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Background: Management of hypercalcemia is based on the manifestation of symptoms and serum calcium levels. It is considered an oncological emergency; therefore, management has to be done on an urgent basis., Aim: In the present study, we analyzed the clinicopathological profile, treatment, and outcome of patients with hypercalcemia in solid malignancies at our institute., Methods: We retrospectively analyzed the medical records of patients diagnosed with cancer and admitted to the department of radiation oncology with hypercalcemia. The parameters studied were age, gender, performance status, date of diagnosis, the primary site of cancer, stage, histopathology, time of presentation of hypercalcemia since initial cancer diagnosis, clinical symptoms, parathyroid hormone levels, liver and renal function tests, bone metastases, management, outcome, and present status., Results: In the present study, 47 patients of hypercalcemia from various solid malignancies were admitted during the study period between 1st January 2018 and 30th April 2022. Head and neck cancer (14, 29.7%) was the most common site of the primary malignancy. Twelve patients had incidental hypercalcemia and were asymptomatic. Management of hypercalcemia included intravenous saline hydration, bisphosphonates, and supportive medication. At the time of analysis, 17 patients were lost to follow-up, 23 patients died, and seven were alive and on follow-up. Median survival was 68.0 days (95% CI: 1.7-134.3 days)., Conclusion: Hypercalcemia of malignancy is considered a metabolic oncological emergency and requires urgent and aggressive management. It gets complicated by a deranged kidney function test. Despite available treatment, it portends an abysmal prognosis., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Gupta et al.)

Hypercalcemia of malignancy is an oncologic emergency due to tumoral factors that stimulate osteoclast-mediated bone resorption. It requires a combination of recommended treatments (i.e., hydration, bisphosphonate and calcitonin), which may be deleterious in patients with compromised cardiac or renal function or may not control serum calcium levels long term. Recurrent or refractory hypercalcemia may preclude the use of chemotherapeutic agents needed to effectively treat the underlying cancer, which is the cause of hypercalcemia. Denosumab, a fully human monoclonal antibody against RANKL, inhibits the maturation, function and survival of osteoclasts. An open-label, single-arm study of denosumab in patients with hypercalcemia of malignancy despite recent bisphosphonate treatment revealed positive results. Thus, the US FDA recently approved denosumab for the indication of hypercalcemia of malignancy, increasing the options available for patients with this debilitating and life-threatening condition. [ABSTRACT FROM AUTHOR]

The article focuses on a study which examines several patients who received denosumab for hypercalcemia of malignancy (HCM) to describe the effects of denosumab on calcium levels. Topics discussed include the baseline demographic and clinical characteristics of the patients, the use of intravenous bisphosphonates as a first-line medication in HCM and trends in individual patient's corrected calcium values from admission.

Hypercalcemia of malignancy is a common finding associated with different types of cancers; however, its association with urothelial carcinoma of the bladder is rare. We report a case of a 69-year-old male with nonmetastatic urothelial carcinoma of the bladder who developed hypercalcemia that failed to respond to medical management, but resolved completely after undergoing resection of the tumor through radical cystectomy.

Hypercalcemia is a common life-threatening complication associated with several malignancies. Parathyroid-related peptide has been shown to cause hypercalcemia in several solid tumors but rarely in penile cancer. We report a case of penile cancer with hypercalcemia causing metastatic visceral calcification in lungs, liver, and stomach detected on bone scan without significant abnormalities on CT scan. [ABSTRACT FROM AUTHOR]

Since its discovery as the principal mediator of humoral hypercalcemia of malignancy, parathyroid hormone-related protein (PTHrP) has emerged as a key player in skeletal complications associated with solid tumor metastasis to bone. In addition to functioning as an endocrine factor, this pleiotropic peptide mediates its actions locally on tumor and stromal cells in paracrine, autocrine, and intracrine fashion when cancer metastasizes to the bone compartment. Multiple splice variants and newly described PTHrP fragments confer diverse functions to PTHrP that extend beyond binding to its common receptor with parathyroid hormone. Here, we summarize the causal role of PTHrP in humoral hypercalcemia of malignancy and its local involvement in the progression of osteolytic and osteoblastic cancer bone metastases. Clinical and preclinical findings describing how PTHrP regulates tumor and stromal cell interactions are summarized, with emphasis on emerging evidence of PTHrP's role in tumorigenesis and cancer cell proliferation. Finally, we examine therapeutic opportunities and limitations to targeting PTHrP directly and indirectly in cancer patients. [ABSTRACT FROM AUTHOR]

Objective: To report the case of a 28-year-old woman who presented with hypercalcemia (total calcium =4.11 mmol/L), elevated parathyroid hormone (PTH) 24.6 pmol/L, normal parathyroid hormone-related peptide 7.8 pg/mL, and a 63 mm x 57 mm, poorly differentiated neuroendocrine carcinoma (small-cell type) pancreatic mass with liver metastases. Investigations and treatment: Hypercalcemia was acutely managed with intravenous fluids, pamidronate and calcitonin. Investigations for multiple endocrine neoplasia type 1 and parathyroid adenoma were initiated. The identified neuroendocrine tumor was treated with cisplatinum/etoposide chemotherapy. Results: The pancreatic mass (56 mm x 49 mm) and metastases decreased in size with chemotherapy and calcium levels normalized. Eight months later, calcium increased to 3.23 mmol/L, PTH increased to 48.2 pmol/L, and the pancreatic mass increased in size to 67 mm x 58 mm. The patient was given a trial of cinacalcet but was unable to tolerate it. Chemotherapy was restarted and resulted in a decrease in the pancreatic mass (49 mm x 42 mm), a reduction in PTH levels (16.6 pmol/L), and calcium levels (2.34 mmol/L). Conclusion: Ectopic PTH secreting tumors should be considered when there is no parathyroid related cause for an elevated PTH. Recognizing the association between PTH and hypercalcemia of malignancy may lead to an earlier detection of an undiagnosed malignancy. [ABSTRACT FROM AUTHOR]

Medullary thyroid carcinoma (MTC) is a rare tumour which frequently occurs in the context of the multiple endocrine neoplasia syndromes, where it coexists with other usually benign tumours. The clinical picture varies and distant metastases are frequently present at diagnosis. Calcitonin levels are elevated in the presence of metastatic disease. Two MTC cases are presented, which had elevated postoperative calcitonin levels. Imaging revealed lung lesions which were originally attributed to metastatic disease from the MTC. However, at follow-up, these cases presented unusual features. The rapid increase in the lung lesions and the development of hypercalcaemia in the first patient suggested a second unrelated tumour. Biopsy of the lung lesion was compatible with lung adenocarcinoma. In the second patient, the appearance of a liver mass, although calcitonin levels remained stable, led to biopsy of the lesion: this was negative for calcitonin and compatible with metastatic lung adenocarcinoma. These MTC cases show that further malignancies may coexist with MTC and may obscure the clinical picture and influence the therapeutic decisions, especially in the case of metastatic disease. Features such as unusual imaging characteristics and the development of hypercalcemia, never encountered in MTC outside the MEN2 syndromes, as well as ‘disproportionately’ low calcitonin levels, incompatible with extensive metastatic disease, were the factors that led to further work-up. Both the cases subsequently proved to carry an unsuspected second malignancy. It is crucial to discriminate the metastatic lesion attributed to MTC from another coexisting primary malignancy, because different therapeutic strategies are needed for each setting. [ABSTRACT FROM AUTHOR]

Abstract: A patient with a primary neuroendocrine tumor of the pancreas, presented with severe hypercalcemia. This hypercalcemia of malignancy (HCM) failed to respond to intensive bisphosphonate treatment and needed continuous enhanced diuresis. Only after successful antitumor therapy did the hypercalcemia subside. Hypercalcemia was associated with increased concentrations of plasma PTHrP, calcitonin and 1,25-(OH)2D3. Bone mineral density was markedly increased. We demonstrated the presence of both PTHrP and calcitonin in the tumor at the mRNA and protein level, using RT-PCR, immunohistochemistry and Western blotting. The high levels of plasma PTHrP and the demonstrated predominant renal mechanism in this case of HCM are suspected to be the cause for its refractoriness to bone resorption inhibitors. Our findings furthermore suggest that the tumoral production of calcitonin and PTHrP might have contributed to the increased bone mineral storage of calcium and thus probably attenuated the development of frank hypercalcemia. [Copyright &y& Elsevier]

Background: Metastasic deposits from malignancies frequently lodge in the skeleton, including the jawbones. Method: A review of the literature was performed in order to provide a coherent overview on the pathogenesis of bone metastasis. Results: Bone metastasis follows complex molecular interactions that enable tumor cells to detach from the primary site, invade the extracellular matrix, intravasate, extravasate, and proliferate within bone. They induce local bone changes that could manifest radiologically as either osteolytic or radiodense. In addition to the direct bone changes, malignancies can elaborate mediators that are released in circulation, leading to generalized osteopenia. Conclusions: The spread of malignant neoplasms to bone is not a random process but rather a cascade of specific molecular events orchestrated through complex interactions between neoplastic cells and their environment. [ABSTRACT FROM AUTHOR]

Humoral hypercalcemia of malignancy is rarely seen in urothelial cancer. In this report, we present a case of an 81-year-old female patient who presented with a markedly elevated calcium level leading to severe altered mental status and was found to have urothelial cancer. To our knowledge, only three cases of urothelial carcinoma with squamous cell differentiation have been reported.

Simple Summary: Thymoma is a tumor of the cranial mediastinum rarely reported in dogs and should be differentiated from mediastinal lymphoma. CT and fine-needle aspirates or core biopsies are helpful in differential diagnosis, but flow cytometry may improve the pre-operative diagnostic ability. In thymomas, paraneoplastic syndromes such as myasthenia gravis and hypercalcemia may develop concurrently with the tumor. Their role as prognostic factors is not well determined. Surgical excision is the treatment of choice, but adjuvant radiotherapy and/or chemotherapy may prolong survival in cases of incomplete excision or if a thymic carcinoma is diagnosed. Local recurrence and metastasis are infrequently reported; therefore, a long survival is expected if the tumor is completely excised or if adjuvant therapy is undertaken. This article reports the authors' experience with 28 dogs affected by 18 thymomas and 10 thymic carcinomas surgically treated from January 2000 to August 2021. The median overall survival time of the entire population was 1137 days; the median disease-free time was 903 days. Dogs with thymic carcinomas had significantly shorter disease-free intervals and shorter, although not statistically significant, survival times. Dogs with Masaoka Stage III tumors had worse outcomes. Thymoma is a tumor rarely reported in dogs and should be differentiated from mediastinal lymphoma. Clinical signs may have a late onset, and thymoma is often diagnosed when symptoms related to the space-occupying effect or paraneoplastic syndromes occur. CT and fine-needle aspirates or core biopsies are helpful in differential diagnosis, but flow cytometry may improve the pre-operative diagnostic ability. Concurrent paraneoplastic syndromes such as myasthenia gravis and hypercalcemia have been reported; however, their role as prognostic factors is not well determined. Surgical excision is the treatment of choice; adjuvant radiotherapy and/or chemotherapy may prolong survival in cases of incomplete excision or when a thymic carcinoma is diagnosed. Local recurrence and metastasis are infrequently reported; therefore, a long survival time is expected if the tumor is completely excised or if adjuvant therapy is undertaken. This article reports the authors' experience with 28 dogs affected by 18 thymomas and 10 thymic carcinomas. The median overall survival in this series was 1173 days, and the median disease-free interval was 903 days. Dogs with thymic carcinoma had significantly shorter disease-free intervals and shorter, although not statistically significant, survival times. Dogs with Masaoka Stage III tumors had worse outcomes. [ABSTRACT FROM AUTHOR]

Hypercalcemia (HCM) occurs in 10-15% of all malignancies, predominantly in patients with solid tumors. This metabolic complication leads to significant morbidity and impairment of quality of life. Recent insights into the pathophysiology of HCM include an understanding of the role of parathyroid-hormone-related peptide and several cytokines secreted by tumors. The osteoclast plays a central role as the final common pathway through which these hormones and cytokines act to cause bone lysis. These findings have led to the development of new treatment strategies. Foremost among these has been the introduction of agents such as the newer bisphosphonates and gallium nitrate, which are potent inhibitors of osteoclast-mediated bone resorption. The clinician can now choose from an array of therapeutic approaches based on a consideration of the mechanisms of action, individual clinical circumstances, efficacy, toxicities and costs of available agents. In addition to their use in the management of HCM, non-toxic drugs that effectively inhibit osteoclast function, such as the bisphosphonates, are playing an emerging role in the palliative treatment of the more common clinical problems of painful lytic bone metastases and osteoporosis. [ABSTRACT FROM AUTHOR]

Parathyroid hormone-related protein (PTHrP) is produced by a wide range of neoplastic and normal cells, including keratinocytes where it may regulate growth and differentiation. Transforming growth factor-β (TGF-β) is a growth factor produced by many cells, including keratinocytes where it regulates epidermal homeostasis. TGF-β has been reported to be cosecreted with PTHrP in some neoplasms and to stimulate PTHrP production by neoplastic keratinocytes. However, the effects of TGF-β on PTHrP production by normal keratinocytes are not well characterized. In this study, we investigated the effects of endogenous and exogenous TGF-β on PTHrP production by normal human foreskin keratinocytes. PTHrP secretion, mRNA expression, and mRNA transcription in vitro were determined by N-terminal radioimmunoassay, ribonuclease protection assay, and transient transfections. PTHrP production and secretion of latent TGF-β activity were greatest in proliferating keratinocytes prior to and at confluence of monolayer cultures. TGF-β1 increased PTHrP mRNA expression by normal keratinocytes in a dose-dependent manner with maximal stimulation at 6-12 h after treatment. In addition, keratinocytes treated with a monoclonal anti-TGF-β antibody expressed decreased levels of PTHrP mRNA. The increased levels of PTHrP mRNA following TGF-β1 treatment were owing, at least partly, to an increase in PTHrP mRNA stability. TGF-β1 failed to activate transcription of the luciferase reporter gene driven by either the human or mouse PTHrP promoters. In conclusion, TGF-β1 functions as a paracrine or autocrine regulator of PTHrP production in normal human keratinocytes, and this may play a role in the regulation of keratinocyte proliferation or differentiation. [ABSTRACT FROM AUTHOR]

Overproduction of parathyroid hormone-related protein (PTHrP) is a major cause of hypercalcemia of malignancy in patients with solid tumors. We measured plasma levels of the protein by a radioimmunoassay (RIA) against PTHrP(5384) and by an immunoradiometric assay (IRMA) against PTHrP(1-86). Of 16 affected patients 7 had elevated PTHrP levels in both assays and 4 had elevated levels in the RIA only. Median levels were about tenfold higher in these patients when measured by RIA (median of 34 versus 2.2 pmol/1). Measurements from both assays were, however, highly correlated with each other in this patient group ( P<0.01). PTHrP was not elevated in 10 normocalcemic patients with lung carcinoma. During long-term follow-up of a patient with a mesothelioma of the pleura, PTHrP levels measured with both assays decreased during chemotherapy in parallel with a normalization of serum calcium. In another hypercalcemic patient suffering from renal carcinoma, PTHrP measured by IRMA decreased by 40% within 12 h after nephrectomy, whereas PTHrP measured by RIA did not show a significant decline. Direct comparison of the assay results thus pointed to the existence of heterogeneity of circulating forms of PTHrP in plasma. In conclusion, both immunoassays detected elevated levels of PTHrP in a fraction of patients with hypercalcemia of malignancy and thus may be a tumor marker during treatment of malignancies. [ABSTRACT FROM AUTHOR]

The treatment of hypercalcemia of malignancy (HCM) consists of enhancing renal calcium excretion, mostly through hydration with isotonic fluids and the use of antiresorptive therapies. Intravenous zoledronic acid is currently the first-line treatment. Subcutaneous denosumab is used for bisphosphonate-refractory hypercalcemia and in patients with renal failure. There is no evidence that bisphosphonates prevent the occurrence of HCM. Conversely, denosumab, compared with zoledronic acid, is associated with a lower risk of HCM, both first episode and recurrence, in patients with breast cancer and multiple myeloma., Competing Interests: Disclosure Nothing to disclose., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Hypercalcemia of malignancy (HCM) is a common complication of advanced cancer. PTH-independent HCM may be mediated through different mechanisms: (1) humoral HCM, caused by the secretion of PTH-related peptide (PTHrP), (2) local osteolysis resulting from metastatic lesions, and (3) calcitriol-mediated hypercalcemia. Calcitriol-mediated HCM in patients with nonlymphomatous solid tumors is thought to be rare., Methods: We performed a retrospective chart review from 2008 to 2017 to characterize further patients at our institution with solid tumors who had HCM with concomitant elevations in calcitriol. Patients with PTH-dependent hypercalcemia and patients with evidence of granulomatous disease were excluded, as were patients with hematologic malignancies. We hypothesized that patients with HCM and elevated calcitriol levels would respond less favorably to treatment with antiresorptive therapy compared with patients with HCM but without calcitriol elevation. We also aimed to assess mortality and determine if PTHrP and phosphorus levels correlate with calcitriol because both factors may alter calcitriol levels., Results: Of 101 eligible patients, calcitriol was elevated in 45 (45%). PTHrP was elevated in 76% of patients with elevated calcitriol compared with 52% of patients without calcitriol elevation. The mean PTHrP value did not differ between patients with HCM and elevated calcitriol (36.3 ± 22 pg/mL) and those without calcitriol elevation (37.4 ± 19 pg/mL). Those with elevated calcitriol levels generally did not respond completely to antiresorptive treatment (80% incomplete response rate), whereas most patients without an elevation in calcitriol responded well to antiresorptive treatment (78% response rate: P < .001). There was no significant difference in the percentage of patients with metastatic bone disease among the 2 groups (49% vs. 55%, respectively). There was no difference in mortality between the 2 groups (P = .14). A weak but significant negative correlation was found between phosphorus and calcitriol (Pearson r = -0.261, P = .016). This correlation was only significant in patients without calcitriol elevation (Pearson r = -0.4, P = .0082). Also, a significant negative correlation was found between PTHrP and phosphorus, again only in patients without calcitriol elevation., Discussion: In the setting of HCM, patients with calcitriol elevation are much less likely to respond to antiresorptive therapy than patients without calcitriol elevation. Because calcitriol elevation did not appear to be correlated with hypophosphatemia or elevated PTHrP, it would appear that calcitriol production under these conditions is autonomous, and not subject to normal physiological controls. These observations indicate that calcitriol elevations in patients with HCM have clinical significance., (© Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Dysregulated bone turnover is an important clinical manifestation of multiple myeloma (MM), and 30% of patients present with hypercalcemia. Serum calcium levels are routinely monitored using total calcium measurements corrected for albumin. However, myeloma-related paraproteins may bind calcium, confounding these measurements., Patients and Methods: We retrospectively analyzed correlation between corrected calcium and ionized calcium in a sample of patients with MM and a control sample of patients with breast or non-small cell lung cancers (n = 200). Multiple linear regression was used to identify variables affecting corrected calcium measurements., Results: Correlation between corrected calcium and ionized calcium was stronger in the control group compared to the MM group (Spearman correlation coefficient 0.85 versus 0.76, respectively). Sensitivity of corrected calcium in identifying hypercalcemia defined by elevated ionized calcium was 36% in patients with MM and 76% in the control group. Multiple linear regression did not reveal variables significantly influencing corrected calcium in the MM group, although serum paraprotein trended toward significance (p = 0.09)., Conclusion: Ionized calcium may be better than corrected calcium for detecting hypercalcemia in patients with MM. Additional analyses are needed to better quantify the clinical impact of paraprotein calcium-binding., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Hypercalcemia of malignancy is a common finding associated with different types of cancers; however, its association with urothelial carcinoma of the bladder is rare. We report a case of a 69-year-old male with nonmetastatic urothelial carcinoma of the bladder who developed hypercalcemia that failed to respond to medical management, but resolved completely after undergoing resection of the tumor through radical cystectomy. [ABSTRACT FROM AUTHOR]

Denosumab is a monoclonal antibody directed against the receptor activator of nuclear factor kappa B ligand (RANKL). Denosumab has been shown to reduce the risk of skeletal-related events, including spinal cord compression, pathologic fracture and hypercalcemia of malignancy in patients with bone metastases. Hypocalcemia is a known side effect of denosumab, occurring in an estimated 8-14% of the patients. Here, we present an asymptomatic patient with stage-5 chronic kidney disease and severe hypocalcemia who had received denosumab 1 month earlier., (Copyright © 2017 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)

Cancer and its therapies may lead to several metabolic emergencies that emergency providers (EPs) should be well-versed in identifying and managing. With prompt recognition and treatment initiation in the emergency department, lives can be saved and quality of life maintained. Most oncologic metabolic emergencies occur in advanced cancer states, but some follow initiation of treatment or may be the presenting syndrome that leads to the cancer diagnosis. This article reviews the 2 most emergent oncologic metabolic diagnoses: tumor lysis syndrome and hypercalcemia of malignancy. A discussion on associated cancers and conditions, pathogenesis and pathophysiology, and management recommendations is included., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Hypercalcemia is a poor prognostic factor associated with malignancy. The signs and symptoms of hypercalcemia that the patients present to the emergency department are vague and often overlap with the general symptoms of cancer itself or the adverse effects of the chemotherapy. Given that the development of hypercalcemia of malignancy can present with imminent danger to the patient and is a treatable condition, emergency physicians should know how to recognize and treat it. It also marks a time at which discussions regarding plans of care should be initiated with the patients. In this report, we describe a simulation case that can be used to train emergency medicine residents to both recognize and treat hypercalcemia of malignancy and to initiate the discussion of goals of care., Competing Interests: The authors have declared that no competing interests exist.

Hypercalcemia is a common life-threatening complication associated with several malignancies. Parathyroid-related peptide has been shown to cause hypercalcemia in several solid tumors but rarely in penile cancer. We report a case of penile cancer with hypercalcemia causing metastatic visceral calcification in lungs, liver, and stomach detected on bone scan without significant abnormalities on CT scan., Competing Interests: There are no conflicts of interest

Cancer and its therapies may lead to several metabolic emergencies that emergency providers (EPs) should be well-versed in identifying and managing. With prompt recognition and treatment initiation in the emergency department, lives can be saved and quality of life maintained. Most oncologic metabolic emergencies occur in advanced cancer states, but some follow initiation of treatment or may be the presenting syndrome that leads to the cancer diagnosis. This article reviews the 2 most emergent oncologic metabolic diagnoses: tumor lysis syndrome and hypercalcemia of malignancy. A discussion on associated cancers and conditions, pathogenesis and pathophysiology, and management recommendations is included., (Copyright © 2014 Elsevier Inc. All rights reserved.)