Prognostic Significance of Urinary Biomarkers in Patients Hospitalized With COVID-19.

RATIONALE & OBJECTIVE: Acute kidney injury (AKI) is common in patients with coronavirus disease 2019 (COVID-19) and associated with poor outcomes. Urinary biomarkers have been associated with adverse kidney outcomes in other settings and may provide additional prognostic information in patients with COVID-19. We investigated the association between urinary biomarkers and adverse kidney outcomes among patients hospitalized with COVID-19. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: Patients hospitalized with COVID-19 (n=153) at 2 academic medical centers between April and June 2020. EXPOSURE: 19 urinary biomarkers of injury, inflammation, and repair. OUTCOME: Composite of KDIGO (Kidney Disease: Improving Global Outcomes) stage 3 AKI, requirement for dialysis, or death within 60 days of hospital admission. We also compared various kidney biomarker levels in the setting of COVID-19 versus other common AKI settings. ANALYTICAL APPROACH: Time-varying Cox proportional hazards regression to associate biomarker level with composite outcome. RESULTS: Out of 153 patients, 24 (15.7%) experienced the primary outcome. Twofold higher levels of neutrophil gelatinase-associated lipocalin (NGAL) (HR, 1.34 [95% CI, 1.14-1.57]), monocyte chemoattractant protein (MCP-1) (HR, 1.42 [95% CI, 1.09-1.84]), and kidney injury molecule 1 (KIM-1) (HR, 2.03 [95% CI, 1.38-2.99]) were associated with highest risk of sustaining primary composite outcome. Higher epidermal growth factor (EGF) levels were associated with a lower risk of the primary outcome (HR, 0.61 [95% CI, 0.47-0.79]). Individual biomarkers provided moderate discrimination and biomarker combinations improved discrimination for the primary outcome. The degree of kidney injury by biomarker level in COVID-19 was comparable to other settings of clinical AKI. There was evidence of subclinical AKI in COVID-19 patients based on elevated injury biomarker level in patients without clinical AKI defined by serum creatinine. LIMITATIONS: Small sample size with low number of composite outcome events. CONCLUSIONS: Urinary biomarkers are associated with adverse kidney outcomes in patients hospitalized with COVID-19 and may provide valuable information to monitor kidney disease progression and recovery.

Sex-specific cardiac phenotype and clinical outcomes in patients with hypertrophic cardiomyopathy.

BACKGROUND: It is unknown whether sex-specific differences in mortality observed in HCM are due to older age of women at presentation, or whether women have greater degree of LV myopathy than men. METHODS: We retrospectively compared clinical/imaging characteristics and outcomes between women and men in our overall cohort composed of 728 HCM patients, and in an age-matched subgroup comprised of 400 age-matched patients. We examined sex-specific differences in LV myopathy, and dissected the influence of age and sex on outcomes. LV myopathy was assessed by measuring LV mass, LVEF, global peak longitudinal systolic strain (LV-GLS), diastolic function (E/A, E/e'), late gadolinium enhancement (LV-LGE) and myocardial blood flow (MBF) at rest/stress. The primary endpoint was a composite outcome, comprising heart failure (HF), atrial fibrillation (AFib), ventricular tachycardia/fibrillation (VT/VF) and death; individual outcomes were defined as the secondary endpoint. RESULTS: Women in the overall cohort were older by 6 years. Women were more symptomatic and more likely to have obstructive HCM. Women had smaller LV cavity size, stroke volume and LV mass, higher indexed maximum wall thickness (IMWT), more hyperdynamic LVEF and higher/similar LV-GLS. Women had similar LV-LGE and E/A, but higher E/e' and rest/stress MBF. Female sex was independently associated with the composite outcome in the overall cohort, and with HF in the overall cohort and age-matched subgroup after adjusting for obstructive HCM, LA diameter, LV-GLS. CONCLUSIONS: Our results suggest that sex-specific differences in LV geometry, hyper-contractility and diastolic function, not greater degree of LV myopathy, contribute to a higher, age-independent risk of diastolic HF in women with HCM.

Right Ventricular Functional Reserve in Pulmonary Arterial Hypertension.

BACKGROUND: Right ventricular (RV) functional reserve affects functional capacity and prognosis in patients with pulmonary arterial hypertension (PAH). PAH associated with systemic sclerosis (SSc-PAH) has a substantially worse prognosis than idiopathic PAH (IPAH), even though many measures of resting RV function and pulmonary vascular load are similar. We therefore tested the hypothesis that RV functional reserve is depressed in SSc-PAH patients. METHODS AND RESULTS: RV pressure-volume relations were prospectively measured in IPAH (n=9) and SSc-PAH (n=15) patients at rest and during incremental atrial pacing or supine bicycle ergometry. Systolic and lusitropic function increased at faster heart rates in IPAH patients, but were markedly blunted in SSc-PAH. The recirculation fraction, which indexes intracellular calcium recycling, was also depressed in SSc-PAH (0.32±0.05 versus 0.50±0.05; P=0.039). At matched exercise (25 W), SSc-PAH patients did not augment contractility (end-systolic elastance) whereas IPAH did (P<0.001). RV afterload assessed by effective arterial elastance rose similarly in both groups; thus, ventricular-vascular coupling declined in SSc-PAH. Both end-systolic and end-diastolic RV volumes increased in SSc-PAH patients to offset contractile deficits, whereas chamber dilation was absent in IPAH (+37±10% versus +1±8%, P=0.004, and +19±4% versus -1±6%, P<0.001, respectively). Exercise-associated RV dilation also strongly correlated with resting ventricular-vascular coupling in a larger cohort. CONCLUSIONS: RV contractile reserve is depressed in SSc-PAH versus IPAH subjects, associated with reduced calcium recycling. During exercise, this results in ventricular-pulmonary vascular uncoupling and acute RV dilation. RV dilation during exercise can predict adverse ventricular-vascular coupling in PAH patients.

Structural and Functional Correlates of Myocardial T1 Mapping in 321 Patients With Hypertrophic Cardiomyopathy.

OBJECTIVE: The aim of this study was to evaluate the structural and functional correlates of T1 mapping in 321 patients with hypertrophic cardiomyopathy (HCM). METHODS: Three hundred twenty-one patients with HCM who underwent cardiac magnetic resonance from 2003 to 2013 were retrospectively identified from our institution's HCM registry. Left ventricular volume, function, late gadolinium enhancement (LGE), and Look-Locker T1 time were quantified. T1 time was normalized to blood pool to calculate T1 ratio. Correlations between LGE%, T1 ratio, and structural and functional features were performed using Pearson correlation coefficient. RESULTS: Late gadolinium enhancement showed stronger correlation with left ventricular mass index (r = 0.41, P < 0.001) compared with T1 ratio (r = -0.17, P = 0.004). Both LGE% and T1 ratio correlated with ejection fraction (r = -0.18 and P = 0.002 vs r = 0.21 and P < 0.001, respectively). E/e' showed correlation with LGE% but not with T1 ratio. CONCLUSIONS: Late gadolinium enhancement was more strongly correlated with the phenotypic expression of HCM compared with T1 ratio.

Predictors of Acute Renal Injury Study (PARIS) among HIV-positive individuals: design and methods.

BACKGROUND: Acute kidney injury (AKI), which is common among HIV-positive individuals, may contribute to the excess burden of chronic kidney disease (CKD) in this patient population; however, conventional clinical methods to detect AKI do not capture kidney injury sufficiently early to prevent irreversible damage. Further, large observational and interventional studies of AKI generally exclude HIV-positive persons in spite of their disproportionate risk. METHODS: The Predictors of Acute Renal Injury Study (PARIS) is a prospective observational cohort study among HIV-positive individuals established to determine the ability of candidate kidney injury biomarkers to predict future hospitalized clinical AKI, to characterize hospitalized subclinical AKI, and to discern the risk of progressive kidney disease following subclinical and clinical AKI. Among the candidate kidney injury markers, we will select the most promising to translate into a clinically viable, multiplex panel of urinary biomarkers which we will integrate with clinical factors to develop a model prognostic of risks for AKI and subsequent kidney function decline. This study has a targeted enrollment of 2000 participants. The overall follow-up of participants consists of two phases: 1) a 5-year active follow-up phase which involves serial evaluations at enrollment, annual clinic visits, and among participants who are hospitalized during this period, an evaluation at index hospitalization and 3 and 12 months post-hospitalization; and 2) a subsequent passive follow-up phase for the duration that the participant receives medical care at The Johns Hopkins Hospital. DISCUSSIONS: This study will serve as an important resource for future studies of AKI by establishing a repository with both ambulatory and inpatient biospecimens, a resource that is currently lacking in existing HIV clinical cohorts and studies of AKI. Upon completion of this study, the resulting prognostic model which will incorporate results from the multiplex HIV-AKI Risk Pane could serve as a pharmacodynamic endpoint for early phase therapeutic candidates for AKI.

Liver Malignancies Treated With Intra-Arterial Therapy: Assessment of Early Response as Quantified by Volumetric Enhancement Using Gadoxetate Disodium.

OBJECTIVE: The aim of the study was to evaluate the value of volumetric contrast-enhanced magnetic resonance imaging (MRI) using gadoxetate disodium in early assessment of treatment response after intra-arterial therapy (IAT). MATERIALS AND METHODS: This prospective study included 21 patients (32 malignant lesions) who underwent MRI using gadoxetate disodium before and early after IAT. Two reviewers reported response by anatomic criteria including Response Evaluation Criteria in Solid Tumor (RECIST), Modified RECIST (mRECIST), and European Association for the Study of Liver Disease and functional criteria including volumetric enhancement in hepatic arterial phase and portal venous phase. Treatment end point was RECIST at 6 months. A 2-sample paired t test was used to compare the mean changes after IAT. A P value of less than 0.05 was considered statistically significant. RESULTS: Responders by RECIST at 6 months did not fulfill partial response by conventional criteria at 1 month, except for mRECIST by reader 2. The mRECIST and European Association for the Study of Liver Disease could not be assessed in a total of 4 and 3 lesions for readers 1 and 2, respectively. However, volumetric measurements were obtained in all lesions and the changes were statistically significant at 1 month for hepatic arterial phase (P = 0.02 and P = 0.008) and portal venous phase (P < 0.0001 and P < 0.0001), as assessed by both readers, respectively. CONCLUSIONS: Volumetric contrast-enhanced MRI using gadoxetate disodium may be a helpful tool to evaluate early treatment response after IAT in malignant liver tumors.

Evaluation of Hepatocellular Carcinoma Tumor Response After Transcatheter Arterial Chemoembolization Using Gadobenate Dimeglumine-Enhanced Liver Magnetic Resonance.

OBJECTIVE: Use of gadobenate dimeglumine-enhanced liver magnetic resonance (MR) for evaluation of hepatocellular carcinoma tumor response after transcatheter arterial chemoembolization (TACE). METHODS: Forty-five patients with hepatocellular carcinoma were imaged with multiphase gadobenate dimeglumine-enhanced MR examination at baseline and 1-month follow-up after TACE. Nodule size, enhancement, and apparent diffusion coefficient were measured for both examinations by 2 reviewers. Changes in tumor nodule size, enhancement, and apparent diffusion coefficient were evaluated using the Student t test. RESULTS: Nineteen of 45 patients completed the study, and a total of 34 hepatocellular carcinoma nodules were analyzed. On the posttreatment follow up, there was no significant change in nodule size. Target lesions demonstrated significant decrease in tumor enhancement after TACE (P < 0.001). Intense contrast accumulation along the periphery of the presumed necrotic tumor on the delayed hepatobiliary phase helped to differentiate viable from non-viable tumor. CONCLUSION: Gadobenate dimeglumine-enhanced liver MR may help differentiate between viable and necrotic tumor after TACE.

Evaluation of Left Ventricular Outflow Tract Obstruction With Four-Dimensional Phase Contrast Magnetic Resonance Imaging in Patients with Hypertrophic Cardiomyopathy-A Pilot Study.

OBJECTIVE: This study aimed to validate 4-dimensional phase contrast (4D PC) cine magnetic resonance imaging (MRI) as a means of evaluating left ventricular outflow tract (LVOT) obstruction in patients with hypertrophic cardiomyopathy (HCM). METHODS: In this institutional review board-approved prospective study, 23 patients with suspected HCM from October 2012 to September 2013 underwent 4D PC MRI. Postprocessed 4D PC pathline cine data were reviewed by 2 blinded reviewers to determine presence or absence of LVOT obstruction. Sensitivity, specificity, and accuracy in 4D PC qualitative and quantitative assessment of LVOT obstruction were calculated using echo as reference standard. RESULTS: Consensus interpretation of 4D PC showed 100.0% (7/7) sensitivity, 75.0% specificity (12/16), and 82.6% (19/23) accuracy in assessment of LVOT obstruction. The 4D PC quantitative estimates of LVOT gradient have 71.4% (5/7) sensitivity, 93.8% (15/16) specificity, and 87.0% (20/23) accuracy in evaluation of LVOT obstruction compared with echo. CONCLUSIONS: The 4D PC MRI can assess for LVOT obstruction in HCM patients.

Diffusion-Weighted Magnetic Resonance Imaging in Distinguishing Between Mucin-Producing and Serous Pancreatic Cysts.

OBJECTIVE: The aim of this study was to evaluate the feasibility and reproducibility of diffusion-weighted imaging in distinguishing between mucin-producing and serous pancreatic cysts. METHODS: Forty-four pancreatic cysts (43 patients, 27 women; mean age, 57 years; 26 mucin-producing cysts, 18 serous cysts) that underwent histological examination or cyst analysis after diffusion-weighted magnetic resonance imaging were retrospectively reviewed. Three blinded readers independently evaluated signal intensity and apparent diffusion coefficient (ADC). Intraobserver and interobserver agreements were calculated. Fisher exact test and Welch t test were used to compare signal intensity and ADC values, respectively, with pathological results. Receiver operating characteristic analysis was used to determine diagnostic accuracy of various thresholds for ADC. A P value less than 0.05 was considered statistically significant. RESULTS: Mean ADC values of the mucin-producing cysts were 3.26 × 10, 3.27 × 10, and 3.35 × 10 mm/s for the 3 readers, respectively. Mean ADC values of the serous cysts were 2.86 × 10, 2.85 × 10, and 2.85 × 10 mm/s for the 3 readers, respectively. Differences in ADC values between the 2 cyst groups were 12.4%, 12.9%, and 14.8% for the 3 readers, respectively (P < 0.001). Intraobserver and interobserver agreement was excellent. A threshold ADC of 3 × 10 mm/s resulted in correct identification of cysts in 77% to 81% of cases, with sensitivity and specificity ranging between 84% and 88% and 66% and 72%, respectively. CONCLUSIONS: Diffusion-weighted imaging may be a helpful tool in distinguishing between mucin-producing and serous pancreatic cysts.

Ambrisentan and Tadalafil Up-front Combination Therapy in Scleroderma-associated Pulmonary Arterial Hypertension.

BACKGROUND: Scleroderma-associated pulmonary arterial hypertension (SSc-PAH) is a rare disease characterized by a very dismal response to therapy and poor survival. We assessed the effects of up-front combination PAH therapy in patients with SSc-PAH. METHODS: In this prospective, multicenter, open-label trial, 24 treatment-naive patients with SSc-PAH received ambrisentan 10 mg and tadalafil 40 mg daily for 36 weeks. Functional, hemodynamic, and imaging (cardiac magnetic resonance imaging and echocardiography) assessments at baseline and 36 weeks included changes in right ventricular (RV) mass and pulmonary vascular resistance as co-primary endpoints and stroke volume/pulmonary pulse pressure ratio, tricuspid annular plane systolic excursion, 6-minute walk distance, and N-terminal pro-brain natriuretic peptide as secondary endpoints. RESULTS: At 36 weeks, we found that treatment had resulted in significant reductions in median (interquartile range [IQR]) RV mass (28.0 g [IQR, 20.6-32.9] vs. 32.5 g [IQR, 23.2-41.4]; P < 0.05) and median pulmonary vascular resistance (3.1 Wood units [IQR, 2.0-5.7] vs. 6.9 Wood units [IQR, 4.0-12.9]; P < 0.0001) and in improvements in median stroke volume/pulmonary pulse pressure ratio (2.6 ml/mm Hg [IQR, 1.8-3.5] vs. 1.4 ml/mm Hg [IQR 8.9-2.4]; P < 0.0001) and mean ( ± SD) tricuspid annular plane systolic excursion (2.2 ± 0.12 cm vs. 1.65 ± 0.11 cm; P < 0.0001), 6-minute walk distance (395 ± 99 m vs. 343 ± 131 m; P = 0.001), and serum N-terminal pro-brain natriuretic peptide (647 ± 1,127 pg/ml vs. 1,578 ± 2,647 pg/ml; P < 0.05). CONCLUSIONS: Up-front combination therapy with ambrisentan and tadalafil significantly improved hemodynamics, RV structure and function, and functional status in treatment-naive patients with SSc-PAH and may represent a very effective therapy for this patient population. In addition, we identified novel hemodynamic and imaging biomarkers that could have potential value in future clinical trials. Clinical trial registered with www.clinicaltrials.gov (NCT01042158).

Volumetric assessment of tumour response using functional MR imaging in patients with hepatocellular carcinoma treated with a combination of doxorubicin-eluting beads and sorafenib.

OBJECTIVE: To prospectively assess treatment response using volumetric functional magnetic resonance imaging (MRI) metrics in patients with hepatocellular carcinoma (HCC) treated with the combination of doxorubicin-eluting bead-transarterial chemoembolization (DEB TACE) and sorafenib. METHODS: A single center study enrolled 41 patients treated with systemic sorafenib, 400 mg twice a day, combined with DEB TACE. All patients had a pre-treatment and 3-4 week post-treatment MRI. Anatomic response criteria (RECIST, mRECIST and EASL) and volumetric functional response (ADC, enhancement) were assessed. Statistical analyses included paired Student's t-test, Kaplan-Meier curves, Cohen's Kappa, and multivariate cox proportional hazard model. RESULTS: Median tumour size by RECIST remained unchanged post-treatment (8.3 ± 4.1 cm vs. 8.1 ± 4.3 cm, p = 0.44). There was no significant survival difference for early response by RECIST (p = 0.93). EASL and mRECIST could not be analyzed in 12 patients. Volumetric ADC increased significantly (1.32 × 10(-3) mm(2)/sec to 1.60 × 10(-3) mm(2)/sec, p < 0.001), and volumetric enhancement decreased significantly in HAP (38.2% to 17.6%, p < 0.001) and PVP (76.6% to 41.2%, p < 0.005). Patients who demonstrated ≥ 65% decrease PVP enhancement had significantly improved overall survival compared to non-responders (p < 0.005). CONCLUSION: Volumetric PVP enhancement was demonstrated to be significantly correlated with survival in the combination of DEB TACE and sorafenib for patients with HCC, enabling precise stratification of responders and non-responders. KEY POINTS: • PVP enhancement is significantly correlated with survival in responders (p < 0.005). • There was no significant survival difference for early response using RECIST (p = 0.93). • mRECIST or EASL could not assess tumour response in 29% of patients.

Response stratification and survival analysis of hepatocellular carcinoma patients treated with intra-arterial therapy using MR imaging-based arterial enhancement fraction.

PURPOSE: To investigate the feasibility that arterial enhancement fraction (AEF) is associated with response of hepatocellular carcinoma (HCC) following intra-arterial therapy (IAT) and to compare AEF response with currently used tumor response metrics. MATERIALS AND METHODS: The AEF, Response Evaluation Criteria in Solid Tumors (RECIST), modified RECIST (mRECIST), and European Association for the Study of the Liver (EASL) of the largest treated index lesion and AEF of the tumor-free hepatic parenchyma was measured on representative axial images in 131 patients (108 male; mean age, 61.9 years). Clinical measures and patient survival were assessed. Statistical analysis included Wilcoxon signed-rank test and the COX proportional hazards model. RESULTS: After IAT, the mean AEF of the tumor decreased by 22% (66.7-44.8%, P < 0.0001), while the mean AEF of the tumor-free parenchyma remained unchanged (27.2-26.5%, P = 0.50). Median survival of all 131 patients with liver cancer was 17 months. Patients were stratified into AEF-responders if they had an AEF-decrease ≥35% (AEF-responders: n = 67; AEF-nonresponders: n = 64). AEF-responders survived longer than nonresponders (34.8 months versus 10.8 months, hazard ratio = 0.39; P < 0.0001). Responders according to RECIST, mRECIST, or EASL did not survive significantly longer compared with nonresponders. CONCLUSION: Evaluating the AEF values based on tri-phasic MRI is associated with tumor response in patients with unresectable HCC treated with IAT.

Assessing liver fibrosis: comparison of arterial enhancement fraction and diffusion-weighted imaging.

PURPOSE: Noninvasive markers have been developed to reduce the need for liver biopsy. The aim of this study was to compare the strength of association of the arterial enhancement fraction (AEF), apparent diffusion coefficient (ADC), and serum biomarkers for staging hepatic fibrosis. MATERIALS AND METHODS: Eighty-five patients with chronic liver disease underwent triple-phase contrast-enhanced MRI, used to calculate AEF, and diffusion-weighted MRI (b = 0,750 s/mm(2) ), used to calculate ADC. Hepatic fibrosis was staged according METAVIR criteria. The overall association of the four biomarkers (AEF, ADC, aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio, and aspartate aminotransferase to platelet ratio index [APRI]) was compared using nonparametric tests and receiver operating characteristic (ROC) curve, using histopathologic analysis as the reference standard. RESULTS: AEF and ADC values differed significantly between histopathologic fibrosis stages. AEF values correlated with fibrosis stage, ADC values correlated negatively with fibrosis stage. Compared with ADC, AEF showed a trend toward an improved capability of discriminating fibrosis stages. A weighted composite score of AEF and ADC had significantly better diagnostic accuracy than ADC alone (P ≤ 0.023). Imaging parameters had a significantly better diagnostic accuracy than AST/ALT ratio or APRI. CONCLUSION: AEF may be able to detect the presence of mild, moderate, and advanced liver fibrosis, and its value is increased with concomitant use of ADC.

Cardiac MR findings and potential diagnostic pitfalls in patients evaluated for arrhythmogenic right ventricular cardiomyopathy.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a familial cardiomyopathy characterized by fibrofatty replacement of the myocardium, ventricular tachycardia, and ventricular dysfunction that affects primarily the right ventricle (RV). This disease is not common but can be seen more frequently in young adults, and clinical manifestations range from no symptoms to lethal arrhythmia and sudden death. The diagnosis of ARVC is challenging and is based on the recently revised international task force criteria. Given the strengths of cardiac magnetic resonance (MR) imaging for depicting the RV, this modality plays an important role in the diagnosis of ARVC. Functional and structural abnormalities of the RV depicted with cardiac MR imaging constitute major and minor criteria in the revised task force criteria. Since the ARVC program was established at our center in 1998, there has been an increased awareness of a number of normal variants that are commonly misinterpreted as showing evidence for ARVC. On the basis of our clinical experience, the overdiagnosis of ARVC appears to reflect two fundamental problems: (a) a lack of awareness of diagnostic criteria that identify major and minor variables to be used for the diagnosis of ARVC, and (b) a lack of familiarity with the normal variants and mimics that may be misinterpreted as showing evidence of ARVC. The purpose of this article is to review the typical patterns of ventricular involvement in ARVC at cardiac MR imaging and to compare those with the patterns of normal variants and other diseases that can mimic ARVC. Online supplemental material is available for this article.

Functional volumetric MRI in assessing treatment response to intra-arterial therapy of primary and secondary liver tumors.

The assessment of tumor response after intra-arterial therapy (IAT) is useful to determine treatment success, to guide future treatments, and to predict patient outcome. Changes in tumor size in the axial plane after transarterial therapies might be delayed with the traditional criteria, whereas cellular tumor changes can be detected earlier by functional metrics such as vascular enhancement and cellular integrity in the entire tumor volume. Magnetic resonance imaging has become an important tool in the evaluation of early tumor response with the introduction of new techniques, such as diffusion-weighted imaging and apparent diffusion coefficient maps, and the development of advanced software to quantify vascular enhancement after IATs. This review discusses the role of treatment response by functional volumetric imaging after IAT in patients with primary and secondary liver tumors.

Multidisciplinary approaches to intrahepatic cholangiocarcinoma.

After hepatocellular carcinoma, intrahepatic cholangiocarcinoma (ICC) is the second most common primary hepatic malignancy. The etiology of ICC in most patients is not known, but its incidence is on the rise worldwide. There are 3 morphologic subtypes of ICC that can be characterized on cross-sectional imaging, mass forming, periductal infiltrating, and intraductal growth; and the radiographic characteristics of ICC may vary based on the subtype. Complete surgical resection remains the only potentially curative option for patients with ICC. Routine lymphadenectomy at the time of surgical resection should be strongly considered, because lymph node status provides important prognostic information. After surgery, the 5-year survival rate for ICC remains poor at only 25% to 35% in most series. Although numerous clinical trials have been conducted using a variety of chemotherapy regimens to treat ICC, systemic options for ICC remain limited. Doublet gemcitabine and cisplatin therapy is currently considered the standard-of-care first-line therapy for patients with advanced disease. Because ICC is typically confined to the liver and systemic chemotherapy traditionally has had only limited efficacy, there has been increasing interest in locoregional therapy. Although locoregional therapy may include intra-arterial therapies, stereotactic radiotherapy, hepatic artery pump therapy, or ablation, most data are limited. The purpose of this article was to provide a multidisciplinary appraisal of the current therapeutic approaches to ICC.

Neuroendocrine liver metastasis treated by using intraarterial therapy: volumetric functional imaging biomarkers of early tumor response and survival.

PURPOSE: To determine if volumetric changes of diffusion-weighted and contrast material-enhanced magnetic resonance (MR) imaging can help assess early tumor response to intraarterial therapy (IAT) in neuroendocrine liver metastasis (NELM). MATERIALS AND METHODS: This retrospective single-center comprehensive imaging analysis was performed in compliance with HIPAA and was institutional review board approved. Informed patient consent was waived. Seventy-one patients (39 men; mean age, 62.3 years) with NELM treated with IAT were analyzed retrospectively. MR studies were performed before and 3-4 weeks after therapy. The index lesion was segmented to provide volumetric functional analysis of apparent diffusion coefficient (ADC) and contrast-enhanced MR imaging in the hepatic arterial phase (HAP) and portal venous phase (PVP). Tumor response was defined as increase in volumetric ADC of 15% or greater and decrease in volumetric enhancement of 25% or greater during the HAP or of 50% or greater during the PVP. Patient overall survival was the primary end point after therapy initiation. Univariate analysis included Kaplan-Meier survival curves. The Cox proportional hazards regression model was used to detect interactions between volumetric ADC and contrast-enhanced MR imaging and to calculate the hazard ratio. RESULTS: There was significant increase in mean volumetric ADC (27%, P < .0001) and significant decrease in mean volumetric enhancement during the HAP (-25.3%, P < .0001) and the PVP (-22.4%, P < .0001) in all patients. Patients who had 15% or greater volumetric ADC increase (n = 49) after therapy had better prognosis than those who had less than 15% increase in volumetric ADC (n = 22) (log-rank test, P < .002). Patients who had 25% or greater decrease in volumetric arterial enhancement (n = 40) or 50% or greater decrease in venous enhancement (n = 18) had better prognosis than those who had less than 25% decrease in volumetric arterial enhancement (n = 31) or less than 50% decrease in venous enhancement (n = 53) (log-rank test, P < .02). CONCLUSION: Volumetric functional MR imaging criteria may act as biomarkers of early response, indicating that these criteria may be important to incorporate in future NELM clinical trials.

Unresectable hepatocellular carcinoma: MR imaging after intraarterial therapy. Part I. Identification and validation of volumetric functional response criteria.

PURPOSE: To identify and validate the optimal thresholds for volumetric functional MR imaging response criteria to predict overall survival after intraarterial treatment (IAT) in patients with unresectable hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Institutional review board approval and waiver of informed consent were obtained. A total of 143 patients who had undergone MR imaging before and 3-4 weeks after the first cycle of IAT were included. MR imaging analysis of one representative HCC index lesion was performed with proprietary software after initial treatment. Subjects were randomly divided into training (n = 114 [79.7%]) and validation (n = 29 [20.3%]) data sets. Uni- and multivariate Cox models were used to determine the best cutoffs, as well as survival differences, between response groups in the validation data set. RESULTS: Optimal cutoffs in the training data set were 23% increase in apparent diffusion coefficient (ADC) and 65% decrease in volumetric enhancement in the portal venous phase (VE). Subsequently, 25% increase in ADC and 65% decrease in VE were used to stratify patients in the validation data set. Comparison of ADC responders (n = 12 [58.6%]) with nonresponders (n = 17 [34.5%]) showed significant differences in survival (25th percentile survival, 11.2 vs 4.9 months, respectively; P = .008), as did VE responders (n = 9 [31.0%]) compared with nonresponders (n = 20 [69.0%]; 25th percentile survival, 11.5 vs 5.1 months, respectively; P = .01). Stratification of patients with a combination of the criteria resulted in significant differences in survival between patients with lesions that fulfilled both criteria (n = 6 [20.7%]; too few cases to determine 25th percentile), one criterion (n = 9 [31.0%]; 25th percentile survival, 6.0 months), and neither criterion (n = 14 [48.3%]; 25th percentile survival, 5.1 months; P = .01). The association between the two criteria and overall survival remained significant in a multivariate analysis that included age, sex, Barcelona Clinic for Liver Cancer stage, and number of follow-up treatments. CONCLUSION: After IAT for unresectable HCC, patients can be stratified into significantly different survival categories based on responder versus nonresponder status according to MR imaging ADC and VE cutoffs.

Unresectable hepatocellular carcinoma: MR imaging after intraarterial therapy. Part II. Response stratification using volumetric functional criteria after intraarterial therapy.

PURPOSE: To assess whether volumetric functional magnetic resonance (MR) results 3-4 weeks after initial intraarterial therapy can aid accurate distinction between responders and nonresponders, to determine whether overall survival (OS) is improved, and to compare volumetric functional MR response with anatomic response criteria (Response Evaluation Criteria in Solid Tumors [RECIST], modified RECIST [mRECIST], European Association for the Study of the Liver [EASL]), as well as α1-fetoprotein [AFP] level. MATERIALS AND METHODS: In this single-institution HIPAA-compliant retrospective, institutional review board-approved study, informed consent was waived; 143 patients with hepatocellular carcinoma underwent intraarterial therapy between October 2005 and February 2011. Volumetric functional MR response (25% or more increase in apparent diffusion coefficient, 65% or more decrease in enhancement) was stratified as follows: Dual-parameter responders fulfilled both criteria, single-parameter responders fulfilled one criterion, and those with stable disease (SD) fulfilled neither. RECIST, mRECIST, EASL, and AFP response criteria were determined. Kaplan-Meier technique, log-rank tests, and the Cox proportional hazards model were used to test whether OS was different per response. RESULTS: OS differed significantly between single-parameter responders and dual-parameter responders (P = .01) and between single-parameter responders and those with SD (P = .001). Dual-parameter responders' response improved OS compared with single-parameter responders; risk of death decreased (hazard ratio [HR] = 0.28, P = .01). In those with SD compared with single-parameter responders, risk of death increased (HR = 2.09, P = .001). RECIST, mRECIST, and EASL stratification was short of significant; most lesions were classified as SD. Baseline AFP level increased in 55 patients; AFP responders versus AFP nonresponders had decreased risk of death (HR = 0.36, P = .002). Agreement between anatomic response criteria and volumetric functional MR findings (κ = 0.06-0.12) and between AFP response and imaging criteria (κ = -0.04 to 0.14) was low. CONCLUSION: Volumetric functional MR response 3-4 weeks after initial intraarterial therapy showed improved OS. Volumetric functional MR was superior to current imaging (RECIST, mRECIST, and EASL) and biochemical (AFP level) response criteria.

MRI arterial enhancement fraction in hepatic fibrosis and cirrhosis.

OBJECTIVE: Fibrosis leads to altered liver hemodynamics. The arterial enhancement fraction, which is defined as the ratio of hepatic arterial perfusion to the total hepatic perfusion, can provide noninvasive assessment of hepatic perfusion. The aim of this study was to show that the arterial enhancement fraction values correlate with histopathologic stage of liver fibrosis, thus providing a reliable noninvasive radiologic alternative to liver biopsy for the detection and staging of hepatic fibrosis. MATERIALS AND METHODS: We evaluated hepatic fibrosis stage (denoted by Metavir score [F]) and arterial enhancement fraction of patients who underwent standard triphasic liver MRI and liver biopsy within 1 year from January 2005 to December 2010. Prototype software was used to calculate the arterial enhancement fraction. Statistical analysis included nonparametric tests and area under the receiver operating characteristic curve (AUC). RESULTS: One hundred fourteen patients (69 men and 45 women; median age, 52.5 years) were divided into groups according to the Metavir score. The mean arterial enhancement fraction was 24.2% ± 11.6% for F0, 35.2% ± 18.7% for F1, 30.2% ± 12.5% for F2, 37.5% ± 16.4% for F3, and 59.8% ± 16.6% for F4. The mean arterial enhancement fraction values differed significantly between Metavir scores (p < 0.001) and showed a positive correlation with Metavir score (r = 0.693; p < 0.001). The optimal mean arterial enhancement fraction cutoffs were 32.96% or more (AUC = 0.8343) for detection of mild fibrosis, 33.33% or more (AUC = 0.8524) for detection of moderate fibrosis, 38.43% or more (AUC = 0.8819) for detection of severe fibrosis, and 45.76% or more (AUC = 0.9161) for detection of cirrhosis. CONCLUSION: Arterial enhancement fraction using triple-phase MRI can provide a reliable noninvasive method to assess hepatic fibrosis.