Endocrine disorders among long-term survivors of childhood head and neck rhabdomyosarcoma.

PURPOSE: Head and neck rhabdomyosarcoma (HNRMS) survivors are at increased risk of developing pituitary dysfunction as an adverse event of radiotherapy. Our aim was to investigate the frequency and risk factors for pituitary dysfunction in these survivors. Secondly, we aimed to compare the prevalence of pituitary dysfunction between survivors treated with external beam radiation therapy (EBRT) and survivors treated with the ablative surgery, moulage technique after loading brachytherapy, and surgical reconstruction (AMORE) procedure. METHODS: Eighty HNRMS survivors treated in London (EBRT based) and Amsterdam (AMORE based: AMORE if feasible, otherwise EBRT) in the period 1990-2010 and alive ≥ 2 years post-treatment were evaluated. Survivors were evaluated in multidisciplinary late-effects clinics, with measurement of linear growth, determination of thyroid function, and growth hormone parameters. Additional data, such as baseline characteristics, anthropometrics, pubertal stage, and the results of additional laboratory investigations, were retrieved from patient charts. RESULTS: Pituitary dysfunction was diagnosed in 24 in 80 (30%) survivors, after a median follow-up time of 11 years. Median time to develop pituitary dysfunction after HNRMS diagnosis was 3.0 years. Risk factors were EBRT-based therapy (odds ratio [OR] 2.06; 95% confidence interval [CI] 1.79-2.46), parameningeal tumour site (OR 1.83; 95% CI 1.60-2.17) and embryonal RMS histology (OR 1.49; 95% CI 1.19-1.90). CONCLUSIONS: Radiotherapy used for the treatment of HNRMS confers a significant risk of the development of pituitary dysfunction. AMORE-based treatment in children with HNRMS resulted in less pituitary dysfunction than treatment with conventional EBRT. Our findings underscore the importance of routine early endocrine follow-up in this specific population.

Enhancement of the inhibitory action of APD on the transformation of osteoclast precursors into resorbing cells after dimethylation of the amino group.

The amino-bisphosphonate APD is distinct from the bisphosphonates EHDP and Cl2MDP by a greater molar potency in vivo as inhibitor of osteoclastic bone resorption and in vitro by a pronounced inhibitory effect on the accession of osteoclast precursors to mineralized matrix. Dimethylation of the aminogroup, which increases the basic properties of this residue but precludes others, like the liability to glucuronidation or acetylation, increased the in vivo potency of this amino bisphosphonate, as well as its in vitro specificity for osteoclast-precursor accession, but decreased its cellular toxicity. The in vitro actions of dimethyl-APD were reversible with administration of PTH. It is concluded that the introduction of a basic residue in bisphosphonates may increase affinity for the specific sites on the mineralized matrix that are involved in directing the accession of precursors and their transformation into actively resorbing osteoclasts.

Two modes of action of bisphosphonates on osteoclastic resorption of mineralized matrix.

Pretreatment of a long bone explant with P-C-P can prevent the osteoclastic resorption of its mineralized matrix, when it is entirely dependent upon activation and accession of extra-osseous osteoclast precursors. When treatment of the explant is postponed until after the development of mature osteoclasts, the P-C-P dose required for an inhibitory effect is increased 100-fold for the amino bisphosphonate APD, but not for EHDP and Cl2MDP. It is concluded that high doses of all P-C-Ps inhibit the resorbing osteoclast, but that low dose of the amino P-C-P can specifically inhibit the accession of osteoclast precursors to mineralized matrix. Both actions require P-C-P binding to the mineral. The relative potencies of the P-C-Ps in the precursor-dependent system correspond to their relative potencies in vivo. This suggests that inhibition of accession underlies the high potency which the aminobisphosphonate has in vivo.

Apposition and resorption of bone during oral treatment with (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate (APD).

The effects of 1.5-2 years oral administration of disodium (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate (APD) on bone metabolism were studied in male and female rats. APD was mixed in the food at levels of 500, 2,000 and 10,000 ppm. A dose-dependent increase in metaphyseal bone was found, indicative of continued inhibition of bone and cartilage resorption. APD did not affect mineralization of bone and cartilage, primary bone formation, or periosteal apposition. A short-term metabolic balance study was performed to compare the effects of oral with subcutaneous APD. Absorption of APD was in the order of 0.2%. Oral APD increased absorption of phosphate, probably by complexation of calcium with APD. The excess absorbed phosphate increased phosphaturia and decreased urinary calcium.