Calcitriol Unleashed: A Rare Culprit in Hypercalcemia Associated With Rare Primary Pancreatic Lymphoma - A Case Report.

Hypercalcemia of Malignancy is a complicated condition often linked to parathyroid hormone, parathyroid hormone-related peptide, or bone metastasis. This report presents a unique case of calcitriol-mediated hypercalcemia in an 89-year-old female with primary pancreatic lymphoma, highlighting the rarity and complexity of this presentation. Initially, the patient's condition was thought to be related to sarcoidosis, but the recurrence of hypercalcemia led to the discovery of pancreatic B-cell lymphoma as the underlying cause. It also emphasizes the need to explore new treatment options. Interestingly, it demonstrates the successful use of cinacalcet in treating calcitriol-induced hypercalcemia in malignancies, which could be a potential therapeutic option for such cases. It also serves as a reminder of the critical need for ongoing research and innovative therapeutic strategies to improve outcomes in managing hypercalcemia caused by malignancies. The case underscores the potential complexities of calcitriol-mediated hypercalcemia, especially in uncommon presentations like primary pancreatic lymphoma.

Hypercalcemia of Malignancy: An Atypical Presentation of Endometrial Carcinoma.

Hypercalcemia of malignancy associated with lung, gastrointestinal, and hematologic malignancies is well-described in the literature but has rarely been reported with gynecologic cancers. Even among gynecologic malignancies represented in literature with hypercalcemia, there are only a handful from endometrial carcinoma. Here we describe an atypical case of a patient with endometrial carcinoma who presented with symptomatic hypercalcemia. This case report investigates the atypical presentation of an endometrial carcinoma.

A Case of Fibroblast Growth Factor Receptor Fusion-Positive Intrahepatic Cholangiocarcinoma With Humoral Hypercalcemia of Malignancy.

Humoral hypercalcemia of malignancy (HHM) comprises the majority of cases with malignancy-related hypercalcemia and is mediated by elevated parathyroid hormone-related peptide (PTHrP). HHM is rare in cholangiocarcinoma and has been reported only in a few case reports and series. We report a case of a 63-year-old male with a history of locally advanced fibroblast growth factor receptor (FGFR) fusion-positive intrahepatic cholangiocarcinoma who presented with recurrent HHM. The first episode of his hypercalcemia occurred 15 months after the initial diagnosis of cholangiocarcinoma and coincided with disease progression. The hypercalcemia was treated with zoledronic acid, and an FGFR inhibitor was started for the treatment of his malignancy. The second hypercalcemia episode occurred nine months later, with evidence of further disease progression. HHM is associated with poor clinical outcomes; a high index of suspicion should be present to identify and treat this complication in cases of cholangiocarcinoma promptly. With an increased understanding of the molecular alterations underlying cholangiocarcinoma, it will also be necessary to further evaluate its co-occurrence with HHM as the specific molecular alterations in this setting could lay the groundwork for targeted therapies and improve risk stratification for these patients.

Paraneoplastic hypercalcemia in a canine patient with a mandibular salivary carcinoma.

OBJECTIVE: To describe a novel presentation of paraneoplastic hypercalcemia caused by a canine salivary carcinoma. ANIMAL: A 6-year-old intact male Husky with hypercalcemia and a spontaneous salivary carcinoma, stage III. CLINICAL PRESENTATION, PROGRESSION, AND PROCEDURES: The dog presented with polyuria, polydipsia, and hypercalcemia. Physical examination revealed a 37 X 43-mm firm mass in the ventrolateral aspect of the right-hand side of the neck, caudal to the temporomandibular joint. Incisional biopsy was suspicious of metastatic carcinoma to the mandibular lymph node. A full-body CT scan found a large, heterogenous, contrast-enhancing mass on the right ventrolateral neck that appeared to be originating from either the mandibular lymph node or right mandibular salivary gland. Parathyroid hormone-related protein was considered within normal reference intervals, and both parathyroid glands appeared ultrasonographically normal. TREATMENT AND OUTCOME: The patient was treated with a marginal surgical excision of the mass, without immediate complications. Histopathology confirmed the presence of a salivary carcinoma with narrow margins of excision and invasion of the mandibular lymph node. Twenty-four hours after surgery, ionized calcium returned to normal reference values and clinical signs completely resolved. CLINICAL RELEVANCE: Hypercalcemia is an urgent pathology with important systemic implications requiring prompt diagnosis and intervention. In this case report, we identify the first salivary carcinoma associated with a paraneoplastic hypercalcemia, including this pathology as a new differential diagnosis. The hypercalcemia resolved with marginal surgical excision, but interestingly the parathyroid hormone-related protein was not overexpressed, meaning that this neoplasia could mediate hypercalcemia by another pathophysiological mechanism.

Parathyroid Hormone-Related Peptide-Producing Gallbladder Cancer Presenting With Humoral Hypercalcemia of Malignancy: A Case Report.

Humoral hypercalcemia of malignancy (HHM) is often reported in cancers derived from the squamous epithelium; however, there are very few reports of HHM in patients with gallbladder cancer. We report a case of a parathyroid hormone-related protein (PTHrP)-producing gallbladder cancer presenting with HHM. A 43-year-old woman presented with appetite loss, nausea, and brown-colored urine. Blood tests revealed that she had hypercalcemia, high serum bilirubin, and high serum parathyroid hormone. Contrast-enhanced computed tomography revealed a gallbladder tumor, liver metastasis, and bile duct obstruction caused by the gallbladder tumor in the hilar region. No bone metastasis was observed. Endoscopic retrograde cholangiopancreatography revealed pancreaticobiliary maljunction. Metal biliary stents were placed, and a transpapillary biopsy of the gallbladder tumor revealed a pathological diagnosis of adenocarcinoma. The patient was diagnosed with HHM due to gallbladder cancer with liver metastasis. Although her hypercalcemia and jaundice improved, her appetite loss and nausea did not improve. Subsequently, the patient developed disseminated intravascular coagulation, and her general condition gradually deteriorated. Due to her poor general condition, chemotherapy could not be administered. The patient died six weeks after visiting our hospital. Although rare, some gallbladder cancers cause HHM due to PTHrP production.

Pulmonary Mucoepidermoid Carcinoma With Multiple Paraneoplastic Syndromes.

Pulmonary mucoepidermoid carcinoma (PMEC) is rare and challenging to diagnose. Its association with paraneoplastic syndromes is poorly described. It is also uncommon for a patient with lung cancer to present with multiple paraneoplastic syndromes. We report a case of a patient with metastatic high-grade PMEC associated with three paraneoplastic syndromes, namely, humoral hypercalcemia of malignancy, ectopic ACTH syndrome, and paraneoplastic leukemoid reaction.

Refractory hypercalcemia of malignancy: a problem with many potential roots.

Hypercalcemia of malignancy (HCM) is a common clinical problem that is associated with considerable morbidity and negative effects on quality of life. Despite the availability of effective medical treatments for HCM, options are needed for cases that are refractory to conventional therapies. In this context, "refractory" refers to reasonable control of calcium in the setting of inpatient hospitalization (after receipt of standard of care therapies, such as continuous intravenous fluids, calcitonin, and intravenous bisphosphonates) with relapse into severe hypercalcemia within days or weeks of discharge from the hospital. Here we discuss drivers of hypercalcemia of malignancy and the physiologic mechanisms whereby they operate to increase serum calcium. Additionally, we discuss multiple available treatments targeted to a given contributory mechanism and also briefly discuss potential future treatments in need of further study.

Treatment Outcomes and Survival in Hypercalcemia of Malignancy: A Grave Metabolic Emergency.

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.

Recurrent distal cholangiocarcinoma and humoral hypercalcemia of malignancy: report of a rare case and literature review.

A 61-year-old Japanese woman presented with epigastric pain and jaundice. Imaging showed the presence of primary distal cholangiocarcinoma (DCC). A subtotal stomach-preserving pancreaticoduodenectomy was performed, followed by chemotherapy using S-1. However, second-line chemotherapy with gemcitabine and cis-diamminedichloroplatinum was required for the treatment of hepatic metastasis of the DCC 3 months following the surgery. Nine months after the surgery, the serum calcium and parathyroid hormone-related peptide concentrations were high, at 16.5 mg/dL and 28.7 pmol/L, respectively, which suggested the presence of humoral hypercalcemia of malignancy (HHM) secondary to the DCC. Moreover, marked leukocytosis, with a white blood cell count of 40,400/µL, was also present. The patient died 11 months after the diagnosis of DCC. Because hypercalcemia of malignancy is associated with a poor prognosis, and HHM and leukocytosis caused by DCC are very rare, we have presented the present case in detail and provide a review of the existing literature.

A Systematic Review Supporting the Endocrine Society Clinical Practice Guideline on the Treatment of Hypercalcemia of Malignancy in Adults.

CONTEXT: Hypercalcemia is a common complication of malignancy that is associated with high morbidity and mortality. OBJECTIVE: To support development of the Endocrine Society Clinical Practice Guideline for the treatment of hypercalcemia of malignancy in adults. METHODS: We searched multiple databases for studies that addressed 8 clinical questions prioritized by a guideline panel from the Endocrine Society. Quantitative and qualitative synthesis was performed. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess certainty of evidence. RESULTS: We reviewed 1949 citations, from which we included 21 studies. The risk of bias for most of the included studies was moderate. A higher proportion of patients who received bisphosphonate achieved resolution of hypercalcemia when compared to placebo. The incidence rate of adverse events was significantly higher in the bisphosphonate group. Comparing denosumab to bisphosphonate, there was no significant difference in the rate of patients who achieved resolution of hypercalcemia. Two-thirds of patients with refractory/recurrent hypercalcemia of malignancy who received denosumab following bisphosphonate therapy achieved resolution of hypercalcemia. Addition of calcitonin to bisphosphonate therapy did not affect the resolution of hypercalcemia, time to normocalcemia, or hypocalcemia. Only indirect evidence was available to address questions on the management of hypercalcemia in tumors associated with high calcitriol levels, refractory/recurrent hypercalcemia of malignancy following the use of bisphosphonates, and the use of calcimimetics in the treatment of hypercalcemia associated with parathyroid carcinoma. The certainty of the evidence to address all 8 clinical questions was low to very low. CONCLUSION: The evidence summarized in this systematic review addresses the benefits and harms of treatments of hypercalcemia of malignancy. Additional information about patients' values and preferences, and other important decisional and contextual factors is needed to facilitate the development of clinical recommendations.

Treatment of Hypercalcemia of Malignancy in Adults: An Endocrine Society Clinical Practice Guideline.

BACKGROUND: Hypercalcemia of malignancy (HCM) is the most common metabolic complication of malignancies, but its incidence may be declining due to potent chemotherapeutic agents. The high mortality associated with HCM has declined markedly due to the introduction of increasingly effective chemotherapeutic drugs. Despite the widespread availability of efficacious medications to treat HCM, evidence-based recommendations to manage this debilitating condition are lacking. OBJECTIVE: To develop guidelines for the treatment of adults with HCM. METHODS: A multidisciplinary panel of clinical experts, together with experts in systematic literature review, identified and prioritized 8 clinical questions related to the treatment of HCM in adult patients. The systematic reviews (SRs) queried electronic databases for studies relevant to the selected questions. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to assess the certainty of evidence and make recommendations. An independent SR was conducted in parallel to assess patients' and physicians' values and preferences, costs, resources needed, acceptability, feasibility, equity, and other domains relevant to the Evidence-to-Decision framework as well as to enable judgements and recommendations. RESULTS: The panel recommends (strong recommendation) in adults with HCM treatment with denosumab (Dmab) or an intravenous (IV) bisphosphonate (BP). The following recommendations were based on low certainty of the evidence. The panel suggests (conditional recommendation) (1) in adults with HCM, the use of Dmab rather than an IV BP; (2) in adults with severe HCM, a combination of calcitonin and an IV BP or Dmab therapy as initial treatment; and (3) in adults with refractory/recurrent HCM despite treatment with BP, the use of Dmab. The panel suggests (conditional recommendation) the addition of an IV BP or Dmab in adult patients with hypercalcemia due to tumors associated with high calcitriol levels who are already receiving glucocorticoid therapy but continue to have severe or symptomatic HCM. The panel suggests (conditional recommendation) in adult patients with hypercalcemia due to parathyroid carcinoma, treatment with either a calcimimetic or an antiresorptive (IV BP or Dmab). The panel judges the treatments as probably accessible and feasible for most recommendations but noted variability in costs, resources required, and their impact on equity. CONCLUSIONS: The panel's recommendations are based on currently available evidence considering the most important outcomes in HCM to patients and key stakeholders. Treatment of the primary malignancy is instrumental for controlling hypercalcemia and preventing its recurrence. The recommendations provide a framework for the medical management of adults with HCM and incorporate important decisional and contextual factors. The guidelines underscore current knowledge gaps that can be used to establish future research agendas.

Parathyroid Hormone Related Peptide Hypercalcemia as a Presentation of Endometrial Clear Cell Carcinoma.

Hypercalcemia is a frequent complication of solid tumors and hematologic malignancies yet is only rarely associated with endometrial clear cell carcinoma. Here we report on a 70-year-old female who presented in the context of hip fracture and was incidentally found to have humoral hypercalcemia of malignancy secondary to endometrial clear cell carcinoma. This rare association makes endometrial cancer one of the differential diagnoses to be considered when assessing incidentally found symptomatic or asymptomatic hypercalcemia in the appropriate patient population.

Hypercalcemia affected in metastatic breast cancer patients without bone metastasis: report of three cases.

BACKGROUND: Since humoral hypercalcemia of malignancy (HHM) in breast cancer patients without bone metastasis is rare, the clinical features of this condition are not fully understood. CASE PRESENTATION: During the recent 12 years, 3602 patients were diagnosed with breast cancer in our institution, and only three patients developed HHM without bone metastasis. They were all recurrent breast cancer patients with visceral metastases including the lung and the liver. It took no more than 2 months since symptomatic onset to hospitalization because of hypercalcemia. The maximum serum calcium concentrations were 15.0 mg/dL or higher. All patients had symptoms related to hypercalcemia. Treatment of hypercalcemia including hydration, calcitonin, bisphosphonate, and diuretics was initially effective in the three patients. However, two of three cases were eventually fatal because of unsuccessful treatment of breast cancer. CONCLUSIONS: The common features of HHM without bone metastasis in breast cancer patients include acute onset, severe symptomatic hypercalcemia, and presence of visceral metastasis. Treatment of hypercalcemia decreased serum calcium level in a short period, while successful treatment of breast cancer was essential for a long-term management of HHM. This report provides a consideration to help elucidate the pathophysiology and medical care of breast cancer patients with HHM without bone metastasis.

Successful Management of Severe Hypercalcemia with Zoledronic Acid: A Report of Two Pediatric Cases.

Severe hypercalcemia associated with vitamin D intoxication or malignancy in children is a rare and life-threatening condition. There is little published experience with Zoledronic acid in the treatment of pediatric severe hypercalcemia. Here, we present two pediatric cases of severe hypercalcemia, one due to vitamin D intoxication and the second to malignancy, in which Zoledronic acid was used as the first-line bisphosphonate in the treatment. While both cases responded well to a single dose of Zoledronic acid, the second case experienced hypocalcemia requiring calcium treatment after Zoledronic acid infusion. Our report shows that Zoledronic acid may be an effective option in the treatment of severe pediatric hypercalcemia, although patients should be followed closely after infusion due to the risk of hypocalcemia. We provide additional published evidence for the effectiveness of Zoledronic acid in correcting severe pediatric hypercalcemia and hope this will encourage future studies with larger numbers of patients.

Paraneoplastic syndromes: A focus on pathophysiology and supportive care.

PURPOSE: This article aims to increase awareness of, outline pathophysiology for, and offer guidance on supportive care strategies for specific endocrine, neurological, and immunological syndromes associated with paraneoplastic syndromes (PNSs). SUMMARY: PNS refers to remote effects that cannot be attributed to the direct or invasive effects of a malignancy. These syndromes are considered clinically important because they may provide early recognition, diagnosis, and management of the malignancy in a timely manner. Many of their presenting symptoms such as ectopic Cushing's syndrome, hypercalcemia of malignancy (HCM), syndrome of inappropriate secretion of antidiuretic hormone (SIADH), neurological dysfunctions, and paraneoplastic autoimmune thrombocytopenia overlap with those of nonneoplastic disorders, yet their pathogenesis and responses to treatments differ. Management of ectopic Cushing's syndrome due to a PNS consists of treatment of the underlying malignancy and its comorbidities. Drug therapies may include ketoconazole, mitotane, metyrapone, somatostatin analogs, and dopamine agonists. Hypercalcemia may be classified into cases with parathyroid hormone (PTH)-dependent causes or PTH-independent causes such as HCM, in which osteoclast inhibitors may be deployed. Treatments of PNS-mediated SIADH include treatment of the underlying malignancy and strategies to increase serum sodium levels. Amifampridine is now considered the first-line agent for paraneoplastic Lambert-Eaton myasthenic syndrome, whereas steroids, intravenous immune globulin, thrombopoietin receptor agonists (eg, romiplostim, eltrombopag, and avatrombopag), fostamatinib, and rituximab may find their niche in treatment of PNS-mediated autoimmune thrombocytopenia. CONCLUSION: Supportive care for PNSs lends opportunities to pharmacists to add quality, value, and safety.

Ectopic parathyroid hormone as a rare aetiology of hypercalcemia with rhabdomyosarcoma: a new treatment strategy with zoledronic acid and Denosumab.

OBJECTIVES: Ectopic parathyroid hormone (PTH) secretion is rare in children with rhabdomyosarcoma, and only a few pediatric cases have been reported to date. Reports of the use of zoledronic acid (ZA) and Denosumab are limited for the treatment of hypercalcemia of malignancy (HCM) in the pediatric population. The aim of presenting this pediatric case of rhabdomyosarcoma accompanied by HCM, secondary to ectopic PTH secretion, was to highlight the benefits of ZA as a first-choice bisphosphonate in this situation with Denosumab as an alternative therapy. CASE PRESENTATION: The patient was diagnosed at 13 years with alveolar rhabdomyosarcoma. Multiple bone metastases first appeared at 15 years, but he remained normocalcemic until 17 years old when serum calcium was 15.1 mg/dL and PTH 249 pg/mL. While serum calcium responded well after ZA and Denosumab cycles, PTH remained elevated, reaching a peak value of 1851 pg/mL during treatment cycles. CONCLUSIONS: We report a patient with rhabdomyosarcoma accompanied by HCM, secondary to ectopic PTH, in whom the HCM was successfully managed with ZA and Denosumab. We believe that ZA should be the bisphosphonate of choice in pediatric HCM with rhabdomyosarcoma, while Denosumab may be another option in ZA-refractory cases.

Hypercalcemia of Malignancy: Time to Pull the Brakes.

Hypercalcemia of malignancy (HOM) is usually seen in advanced stage and carries a poor prognosis. Survival outcomes are dismal and most of the patients are unable to receive subsequent definite anti-cancer therapy. There is lack of any retrospective or prospective data regarding hypercalcemia of malignancy in Indian population. We aim to describe survival outcomes in hypercalcemia associated with solid organ malignancies. Forty-five patients diagnosed with HOM associated with solid organ malignancies were included in the study. Patients were followed up till death. Clinical features and survival outcomes were noted. Squamous cell carcinoma of head and neck region and lung comprised most of the cases associated with HOM. Most of the patients presented with poor performance status. Median overall survival (OS) was 20 days (2-78 days). Median OS was 35 days (9-58 days) in those who received definite anti-cancer therapy. Four-week mortality rate was estimated as 59.5%, while this increased to 75.7% within 6 weeks from the diagnosis of hypercalcemia. Survival outcomes are poor after the diagnosis of hypercalcemia in cancer patients. Best supportive care including hospice care should be strongly considered at this point of time instead of definite systemic anti-cancer therapy.

Development of a PTHrP chemiluminescent immunoassay to assess humoral hypercalcemia of malignancy.

BACKGROUND: Parathyroid hormone related peptide (PTHrP) measurements are helpful in the evaluation and management of individuals suspected of humoral hypercalcemia of malignancy (HHM). AIM: To develop a chemiluminescent assay for PTHrP quantitation, establish reference intervals, and evaluate its clinical performance. METHOD: PTHrP 1-86 was measured using a polyclonal rabbit antibody (capture) and an acridinium ester labeled goat polyclonal antibody for chemiluminescent detection. RESULTS: Assay imprecision was < 9% (intra-assay) and < 15% (inter-assay). The analytical measuring range was 0.16-50.5 pmol/L. No significant cross-reactivity was observed for PTH (1-84), PTHrP (107-139), and PTHrP (1-36); whereas PTHrP (38-94) showed 8.3% cross-reactivity. Comparison with the pre-existing Mayo assay showed a positive bias: new assay = 2.24 (pre-existing assay)-0.30 and r2 = 0.96. The reference interval was ≤ 0.7 pmol/L, however, a cut-off of ≤ 4.2 pmol/L yielded increased specificity (98%). Comparison of patients with HHM versus those without HHM resulted in an area under the ROC curve of 0.99. A significant inverse relationship between eGFR and PTHrP was observed (r = 0.738). PTHrP concentrations in patients with Chronic Kidney Disease (CKD) were ≤ 4.2 pmol/L. CONCLUSION: This assay is specific for PTHrP 1-86. A clinical decision limit of 4.2 pmol/L was sensitive and specific for patients with HHM.

Neuroendocrine Carcinoma as a Cause of Humoral Hypercalcemia of Malignancy: A Case of a Patient With Elevated Parathyroid Hormone-Related Protein.

Humoral hypercalcemia of malignancy (HHM) is a paraneoplastic syndrome caused by elevations in parathyroid hormone-related protein (PTH-rP). HHM often presents in patients with squamous cell carcinomas of the lung, head, and neck, as well as breast, ovarian, renal, and bladder carcinomas. HHM associated with neuroendocrine carcinoma (NEC) is rarely observed. Here, we report a case of NEC-associated HHM refractory to standard calcium-reducing therapies but improved with the off-label addition of cinacalcet. A 31-year-old male with metastatic NEC presented to the emergency department (ED) with symptoms of nausea, emesis, constipation, and progressive weakness. He was being treated via a clinical trial at a tertiary referral center after failing standard therapies. He had recently been admitted at an outside facility for hypercalcemia, which had been managed with denosumab (120 mg subcutaneously) over the previous four weeks. He was admitted from the ED with a serum calcium of 14.6 mg/dL, potassium of 2.9 mmol/L, and phosphate of 1.2 mg/dL; ionized calcium was elevated at 8.0 mg/dL. Despite hydration and aggressive electrolyte replacement, his calcium increased to 15.5 mg/dL. Further laboratory evaluation revealed parathyroid hormone (PTH) of 6 pg/mL (10-65 pg/mL), 25-hydroxyvitamin D of 25 ng/mL (25-80 ng/mL), 1,25-dihydroxyvitamin D of 513 pg/mL (18-64 pg/mL), and PTH-rP of 25 pmol/L (<2.5 pmol/L), consistent with HHM. Calcitonin was avoided due to a prior hypersensitivity reaction. He received prednisone 10 mg daily and pamidronate 90 mg IV, and his calcium improved to 11.5 mg/dL. He was discharged and investigational therapy was resumed. This therapy failed, and he did not qualify for additional cancer therapy due to refractory hypercalcemia. He was started on cinacalcet, and his calcium decreased enough to permit further cancer treatment. He had multiple hospitalizations with fluctuating calcium levels and ultimately died several months later after sustaining a subarachnoid hemorrhage from a fall. In conclusion, we report a rare case of HHM associated with NEC. While many cases of HHM are effectively managed with hydration, calcitonin, antiresorptive therapies, and glucocorticoids, some are refractory. Our patient was refractory and differed from most patients with HHM in at least two ways. As mentioned previously, NEC causing HHM is quite uncommon (~2% of cases); it is unclear, but this malignancy might predispose to refractory hypercalcemia. Our patient's elevated vitamin D may also have made his HHM more resistant to treatment. Ultimately, while not first line, cinacalcet was an effective treatment in our patient. This provides additional evidence that cinacalcet may be considered for refractory hypercalcemia secondary to malignancy.