Bang-Bin Chen

Dynamic contrast-enhanced magnetic resonance imaging biomarkers predict survival and response in hepatocellular carcinoma patients treated with sorafenib and metronomic tegafur/uracil

BACKGROUND & AIMS Sorafenib plus metronomic tegafur/uracil therapy can induce tumor stabilization in advanced hepatocellular carcinoma (HCC) patients. This study evaluated the correlation of vascular response measured by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and the clinical outcome. METHODS DCE-MRI was performed in advanced HCC patients treated with sorafenib (800 mg/d) plus tegafur/uracil (250 mg/m(2)/d based on tegafur) at baseline and after 14 days of treatment. An operator-defined region of interest was placed in the most strongly enhanced area of the tumor to measure the pharmacokinetic parameter K(trans). Changes in K(trans) after treatment were correlated with the best tumor response and survival. RESULTS Thirty-one patients were evaluable. There were one partial response (PR), 18 stable disease (SD), and 12 progressive disease (PD) according to the Response Evaluation Criteria in Solid Tumors (RECIST). Baseline K(trans) was higher in patients with PR or SD (median 1215.2 × 10(-3)/min, range 582.5-4555.3 × 10(-3)/min) than patients with PD (median 702.0 × 10(-3)/min, range 375.2-1938.0 × 10(-3)/min, p = 0.008). After 14 days of study treatment, the median K(trans) change was -47.1% (range -87.0 to -18.0%) in patients with PR or SD, and 9.6% (range -44.8 to +81%) in those with PD (p<0.001). A vascular response, defined by a 40% or greater decrease in K(trans) after 14 days of study treatment, correlated with longer progression-free survival (median 29.1 vs. 8.7 weeks, p = 0.033) and overall survival (median 53.0 vs. 14.9 weeks, p = 0.016). Percentage of K(trans) change after treatment is an independent predictor of tumor response, progression-free survival, and overall survival. CONCLUSIONS K(trans) measured by DCE-MRI correlated well with tumor response and survival in HCC patients who received sorafenib plus metronomic tegafur/uracil therapy.

Dynamic contrast-enhanced magnetic resonance imaging with Gd-EOB-DTPA for the evaluation of liver fibrosis in chronic hepatitis patients

AbstractObjectivesTo develop a non-invasive MRI method for evaluation of liver fibrosis, with histological analysis as the reference standard.MethodsThe study protocol was approved by the Institutional Review Board for Human Studies of our hospital, and written informed consent was obtained from all subjects. Seventy-nine subjects who received dynamic contrast-enhanced MRI (DCE-MRI) with Gd-EOB-DTPA were divided into three subgroups according to Metavir score: no fibrosis (n = 30), mild fibrosis (n = 34), and advanced fibrosis (n = 15). The DCE-MRI parameters were measured using two models: (1) dual-input single-compartment model for arterial blood flow (Fa), portal venous blood flow, total liver blood flow, arterial fraction (ART), distribution volume, and mean transit time; and (2) curve analysis model for Peak, Slope, and AUC. Statistical analysis was performed with Student’s t-test and the nonparametric Kruskal-Wallis test.ResultsSlope and AUC were two best perfusion parameters to predict the severity of liver fibrosis (>F2 vs. ≦F2). Four significantly different variables were found between non-fibrotic versus mild-fibrotic subgroups: Fa, ART, Slope, and AUC; the best predictor for mild fibrosis was Fa (AUROC:0.701).ConclusionsDCE-MRI with Gd-EOB-DTPA is a noninvasive imaging, by which multiple perfusion parameters can be measured to evaluate the severity of liver fibrosis. Key Points • Dynamic Gd-EOB-DTPA contrast-enhanced-MRI can help evaluate the severity of liver fibrosis.• Slope and AUC were two best perfusion parameters to predict severity.• Absolute arterial blood flow was the best predictor for mild fibrosis.

Bone marrow angiogenesis magnetic resonance imaging in patients with acute myeloid leukemia: peak enhancement ratio is an independent predictor for overall survival.

Emerging evidence suggests that progression of hematologic malignancies is associated with angiogenesis. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can provide global and functional imaging of tumor angiogenesis. In this study, we performed bone marrow DCE-MRI prospectively at diagnosis and after induction chemotherapy in 78 de novo acute myeloid leukemia (AML) patients and correlated it with treatment outcome. An algorithm to assess bone marrow angiogenesis by measuring the DCE-MRI time-intensity curve pixel by pixel was developed using 3 distinct parameters: peak enhancement ratio (Peak) to indicate tissue blood perfusion; amplitude (Amp) to reflect vascularity; and volume transfer constant (K trans) to indicate vascular permeability. The Peak and Amp decreased significantly at remission status after induction chemotherapy. Patients with higher Peak or Amp at diagnosis had shorter overall survival and disease-free survival than others. Cox multivariate analysis identified higher Peak value (hazard ratio, 9.181; 95% confidence interval, 1.740-48.437; P = .009) as an independent predictor for overall survival in addition to unfavorable karyotype and old age. Our findings provide evidence that increased bone marrow angiogenesis measured by DCE-MRI can predict adverse clinical outcome in AML patients. DCE-MRI may help to select high-risk phenotype AML patients for tailored antiangiogenic therapy and to monitor treatment response.

Clinical Practice Guidelines for Hepatocellular Carcinoma Differ between Japan, United States, and Europe

Hepatocellular carcinoma (HCC) is a malignant tumor that is the fifth most common type of cancer and the third leading cause of cancer-related death globally. Although HCC was once thought to be a special type of cancer prevalent only in Southeast Asia and Africa, it has rapidly become more common in other regions, particularly Europe and the United States, which has led to greater interest in the diagnosis and treatment of HCC worldwide. Consequently, the American Association for the Study of Liver Diseases (AASLD) [1] and the European Association for the Study of the Liver and the European Organisation for Research and Treatment of Cancer (EASL-EORTC) [2] have published clinical practice guidelines for liver cancer. In Japan, the first edition of evidence-based clinical practice guidelines was published in 2005 [3, 4], followed by a revised edition in 2009 and a third revision in 2013 [5, 6]. In addition, 1 or 2 years after the publication of each revised edition of the evidence-based treatment guidelines, The Japan Society of Hepatology (JSH) has also published consensusbased clinical practice manuals for HCC. The first edition was published in 2007 and the second edition in 2010 [7, 8]. A third edition will be published in 2015. In this article, differences between the aforementioned European and American clinical practice guidelines and Japanese clinical practice guidelines will be discussed. Specifically, as these guidelines primarily consist of both a surveillance and diagnostic algorithm and a treatment algorithm, each component of the algorithms will be explained in detail.

Dynamic Contrast-enhanced MR Imaging Measurement of Vertebral Bone Marrow Perfusion May Be Indicator of Outcome of Acute Myeloid Leukemia Patients in Remission

PURPOSE To examine whether dynamic contrast material-enhanced (DCE) magnetic resonance (MR) imaging measurement of bone marrow perfusion in acute myeloid leukemia (AML) patients in complete remission (CR) is associated with outcome and survival. MATERIALS AND METHODS After institutional review board approval and informed consent were obtained, from September 2004 to October 2007, 51 patients (29 women, 22 men; mean age, 43.5 years; range, 17-66 years) agreed to undergo DCE MR imaging to assess bone marrow perfusion, among 96 patients with newly diagnosed de novo AML who had received induction chemotherapy and achieved CR. Two semiquantitative parameters (peak and slope) and another three quantitative parameters (amplitude, K(ep) [efflux rate constant], and K(el) [elimination rate constant]) were calculated. Overall survival (OS) and relapse-free survival (RFS) were assessed with the Kaplan-Meier model, while differences between patient groups with high and low DCE MR imaging parameter values were assessed by using the two-sided log-rank test. RESULTS The median follow-up was 25.9 months. Univariate analysis results showed that high values of peak (≥0.42), slope (≥0.0235), amplitude (≥0.03), and K(ep) (≥0.0082) were associated with shorter OS (P = .004, 0.01, 0.034, and 0.026, respectively). Besides, a high value of K(ep) was also associated with shorter RFS (P = .008). When age, sex, and initial karyotype at diagnosis were included in multivariate Cox proportional hazards analysis, the results showed that only K(ep), but not other DCE MR imaging parameters, was an independent factor for OS (relative risk [RR], 30.305; P = .021) and RFS (RR, 6.477; P = .009). CONCLUSION Bone marrow perfusion measured with DCE MR imaging in AML patients in CR can be an indicator of outcome and survival. K(ep) measured with kinetic modeling was useful and significantly associated with RFS, while heuristic parameters (peak and slope) were not.

Bevacizumab Preconditioning Followed by Etoposide and Cisplatin Is Highly Effective in Treating Brain Metastases of Breast Cancer Progressing from Whole-Brain Radiotherapy

Purpose: We hypothesized that a window period between bevacizumab and cytotoxic agents may enhance drug delivery into tumor tissue through bevacizumab-induced vascular normalization in patients with brain metastases of breast cancer (BMBC). Experimental Design: A single-arm phase II study was conducted in which BMBC patients refractory to whole-brain radiotherapy (WBRT) were enrolled. In a 21-day cycle, patients received bevacizumab (15 mg/kg) on day 1, which, with a 1-day window period, was followed by etoposide (70 mg/m2/day; days 2–4) and cisplatin (70 mg/m2; day 2; BEEP regimen). The BEEP regimen was administered for a maximum of 6 cycles. The primary endpoint was the central nervous system (CNS)–objective response rate according to volumetric response criteria. Results: A total of 35 patients were enrolled between January 2011 and January 2013. The median age was 54.3 years (range, 33–75); 19 patients (54.3%) had an Eastern Cooperative Oncology Group performance status of 2 or 3. Twenty-seven patients [77.1%; 95% confidence interval (CI), 59.9–89.6] achieved a CNS-objective response, including 13 patients (37.1%) with a ≥80% volumetric reduction of CNS lesions. With a median follow-up of 16.1 months, the median CNS progression-free survival and overall survival times were 7.3 months (95% CI, 6.5–8.1) and 10.5 months (95% CI, 7.8–13.2), respectively. Common grade 3 or 4 toxicities included neutropenia (30.8%) and infection (21.3%). Conclusions: By administering bevacizumab 1 day before etoposide and cisplatin, the BEEP regimen appeared highly effective in BMBC refractory to WBRT. Further study of vascular normalization window concept is warranted. Clin Cancer Res; 21(8); 1851–8. ©2015 AACR.

DCE-MRI in hepatocellular carcinoma-clinical and therapeutic image biomarker

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) enables tumor vascular physiology to be assessed. Within the tumor tissue, contrast agents (gadolinium chelates) extravasate from intravascular into the extravascular extracellular space (EES), which results in a signal increase on T1-weighted MRI. The rate of contrast agents extravasation to EES in the tumor tissue is determined by vessel leakiness and blood flow. Thus, the signal measured on DCE-MRI represents a combination of permeability and perfusion. The semi-quantitative analysis is based on the calculation of heuristic parameters that can be extracted from signal intensity-time curves. These enhancing curves can also be deconvoluted by mathematical modeling to extract quantitative parameters that may reflect tumor perfusion, vascular volume, vessel permeability and angiogenesis. Because hepatocellular carcinoma (HCC) is a hypervascular tumor, many emerging therapies focused on the inhibition of angiogenesis. DCE-MRI combined with a pharmacokinetic model allows us to produce highly reproducible and reliable parametric maps of quantitative parameters in HCC. Successful therapies change quantitative parameters of DCE-MRI, which may be used as early indicators of tumor response to anti-angiogenesis agents that modulate tumor vasculature. In the setting of clinical trials, DCE-MRI may provide relevant clinical information on the pharmacodynamic and biologic effects of novel drugs, monitor treatment response and predict survival outcome in HCC patients.

Preoperative Diagnosis of Gastric Tumors by Three-dimensional Multidetector Row CT and Double Contrast Barium Meal Study: Correlation with Surgical and Histologic Results

BACKGROUND/PURPOSE Recent three-dimensional multidetector row computed tomography (3D MDCT) can provide detailed images of a gastric tumor, including its general contour, location and depth. We therefore evaluated the efficacy of MDCT in the differential diagnosis and staging of gastric tumors in patients prepared for surgery. METHODS Seventy-nine patients with gastric tumors identified by gastric optical endoscopy were admitted for preoperative evaluation. All patients received double-contrast barium meal (DCBM) study and abdominal MDCT with 3D reconstruction before surgery. We compared the accuracy of MDCT with DCBM study in detecting and differentiating gastric tumors. In addition, the MDCT findings were correlated with surgical and pathologic results in gastric cancers for Borrmann type, T and N stages. RESULTS Among the 79 patients with gastric tumors, there were 24 cases of early gastric cancer, 40 cases of advanced gastric cancer, 12 cases of gastrointestinal stromal tumor, and three cases of gastric lymphoma. Both MDCT and DCBM were very accurate in picking up the lesions (100%). The diagnostic accuracies of MDCT and DCBM were similar (94% vs. 96%) in differentiating mucosal and submucosal lesions as well as classification of Borrmann type in advanced gastric cancer (70% vs. 63%). In 64 patients with gastric cancers, there was good correlation between MDCT images and pathology in 73% of T staging and 69% of N staging. CONCLUSION MDCT has a similar high accuracy in the preoperative diagnosis of different gastric tumors compared with DCBM and provides additional information including tumor depth, lymph node and hepatic metastasis. Therefore, MDCT may be used as a primary tool for preoperative tumor diagnosis and staging.

Changes in magnetic resonance bone marrow angiogenesis on day 7 after induction chemotherapy can predict outcome of acute myeloid leukemia

Recently, dynamic contrast-enhanced magnetic resonance imaging has been shown to be a non-invasive technique that provides global and functional imaging of bone marrow angiogenesis in acute myeloid leukemia. To assess the clinical implication of changes in angiogenesis shortly after induction chemotherapy, dynamic contrast-enhanced magnetic resonance imaging was performed prospectively before treatment (day 0) and on day 7 in 80 patients with de novo acute myeloid leukemia. We demonstrated that a post-therapeutic reduction in Peak (negative ΔPeak) compared with the day 0 value was significantly associated with a higher chance of achieving complete remission, and better overall and disease free survival (P=0.022, 0.003 and 0.007, respectively). Cox’s multivariate analysis also identified negative ΔPeak value as an independent good prognostic factor for overall and disease free survival. Our findings provide evidence that the change of Peak on day 7 relative to pre-treatment levels may be a relevant biomarker for early identification of patients who may fail conventional induction chemotherapy (ClinicalTrials.gov Identifier: NCT00172562).

Consensus Development from the 5th Asia-Pacific Primary Liver Cancer Expert Meeting (APPLE 2014)

A key mission of the Asia-Pacific Primary Liver Cancer Expert (APPLE) Association is to ensure a coherent view for management of hepatocellular carcinoma (HCC) and to advance new treatment for this difficult disease. At the 5th APPLE meeting, held in July 2014 in Taipei, Taiwan, an APPLE consensus development program was established to facilitate discussion among experts in the Asia-Pacific region on pertinent issues for HCC management, including (1) surgery for intermediate/advanced-stage disease, (2) prevention of HCC recurrence after curative treatment, (3) optimizing imaging diagnosis, (4) radiotherapy: current practice and future clinical trials, and (5) the role of cytotoxic chemotherapy. A pre-congress questionnaire was undertaken with the consensus development committee members to help understand the current practice patterns for HCC in the Asia-Pacific region and to identify issues relating to optimal patient care and further clinical trials for which consensus needs to be developed. In this report, the results of the questionnaire are presented, and the pertinent issues identified by each consensus group for further discussion and consensus development are summarized.