L-asparaginase anti-tumor activity in pancreatic cancer is dependent on its glutaminase activity and resistance is mediated by glutamine synthetase.

l-Asparaginase is a cornerstone of acute lymphoblastic leukemia (ALL) therapy since lymphoblasts lack asparagine synthetase (ASNS) and rely on extracellular asparagine availability for survival. Resistance mechanisms are associated with increased ASNS expression in ALL. However, the association between ASNS and l-Asparaginase efficacy in solid tumors remains unclear, thus limiting clinical development. Interestingly, l-Asparaginase also has a glutaminase co-activity that is crucial in pancreatic cancer where KRAS mutations activate glutamine metabolism. By developing l-Asparaginase-resistant pancreatic cancer cells and using OMICS approaches, we identified glutamine synthetase (GS) as a marker of resistance to l-Asparaginase. GS is the only enzyme able to synthesize glutamine, and its expression also correlates with l-Asparaginase efficacy in 27 human cell lines from 11 cancer indications. Finally, we further demonstrated that GS inhibition prevents cancer cell adaptation to l-Asparaginase-induced glutamine starvation. These findings could pave the way to the development of promising drug combinations to overcome l-Asparaginase resistance.

Hypocalcaemia after total thyroidectomy: incidence, control and treatment.

INTRODUCTION: Hypocalcaemia, although usually transitory, is the most frequent complication after total thyroidectomy. OBJECTIVE: To identify factors associated with a higher risk of hypoparathyroidism and related to aetiology and surgical procedure. MATERIALS AND METHODS: A total of 254 total thyroidectomies were analysed for the incidence of transitory or permanent hypocalcaemia based on the relationship with etiological and surgical factors. RESULTS: Transient hypocalcaemia was present in 29.1% of the cases and permanent hypocalcemia was present in 4.7%. Postoperative hypocalcaemia was lower in patients with completion thyroidectomy than in patients that underwent total thyroidectomy in a single operation, 12% vs. 31%. Patients with Graves-Basedow disease developed postoperative hypocalcaemia in 50% of the cases. Mean recovery time of parathyroid function was 5.2 months, with 72.2% of the patients recovering before 6 months. CONCLUSIONS: Postoperative hypocalcaemia is a frequent complication of total thyroidectomy, but it is seldom permanent. Patients with Graves-Basedow disease have a higher incidence of postoperative hypocalcaemia and need closer follow-up. Postoperative calcium level analysis at 24 and 48 h after surgery is not useful for rapid identification of patients at high risk of hypocalcaemia.