Understanding K trans: a simulation study based on a multiple-pathway model.

The transfer constant K trans is commonly employed in dynamic contrast-enhanced MRI studies, but the utility and interpretation of K trans as a potential biomarker of tumor vasculature remains unclear. In this study, computer simulations based on a comprehensive tracer kinetic model with multiple pathways was used to provide clarification on the interpretation and application of K trans. Tissue concentration-time curves pertaining to a wide range of transport conditions were simulated using the multiple-pathway (MP) model and fitted using the generalized kinetic (GK) and extended GK models. Relationships between K trans and plasma flow F p, vessel permeability PS and extraction rate EF p under various transport conditions were assessed by correlation and regression analysis. Results show that the MP model provides an alternative two-tier interpretation of K trans based on the vascular transit time. K trans is primarily associated with F p and EF p respectively, in the slow and rapid vascular transit states, independent of the magnitude of PS. The relative magnitudes of PS and F p only serve as secondary constraints for which K trans can be further associated with EF p and PS in the slow and rapid transit states, respectively.

Intravoxel incoherent motion and diffusion tensor imaging of early renal fibrosis induced in a murine model of streptozotocin induced diabetes.

INTRODUCTION: To assess if parameters in intravoxel incoherent motion (IVIM) and diffusion tensor imaging (DTI) can be used to evaluate early renal fibrosis in a mouse model of diabetic nephropathy. MATERIALS & METHODS: In a population of 38 male CD1 mice (8weeks old, 20-30g), streptozotocin induced diabetes was created in 20 mice via a single intraperitoneal injection of streptozotocin at 150mg/kg, while 18 mice served as control group. IVIM parameters were acquired at 0, 12 and 24weeks after injection of streptozotocin using a range of b values from 0 to 1200s/mm2. DTI parameters were obtained using 12 diffusion directions and lower b values of 0, 100 and 400s/mm2. DTI and IVIM parameters were obtained using region of interests drawn over the renal parenchyma. Histopathological analysis of the right kidney was performed in all mice. Results were analyzed using an unpaired t-test with P<0.05 considered statistically significant. RESULTS: Renal cortex fractional anisotropy (FA) was significantly lower in the diabetes group at week 12 as compared with the control group. Renal cortex apparent diffusion coefficient and tissue diffusivity were significantly higher in the diabetes group at week 12 compared with the control group at 12weeks. Blood flow was significantly decreased at the renal medulla at 24weeks. Histopathological analysis confirmed fibrosis in the diabetes group at 24weeks. CONCLUSION: FA is significantly reduced in diabetic nephropathy. FA might serve a potential role in the detection and therapy monitoring of early diabetic nephropathy.

A phase Ib study of selumetinib (AZD6244, ARRY-142886) in combination with sorafenib in advanced hepatocellular carcinoma (HCC).

BACKGROUND: Treatment with sorafenib, although associated with inhibition of tumour growth and angiogenesis in in vivo studies, leads to up-regulation of pERK. The addition of MEK inhibition could potentially abrogate this effect and potentiate anti-tumour activity. This phase I study investigated the maximum tolerated dose (MTD), safety, tolerability, pharmacokinetics (PK) and biomarker correlates of selumetinib combined with sorafenib in patients with advanced hepatocellular carcinoma (HCC). METHODS: Patients with Child-Pugh (CP) score ≤7 were treated with 400 mg twice daily of sorafenib with escalating doses of selumetinib in a 3 + 3 study design. The dose-limiting toxicity (DLT) evaluation period was 28 days. PK of selumetinib was determined. Angiogenic effect was evaluated with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). RESULTS: Twenty-seven patients of Asian ethnicity were enrolled. The MTD was selumetinib 75 mg daily with sorafenib 400 mg twice daily. DLT included grade 3 transaminitis, diarrhoea and fatigue. Most common treatment-related adverse events at MTD (all grades) were diarrhoea (85%), rash (59%), hypertension (44%), fatigue (30%), anorexia (22%) and hand-foot syndrome (22%). Four patients (15%) had PR and 13 (48%) had SD. PR or SD was observed for ≥6 months in seven patients. The median overall survival was 14.4 months. Selumetinib exposures in combination with sorafenib were comparable to other monotherapy studies. A reduction in permeability-surface area product noted in DCE-MRI with treatment correlated with worse survival outcomes. CONCLUSION: The MTD of selumetinib was 75 mg daily when combined with sorafenib 400 mg twice a day in CP ≤7 HCC. Acceptable adverse events and encouraging anti-tumour activity warrant further evaluation. DCE-MRI findings deserve prospective evaluation. CLINICALTRIALSGOV IDENTIFIER: NCT01029418.

Dynamic contrast-enhanced magnetic resonance imaging: applications in oncology.

Dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) allows functional characterisation of tissue perfusion characteristics and acts as a biomarker for tumour angiogenesis. It involves serial acquisition of MRI images before and after injection of contrast, as such, tissue perfusion and permeability can be assessed based on the signal enhancement kinetics. The ability to evaluate whole tumour volumes in a non-invasive manner makes DCE MRI especially attractive for potential oncological applications. Here we provide an overview of the current research involving DCE MRI as a biomarker for the diagnosis and characterisation of malignancies, prediction of the therapeutic response and survival outcomes, as well as radiation therapy planning.

Assessment of tumor blood flow distribution by dynamic contrast-enhanced CT.

A distinct feature of the tumor vasculature is its tortuosity and irregular branching of vessels, which can translate to a wider dispersion and higher variability of blood flow in the tumor. To enable tumor blood flow variability to be assessed in vivo by imaging, a tracer kinetic model that accounts for flow dispersion is developed for use with dynamic contrast-enhanced (DCE) CT. The proposed model adopts a multiple-pathway approach and allows for the quantification of relative dispersion in the blood flow distribution, which reflects flow variability in the tumor vasculature. Monte Carlo simulation experiments were performed to study the possibility of reducing the number of model parameters based on the Akaike information criterion approach and to explore possible noise and tissue conditions in which the model might be applicable. The model was used for region-of-interest analysis and to generate perfusion parameter maps for three patient DCE CT cases with cerebral tumors, to illustrate clinical applicability.

Adjuvant hepatic intra-arterial iodine-131-lipiodol following curative resection of hepatocellular carcinoma: a prospective randomized trial.

BACKGROUND: The purpose of the present study was to determine whether intrahepatic injection of (131)I-lipiodol (Lipiodol) is effective against recurrence of surgically resected hepatocellular carcinoma (HCC). METHODS: From June 2001 through March 2007, this nationwide multi-center prospective randomized controlled trial enrolled 103 patients 4-6 weeks after curative resection of HCC with complete recovery (52: Lipiodol, 51: Control). Follow-up was every 3 months for 1 year, then every 6 months. Primary and secondary endpoints were recurrence-free survival (RFS) and overall survival (OS), respectively, both of which were evaluated by the Kaplan-Meier technique and summarized by the hazard ratio (HR). The design was based on information obtained from a similar trial that had been conducted in Hong Kong. RESULTS: The Lipiodol group showed a small, and nonsignificant, improvement over control in RFS (HR = 0.75; 95 % confidence interval [95 % CI] 0.46-1.23; p = 0.25) and OS (HR = 0.88; 95 % CI 0.51-1.51; p = 0.64). Only two serious adverse events were reported, both with hypothyroidism caused by (131)I-lipiodol and hepatic artery dissection during angiography. CONCLUSIONS: The randomized trial provides insufficient evidence to recommend the routine use of (131)I-lipiodol in these patients.

A Phase 1 dose-finding and pharmacodynamic study of rapamycin in combination with bevacizumab in patients with unresectable hepatocellular carcinoma.

BACKGROUND & AIMS: Preclinical studies have demonstrated the additive effect of rapamycin with bevacizumab for hepatocellular carcinoma treatment. We conducted a Phase 1 study to evaluate the safety and pharmacokinetics of the combination in patients with hepatocellular carcinoma. METHODS: Adult participants with advanced hepatocellular carcinoma received intravenous bevacizumab (5mg/kg every 14 days) and oral rapamycin (1-6 mg/day; 3+3 dose escalation design). Computed tomography assessed tumour response and treatment safety. Pharmacokinetics assessment established rapamycin blood concentrations pre- and post-dose. Dynamic contrast-enhanced computed tomography analysed the tumour region for blood flow, permeability surface area product, fractional intravascular blood volume and extracellular-extravascular volume. RESULTS: Twenty-four participants were treated. There were two dose limiting toxicities with rapamycin 5mg: grade 3 thrombocytopenia and grade 3 mucositis. The maximally tolerated dose of rapamycin was 4 mg. Adverse events (grade 1-2) included hyperglycaemia (83%), thrombocytopenia (75%), fatigue (46%), mucositis (46%), anorexia (42%), diarrhoea (33%) and proteinuria (12.5%). Of 20 evaluable participants, one reached complete response that lasted 4.5 months, two reached partial response, 14 reached stable disease and three had progressive disease. Median overall survival was 9.4 months; progression-free survival was 5.5 months. Dose level and steady state area under the concentration time curve for hour zero to infinity of rapamycin correlated inversely with blood flow rate and change in permeability-surface area. After 22 days of treatment, there were significant reductions from baseline in blood flow rate, permeability-surface area and fractional intracellular blood volume. CONCLUSIONS: The recommended Phase 2 dose of rapamycin is 4 mg in combination with bevacizumab. Evidence of anti-vascular activity was observed together with promising clinical activity.

In vivo measurement of gadolinium diffusivity by dynamic contrast-enhanced MRI: a preclinical study of human xenografts.

Compartmental tracer kinetic models currently used for analysis of dynamic contrast-enhanced MRI data yield poor fittings or parameter values that are unphysiological in necrotic regions of the tumor, as these models only describe microcirculation in perfused tissue. In this study, we explore the use of Fick's law of diffusion as an alternative method for analysis of dynamic contrast-enhanced MRI data in the necrotic regions. Xenografts of various human cancer cell lines were implanted in 14 mice that were subjected to dynamic contrast-enhanced MRI performed using a spoiled gradient recalled sequence. Tracer concentration was estimated using the variable flip angle technique. Poorly perfused and necrotic tumor regions exhibiting delayed and slow enhancement were identified using a k-means clustering algorithm. Tracer behavior in necrotic regions was shown to be consistent with Fick's diffusion equation and the in vivo gadolinium diffusivity was estimated to be 2.08 (±0.88) × 10(-4) mm(2)/s. This study proposes the use of gadolinium diffusivity as an alternative parameter for quantifying tracer transport within necrotic tumor regions.

Interpretation and applicability of empirical tissue enhancement metrics in dynamic contrast-enhanced MRI based on a multiple pathway model.

Computer simulations based on a physiologically realistic tracer kinetic model with multiple pathways was used to provide insights on the applicability and interpretation of tissue enhancement metrics such as the maximum slope, peak enhancement and area under curve, commonly used in dynamic contrast-enhanced (DCE) MRI. Results show that physiological conditions of the tissue that could affect the accuracy of the maximal slope method include a high blood flow, increased variability of flow within the vasculature or a low vascular volume. Interestingly, changes in permeability and interstitial volume might not affect the accuracy of the maximal slope method. Time-to-peak and peak value of the tissue enhancement curve are not strictly properties of the tissue alone, and they cannot be linearly related to intrinsic tissue parameters such as blood flow, blood volume, capillary permeability, interstitial volume and mean transit time. Similar to the normalized initial area under tissue concentration curve, an alternative estimate of the total tracer distribution volume can be simply given by the ratio of tracer concentration in the tissue and artery sampled at the final DCE scan.

Dynamic contrast-enhanced MRI of neuroendocrine hepatic metastases: A feasibility study using a dual-input two-compartment model.

Neuroendocrine hepatic metastases exhibit various contrast uptake enhancement patterns in dynamic contrast-enhanced MRI. Using a dual-input two-compartment distributed parameter model, we analyzed the dynamic contrast-enhanced MRI datasets of seven patient study cases with the aim to relate the tumor contrast uptake patterns to parameters of tumor microvasculature. Simulation studies were also performed to provide further insights into the effects of individual microcirculatory parameter on the tumor concentration-time curves. Although the tumor contrast uptake patterns can be influenced by many parameters, initial results indicate that hepatic blood flow and the ratio of fractional vascular volume to fractional interstitial volume may potentially distinguish between the patterns of neuroendocrine hepatic metastases.

Graft-vs-tumor effect in patients with advanced nasopharyngeal cancer treated with nonmyeloablative allogeneic PBSC transplantation.

While nonmyeloablative peripheral blood stem cell transplantation (NST) has shown efficacy against several solid tumors, it is untested in nasopharyngeal cancer (NPC). In a phase II clinical trial, 21 patients with pretreated metastatic NPC underwent NST with sibling PBSC allografts, using CY conditioning, thymic irradiation and in vivo T-cell depletion with thymoglobulin. Stable lymphohematopoietic chimerism was achieved in most patients and prophylactic CYA was tapered at a median of day +30. Seven patients (33%) showed partial response and three (14%) achieved stable disease. Four patients were alive at 2 years and three showed prolonged disease control of 344, 525 and 550 days. With a median follow-up of 209 (4-1147) days, the median PFS was 100 days (95% confidence interval (CI), 66-128 days), and median OS was 209 days (95% CI, 128-236 days). Patients with chronic GVHD had better survival-median OS 426 days (95% CI, 194-NE days) vs 143 days (95% CI, 114-226 days) (P=0.010). Thus, NST may induce meaningful clinical responses in patients with advanced NPC.

High temporal resolution dynamic contrast-enhanced MRI at 7 Tesla: a feasibility study with mouse liver model.

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has been widely applied to evaluate microcirculatory parameters in clinical settings. However, pre-clinical studies involving DCE-MRI of small animals remain challenging with the requirement for high spatial and temporal resolution for quantitative tracer kinetic analysis. This study illustrates the feasibility of applying a high temporal resolution (2 s) protocol for liver imaging in mice by analyzing the DCE-MRI datasets of mice liver with a dual-input two-compartment tracer kinetic model. Phantom studies were performed to validate the T(1) estimates derived by the proposed protocol before applying it in mice studies. The DCE-MRI datasets of mice liver were amendable to tracer kinetic analysis using a dual-input two-compartment model. Estimated micro-circulatory parameters were consistent with liver physiology, indicating viability of applying the technique for pre-clinical drug developments.

Sunitinib (SUTENT, SU11248) suppresses tumor growth and induces apoptosis in xenograft models of human hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the fifth most common and third deadliest primary neoplasm. Since HCC is a particularly vascular solid tumor, we determined the antitumor and antiangiogenic activities of sunitinib malate, a potent inhibitor of two receptors involved in angiogenesis - vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR). In the present study, we reported that treatment of HepG2 and SK-Hep-1 cells with sunitinib led to growth inhibition and apoptosis in a dose-dependent fashion. Sunitinib inhibited phosphorylation of VEGFR-2 at Tyr951 and PDGFR-beta at Tyr1021 both in vitro and in vivo. Sunitinib also suppressed tumor growth of five patient-derived xenografts. Sunitinib-induced tumor growth inhibition was associated with increased apoptosis, reduced microvessel density and inhibition of cell proliferation. This study provides a strong rationale for further clinical investigation of sunitinib in patients with hepatocellular carcinoma.

Differentiation of benign and malignant parotid tumors using deconvolution-based perfusion CT imaging: feasibility of the method and initial results.

AIM: We evaluated the feasibility of perfusion CT (CTP) of the parotid gland and attempted to differentiate benign from malignant tumors. MATERIALS AND METHODS: CTP was performed in 17 patients with benign tumors and 10 patients with malignant parotid tumors. Data were postprocessed by using deconvolution-based perfusion analysis. Postprocessing-generated maps showed blood flow (BF), blood volume (BV), mean transit time (MTT), and capillary permeability surface product (PS). Regions of interest were placed through the tumor site and the contralateral healthy parotid tissue. Ratios of the perfusion values between the tumors and the contralateral healthy structures were also calculated. Pearson correlation coefficients were determined to compare the agreement between the two readers. RESULTS: Perfusion maps of all tumors were successfully obtained. High Pearson correlation coefficients comparing the two readers' visually measured abnormalities were observed (r=0.79-0.86, P=0.001) for all perfusion maps, The MTT and PS values between malignant and benign tumors were not significantly different. The BF and BV values were statistically significant different between the benign and malignant tumors (0.00

Pedunculated HCC or adrenal metastasis: a diagnostic conundrum.

Hepatocellular carcinoma (HCC) is the commonest primary liver tumour. Recurrences are common in the liver although extrahepatic metastases can occur and frequently involve the adrenals. When this occurs in the right adrenal gland, it can be confused with an exophytic HCC arising from the posterior surface of the liver. The distinction between a primary HCC and a metastasis is important but can be difficult in this clinical setting. We report a 52-year-old man with recurrent HCC presenting as an "exophytic" posterior liver surface lesion that was actually a right adrenal metastasis. Although right-sided adrenal metastases of HCC can be difficult to distinguish from intrahepatic recurrences, even with modern diagnostic imaging, management either way involves surgical exploration and resection whenever possible.

Sclerosing haemangioma mimicking hepatocellular carcinoma.

Sclerosing haemangioma is a rare variant of hepatic haemangioma. The radiological features on computed tomography and magnetic resonance imaging may not be typical for haemangioma and can be confused with hepatocellular carcinoma. We report sclerosing haemangioma occurring in a 65-year-old woman where the radiological features raise the possibility of hepatocellular carcinoma.

Focal nodular hyperplasia presenting as acute abdomen.

Focal nodular hyperplasia (FNH) is a benign liver tumour with an asymptomatic course, rarely causing complications. When the diagnosis is certain, only watchful observation is necessary. We highlight an interesting case of a 42-year-old woman with a FNH that ruptured and became haemorrhagic, thus presenting as an acute surgical abdomen. The diagnosis was only established after surgical resection with histopathological confirmation. Although haemorrhage of hepatic FNH is extremely rare, this case highlights the small risk of rupture in large lesions.