Hepatitis C Virus Infection in the Elderly in the Era of Direct-Acting Antivirals: Evidence from Clinical Trials and Real Life.

The introduction of direct-acting antiviral agents (DAAs) into clinical practice has revolutionized the therapeutic approach to patients with chronic hepatitis C virus (HCV) infection. According to the most recent guidelines, the first line of treatment for HCV infection involves the use of one of three pan-genotypic DAA combinations, sofosbuvir/velpatasvir (SOF/VEL), glecaprevir/pibrentasvir (GLE/PIB), and sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX). These drugs have been shown to be effective and safe in numerous clinical trials and real-world studies, but special populations have been neglected. Among the special populations to be treated are elderly patients, whose numbers are increasing in clinical practice. The management of these patients can be challenging, in particular due to multiple comorbidities, polypharmacotherapy, and potential drug-drug interactions. This narrative review aims to summarize the current scientific evidence on the efficacy and safety of DAAs in the elderly population, both in clinical trials and in real-life settings. Although there is still a paucity of real-world data and no clinical trials have yet been conducted in the population aged ≥ 75 years old, some considerations about the efficacy and safety of DAAs in the elderly can be made based on the results of these studies. The pan-genotypic associations of DAAs appear to be as efficacious and safe in the elderly population as in the general population; this is both in terms of similar sustained virologic response (SVR) rates and similar frequencies of adverse events (AEs). However, further studies specifically involving this patient population would be necessary to confirm this evidence.

Impact of Oocyte Extract Supplement on Quality of Life after Hepatectomy for Liver Tumours: A Prospective, Multicentre, Double-Blind Randomized Clinical Trial.

BACKGROUND: Previous studies on oocyte extract supplementation showed benefits in patients with liver tumours. In this trial, we hypothesized that the oocyte extract supplement impacted the QoL after hepatectomy for hepatocellular carcinoma and intrahepatic cholangiocarcinoma. METHODS: This was a multicentre, double-blind, randomized clinical trial designed to assess the QoL of patients receiving a supplement of oocyte extract or placebo postoperatively. QoL was assessed using the Short Form-36 questionnaire in participants randomly assigned to treatment (Synchrolevels) or placebo. All study personnel and participants were masked to treatment assignment. The endpoint was the change in the QoL score. RESULTS: Between June 2018 and September 2022, 66 of 128 expected patients were considered as per interim analysis, of which 33 were assigned to the treatment and 33 to the placebo group. Baseline and clinicopathological characteristics were similar between the two groups. In the treatment group, the health, mental and psychological status improved for many of the items considered, reaching statistical significance, while in the placebo group, those items either did not change or were impaired in comparison with the corresponding baseline. CONCLUSIONS: Supplementation with oocyte extract modifies QoL after liver surgery by enhancing functional recovery. Further in-depth studies are required to confirm this evidence.

Stereotactic Radiotherapy after Incomplete Transarterial (Chemo-) Embolization (TAE\TACE) versus Exclusive TAE or TACE for Treatment of Inoperable HCC: A Phase III Trial (NCT02323360).

Background: Hepatocellular carcinoma (HCC) is the most frequent liver malignancy and a leading cause of cancer death in the world. In unresectable HCC patients, transcatheter arterial (chemo-) embolization (TAE/TACE) has shown a disease response in 15-55% of cases. Though multiple TAE/TACE courses can be administered in principle, Stereotactic Body Radiotherapy (SBRT) has emerged as an alternative option in the case of local relapse following multiple TAE/TACE courses. Methods: This is a single-center, prospective, randomized, controlled, parallel-group superiority trial of SBRT versus standard TAE/TACE for the curative treatment of the intermediate stage of HCC after an incomplete response following TAE/TACE (NCT02323360). The primary endpoint is 1-year local control (LC): 18 events were needed to assess a 45% difference (HR: 0.18) in favor of SBRT. The secondary endpoints are 1-year Progression-Free Survival (PFS), Distant Recurrence-Free Survival (DRFS), Overall Survival (OS) and the incidence of acute and late complications. Results: At the time of the final analysis, 40 patients were enrolled, 19 (49%) in the TAE/TACE arm and 21 (51%) in the SBRT arm. The trial was prematurely closed due to slow accrual. The 1- and 2-year LC rates were 57% and 36%. The use of SBRT resulted in superior LC as compared to TAE/TACE rechallenge (median not reached versus 8 months, p = 0.0002). PFS was 29% and 16% at 1 and 2 years, respectively. OS was 86% and 62% at 1 year and 2 years, respectively. In the TAE arm, PFS was 13% and 6% at 1 and 2 years, respectively. In the SBRT arm, at 1 and 2 years, PFS was 37% and 21%, respectively. OS at 1 and 2 years was 75% and 64% in the SBRT arm and 95% and 57% in the TACE arm, respectively. No grade >3 toxicity was recorded. Conclusions: SBRT is an effective treatment option in patients affected by inoperable HCC experiencing an incomplete response following ≥1 cycle of TAE/TAC.

Myosteatosis Is Not Associated with Complications or Survival in HCC Patients Undergoing Trans Arterial Embolization.

Alterations in nutritional status, in particular sarcopenia, have been extensively associated with a poor prognosis in cirrhotic patients regardless of the etiology of liver disease. Less is known about the predictive value of myosteatosis, defined as pathological fat infiltration into the skeletal muscle. We retrospectively analyzed a cohort of 151 cirrhotic patients with unresectable hepatocellular carcinoma (HCC) who underwent their first trans-arterial embolization (TAE) between 1 March 2011 and 1 July 2019 at our Institution. Clinical and biochemical data were collected. Sarcopenia was assessed using the L3-SMI method while myosteatosis with a dedicated segmentation suite (3D Slicer), using a single slice at an axial plane located at L3 and calculating the IMAC (Intramuscular Adipose Tissue Content Index). The sex-specific cut-off values for defining myosteatosis were IMAC > −0.44 in males and >−0.31 in females. In our cohort, 115 (76%) patients were included in the myosteatosis group; 128 (85%) patients had a coexistent diagnosis of sarcopenia. Patients with myosteatosis were significantly older and showed higher BMI than patients without myosteatosis. In addition, male gender and alcoholic- or metabolic-related cirrhosis were most represented in the myosteatosis group. Myosteatosis was not associated with a different HCC burden, length of hospitalization, complication rate, and readmission in the first 30 days after discharge. Overall survival was not influenced by the presence of myosteatosis.

Risk Stratification of Cholangiocarcinoma Patients Presenting with Jaundice: A Retrospective Analysis from a Tertiary Referral Center.

Cholangiocarcinomas (CCAs) are a heterogeneous group of tumors that arise from the biliary tract. Jaundice is a common clinical presentation; however, the prognostic impact of this symptom is poorly understood, and current management recommendations lack solid evidence. We aim to assess the clinical outcomes and predictive factors of CCA patients presenting with jaundice in the Emergency Room (ER). We retrospectively analyzed all consecutive ER cases presenting with jaundice between January 2010 and December 2017. During the study period, 403,766 patients were admitted to the ER, 1217 (0.3%) presented with jaundice, and in 200 (0.049%), the diagnosis was CCA. CCA cases increased during the study period (p for trend 0.026). Most of them presented with advance disease (stage III 46.5%, stage IV 43.5%) and median survival was 4.5 months (95% CI 3.4-6.0). Factors associated with better survival were age, stage of disease, presence of jaundice at the moment of diagnosis, and lack of concomitant viral hepatitis. A nomogram was constructed that significantly predicts 1-month, 6-month, and 1-year survival after patients' admission. In conclusion, the majority of CCA patients presenting with jaundice to the ER have advanced disease and poor prognosis. Risk stratification of these patients can allow tailored management.

Veno-Arterial Extracorporeal Membrane Oxygenation in the Adult: A Bridge to the State of the Art.

Despite the technological advancements in the last 40 years, conditions such as refractory cardiogenic shock and cardiac arrest still present a very high mortality rate in real-world clinical practice. In this light, we have reviewed the techniques, indications, contraindications, and results of the socalled Veno-Arterial Extracorporeal Circulatory Membrane Oxygenation (VA-ECMO) in the adult population to evaluate the current results of this temporary cardio-pulmonary support as salvage and/or bridge therapy in the patient suffering from refractory cardiogenic shock or cardio-circulatory arrest. The results are encouraging, especially in the setting of refractory cardiogenic shock and in-hospital cardiac arrest. Among a selected population, the prompt institution of a VA-ECMO may radically change the prognosis by sustaining vital functions while looking for the leading cause or waiting for the reversal of the temporary cardio-respiratory negative condition. The future directions aim to standardized and shared protocols, miniaturization of the machines, and possibly the institution of specialized "ECMO teams" for in and the out-of-hospital institution of the tool.

Correction: Sarcopenia as a predictor of survival in patients undergoing bland transarterial embolization for unresectable hepatocellular carcinoma.

[This corrects the article DOI: 10.1371/journal.pone.0232371.].

Sarcopenia as a predictor of survival in patients undergoing bland transarterial embolization for unresectable hepatocellular carcinoma.

Sarcopenia has been associated with lower overall survival in patients with cirrhosis and hepatocellular carcinoma (HCC) undergoing surgical resection, TACE, TARE, or transplantation. This monocentric study evaluated the prognostic significance of sarcopenia in patients affected by HCC who received bland transarterial embolization (TAE) therapy, by analyzing its impact on survival and treatment-related complications. All consecutive patients who underwent the 1st TAE between March 1st 2011 and July 1st 2019 in our Institution were retrospectively studied. To evaluate sarcopenia, the skeletal muscle index (SMI) was calculated by normalizing the cross-sectional muscle area at the level of L3 on an abdominal CT scan prior to embolization (cm2) by patient height (m2). SMI cut-off values for sarcopenia were considered ≤ 39 cm2/m2 for women and ≤55 cm2/m2 for men. Data about age, gender, body mass index (BMI), underlying liver disease, liver function, MELD score, Child-Pugh score, multifocal disease, performance status, previous interventions, length of stay (LOS), complications after the procedure, readmission rate within 30 days, survival time from TAE and total number and type of TAE received following the first procedure were collected. From 2011 to 2019, 142 consecutive patients underwent 305 TAEs. Observation time ranged from 1.4 to 100.5 months (median 20.1 SD = 22). Sarcopenia at baseline was present in 121 (85%) patients. Overall 87 (61.2%) patients died during follow-up with survival rates at 1-, 2-, 3-, 4-, and 5-year of 71%, 41%, 22%, 16% and 11% respectively. After multivariate analysis sarcopenia (HR = 2.22, p = 0.046), previous ablation/resection (HR = 0.51, p = 0.005) and multifocal disease (HR = 1.84, p = 0.02) were associated with reduced survival. Sarcopenia did not influence the safety of TAE in terms of LOS (2 days vs 1.5 days, p = 0.2), early complications rate (8% vs 5%, p = 0.5) and readmission rate within 30 days (7% vs 5%, p = 0.74). Sarcopenia, estimated by the L3SMI method, is an emerging prognostic factor in patients with HCC undergoing bland TAE therapy as it is associated with increased mortality, without impairing the safety of the locoregional treatment. Measures to ameliorate the SMI, such as nutritional support and physical exercise, should be evaluated in clinical trials for HCC patients receiving liver embolization to determine their impact on overall survival.

Percutaneous transhepatic endoscopic lithotripsy of biliary stones with holmium laser for the treatment of recurrent cholangitis.

PURPOSE: To evaluate the efficacy and safety of percutaneous transhepatic endoscopic holmium laser biliary lithotripsy (PTBL) to treat recurrent cholangitis due to intra/extrahepatic stones, in patients not candidate for traditional endoscopic treatment. MATERIALS AND METHODS: We retrospectively evaluated 28 patients (M:F = 19:9, mean age = 65 years, SD = 14) undergoing 43 PTBL for stone-related recurrent cholangitis from January 1, 2012 to January 31, 2019 in a single academic center. Data collected included demographics, location and number of stones, clinical success after one (primary) or more than one (secondary) PTBL, procedure time, duration of hospital stay, number of retreatments and post-procedural complications. Clinical success was defined as the resolution of cholangitis at 30-day follow-up. RESULTS: PTBL were successful for 23/28 (82%) patients, 16 (57%) with one and 7 (88%) with repeat procedures. The remaining 5 (18%) patients were finally treated with surgery (3, 11%) or further antibiotics (2, 7%). PTBL were performed to treat intrahepatic stones (22 treatments, 51%), extrahepatic (14, 33%), and both intra/extrahepatic (7, 16%). One to three stones were found in 12/43 (28%) PTBL, more than three in 31/43 (72%). Single PTBL was performed in 20/28 (71%) patients, two in 3/28 (11%), three in 3/28 (11%), and four in 2/28 (7%). Median procedure duration was 115 (29-210, 95% CI 101-129) minutes; median hospital stay was 5.5 (2-42) days. The only major complication was the breakage of a guidewire tip, surgically retrieved; minor complications included one aspiration pneumonia and three instances of intrahepatic hemorrhage, treated conservatively. CONCLUSIONS: PTBL was clinically successful in the 82% of patients not candidate for endoscopic treatment, with a low complication rate.

Survival analysis of 230 patients with unresectable hepatocellular carcinoma treated with bland transarterial embolization.

Locoregional therapies for hepatocellular carcinoma (HCC) include endovascular treatments such as chemoembolization (TACE) and bland embolization (TAE). TACE is the most adopted technique, despite a lack of definitive evidence of superiority over TAE, which is less costly and better tolerated due to the absence of chemotherapy. However, few studies have reported data on TAE monotherapy for unresectable HCC. We report our results in a cohort of 230 patients with unresectable HCC treated with TAE (TAE with 40-100micron microparticles, TAE with microparticles plus n-butyl-2-cyanoacrylate, TAE with Lipiodol) over the course of seven years. Thirty-seven patients (14%) were down-staged during observation and also received a percutaneous ablation. We observed 1-, 2-, 3-, 4- and 5-year rates of 84,8%, 58,7%, 38,3%, 28,3%, and 18,7%. Patients who also received percutaneous treatment performed best. Our results broaden the body of evidence for the use of TAE in advanced HCC.

High-Sensitivity C-Reactive Protein and Acute Kidney Injury in Patients with Acute Myocardial Infarction: A Prospective Observational Study.

Background. Accumulating evidence suggests that inflammation plays a key role in acute kidney injury (AKI) pathogenesis. We explored the relationship between high-sensitivity C-reactive protein (hs-CRP) and AKI in acute myocardial infarction (AMI). Methods. We prospectively included 2,063 AMI patients in whom hs-CRP was measured at admission. AKI incidence and a clinical composite of in-hospital death, cardiogenic shock, and acute pulmonary edema were the study endpoints. Results. Two-hundred-thirty-four (11%) patients developed AKI. hs-CRP levels were higher in AKI patients (45 ± 87 vs. 16 ± 41 mg/L; p < 0.0001). The incidence and severity of AKI, as well as the rate of the composite endpoint, increased in parallel with hs-CRP quartiles (p for trend <0.0001 for all comparisons). A significant correlation was found between hs-CRP and the maximal increase of serum creatinine (R = 0.23; p < 0.0001). The AUC of hs-CRP for AKI prediction was 0.69 (p < 0.001). At reclassification analysis, addition of hs-CRP allowed to properly reclassify 14% of patients when added to creatinine and 8% of patients when added to a clinical model. Conclusions. In AMI, admission hs-CRP is closely associated with AKI development and severity, and with in-hospital outcomes. Future research should focus on whether prophylactic renal strategies in patients with high hs-CRP might prevent AKI and improve outcome.

Improvement of neutrophil gelatinase-associated lipocalin sensitivity and specificity by two plasma measurements in predicting acute kidney injury after cardiac surgery.

INTRODUCTION: Acute kidney injury (AKI) remains among the most severe complication after cardiac surgery. The aim of this study was to evaluate the neutrophil gelatinase-associated lipocalin (NGAL) as possible biomarker for the prediction of AKI in an adult cardiac population. MATERIALS AND METHODS: Sixty-nine consecutive patients who underwent cardiac surgeries in our hospital were prospectively evaluated. In the intensive care unit (ICU) NGAL was measured as a new biomarker of AKI besides serum creatinine (sCrea). Patients with at least two factors of AKI risk were selected and samples collected before the intervention and soon after the patient's arrival in ICU. As reference standard, sCrea measurements and urine outputs were evaluated to define the clinical AKI. A Triage Meter for plasma NGAL fluorescence immunoassay was used. RESULTS: Acute kidney injury occurred in 24 of the 69 patients (35%). Analysis of post-operative NGAL values demonstrated an AUC of 0.71, 95% CI (0.60 - 0.82) with a cut-off = 154 ng/mL (sensitivity = 76%, specificity = 59%). Moreover, NGAL after surgery had a good correlation with the AKI stage severity (P ≤ 0.001). Better diagnostic results were obtained with two consecutive tests: sensitivity 86% with a negative predictive value (NPV) of 87%. At 10-18 h after surgery sCrea measurement, as confirmatory test, allowed to reach a more sensitivity and specificity with a NPV of 96%. CONCLUSIONS: The assay results showed an improvement of NGAL diagnostic accuracy evaluating two tests. Consequently, NGAL may be useful for a timely treatment or for the AKI rule out in ICU patients.

Acute Kidney Injury in Diabetic Patients With Acute Myocardial Infarction: Role of Acute and Chronic Glycemia.

BACKGROUND: In acute myocardial infarction, acute hyperglycemia is a predictor of acute kidney injury (AKI), particularly in patients without diabetes mellitus. This emphasizes the importance of an acute glycemic rise rather than glycemia level at admission. We investigated whether, in diabetic patients with acute myocardial infarction, the combined evaluation of acute and chronic glycemic levels may have better prognostic value for AKI than admission glycemia. METHODS AND RESULTS: At admission, we prospectively measured glycemia and estimated average chronic glucose levels (mg/dL) using glycosylated hemoglobin (HbA1c), according to the following formula: 28.7×HbA1c (%)-46.7. We evaluated the association with AKI of the acute/chronic glycemic ratio and of the difference between acute and chronic glycemia (ΔA-C). We enrolled 474 diabetic patients with acute myocardial infarction. Of them, 77 (16%) experienced AKI. The incidence of AKI increased in parallel with the acute/chronic glycemic ratio (12%, 14%, 22%; P=0.02 for trend) and ΔA-C (13%, 13%, 23%; P=0.01) but not with admission glycemic tertiles (P=0.22). At receiver operating characteristic analysis, the acute/chronic glycemic ratio (area under the curve: 0.62 [95% confidence interval, 0.55-0.69]; P=0.001) and ΔA-C (area under the curve: 0.62 [95% confidence interval, 0.54-0.69]; P=0.002) accurately predicted AKI, without difference in the area under the curve between them (P=0.53). At reclassification analysis, the addition of the acute/chronic glycemic ratio and ΔA-C to acute glycemia allowed proper AKI risk prediction in 16% of patients. CONCLUSIONS: In diabetic patients with acute myocardial infarction, AKI is better predicted by the combined evaluation of acute and chronic glycemic values than by assessment of admission glycemia alone.

Diagnostic accuracy of ¹¹C-choline PET/CT in comparison with CT and/or MRI in patients with hepatocellular carcinoma.

PURPOSE: In recent decades, the use of radiopharmaceuticals in the assessment of hepatocellular carcinoma (HCC) has become established, and new findings indicate that radiolabelled choline has considerable potential in this setting. Therefore, in this study we aimed to assess the diagnostic role of (11)C-choline positron emission tomography (PET)/CT, compared with conventional imaging with CT/MRI, in patients with HCC. METHODS: The study population comprised 45 patients (male to female ratio = 37:8, median age 70.5 years) referred to our institution owing to HCC: 27 at initial diagnosis and 18 for restaging after recurrence. In all cases we performed whole-body (11)C-choline PET/CT and compared its findings with contrast-enhanced CT (n = 35) or MRI (n = 29) or both (n = 15) for a total of 50 paired scans. The reference standard was either histological proof (21 patients) or a multidisciplinary consensus. Diagnostic accuracy was then determined in a scan-based (SBA) and a lesion-based analysis (LBA). RESULTS: On SBA the sensitivity and specificity for PET were 88 and 90 %, respectively, whereas for CT/MRI they were 90 and 73 %, respectively (p > 0.05). On LBA the overall sensitivity and specificity were 78 and 86 %, respectively, for PET vs 65 and 55 % for CT/MRI. Overall we investigated 168 disease sites, of which 100 were in the liver and 68 were extrahepatic. When considering only liver lesions, (11)C-choline PET and CT/MRI showed an accuracy of 66 and 85 %, respectively, while for extrahepatic lesions PET showed an accuracy of 99 %, while the accuracy of CT/MRI was 32 %. In both cases, there was a statistically significant difference in accuracy between the two modalities (p < 0.01). Combination of the PET results with those of CT/MRI resulted in the highest diagnostic accuracy in both analyses, at 92 % for SBA and 96 % for LBA. In 11 patients (24 %) the PET findings modified the therapeutic strategy, the modification proving appropriate in 10 of them. CONCLUSION: (11)C-Choline PET showed good accuracy in investigating patients with HCC and prompted a change in treatment planning in almost one fourth of patients. The main strength of (11)C-choline PET/CT resides in its ability to detect extrahepatic HCC localizations, but the combination with conventional imaging modalities allowed for the highest diagnostic accuracy.