4090 Background: Evidence suggests that hyperactivated fibroblast growth factor 4 (FGFR4) signaling pathway leads to enhanced tumor growth. Targeting FGFR4 may have therapeutic benefit in tumors with altered FGF19 signaling. A phase I study (NCT02834780) was undertaken to assess H3B-6527, a highly selective covalent FGFR4 inhibitor, in patients with HCC/ICC. Methods: Adults with advanced HCC/ICC, ECOG PS 0-1, well compensated liver function, who progressed after > one prior therapy, received H3B-6527 po daily (QD) or twice-daily (bid) on a 21-day cycle following a 3+3 design. Doses ranged from 300-2000mg QD or 500-700mg BID. Patients in dose escalation were treated regardless of FGF19 status. Patients in expansion had FGF19+ tumors by mRNA testing. Adverse events (AEs), and pharmacokinetics (PK) were assessed. Response was determined by RECIST 1.1/mRECIST imaging every 6 weeks. Results: Study enrollment is complete at 128 patients. Ninety HCC patients were treated (QD = 48, bid = 42). ICC enrollment was suspended after 38 patients due to limited efficacy. No dose-limiting toxicities were seen and no grade 4-5 treatment related AEs have been observed. Recommended Phase II dose for H3B-6527 is 1000mg QD based upon safety, efficacy, and PK data. Grade 3 TEAEs have occurred in 12.5% of patients on QD dosing. Treatment related TEAEs were seen in 62.5% of patients on the QD schedule, with diarrhea (45.8%), fatigue (12.5%), and nausea (12.5%) most frequent. Drug discontinuation due to AEs for QD dosing was 8.3%. Interim data analysis shows that, for HCC patients with >2 prior lines of therapy treated on QD schedule, overall survival was 10.6m, progression-free survival 4.1m, overall response rate 16.7% (all partial responses), and clinical benefit rate 45.8% (responders + durable stable disease >17 weeks). H3B-6527 Cmax and AUC were lower at 300 mg dose but then similar across 500–2000 mg doses. Following oral administration of 1000 mg fasted, H3B-6527 plasma concentration reached peak at a Tmax of ̃2-3 hours and then decayed exponentially, with terminal half-life of ̃4-5 hours. There was no accumulation following QD dose. Dosing with food did not meaningfully change H3B-6527 plasma exposure. Conclusions: H3B-6527 was well tolerated and demonstrated a favorable toxicity and safety profile and encouraging clinical activity in heavily pretreated HCC patients. Final trial results will be presented at conference. Clinical trial information: NCT02834780.

Delirium, a mental disorder that becomes established over a few hours or days, is characterised by fluctuating attention and cognitive states. This article reviews the disorder, which has all the features of an important geriatric syndrome: it appears mainly in persons older than 65 years of age, is closely linked with very prevalent diseases and complications arising in the elderly, and is the mode of presentation of many other diseases in this age group. We discuss diagnostic, clinical preventive and therapeutic aspects and analyse the most common risk and precipitating factors in our hospitalised patients from the viewpoint of clinical practice. Finally, we propose a scheme for the prevention and treatment of delirium.

Bone metastasis infrequently appears as the first manifestation of hepatocellular calcinoma (HCC), and in any case in most patients the primary tumour is detected a few months after its development. We report the case of a patient with alcoholic liver disease, increased levels of alpha-fetoprotein, and no evidence of hepatic lesion in the different imaging modalities, in whom metastasis of HCC was detected in the ribs, whereas the primary tumour was not diagnosed until 15 months later. We believe that all patients with increased levels of alpha-fetoprotein should be tested in an intensified search for HCC and possible metastases, given that hepatic lesions may not be detected until many months alter the diagnosis of metastatic disease.

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