Cancer-associated Hypercalcemia Research Articles

Cancer-associated hypercalcemia signals through the hindbrain to cause anorexia

Cancer-associated hypercalcemia signals through the hindbrain to cause anorexia

Hypercalcemia in children

Hypercalcemia is a result of a wide range of hereditary and acquired conditions encountered by general physicians and pediatricians. Calcium participates in several key physiological functions, control of blood coagulation, bone calcification. Calcium homeostasis is tightly regulated by the interplay between absorption from the small intestine and renal tubular reabsorption, bone remodeling, and disposal through the gut and the kidney. These processes are regulated by local and circulating factors. The two main hormones influencing the homeostasis of calcium are PTH and calcitriol. Cancer-associated hypercalcemia and primary hyperparathyroidism are the most frequent causes of hypercalcemia in adults. In neonates and infants, one should look first at genetic and iatrogenic etiologies. The clinical manifestations of hypercalcemia in children are nonspecific due to damage to various organs and systems and depend on the degree of blood calcium level. Mild hypercalcemia is asymptomatic and often discovered during routine blood work. Moderate and severe hypercalcemia may cause cardiac arrhythmias, affect the nervous system. The differential diagnosis of the possible etiologies of hypercalcemia should start with the assessment of serum parathyroid hormone (PTH) concentration. The causes of hypercalcemia can be divided between PTH-mediated and non-PTH-mediated. Identification of the main causes of hypercalcemia contributes to the timely elimination of trigger factors, beginning of treatment, correction of nutrition and lifestyle. The article highlights physiological mechanisms of calcium homeostasis, clinical manifestations, diagnostic algorithms and treatment of hypercalcemia in children.

A novel alendronate functionalized nanoprobe for simple colorimetric detection of cancer-associated hypercalcemia.

The calcium (Ca2+) ion concentration in the blood serum is tightly regulated, and any abnormalities in the level of serum calcium ions are associated with many potentially dangerous diseases. Thus, monitoring of the Ca2+ ion concentration in the blood serum is of fundamental importance. Gold nanoparticle (GNP)-based colorimetric biosensors have enormous potential in clinical diagnostic applications due to their simplicity, versatility, and unique optical properties. In this study, we have developed an alendronate functionalized gold nanoparticle (GNP-ALD) system for the measurement of Ca2+ ion concentration in biological samples. The GNP-ALD system showed higher sensitivity towards the Ca2+ ion compared to adenosine diphosphate (ADP) or adenosine triphosphate (ATP). The strong interaction between the Ca2+ ion and ALD at the GNP/solution interface resulted in significant aggregation of the ALD conjugated GNPs, and induced a color change of the solution from red to blue, which could be visually observed with the naked eye. The interaction between the Ca2+ ion and GNP-ALD was characterized by UV-visible spectroscopy, transmission electron microscopy (TEM) imaging, and dynamic light scattering (DLS) analysis. Under the optimized conditions, the lower limit of Ca2+ ion detection using this method was found to be 25 μM and a linear response range from 25 μM to 300 μM Ca2+ ions was obtained with excellent discrimination against other metal ions. The GNP-ALD nanoprobe could successfully determine the ionized Ca2+ concentration in various serum samples and the results were validated using a commercial calcium assay kit. Moreover, as a practical application, we demonstrated the utility of this nanoprobe for the detection of cancer-associated hypercalcemia in a mouse model.

Ovarian cancer presenting with hypercalcemia: two cases with similar manifestations but different mechanisms.

Hypercalcemia presenting in ovarian cancer is uncommon in the clinic. Here, two cases of ovarian epithelial carcinoma that presented with severe hypercalcemia were reported, with a review of the literature. The laboratory findings and stepwise clinical investigations of these two cases differed, indicating distinct underlying causes of hypercalcemia. In case one, the serum levels and immunostaining for parathyroid hormone-related protein (PTHrP) verified humoral hypercalcemia of malignancy (HHM). In case two, the high level of parathyroid hormone (PTH) and the scintigraphy scan showing parathyroid gland adenoma confirmed primary hyperparathyroidism-induced hypercalcemia. Both patients received optimal cytoreductive operation and adjuvant chemotherapy but showed different outcomes respectively. This article focused on differential diagnosis of ovarian cancer-associated hypercalcemia, by stepwise imaging and laboratory investigation, and the appropriate therapy should be considered based on the different etiologies.

Animal Models of Cancer-Associated Hypercalcemia.

Cancer-associated hypercalcemia (CAH) is a frequently-occurring paraneoplastic syndrome that contributes to substantial patient morbidity and occurs in both humans and animals. Patients with CAH are often characterized by markedly elevated serum calcium concentrations that result in a range of clinical symptoms involving the nervous, gastrointestinal and urinary systems. CAH is caused by two principle mechanisms; humorally-mediated and/or through local osteolytic bone metastasis resulting in excessive calcium release from resorbed bone. Humoral hypercalcemia of malignancy (HHM) is the most common mechanism and is due to the production and release of tumor-associated cytokines and humoral factors, such as parathyroid hormone-related protein (PTHrP), that act at distant sites to increase serum calcium concentrations. Local osteolytic hypercalcemia (LOH) occurs when primary or metastatic bone tumors act locally by releasing factors that stimulate osteoclast activity and bone resorption. LOH is a less frequent cause of CAH and in some cases can induce hypercalcemia in concert with HHM. Rarely, ectopic production of parathyroid hormone has been described. PTHrP-mediated hypercalcemia is the most common mechanism of CAH in human and canine malignancies and is recognized in other domestic species. Spontaneous and experimentally-induced animal models have been developed to study the mechanisms of CAH. These models have been essential for the evaluation of novel approaches and adjuvant therapies to manage CAH. This review will highlight the comparative aspects of CAH in humans and animals with a discussion of the available animal models used to study the pathogenesis of this important clinical syndrome.

Cancer-associated hypercalcemia: Retrospective study of 150 patients

Introduction Une hypercalcemie est frequemment retrouvee chez les patients atteints de cancer. L’objectif de cette etude etait d’evaluer l’epidemiologie et les criteres pronostiques des hypercalcemies d’origine tumorale sur une large serie de patients atteints de cancer.

Cancer-associated hypercalcemia: validation of a bedside prognostic score

Until now, there was no validated and reliable tool to estimate life expectancy among patients with cancer-associated hypercalcemia (CAH). This study aimed to validate a prognostic score previously published. We studied a new cohort of 252 patients with CAH. Our prognostic score based on the four poor-prognosis factors (liver metastasis, squamous cell carcinoma, hypoalbuminemia, and calcemia >2.83 mmol) was implemented to this cohort. The accuracy of this score for the prediction of 90-day mortality was estimated with area under the curve of the receiver operator curve (AUC-ROC). Among this validation cohort, patients with score = 0 experienced a median overall survival of 797 days; whereas, patients with score >/=1 (at least one poor-prognosis factor) had median overall survival of 49 days (p < 0.0001). The AUC-ROC for the prediction of 90-day mortality were 0.88 (0.76-0.86) and 0.67 (0.61-0.74) in the development cohort and in the validation cohort, respectively. We have validated a reliable bedside prognostic score for CAH.

A case of osteonecrosis of the jaw in a breast cancer patient with bone metastases receiving long-term treatment with bisphosphonates

Bisphosphonates (BPs) are often used for the treatment of several diseases such as osteoporosis, cancer-associated hypercalcemia, and osteolytic bone metastasis. Recently, there have been reports of osteonecrosis of the jaw (ONJ) in cancer patients whose treatment regimens include BPs. In this case report, we describe complications and treatment of ONJ in a breast cancer patient with bone metastases who received long-term treatment with BPs. A 70-year-old woman underwent modified radical mastectomy on her left breast cancer and received oral 5-fluorouracil derivatives for 2 years in another hospital. Eleven years after the surgery, she came to our hospital complaining of spinalgia and was diagnosed with recurrent breast cancer with multiple metastases to the stomach, liver, multiple lymph nodes, and spine. After surgery for spine metastases, she was given a combination therapy of trastuzumab (initial bolus: 170 mg/body, followed by two or more cycles of 85 mg/body) every week, docetaxel (100 mg/body) every 3 weeks, and BPs (90 mg/body) every 4 weeks. About 1 year and 4 months later, she complained of pain in her right maxilla; biopsy revealed ONJ. Medical oncologists need to recognize ONJ as a serious side effect of BP treatment; dentists and oral and maxillofacial surgeons need to thoroughly consult patients regarding the administration of BPs and have them make an informed consent.

Cancer-associated hypercalcemia treated with intravenous diphosphonates: a survival and prognostic factor analysis

Cancer-associated hypercalcemia (CAH) is the most frequent metabolic disorder in cancer patients. We retrospectively reviewed the outcome and prognostic factors for patients with CAH being treated with standard intravenous disphosphonates. Two hundred sixty patients were reviewed. Overall survival and prognostic factors were analyzed. Relative risks (RR) for early death (within 60 days) were assessed (Fischer exact test and logistic regression model). Median survival was 64 days (range, 12-1,955+). Multivariate analysis identified the following factors as poor survival predictors: serum corrected calcium >2.83 mmol/l [hazard ratio (HR) = HR 2.21], albuminemia <35.5 (HR 2.41), squamous cell carcinoma (HR 2.64), bone metastasis (HR 1.44), and liver metastasis (HR 2..22). One hundred twenty-one patients died within 60 days. For those patients, the logistic regression model identified four independent predicting factors for early death: calcemia >2.83 mmol/l (RR 5.07), hypoalbuminemia (RR 7.42), liver metastasis (RR 4.34), and squamous cell carcinomas (RR 2.21). Despite intravenous diphosphonate, CAH is still associated with poor outcome. Simple bedside parameters may estimate the risk of early deaths.

Bisphosphonates and osteonecrosis of the jaws

The osteonecrosis of the jaws (ONJ) has been reported occasionally in cancer patients treated with radiotherapy and chemotherapy. However, bisphosphonate (BP)-associated ONJ in patients with cancer such as multiple myeloma, breast cancer and prostate cancer mainly administered with intravenous BPs has been first reported in 2003. Since then, many cases over 2,500 are accumulating worldwide. Since BPs are often used for osteoporosis, cancer-associated hypercalcemia and osteolytic bone metastasis, it is speculated that ONJ cases will increase in Japan where a small number of them were reported until now. Most of ONJ in cancer patients receiving BP administration occur after dental treatments such as tooth extraction, periodontal surgery and dental implants, and do not respond to conventional treatment modalities such as debridement, antibiotic therapy and hyperbaric oxygen therapy. No effective therapy for ONJ is established yet and empirical conservative therapy is recommended in the guidelines for prevention, diagnosis, and treatment of ONJ. Therefore, dentists and oral and maxillofacial surgeons need to recognize ONJ as a serious side effect of BPs and to make informed consent to the patients and a close consultation with medical oncologists for administration of BPs.

Increased fibroblast growth factor-like autoantibodies in serum from a subset of patients with cancer-associated hypercalcemia

Basic fibroblast growth factor (bFGF) is a potent tumor angiogenesis factor which lacks an amino-terminal signal sequence and does not normally circulate in serum from normal subjects. Naturally-occurring autoantibodies which mimicked basic fibroblast growth factor were described in serum from patients with multiple endocrine neoplasia type 1 prolactinoma or sporadic growth-hormone-secreting adenoma associated with increased bFGF. Since bFGF was increased in serum from a variety of cancers, we used endothelial cell proliferation assay(s) to test for bioactivity in the IgG fraction of serum from 56 patients with cancer-associated hypercalcemia, and normal or control subjects. We now report increased IgG-like endothelial cell activity in serum from a hyper prolactinemic subset (4/19 breast cancer; 1/14 renal cancer; 0/23 lung cancer) of cancer-associated hypercalcemic subjects. Highest activity was found in serum from three breast cancer patients who suffered spinal cord compression/metastases. The activity had properties of antiidiotype bFGF antibodies including reaction with anti-human IgG antibodies, and complete neutralization by rabbit antibodies to intact bFGF. The activity in endothelial cells persisted after storage at 0–4 C for 5 yrs; and [prepared by SDS-PAGE and immunoblotting with anti-human IgG] had apparent mol wt corresponding to the heavy chains of IgG. Serum IgG-like activity from 5 of 5 breast cancer patients and 2 of 2 prostate cancer subjects tested [prepared by anti-bFGF antibody, protein-A immunoaffinity, and hydroxyapatite (HA) chromatography] yielded peak HA-adsorbed activity that eluted with 0.4 M sodium phosphate, and was neutralized 70% by antibodies to intact bFGF. Cancer sera mean peak specific activity (12.0 ng-eq bFGF/ug protein) (n = 7) significantly exceeded (P < 0.001) normal sera mean peak specific activity (0.46 ng-eq bFGF/ug protein) (n = 6) in the 0.4 M sodium phosphate eluate fraction from hydroxyapatite columns. These results imply that long-lasting, bioactive FGF-like autoantibodies may arise spontaneously (and contribute to pathophysiology) in subsets of cancer patients with osseous metastases.

Effect of intravenous bisphosphonates on release of basic fibroblast growth factor in serum of patients with cancer-associated hypercalcemia

Basic fibroblast growth factor (bFGF) is a potent tumor angiogenesis factor and normal constituent of bone extracellular matrix which does not normally circulate in serum of nonpregnant adult humans. We examined the effects of acute administration of intravenous bisphosphonates on release of bFGF in human serum. Twenty seven men and women (mean age, 64 yr) with cancer-associated hypercalcemia, the majority of whom had osseous metastases, were treated once with an intravenous bisphosphonate. Nearly all twelve patients with elevated baseline serum bFGF ranging from 5–27 pg/mL showed significant decreases in serum bFGF (2–7 days) after iv bisphosphonate treatment. The mathematical product of the patients' initial serum bFGF and intial serum calcium concentration, the 'Ca x bFGF product', was significantly negatively (r = −0.91, P < 0.001) correlated with the acute change in serum bFGF level. No consistent relationship was observed between serum bFGF and serum parathyroid hormone related peptide (PTHrP) levels in the hypercalcemic cancer patients. In a subset of patients with non-hematological malignancies and low baseline serum bFGF, acute changes in serum bFGF were significantly negatively (r = −0.66, P < 0.01) correlated with acute change in serum calcium concentration. These results indicate that release of bFGF in serum of patients with cancer-associated hypercalcemia likely depends predominantly on increased bone resorption. Acute change in low serum levels of bFGF in patients with cancer-associated hypercalcemia treated with intravenous bisphosphonates may be physiologically inversely regulated by acute change in the serum calcium concentration.

Relationship of plasma bone cytokines with hypercalcemia in cancer patients

The pathogenesis of cancer-associated hypercalcemia is not yet completely understood. This syndrome appears to be a consequence of the tumor production of humoral factors, mainly parathyroid hormone related protein (PTHrP). However, patients with humoral hypercalcemia of malignancy have features suggesting that factors other than PTHrP might play a role in this syndrome. We performed a case-control study in cancer patients with and without hypercalcemia. A total of 105 patients with a variety of tumors, 60 of them with hypercalcemia (corrected serum calcium over 2.6 mmol/l), and 45 without hypercalcemia. In a previous study, we demonstrated that plasma PTHrP was highly associated with hypercalcemia in these patients. In the present study, we measured the plasma levels of various bone cytokines: interleukin-1β (IL-1β), interleukin-6 (IL-6), transforming growth factor (TGF) α, and tumor necrosis factor (TNF) α, in these cancer patients. We also determined C-terminal type I procollagen (PICP) and C-terminal telopeptide of type I collagen (ICTP), bone formation and bone resorption markers, respectively, in serum in these patients. We found that these osteolytic cytokines do not increase in plasma by the presence of hypercalcemia. In fact, using a logistic regression analysis, a significant ( P<0.02) association was found between the low plasma levels of IL-1β and TGFα and hypercalcemia, independent of plasma PTHrP and the presence of bone metastasis, in these patients. No significant association between the plasma levels of IL-6 or TNFα and hypercalcemia was found in these cancer patients. Serum ICTP correlated ( r=0.35; P=0.008) with hypercalcemia in these patients, but none of the cytokines studied in plasma correlated with either ICTP or PICP in these hypercalcemic patients. Our data indicate that the circulating levels of several bone cytokines are not enhanced by PTHrP in hypercalcemic cancer patients. The mechanism responsible for the association between the low plasma levels of some of these cytokines and hypercalcemia in these patients remains obscure. However, this finding does not rule out the possible local bone effects of these cytokines, contributing to hypercalcemia in cancer patients.

Parathyroid hormone-related protein, parathyroid hormone, and vitamin D in hypercalcemia of malignancy

The pathogenesis of cancer-associated hypercalcemia is not yet completely understood. In the majority of cancer patients, hypercalcemia appears to be a consequence of the tumor production of parathyroid hormone (PTH)-related protein (PTHrP). However, patients with humoral hypercalcemia of malignancy, in contrast to those with primary hyperparathyroidism, have an uncoupled bone turnover, and they usually have low circulating levels of 1,25(OH)2D3. We performed a case-control study to assess the relationship of plasma PTHrP, PTH and 1,25(OH)2D3 with hypercalcemia in cancer patients with a variety of tumors. Sixty of these patients had hypercalcemia, and 45 were normocalcemic. We measured PTHrP and PTH by immunoradiometric assay (Nichols), and 1,25(OH)2D3 by radioreceptor assay (Nichols), in plasma in both groups of cancer patients. Using a logistic regression analysis, we found that the higher PTHrP in plasma, the higher association with hypercalcemia occurred in these patients. In addition, the decreased plasma levels of PTH and 1,25(OH)2D3 in the majority of cancer patients were found to be significantly associated with hypercalcemia. Our results indicate that the combined determination of PTH, PTHrP and 1,25(OH)2D3 in plasma represents a more comprehensive approach to the investigation of hypercalcemia in cancer patients. Our data also support the role of PTHrP as a humoral factor responsible for hypercalcemia in these patients.

A Clinical study on the Hypercalcemia in Primary Bronchogenic Carcinoma

Background: Lung cancer-associated hypercalcemia is one of the most disabling and life-threatening paraneoplastic disorders. Humoral hypercalcemia is responsible for most lung cancer-associated hypercalcemia. Patients with hypercalcemia are usually in the advanced stage with obvious bulky tumor and carry a poor prognosis. Materials and Methods: Total 29 patients satisfied the following criteria: histologically proven primary lung cancer, corrected calcium level 10.5 mg/dL, and symptoms which could possibly be attributed to hypercalcemia. In this retrospective study, we evaluated the various clinical aspects of hypercalcemia, in relation to cancer stage, histologic cell type, mass size, bone metastasis, performance status, and other possible characteristics. Results: Total 29 lung cancer patients with hypercalcemia were studied, and most of them had squamous cell carcinoma in their histologic finding. The incidence of hypercalcemia was significantly higher between 50 and 69 years of age, and in the advancement of cancer stage. Although serum calcium level showed positive correlation with mass size, performance status, and bone metastasis, it was not significant statistically. Altered consciousness was significantly more frequent in the patients with higher serum calcium level. There were no differences in effectiveness among therapeutic regimens. Hypercalcemia was more frequently in the later stage of disease than during the initial diagnosis of lung cancer. Most of the patients died within 1 month after development of hypercalcemia. Conclusion: We concluded that hypercalcemia in lung cancer is related to extremely poor prognosis, and may be one of the causes of death and should be treated aggressively to prevent sudden deterioration or death.

Correlation of mechanistic data and histopathology in the evaluation of selected toxic endpoints of the endocrine system

The objective of this review is to correlate endocrinologic data from mechanistic studies with quantitative histopathology in selected examples of toxic endpoints of the endocrine system in laboratory animals. Mechanistic data can aid in the interpretation of animal toxicology findings and help clarify their significance in risk assessment. Endocrine organs of rodents frequently undergo proliferative changes with advancing age and following chronic exposure to large doses of xenobiotic chemicals, and the sensitivity of rodent endocrine tissues appears to be increasing. Many xenobiotic chemicals in large doses disrupt thyroid function in rodents either by a direct effect on the thyroid influencing synthesis of thyroid hormones or by adversely influencing their peripheral metabolism. A number of chemicals disrupt thyroid function by inhibiting the important enzyme, thyroperoxidase (TPO). A contemporary example of a chemical acting as TPO-inhibitor is sulfamethazine. In short-term mechanistic studies in rats there was a log–dose response relationship in circulating levels of thyroid and pituitary hormones plus a similar non-linear dose-response in morphologic changes in thyroid follicular cells. Endocrinologic data from mechanistic studies and histopathologic/ultrastructural findings will also be presented for the effects of the food color, FDC Red No. 3 (Erythrosine), on the thyroid gland in rats and parathyroid hormone-related protein (a major causative factor in cancer-associated hypercalcemia) on parathyroid chief cells in mice.

The role of interleukin-6 in the induction of hypercalcemia in renal cell carcinoma transplanted into nude mice.

Hypercalcemia is a well known complication of renal cell carcinoma (RCC). As RCCs can produce IL-6, and IL-6 may stimulate bone resorption and cause mild hypercalcemia, we examined whether IL-6 is involved in renal cancer-associated hypercalcemia in vivo. Three human renal cell carcinoma tumor lines (RC-8, RC-9, and NC-65) growing in nude mice were studied. Tumors were implanted s.c., and parameters of bone metabolism and serum human IL-6 levels were determined in relation to tumor volume (TV). All three tumor lines secreted human IL-6, although in different quantities. The maximum level of IL-6 in RC-8 was 434 pg/ml (TV, 200 mm3), that in RC-9 was 81 pg/ml (TV, 1800 mm3), and that in NC-65 was 2368 pg/ml (TV, 1800 mm3). Hypercalcemia developed in RC-8 and RC-9 tumor-bearing animals, but not in NC-65-bearing animals. The hypercalcemia in both RC-8 and RC-9 tumor lines was associated with elevated levels of PTH-related peptide (PTHrP) and loss of trabecular bone volume. Serum calcium and phosphate concentrations showed an almost linear relationship with plasma PTHrP independently of the tumor line and serum IL-6 levels. No hypercalcemia occurred in the NC-65 animals, which had the highest levels of IL-6, but no detectable plasma PTHrP and PTHrP messenger RNA expression in the tumor. Administration of neutralizing antibodies to IL-6 to RC-8 animals normalized serum calcium concentrations and PTHrP values and induced a significant inhibition of tumor growth. No such effect on tumor growth of anti-IL-6 was seen in the other two tumor lines. The normalization of serum calcium in RC-8 mice is most likely attributed to the growth-inhibiting effect of anti-IL-6 on RC-8 tumor. We conclude that IL-6 secreted by RCC does not contribute directly to hypercalcemia, but may enhance hypercalcemia by stimulating the tumor growth of a subpopulation of PTHrP-secreting carcinomas.

Pamidronate for Cancer-Associated Hypercalcemia-Reply

<h3>In reply</h3> Anand and Anand raised some interesting questions about the treatment of cancer-associated hypercalcemia. The role of parathyroid hormone—related protein (PTHrP) in cancer-associated hypercalcemia is the focus of intense research. Many studies^1-4suggest that increased PTHrP levels negatively influence the response of hypercalcemia to bisphosphonates. Walls et al⁴reported that circulating PTHrP significantly reduced the effectiveness of pamidronate in patients with no bone metastases. However, in two randomized, prospective, double-blind studies^5,6of cancer-associated hypercalcemia, we demonstrated that the efficacy of pamidronate therapy was similar in patients with and without bone metastases. Some studies³have shown a positive correlation between increased PTHrP concentrations and corrected serum calcium levels, but others^1,2have not confirmed this. Many different PTHrP detection methods are currently in use.^7,8This makes it difficult to compare the relative role of PTHrP in published studies. Additionally, the prediction of a poor response

Pamidronate for Cancer-Associated Hypercalcemia

The article by Gucalp and colleagues, 1 comparing rapid and slow intravenous infusion regimens of pamidronate in the treatment of malignancy-associated hypercalcemia, was interesting and informative. In this context, I would like to draw the authors' attention to some further data concerning this subject. The authors took into account several laboratory parameters in the randomized groups of patients receiving either a 4- or 24-hour infusion of 60 mg of pamidronate. Two other parameters have, however, also been shown to affect the response of tumor-induced hypercalcemia to pamidronate. Gurney and associates 2 showed that the concentration of parathyroid hormone-related protein is an important predictor of this response. An undetectable level of parathyroid hormone-related protein (

Pamidronate for cancer-associated hypercalcemia

Pamidronate for cancer-associated hypercalcemia