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.

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.

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.

Effects of orchiectomy and testosterone replacement therapy on redox balance and salivary gland function in Wistar rats.

The objective of this study was to investigate the effects of orchiectomy (ORX) and testosterone replacement therapy (TRT) on redox balance and function of salivary glands. Forty-five young adult male Wistar rats (3 months old) were either castrated bilaterally or underwent fictitious surgery (SHAM) and were subsequently distributed into 3 groups: SHAM, ORX, and TRT (castrated rats that received an intramuscular injection of testosterone cypionate 10 mg/kg/weekly). All treatments started 4 weeks after castration (4 months old) and lasted 4 weeks (5 months old). At the end of treatment, pilocarpine-induced salivary secretion was collected to analyze salivary flow rate and biochemistry composition, and the parotid (PG) and submandibular (SMG) glands were sampled for redox balance markers and histomorphometric analyses. ORX increased salivary flow rate, calcium, phosphate, and chloride, and decreased total protein and amylase, while not changing the salivary buffer capacity, pH, sodium, and potassium compared to SHAM. TRT restored all salivary parameters to SHAM values. ORX increased oxidative lipid and protein damage, total antioxidant capacity, and uric acid in both salivary glands compared to SHAM. Superoxide dismutase, catalase, and glutathione peroxidase activities were greater only in the SMG of the ORX group in relation to SHAM. ORX decreased duct and acini area, while increasing connective tissue in the PG. On the other hand, ORX reduced duct area and increased acini area in the SMG compared to SHAM. TRT restored the redox balance and histomorphometric parameters to close to SHAM values in both salivary glands. Orchiectomy-induced salivary gland dysfunction was characterized by an increase in the salivary flow rate and changes in the secretion of total protein, amylase, and electrolytes, which are key factors, considered important for maintaining oral health status. To sum up, orchiectomy impaired the redox balance of the salivary glands. Our results also showed that TRT reversed the oxidative damage, morphological alterations, and salivary gland dysfunction induced by orchiectomy. Therefore, these results suggest an important action of testosterone on the redox balance and secretory ability of salivary glands.

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.

Stress hormones promote DNA damage in human oral keratinocytes.

Chronic stress increases the systemic levels of stress hormones norepinephrine and cortisol. As well as tobacco-specific carcinogen NNK (4-(methylnitrosamine)-1-(3-pyridyl)-1-butanone), they can induce expressive DNA damage contributing to the cancer development. However, it is unknown whether stress hormones have genotoxic effects in oral keratinocytes. This study investigated the effects of stress hormones on DNA damage in a human oral keratinocyte cell line (NOK-SI). NOK-SI cells stimulated with norepinephrine or cortisol showed higher DNA damage compared to untreated cells. Norepinephrine-induced DNA damage was reversed by pre-treatment with beta-adrenergic blocker propranolol. Cells treated with NNK combined to norepinephrine displayed reduced levels of caspases 3 and 7. Cortisol also reduced the activity of pro-apoptotic enzymes. NNK or norepinephrine promoted single-strand breaks and alkali-label side breaks in the DNA of NOK-SI cells. Pre-treatment of cells with propranolol abolished these effects. Carcinogen NNK in the presence or absence of cortisol also induced DNA damage of these cells. The genotoxic effects of cortisol alone and hormone combined with NNK were blocked partially and totally, respectively, by the glucocorticoid receptor antagonist RU486. DNA damage promoted by NNK or cortisol and carcinogen combined to the hormone led to intracellular γH2AX accumulation. The effects caused by NNK and cortisol were reversed by propranolol and glucocorticoid receptor antagonist RU486, respectively. Propranolol inhibited the oxidation of basis induced by NNK in the presence of DNA-formamidopyrimidine glycosylase. DNA breaks induced by norepinephrine in the presence or absence of NNK resulted in higher 8OHdG cellular levels. This effect was also induced through beta-adrenergic receptors. Together, these findings indicate that stress hormones induce DNA damage of oral keratinocytes and could contribute to oral carcinogenesis.

Social isolation stress facilitates chemically induced oral carcinogenesis.

Social isolation has affected a large number of people and may lead to impairment of physical and mental health. Although stress resulting from social isolation may increase cancer progression, its interference on tumorigenesis is poorly known. In this study, we used a preclinical model to evaluate the effects of social isolation stress on chemically induced oral carcinogenesis. Sixty-two 21-day-old male Wistar rats were divided into isolated and grouped groups. After 90 days of age, the rats from both groups underwent oral carcinogenesis with 4-nitroquinoline 1-oxide (4NQO) for 20 weeks. All rats were assessed for depressive-like behavior and euthanized for oral squamous cell carcinoma (OSCC) diagnosis and measurement of inflammatory mediators in the tumor microenvironment. Social isolation stress increased the OSCC occurrence by 20.4% when compared to control. Isolated rats also showed higher tumor volume and cachexia than the grouped rats. Social isolation did not induce changes in the depressive-like behavior after carcinogenic induction. Tumors from stressed rats had increased levels of the inflammatory mediators, TNF-alpha, IL1-beta and MCP-1. The concentrations of TNF-alpha and MCP-1 were significantly increased in the large tumors from isolated animals. Higher tumor levels of TNF-alpha, IL-6, IL1-beta and MCP-1 were positively correlated with OSCC growth. This study provides the first evidence that social isolation stress may facilitate OSCC occurrence and tumor progression, an event accompanied by increased local levels of inflammatory mediators.

Beta-adrenergic blocker inhibits oral carcinogenesis and reduces tumor invasion.

PURPOSE: Beta-adrenergic signaling can influence cancer progression and the use of beta blockers as adjuvant drugs in oncologic patients has been suggested. However, the involvement of beta-adrenergic blockers in tumorigenesis is poorly understood. This study investigated the action of beta-adrenergic blocker propranolol on tumor onset using a preclinical model of chemically induced oral cancer. METHODS: Thirty-two male Wistar rats were subjected to daily subcutaneous injection of beta-blocker propranolol (10 mg/kg; SubQ), while another 32 rats received only a PBS injection (sham group). One week after starting propranolol treatment, all rats were submitted to chemical induction of oral carcinogenesis with 4-nitroquinoline-1-oxide (4NQO). After 16 weeks, they were assessed for occurrence of oral squamous cell carcinoma (OSCC), in addition to measurement of tumor volume and thickness, and tissue levels of cytokines IL-6, TNF-alpha and IL-10 in the tumor microenvironment. RESULTS: Propranolol treatment reduced the occurrence of OSCC by 31%, 95% CI ( - 127, 216). Beta-adrenergic blocker significantly decreased thickness of OSCC when compared with PBS. Rats treated with propranolol exhibited a lower tumor volume when compared with control rats, but this result did not reach statistical significance. Tumors from propranolol-treated rats exhibited reduced concentrations of pro-inflammatory cytokines IL-6 and TNF-α. There was no difference in the IL-10 levels between tumors from propranolol- and sham-treated rats. CONCLUSION: Beta-adrenergic signaling may be one of the mechanisms associated with chemically induced oral carcinogenesis.

Pineal gland protects against chemically induced oral carcinogenesis and inhibits tumor progression in rats.

Clinical investigations suggest that melatonin suppression and circadian dysfunction may be related to cancer development in shift workers. Studies also show that melatonin suppression after pinealectomy increases cancer incidence in preclinical models. However, no study evaluated the influence of pinealectomy on oral cancer development. In the current study, we investigated the effects of pinealectomy on oral squamous cell carcinoma (OSCC) occurrence and progression in rats. Rats submitted to sham surgery were used as control. Pinealectomy promoted an increase of 140% in OSCC occurrence when compared to sham animals. Tumors from pinealectomized rats displayed a higher volume and thickness than the tumors from sham-operated animals. Pinealectomy induced atrophy of the epithelium adjacent to the oral lesions. Pinealectomized rats showed higher mean number of tumor-associated macrophages and eosinophils in the invasive front of OSCC. In addition, nuclear overexpression of ERK1/2 and p53 was also observed in the front of carcinomas from pinealectomized rats. These results reveal that pineal gland plays a protective role against oral carcinogenesis. The melatonin suppression caused by the pinealectomy might contribute to oral cancer development by acting on ERK1/2 and p53 pathways and regulating tumor inflammation.

Diagnosis and Treatment of Oral Venous Malformation in a Child.

Venous malformations (VMs) are congenital disorders that constitute about 40% of all vascular anomalies. These lesions do not regress spontaneously and may increase in size during childhood. The case of a 10-year-old girl with an extensive oral VM is reported. Intraoral examination revealed the presence of purplish nodules in the alveolar mucosa and gingiva from anterior maxilla. Doppler ultrasound showed a well-defined hypoechoic image and increased vascularization with low blood flow for the alveolar mucosa lesion. The patient was submitted to intralesional injections of the ethanolamine oleate/mepivacaine sclerosing solution. After four sessions, there was a significant reduction of the lesions. However, the patient abandoned the treatment and the oral VM grew progressively. After 1 year, sclerotherapy was resumed and performed weekly. After 10 session of sclerotherapy, the oral VM totally regressed. The childhood is a critical period for oral VM growth. Doppler ultrasound and sclerotherapy can be effective for the management of extensive lesions in children.

Melatonin suppression increases the incidence and progression of chemically induced oral cancer in rats / Supressão de melatonina aumenta a incidência e progressão do câncer de boca induzido quimicamente em ratos

Estudos sugerem que a supressão de melatonina e disfunção circadiana em trabalhadores noturnos podem estar relacionadas ao desenvolvimento e à progressão do câncer. Pesquisas têm mostrado também que a incidência tumoral pode ser aumentada pela pinealectomia. Entretanto, nenhum estudo avaliou a influência da cirurgia de pinealectomia sobre o desenvolvimento e a progressão do câncer de boca. No presente estudo, nós investigamos os efeitos da supressão de melatonina sobre a ocorrência e a progressão tumoral um modelo pré-clínico de câncer de boca induzido quimicamente. Nós demonstramos, pela primeira vez, que ratos pinealectomizados tiveram maior ocorrência de carcinoma espinocelular de boca, comparado aos animais controle. Ratos pinealectomizados também exibiram volume e espessura tumorais cerca de 3 e 2 vezes maior que animais sham, respectivamente. Além disso, pinealectomia induziu atrofia do epitélio não-tumoral adjacente às lesões bucais. Os ratos pinealectomizados apresentaram maior resposta inflamatória no front de invasão tumoral, caracterizada principalmente pelo aumento do número de eosinófilos e macrófagos associados ao tumor. Tumores de ratos submetidos à pinealectomia exibiram maior imunoexpressão de ERK1/2 e p53 no microambiente tumoral. Estes resultados revelam que a supressão de melatonina acelera o desenvolvimento e a progressão do câncer de boca associado ao aumento de eosinófilos e macrófagos no front de invasão tumoral e maior expressão de ERK1/2 e p53 no microambiente tumoral(AU)

Studies suggest that melatonin suppression and circadian dysfunction in shift workers can be related to cancer risk. Furthermore, investigations have shown that pinealectomy promotes higher tumor incidence in rats. However, no study evaluated the influence of pinealectomy surgery on oral cancer onset and progression. In the current study, we investigated the effects of melatonin suppression on tumor occurrence and progression in a preclinical model of oral cancer. We demonstrated for the first time that pinealectomized rats had higher oral squamous cell carcinoma occurrence than sham animals. Furthermore, pinealectomized animals displayed tumor volume and thickness about 3 times and twice higher than sham-operated rats, respectively. Moreover, pinealectomy induced atrophy of non-tumor epithelium adjacent to the oral lesions. Pinealectomized rats showed higher mean number of tumor-associated macrophages and eosinophils in the carcinoma invasion front. In addition, tumors from pinealectomized rats displayed increased immunoexpression of ERK1/2 and p53 in the tumor microenvironment. These results reveal that melatonin suppression promotes higher oral cancer occurrence and progression associated with increasing of inflammatory cells and ERK1/2 and p53 expressions in the tumor microenvironment(AU)