Prospective Assessment of Treatment-Induced Liver Injury as a Cause of Diffuse Pathologic Hepatic Enhancement in Contrast-Enhanced Ultrasound.

OBJECTIVE: A hypo-enhancement of the liver in contrast-enhanced ultrasound (CEUS), pathologic one-minute hepatic enhancement (pOMHE), was recently observed in 70% of allogeneic hematopoietic stem cell transplantation patients with a high-risk profile for veno-occlusive disease (VOD). Whether pOMHE was a pre-clinical sign of VOD or an unspecific feature of liver damage secondary to intensive chemotherapy is unclear. METHODS: To investigate this, we studied CEUS patterns in patients receiving high-dose chemotherapy prior to autologous hematopoietic stem cell transplantation (auto-HSCT) or intensive induction therapy (IT) for the treatment of acute leukemia. From April 2020 to May 2021, patients undergoing auto-HSCT (n = 20) or acute leukemia patients prior to IT (n = 20) were included. All patients underwent a B-mode ultrasound and CEUS of the liver and spleen before treatment (d0) and on day 10 (d10) after therapy start. The one-minute hepatic enhancement was quantified. An optical density of liver enhancement less than 90% compared with the spleen was considered pathologic (pOMHE). Clinical and laboratory parameters used to assess a drug-induced liver injury (DILI) were documented. RESULTS: The OMHE was normal (d0 and d10) in 36 (90%) patients. After IT, 2 of 20 patients had a pOMHE. A DILI grade IV was diagnosed in one case and hyperfibrinolysis in the second case. In 2 of 20 (5%) auto-HSCT patients a pOMHE was observed at d10 without clinical symptoms. CONCLUSION: Chemotherapy-induced effects are not the cause of a pathologic liver enhancement. In contrast, severe DILI or hyperfibrinolysis can be associated with pOMHE.

Assessment of hepatic veno-occlusive disease/sinusoidal obstruction syndrome using different scanning approaches for the ultrasonographic evaluation of portal vein blood flow and hepatic artery resistive index in hematopoietic stem cell transplant recipients.

PURPOSE: Sinusoidal obstruction syndrome (SOS) is a fatal complication of hematopoietic stem cell transplantation (HSCT). Previously, we established a scoring system (Hokkaido ultrasound-based scoring system-10; HokUS-10) comprising 10 ultrasound parameters for SOS diagnosis. In HokUS-10, the portal vein time-averaged flow velocity (PV TAV) and hepatic artery resistive index (HA RI) are measured using subcostal scanning. However, measurement errors and delineation difficulties occur. Therefore, we aimed to prospectively evaluate PV TAV and HA RI measurements obtained via intercostal scanning as an alternative method to subcostal scanning and determine their cutoff values. METHODS: HokUS-10 was administered before and after HSCT. PV TAV and HA RI were measured on subcostal and right intercostal scans. RESULTS: We performed 366 scans on 74 patients. The median value (range) of PV TAV in the main and right portal veins was 15.0 cm/s (2.2-49.6 cm/s) and 10.5 cm/s (1.6-22.0 cm/s), respectively. A low correlation was observed between the two values (r = 0.39, p < 0.01). The highest diagnostic value of the right portal vein was less than 8.0 cm/s. The median value (range) of HA RI in the proper and right hepatic arteries was 0.72 (0.52-1.00) and 0.70 (0.51-1.00), respectively. A strong correlation was observed between the two values (r = 0.65, p < 0.01). The highest diagnostic value of the right HA RI was 0.72 or higher. CONCLUSION: Quantitative measurement of PV TAV and HA RI using intercostal scanning can be appropriately performed as an alternative method to using subcostal scanning.

Quantitative CT assessment by histogram and volume ratio in pyrrolizidines alkaloids-induced hepatic sinusoidal obstruction syndrome.

OBJECTIVE: To quantitatively assess hypoattenuation volume ratio and hepatic parenchymal hypoattenuation on contrast enhanced computed tomography (CECT) in patients with pyrrolizidines alkaloids (PAs)-induced hepatic sinusoidal obstruction syndrome (HSOS), and evaluate the correlations of the CT-based quantitative values with clinical factors. METHODS: Thirty-five patients with PAs-induced HSOS who underwent CECT were retrospectively enrolled. The ratio of hypoattenuation volume to total liver volume, and changes in damaged area-to-normal liver density ratio (ΔDR) derived from histogram on portal venous phase were quantitatively measured. Heterogeneous hypoattenuation (CT score) scored by hypoattenuation volume ratio and ΔDR were calculated. The correlation between imaging findings and clinical factors was analyzed using Pearson correlation test. RESULTS: Liver function tests were abnormal in most patients, the mean Hounsfield unit (HU) of damaged area (58.68 ± 17.3) was significantly lower (P < 0.001) than the corresponding normal liver (82.27 ± 23.97). Heterogeneous hypoattenuation were mild in 13 patients (37 %), moderate in 16 patients (46 %), and severe in 6 patients (17 %). ΔDR derived from histogram was positively correlated (weakly to moderately) with total bilirubin (r = 0.341, P = 0.045), direct bilirubin (r = 0.385, P = 0.022), and alkaline phosphatase (r = 0.491, P = 0.003), while such correlation was not observed in hypoattenuation volume ratio. The severity of heterogeneous hypoattenuation scored by hypoattenuation volume ratio and ΔDR was positively correlated (weakly) with prothrombin time (r = 0.357, P = 0.035), international normalized ratio (r = 0.363, P = 0.032), alkaline phosphatase (r = 0.359, P = 0.034), and model for end-stage liver disease (MELD) score (r = 0.347, P = 0.041). CONCLUSION: Heterogeneous hypoattenuation scored by volume ratio and ΔDR on CECT provides a non-invasive approach in evaluating the severity of PAs-induced HSOS.

Veno-occlusive Disease in HSCT Patients: Consensus-based Recommendations for Risk Assessment, Diagnosis, and Management by the GITMO Group.

Variation in clinical practice affects veno-occlusive disease management, mainly in patients who undergo allogeneic hematopoietic stem cell transplantation. Disputes about diagnostic criteria, treatment, and prophylaxis, due to the lack of high-quality data, are at the base of this variability. With the aim of limiting inconsistency in clinical care, thus improving both patient outcomes and data collection reliability, the Italian Society of Stem cell transplant (Gruppo Italiano Trapianto Midollo Osseo e Terapia Cellulare) launched a collaborative effort to formulate recommendations based on integration of available evidence and expert's consensus. A systematic method, according to US National Institute of Health guidelines and Italian National System for Guidelines, was used. Twenty-nine recommendations were approved with a strong (20) or weak (9) level of agreement, while 26 were rejected. In particular, the panel pointed out the need to achieve an early diagnosis, encouraging the adoption of European Society for Blood and Marrow Transplantation criteria and the prompt use of ultrasonography. Moreover, our experts strongly recommended in favor of prophylactic use of ursodeoxycholic acid. As soon as a veno-occlusive disease diagnosis is established, treatment with defibrotide should be started for at least 21 days. A number of areas of uncertainty, particularly concerning risk stratification and use of diagnostic tools such as elastography has been identified and discussed.

Magnetic resonance assessment of sinusoidal obstruction syndrome after neoadjuvant chemotherapy for colorectal liver metastases is not reproducible.

BACKGROUND: Sinusoidal obstruction syndrome (SOS) due to chemotherapy can cause severe hepatotoxicity, leading to impaired outcome in patients with colorectal cancer. A previous study introduced gadoxetic acid-enhanced magnetic resonance imaging (Gd-EOB-MRI) to diagnose SOS. PURPOSE: To assess the reproducibility of Gd-EOB-MRI-based SOS diagnosis and its relationship with response to chemotherapy and long-term outcome. MATERIAL AND METHODS: Twenty-six Gd-EOB-MRI scans of patients undergoing chemotherapy for colorectal liver metastases (CRLM) were retrospectively analyzed. Three radiologists, blinded to clinical data, independently scored presence and severity of SOS on a 5-point scale (0, definitely not present to 4, definitely present). Patients with a score ≥3 were considered SOS+. Inter-observer agreement between readers was assessed with kappa statistics. Response (RECIST 1.1.), occurrence of new CRLM during follow-up (hepatic progression) and overall survival (OS) were compared between patients with and without SOS. RESULTS: The inter-observer agreement of SOS scores was poor, with quadratic kappas of 0.17-0.40. For the binary outcome of SOS+ (confidence level [CL] 3-4) vs. SOS- (CL 0-2) agreement was poor, with kappas of 0.03-0.37. Median follow-up was 24 months (range 4-44 months). Response and OS between patients with and without SOS did not differ significantly for any of the readers. CONCLUSION: Inter-observer agreement for the diagnosis of SOS on Gd-EOB-MRI is poor. No significant correlation with relevant outcomes was found for any of the readers. Therefore, MRI for SOS diagnosis might be less useful than previously reported. Other techniques should be explored to accurately diagnose SOS in absence of histological confirmation.

Non-Gaussian Diffusion Models and T1 rho Quantification in the Assessment of Hepatic Sinusoidal Obstruction Syndrome in Rats.

BACKGROUND: Non-Gaussian diffusion models and T1 rho quantification may reflect the changes in tissue heterogeneity in hepatic sinusoidal obstruction syndrome (SOS). PURPOSE: To investigate the feasibility of diffusion kurtosis imaging (DKI), stretched exponential model (SEM), and T1 rho quantification in detecting and staging SOS in a monocrotaline (MCT)-induced rat model. STUDY TYPE: Animal study. POPULATION: Thirty male Sprague-Dawley rats gavaged with MCT to induce hepatic SOS and six male rats without any intervention. FIELD STRENGTH/SEQUENCE: 3.0T, DWI with five b-values (0-2000 s/mm2 ) and T1 rho with five spin lock times (1-60 msec). ASSESSMENT: MRI was performed 1 day before and 1, 3, 5, 7, and 10 days after MCT administration. The corrected apparent diffusion coefficient (Dapp ), kurtosis coefficient (Kapp ), distributed diffusion coefficient (DDC), and intravoxel water molecular diffusion heterogeneity (α) were calculated from the corresponding non-Gaussian diffusion model. The T1 rho value was calculated using a monoexponential model. Specimens obtained from the six timepoints were categorized into normal liver (n = 6), early-stage (n = 16), and late-stage (n = 14) SOS in accordance with the pathological score. STATISTICAL TESTS: Parametric statistical methods and receiver operating characteristic (ROC) curves were employed to determine diagnostic accuracy. RESULTS: The Dapp , Kapp , DDC, α, and T1 rho values were correlated with pathological score with r values of -0.821, 0.726, -0.828, -0.739, and 0.714 (all P < 0.001), respectively. DKI (combined Dapp and Kapp ) and SEM (combined DDC and α) were better than T1 rho for staging SOS. The areas under the ROC curve of DKI, SEM, and T1 rho for differentiating normal liver and early-stage SOS were 0.97, 1.00, and 0.79, whereas those of DKI, SEM, and T1 rho for differentiating early-stage and late-stage SOS were 1.00, 0.97, and 0.92, respectively. DATA CONCLUSION: DKI, SEM, and T1 rho may be helpful in staging SOS. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 2 J. Magn. Reson. Imaging 2020;52:1110-1121.

Editorial for "Non-Gaussian Diffusion Models and T1rho Quantification in the Assessment of Hepatic Sinusoidal Obstruction Syndrome in Rats".

LEVEL OF EVIDENCE: 5 TECHNICAL EFFICACY STAGE: 2 J. Magn. Reson. Imaging 2020;52:1122-1123.

Assessment of hepatic sinusoidal obstruction syndrome with intravoxel incoherent motion diffusion-weighted imaging: An experimental study in a rat model.

BACKGROUND: Intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI) parameters may reflect perfusion and diffusion changes in hepatic sinusoidal obstruction syndrome (SOS). PURPOSE: To investigate the feasibility of IVIM-DWI in the noninvasive assessment of hepatic SOS in an experimental rat model. STUDY TYPE: Animal study. POPULATION/SUBJECTS: Forty-four rats were administered different doses (90 or 160 mg/kg) of monocrotaline by gavage either 48 or 72 hours before MRI to induce different degrees of hepatic SOS, and another 10 rats served as controls. FIELD STRENGTH/SEQUENCE: 3T scanner, IVIM-DWI using nine b values (0-800 sec/mm2 ). ASSESSMENT: Histologically, rats were classified as having none (n = 10), mild (n = 8), moderate (n = 19), or severe SOS (n = 17). The apparent diffusion coefficient (ADC) and IVIM-derived parameters (D: true diffusion coefficient, D*: pseudo-diffusion coefficient, and f: perfusion fraction) of the liver parenchyma were measured. STATISTICAL TESTS: IVIM-DWI parameters were compared according to histologic grades of SOS (none, mild, moderate, and severe), and receiver operating characteristic (ROC) curve analysis was performed to determine the diagnostic accuracy. RESULTS: ADC, D, and f of the liver parenchyma were significantly different according to SOS severity groups (Ps < 0.01) and significantly decreased as SOS severity increased (rho = -0.323, -0.313, and -0.700; P = 0.017, 0.021, and <0.001, respectively). Means of f in none, mild, moderate, and severe SOS were 17.2%, 13.3%, 12.3%, and 11.1%, respectively. Among ADC and IVIM-derived parameters, f provided the highest area under the ROC curves for detecting ≥mild, ≥moderate, and severe SOS (0.991, 0.890, and 0.803, respectively). DATA CONCLUSION: IVIM-DWI may be useful in the diagnosis and severity assessment of hepatic SOS. LEVEL OF EVIDENCE: 2 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2020;51:81-89.

Role of Virtual Touch Tissue Imaging Quantification in the Assessment of Hepatic Sinusoidal Obstruction Syndrome in a Rat Model.

OBJECTIVES: To investigate the value of liver stiffness in rats with various degrees of hepatic sinusoidal obstruction syndrome (HSOS) induced by monocrotaline by comparing liver histopathologic findings. METHODS: Seventy rats were randomly divided into a control group (n = 10), a low-dose monocrotaline group (n = 30), and a high-dose monocrotaline group (n = 30). After successful modeling, the liver shear wave velocity (SWV) by Virtual Touch tissue imaging quantification (Siemens Medical Solutions, Mountain View, CA) and the alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin levels of the groups were obtained on days 3 and 5, and the intergroup differences were compared. Liver histopathologic characteristics were analyzed to evaluate the degrees of HSOS, and the scores were recorded. RESULTS: On days 3 and 5, the total bilirubin, AST, and ALT, levels and liver SWV in the low- and high-dose groups were elevated; the portal vein velocity (PVV) of these groups was decreased compared with the control group; and the high-dose rats showed higher serum AST and ALT levels than the low-dose rats. The high-dose rats had a lower PVV than the low-dose rats at day 3. The liver SWV values had significant correlations with the histologic score and PVV. In a multivariate analysis, the liver SWV (ß = 0.813; P < .001) was independently associated with the histopathologic score. CONCLUSIONS: Liver stiffness as measured by Virtual Touch tissue imaging quantification increases with the severity of HSOS and can be recommended as a marker for diagnosis and assessment of HSOS.

Preoperative assessment of chemotherapeutic associated liver injury based on indocyanine green retention test.

BACKGROUND: The aim of the study was to assess the capacity of indocyanine green retention test at 15 min (ICGR15) to predict chemotherapeutic-associated liver injuries (CALI). METHODS: Patients undergoing liver resection for CLM that received preoperative oxaliplatin and/or irintecan-based chemotherapy within 3 months before surgery and scheduled first hepatectomy were considered. RESULTS: 166 out of 983 patients treated between 01/2001 and 04/2014 fulfilled the inclusion criteria. The median number of cycles of preoperative chemotherapy was 6.0 ± 4.87. Chemotherapy was mainly based on oxaliplatin in 123 (74.1%). Bevacizumab was associated in 51(31%) patients. A total of 102 (61.4%) patients had at least 1 CALI. Grade 2-3 steatosis occurred in 56 (33.7%) patients and steatohepatitis in19(11.5%). Sinusoidal obstructive syndrome (SOS) was presented in 93 (56%) patients. 23(13.8%) patients had nodular regeneration hyperplasia. At multivariate analysis the only predictive factor of ICGR≥10% was age≥65 years (p = 0.001). A median split (ICGR15 = 8%) was used to categorized ICGR15 value. Multivariate analysis showed that age≥ 65 [OR 2.530 (CI95% 1.28-4.97) p < 0.001], male sex [OR 2.614 (CI95% 1.31-5.20) p < 0.001], SOS [OR 1.954 (CI95% 1.00-3.81) p = 0.050] and administration of Bevacizumab [OR 2.201 (CI95% 1.07-4.50) p = 0.031] were predictive factors for ICGR≥8%. CONCLUSIONS: ICGR15 test can predict the diagnosis of SOS. High ICGR15 value is more common in elderly male patients and after bevacizumab administration.