Interoperator Reliability of Lung Ultrasound during the COVID-19 Pandemic.

AIM: Lung ultrasound (LUS) is a reliable, radiation-free, and bedside imaging technique used to assess several pulmonary diseases. Although COVID-19 is diagnosed with a nasopharyngeal swab, detection of pulmonary involvement is crucial for safe patient discharge. Computed tomography (CT) is currently the gold standard. To treat paucisymptomatic patients, we have implemented a "fast track" pathway in our emergency department, using LUS as a valid alternative. Minimal data is available in the literature about interobserver reliability and the level of expertise needed to perform a reliable examination. Our aim was to assess these. MATERIALS AND METHODS: This was a single-center prospective study. We enrolled 96 patients. 12 lung areas were explored in each patient with a semiquantitative assessment of pulmonary aeration loss in order to obtain the LUS score. Scans were performed by two different operators, an expert and a novice, who were blinded to their colleague's results. RESULTS: 96 patients were enrolled. The intraclass correlation coefficient (ICC) showed excellent agreement between the expert and the novice operator (ICC 0.975; 0.962-0.983); demographic features (age, sex, and chronic pulmonary disease) did not influence the reproducibility of the method. The ICC was 0.973 (0.950-0.986) in males, 0.976 (0.959-0.986) in females; 0.965 (0.940-0.980) in younger patients (≤ 46 yrs), and 0.973 (0.952-0.985) in older (> 46 yrs) patients. The ICC was 0.967 (0.882-0.991) in patients with pulmonary disease and 0.975 (0.962-0.984) in the other patients. The learning curve showed an increase in interobserver agreement. CONCLUSION: Our results confirm the feasibility and reproducibility of the method among operators with different levels of expertise, with a rapid learning curve.

Cholangiocarcinoma in Cirrhosis: Value of Hepatocyte Specific Magnetic Resonance Imaging.

BACKGROUND: The diagnosis of intrahepatic cholangiocellular carcinoma (ICC) remains elusive at imaging, which is a critical issue in cirrhotic patients in whom a diagnosis of hepatocellular carcinoma (HCC) can be established only by imaging. AIM: The aim of the study was to evaluate the potential of MRI in the diagnosis of ICC in cirrhosis using 'hepatocyte-specific' Gadolinium (Gd)-based contrast agents. METHODS: Sixteen histologically proven and retrospectively identified ICCs on cirrhosis were investigated with hepatocyte-specific magnetic resonance contrast agents (6 in Bologna with Gd-EOB-DTPA and 10 in Milan with Gd-BOPTA). The control group consisted of 41 consecutively and prospectively collected nodules (31 HCCs) imaged with Gd-EOB-DTPA. RESULTS: Fifteen ICC nodules (94%) displayed hypointensity in the hepatobiliary phase, suggesting malignancy. Thirteen cholangiocarcinomas (81%) showed hyperenhancement in the venous phase. Only 2 cholangiocarcinoma nodules showed hypoenhancement in the venous phase, corresponding to washout, in both cases preceded by rim enhancement in arterial phase. All the hepatocarcinomas showed hypointensity in hepatobiliary phase, but was always preceded by hypointensity in the venous phase; arterial rim enhancement was never observed in any hepatocarcinoma or regenerative nodule. CONCLUSIONS: MRI with hepatocyte-specific Gd-based contrast agents showed a pattern of malignancy in almost all the ICCs, concurrently avoiding misdiagnosis with hepatocarcinoma. These findings suggest a greater diagnostic capacity for this technique compared with the results of MRI with conventional contrast agents reported in the literature in this setting.

Evaluation of the impact of transient interruption of antiangiogenic treatment using ultrasound-based techniques in a murine model of hepatocellular carcinoma.

BACKGROUND: Development of escape pathways from antiangiogenic treatments was reported to be associated with enhanced tumor aggressiveness and rebound effect was suggested after treatment stop. Aim of the study was to evaluate tumor response simulating different conditions of administration of antiangiogenic treatment (transient or definitive treatment stop) in a mouse model of hepatocellular carcinoma. METHODS: Subcutaneous tumors were created by inoculating 5 × 10(6) Huh7 cells into the right flank of 14 nude mice. When tumor size reached 5-10 mm, mice were divided in 3 groups: group 1 was treated with placebo, group 2 was treated with sorafenib (62 mg/kg via gavage) but temporarily suspended from day +5 to +9, whereas in group 3 sorafenib was definitively stopped at day +5. At day +13 all mice were sacrificed, collecting masses for Western-Blot analyses. Volume was calculated with B-mode ultrasonography at day 0, +5, +9, +11 and +13. VEGFR2-targeted contrast-enhanced ultrasound using BR55 (Bracco Imaging) was performed at day +5 and +13 and elastonosography (Esaote) at day +9 and +11 to assess tumor stiffness. RESULTS: Median growth percentage delta at day +13 versus day 0 was 197% (115-329) in group 1, 81% (48-144) in group 2 and 111% (27-167) in group 3. Median growth delta at day +13 with respect to day +5 was 79% (48-127), 37% (-14128) and 81% (15-87) in groups 1, 2 and 3, respectively. Quantification of targeted-CEUS at day +13 showed higher values in group 3 (509 Arbitrary Units AI, range 293-652) than group 1 (275 AI, range 191-494) and group 2 (181 AI, range 63-318) (p=0.033). Western-Blot analysis demonstrated higher VEGFR2 expression in group 3 with respect to group 1 and 2. CONCLUSIONS: A transient interruption of antiangiogenic treatment does not impede restoration of tumor response, while a definitive interruption tends to stimulate a rebound of angiogenesis to higher level than without treatment.

Lung ultrasound in the COVID-19 era: a lesson to be learned for the future.

Lung Ultrasound (LUS) is a reliable, radiation free and bedside imaging technique to assess several pulmonary diseases. Although the diagnosis of COVID-19 is made with the nasopharyngeal swab, detection of pulmonary involvement is key for a safe patient management. LUS is a valid alternative to explore, in paucisymptomatic self-presenting patients, the presence and extension of pneumonia compared to High Resolution Computed Tomography (HRCT) that represent the gold standard. This is a single-centre prospective study with 131 patients enrolled. Twelve lung areas were explored reporting a semiquantitative assessment to obtain the LUS score. Each patient performed reverse-transcription polymerase chain reaction test (rRT-PCR), hemogasanalysis and HRCT. We observed an inverse correlation between LUSs and pO2, P/F, SpO2, AaDO2 (p value < 0.01), a direct correlation with LUSs and AaDO2 (p value < 0.01). Compared with HRCT, LUS showed sensitivity and specificity of 81.8% and 55.4%, respectively, and VPN 75%, VPP 65%. Therefore, LUS can represent an effective alternative tool to detect pulmonary involvement in COVID-19 compared to HRCT.

CovHos score for predicting severe respiratory failure in COVID-19 patients presenting at the emergency department.

Hospitalization of COVID-19 patients in low-intensity wards may put patients at risk in case of clinical deterioration. We tested CovHos score in predicting severe respiratory failure (SFR) at emergency department (ED) admission. This is a monocentric observational prospective study enrolling adult COVID-19 patients admitted to the ED of IRCCS AOU di Bologna Policlinico S.Orsola in October 2020, both discharged and hospitalized. Patients were then dichotomized based on days from symptoms onset. Main outcome was the occurrence of SRF. Receiver operating characteristic (ROC) analysis was used to identify cut-off and corresponding accuracy. A CovHos cut-off of 22 yielded a sensitivity of 84.7% and specificity of 75.3% in predicting SRF (AUROC 0.856; CI 95% 0.813-0.898). In patients with symptoms onset up to 8 days, a CovHos cut-off of 22 was able to predict SRF with a sensitivity of 91.7% and a specificity of 78.6% (AUROC 0.901; CI 95% 0.861-0.941). Negative predictive value (NPV) was 97.1%. A CovHos score lower than 22, in patients with COVID-19 symptoms onset dated 8 or less days prior to the ED admittance, had a NPV of 97.1% for the development of SRF, meaning that almost none of those patients will evolve into SRF and could be therefore suitable for a lower intensity of care.

Prediction of Conventional Oxygen Therapy Failure in COVID-19 Patients With Acute Respiratory Failure by Assessing Serum Lactate Concentration, PaO2/FiO2 Ratio, and Body Temperature.

One of the challenges that emerged during the coronavirus disease 2019 (COVID-19) pandemic and is still relevant today is the need to identify patients with acute respiratory failure (ARF) who could benefit from conventional oxygen therapy (COT) - oxygen supplementation with nasal cannulas, Venturi masks, and non-rebreather masks - without recurring to advanced respiratory therapy, such as high-flow nasal cannula (HFNC), continuous positive airway pressure (CPAP), non-invasive ventilation (NIV), or invasive mechanical ventilation. The aim of the study was to develop a clinical tool able to predict the failure of COT in COVID-19 patients presenting to the emergency department (ED) with ARF. This was a retrospective monocentric cohort study carried out in the ED of the University Hospital of Bologna Sant'Orsola-Malpighi Polyclinic, Italy. The cohort comprised 101 COVID-19 patients with ARF from the first pandemic wave who received COT. This cohort was used to develop a scale that considers serum lactate concentration, partial arterial oxygen pressure/inspired oxygen fraction (PaO2/FiO2) ratio, and body temperature to predict COT failure, referred to as the Lactate, Oxygenation, and Temperature (LOT) score. The highest possible score was 17 points. The LOT score was associated with COT failure (area under the receiver operating curve or AUROC = 0.79, 95% CI 0.69 - 0.89, p < 0.001); the cut-off value of > 5 points had optimal predictive power and showed significantly higher 30-day mortality (log-rank χ2 = 28,828, p < 0.0001). The LOT score was able to effectively predict COT failure in COVID-19 patients with ARF. Patients with LOT score > 5 had a very high risk of therapy failure, and more advanced respiratory therapies must be considered in these patients.

CovHos, a New Score to Predict the Need of Hospitalization for Coronavirus Disease 2019 (COVID-19) Patients at the Emergency Department.

INTRODUCTION AND AIM: As first receivers of suspected coronavirus disease 2019 (COVID-19) patients, clinicians of the Emergency Department (ED) have to rapidly perform the first clinical assessment evaluating the intensity of care needed. So far, clear management guidelines still lack. We identified variables associated with hospitalization in order to give a quick tool to assist clinicians in stratifying cases based on the severity at their arrival at the ED and in predicting the need for hospital care.  Methods: This is a monocentric observational prospective study enrolling COVID-19 patients. A score for hospitalization prediction (CovHos Score) was created using variables associated with hospitalization at multivariate analysis and then validated on an internal subsequent cohort. RESULTS: A total of 667 patients were included; 465 (69.7%) were hospitalized and 108 (16.2%) died at 30-days follow-up. In a multivariate analysis, male sex, age>65, alveolar-to-arterial oxygen gradient percentage increase compared to that expected for age, neutrophils/lymphocytes ratio and C-reactive protein levels were significantly associated with a higher rate of hospital admission. A CovHos score cut-off of 12 points predicted hospitalization with 85% sensitivity and 82.4 % specificity (area under a receiver operating characteristic curve [AUROC] = 0.909, 95% CI 0.884 - 0.935). Similar results were obtained in the validation court. A cut-off of 22 has 79% sensitivity and 77% specificity in predicting mortality (AUROC = 0.824; 95% CI 0.782-0.866); sensitivity and specificity were respectively 71.4% and 71.3% in the validation group. CONCLUSIONS: Although medical judgment still remains crucial, the CovHos score is an effective tool to assist emergency clinicians in predicting the need for hospitalization or to optimize allocation in a shortage of hospital resources.

Role of ROX index in the first assessment of COVID-19 patients in the emergency department.

During the first outbreak of Coronavirus disease 2019 (COVID-19) Emergency Departments (EDs) were overcrowded. Hence, the need for a rapid and simple tool to support clinical decisions, such as the ROX index (Respiratory rate - OXygenation), defined as the ratio of peripheral oxygen saturation and fraction of inspired oxygen, to respiratory rate. The aim of the study was to evaluate the accuracy of the ROX index in predicting hospitalization and mortality in patients with a diagnosis of COVID-19 in the ED. The secondary outcomes were to assess the number of readmissions and the variations in the ROX index between the first and the second admission. This was an observational prospective monocentric study, carried out in the ED of Sant'Orsola-Malpighi Hospital in Bologna, Italy. Five hundred and fifty-four consecutive patients with COVID-19 were enrolled and the ROX index was calculated. Patients were followed until hospital discharge or death. A ROX index value < 25.7 was associated with hospitalization (area under the curve [AUC] = 0.737, 95% CI 0.696-0.779, p < 0.001). The ROX index < 22.3 was statistically related to higher 30-day mortality (AUC = 0.764, 95% CI 0.708-0.820, p < 0.001). Eight patients were discharged and returned to the ED within the subsequent 7 days, their mean ROX index was 30.3 (6.2; range 21.9-39.4) at the first assessment and 24.6 (5.5; 14.5-29.5) at the second assessment, (p = 0.012). The ROX index, together with laboratory, imaging and clinical findings, correlated with the need for hospital admission, mechanical ventilation and mortality risk in COVID-19 patients.

A benign tumour of the liver mimicking malignant liver disease--cholangiocellular adenoma.

OBJECTIVE: To describe three patients with liver lesions mimicking malignant tumours diagnosed finally, using contrast-enhanced ultrasound, as cholangiocellular adenoma (bile duct adenoma). MATERIAL AND METHODS: Focal liver lesions found incidentally in three patients. Contrast-enhanced ultrasound was with use of Siemens or Esaote equipment, low MI technique, after an intravenous bolus of 2.4 ml Sonovue (Bracco, Italy). RESULTS: Lesions were 9 mm, 15 mm and 20 mm in diameter and all were enhanced in the arterial phase and hypo-enhanced in the portal venous and late phases, suggesting their malignant nature. In two patients, no primary liver tumour was found, and in the third patient, previously resected for breast cancer, a tissue specimen was considered useful for characterizing tumour receptors for more targeted chemotherapy, the lesion being assumed metastatic in nature. Transcutaneous core biopsies were performed in all three patients. Pathological analysis (including the reference pathology) revealed cholangiocellular adenoma in all of them. CONCLUSION: Cholangiocellular adenoma is a rare entity and can be a reason for possible false malignant diagnosis using contrast-enhanced ultrasound. Follow-up examinations are recommended.

Imaging of combined hepatocellular-cholangiocarcinoma in cirrhosis and risk of false diagnosis of hepatocellular carcinoma.

Background: Diagnosis of hepatocellular carcinoma can be achieved by imaging in cirrhotic patients. Combined hepatocellular-cholangiocarcinoma is a primary liver tumor and its imaging patterns have been poorly investigated. Misdiagnosis for either hepatocellular carcinoma or benign lesions can occur. We aimed to evaluate the enhancement pattern of combined hepatocellular-cholangiocarcinoma in cirrhosis with imaging techniques and to estimate the risk of misdiagnosis for hepatocellular carcinoma. Methods: All histology-confirmed combined hepatocellular-cholangiocarcinoma in cirrhosis seen in two Italian centers between 2003 and 2016, in which at least one imaging technique had been performed, was retrospectively collected. The enhancement pattern was analyzed for all available imaging modalities. Results: A total of 37 combined hepatocellular-cholangiocarcinoma nodules were identified. Contrast-enhanced ultrasound, computed tomography, and magnetic resonance imaging had been performed in 27, 34, and 17 nodules, respectively. Contrast-enhanced ultrasound was at higher risk of misdiagnosis for pure hepatocellular carcinoma than computed tomography (p = 0.005) or magnetic resonance imaging (p = 0.040). Only six of 24 combined hepatocellular-cholangiocarcinoma lesions submitted to both contrast-enhanced ultrasound and computed tomography showed coincident patterns; contrast-enhanced ultrasound correctly suggested a condition of malignancy in a higher number of cases than computed tomography (p < 0.001) and magnetic resonance imaging (p = 0.002). Conclusions: Contrast-enhanced ultrasound misdiagnosed a higher number of combined hepatocellular-cholangiocarcinoma as hepatocellular carcinoma than computed tomography and magnetic resonance imaging. However, the latter techniques were able to identify features of malignancy less often.

Transarterial chemoembolization vs bland embolization in hepatocellular carcinoma: A meta-analysis of randomized trials.

BACKGROUND: Although transarterial chemoembolization is considered the standard of care for intermediate hepatocellular carcinoma patients, robust data in favor of a clear superiority of chemoembolization (with chemotherapy injection) over bland embolization are lacking. OBJECTIVE: The objective of this article is to systematically analyze the results provided by randomized controlled trials comparing these two treatments in hepatocarcinoma patients. METHODS: A computerized bibliographic search on the main databases was performed. Survival rates assessed at one, two, and three years, objective response, one-year progression-free survival, and severe adverse event rate were analyzed. Comparisons were performed by using the Mantel-Haenszel test in cases of low heterogeneity or DerSimonian and Laird test in cases of high heterogeneity. RESULTS: Six trials with 676 patients were included. No difference in one-year (risk ratio: 0.93, 0.85-1.03, p = 0.16), two-year (risk ratio: 0.88, 0.74-1.06, p = 0.18) and three-year survival (risk ratio: 0.97, 0.74-1.27, p = 0.81) was observed. Objective response and one-year progression-free survival showed no significant difference between the two treatments (p = 0.36 and p = 0.40, respectively). A statistically significant increase in severe toxicity after chemoembolization was found (risk ratio: 1.44, 1.08-1.92, p = 0.01), although this result could be affected by the heterogeneity of techniques adopted. CONCLUSIONS: Our meta-analysis demonstrates a non-superiority of transarterial chemoembolization with respect to bland embolization in hepatocarcinoma patients.

Differences in liver stiffness values obtained with new ultrasound elastography machines and Fibroscan: A comparative study.

BACKGROUND AND AIMS: Whether Fibroscan thresholds can be immediately adopted for none, some or all other shear wave elastography techniques has not been tested. The aim of the present study was to test the concordance of the findings obtained from 7 of the most recent ultrasound elastography machines with respect to Fibroscan. METHODS: Sixteen hepatitis C virus-related patients with fibrosis ≥2 and having reliable results at Fibroscan were investigated in two intercostal spaces using 7 different elastography machines. Coefficients of both precision (an index of data dispersion) and accuracy (an index of bias correction factors expressing different magnitudes of changes in comparison to the reference) were calculated. RESULTS: Median stiffness values differed among the different machines as did coefficients of both precision (range 0.54-0.72) and accuracy (range 0.28-0.87). When the average of the measurements of two intercostal spaces was considered, coefficients of precision significantly increased with all machines (range 0.72-0.90) whereas of accuracy improved more scatteredly and by a smaller degree (range 0.40-0.99). CONCLUSIONS: The present results showed only moderate concordance of the majority of elastography machines with the Fibroscan results, preventing the possibility of the immediate universal adoption of Fibroscan thresholds for defining liver fibrosis staging for all new machines.

In Hepatocellular Carcinoma miR-221 Modulates Sorafenib Resistance through Inhibition of Caspase-3-Mediated Apoptosis.

Purpose: The aberrant expression of miR-221 is a hallmark of human cancers, including hepatocellular carcinoma (HCC), and its involvement in drug resistance, together with a proved in vivo efficacy of anti-miR-221 molecules, strengthen its role as an attractive target candidate in the oncologic field. The discovery of biomarkers predicting the response to treatments represents a clinical challenge in the personalized treatment era. This study aimed to investigate the possible role of miR-221 as a circulating biomarker in HCC patients undergoing sorafenib treatment as well as to evaluate its contribution to sorafenib resistance in advanced HCC.Experimental Design: A chemically induced HCC rat model and a xenograft mouse model, together with HCC-derived cell lines were employed to analyze miR-221 modulation by Sorafenib treatment. Data from the functional analysis were validated in tissue samples from surgically resected HCCs. The variation of circulating miR-221 levels in relation to Sorafenib treatment were assayed in the animal models and in two independent cohorts of patients with advanced HCC.Results: MiR-221 over-expression was associated with Sorafenib resistance in two HCC animal models and caspase-3 was identified as its target gene, driving miR-221 anti-apoptotic activity following Sorafenib administration. Lower pre-treatment miR-221 serum levels were found in patients subsequently experiencing response to Sorafenib and an increase of circulating miR-221 at the two months assessment was observed in responder patients.Conclusions: MiR-221 might represent a candidate biomarker of likelihood of response to Sorafenib in HCC patients to be tested in future studies. Caspase-3 modulation by miR-221 participates to Sorafenib resistance. Clin Cancer Res; 23(14); 3953-65. ©2017 AACR.

Ongoing challenges in the diagnosis of hepatocellular carcinoma.

In 2001, the European Association for the Study of the Liver (EASL) endorsed the possibility of achieving a non-invasive diagnosis of Hepatocellular Carcinoma (HCC) for the first time. Since then, various refinements of the criteria and techniques capable of achieving this diagnosis and the role of plasma and tissue oncomarkers have been reported in the literature and have been accepted to different extents in various geographical areas. Such tools can also potentially imply prognostic significance. The present article critically discusses some of the most relevant and debated challenges which have emerged in this field, including the role of contrast-enhanced ultrasound, and of hepatocyte-specific magnetic resonance contrast agents, the pitfall of transient hepatic attenuation differences, the reliability of biopsy and the status of biomarkers.