How and when to use temozolomide to treat aggressive pituitary tumours.

Temozolomide is an oral chemotherapy used to treat aggressive pituitary tumours since 2006. It is inexpensive and well tolerated, the main side effects are fatigue, nausea and cytopenia. Overall the studies demonstrate approximately 70% response rate for temozolomide, if response is defined radiologically as complete, partial response or stable disease. Using the more stringent criteria of complete or partial response, the success rate is near 40%. Functioning tumours respond more frequently than non-functioning tumours. Tumours which are depleted of methyl guanine methyltransferase (MGMT), as assessed by immunohistochemistry, also are more likely to respond. Temozolomide has an established role in treating pituitary tumours which have demonstrated metastases or which are refractory and progressing, despite all conventional treatment (so-called salvage treatment). The challenge is to offer temozolomide earlier in the pathway if appropriate. Tumours which demonstrate aggressive clinical behaviour (defined as clinically relevant growth despite optimal treatment) should be considered for temozolomide. One common situation when this might occur is tumour progression after surgery and radiotherapy. It is unnecessary to wait until salvage treatment is required. Anticipated (but not yet demonstrated) aggressive behaviour can be regarded as a potential indication for temozolomide, but there is currently insufficient evidence to recommend this. Ideally a trial should assess this potential indication. Early treatment could be considered in selected cases when high levels of proliferation and invasion were demonstrated, causing significant clinical concern.

GLP-1 and glucagon secretion from a pancreatic neuroendocrine tumor causing diabetes and hyperinsulinemic hypoglycemia.

CONTEXT: Glucagon-like peptide-1 (GLP-1) is a gut peptide that promotes insulin release from pancreatic ß-cells and stimulates ß-cell hyperplasia. GLP-1 secretion causing hypoglycemia has been described once from an ovarian neuroendocrine tumor (NET) but has not been reported from a pancreatic NET (pNET). OBJECTIVE: A 56-yr-old male with a previous diagnosis of diabetes presented with fasting hypoglycemia and was found to have a metastatic pNET secreting glucagon. Neither the primary tumor nor metastases stained for insulin, whereas the resected normal pancreas showed histological evidence of islet cell hyperplasia. We provide evidence that GLP-1 secretion from the tumor was the cause of hyperinsulinemic hypoglycemia. METHODS: GLP-1 levels were determined in the patient, and immunohistochemistry for GLP-1 was performed on the tumor metastases. Ex vivo tissue culture and a bioassay constructed by transplantation of tumor into nude mice were performed to examine the tumor secretory products and their effects on islet cell function. RESULTS: The patient had high levels of glucagon and GLP-1 with an exaggerated GLP-1 response to oral glucose. Immunohistochemistry and primary tissue culture demonstrated secretion of glucagon and GLP-1 from the tumor metastases, whereas insulin secretion was almost undetectable. Ex vivo coculture of the tumor with normal human islets resulted in inhibition of insulin release, and transplanted mice developed impaired glucose tolerance. CONCLUSIONS: This is the first description of glucagon and GLP-1 secretion from a metastatic pNET causing sequential diabetes and hypoglycemia. Hypoglycemia was caused by insulin secretion from hyperplastic ß-cells stimulated by tumor-derived GLP-1.