Prolonged Hypophosphatemia and Intensive Care After Curative Surgery of Tumor Induced Osteomalacia: A Case Report.

Introduction: Rare FGF23-producing mesenchymal tumors lead to paraneoplastic tumor-induced osteomalacia (TIO) presenting with phosphate wasting, hypophosphatemia, chronic hypomineralization of the bone, fragility fractures and muscle weakness. Diagnosis of TIO requires exclusion of other etiologies and careful search for a mesenchymal tumor that often is very small and can appear anywhere in the body. Surgical removal of the tumor is the only definitive treatment of TIO. Surgical complications due to chronic hypophosphatemia are not well recognized. Case Description: The current case describes severe fragility fractures in a 58-year-old woman, who lost her ability to walk and was bedridden for two years. First, the initial diagnostic laboratory work-up did not include serum phosphorus measurements, second, the suspicion of adverse effects of pioglitazone as an underlying cause delayed correct diagnosis for at least two years. After biochemical discovery of hyperphosphaturic hypophosphatemia at a tertiary referral centre, a FGF23-producing tumor of the mandible was discovered on physical examination, and then surgically removed. Postoperatively, severe hypophosphatemia and muscle weakness prolonged the need for ventilation support, intensive care and phosphate supplementation. After two years of rehabilitation, the patient was able to walk short distances. The tumor has not recurred, and serum phosphate concentration has remained within normal limits during 3.5 years of follow-up. Conclusions: The case report illustrates knowledge gaps in the diagnostic work-up of rare causes of low bone mass and fragility fractures. Compared to other low phosphate conditions, surgical recovery from TIO-induced hypophosphatemia warrants special attention. Increased alkaline phosphatase concentration may indicate impaired postsurgical recovery due to prolonged hypophosphatemia, underlining the need for proactive perioperative correction of hypophosphatemia.

Occult phosphaturic mesenchymal tumour of femur cortex causing oncogenic osteomalacia - diagnostic challenges and clinical outcomes.

BACKGROUND: Tumor induced osteomalacia (TIO) are extremely rare paraneoplastic syndrome with less than 300 reported cases. This report highlights the pitfalls and challenges in diagnosing and localizing TIO in patients with refractory and resistant osteomalacia. PATIENT AND METHODS: 41- year gentleman with 4-year history of musculoskeletal weakness and pathologic fractures presented in wheelchair bound incapacitated state of 1-year duration. Investigations were significant for severe hypophosphatemia, severe phosphaturia, normal serum calcium, reduced 1,25-dihydroxy vitamin-D, elevated ALP, elevated intact parathyroid hormone (iPTH), and pseudo-fractures involving pelvis and bilateral femur. Whole body MRI and 99mTc methylene diphosphonate bone-scan were also normal. Whole body FDG-PET scan involving all 4 limbs revealed a small FDG avid lesion at lateral border of lower end of left femur (SUV max 3.9), which was well characterized on 3-dimensional CT reconstruction. Plasma C-terminal fibroblast growth factor (FGF)-23 was 698 RU/ mL (normal < 150 RU/ml). Wide surgical excision of the tumor was done. Histopathology confirmed mesenchymal tumor of mixed connective tissue variant. Serum phosphorous normalized post-surgery day-1. High dose oral calcium and vitamin-D was continued. FGF-23 normalized post surgery (73RU/ml). Physical strength improved significantly and now he is able to walk independently. CONCLUSION: TIO is frequently confused with normocalcemic hyperparathyroidism and vitamin-D resistant rickets/osteomalacia, which increases patient morbidity. Imaging for tumor localization should involve whole body from head to tip of digits, cause these tumors are notoriously small and frequently involve digits of hands and legs. Complete surgical removal of the localized tumor is key to good clinical outcomes.

Two cases of humoral hypercalcemia of malignancy complicating infantile fibrosarcoma.

We report two infants with infantile fibrosarcoma (IFS) complicated by severe hypercalcemia. Assessment demonstrated suppressed parathyroid hormone and 1,25-dihydroxyvitamin D levels with elevated circulating levels of parathyroid hormone related protein, indicating the diagnosis of humoral hypercalcemia of malignancy (HHM). HHM is a paraneoplastic syndrome rarely associated with pediatric malignancies. Hypercalcemia manifested clinically with neurologic symptoms and soft tissue calcium deposition and required aggressive management with intravenous fluids, diuretics, and supplemental electrolytes. Following treatment with neoadjuvant chemotherapy, serum calcium levels precipitously declined requiring calcium repletion. These cases highlight the improvement of hypercalcemia secondary to HHM following chemotherapy.

Locally aggressive and multifocal phosphaturic mesenchymal tumors: two unusual cases of tumor-induced osteomalacia.

Tumor-induced osteomalacia (TIO) has long been recognized as a clinical paraneoplastic syndrome. The identification of a unique histopathologic entity, the phosphaturic mesenchymal tumor (PMT), as a distinct etiology for TIO has been a more recent discovery. The majority of published cases describe a solitary, non-aggressive appearing soft tissue or osseous lesions in patients with osteomalacia; aggressive appearing or multifocal lesions appear to be exceedingly rare. These tumors characteristically secrete fibroblast growth factor 23 (FGF23). Elevated serum levels of FGF23 result in phosphate wasting and osteomalacia. In the majority of cases, laboratory abnormalities and clinical signs and symptoms of osteomalacia precede identification of the causative lesion by years. Following diagnosis, complete resection with wide margins to prevent local recurrence is most often curative. Imaging characteristics of PMT are diverse and remain incompletely defined, as the majority of previous publications are outside of the radiologic literature. We present multiple imaging modalities in two cases of patients with debilitating osteomalacia and unusual appearing PMTs: one with a locally aggressive lesion leading to pathologic fracture, the second presenting with exceedingly rare multifocal PMT.

Denosumab in hypercalcemia of malignancy: a case series.

BACKGROUND: Denosumab is a nuclear factor-kappa ligand monoclonal antibody whose FDA-approved indications include treatment of osteoporosis, bone loss with certain anticancer hormonal agents, and prevention of skeletal-related events in patients with bone metastases from solid tumors. In clinical trials, the incidence of severe hypocalcemia has been reported as 3.1-10.8%. To date, case reports and two clinical trials have reported the use of denosumab in the management of hypercalcemia of malignancy. No reports of denosumab-induced hypocalcemia have been reported for the hypercalcemia of malignancy population. METHODS: We performed a retrospective chart review of all patients who received denosumab for hypercalcemia of malignancy to describe the effects of denosumab on calcium levels at our institution. RESULTS: Seven patients received doses of denosumab for hypercalcemia of malignancy. The most common tumor types were breast cancer (n = 3) and hematologic malignancies (n = 2). All patients had bone involvement. Two patients received single doses of 60 mg. The other five patients received 120 mg. The mean corrected calcium levels were 13.7 mg/dL and 12.24 mg/dL for the days of admission and denosumab administration, respectively (p = 0.1889). The mean corrected calcium level for the last known value was 9.92 mg/dL, while in house (p = 0.0016). Supportive care prior to denosumab included hydration (n = 7), bisphosphonates (n = 6), and calcitonin (n = 5). One patient had a calcium level of 6.6 mg/dL on day 4 after denosumab, requiring calcium supplementation and telemetry. Of the seven patients treated with denosumab for hypercalcemia of malignancy at our institution, six patients were discharged alive. Of these, one patient died two days after discharge. Last-known follow-up was a median of 26 days, range, 3-195, for all patients. CONCLUSIONS: Denosumab helped decrease calcium in patients with hypercalcemia of malignancy. However, symptomatic hypocalcemia may result from denosumab in hypercalcemia of malignancy.

Refractory hypercalcaemia secondary to parathyroid carcinoma: response to high-dose denosumab.

OBJECTIVE: Hypercalcaemia is an important cause of increased morbidity and mortality in patients with parathyroid carcinoma. Surgical resection is the mainstay of treatment but, equally, managing hypercalcaemia is of paramount importance. At present, few therapies have been shown to be effective in the most severe cases. This report describes the efficacy of denosumab in a patient with parathyroid carcinoma when conventional therapies had been shown to be relatively ineffective.SUBJECT, METHODS AND RESULTS: A 50-year-old man presented with symptomatic hypercalcaemia 1 year after the surgery for his parathyroid carcinoma. Investigations revealed raised serum calcium and parathyroid hormone concentrations consistent with the recurrence of the disease. Imaging failed to localise any surgically remediable foci. Medical management with loop diuretics, calcimimetics and bisphosphonates failed to provide a sustained response. Denosumab, as a monthly injection, led to a gradual decrement in his peak calcium concentrations with the values now persistently below 3 mmol/l. CONCLUSIONS: Denosumab, a fully human MAB that binds to the 'receptor activator of nuclear factor κB ligand (RANKL)', was shown to have a profound effect in modulating malignant hypercalcaemia. This medication should be considered as an effective option in patients with refractory hypercalcaemia secondary to parathyroid carcinoma.

[Malignant hypercalcemia after treatment of breast cancer]. / Hypercalcémie maligne après traitement d'un cancer du sein.

A premenopausal woman developed hypercalcemia 30 months after treatment for infiltrating breast cancer. After bone metastases had been excluded, primary hyper parathyroidism was suspected. A parathyroid adenoma was removed and histologically confirmed. Hypercalcemia persisted, associated with low plasma phosphate and severely depressed plasma parathormone (PTH) levels. Further investigations showed liver metastases from the primary breast cancer and also secretion of a PTH-like substance. Anti-tumoral treatment was effective on the liver metastases and also normalized calcemia and the PTH-like substance, demonstrating the existence of a paraneoplastic syndrome related to the secretion of a PTH-like substance by disseminated liver metastases of primary breast cancer.

[Clinical importance of changes in thrombocytic hemostasis in lung cancer]. / Klinicheskoe znachenie izmenenii trombotsitarnogo gemostaza pri rake legkogo.

Clinico-laboratory examinations of 86 patients have shown that lung cancer develops against the background of activation of the thrombocytic link of hemostasis which manifested itself in thrombocytosis, greater degree of destruction of the lysosomal membranes, lower energy resources of the cells, their tendency to slow and little reversible aggregation. The authors consider that the indicators of the ADP-induced aggregation of thrombocytes may be used for prognosis of postoperative pyo-inflammatory and thromboembolic complications. HBO is good for correction of alterations in the thrombocytic link of hemostasis in lung cancer and its suppurative complications.