Osteoclastogenesis inhibitory factor exhibits hypocalcemic effects in normal mice and in hypercalcemic nude mice carrying tumors associated with humoral hypercalcemia of malignancy

Osteoclastogenesis inhibitory factor (OCIF) is a novel secreted protein that inhibits osteoclastogenesis both in vitro and in vivo. In this study, we examined the effects of OCIF on serum calcium (Ca) concentrations in normal mice and in hypercalcemic nude mice carrying tumors associated with humoral hypercalcemia of malignancy. In normal mice, a single intraperitoneal injection of OCIF reduced serum Ca levels in a dose-dependent manner. Significant decrease in serum Ca (by 1.6 ± 0.3 mg/dL, n = 5) was observed 2 h after the injection of OCIF at 20 mg/kg and the hypocalcemic effect continued for up to 12 h. Serum phosphate (Pi) concentrations also decreased in response to OCIF. Urinary excretion of Ca, Pi, and creatinine did not change significantly after injection of OCIF or vehicle. In hypercalcemic, tumor-bearing nude mice, a single intraperitoneal injection of OCIF at 20 mg/kg resulted in a dramatic decrease in serum Ca (maximal decrease 2.8 ± 0.37 mg/dL, n = 11), which continued for up to 24 h. The results suggest that OCIF decreased serum Ca through its inhibitory effect on bone resorption. Furthermore, it is suggested that OCIF has therapeutic potential for the treatment of hypercalcemic conditions such as malignancy-associated hypercalcemia.     

国产唑来膦酸治疗肿瘤高钙血症多中心Ⅱ期临床观察

Objective： To evaluate the effect and safety of clinical use of zoledronic acid in the treatment of malignant hypercalcemia. Methods： A multi-center, open phase II clinical trial was conducted in 15 cases with malignant hypercalcemia who received zoledronic acid intravenously for 15 min. The level of blood calcium and side effects were recorded regularly within 28 days after injection. Results： One case was dropped out due to bad compliance. The complete response rate （the corrected serum calcium was reduced to normal level） was 100.00% （14/14）. The medium time of complete response rate was 5.07 days. The medium maintain time was 22.30 days. Slight, or moderate fever was observed. Conclusion： Zoledronic acid can effectively reduce the malignant hypercalcemia. The use of zoledronic acid appears to be safety and convenient.     

Transfer of 45Ca and 36Cl at the blood-nerve barrier of the sciatic nerve in rats fed low or high calcium diets

Unidirectional fluxes of 45Ca, 36Cl, and of [3H]mannitol from blood into the sciatic nerve and cerebral cortex were determined from 5- and 15-min uptakes of these tracers after an intravenous (i.v.) bolus injection in awake rats. Rats were fed diets for 8 wk, that had either a low (0.01% wt/wt), normal (0.67%), or high (3%) Ca content. Plasma [Ca] was 32% less and 11% more in rats fed low (LOCA) and high Ca diets (HICA), respectively, than in rats fed a normal Ca diet (CONT). The mean permeability-surface area product (PA) of 45Ca at the blood-nerve barrier was about eightfold higher than at the blood-brain barrier in the same animals and did not differ significantly between groups (greater than 0.05). Mean PA ratios of 45Ca/36Cl for the blood-nerve and blood-brain barriers in CONT rats, 0.52 +/- 0.04 and 0.40 +/- 0.02, respectively, were not significantly different from corresponding ratios in LOCA and HICA groups, and corresponded to the aqueous limiting diffusion ratio (0.45). Our results show no evidence for concentration-dependent transport of Ca over a plasma [Ca] range of 0.8-1.4 mmol/liter at the blood-nerve barrier of the rat peripheral nerve, and suggest that Ca and Cl exchange slowly between nerve and blood via paracellular pathways.     

Hypercalcemia and pancreatic endocrine neoplasia with elevated PTH-rP: Report of two new cases and subject review

Humoral hypercalcemia of malignancy is widely associated with tumor production of parathyroid hormone related protein (PTH-rP). This peptide functions in endocrine, autocrine and paracrine mechanisms in a manner similar to PTH; increasing renal uptake of calcium, decreasing retention of phosphorous, and stimulating adenylate cyclase and phospholipase C. Although PTH-rP production has been well documented in neoplasms of the exocrine pancreas, we present here two cases of endocrine pancreatic neoplasms elaborating PTH-rP. We then review the literature of previous cases and delve into the pathophysiology of this peptide.     

Malignant fibrous histiocytoma of bone: an ultrastructural study

An ultrastructural study of a case of malignant fibrous histiocytoma of bone in a 16-year-old skeletally mature female is presented. There were multiple metastatic bone lesions and a marked hypercalcemia. The cell population was similar to that found in soft tissue malignant fibrous histiocytoma lesions and comprised undifferentiated cells, fibroblastlike cells, histiocytes, and multinucleated giant cells. Occasional myofibroblasts and transitional cells with histiocytic and fibroblastic components were seen. The histiocytes were characterized by prominent Golgi bodies. Although there were many fibroblastlike cells, the rough endoplasmic reticulum was rarely as extensive or as well organized as in normal fibroblasts. The giant cells did not have the ultrastructural characteristics of osteoclasts, i.e., the clear zones and ruffled borders. Zonula adherens (belt desmosome) junctions were seen, but in general, intercellular junctions were poorly developed as to length and extent.     

Hypercalcemia in breast cancer

Hypercalcemia is relatively frequent in malignancy with or without osteolytic bone metastases. It is thought that neoplastic cells may secrete substances which not only stimulate osteoclastic activity but are also capable of modifying the absorption, excretion, and resorption of calcium and phosphate ions. Since 1987, we have studied 24 breast cancer patients with hypercalcemia (22 with bone metastases and two without). The group of 22 patients with bone metastases were divided into two subgroups. The first consisted of 10 patients with high serum levels of humoral factors, such as parathyroid hormone-related protein (PTHrP), and/or prostaglandin E₂ (PGE₂) and/or interleukin 1 (IL-1), and high levels of bone markers, such as alkaline phosphatase, bone Gla protein and urinary hydroxyproline. The second subgroup consisted of 12 patients with high levels of bone markers alone. Bone histologic analysis showed an osteoclastic activation surrounding metastatic tumor tissue in six out of 10 patients of the first subgroup, while an evident osteolysis caused by the tumor cells was noted in seven out of 12 patients of the second subgroup. The two patients without bone metastases showed normal biochemistry and bone histologic examination. The authors, having tried to explain the pathogenesis of hypercalcemia, emphasize the importance of humoral factors secreted by tumor cells as a direct or indirect cause of hypercalcemia. The origin of hypercalcemia remains unclear in two patients without bone metastases.     

Familial hyperparathyroidism syndromes

Primary hyperparathyroidism is a common endocrine disorder and the most prevalent cause of hypercalcemia worldwide. While most cases are sporadic, 5–10% of cases are inherited as part of a familial syndrome: multiple endocrine neoplasia (MEN-1, MEN-2A, MEN-4), hyperparathyroidism jaw-tumor syndrome (HPT-JT), familial hypocalciuric hypercalcemia (FHH), neonatal severe hyperparathyroidism (NSHPT), autosomal dominant moderate hyperparathyroidism (ADMH), or familial isolated hyperparathyroidism (FIHPT). Recent developments in molecular pathology identified specific germline mutations (MEN1, RET, CDKIs, CDC73/HRPT2, CaSR, GNA11, AP2S1) implicated in their pathogenesis. In contrast to sporadic primary hyperparathyroidism which is usually caused by a solitary parathyroid adenoma, hereditary hyperparathyroidism tend to present with multiglandular parathyroid disease, with variable penetrance according to the genetic syndrome. As a result, the clinical severity of each familial condition varies tremendously, resulting in distinct prognosis and treatment strategies. With the advent of molecular testing, genetic subtyping has become an integral part of treatment decision making, requiring correlation with clinical and pathologic findings. This review provides an update on the current knowledge of hereditary hyperparathyroidism and its associated genetic syndromes.     

Case Report: Severe Hypercalcemia Mimicking St-Segment Elevation Myocardial Infarction

The identification of ST-segment elevation on the electrocardiogram is an integral part of decision making in patients who present with suspected ischemia. Unfortunately, ST-segment elevation is nonspecific and may be caused by noncardiac causes such as electrolyte abnormalities. We present a case of ST-segment elevation secondary to hypercalcemia in a patient with metastatic cancer.