Hypercalcaemia in relapsed medulloblastoma 8 years post-diagnosis; evidence to support PTHrP production by medulloblastoma cells
ABSTRACT A 19-year-old male presented with symptomatic hypercalcaemia as the first manifestation of relapsed metastatic medulloblastoma. Management at the time of the initial presentation 8 years earlier was with surgical excision and craniospinal radiotherapy. His biochemistry at the time of relapse and studies of medulloblastoma cell lines provide an insight into the pathogenesis of his hypercalcaemia.
Parathyroid hormone-related protein (PTHrP) was measured by immunoradiometric assay in blood, and in conditioned and control media from three medulloblastoma cell lines following 72 h growth.
The histology at initial presentation (11 years of age) and at the time of relapse (with bone marrow infiltration and widespread bony metastases) demonstrated medulloblastoma. Ionised calcium concentrations at relapse were 2.89 mmol/l and serum PTHrP levels were increased at the same time (2.7 pmol/l; normal range: 0.7-1.8 pmol/l). There was evidence of PTHrP production by one cell line (MHH-MED-8A) while results for both other lines tested were below the limit of detection.
Relapse 8 years after diagnosis is unusual in medulloblastoma and for this relapse to manifest as hypercalcaemia is also very uncommon. Our investigations suggest that the clinical picture was a reflection of PTHrP production by medulloblastoma cells.
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ABSTRACT: Human parathyroid hormone-related protein (hPTHrP), identified in patients with paraneoplastic hypercalcemia and expressed by different cell types during development and adult life, plays important roles in many human neoplasms. Immunohistochemical and RT-PCR analyses of hPTHrP and human parathyroid hormone receptor type 1 (PTHR-1) in primary medulloblastoma confirmed their expression in both classic and desmoplastic variants at RNA and protein levels. To evaluate the functional role of hPTHrP, DAOY and D283 medulloblastoma and U87MG glioma cells, expressing high levels of hPTHrP and PTHR-1, were treated with anti-sense oligonucleotides for hPTHrP. Anti-sense treatment produced in all cell lines a decrease of cell proliferation and clonogenic activity and an increase of apoptosis, while addition of exogenous hPTHrP (1-37) prevented these effects. Anti-sense induced the increase of Caspase-3, Fas (CD95) mRNAs and Bax/Bcl-2 mRNA ratio after 12 h of cell treatment. Exogenous hPTHrP (1-37) increased intracellular Ca(2+) concentration in DAOY cells as revealed by FURA. Anti-sense treated cells showed a significant decrease of steady-state levels of intracellular Ca(2+), which was reverted by addition of exogenous hPTHrP (1-37). This study indicates that hPTHrP and PTHR-1 are expressed in medulloblastoma and could promote tumor growth, protecting cells from apoptosis.Acta Neuropathologica 09/2007; 114(2):135-45. DOI:10.1007/s00401-007-0212-y · 10.76 Impact Factor
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ABSTRACT: Hypercalcaemia is a far less common finding in children than in adults. It may present with characteristic symptoms or may be identified as a coincidental finding in children investigated for a variety of complaints. Assessment of hypercalcaemia requires an understanding of the normal physiological regulation of plasma calcium by the combined actions of parathyroid hormone, 1,25-dihydroxyvitamin D(3) and the calcium sensing receptor. Hypercalcaemia will usually require treatment using a number of different modalities but occasionally it can be due to a benign asymptomatic condition that requires no intervention. This article presents a logical approach to the investigation and subsequent management of this condition.Archives of Disease in Childhood 03/2012; 97(6):533-8. DOI:10.1136/archdischild-2011-301284 · 2.90 Impact Factor