Analysis of patient's X-ray exposure in hepatic chemosaturation procedures: a single center experience.

BACKGROUND: Hepatic chemosaturation is a technique in which a high dose of the chemotherapeutic agent melphalan is administered directly into the liver while limiting systemic side effects. We reviewed our institutional experience regarding patient's X-ray exposure caused by the procedure. METHODS: Fifty-five procedures, performed between 2016 and 2020 in 18 patients by three interventional radiologists (radiologist), were analyzed regarding the patient's exposure to radiation. Dose-area-product (DAP) and fluoroscopy time (FT) were correlated with the experience of the radiologist and whether the preprocedural evaluation (CS-EVA) and the procedure were performed by the same radiologist. Additionally, the impact of previous liver surgery on DAP/FT was analyzed. RESULTS: Experienced radiologist require less DAP/FT (50 ± 18 Gy*cm2/13.2 ± 3.84 min vs. 69 ± 20 Gy*cm2/15.77 ± 7.82 min; p < 0.001). Chemosaturations performed by the same radiologist who performed CS-EVA required less DAP/FT (41 ± 12 Gy*cm2/11.46 ± 4.41 min vs. 62 ± 11 Gy*cm2/15.55 ± 7.91 min; p < 0.001). Chemosaturations in patients with prior liver surgery with involvement of the inferior cava vein required significantly higher DAP/FT (153 ± 27 Gy*cm2/25.43 ± 4.57 min vs. 56 ± 25 Gy*cm2/14.44 ± 7.55 min; p < 0.001). CONCLUSION: There is a significant learning curve regarding the procedure of hepatic chemosaturation. Due to dose reduction the evaluation and chemosaturation therapy should be performed by the same radiologist. Procedures in patients with previous liver surgery require higher DAP/FT.

Similar risk of hepatocellular carcinoma during long-term entecavir or tenofovir therapy in Caucasian patients with chronic hepatitis B.

BACKGROUND & AIMS: A recent study in Asian patients with chronic hepatitis B (CHB) reported that the incidence of hepatocellular carcinoma (HCC) was lower in patients treated with tenofovir disoproxil fumarate (TDF) than entecavir (ETV), but this finding remains controversial. We aimed to identify any differences in HCC incidence, or other patient outcomes, between patients receiving TDF or ETV in the well monitored, multicenter European PAGE-B cohort. METHODS: We included 1,935 Caucasians with CHB, with or without compensated cirrhosis, treated with ETV (n = 772) or TDF (n = 1,163) monotherapy. Mean follow-up was 7.1 ± 3.0 years from ETV/TDF onset. RESULTS: The 5-year cumulative HCC incidence was 5.4% in ETV- and 6.0% in TDF-treated patients (log-rank, p = 0.321), with no significant difference in any patient subgroup (with or without cirrhosis, naïve or experienced to oral antiviral(s) [total, with or without cirrhosis]). In multivariable Cox regression analyses, the hazard of HCC was similar between ETV- and TDF-treated patients after adjustment for several HCC risk factors. ETV- and TDF-treated patients had similar rates of on-therapy biochemical and virological remission, HBsAg loss, liver transplantation and/or death. Elastographic reversion of cirrhosis at year 5 (liver stiffness <12 kPa) was observed in 245/347 (70.6%) patients with pretreatment cirrhosis, being more frequent in TDF- than ETV- treated patients (73.8% vs. 61.5%, p = 0.038). CONCLUSION: In Caucasian patients with CHB, with or without cirrhosis, long-term ETV or TDF monotherapy is associated with similar HCC risk, rates of biochemical/virological remission, HBsAg loss and liver transplantation or death, but elastographic reversion of cirrhosis at year 5 was more frequent with TDF. LAY SUMMARY: In a large cohort of Caucasians with chronic hepatitis B treated with entecavir (ETV) or tenofovir disoproxil fumarate (TDF) monotherapy, cumulative rates of hepatocellular carcinoma did not differ (up to 12 years). Nor did rates of biochemical/virological remission, HBsAg loss and liver transplantation or death. However, elastographic reversion of cirrhosis at year 5 was more frequent in TDF- than ETV-treated patients with pretreatment cirrhosis.

Hepatocellular carcinoma prediction beyond year 5 of oral therapy in a large cohort of Caucasian patients with chronic hepatitis B.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) may develop in patients with chronic hepatitis (CHB) even after 5 years of oral therapy and cannot be easily predicted. We assessed predictors of HCC development and the need for HCC surveillance in this setting. METHODS: Of 1,951 adult Caucasians with CHB included in the PAGE-B cohort, 1,427 (73%) had completed >5 years of follow-up under therapy without developing HCC by year 5. Median follow-up was 8.4 years from treatment onset. Points-based risk scores were developed to predict HCC risk after year 5. RESULTS: In years 5-12, HCC was diagnosed in 33/1,427 (2.3%) patients with cumulative incidences of 2.4%, 3.2% and 3.8% at 8, 10 and 12 years, respectively. Older age or age >50 years, baseline cirrhosis and liver stiffness (LSM) ≥12 kPa at year 5 were independently associated with increased HCC risk. The HCC incidence was lower in non-cirrhotics than cirrhotics at baseline with year-5 LSM <12; among cirrhotics at baseline, it was lower in those with year-5 LSM <12 than ≥12 kPa. CAGE-B score was based on age at year 5 and baseline cirrhosis in relation to LSM at year 5 and SAGE-B score was based only on age and LSM at year 5 (c-index = 0.809-0.814, 0.805-0.806 after bootstrap validation). Both scores offered 100% negative predictive values for HCC development in their low risk groups. CONCLUSIONS: In Caucasians with CHB, the HCC risk after the first 5 years of antiviral therapy depends on age, baseline cirrhosis status and LSM at year 5. CAGE-B and particularly SAGE-B represent simple and reliable risk scores for HCC prediction and surveillance beyond year 5 of therapy. LAY SUMMARY: In Caucasians with chronic hepatitis B, the risk of hepatocellular carcinoma after the first 5 years of entecavir or tenofovir therapy depends on age, baseline cirrhosis status and liver stiffness at year 5, which can provide simple and reliable risk scores for hepatocellular carcinoma prediction and surveillance beyond year 5. In patients with cirrhosis at baseline, liver stiffness <12 kPa at year 5 is associated with lower HCC risk, but surveillance may be still required.

Prognostic Factors for Postoperative Bleeding Complications and Prolonged Intensive Care after Percutaneous Hepatic Chemosaturation Procedures with Melphalan.

Percutaneous hepatic melphalan perfusion (chemosaturation) in patients with liver metastases is known to be associated with procedure-related hemodynamic depression and coagulation impairment, which may cause bleeding complications and/or a prolonged intensive care unit length of stay (ICU LOS). We retrospectively analyzed possible predictive factors for bleeding complications and an ICU LOS > 1 d in a cohort of 31 patients undergoing 90 chemosaturation procedures. Using a multivariable mixed-model approach, we identified the amount of perioperative fluid volume (OR 12.0, 95% CI 2.3-60.0, p = 0.003) and protamine (OR 0.065, 95% CI 0.007-0.55, p = 0.012) to be associated with bleeding complications. Furthermore, the amount of perioperative fluid volume was associated with an ICU LOS > 1 d (OR 5.2, 95% CI 1.4-19.0, p = 0.011). Heparin dosage, melphalan dosage, extracorporeal circulation time, and noradrenaline dosage had no significant effects on outcomes. Protamine use was not associated with anaphylactic or thromboembolic complications. Despite the limited sample size, these results suggest a restrictive perioperative fluid regime to be beneficial, and support the use of protamine for heparin reversal after chemosaturation procedures. Further prospective randomized trials are needed to confirm these findings.

Repeated percutaneous hepatic perfusion with melphalan can maintain long-term response in patients with liver cancers.

Chemosaturation (CS; CHEMOSAT®, Delcath Systems Inc.) temporarily administers melphalan into the liver by percutaneous hepatic perfusion (PHP). CS-PHP can effectively control growth in liver tumors, but efficacy and tolerability of sequential treatments are unclear. We analyzed outcomes of sequential CS-PHP treatment. Patients with either unresectable intrahepatic metastases of ocular melanoma (OM, n = 9), cholangiocarcinoma (CCA, n = 3), or hepatocellular carcinoma (HCC, n = 1) were recruited retrospectively. Response was assessed by tomography imaging. Ten patients (mean age 60 years) with more than one CS-PHP treatment were included. CS-PHP was administered 2-6 times in the OM patients, 3 times in the CCA, and the HCC patient received 6 treatments. Overall response rate (ORR) to CS-PHP was 80%, and stable disease was achieved in one patient. Median hepatic progression-free survival (hPFS) was 336 days (range 0-354) for OM, 251 days for the CCA patient, and 256 days for the HCC patient. At the end of observation (153-701 days after first CS-PHP), 6/10 patients were still alive (5/9 with OM, 0 with CCA, and 1 with HCC). Death cases were not related to CS-PHP. Adverse events were mostly hematologic, grade I-IV, and self-resolving. The liver function was not deteriorated by CS-PHP. We conclude that repeated CS-PHP treatments were effective and well tolerated in the long term.

The Liver Maximum Capacity Test (LiMAx) Is Associated with Short-Term Survival in Patients with Early Stage HCC Undergoing Transarterial Treatment.

Transarterial chemoembolization (TACE) and transarterial radioembolization (TARE) are recommended to treat patients with early or intermediate hepatocellular carcinoma (HCC). The liver maximum capacity test (LiMAx) has been supposed to predict the risk of post-interventional liver failure. We investigated the correlation of LiMAx with short-term survival as primary endpoint and the occurrence of adverse events after therapy as secondary endpoint. Our study cohort prospectively included 69 patients receiving TACE (n = 57) or TARE (n = 12). LiMAx test and serological analyses were performed on the day before and 4 weeks after treatment. Hepatic and extrahepatic complications were monitored for 4 weeks. The LiMAx results were not associated with altered liver function and the occurrence of adverse events. The survival rates of patients with BCLC A with LiMAx ≤ 150 µg/kg/h were lower after 30 days (75.0 ± 15.3% vs. 100%, p = 0.011), 90 days (62.5 ± 17.7% vs. 95.8 ± 4.1%, p = 0.011) and 180 days (50.0 ± 17.7% vs. 95.8 ± 4.1%, p = 0.001) compared to those with higher LiMAx levels. The LiMAx test is not suitable to predict liver function abnormalities or the occurrence of complications 4 weeks after therapy but enables the identification of patients with early stage HCC and reduced short-term survival after treatment.

Percutaneous hepatic melphalan perfusion: Single center experience of procedural characteristics, hemodynamic response, complications, and postoperative recovery.

BACKGROUND: Percutaneous hepatic melphalan perfusion (PHMP) for the selective treatment of hepatic metastases is known to be associated with procedural hypotension and coagulation disorders. Studies on anesthetic management, perioperative course, complications, and postoperative recovery in the intensive care unit (ICU) have not been published. METHODS: In a retrospective observational study, we analyzed consecutive patients who were admitted for PHMP over a 6-year period (2016-2021). Analyses included demographic, treatment, and outcome data with regard to short-term complications until ICU discharge. RESULTS: Fifty-three PHMP procedures of 16 patients were analyzed. In all of the cases, procedure-related hypotension required the median (range) highest noradrenaline infusion rate of 0.5 (0.17-2.1) µg kg min-1 and fluid resuscitation volume of 5 (3-14) liters. Eighty-four PHMP-related complications were observed in 33 cases (62%), of which 9 cases (27%) involved grade III and IV complications. Complications included airway constriction (requiring difficult airway management), vascular catheterization issues (which resulted in the premature termination of PHMP, as well as to the postponement of PHMP and to the performance of endovascular bleeding control after PHMP), and renal failure that required hemodialysis. Discharge from the ICU was possible after one day in most cases (n = 45; 85%); however, in 12 cases (23%), prolonged mechanical ventilation was required. There were no procedure-related fatalities. CONCLUSIONS: PHMP is frequently associated with challenging cardiovascular conditions and complications that require profound anesthetic skills. For safety reasons, PHMP should only be performed in specialized centers that provide high-level hospital infrastructures and interdisciplinary expertise.

Predictive performance of newer Asian hepatocellular carcinoma risk scores in treated Caucasians with chronic hepatitis B.

BACKGROUND & AIMS: Recently, several risk scores for prediction of hepatocellular carcinoma (HCC) were developed in cohorts of treated Asian patients with chronic hepatitis B (CHB), but they have not been assessed in non-Asian patients. We evaluated the predictability and comparative utility of our PAGE-B and recent Asian HCC risk scores in nucleos(t)ide analogue (NA)-treated adult Caucasian patients with CHB, with or without well-documented compensated cirrhosis but not previous diagnosis of HCC. METHODS: We included 1,951 patients treated with entecavir/tenofovir and followed up for a median of 7.6 years. The c-statistic was used to estimate the predictability of PAGE-B, HCC-Rescue, CAMD, mPAGE-B, and AASL score for HCC development within 5 or 10 years. The low- and high-risk group cut-offs were used for estimation of negative (NPV) and positive predictive values (PPV), respectively. RESULTS: HCC developed in 103/1,951 (5.3%) patients during the first 5 years and in another 39/1,428 (2.7%) patients between years 5 and 10. The 3-, 5-, and 10-year cumulative HCC rates were 3.3%, 5.9%, and 9.6%, respectively. All scores offered good 5- and 10-year HCC prediction (c-statistic: 0.78-0.82). NPVs were always >99% (99.3-100%), whereas PPV ranged between 13% and 24%. CONCLUSIONS: In NA-treated Caucasian patients with CHB including compensated cirrhosis, HCC risk scores developed in NA-treated Asian patients offer good 5- and 10-year HCC predictability, similar to that of PAGE-B. PAGE-B and mPAGE-B scores are simpler in clinical practice, as they do not require an accurate diagnosis of cirrhosis, but the addition of albumin in mPAGE-B score does not seem to offer an advantage in patients with well compensated liver disease. LAY SUMMARY: Several risk scores for prediction of hepatocellular carcinoma (HCC) were recently developed in cohorts of treated Asian patients with chronic hepatitis B (CHB). In Caucasian patients with CHB treated with oral antivirals, newer Asian HCC risk scores offer good 5- and 10-year HCC predictability, similar to that of PAGE-B. For clinical practice, PAGE-B and mPAGE-B scores are simpler, as they do not require an accurate diagnosis of cirrhosis.

Polysialic acid interacts with lactoferrin and supports its activity to inhibit the release of neutrophil extracellular traps.

Polysialic acid (polySia) is a linear carbohydrate polymer consisting of N-acetylneuraminic acid residues and is involved in several physiological processes. In the present study, we identified the multifunctional protein lactoferrin as a novel interaction partner for polySia. Lactoferrin co-precipitated when polySia was isolated from human blood, milk, and semen samples. The interaction between polySia and lactoferrin was verified using a native gel electrophoresis application, demonstrating that such interaction depends on the degree of polymerization. The interaction between the molecules could be inhibited by an antibody against lactoferricin (LFcin), which suggests that the LFcin domain of lactoferrin represents the potential binding area for sialic acid polymers. Because lactoferrin inhibits the formation of neutrophil extracellular traps (NETs), the potential impact of polySia on this function of lactoferrin was tested. Intriguingly, we observed that polySia increases the efficiency of lactoferrin to prevent the release of NET fibers. PolySia alone shows no activity. Therefore, together with lactoferrin, polySia may represent a natural regulatory system of NET release.