Real-world data on the management of pazopanib-induced liver toxicity in routine care of renal cell cancer and soft tissue sarcoma patients.

PURPOSE: Pazopanib is known to cause liver toxicity. A relationship between pazopanib exposure and alanine transaminase elevations has been described in clinical trials. This study investigated the relation between pazopanib exposure and liver toxicity in real-world patients and evaluated the management of pazopanib-induced liver toxicity in routine care. METHODS: A retrospective observational cohort study was performed in patients treated with pazopanib in whom pazopanib exposure was measured. The percentage of patients with and without liver toxicity during treatment with pazopanib was calculated as well as the average pazopanib exposure in both groups. Furthermore, the management of patients with liver toxicity was evaluated. RESULTS: Liver toxicity was observed in 25 out of the 133 patients included (19%). Pazopanib exposure was comparable in patients with or without liver toxicity (27.7 mg/L versus 28.1 mg/L). Seven patients permanently discontinued pazopanib after the occurrence of liver toxicity. Of the remaining 18 patients, continuation or restart of pazopanib after liver toxicity was successful in 16 patients and half of these patients were able to safely continue pazopanib at the same dose as prior to liver toxicity for the remaining duration of treatment. CONCLUSION: Our study did not demonstrate a clear relationship between pazopanib exposure and the occurrence of pazopanib-induced liver toxicity. Half of the patients were able to safely continue or restart pazopanib treatment after liver toxicity and received the same dose as prior to drug withdrawal. Successful interventions to address pazopanib-induced toxicity in the clinic led to an algorithm for the management of pazopanib-induced liver toxicity.

Prevention of hepatic encephalopathy by administration of rifaximin and lactulose in patients with liver cirrhosis undergoing placement of a transjugular intrahepatic portosystemic shunt (TIPS): a multicentre randomised, double blind, placebo controlled trial (PEARL trial).

INTRODUCTION: Cirrhotic patients with portal hypertension can suffer from variceal bleeding or refractory ascites and can benefit from a transjugular intrahepatic portosystemic shunt (TIPS). Post-TIPS hepatic encephalopathy (HE) is a common (20%-54%) and often severe complication. A prophylactic strategy is lacking. METHODS AND ANALYSIS: The Prevention of hepatic Encephalopathy by Administration of Rifaximin and Lactulose in patients with liver cirrhosis undergoing placement of a TIPS (PEARL) trial, is a multicentre randomised, double blind, placebo controlled trial. Patients undergoing covered TIPS placement are prescribed either rifaximin 550 mg two times per day and lactulose 25 mL two times per day (starting dose) or placebo 550 mg two times per day and lactulose 25 mL two times per day from 72 hours before and until 3 months after TIPS placement. Primary endpoint is the development of overt HE (OHE) within 3 months (according to West Haven criteria). Secondary endpoints include 90-day mortality; development of a second episode of OHE; time to development of episode(s) of OHE; development of minimal HE; molecular changes in peripheral and portal blood samples; quality of life and cost-effectiveness. The total sample size is 238 patients and recruitment period is 3 years in six hospitals in the Netherlands and one in Belgium. ETHICS AND DISSEMINATION: This study protocol was approved in the Netherlands by the Medical Research Ethics Committee of the Academic Medical Centre, Amsterdam (2018-332), in Belgium by the Ethics Committee Research UZ/KU Leuven (S62577) and competent authorities. This study will be conducted in accordance with Good Clinical Practice guidelines and the principles of the Declaration of Helsinki. Study results will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBERS: ClinicalTrials.gov (NCT04073290) and EudraCT database (2018-004323-37).

Cardiac function in relation to myocardial injury in hospitalised patients with COVID-19.

BACKGROUND: Previous studies have reported on myocardial injury in patients with coronavirus infectious disease 19 (COVID-19) defined as elevated cardiac biomarkers. Whether elevated biomarkers truly represent myocardial dysfunction is not known. The aim of this study was to explore the incidence of ventricular dysfunction and assess its relationship with biomarker analyses. METHODS: This cross-sectional study ran from April 1 to May 12, 2020, and consisted of all consecutively admitted patients to the Radboud university medical centre nursing ward for COVID-19. Laboratory assessment included high-sensitivity Troponin T and N­terminal pro-B-type natriuretic peptide (NT-proBNP). Echocardiographic evaluation focused on left and right ventricular systolic function and global longitudinal strain (GLS). RESULTS: In total, 51 patients were included, with a median age of 63 years (range 51-68 years) of whom 80% was male. Troponin T was elevated (>14 ng/l) in 47%, and a clinically relevant Troponin T elevation (10â€¯× URL) was found in three patients (6%). NT-proBNP was elevated (>300 pg/ml) in 24 patients (47%), and in four (8%) the NT-proBNP concentration was >1,000 pg/ml. Left ventricular dysfunction (ejection fraction <52% and/or GLS >-18%) was observed in 27%, while right ventricular dysfunction (TAPSE <17 mm and/or RV S' < 10 cm/s) was seen in 10%. There was no association between elevated Troponin T or NT-proBNP and left or right ventricular dysfunction. Patients with confirmed pulmonary embolism had normal right ventricular function. CONCLUSIONS: In hospitalised patients, it seems that COVID-19 predominantly affects the respiratory system, while cardiac dysfunction occurs less often. Based on a single echocardiographic evaluation, we found no relation between elevated Troponin T or NT-proBNP, and ventricular dysfunction. Echocardiography has limited value in screening for ventricular dysfunction.

Biochemical Effects on the Liver of 1 Month of Alcohol Abstinence in Moderate Alcohol Consumers.

SHORT SUMMARY: : In this study in healthy moderate alcohol consumers, we observe that one month of alcohol abstinence results in decreased gamma-glutamyl transferase levels, which return to baseline levels after resumption of alcohol consumption.

Esophagogastric junction distensibility in the management of achalasia patients: relation to treatment outcome.

BACKGROUND: Achalasia is characterized by a functional esophagogastric junction (EGJ) obstruction. The functional luminal imaging probe (EndoFLIP) is a method to assess EGJ distensibility. In a homogeneous group of newly diagnosed achalasia patients treated with pneumatic dilation (PD), we aimed (i) to determine whether the assessment of EGJ distensibility has added value in the management of achalasia patients and (ii) to evaluate whether EGJ distensibility differs between achalasia subtypes. METHODS: Twenty-six newly diagnosed achalasia patients were treated by graded PD (30 and 35 mm) separated by 1 week. EGJ distensibility was measured with the EndoFLIP technique before and after 30 mm PD. Good clinical outcome was defined as an Eckardt score <4 at 1-year follow-up. Fifteen healthy controls underwent an EndoFLIP measurement as control group. KEY RESULTS: Newly diagnosed achalasia patients had reduced EGJ distensibility compared to healthy controls (0.9 [0.7-1.5] vs 3.4 [2.7-4.2] mm(2) /mmHg, p < 0.01), and EGJ distensibility was lower in type II compared to type I patients (0.8 [0.7-1.1] vs 1.5 [0.9-1.9] mm(2) /mmHg, p = 0.02). EGJ distensibility was increased after PD from 0.9 (0.7-1.5) to 4.2 (3.0-5.7) mm(2) /mmHg (p < 0.001). No difference was found in EGJ distensibility directly after PD between patients with good and poor clinical outcome at 1-year follow-up. CONCLUSIONS & INFERENCES: Assessment of EGJ distensibility with the EndoFLIP technique is able to demonstrate the functional EGJ obstruction in newly diagnosed achalasia patients and EGJ distensibility differs between achalasia subtypes. Although PD improves EGJ distensibility, assessment of EGJ distensibility with a limited number of distension steps provides no additional information that is useful for clinical evaluation and management of achalasia patients.

Self-expandable metal stents as definitive treatment for esophageal variceal bleeding.

The use of self-expandable metal stents (SEMS) has occasionally been described for the treatment of uncontrollable esophageal variceal bleeding (EVB) as a bridge to an alternative treatment option (i. e. transjugular intrahepatic portosystemic shunt [TIPS]). It is currently not known whether SEMS placement is appropriate for more than temporary hemostasis. This case series report describes five patients in whom EVB could not be controlled with variceal band ligation and who were not suitable to undergo a TIPS procedure at the time of bleeding. SEMS were placed in these patients with the intent of definitive treatment. Successful initial hemostasis was achieved in all five patients, and sustained hemostasis occurred in four. Stents were removed from two patients after > 14 days and remained in situ until death in three other patients (range 6 - 214 days). No complications related to this longer duration were observed. In one case, TIPS could be performed at a later stage. SEMS could be a definitive treatment for uncontrollable esophageal bleeding in patients with a limited life expectancy or those unsuitable for TIPS at the time of bleeding.

Hemospray in the treatment of upper gastrointestinal hemorrhage in patients on antithrombotic therapy.

Patients on antithrombotic therapy (ATT) have the highest risk of ongoing bleeding and mortality. Hemospray (Cook Medical, Winston-Salem, North Carolina, USA) is a novel hemostatic agent for the treatment of upper gastrointestinal bleeding (UGIB). Initial reports on its use appear promising in terms of initial hemostasis and rebleeding rates. It is unknown whether this also pertains to patients on ATT. The aim of the current study therefore was to evaluate the efficacy of Hemospray in the treatment of UGIB in patients taking ATTs. A total of 16 unselected consecutive patients with UGIB who were treated with Hemospray were analyzed (eight taking ATT for various indications and eight not on ATT). Initial hemostasis was achieved after Hemospray application in 5 /8 patients on ATT (63 %) and in all eight patients not on therapy (P = 0.20). Rebleeding rates were similar in both groups. These preliminary data on the use of Hemospray in the management of UGIB are promising in both patients with and without ATT; however, caution should be exercised for its use in patients on ATT with spurting arterial bleeding.

Hepatitis B virus suppresses the functional interaction between natural killer cells and plasmacytoid dendritic cells.

Natural killer cells (NK) are one of the key players in the eradication and control of viral infections. Infections with the hepatitis B virus (HBV) may lead to persistence in a subgroup of patients, and impaired NK cell functions have been observed in these patients. Crosstalk with other immune cells has been shown to modulate the function of NK cells. We studied the functional crosstalk between NK cells and plasmacytoid dendritic cell (pDC) and its modulation by HBV. Healthy human peripheral blood-derived NK cells and pDC were purified and cocultured in the presence or absence of HepG2.2.15-derived HBV under various in vitro conditions. The functionality of NK cells was assessed by evaluation of activation markers, cytokine production and cytotoxicity of carboxyfluorescein succinimidyl ester-labelled K562 target cells by flow cytometry or immunoassays. Additionally, the crosstalk was examined using NK and pDC from patients with chronic HBV. The activation of NK cells in cocultures with pDC, as demonstrated by CD69, CD25 and HLA-DR, was not affected by the presence of HBV. Similarly, when cocultured with pDC, the cytotoxic potential of NK cells was not influenced by HBV. However, HBV significantly inhibited pDC-induced IFN-γ production by NK cells both in the presence and in the absence of CpG. As HBV did not affect cytokine-induced IFN-γ production by NK cells cultured alone, the suppressive effect of HBV on NK cell function was mediated via interference with pDC-NK cell interaction. In contrast to other viruses, HBV does not activate pDC-NK cell interaction but inhibits pDC-induced NK cell function. In parallel with NK cells of patients with chronic HBV, which show diminished cytokine production with normal cytotoxicity, HBV specifically suppressed pDC-induced IFN-γ production by NK cells without affecting their cytolytic ability. These data demonstrate that HBV modulates pDC-NK cell crosstalk, which may contribute to HBV persistence.