Mechanisms of acute hypercalcemia in pediatric patients following the interruption of Denosumab.

PURPOSE: Denosumab is a fully human monoclonal anti-RANK-L antibody that is clinically used to counteract the bone loss induced by exacerbated osteoclast activity. Indeed, its binding to RANK-L prevents the interaction RANK-L/receptor RANK that is essential for osteoclastogenesis and bone resorbing activity. Although there are many medications available to treat bone loss diseases, including bisphosphonates, Denosumab is highly effective since it reduces the bone erosion. The use in pediatric patients is safe. However, some concerns are related to the interruption of the treatment. Indeed, in this study, we reported hypercalcemia in two pediatric patients and alterations of circulating osteoclast precursors. METHODS: Peripheral Blood Mononuclear Cells (PBMC) were isolated from two pediatric patients with hypercalcemia after Denosumab interruption and from 10 controls. Cytofluorimetric analysis and in vitro osteoclastogenesis experiments were performed. RESULTS: Increase of CD16-CD14+CD11b+ cells was revealed in PBMC from patients reflecting the enhanced in vitro osteoclastogenesis. CONCLUSION: Our data suggest that precautions must be taken when Denosumab therapy is interrupted and gradual decrease of dose and/or timing of treatment should be performed. To prevent the onset of hypercalcemia that could be in the discontinuation phase, cytofluorimetric analysis of PBMC should be performed to evaluate osteoclast precursors.

IL-4 induces the formation of multinucleated giant cells and expression of ß5 integrin in central giant cell lesion.

BACKGROUND: It is now well established that IL-4 has a central role in the development of monocytes to multinucleated giant cells (MGCs) by inducing the expression of integrins on the surface of monocytes. The aim of this study was to investigate the potential role of IL-4 in induction of ß5 integrin expression in the peripheral blood samples of patients with giant cell granuloma. MATERIAL AND METHODS: Monocytes were isolated from peripheral blood samples of patients with central giant cell granuloma (CGCG) and healthy controls using human Monocyte Isolation Kit II. Isolated monocytes were then cultured in the absence or presence of IL-4 (10 and 20 ng/mL), and following RNA extraction and cDNA synthesis, Real-time PCR was performed to determine the level of ß5 integrin expression. The formation of CGCGs and morphological analyses were done under light microscopy. For confirmation of CGCGs, immunocytochemistry technique was also carried out by anti-RANK (receptor-activator of NF-κB ligand) antibody. RESULTS: In both patient and control groups, ß5 levels were significantly enhanced by increasing the IL-4 dose from 10 to 20 ng/mL. In addition, these differences were significant between patient and control groups without IL-4 treatment. On the other hand, the number of cells which expressed RANK and therefore the number of giant cells were significantly higher in the patient group in comparison to controls, as assessed by immunohistochemistry evaluations. CONCLUSIONS: In this study, we showed an elevation in the expression levels of ß5 integrin when stimulated by IL-4. It is strongly indicated that this integrin acts as an important mediator during macrophage to macrophage fusion and development of giant cells.

Orbital involvement in craniofacial brown tumors.

PURPOSE: To describe the clinical and radiologic features of orbital involvement in craniofacial brown tumors and to compare the rate of brown tumors in primary and secondary hyperparathyroidism. METHODS: A retrospective hospital-based study of 115 patients with chronic kidney disease and secondary hyperparathyroidism and 34 with primary hyperparathyroidism was conducted. Laboratory results such as serum levels of alkaline phosphatase, calcium, phosphorus, and parathyroid hormone were recorded. Demographic data (age, sex, duration of disease) and image findings (bone scan scintigraphy, skull and long bone x-rays, CT) were also obtained. The main outcome measures were analysis of clinical, biochemical, and radiologic findings of all patients. RESULTS: Of the 115 patients with chronic kidney disease, 10 (8.7%) had brown tumors in different bones of the skeleton. Five patients had lesions in the craniofacial bones. The maxilla, mandible, maxillary sinus, and nasal cavity were the most affected sites. The orbit was involved in 2 patients with lesions arising in the maxillary and ethmoid sinuses. One patient had facial leontiasis. All patients with brown tumors had extremely high levels of parathyroid hormone (>1,000 pg/ml, normal values 10-69 pg/ml) and alkaline phosphatase (>400 U/l, normal values 65-300 U/l). The mean serum levels of phosphorus and calcium were not abnormal among the patients with brown tumors. Age and time of renal failure were similar for patients with and without brown tumors. Among the patients with primary hyperparathyroidism, only 2 (5.8%) had brown tumors, and in just 1, the lesion was localized in the craniofacial skeleton. A 2-tailed Z test applied to compare the proportion of occurrence of brown tumors in the 2 groups revealed that the difference at the 90% of confidence level was not significant. CONCLUSIONS: Brown tumors are equally found in secondary and primary hyperparathyroidism. Craniofacial brown tumors involve the orbit, usually because of the osteodystrophy process that involves the maxilla and paranasal sinuses. The lesions do not necessarily need to be excised and may regress spontaneously after the control of hyperparathyroidism.

DNA analysis of the SH3BP2 gene in patients with aggressive central giant cell granuloma.

A mutation of the SH3BP2 gene is known to cause cherubism. As there are clinical and histopathological similarities between central giant cell granuloma and cherubism, we made a constitutional DNA analysis of the SH3BP2 gene in four patients with aggressive giant cell granuloma (having one or more of the following features pain, paraesthesia, rapid growth, or root resorption). We found no mutations in the SH3BP2 gene, which indicates that cherubism is a separate entity. However, a somatic mutation in a specific group of cells could cause the focal lesions in giant cell granuloma. Further DNA analysis of the tissue of giant cell granulomas therefore seems indicated.

Laparoscopic-assisted partial ileectomy for crohn's disease associated with chronic anemia due to frequent hemorrhage.

Crohn's disease can involve any part of the gastrointestinal tract. Although good conservative treatment is given as soon as possible, most patients with this disease will eventually require surgery. We encountered a case of Crohn's disease associated with anemia which we treated with laparoscopic-assisted ileectomy. The postoperative course was satisfactory. The most important characteristic of Crohn's disease, fat wrapping and extending over the serosal surface toward the antimesenteric border, was observed in the ileum, distinguishing the disease and pinpointing the lesion accurately. This surgical method has an advantage over open surgery in that the recovery time is shorter and incisions are smaller, allowing easier surgery in the future, shortening the patient's hospital stay, and improving the patient's quality of life.

Idiopathic giant cell granulomatous hypophysitis with hypopituitarism, right abducens nerve paresis and masked diabetes insipidus.

A 38-year-old man presented with headache, fever, and double vision associated with right abducens nerve paresis. He had neither nuchal rigidity nor visual field defect. Laboratory data revealed elevated erythrocyte sedimentation rate (ESR), eosinophilia, and lymphocytic pleocytosis in the cerebrospinal fluid (CSF). Provocation tests of pituitary hormones showed partial hypopituitarism. Magnetic resonance imaging (MRI) revealed swelling of the hypophysis and a mass lesion expanding into the right cavernous sinus. The supplement dose of dexamethasone for hypothalamic hypocortisolism manifested diabetes insipidus. Biopsy, carried out through the transsphenoidal approach, revealed giant cell granuloma. Systemic granulomatous diseases were ruled out, and the lesion was considered to be idiopathic giant cell granulomatous hypophysitis. Right abducens nerve paresis, diabetes insipidus and dysfunction of the anterior lobe were amended by the treatment with prednisolone for 4 months, and findings of the pituitary gland and stalk were normalized. The present case shows that glucocorticoid has an effect on amendment of idiopathic giant cell granulomatous hypophysitis.

Highly aggressive brown tumour of the maxilla as first manifestation of primary hyperparathyroidism.

A case is presented of a 62-year-old man with a right maxillary swelling for the previous three months. The lesion was expansive and osteolytic, with invasion of the adjacent maxillary sinus, nasal and pterygomaxillary fossae and floor of the orbit. Histology revealed the presence of an intrabony giant cell lesion. Blood tests demonstrated elevations in calcium (16.2 mg/dl) and parathyroid hormone (PTH) concentrations (841 pg/ml). This suggested the diagnosis of hyperparathyroidism initially manifesting as a brown tumour of the maxilla. Posterior explorations confirmed the existence of an underlying ectopic parathyroid adenoma as the cause of the condition.

The diagnosis and treatment of central giant cell granuloma.

This report reviews the literature involving the central giant cell granuloma. Diagnosis and treatment is presented. The article reports the case of a child who was initially seen in her general dentist's office, then referred to an oral and maxillofacial surgeon. Differential diagnoses of both benign and malignant lesions related to the central giant cell tumor are discussed.

Multiple recurrent giant cell lesions associated with high circulating levels of parathyroid hormone-related peptide in a young adult.

Parathyroid hormone-related peptide (PTHrP, PLP) has previously been identified and assays are now available which can be used in clinical situations. A case is reported of a normocalcaemic young adult female in whom multifocal recurrent giant cell osteolytic lesions in the maxilla and elsewhere were associated with a raised plasma level of parathyroid hormone-related peptide. The lesions were histologically identical to reparative giant cell granuloma of the jaws and to osteitis fibrosa cystica associated with hyperparathyroidism.