Evaluation of ear, nose, and throat-screening in liver transplantation candidates:A retrospective cohort study

Background:Patients with end-stage liver disease can be treated with a liver transplantation (LT). Before listing, candidates are subjected to a screening procedure according to the EASL Clinical Practice Guidelines for LT. In our hospital, this includes an ear, nose, and throat (ENT) examination, directed towards the identification of (asymptomatic) infections and head and neck malignancies.Methods:We retrospectively reviewed all ENT screening examinations in LT candidates from 2007 to 2022. The screening consisted of a visit to the ENT outpatient clinic combined with sinus radiography.Results:ENT screening was performed in 1099 patients. Sixty-one cases were identified, either diagnosed with an infection (n = 58, almost exclusively sinusitis) or a neoplasm (n = 3, of which two malignancies). With binary logistic regression, we could not identify significant risk factors for diagnosing sinusitis. 711 patients underwent LT. After LT, two patients developed a novel malignancy of the head and neck area, while 14 patients were diagnosed with sinusitis, two of the latter already showed opacification on sinus radiography during screening. Despite immunosuppressive drugs, no complicated sinusitis was observed.Conclusion:Sinusitis or a neoplasm was diagnosed in almost 6% in a large cohort of LT candidates. Although almost a third of sinusitis patients were not treated accordingly, we did not observe any complicated sinusitis after LT. A more conservative approach to sinusitis may therefore be justified in LT candidates, especially in asymptomatic cases. At our institution, we aim to refer only those patients with specific ENT complaintsimage.This study aimed to evaluate the outcome of routine ear, nose, and throat screening in a large cohort of liver transplantation candidates. Note that, 6% were diagnosed with either sinusitis or a neoplasm. We did not observe any complicated sinusitis after transplantation. A more conservative approach may therefore be justified, especially in asymptomatic cases.imag

Evaluation of ear, nose, and throat-screening in liver transplantation candidates:A retrospective cohort study

Background:Patients with end-stage liver disease can be treated with a liver transplantation (LT). Before listing, candidates are subjected to a screening procedure according to the EASL Clinical Practice Guidelines for LT. In our hospital, this includes an ear, nose, and throat (ENT) examination, directed towards the identification of (asymptomatic) infections and head and neck malignancies.Methods:We retrospectively reviewed all ENT screening examinations in LT candidates from 2007 to 2022. The screening consisted of a visit to the ENT outpatient clinic combined with sinus radiography.Results:ENT screening was performed in 1099 patients. Sixty-one cases were identified, either diagnosed with an infection (n = 58, almost exclusively sinusitis) or a neoplasm (n = 3, of which two malignancies). With binary logistic regression, we could not identify significant risk factors for diagnosing sinusitis. 711 patients underwent LT. After LT, two patients developed a novel malignancy of the head and neck area, while 14 patients were diagnosed with sinusitis, two of the latter already showed opacification on sinus radiography during screening. Despite immunosuppressive drugs, no complicated sinusitis was observed.Conclusion:Sinusitis or a neoplasm was diagnosed in almost 6% in a large cohort of LT candidates. Although almost a third of sinusitis patients were not treated accordingly, we did not observe any complicated sinusitis after LT. A more conservative approach to sinusitis may therefore be justified in LT candidates, especially in asymptomatic cases. At our institution, we aim to refer only those patients with specific ENT complaintsimage.This study aimed to evaluate the outcome of routine ear, nose, and throat screening in a large cohort of liver transplantation candidates. Note that, 6% were diagnosed with either sinusitis or a neoplasm. We did not observe any complicated sinusitis after transplantation. A more conservative approach may therefore be justified, especially in asymptomatic cases.imag

Development of a set of patient reported outcome measures for patients with benign liver tumours and cysts:patient focus groups and systematic review

BACKGROUND: Patient reported outcome measures (PROMs) may be useful for patients with benign liver tumours and cysts (BLTC) to evaluate the impact of treatment and/or guide shared decision making. Yet, a set of PROMs relevant to patients with BLTC is currently unavailable. In this study, we selected a PROMs set for patients with BLTC. METHODS: Potentially relevant patient reported outcomes (PROs) were selected by psychologist-researchers based on keywords used or suggested by participants of two virtual focus groups meetings consisting of thirteen female BLTC patients with a median age of 50 years. Subsequently, patients were asked to report their most relevant PROs. PROMs identified by systematic literature review and computerized adaptive tests (CATs) in the Patient-Reported Outcomes Measurement Information System (PROMIS) were considered in selecting the final PROMs set to assess relevant outcomes. RESULTS: The most important PROs were: insecurity/anxiety (11/12 patients), pain (9/12 patients), fatigue (8/12 patients), and limitations in daily life (5/12 patients). The literature review included 23 studies, which used various generic and disease-specific PROMs, often not measuring (all) relevant PROs. The final selected PROMs set included numerical rating scales for pain, two questions on overall health and quality of life and four PROMIS CATs. CONCLUSIONS: A PROMs set generically and efficiently measuring outcomes relevant for patients with BLTC was developed and may be used in future research and clinical practice. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s41687-022-00531-1

The value of sorafenib trough levels in patients with advanced hepatocellular carcinoma - a substudy of the SORAMIC trial.

Background: Sorafenib for advanced hepatocellular carcinoma (HCC) is dose adjusted by toxicity. Preliminary studies have suggested an association between plasma concentrations of sorafenib and its main metabolite (M2) and clinical outcomes. This study aimed to validate these findings and establish target values for sorafenib trough concentrations.Methods: Patients with advanced HCC were prospectively recruited within a multicenter phase II study (SORAMIC). Patients with blood samples available at trough level were included for this pharmacokinetic (PK) substudy. Trough plasma concentrations of sorafenib and its main metabolite (M2) were associated with sorafenib-related toxicity and overall survival (OS).Results: Seventy-four patients were included with a median OS of 19.7 months (95% CI 16.1-23.3). Patients received sorafenib for a median of 51 weeks (IQR 27-62) and blood samples were drawn after a median of 25 weeks (IQR 10-42). Patients had a median trough concentration of 3217 ng/ml (IQR 2166-4526) and 360 ng/ml (IQR 190-593) with coefficients of variation of 65% and 146% for sorafenib and M2, respectively. Patients who experienced severe sorafenib-related toxicity received a lower average daily dose (551 vs 730 mg/day, p = .003), but showed no significant differences in sorafenib (3298 vs 2915 ng/ml, p = .442) or M2 trough levels (428 vs 283 ng/ml, p = .159). Trough levels of sorafenib or M2 showed no significant association with OS.Conclusions: In patients with advanced HCC treated with sorafenib, the administered dose, trough levels of sorafenib or M2, and clinical outcomes were poorly correlated. Toxicity-adjusted dosing remains the standard for sorafenib treatment

Rifaximin stimulates nitrogen detoxification by PXR-independent mechanisms in human small intestinal organoids

BACKGROUND AND AIMS: Recurrent hepatic encephalopathy (HE) is characterized by hyperammonaemia in combination with neuropsychiatric abnormalities and is treated with lactulose and rifaximin. Rifaximin is a pregnane X receptor (PXR) agonist with low systemic and high intestinal bioavailability. The mechanisms by which it alleviates HE are unclear. We used human small intestinal (hSI) organoids to study whether rifaximin, via PXR activation, affects the epithelial biotransformation machinery, and to gain understanding of its low systemic availability. METHODS: We generated PXR knockdown hSI organoids via lentiviral delivery of short hairpin RNAs. Organoids were cultured for 24 h with rifaximin or rifampicin. RNA-sequencing and metabolomics were performed to analyse gene expression and amino acid metabolism. Luminal rifaximin was quantified by photospectrometry. RESULTS: Treatment of wild-type hSI organoids with rifaximin resulted in >twofold differential expression of 131 genes compared to DMSO. These effects were largely PXR independent and related to amino acid metabolism. Rifaximin decreased expression of glutaminase-2 and increased expression of asparagine synthetase and solute carrier 7A11, thereby increasing intracellular glutamine and asparagine concentrations, indicating active ammonia detoxification. Rifaximin was apically excreted into the lumen in an ATP binding cassette B1 (ABCB1)-dependent manner. CONCLUSIONS: Rifaximin-after uptake into enterocytes-stimulates intracellular nitrogen detoxification by PXR-independent mechanisms. Active apical excretion of rifaximin by ABCB1 into the intestinal lumen explains its low systemic bioavailability. Our study implies that rifaximin, next to modulation of the microbiome, has direct effects on ammonia scavenging in the human small intestinal epithelium

Hepatocellular adenoma in men:A nationwide assessment of pathology and correlation with clinical course

BACKGROUND & AIMS: Hepatocellular adenomas (HCA) rarely occur in males, and if so, are frequently associated with malignant transformation. Guidelines are based on small numbers of patients and advise resection of HCA in male patients, irrespective of size or subtype. This nationwide retrospective cohort study is the largest series of HCA in men correlating (immuno)histopathological and molecular findings with the clinical course. METHODS: Dutch male patients with available histological slides with a (differential) diagnosis of HCA between 2000 and 2017 were identified through the Dutch Pathology Registry (PALGA). Histopathology and immunohistochemistry according to international guidelines were revised by two expert hepatopathologists. Next generation sequencing (NGS) was performed to confirm hepatocellular carcinoma (HCC) and/or subtype HCA. Final pathological diagnosis was correlated with recurrence, metastasis and death. RESULTS: A total of 66 patients from 26 centres fulfilling the inclusion criteria with a mean (±SD) age of 45.0 ± 21.6 years were included. The diagnosis was changed after expert revision and NGS in 33 of the 66 patients (50%). After a median follow‐up of 9.6 years, tumour‐related mortality of patients with accessible clinical data was 1/18 (5.6%) in HCA, 5/14 (35.7%) in uncertain HCA/HCC and 4/9 (44.4%) in the HCC groups (P = .031). Four B‐catenin mutated HCA were identified using NGS, which were not yet identified by immunohistochemistry and expert revision. CONCLUSIONS: Expert revision with relevant immunohistochemistry may help the challenging but prognostically relevant distinction between HCA and well‐differentiated HCC in male patients. NGS may be more important to subtype HCA than indicated in present guidelines

PD-L1, Galectin-9 and CD8+ tumor-infiltrating lymphocytes are associated with survival in hepatocellular carcinoma

Novel systemic treatments for hepatocellular carcinoma (HCC) are strongly needed. Immunotherapy is a promising strategy that can induce specific antitumor immune responses. Understanding the mechanisms of immune resistance by HCC is crucial for development of suitable immunotherapeutics. We used immunohistochemistry on tissue-microarrays to examine the co-expression of the immune inhibiting molecules PD-L1, Galectin-9, HVEM and IDO, as well as tumor CD8+ lymphocyte infiltration in HCC, in two independent cohorts of patients. We found that at least some expression in tumor cells was seen in 97% of cases for HVEM, 83% for PD-L1, 79% for Gal-9 and 66% for IDO. In the discovery cohort (n = 94), we found that lack of, or low, tumor expression of PD-L1 (p < 0.001), Galectin-9 (p < 0.001) and HVEM (p < 0.001), and low CD8+TIL count (p = 0.016), were associated with poor HCC-specific survival. PD-L1, Galectin-9 and CD8+TIL count were predictive of HCC-specific survival independent of baseline clinicopathologic characteristics and the combination of these markers was a powerful predictor of HCC-specific survival (HR 0.29; p <0.001). These results were confirmed in the validation cohort (n = 60). We show that low expression levels of PD-L1 and Gal-9 in combination with low CD8+TIL count predict extremely poor HCC-specific survival and it requires a change in two of these parameters to significantly improve prognosis. In conclusion, intra-tumoral expression of these immune inhibiting molecules was observed in the majority of HCC patients. Low expression of PD-L1 and Galectin-9 and low CD8+TIL count are associated with poor HCC-specific survival. Combining immune biomarkers leads to superior predictors of HCC mortality

Decompensation as initial presentation in patients with liver cirrhosis is associated with an increased risk of future decompensation and mortality

Background and Aims: The clinical course of patients with liver cirrhosis and adherence to hepatocellular carcinoma (HCC) screening guidelines are not well studied in the Netherlands. We investigated this and potential risk factors for decompensation and transplant-free survival (TFS) in a large regional cohort. Methods: We performed a retrospective cohort study of patients with confirmed liver cirrhosis in Amsterdam, the Netherlands. Clinical parameters, decompensation events, development of HCC, and medication use were extracted from medical records. Results: In total, 681 hospitalized and outpatients were included. Mortality risk was increased by: age (aHR 1.07, p < 0.01), smoking (aHR 1.83, p < 0.01), decompensated initial presentation (aHR 1.43, p = 0.04) and increased MELD (aHR 1.07, p < 0.01). PPI use tended to increase mortality risk (aHR 1.35, p = 0.05). The risk of future decompensation was increased with increased age (aHR 1.02, p < 0.01), decompensated initial presentation (aHR 1.37, p = 0.03) and alcohol misuse as etiology (aHR 1.34, p = 0.04). Adequately screened patients for HCC had a longer TFS compared to patients who were not (48 vs 22 months), p < 0.01). Conclusions: In patients with cirrhosis, decompensation at initial presentation was associated with an increased risk of future decompensation and mortality. Alcoholic cirrhosis was associated with an increased risk of future decompensation. Adequate HCC surveillance was associated with markedly better survival

Hepatitis B Virus Pregenomic RNA Is Present in Virions in Plasma and Is Associated With a Response to Pegylated Interferon Alfa-2a and Nucleos(t)ide Analogues

Treatment of patients with chronic hepatitis B (CHB) with nucleos(t)ide analogues (NAs) suppresses hepatitis B virus (HBV) DNA production but does not affect the synthesis of the RNA pregenome or HBV messenger RNA. Whether HBV RNA-containing particles continue to be secreted into the bloodstream remains controversial. We developed a sensitive polymerase chain reaction (PCR) assay to quantify the HBV RNA load in a supernatant of NA-treated HepG2-2.2.15 cells and in plasma specimens from 20 patients with CHB who were receiving NA therapy and 86 patients treated with pegylated interferon alfa (Peg-IFN) and adefovir. Treatment of HepG2-2.2.15 cells with NAs for 9 days reduced HBV DNA levels (by 1.98 log10 copies/mL), whereas HBV RNA levels increased (by 0.47 log10 copies/mL; P < .05). During long-term NA treatment of patients with CHB, HBV RNA levels remained higher than HBV DNA levels. Peg-IFN-based treatment induced a stronger decrease in the HBV RNA load than NA monotherapy, and this decline was more pronounced in responders than in nonresponders. In HBV e antigen-negative patients, a lower baseline plasma HBV RNA level was independently associated with response to Peg-IFN and adefovir (odds ratio, 0.44; P = .019). Immunoprecipitation with HBV core antigen-specific antibodies after removal of the HBV surface antigen envelope demonstrated the association of plasma HBV RNA with virions. HBV RNA is present in virions in plasma specimens from patients with CHB. HBV RNA levels vary significantly from those of established viral markers during antiviral treatment, which highlights its potential as an independent marker in the evaluation of patients with CH