Proton Pump Inhibitor Use Is Associated with an Increased Frequency of New or Worsening Hepatic Encephalopathy after Transjugular Intrahepatic Portosystemic Shunt Creation.

PURPOSE: To determine whether proton pump inhibitor (PPI) use increases the rate of new or worsening hepatic encephalopathy (HE) after transjugular intrahepatic portosystemic shunt (TIPS) creation. MATERIALS AND METHODS: In this retrospective study, 284 of 365 patients who underwent TIPS creation from January 1, 2005, to December 31, 2016, were analyzed (186 male, mean age 56 y, range 19-84 y). Dates of PPI use and dates of new or worsening HE, defined as hospitalization or escalation in outpatient medical management, were extracted from medical records. Mixed-effects negative binomial regression was used to test for an association between PPI usage and HE. RESULTS: After TIPS creation, among 168 patients on PPIs chronically, there were 235 episodes of new or worsening HE in 106,101 person-days (0.81/person-year). Among 55 patients never on PPIs, there were 37 episodes in 31,066 person-days (0.43/person-year). Among 61 patients intermittently taking PPIs, there were 78 episodes in 37,710 person-days while on PPIs (0.75/person-year) and 25 episodes in 35,678 person-days while off PPIs (0.26/person-year). In univariate regression, PPI usage was associated with a 3.34-fold increased rate of new or worsening HE (incidence rate ratio [IRR] 3.34; P < .001). In multivariate regression, older age (IRR 1.05; P < .001), male sex (IRR 1.58; P = .023), higher Model for End-Stage Liver Disease score (IRR 1.06; P = .015), previous HE or HE-preventive medication use (IRR 1.51; P = .029), and PPI use (IRR 3.19; P < .001) were significant risk factors. Higher PPI doses were associated with higher rates of HE (IRR 1.16 per 10 mg omeprazole equivalent; P = .046). CONCLUSIONS: PPI usage is associated with increased rates of new or worsening HE after TIPS creation.

Phase 1 trial of the proteasome inhibitor bortezomib and pegylated liposomal doxorubicin in patients with advanced hematologic malignancies.

Proteasome inhibitors, a novel class of chemotherapeutic agents, enhance the antitumor efficacy of anthracyclines in vitro and in vivo. We therefore sought to determine the maximum tolerated dose (MTD) and dose-limiting toxicities of bortezomib and pegylated liposomal doxorubicin (PegLD). Bortezomib was given on days 1, 4, 8, and 11 from 0.90 to 1.50 mg/m2 and PegLD on day 4 at 30 mg/m2 to 42 patients with advanced hematologic malignancies. Grade 3 or 4 toxicities in at least 10% of patients included thrombocytopenia, lymphopenia, neutropenia, fatigue, pneumonia, peripheral neuropathy, febrile neutropenia, and diarrhea. The MTD based on cycle 1 was 1.50 and 30 mg/m2 of bortezomib and PegLD, respectively. However, due to frequent dose reductions and delays at this level, 1.30 and 30 mg/m2 are recommended for further study. Pharmacokinetic and pharmacodynamic studies did not find significant drug interactions between these agents. Antitumor activity was seen against multiple myeloma, with 8 of 22 evaluable patients having a complete response (CR) or near-CR, including several with anthracycline-refractory disease, and another 8 having partial responses (PRs). One patient with relapsed/refractory T-cell non-Hodgkin lymphoma (NHL) achieved a CR, whereas 2 patients each with acute myeloid leukemia and B-cell NHL had PRs. Bortezomib/PegLD was safely administered in this study with promising antitumor activity, supporting further testing of this regimen.

Clinical course of thrombocytopenia in patients treated with imatinib mesylate for accelerated phase chronic myelogenous leukemia.

We studied 28 patients with accelerated phase chronic myelogenous leukemia (CML) who were enrolled on the Novartis expanded access study 114. Diagnosis of accelerated phase CML was based on karyotypic evolution (n = 9) and hematologic criteria (n = 18). All patients were begun on 600 mg/day of imatinib mesylate. Dose reductions to 400 mg/day and then 300 mg/day were prescribed for an absolute neutrophil count (ANC) of <0.5/microl or a platelet count of <20,000/microl. Twenty-seven of the 28 patients continued treatment for a median of 34 weeks. Eleven patients developed thrombocytopenia following an average of 8.4 +/- 1.4 weeks of therapy. The onset of thrombocytopenia was associated with disease progression in one patient and a decline in bone marrow megakaryocytes in the other 10. Nine patients recovered to a platelet count of >20,000/microl after an average of 19.7 +/- 1.8 weeks. Patients who developed thrombocytopenia had a longer duration of disease (9.39 vs. 4.35 years; P < 0.01) and were more likely to be diagnosed with accelerated phase CML by hematologic criteria. Hematologic responses in patients with and without thrombocytopenia were comparable; however, 31.3% of patients without thrombocytopenia had a complete cytogenetic response compared to none of those with thrombocytopenia. Grade III-IV thrombocytopenia is common in accelerated phase CML and may be a marker for the inability to achieve cytogenetic response using single agent imatinib mesylate.