Contemporary Biological Insights and Clinical Management of Craniopharyngioma.

Craniopharyngiomas (CPs) are clinically aggressive tumors because of their invasive behavior and recalcitrant tendency to recur after therapy. There are 2 types based on their distinct histology and molecular features: the papillary craniopharyngioma (PCP), which is associated with BRAF-V600E mutations and the adamantinomatous craniopharyngioma (ACP), characterized by mutations in CTNNB1 (encoding ß-catenin). Patients with craniopharyngioma show symptoms linked to the location of the tumor close to the optic pathways, hypothalamus, and pituitary gland, such as increased intracranial pressure, endocrine deficiencies, and visual defects. Treatment is not specific and mostly noncurative, and frequently includes surgery, which may achieve gross total or partial resection, followed by radiotherapy. In cystic tumors, frequent drainage is often required and intracystic instillation of drugs has been used to help manage cyst refilling. More recently targeted therapies have been used, particularly in PCP, but also now in ACP and clinical trials are underway or in development. Although patient survival is high, the consequences of the tumor and its treatment can lead to severe comorbidities resulting in poor quality of life, in particular for those patients who bear tumors with hypothalamic involvement. Accordingly, in these patients at risk for the development of a hypothalamic syndrome, hypothalamus-sparing treatment strategies such as limited resection followed by irradiation are recommended. In this review, we provide an update on various aspects of CP, with emphasis on recent advances in the understanding of tumor pathogenesis, clinical consequences, management, and therapies.

Could setmelanotide be the game-changer for acquired hypothalamic obesity?

Children with acquired hypothalamic obesity, e.g. following treatment for pediatric craniopharyngioma are at great risk for metabolic syndrome, cardiovascular health problems and premature mortality. Treatment for acquired hypothalamic obesity has thus far been disappointing. Several interventions were reported to be partially successful, including dextro-amphetamine and GLP-1R agonists, although results in acquired hypothalamic obesity are conflicting. Disruption of signaling through the melanocortin-4 receptor (MC4R) pathway results in hyperphagia and severe early-onset hypothalamic obesity. Recently, the MC4R agonist setmelanotide has shown promising results in children with genetic forms of hypothalamic obesity; POMC, PCSK1 and LEPR. Patient quotes such as "we have our family life back" illustrate the magnitude of the effect. Targeted hormone replacement therapy with a MC4R agonist for acquired hypothalamic obesity could be a game-changer. Preliminary results of setmelanotide treatment in 14, mostly pediatric, patients with acquired hypothalamic obesity are promising. The FDA has recommended that a prospective, randomized, blinded trial be conducted over a 12 months treatment period, comparable to pivotal trials for other obesity drugs. It may be discussed whether setmelanotide should be regarded as an obesity drug or whether it may be envisioned as an agent for hypothalamic substitution therapy. In this commentary we discuss the trial that is currently recruiting patients with acquired hypothalamic obesity.

The Postopera tive Quality of Life in Children and Adolescents with Craniopharyngioma.

BACKGROUND: Craniopharyngioma is a tumor of low histological malignancy resulting from an anomaly of embryonic development. Affected children and adolescents are being studied with respect to their quality of life, progression-free survival, and overall survival in the framework of the ongoing KRANIOPHARYNGEOM 2007 project. METHODS: This prospective, multicenter project consists of a randomized trial with an adaptive design combined with a purely observational study. The randomized, unblinded trial includes patients whose tumors have been incompletely resected and is intended to compare the outcomes of immediate postoperative radiotherapy versus radiotherapy on progression. Its primary endpoint is quality of life as assessed subjectively by the patients them- selves with the "Pediatric Quality of Life" questionnaire (PEDQOL). In exploratory analyses, linear mixed models were used to study the effect of further factors on quality of life. RESULTS: An interim intention-to-treat analysis of the randomized trial revealed only minor differences between the treatment arms with respect to quality of life (n = 24). The exploratory analyses (n = 131) showed that preoperative involvement of, or operative damage to, the anterior and posterior regions of the hypothalamus was associated with a lower quality of life. Complete resection was followed by a lower quality of life than incomplete resection. Radiotherapy, a common treatment for tumors that progress after incomplete resection, was also associated with a lower quality of life. CONCLUSION: Hypothalamus-sparing treatment approaches are recommended to optimize the quality of life of children and adolescents with cranio- pharyngioma. The available evidence does not support any recommendation as to when radiotherapy should be performed after incomplete resection so that the best quality of life can be achieved.

Surgical strategies in childhood craniopharyngioma.

Craniopharyngiomas are biologically benign lesions (WHO Grade 1) of the sellar and suprasellar region, associated with a serious morbidity. About 50% of these tumors become clinically apparent during childhood. Clinical symptoms include headaches, chiasm syndrome, hydrocephalus, pituitary insufficiencies, and obesity. Growth arrest is a typical symptom in children. The treatment of craniopharyngiomas includes surgery as well as radiotherapy. The goal of surgery varies according to the tumor location and extension and may range from complete resection to biopsy. Surgical complications are well known and cause constant evaluation of surgical strategies. Diencephalic obesity is related to surgical manipulation of hypothalamic tissue. Therefore, a classification system for craniopharyngiomas based on preoperative MRI is suggested by the authors. Recurrences are frequent in craniopharyngiomas, even after complete or gross-total resection. Radiotherapy is therefore recommended to patients with incomplete resections. However, the ideal time for radiotherapy after surgery is under discussion. The treatment of craniopharyngiomas requires an interdisciplinary and multimodal approach. Each patient should receive an individually tailored treatment. Surgically, different approaches as well as different degrees of resection can be considered, depending on tumor location and tumor extension.