Malignancy-associated Hypercalcemia Research Articles

PTHrP Regulates Fatty Acid Metabolism via Novel lncRNA in Breast Cancer Initiation and Progression Models.

Parathyroid hormone-related peptide (PTHrP) is the primary cause of malignancy-associated hypercalcemia (MAH). We previously showed that PTHrP ablation, in the MMTV-PyMT murine model of breast cancer (BC) progression, can dramatically prolong tumor latency, slow tumor growth, and prevent metastatic spread. However, the signaling mechanisms using lineage tracing have not yet been carefully analyzed. Here, we generated Pthrpflox/flox; Cre+ mT/mG mice (KO) and Pthrpwt/wt; Cre+ mT/mG tumor mice (WT) to examine the signaling pathways under the control of PTHrP from the early to late stages of tumorigenesis. GFP+ mammary epithelial cells were further enriched for subsequent RNA sequencing (RNAseq) analyses. We observed significant upregulation of cell cycle signaling and fatty acid metabolism in PTHrP WT tumors, which are linked to tumor initiation and progression. Next, we observed that the expression levels of a novel lncRNA, GM50337, along with stearoyl-Coenzyme A desaturase 1 (Scd1) are significantly upregulated in PTHrP WT but not in KO tumors. We further validated a potential human orthologue lncRNA, OLMALINC, together with SCD1 that can be regulated via PTHrP in human BC cell lines. In conclusion, these novel findings could be used to develop targeted strategies for the treatment of BC and its metastatic complications.

S3016 Hepatocellular Carcinoma as an Uncommon Cause of PTHrP-Mediated Hypercalcemia

Introduction: Humoral hypercalcemia of malignancy driven by PTHrP is a syndrome frequently associated with squamous cell carcinoma. We present a case of humoral hypercalcemia as a rare manifestation of hepatocellular carcinoma and describe the impact of early diagnosis on patient care. Case Description/Methods: A 67-year-old male with HCC presented to the emergency department with subacute confusion, constipation, and lower extremity weakness. Physical exam revealed tangential thinking and no asterixis. Serum calcium was 14.8 (corrected to 15.3), creatinine 1.36 (baseline 0.8), AST 141, ALT 32, and AFP 135 (all previously normal). Imaging revealed new liver lesions in multiple segments, enlarged lymph nodes in the porta hepatis, widespread lytic lesions in the spine, calvarium, and facial bones with a 3.4 cm x 2.4 cm left orbital wall mass consistent with metastatic disease. Serum calcium levels normalized with IV fluids, calcitonin, and zolendronic acid. The PTHrP was elevated at 79. Vitamin D levels, SPEP and UPEP were normal. He returned one week later with recurrent severe hypercalcemia. No further cancer treatment options were available so the patient elected for hospice services and died at home. Discussion: Malignancy is the most common cause of hypercalcemia in the inpatient setting. Malignancy-associated hypercalcemia occurs through three distinct mechanisms – humoral (PTHrP mediated), lytic bone lesions, and increased absorption due to excess 1,25 vitamin D production by the cancer. Most cases of HCC-associated hypercalcemia are due to metastatic lytic bone lesions. Less than 10% of cases are attributable to PTHrP, which is severe and often refractory. The mechanism for this is unknown but may be related to an underlying paraneoplastic syndrome and downstream metabolic derangements. Humoral hypercalcemia in patients with HCC is associated with a more advanced TNM stage and higher tumor burden. In a study of 534 patients with HCC, 6.3% had humoral hypercalcemia and had worse prognoses by Child-Pugh scores. Another study of 165 patients with HCC and PTHrP-mediated hypercalcemia found a median survival time of 15 days. Early recognition of humoral hypercalcemia in patients with HCC is essential given its association with higher mortality. Doing so can help providers expedite locoregional therapy or guide goals of care discussions with their patients.

Treatment of malignancy-associated hypercalcemia with cinacalcet: a paradigm shift

Palliation of symptoms related to malignancy-associated hypercalcemia (MAH) is essential and clinically meaningful for patients, given the continued poor prognosis, with high morbidity and mortality associated with this disease process. Historically, agents have been temporizing, having no impact on patient morbidity nor survival. We suggest that cinacalcet can be an efficacious agent to be taken orally, reducing patients’ time in the hospital/clinic settings. It is well-tolerated and maintains serum calcium levels in the normal range, while targeted cancer treatments can be employed. This has a direct, major impact on morbidity. Maintaining eucalcemia can increase quality of life, while allowing targeted therapies time to improve survival. Given that our case (and others) showed calcium reduction in MAH, there is promising evidence that cinacalcet can be more widely employed in this setting. Future consideration should be given to studies addressing the efficacy of cinacalcet in calcium normalization, improvement of quality of life, and impact on survival in patients with MAH. Though the exact mechanism of action for cinacalcet’s reduction in calcium in this setting is not currently known, we can still afford patients the possible benefit from it.

Severity of Ionized Hypercalcemia and Hypocalcemia Is Associated With Etiology in Dogs and Cats.

Background: Calcium disorders are common in small animals, but few studies have investigated the etiology of ionized hypercalcemia and hypocalcemia in large populations. This study aimed to determine the incidence of ionized calcium disorders in dogs and cats treated at a tertiary referral clinic and to describe the associated diseases.Methods: An electronic database of electrolyte analyses conducted at the Cornell University Hospital for Animals from 2007 to 2017 was searched. Dogs and cats with ionized hypercalcemia or hypocalcemia were identified based on institution reference intervals. Duplicate case entries were removed. Medical records were reviewed to identify the cause of the calcium abnormality. Chi-squared analysis with Bonferroni adjustment was performed to compare frequencies of disease processes between mild and moderate-severe disturbances.Results: The database included 15,277 dogs and 3,715 cats. Hypercalcemia was identified in 1,641 dogs and 119 cats. The incidence of canine and feline hypercalcemia was 10.7 and 3.2%, respectively. Hypocalcemia was identified in 1,467 dogs and 450 cats. The incidence of canine and feline hypocalcemia was 9.6% and 12.1%, respectively. The most common pathologic causes of hypercalcemia in dogs were malignancy-associated (12.9%), parathyroid-dependent (4.6%) and hypoadrenocorticism (1.7%). In cats, malignancy-associated hypercalcemia (22.7%), kidney injury (13.4%) and idiopathic hypercalcemia (12.6%) were most common. Dogs presenting with moderate-severe hypercalcemia vs. mild hypercalcemia were significantly more likely to have hyperparathyroidism, malignancy-associated hypercalcemia or hypervitaminosis D, whereas cats were significantly more likely to have malignancy-associated hypercalcemia or idiopathic hypercalcemia. The most common pathologic causes of hypocalcemia in dogs were critical illness (17.4%), kidney injury (10.4%) and toxicity (7.5%). In cats, kidney injury (21.6%), urethral obstruction (15.1%), and critical illness (14.7%) were most frequent. Dogs presenting with moderate-severe hypocalcemia were significantly more likely to have hypoparathyroidism, kidney injury, eclampsia or critical illness, whereas cats were significantly more likely to have kidney injury, soft tissue trauma or urethral obstruction.Conclusions: Mild calcium disturbances are most commonly associated with non-pathologic or transient conditions. Malignancy-associated hypercalcemia is the most common cause of ionized hypercalcemia in dogs and cats. Critical illness and kidney injury are frequent causes of ionized hypocalcemia in both species.

Parathyroid Hormone-Related Protein (PTHrP): An Emerging Target in Cancer Progression and Metastasis.

PTHrP was first discovered as the most common mediator of malignancy-associated hypercalcemia. Subsequently, the discovery of its ubiquitous expression in normal tissues unraveled its role as a physiological autocrine/paracrine regulator. The significance of PTHrP in cancer is not confined to malignancy-associated hypercalcemia, and sufficient evidence now also supports its role in skeletal metastasis through its modulation of bone turnover. Furthermore, our own studies have recently shown the critical role of PTHrP in breast cancer initiation, growth, and metastasis. More recently, we have provided new evidence that overexpression of PTHrP is associated with higher incidence of brain metastasis and decreased overall survival in triple-negative breast cancer patients. Further mechanistic studies in human and mouse model are necessary to fully understand the role of PTHrP in tumor progression and metastasis.

Abstract 1995: PTHrP drives tumor initiation signaling pathways in the PyMT model of breast cancer progression

Abstract Parathyroid hormone-related peptide (PTHrP) was first discovered in cancer patients as the primary cause of malignancy associated hypercalcemia (MAH) & is overexpressed in most human breast tumors. We previously showed that PTHrP ablation, in the MMTV-PyMT murine model of breast cancer progression can dramatically prolong tumor latency, slows tumor growth & metastases. Here we examined the signaling pathways under the control of PTHrP in the pre-neoplastic stage of tumor development (hyperplasia) by generating MMTV-PyMT model in which the mammary epithelium, expressing membrane-targeted GFP, is distinguished from the membrane-targeted red fluorescent backlight of stromal & nonepithelial-derived mammary tissues. We constructed Pthrpflox/flox; Cre+ mT/mG tumor mice (PTHrP conditional KO) & Pthrpwt/wt; Cre+ mT/mG tumor mice (WT control). Next, we applied FACS to enrich the GFP+ mammary epithelial cells isolated from PTHrP KO & control tissues for subsequent RNAseq analyses. We then examined differentially expressed genes (DEGs) by comparing purified cell populations from PTHrP KO & control tissues. We identified 939 DEGs (p value <0.01) & used DAVID bioinformatics resources to systematically analyze the KEGG pathways. Among the most significant pathways, extracellular matrix (ECM), focal adhesion,PI3K-Akt, RAS and WNT pathways were up-regulated in WT control cells compared to KO cells. In summary, PTHrP controls critical signaling pathways involved in breast cancer initiation at the pre-neoplastic stage & suggests that PTHrP ablation is a promising therapeutic strategy in breast cancer. Citation Format: Rui Zhang, Jiarong Li, Dunarel Badescu, Andrew Karaplis, Jiannis Ragoussis, Richard Kremer. PTHrP drives tumor initiation signaling pathways in the PyMT model of breast cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1995.

Abstract 3062: Ablation of parathyroid hormone-related protein in the triple negative human breast cancer line MDA-MB-231 inhibits its cancer stem cell phenotype

Abstract Parathyroid hormone-related protein (PTHrP) is a pleiotropic hormone involved in a wide range of developmental & physiological processes. It is also dysregulated in advanced cancers where it causes malignancy-associated hypercalcemia & plays a major role in the progression of bone metastases. We have shown previously that PTHrP ablation delays tumor initiation & that it is preferentially expressed in triple negative breast cancer (TNBC).Here we investigated how PTHrP can influence the phenotype of the human TNBC cell line MDA-MB231 using CRISPR/cas 9 knockout technology. We used U6G RNA-Cas9-2A-red fluorescence protein (RFP) vector with a human PTHrP specific guide RNA directed to exon 4(knockout/KO) or an empty vector as control. PTHrP KO cells (RFP+) were isolated using AutoMacs Pro Separator & single cells were exp&ed in 96 well plates. Positive clones were confirmed by DNA sequencing. Real time PCR & immunofluorescence staining confirmed that 5/96 KO clones had between 95-99% decrease in PTHrP expression compared to control cells. We then assessed cancer stem cell (CSC) characteristics of both KO & control cell lines. Mammosphere formation was reduced by over 60% in KO cells. Stem cell phenotype assessed by ALDH1 & CD44+/CD24 low using FACS analysis were significantly reduced by over 30% in KO cells. Cell morphology analysis showed a shift from a mesenchymal phenotype towards an epithelial phenotype. Overall our data show that PTHrP regulates TNBC towards a more aggressive phenotype & suggest that it could be targeted therapeutically. Citation Format: Jiarong Li, Louis Doré-Savard, Karine Sellin, Anne Camirand, Richard Kremer. Ablation of parathyroid hormone-related protein in the triple negative human breast cancer line MDA-MB-231 inhibits its cancer stem cell phenotype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3062.

Bone and calcium metabolism associated with malignancy. Malignancy-associated hypercalcemia.

Hypercalcemia is a poor prognostic factor and can be a direct cause of death in patients with malignancy. Here we provide a brief overview of pathology, etiology and management of malignancy associated hypercalcemia(MAH). MAH can be divided into two categories:humoral hypercalcemia of malignancy(HHM)caused by a systemic soluble factor secreted by the tumor;and local osteolytic hypercalcemia(LOH)in which tumor cells in situ enhance bone resorption. The standard treatment of MAH is intense hydration along with antiresorptive medications such as calcitonin, bisphosphonate and denosumab.

The Changing Profile of Hypercalcemia in Hospital Populations

Hypercalcemia is a relatively common condition in hospitalized patients. Malignancy is still the most common etiology for hypercalcemia in hospitalized populations. Much insight has been gained into the pathogenesis of malignancy-associated hypercalcemia (MAHC) over the last three decades. The classical primary hyperparathyroidism (PHPT) used to be a severe debilitating disease, usually involving bones and kidneys, needing hospital-based management. However, over the past five decades in the Western world and one decade in the Eastern countries, more and more cases of asymptomatic PHPT are being diagnosed. This population is detected with mild hypercalcemia on routine biochemical screening without any overt clinical features. Overzealous correction of asymptomatic vitamin D deficiency has led to the emergence of another type of hypercalcemia, called vitamin D toxicosis. This is not uncommonly seen, especially in countries where megadoses of injectable vitamin D preparations are easily accessible. Hypercalcemia of advanced chronic liver disease (CLD), a poorly understood and uncommonly reported condition is usually seen in hospitals having large volume hepatological services. Hypercalcemia due to chronic infective granulomatous diseases (like tuberculosis) in underdeveloped nations and granulomatous reactions to cosmetic filling materials in developed nations contribute significantly to non-parathyroid group of hypercalcemia. In conclusion, the pattern of hypercalcemia in hospitalized patients has changed considerably over the last five decades. Clinicians should be aware of these changing patterns so that appropriate diagnosis and treatment can be offered to the patients.

57-Year-Old Man With Hip Pain and Lytic Bone Lesions

57-year-old man presented to his primary care physician with a 2-year history of progressive right hip pain. His medical history was notable for hyperlipidemia. He was up-to-date on sex- and agespecific cancer screening. The patient had no history of chest pain, palpitations, shortness of breath, cough, or other cardiac, respiratory, neurologic, or visual symptoms. He had no recent travel history or occupational or social contact with persons who were ill. Physical examination revealed an obese man (body mass index [calculated as weight in kilograms divided by height in meters squared], 40.34 kg/m 2 ) with normal vital signs and unremarkable findings on cardiac, respiratory, abdominal, neurologic, and lymphatic examination. No pain or tenderness was elicited on examination. He was treated initially with nonopioid pain medications. Sacroiliac corticosteroid injections were minimally beneficial. Results of a complete blood cell count (CBC) and electrolyte panel were normal with the exception of an elevated serum calcium level of 11.7 mg/dL (reference range, 8.9-10.1 mg/dL). Ultimately, magnetic resonance imaging (MRI) of his lumbar spine revealed numerous punched-out lytic lesions in the lumbar vertebra and pelvis. He underwent computed tomography (CT) of his chest, abdomen, and pelvis that identified further lytic lesions as well as multiple splenic lesions concerning for metastases. Two separate CT-guided bone biopsy samples of the lytic lesions in the lumbar vertebra did not elicit an etiology of the lesions.

Emergency Management of Malignancy-Associated Hypercalcemia.

The most common cause of hypercalcemia in the emergency department (ED) is malignancy-associated hypercalcemia (MAH), which can be caused by direct bone resorption from bone metastases, vitamin D secreting malignancies, and increased parathyroid hormone (PTH) or PTH-related protein (PTHrP) levels. Malignancy-associated hypercalcemia is associated with a very poor prognosis, with half of the patients dying within a month of diagnosis. Management consists of adequate hydration, bisphosphonate therapy, and correction of other abnormal electrolyte levels. Currently, no therapies have demonstrated an effect on mortality and are therefore viewed only as a means of stabilizing the patient until the underlying condition can be treated. All MAH patients should receive an oncology consult as soon as possible so they are able to receive treatment for the causative malignancy and increase their chance of survival.

Emergency Management of Malignancy-Associated Hypercalcemia

Emergency Management of Malignancy-Associated Hypercalcemia

Malignancy associated hypercalcaemia-responsiveness to IV bisphosphonates and prognosis in a palliative population.

Hypercalcaemia is a potentially fatal paraneoplastic complication of malignancy. It primarily manifests during the advanced phase of cancer, with the life expectancy of patients ranging from weeks to months. The mainstay of treatment is with bisphosphonates, but these are not frequently used in a palliative population due to potential conflict with goals of care. The goals of this study was to determine the reversibility of hypercalcaemia amongst patients whose underlying malignancy is not being treated and assess whether correction results in improvement in symptoms attributable to hypercalcaemia, while identifying risk factors that can predict responsiveness. We conducted a retrospective cohort study of 63 patients aged >18 years who were admitted to the St Joseph's Palliative Care Unit, Australia between 2007 and 2013, having evidence of malignancy-associated hypercalcaemia which was treated with bisphosphonates. We assessed the response to bisphosphonates based on improvement of symptoms attributable to hypercalcaemia, as well as a reduction in serum calcium. We used the Kaplan-Meier survival method and parametric survival analysis to estimate the effect of the independent variables on time till death. Thirty-six of sixty three patients achieved normocalcaemia following treatment with an intravenous bisphosphonate. Complete response was influenced by the number of instances of hypercalcaemia in the past and patient factors, such as age and albumin levels. We found that a reduction in calcium level was associated with a significantly prolonged survival, as well as symptomatic improvement, irrespective of whether normocalcaemia was achieved. Our study suggests that bisphosphonates can be recommended as a palliative measure for selected patients to improve symptoms and prolong survival.

Parathyroid Hormone-Related Protein in Hypercalcemia of Malignancy

Parathyroid hormone-related protein (PTHrP) is a common cause of malignancy-associated hypercalcemia. In this retrospective case series covering 11

Peripheral T-cell lymphoma with hypercalcemic crisis as a primary symptom accompanied by polymyositis: A case report and review of the literature.

The present study reports the case of a 61-year-old male with polymyositis who presented with exacerbated weakness in the lower limbs and a recurrent fever that had persisted for one month. Positron emission tomography/computed tomography scans revealed multiple regions of elevated fluorodeoxyglucose metabolism in the lymph nodes, lungs, liver, spleen and bones. While symptoms of nonchalance and confusion were identified on admission, the patient’s serum calcium level was high at 3.87 mmol/l, so a hypercalcemic crisis was confirmed. A biopsy of the right lingual lymph node revealed peripheral T-cell lymphoma, not otherwise specified. The serum calcium level was restored to within the normal range following emergency measures, such as saline rehydration, diuretics, calcitonin and glucocorticoids, and partial remission was achieved following two courses of chemotherapy. The study may improve our present understanding of the diagnosis and treatment of cancer-associated myositis (CAM) and malignancy-associated hypercalcemia.

Treatment of malignancy associated hypercalcemia

Malignancy associated hypercalcemia (MAH) is a paraneoplastic syndrome that impairs the quality of life and that can be a direct cause of death. MAH is classified into two major categories : humoral hypercalcemia of malignancy (HHM) and local osteolytic hypercalcemia (LOH) . Bisphosphonates are the gold standard of treatment for MAH, because enhanced resorption causing a massive calcium mobilization from bone plays a central role in the pathogenesis of MAH. Calcitonin can be used initially as an adjunctive therapy, because it takes a few days for bisphosphonates to be effective. Saline infusion is also necessary to improve dehydration and renal insufficiency inevitably accompanying MAH.

Derangements of mineral metabolism associated with tumors

Bone as a hard tissue has several functions such as supporting our body and protecting internal organs. In addition, bone has a pivotal role in the regulation of circulatory mineral concentrations. Therefore, abnormal bone metabolism is sometimes accompanied by deranged serum calcium or phosphate levels as shown in patients with malignancy-associated hypercalcemia (MAH) or tumor-induced osteomalacia (TIO) . Parathyroid hormone-related protein, PTHrP, was cloned as a major humoral factor causing MAH. Similarly, fibroblast growth factor 23, FGF23, was identified as a causative factor for TIO. Therefore, MAH and TIO are not only important in clinical practice but also gave us deep insights into the mechanisms of mineral homeostasis, and bone and cartilage metabolism.

Treatment of malignancy-associated hypercalcemia

Malignancy-associated hypercalcemia (MAH) is caused by tumor over-production of parathyroid hormone-related protein (PTHrP), or by locally enhanced bone resorption in metastatic lesions of solid cancers. Medical treatment of MAH includes hydration by saline infusion, loop diuretics to promote urinary calcium excretion and anti-resorptives such as calcitonin and bisphosphonates. Particularly, bisphosphonates are the current mainstay for MAH treatment : they not only inhibit osteoclastic bone resorption to ameliorate hypercalcemia but can also alleviate bone pain and can even prevent cancer cell expansion in bone metastatic lesions.

Unusual 18F-FDG PET/CT finding of an oxyphil parathyroid adenoma in a patient with Hodgkin's Lymphoma

Malignancy-associated hypercalcemia is a complication of advanced tumours that is associated to a poor prognosis. Thorough evaluation to establish its cause is essential because some patients may actually have undiagnosed primary hyperparathyroidism. We report a case of a patient affected by Hodgkin's Lymphoma and persistent hypercalcemia with an incidental (18)F-FDG PET/CT finding in the anterior neck region, not ascribable to malignancy, confirmed with (99m)Tc-sestamibi scintigraphy. It was removed by minimally invasive surgery. It was shown to be an oxyphil parathyroid adenoma localized in an unusual site.

Hypercalcemia in Patients Treated with Oral Bisphosphonates for Tumor-Induced Osteolysis

Objective: Hypercalcemia as the consequence of an excessive bone resorption is a common complication in patients with cancer. The aim of the study was to analyze the prevalence of hypercalcemia in patients with tumor-induced osteolysis starting therapy with bisphosphonates.Methods: The questionnaire-based survey (data collected during three consecutive examinations within a 3-month period) was conducted among 1,450 patients treated with bisphosphonates for tumor-induced osteolysis.Results: Hypercalcemia was found in 8.7% respondents starting the treatment with bisphosphonates. The most common cause of malignancy-associated hypercalcemia was prostate cancer, multiple myeloma and breast cancer. On the other hand, hypercalcemia was the most prevalent among patients with multiple myeloma, metastatic cancer of an unknown primary origin and bladder cancer. Metastases were reported in 342 patients, while pathological fractures in 37. The normalization of calcium level was obtained in 91.4% of the patients treated with bisphosphonates, mostly clodronate. During the bisphosphonate therapy, pathological fractures occurred in 4.6% of patients and the percentage of the patients reporting bone pain decreased from 79.9% to 30.9%.Conclusion: Multiple myeloma, prostate and breast cancer are the most common causes of hypercalcemia of malignancy in patients with tumor-induced osteolysis starting therapy with bisphosphonates.