular canal that corresponds to a small branch of the infraorbital canal. This study aimed at assessing the knowledge and detection performance of CS amongst dentists and dental students. MATERIALS AND METHODS: Four-hundred and five dentists and dental students answered a questionnaire with three parts: 1. Socio-demographical; 2. Clinical cases with cone- beam computed tomography (CBCT) sections showing CS and 3. Previous knowledge about CS. The chi-squared test and Spearman's correlation test were used to compare results as appropriate. p-values below .05 were considered statistically significant. RESULTS: Most participants did not identify CS in any CBCT. There was an association between the number of correct answers and dental specialties. Most individuals had not learned about CS previously. There was an association between past knowledge of CS and gender, highest academic degree, working environment, dental specialty and number of correct answers but not with age or experience in Dentistry. CONCLUSION: This study suggests that most dentists are not aware about CS and do not know how to diagnose it. Previous knowledge about CS positively influenced its identification in CBCT.

Pleomorphic sarcoma of maxillary sinus: Clinical report of a patient initially diagnosed with denture-induced fibrous hyperplasia.

Undifferentiated pleomorphic sarcoma is a high-grade soft-tissue malignant tumor that is rare in the head and neck region. A 74-year-old woman displayed a large nodular lesion in the maxillary alveolar mucosa, which was initially identified as denture-related fibrous hyperplasia. Although her prosthodontist has adjusted the maxillary complete denture to relieve pressure on the lesion, it increased in size over time. Computed tomography images of the maxillary sinus showed an extensive destructive lesion. A biopsy was performed, and microscopic examination revealed a poorly differentiated malignancy with numerous spindle cells. Immunohistochemistry reactions were negative for CD45, CD30, CD68, CD34, cytokeratin, S100, desmin, and smooth muscle actin. These findings led to the diagnosis of an undifferentiated pleomorphic sarcoma of the maxillary sinus.