Phase I study of panobinostat and imatinib in patients with treatment-refractory metastatic gastrointestinal stromal tumors.

BACKGROUND: Panobinostat, a pan-deacetylase inhibitor, overcomes imatinib resistance in preclinical models of gastrointestinal stromal tumours (GIST). Here we determined the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of panobinostat in combination with imatinib (IM) for treatment of patients with refractory GIST. METHODS: Following a 7-day run-in phase of IM (400 mg per day), escalating doses of panobinostat were added following a '3 plus 3' design. Twelve heavily pretreated GIST patients were enrolled in two dose levels. RESULTS: Most common adverse events were thrombocytopenia, anaemia, fatigue, creatinine elevation, nausea, emesis and diarrhoea. Twenty micrograms of panobinostat and 400 mg IM were declared the MTD. Pharmacologically active concentrations of panobinostat and IM were achieved as evidenced by histone H3 acetylation in blood mononuclear cells in vivo and inhibition of the IM-resistant KIT (D816) mutation in vitro. In FDG-PET-CT scans after IM run-in and following 3 weeks panobinostat treatment, 1 out of 11 evaluable patients showed a metabolic partial response, 7 patients were metabolically stable and 3 patients progressed. Longest treatment duration was 17 weeks (median 6). CONCLUSION: Panobinostat and IM can be administered at doses achieving target inhibition in vivo. Further clinical exploration of patients with treatment-refractory GIST is warranted. Correlative studies in this trial may help to optimise dosing schedules in GIST.

[Gastrointestinal stromal tumour (GIST): current standards in multimodal management]. / Gastrointestinaler Stromatumor (GIST): Aktueller Stand der multimodalen Therapie.

Gastrointestinal stromal tumours (GIST) are the most frequent mesenchymal tumours of the gastrointestinal tract. The gold standard therapy is their complete surgical removal with safety margins of 1-2 cm. Intraoperative damage to the tumour must be avoided because tumour rupture carries a very high risk of peritoneal spread. Since metastases to lymph nodes in general does not occur in GIST a lymph node dissection is not indicated. Depending on the size of the tumour, the number of mitoses and the localisation of the primary tumour, the risk of recurrence after potentially curative resection is considerable in many cases. Patients with intermediate and high risk according to Miettinens classification should receive adjuvant treatment with imatinib. Exceptions are those patients whose tumours exhibit a mutation in exon 18, D842V of PDGFRA. According to current data the therapy is continued for 3 years. This leads not only to a significant improvement of the progression-free survival in comparison to therapy for 1 year but also, especially, to an improvement of overall survivial. In the case of local advanced tumours that can only be resected by a mutilation operation, a primary systemic therapy with imatinib should be initiated on account of its extremely high efficacy. Standard therapy for local advanced or metastasizing GIST is imatinib at a dose of 400 mg/day. Patients with mutations in KIT exon 9 should be treated with 800 mg imatinib/day, since they profit from a significantly longer progression-free survival. Therapy with imatinib should always be continued up to progression or intolerance. In the case of progression under 400 mg imatinib the ESMO guidelines recommend a dose increase to 800 mg/day as about a third of the patients respond to this higher dose. In the case of further progression a switch to second-line therapy with sunitinib is recommended. After exploitation of all registered therapy options the patients should be offered an experimental therapy within the framework of a clinical trial.

Functional differentiation of the pituitary gland during development of the domestic ring dove (Streptopelia roseogrisea).

The development and differentiation of the anterior pituitary gland was studied in the domestic ring dove (Streptopelia roseogrisea) and compared with the pattern of body growth. By combining histochemical staining techniques with immunohistochemical methods, cells producing prolactin (PRL), growth hormone (GH), thyrotropic hormone (TSH), and adrenocorticotropic hormone were identified in the pituitary of the developing ring dove. The distribution of the four cell types within the anterior pituitary was illustrated by three-dimensional reconstruction from immunohistochemically stained serial sections. The pattern, which was shown to change through embryonic and juvenile development, was described and compared with examples from other vertebrate classes. The analysis of body growth showed that the development of the nestlings could be divided into two distinct growth phases. The first seven days were characterized by a consistently high rate of body growth, whereas after Day seven the growth rate was markedly reduced. Although GH-immunoreactive cells formed the dominant cell type in the pituitary during the whole postembryonic development, there was no correlation between the rate of body growth and the abundance of GH-immunoreactive cells in the pituitary. In contrast, changes in the abundance of PRL- and TSH-immunoreactive cells were observed simultaneously with the transition from the first to the second growth phase. The proportion of PRL-immunoreactive cells was relatively high during the first seven days, whereas TSH-immunoreactive cells became more abundant during the second growth phase. It is therefore postulated that PRL and TSH play an important role in the regulation of the growth pattern in the ring dove.