Objective: Congenital hyperinsulinism is the most common cause of persistent hypoglycemia in infancy (HI), leading to severe neurologic disabilities if not promptly treated. The recent application of positron emission tomography (PET)/computed tomography (CT) scanning with 18-fluoro-L-3,4 dihydroxyphenylalanine improved the ability to distinguish the two histopathologic forms of HI (focal and diffuse), whose differentiation heavily influences the therapeutic management of the patient. Case report: We describe the case of a patient presenting with severe hypoglycemia from infancy. High concentration of insulin suggested the diagnosis of congenital hyperinsulinism. No metabolic disorders related to amino acid, organic acids or fatty acid oxidation were detected. Medical treatment was able to obtain a satisfactory metabolic response. Results: The patient underwent PET/CT scanning, revealing a diffuse form of the disease. The absence of mutations in KCNJ11 and ABCC8 genes (responsible for 50% of HI cases), and whole genome single nucleotide polymorphisms analysis by microarray suggested the HADH gene as a likely candidate. Sequence analysis revealed a novel homozygous nonsense mutation (R236X) in HADH gene. Conclusions: This case indicates that mutations of the HADH gene should be sought in hyperinsulinemic patients in whom diffuse form of HI and autosomal recessive inheritance can be presumed when KCNJ11 and ABCC8 genes mutational screening is negative, even in the absence of altered organic acids and acylcarnitines concentration.
Background:Nab-paclitaxel–gemcitabine combination significantly improved overall survival over gemcitabine in metastatic pancreatic adenocarcinoma. A phase 1b trial was performed (ClinicalTrials.gov number, NCT01730222) to determine the recommended phase 2 dose (RP2D) of nab-paclitaxel in combination with cisplatin, capecitabine, and gemcitabine at fixed dose (800, 30, and 1250 mg m−2 every 2 weeks, respectively; PAXG regimen).Methods:Nab-paclitaxel doses were escalated from 100 (level one) to 125 (level two) and 150 mg m−2 (level three) every 2 weeks in cohorts of 3–6 patients with pathologically confirmed unresectable or borderline resectable pancreatic adenocarcinoma.Results:Between Dec 2012 and Apr 2014, 24 patients were enroled (3 at level one, 5 at level two, 16 at level three) and received 117 cycles of PAXG. No dose-limiting toxicity occurred and level three was the RP2D. At this dose, nab-paclitaxel dose-intensity was 91%. Worse per patient grade 3/4 toxicity were neutropenia 25/31% fatigue 19% anaemia and hand-foot syndrome 12%, nausea 6%, and febrile neutropenia 6%. A partial response (PR) was observed in 16 (67%) and stable disease (SD) in 8 patients (33%). Among 21 patients with a baseline positive positron emission tomography (PET) scan, a complete metabolic response was observed in 9 (43%), PR in 10 (48%), SD in 2. CA19-9 decreased by ⩾49% in all the 19 patients with elevated basal value. Six patients were resected after chemotherapy. Progression-free survival at 6 months (PFS-6) was 96%.Conclusions:The RP2D of nab-paclitaxel in the PAXG regimen was 150 mg m−2 every 2 weeks. The preliminary results are promising and warrant further exploration.
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