Increased CD14+ and decreased CD14- populations of monocytes 48 h after zolendronic acid infusion in breast cancer patients.

It has been proposed that bisphosphonates cause osteonecrosis of the jaws through impairment of the monocyte population function and proliferation. Such changes have been confirmed in jaw tissues, ex vivo. In this clinical study, we report for the first time a similar pattern of changes in peripheral blood monocytes. INTRODUCTION: The aim of this study is to examine the effect of zolendronic acid administration in the peripheral blood white cell population, seeking a plausible pathophysiological link between bisphosphonates and osteonecrosis of the jaw. METHODS: Twenty-four breast cancer patients, under zolendronic acid treatment for bone metastasis, were included. Peripheral blood samples were obtained prior to and 48 h following zolendronic acid administration. Flow cytometry gated at leukocyte, monocyte, and the granulocyte populations for the CD4/CD8/CD3, CD3/CD16+56/CD45/CD19, CD14/CD123, and CD14/23 stainings were performed. RESULTS: We were able to record a number of changes in the white cell populations after 48 h of zolendronic acid administration. Most importantly, in the monocyte populations, we were able to detect statistically significant increased populations of CD14+/CD23+ (p = 0.038), CD14+/CD23- (p = 0.028), CD14+/CD123+ (p = 0.070, trend), and CD14+/CD123- (p = 0.043). In contrast, statistically significant decreased populations of CD14-/CD23+ (p = 0.037) and CD14-/CD123+ (p = 0.003) were detected. CONCLUSIONS: Our results provide evidence supporting the hypothesis that bisphosphonate administration modifies the monocyte-mediated immune response. An increase of CD14+ peripheral blood monocyte (PBMC) populations along with a decrease of CD14- PBMC populations has been recorded. The latter finding is in accordance with limited-currently existing-evidence and warrants further elucidation.

Is copper chelation an effective anti-angiogenic strategy for cancer treatment?

Angiogenesis and the acquisition of an angiogenic phenotype is important for cancer cell proliferation. Copper in an essential trace element that participates in many enzymatic complexes like the cytochrome c, superoxide dismutase and lysyl oxidase and it is involved in processes, like embryogenesis, growth, angiogenesis and carcinogenesis. In particular, its involvement in carcinogenesis was described for the first time in oral submucous fibrosis, where fibroblasts produce large amounts of collagen in the presence of copper. Copper's action in carcinogenesis is two-fold: (1) it participates in reactions with an increased redox potential that result in the production of oxidative products and oxidative stress. Through this mechanism, copper may cause DNA mutations in the nucleus and mitochondria or alterations to membrane phospholipids, (2) it participates in angiogenesis even in the absence of angiogenic molecules, as it was reported for the first time in rabbit cornea models with copolymer pellets charged with PGE1. Copper chelation regimens like penicillamine and tetrathiomolybdate are being described in the literature as having anti-angiogenic, anti-fibrotic and anti-inflammatory actions. Animal models of brain cancer that evaluated the anti-angiogenic properties of copper, have proven evidence of the reduction of tumor's microvascular supply, tumor volume and vascular permeability after plasma copper levels reduction. Interestingly, plasma copper levels reduction was shown to suppress micrometastases generation in mice models of breast cancer. We hypothesize that copper chelation therapy: increases oxidative stress in cancer cells to a level that does not allow survival because of the reduction of anti-oxidative enzymes production. It may also result in inhibition of angiogenesis and of the initiation of the angiogenic switch, because copper normally enhances endothelial cell migration and proliferation, improves binding of growth factors to endothelial cells and enhances the expression of angiogenic molecules. Copper chelation may also reduce extracellular matrix degradation and cancer spread, through reduction of MMP-9 production and probably of other collagenases and may inhibit propagation of micrometastases. However, copper chelation therapy may enhance angiogenesis through reduction of thrombospondin-1, that results into an increase in VEGF-VEGFR2 complexes and a high level of active MMP-9. These hypotheses help in understanding of the anti-angiogenic action of copper chelation therapies and of the complex network of interactions between copper and other molecules involved in angiogenesis. It may also stimulate further research regarding differences in copper metabolism, the effects of anti-copper regimens on organs, the development of resistance, and their possible angiogenic action through thrombospondin expression reduction.

Expression of N-cadherin in salivary gland tumors.

OBJECTIVE: To detect immunohistochemically the N-cadherin expression in different types of benign and malignant salivary gland tumors in an attempt to note any possible correlation to their development, stage and invasive properties. MATERIALS AND METHODS: N-cadherin expression was examined in tissue specimens from 49 salivary gland tumors including: pleomorphic adenomas (4), Warthin's tumors (10), and myoepitheliomas (4) (benign tumors), as well as adenoid cystic carcinomas (14), mucoepidermoid carcinomas (4), polymorphous low-grade adenocarcinomas (6), and adenocarcinomas not otherwise specified (5) (malignant tumors). Twelve specimens of normal salivary glands were used as control. The perineural invasion and stage of malignant salivary gland tumors were evaluated. Immunohistochemical procedure was performed automatically using the Bond Polymer Refine Detection Kit. RESULTS: N-cadherin expression was not found in normal salivary glands. In benign salivary gland tumors, N-cadherin along membranes of neoplastic cells as well as in centrocytes of lymphoid germinal centers was seen in 1 and 4 cases of Warthin's tumors, respectively. Varied degree of N-cadherin expression was found in 13 (45%) cases of malignant salivary gland tumors. N-cadherin expression was significantly correlated with perineural invasion (χ(2) = 11.7, p < 0.0001), but not with stage of malignant salivary gland tumors. CONCLUSION: N-cadherin expression was observed in malignant salivary gland tumors and could be an indicator of potentially aggressive behavior. N-cadherin expression by tumor cells could be attributed to perineural invasion.

Bone-vasculature interactions in the mandible: is bone an angiogenic tissue?

Starting from early stages of craniofacial development, the leading role of vasculature, in particular endothelial progenitor cells, becomes apparent. They are probably the cells that synthesize the appropriate bone morphogenetic protein (BMP), that precedes neural crest cell migration and determines their final destination and skeletal development. During postnatal osteosynthesis in the mandible, angiogenesis similarly goes before osteosynthesis, regulates this process with the production of BMP-2 and serves as a scaffold for osteoblasts. This growth factor is involved in bone metabolism and bone injury repair. The dependence of bone from vasculature, is better understood when looking to osseous changes that result from vasculopathies and arteritides, like in diabetes mellitus and polyarteritis nodosa respectively, that affect the mandible more frequently than previously suspected. These changes are not only the result of a dysregulation of osteoblasts and osteoclasts, but of a complex network of factors that affect the vasculature, like VEGF and hypoxia. Abnormal vasculature results in qualitatively degradated bone, with an atypical architecture or even in bone necrosis. The dynamic interplay between vasculature and bone of the mandible, with the vasculature endothelium playing an initiating and regulatory role in osteosynthesis, supports the hypothesis of an angiogenic origin of bone. This hypothesis, helps in understanding of bone pathology, like avascular necrosis and of the impact of interventions and medications that affect vasculature, on bone metabolism.

Molecularly targeted drugs for the treatment of cancer: oral complications and pathophysiology.

BACKGROUND: Targeted cancer therapy is a new approach for the treatment of cancer. It involves a specific molecular target, mainly a receptor that serves as a target for monoclonal antibodies or tyrosine kinase inhibitors. Side-effects of these new regimens are described to be mild, compared to those of classical chemotherapy. There is a lack in the documentation and understanding of oral complications related to molecularly targeted drugs. METHODS: In this review, we tried to make a systematic review of the databases Pubmed and Scopus, using "targeted cancer therapy" and "oral", or "mucositis", or "stomatitis", or "bleeding", or "hemorrhage" as search terms. Specific drug name searches were not conducted. The search yielded 97 results. Only articles related to EGFR and VEGFR inhibition were selected. Finally 13 articles met the criteria. RESULTS are discussed and possible pathogenetic mechanisms for the complications of targeted cancer therapy regimens are presented. RESULTS: It appears that the most serious side-effect is mucositis/stomatitis that may affect the whole gastrointestinal tract. It rarely results in treatment discontinuation. Reduced saliva secretion, xerostomia and dysphagia can be severe with some regimens and interfere with food uptake. Osteonecrosis, wound healing impairment, spontaneous gingival bleeding and dysgeusia were also reported. CONCLUSIONS: Considering these data it is obvious that symptoms related to cancer treatment should be considered in the context of the holistic management of patients. Oral complications should not be ignored but recorded during physical examination, because they may significantly impair daily activities and patients' quality of life.

Distant bone metastases from carcinoma of the lip: a report of four cases.

The lip is estimated to be the most frequent location for carcinoma of the oral cavity. It occurs more frequently in men, especially those with a history of exposure to sunlight. Despite the usually effective management, regional and occasionally distant metastases do occur, especially in advanced stages. In this retrospective analysis of patients with labial carcinoma presenting with distant bone metastases in 1995-2003, the extremely limited number of patients did not allow for multivariate data analysis. From a cohort of 415 patients presenting with lip lesions, 186 cases were diagnosed as carcinoma and managed accordingly. Four patients (2.14%) showed distant bone metastases, one with concurrent axillary node metastasis. Patient demographics, tumour characteristics, case management and survival were evaluated. The distant metastasis patients were of clinical stages II-IV; initial management was wide local excision with reconstruction for all cases, with one undergoing concurrent neck dissection and one adjuvant radiotherapy. Time for distant bone metastasis was 9-21 months, subsequent survival 3-14 months and overall survival 13-35 months. Distant metastases from labial carcinoma are rare, not exceeding 2%. Metastasis to bone and axillary lymph nodes is exceptionally rare and can be attributed to either inadequate initial management or aggressive tumour behaviour.

Nager syndrome (preaxial acrofacial dysostosis): a case report.

The Nager syndrome is a rare condition associated with craniofacial malformations such as micrognathia, zygomatic hypoplasia, cleft palate, and preaxial limb deformities. This report features a case of the Nager syndrome occurring in a 4-year-old boy showing microdontia, thumb duplication and radioulnar synostosis, and ventricular septum defect, characteristics not usually encountered in the published cases.

Orthopedically induced condylar growth in a patient with hemifacial microsomia.

OBJECTIVE: Hemifacial microsomia is a congenital abnormality that causes three-dimensional facial asymmetry, affection of the dental occlusion, and failure of growth of the midface in the growing child. This report outlines orthopedically induced condylar growth in a patient with hemifacial microsomia. PATIENT: A 7-year-old girl with hemifacial microsomia, complete absence of the left mandibular condyle, and severe facial asymmetry was treated orthopedically in an early stage by means of a functional appliance. Functional therapy was instituted to stretch the deficient soft tissues to guide and promote skeletal growth and stimulate the affected areas. The treatment was completed with fixed appliances. RESULTS: The effect of the therapy was an excessive change in condylar growth in the affected side. Facial asymmetry was corrected and a symmetric mouth opening was established. CONCLUSIONS: The treatment of patients with hemifacial microsomia should be initiated early enough so that the stimulus could in some degree normalize the deficient tissues and induce bone apposition, and in some cases surgical intervention could be avoided.

Treatment of squamous cell carcinoma of the anterior faucial pillar-retromolar trigone.

Cancer of the anterior faucial pillar-retromolar trigone is an uncommon head and neck tumor, which has historically been shown to be associated with poor prognosis. In this retrospective study, we reviewed our experience with primary surgery followed by postoperative radiation therapy in order to determine the impact of our treatment protocols on patients' outcome. Between January 1994 and December 1998, 31 patients with histologically proven squamous cell carcinoma (SCC) of the anterior faucial pillar-retromolar trigone were treated in our department. Surgical excision of the primary lesion and ipsilateral neck dissection were performed in all patients. Reconstruction was accomplished using masseter muscle flap or tongue flap. Postoperatively, most patients (90%) received radiation therapy (51-58 Gy) to the primary side and neck. Adjuvant chemotherapy was offered if histologic signs of aggressive behavior were identified. Four out of 31 patients were initially seen at stage I or II and 27 patients at stage III or IV of the disease. Metastatic disease was demonstrated in 78% of ipsilateral neck nodes. Occult metastases were found in 64% of clinically N0 necks. The 3-year loco-regional recurrence rates were 44.8%. SCC of retromolar trigone is considered as an aggressive and insidious tumor. The reconstruction of the deficit of the anterior faucial pillar-retromolar area with masseter muscle flap is a reliable, safe and absolutely functional method.

Shprintzen-Goldberg syndrome: case report.

OBJECTIVE: The Shprintzen-Goldberg syndrome is an extremely rare syndrome with a characteristic face. This is one of a group of disorders characterized by craniosynostosis and marfanoid features. The aim of this study was to present a new sporadic case of the syndrome and describe in detail the findings at the maxillofacial region.

Double mandibular osteotomy with coronoidectomy for tumours in the parapharyngeal space.

Removal of deep-lobe parotid tumours from the parapharyngeal space is often difficult because of limited surgical access and the critical vascular and neurologic structures nearby. Mandibulotomy, when necessary, is useful for improving wider visibility and control of the vascular bundle and facial nerve, but may cause damage to the inferior dental and lingual nerves. The double mandibular osteotomy with coronoidectomy gives excellent access and avoids damage to these nerves.

Early extraction of the mandibular third molar in case of eruption disturbances of the second molar.

PURPOSE: General consensus has been reached on extracting mandibular third molars when they are involved in pathologic processes. However, early extraction is advisable in cases of eruption disturbances of the mandibular second molar, before or during orthodontic treatment. METHODS: Thirty-two patients with early extraction of the mandibular third molar before or during orthodontic treatment were examined. RESULTS: In these cases either the presence of the third molar presented an obstacle in the eruption path of the second, or third molar germ removal was considered beneficial to the course of orthodontic treatment. CONCLUSIONS: Early extraction of the mandibular third molar facilitates the eruption of the second molar, especially in cases where evidence of crowding and lack of space in the posterior mandibular region exist. Orthodontic treatment may, in some cases, aggravate eruption disturbances of the second molar.

Submerged teeth.

Submersion occurs when a previously erupted tooth becomes embedded in the oral tissues. The purpose of this paper is to examine the distribution, the degree of re-impaction, the rate of congenital absence of the successor buds and the treatment in 28 submerged teeth in 17 patients.

Testicular embryonal carcinoma metastatic to the labial mucosa of the upper lip.

An unusual case of testicular embryonal carcinoma metastatic to the labial mucosa of the upper lip is reported. The clinical features and the management of the metastatic oral lesion are presented. In patients with known systemic malignancy, oral swellings may be an indication of a metastatic deposit.

Bilateral metastatic breast angiosarcoma to the mandibular gingiva: case report.

Metastases to the jaws and oral soft tissues are rare. A case of breast angiosarcoma metastatic to the mandible and the gingiva, bilaterally in the premolar area is presented. The clinical, histological features and the management of the metastatic oral lesions are reported. Our case emphasises the possibility that in patients with history of breast angiosarcoma, oral inflammatory-like lesions may be an indication of a metastatic deposit.

Traumatic cervical cystic hygroma.

An unusual case of traumatic cervical cystic lymphangioma in an adult man is presented.

Merkel cell carcinoma in a patient with Recklinghausen neurofibromatosis.

A rare case is described of Merkel cell carcinoma of the cheek arising in a cutaneous neurofibroma in a patient with Recklinghausen neurofibromatosis. The relevant literature is reviewed.

Hemifacial atrophy secondary to poliomyelitis.

A 25-year-old woman is presented with hemifacial atrophy due to unilateral bulbar poliomyelitis infection. Although bulbar poliomyelitis is not an uncommon disease, it is rarely a cause of hemifacial asymmetry.