Inferring FDG-PET-positivity of lymph node metastases in proven lung cancer from contrast-enhanced CT using radiomics and machine learning.

BACKGROUND: We evaluated the role of radiomics applied to contrast-enhanced computed tomography (CT) in the detection of lymph node (LN) metastases in patients with known lung cancer compared to 18F-fluorodeoxyglucose positron emission tomography (PET)/CT as a reference. METHODS: This retrospective analysis included 381 patients with 1,799 lymph nodes (450 malignant, 1,349 negative). The data set was divided into a training and validation set. A radiomics analysis with 4 filters and 6 algorithms resulting in 24 different radiomics signatures and a bootstrap algorithm (Bagging) with 30 bootstrap iterations was performed. A decision curve analysis was applied to generate a net benefit to compare the radiomics signature to two expert radiologists as one-by-one and as a prescreening tool in combination with the respective radiologist and only the radiologists. RESULTS: All 24 modeling methods showed good and reliable discrimination for malignant/benign LNs (area under the curve 0.75-0.87). The decision curve analysis showed a net benefit for the least absolute shrinkage and selection operator (LASSO) classifier for the entire probability range and outperformed the expert radiologists except for the high probability range. Using the radiomics signature as a prescreening tool for the radiologists did not improve net benefit. CONCLUSIONS: Radiomics showed good discrimination power irrespective of the modeling technique in detecting LN metastases in patients with known lung cancer. The LASSO classifier was a suitable diagnostic tool and even outperformed the expert radiologists, except for high probabilities. Radiomics failed to improve clinical benefit as a prescreening tool.

Safety Analysis of Iobitridol as a Nonionic Contrast Medium: A Postmarketing Multicenter Surveillance Study With 94,960 Patients Almost 20 Years After Introduction.

OBJECTIVES: Our study sought to reevaluate the safety and diagnostic efficacy of iobitridol as a nonionic contrast medium after almost 20 years of use. MATERIALS AND METHODS: This noninterventional postmarketing surveillance noncontrolled, multicenter (168 centers in Germany) study enrolled 94,960 patients receiving intravenous or intra-arterial iobitridol. The majority of the adjusted population (n = 92,550, 98.2%) underwent either computed tomography examination (n = 46,502, 49.3%) or intravenous urography (n = 46,048, 48.8%). A standardized questionnaire was used to ascertain patient's information, known risk factors, renal function status, premedication, type of examination, injection of contrast agent, imaging quality, diagnostic value, and safety. RESULTS: A total of 469 patients (0.49%) experienced an adverse event (AE), and 24 patients (0.025%) reported a serious AE (SAE). All patients recovered and no fatal event occurred. The prevalence of AE was significantly higher in patients with at least one risk factor, with premedication, with a history of AE, in female and patients younger than 60 years old (P < 0.05). Presence of at least one risk factor is the only predictive factor for the prevalence of SAE (P = 0.042). In patients with a history of AE, premedication did not significantly lower the AE rate (P = 0.737). No statistically significant difference in the prevalence of AE between the different combination of cortisone and/or antihistamines as pretreatment was found. CONCLUSIONS: Iobitridol is a safe contrast medium with a high tolerability and efficacy. Presence of risk factors such as cardiovascular diseases, allergies, or asthma was the only significant predictive factor for an AE and an SAE. Premedication did not significantly lower the occurrence of an AE and an SAE.

Intra-arterial therapy of neuroendocrine tumour liver metastases: comparing conventional TACE, drug-eluting beads TACE and yttrium-90 radioembolisation as treatment options using a propensity score analysis model.

OBJECTIVES: To compare efficacy, survival outcome and prognostic factors of conventional transarterial chemoembolisation (cTACE), drug-eluting beads TACE (DEB-TACE) and yttrium-90 radioembolisation (Y90) for the treatment of liver metastases from gastroenteropancreatic (GEP) neuroendocrine tumours (NELM). METHODS: This retrospective analysis included 192 patients (58.6 years mean age, 56% men) with NELM treated with cTACE (N = 122), DEB-TACE (N = 26) or Y90 (N = 44) between 2000 and 2014. Radiologic response to therapy was assessed according to Response Evaluation Criteria in Solid Tumours (RECIST) and World Health Organization (WHO) criteria using periprocedural MR imaging. Survival analysis included propensity score analysis (PSA), median overall survival (MOS), hepatic progression-free survival, Kaplan-Meier using log-rank test and the uni- and multivariate Cox proportional hazards model (MVA). RESULTS: MOS of the entire study population was 28.8 months. As for cTACE, DEB-TACE and Y90, MOS was 33.8 months, 21.7 months and 23.6 months, respectively. According to the MVA, cTACE demonstrated a significantly longer MOS as compared to DEB-TACE (p <.01) or Y90 (p = .02). The 5-year survival rate after initial cTACE, DEB-TACE and Y90 was 28.2%, 10.3% and 18.5%, respectively. CONCLUSIONS: Upon PSA, our study suggests significant survival benefits for patients treated with cTACE as compared to DEB-TACE and Y90. This data supports the therapeutic decision for cTACE as the primary intra-arterial therapy option in patients with unresectable NELM until proven otherwise. KEY POINTS: • cTACE achieved a significantly longer overall survival in patients with unresectable NELM. • Patients treated with cTACE showed a prolonged hepatic progression-free survival. • cTACE, DEB-TACE and Y90 radioembolisation demonstrated comparable safety and toxicity profiles. • Age >70 years, extrahepatic metastases and tumour burden >50% were identified as negative predictors. • Propensity score analysis suggests the superiority of cTACE over DEB-TACE and Y90.

Advanced-stage hepatocellular carcinoma with portal vein thrombosis: conventional versus drug-eluting beads transcatheter arterial chemoembolization.

OBJECTIVES: Our study sought to compare the overall survival in patients with hepatocellular carcinoma (HCC) and portal venous thrombosis (PVT), treated with either conventional trans-arterial chemoembolization (cTACE) or drug-eluting beads (DEB) TACE. METHODS: This retrospective analysis included a total of 133 patients, treated without cross-over and compared head-to-head by means or propensity score weighting. Mortality was compared using survival analysis upon propensity score weighting. Adverse events and liver toxicity grade ≥3 were recorded and reported for each TACE. In order to compare with historical sorafenib studies, a sub-group analysis was performed and included patients who fulfilled the SHARP inclusion criteria. RESULTS: The median overall survival (MOS) of the entire cohort was 4.53 months (95 % CI, 3.63-6.03). MOS was similar across treatment arms, no significant difference between cTACE (N = 95) and DEB-TACE (N = 38) was observed (MOS of 5.0 vs. 3.33 months, respectively; p = 0.157). The most common adverse events after cTACE and DEB- TACE, respectively, were as follows: post-embolization syndrome [N = 57 (30.0 %) and N = 38 (61.3 %)], diarrhea [N = 3 (1.6 %) and N = 3 (4.8 %)], and encephalopathy [N = 11 (5.8 %) and N = 2 (3.2 %)]. CONCLUSION: Our retrospective study could not reveal a difference in toxicity and efficiency between cTACE and DEB-TACE for treatment of advanced stage HCC with PVT. KEY POINTS: • Conventional TACE (cTACE) and drug-eluting-beads TACE (DEB-TACE) demonstrated equal safety profiles. • Survival rates after TACE are similar to patients treated with sorafenib. • Child-Pugh class and tumor burden are reliable predictors of survival.

Preclinical Benefit of Hypoxia-Activated Intra-arterial Therapy with Evofosfamide in Liver Cancer.

PURPOSE: To evaluate safety and characterize anticancer efficacy of hepatic hypoxia-activated intra-arterial therapy (HAIAT) with evofosfamide in a rabbit model. EXPERIMENTAL DESIGN: VX2-tumor-bearing rabbits were assigned to 4 intra-arterial therapy (IAT) groups (n = 7/group): (i) saline (control); (ii) evofosfamide (Evo); (iii) doxorubicin-lipiodol emulsion followed by embolization with 100-300 µm beads (conventional, cTACE); or (iv) cTACE and evofosfamide (cTACE + Evo). Blood samples were collected pre-IAT and 1, 2, 7, and 14 days post-IAT. A semiquantitative scoring system assessed hepatocellular damage. Tumor volumes were segmented on multidetector CT (baseline, 7/14 days post-IAT). Pathologic tumor necrosis was quantified using manual segmentation on whole-slide images. Hypoxic fraction (HF) and compartment (HC) were determined by pimonidazole staining. Tumor DNA damage, apoptosis, cell proliferation, endogenous hypoxia, and metabolism were quantified (γ-H2AX, Annexin V, caspase-3, Ki-67, HIF1α, VEGF, GAPDH, MCT4, and LDH). RESULTS: cTACE + Evo showed a similar profile of liver enzymes elevation and pathologic scores compared with cTACE. Neither hematologic nor renal toxicity were observed. Animals treated with cTACE + Evo demonstrated smaller tumor volumes, lower tumor growth rates, and higher necrotic fractions compared with cTACE. cTACE + Evo resulted in a marked reduction in the HF and HC. Correlation was observed between decreases in HF or HC and tumor necrosis. cTACE + Evo promoted antitumor effects as evidenced by increased expression of γ-H2AX, apoptotic biomarkers, and decreased cell proliferation. Increased HIF1α/VEGF expression and tumor glycolysis supported HAIAT. CONCLUSIONS: HAIAT achieved a promising step towards the locoregional targeting of tumor hypoxia. The favorable toxicity profile and enhanced anticancer effects of evofosfamide in combination with cTACE pave the way towards clinical trials in patients with liver cancer. Clin Cancer Res; 23(2); 536-48. ©2016 AACR.

Improved Visibility of Metastatic Disease in the Liver During Intra-Arterial Therapy Using Delayed Arterial Phase Cone-Beam CT.

PURPOSE: To compare the visibility of liver metastases on dual-phase cone-beam CT (DP-CBCT) and digital subtraction angiography (DSA), with reference to preinterventional contrast-enhanced magnetic resonance imaging (CE-MRI) of the liver. METHODS: This IRB-approved, retrospective study included 28 patients with neuroendocrine (NELM), colorectal (CRCLM), or sarcoma (SLM) liver metastases who underwent DP-CBCT during intra-arterial therapy (IAT) between 01/2010 and 10/2014. DP-CBCT was acquired after a single contrast agent injection in the tumor-feeding arteries at early and delayed arterial phases (EAP and DAP). The visibility of each lesion was graded by two radiologists in consensus on a three-rank scale (complete, partial, none) on DP-CBCT and DSA images using CE-MRI as reference. RESULTS: 47 NELM, 43 CRCLM, and 16 SLM were included. On DSA 85.1, 44.1, and 37.5 % of NELM, CRCLM, and SLM, were at least partially depicted, respectively. EAP-CBCT yielded significantly higher sensitivities of 88.3 and 87.5 % for CRCLM and SLM, respectively (p < 0.01), but not for NELM (89.4 %; p = 1.0). On DAP-CBCT all NELM, CRCLM, and SLM were visible (p < 0.001). Complete depiction was achieved on DSA for 59.6, 16.3, and 18.8 % of NELM, CRCLM, and SLM, respectively. The complete depiction rate on EAP-CBCT was significantly higher for CRCLM (46.5 %; p < 0.001), lower for NELM (40.4 %; p = 0.592), and similar for SLM (25 %, p = 0.399). On DAP-CBCT however, the highest rates of complete depiction were found-NELM (97.8 %; p = 0.008), CRCLM (95.3 %; p = 0.008), and SLM (100 %; p < 0.001). CONCLUSION: DAP-CBCT substantially improved the visibility of liver metastases during IAT. Future studies need to evaluate the clinical impact.

Aortic Valve Pathology in Patients Supported by Continuous-Flow Left Ventricular Assist Device.

BACKGROUND: Continuous-flow left ventricular assist devices (CF-LVAD) may induce pathological changes to the aortic wall and aortic valve. We assessed histological changes in the relevant anatomic structures exposed to continuous flow over time and compared the histological results with clinical features in patients supported with CF-LVAD. METHODS AND RESULTS: A retrospective histological analysis was performed of 38 explanted hearts supported with CF-LVAD from patients who received heart transplantation between July 2003 and February 2014. Sections of formalin-fixed paraffin-embedded tissue showing the continuity of aortic wall and left-sided valves were examined histologically. Thickness of aorta, aortic root and aortic valve as well as 3 layers of the aortic cusps were measured individually on Elastica van Gieson-stained slides using specific software. Clinical parameters concerning aortic valve dysfunction were evaluated and validated against the histology. The aortic valve spongiosa and fibrosa layers showed no significant differences in thickness with regard to support duration or occurrence of aortic insufficiency. Longer CF-LVAD support duration correlated with a thinner aortic valve ventricularis layer (rS=-0.496). CONCLUSIONS: Long-term CF-LVAD support appears to cause involution of the ventricularis layer of the aortic valve cusp, consistent with more pronounced degenerative change with longer LVAD exposure, which may be explained by continuous coaptation of the cusps. (Circ J 2016; 80: 1371-1377).

90Y Radioembolization of Colorectal Hepatic Metastases Using Glass Microspheres: Safety and Survival Outcomes from a 531-Patient Multicenter Study.

UNLABELLED: Hepatic metastases of colorectal carcinoma are a leading cause of cancer-related mortality. Most colorectal liver metastases become refractory to chemotherapy and biologic agents, at which point the median overall survival declines to 4-5 mo. Radioembolization with (90)Y has been used in the salvage setting with favorable outcomes. This study reports the survival and safety outcomes of 531 patients treated with glass-based (90)Y microspheres at 8 institutions, making it the largest (90)Y study for patients with colorectal liver metastases. METHODS: Data were retrospectively compiled from 8 institutions for all (90)Y glass microsphere treatments for colorectal liver metastases. Exposure to chemotherapeutic or biologic agents, prior liver therapies, biochemical parameters before and after treatment, radiation dosimetry, and complications were recorded. Uni- and multivariate analyses for predictors of survival were performed. Survival outcomes and clinical or biochemical adverse events were recorded. RESULTS: In total, 531 patients received (90)Y radioembolization for colorectal liver metastases. The most common clinical adverse events were fatigue (55%), abdominal pain (34%), and nausea (19%). Grade 3 or 4 hyperbilirubinemia occurred in 13% of patients at any time. The median overall survival from the first (90)Y treatment was 10.6 mo (95% confidence interval, 8.8-12.4). Performance status, no more than 25% tumor burden, no extrahepatic metastases, albumin greater than 3 g/dL, and receipt of no more than 2 chemotherapeutic agents independently predicted better survival outcomes. CONCLUSION: This multiinstitutional review of a large cohort of patients with colorectal liver metastases treated with (90)Y radioembolization using glass microspheres has demonstrated promising survival outcomes with low toxicity and low side effects. The outcomes were reproducible and consistent with prior reports of radioembolization.

How I do it: a practical database management system to assist clinical research teams with data collection, organization, and reporting.

RATIONALE AND OBJECTIVES: The objective of this study was to demonstrate that an intra-arterial liver therapy clinical research database system is a more workflow efficient and robust tool for clinical research than a spreadsheet storage system. The database system could be used to generate clinical research study populations easily with custom search and retrieval criteria. MATERIALS AND METHODS: A questionnaire was designed and distributed to 21 board-certified radiologists to assess current data storage problems and clinician reception to a database management system. Based on the questionnaire findings, a customized database and user interface system were created to perform automatic calculations of clinical scores including staging systems such as the Child-Pugh and Barcelona Clinic Liver Cancer, and facilitates data input and output. RESULTS: Questionnaire participants were favorable to a database system. The interface retrieved study-relevant data accurately and effectively. The database effectively produced easy-to-read study-specific patient populations with custom-defined inclusion/exclusion criteria. CONCLUSIONS: The database management system is workflow efficient and robust in retrieving, storing, and analyzing data.

Identifying Staging Markers for Hepatocellular Carcinoma before Transarterial Chemoembolization: Comparison of Three-dimensional Quantitative versus Non-three-dimensional Imaging Markers.

Purpose To test and compare the association between radiologic measurements of lesion diameter, volume, and enhancement on baseline magnetic resonance (MR) images with overall survival and tumor response in patients with unresectable hepatocellular carcinoma (HCC) treated with transarterial chemoembolization (TACE). Materials and Methods This HIPAA-compliant retrospective, single-institution analysis was approved by the institutional review board, with waiver of informed consent. It included 79 patients with unresectable HCC who were treated with TACE. Baseline arterial phase contrast material-enhanced (CE) MR imaging was used to measure the overall and enhancing tumor diameters. A segmentation-based three-dimensional quantification of the overall and enhancing tumor volumes was performed in each patient. Numeric cutoff values (5 cm for diameters and 65 cm(3) for volumes) were used to stratify the patient cohort in two groups. Tumor response rates according to Response Evaluation Criteria in Solid Tumors (RECIST), modified RECIST (mRECIST), and European Association for the Study of the Liver (EASL) guidelines were recorded for all groups. Survival was evaluated by using Kaplan-Meier analysis and was compared by using Cox proportional hazard ratios (HRs) after univariate and multivariate analysis. Results Stratification according to overall and enhancing tumor diameters did not result in a significant separation of survival curves (HR, 1.4; 95% confidence interval [CI]: 0.7, 2.5; P = .234; and HR, 1.6; 95% CI: 0.9, 2.8; P = .08, respectively). The stratification according to overall and enhancing tumor volume achieved significance (HR, 1.8; 95% CI: 0.9, 3.4; P = .022; and HR, 1.8; 95% CI: 1.1, 3.1; P = .017, respectively). As for tumor response, higher response rates were observed in smaller lesions compared with larger lesions, when the 5-cm threshold (27% vs 15% for mRECIST and 45% vs 24% for EASL) was used. Conclusion As opposed to anatomic tumor diameter as the most commonly used staging marker, volumetric assessment of lesion size and enhancement on baseline CE MR images is strongly associated with survival of patients with HCC who were treated with TACE.

Transarterial chemoembolization in soft-tissue sarcoma metastases to the liver - the use of imaging biomarkers as predictors of patient survival.

BACKGROUND: The clinical management of patients with metastatic soft-tissue sarcoma of the liver is complicated by the paucity of reliable clinical data. This study evaluated the safety profile, survival outcome as well as the role of imaging biomarkers of tumor response in metastatic soft-tissue sarcoma (mSTS) of the liver treated with conventional transarterial chemoembolization (cTACE). MATERIALS/METHODS: This retrospective analysis included 30 patients with mSTS of the liver treated with cTACE. The safety profile, overall survival (OS) and progression-free survival (PFS) after the procedure were evaluated. Tumor response in each patient was assessed using RECIST, modified (m) RECIST and EASL guidelines. In addition, a 3D quantification of the enhancing tumor volume (quantitative [q] EASL) was performed. For each method, patients were classified as responders (R) and non-responders (NR), and evaluated using Kaplan-Meier and multivariate Cox proportional hazard ratio (HR) analysis. RESULTS: No Grade III or IV toxicities were reported in a total of 77 procedures (mean, 2.6/patient). Median OS was 21.2 months (95% CI, 13.4-28.9) and PFS was 6.3 months (95% CI, 4.4-8.2). The enhancement-based techniques identified 11 (44%), 12 (48%) and 12 (48%) patients as R according to EASL, mRECIST and qEASL, respectively. No stratification was achieved with RECIST. Multivariate analysis identified tumor response according to mRECIST and qEASL as reliable predictors of improved patient survival (P=0.019; HR 0.3 [0.1-0.8] and P=0.006; HR 0.2 [0.1-0.6], respectively). CONCLUSION: This study confirmed the role of cTACE as a safe salvage therapy option in patients with mSTS of the liver. The demonstrated advantages of enhancement-based tumor response assessment techniques over size-based criteria validate mRECIST and qEASL as preferable methods after intraarterial therapy.