Background: Hypothalamic obesity has major impact on prognosis and quality of life (QoL) in childhood craniopharyngioma. Patients and methods: For this study, 120 patients were prospectively recruited during 2001 and 2007 and evaluated after 3 years of follow-up (KRANIOPHARYNGEOM 2000). Body mass index (BMI) and QoL at diagnosis and 36 months after diagnosis were analysed based on the reference assessment of tumour localisation and post-surgical hypothalamic lesions. Treatment was analysed based on the neurosurgical strategy of 50 participating neurosurgical centres, the centre size based on the patient load. Results: BMI SDS at diagnosis was similar in patients with or without hypothalamic involvement. Surgical lesions of anterior and posterior hypothalamic areas were associated with higher increase in BMI SDS during 36 months post-diagnosis compared with patients without or only anterior lesion (C1.8 BMISD, PZ0.033, C2.1 BMISD; PZ0.011), negative impact on QoL in patients with posterior hypothalamic lesions. Surgical strategies varied among the 50 neurosurgical centres (three largesized, 24 middle-sized and 23 small-sized centres). Patients treated in small-sized centres presented with a higher rate of hypothalamic involvement compared with those treated in the middle-and largesized centres. Treatment in large-sized centres was less radical, and the rates of complete resection and hypothalamic surgical lesions were lower in large-sized centres than those of the middle-and smallsized centres. However, a multivariable analysis showed that pre-operative hypothalamic involvement was the only independent risk factor for severe obesity (PZ0.002). Conclusions: Radical neurosurgical strategies leading to posterior hypothalamic lesions are not recommended due to the potential to exacerbate hypothalamic obesity and impaired QoL. Treatment should be confined to experienced multidisciplinary teams.

This report is a review of findings on the diagnosis, treatment, clinical course, and prognosis of craniopharyngioma patients. Craniopharyngiomas are rare, partly cystic and calcified embryonic malformations of the sellar/parasellar region with low histological grade (WHO I°). A bimodal age distribution has been shown, with peak incidence rates in childhood-onset at 5-14 years and adult-onset craniopharyngioma at 50-74 years. Clinical manifestations are related to hypothalamic/pituitary deficiencies, visual impairment, and increased intracranial pressure. If the tumor is favorably localized, the therapy of choice is complete resection, with care taken to preserve optical and hypothalamic functions. In patients with unfavorable tumor localization (i.e., hypothalamic involvement), recommended therapy is a limited hypothalamus-sparing surgical strategy followed by local irradiation. Although overall survival rates are high (92%), recurrences and progressions are frequent. Irradiation has proven effective in reducing recurrences and progression, and timing of postsurgical irradiation in childhood-onset cases is currently under investigation in a randomized multinational trial (KRANIOPHARYNGEOM 2007). Anatomical involvement and/or surgical lesions of posterior hypothalamic areas can result in serious quality of life-compromising sequelae such as hypothalamic obesity, psychopathological symptoms, and/or cognitive problems. It is crucial that craniopharyngioma be managed as a frequently chronic disease, providing ongoing care of pediatric and adult patients' clinical and quality of life consequences by experienced multidisciplinary teams.

Hypothalamic tumor involvement and familial disposition for obesity are risk factors for the development of severe obesity in patients with craniopharyngioma. As weight gain starts early after diagnosis and severe obesity causes a reduction in QoL, early therapeutic efforts should be considered in patients at risk. To confirm our results the prospective multicenter study Kraniopharyngeom 2000 on children and adolescents with craniopharyngioma was initiated (www.kraniopharyngeom.com).

We analyzed whether childhood craniopharyngioma predisposes to obesity and growth impairment. Height/length, body mass index (BMI), and hypothalamic involvement were evaluated in 90 patients at standardized ages and time points before, after, and at the time of diagnosis. Relevant decreases in height sd score (SDS) started at 10-12 months of age and persisted until diagnosis of childhood craniopharyngioma. Relevant increases in BMI SDS were detectable between 4 and 5 yr of age. Postoperative BMI SDS (yr 1-6) had a weak positive correlation with BMI SDS at the time of diagnosis. In linear regression analysis, hypothalamic tumor involvement (P < 0.001), ponderal index at birth (P = 0.014), and BMI SDS at age 6-7 months (P = 0.029) and at age 5 yr (P < 0.001) had relevant and independent impacts on the development of obesity. Patients with hypothalamic involvement (n = 48) presented lower ponderal index and BMI SDS at birth and higher BMI SDS at the time of diagnosis (P < 0.001) as well as during annual follow-up (P < 0.001) compared with patients without hypothalamic involvement (n = 42). From childhood (3.5-4 yr) to the time of diagnosis, growth rates were reduced for patients with hypothalamic tumor involvement. Patients without hypothalamic involvement presented reduced growth rates in early infancy (age 10-12 months) that persisted until diagnosis. We conclude that reduced growth rates occur quite early in history; BMI SDS increases occur later and are predictive of obesity. Hypothalamic involvement is the major risk factor for obesity in patients with childhood craniopharyngioma.

Patients with childhood-onset craniopharyngioma (CP) often suffer from obesity. We evaluated two important etiological factors of obesity development, energy intake and physical activity. Energy intake was supposed to be high due to a disturbed hypothalamic regulation of appetite. We used a validated nutritional diary to determine the 1-wk food intake in 27 CP patients (12 with intrasellar tumors and 15 with hypothalamic tumors) and 1027 controls who were a representative sample of the 7- to 16-yr-old German population. In 2 accelerometry settings, we determined movement counts indicating physical activity. Nineteen CP patients were comparable to 26 controls for age and body mass index. One setting was a clinical one during weight reduction; the other was an out-patient setting. Daily energy intake was 1916 +/- 677 kcal (mean +/- SD) in intrasellar CP patients, 2075 +/- 877 kcal in hypothalamic CP patients, and 2476 +/- 815 kcal in non-CP controls. Patients suffering from CP showed fewer movement registrations [clinical setting, 228 vs. 298 cpm for obese controls (P = 0.01); out-patient setting, 228 vs. 282 cpm for controls (P = 0.08)]. Differences were most pronounced during leisure time (382 cpm in CP patients vs. 546 cpm in obese controls; P = 0.002; clinical setting). Our findings suggest that reduced physical activity, rather than increased energy intake, in CP patients is responsible for the obesity development noted in these subjects.

Most estrogen receptor-negative breast cancer cells, including Hs578T cells, express mRNAs encoding insulin-like growth factor-binding protein (IGFBP)-3, as well as transforming growth factor (TGF)-beta receptors. Our previous studies (Oh, Y., Muller, H. L., Lamson, G., and Rosenfeld, R. G. (1993) J. Biol. Chem. 268, 14964-14971; Oh, Y., Muller, H. L., Pham, H. M., and Rosenfeld, R. G. (1993) J. Biol. Chem. 268, 26045-26048) have demonstrated a significant inhibitory effect of exogenous IGFBP-3 on Hs578T cell growth and existence of IGFBP-3-specific receptors that may mediate those direct inhibitory effect of IGFBP-3. TGF-beta is also a potent growth inhibitor in human breast cancer cells in vitro and regulates IGFBP-3 production in different cell systems, suggesting that IGFBP-3 is a major anti-proliferative factor and a key element for TGF-beta-induced growth inhibition in human breast cancer cells. In support of this hypothesis, we have demonstrated using Hs578T cells that: 1) TGF-beta stimulates IGFBP-3 gene expression and production prior to its inhibition of cell growth, 2) treatment with an IGFBP-3 antisense oligodeoxynucleotide selectively inhibits TGF-beta-induced IGFBP-3 synthesis and cell growth inhibition, and 3) treatment with IGF-II and IGF-II analogs diminish TGF-beta effects by blocking TGF-beta-induced binding of IGFBP-3 to the cell surface. These findings suggest that IGFBP-3 is a major anti-proliferative factor and a key element in TGF-beta-induced growth inhibition in human breast cancer cells.

Total resection is the treatment of choice in patients with favorable tumor localization, with extreme care taken to preserve hypothalamic-pituitary and optical nerve functions. When tumor localization is unfavorable, i.e. involvement of hypothalamic or optic structures, a limited resection followed by local irradiation is recommended. Optimal timing of recurrence-inhibiting irradiation after incomplete resection is currently under investigation in an international trial. The rarity of the disease, coupled with limited surgical options, dictates that treatment and long-term monitoring of consequences should be confined to experienced multidisciplinary teams.

OS and QoL are impaired by HI in long-term survivors of CP. HI is associated with severe obesity, which plateaus after 12 years. OS/PFS are not related to degree of resection, but gross-total resection should be avoided in cases of HI to prevent further hypothalamic damage, which exacerbates sequelae.