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.

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.

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.

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.

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

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.

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.

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.

Clinical mimicry of hepatocellular carcinoma: imaging-pathological correlation.

This pictorial essay aims to show the clinical mimicry of hepatocellular carcinoma (HCC) and its diagnostic difficulty, and to create awareness among clinicians and radiologists of potential diagnostic pitfalls. A selected consecutive series of hepatectomies with proven HCC over a three-year period, identifying clinical presentation, blood results and imaging of patients with difficult preoperative diagnosis, was reviewed. The imaging of the focal liver lesions is presented pictorially with pathological correlation. Six patients out of 34 cases of resected HCC were diagnosed to have benign (three liver abscesses) and neoplastic (one Klatskin tumour, one colorectal liver metastasis, one gallbladder cancer) conditions. Compared to the rest in the series, all six patients had normal serum alpha fetoprotein levels. On computed tomography, the mosaic appearance of HCC mimicked locules of liver abscess while HCC with pseudocapsule (rim enhancement) was misdiagnosed as unilocular abscess or metastatic lesion. Arterial enhancement on contrast-enhanced triphasic computed tomography was useful in diagnosis of HCC. In summary, HCC can mimic benign and neoplastic clinical syndromes. The diagnosis of liver abscess can delay subsequent diagnosis of HCC and potentially complicate the treatment plan. Contrast-enhanced triphasic computed tomography or magnetic resonance imaging is useful to resolve difficult diagnosis, especially when the serum alpha fetoprotein level is not raised.

Retreatment with chimeric CD 20 monoclonal antibody in a patient with nodal marginal zone B-cell lymphoma.

A patient with advanced and chemotherapy-refractory nodal marginal zone B-cell lymphoma was given a course of chimeric CD 20 monoclonal antibody Rituximab. Partial response was observed without any major toxicities. Retreatment with Rituximab for disease progression six months after the first course led to partial remission. Adjuvant radiotherapy was given for the residual disease and, currently, patient's disease remains stable eight months after the second course of Rituximab. This case demonstrates the therapeutic efficacy and feasibility of retreatment with Rituximab for relapsed or refractory low grade lymphoma.

Percutaneous drainage of liver abscess complicated by hepato-venous fistula.

Severe systemic sepsis after percutaneous drainage of liver abscess is rare. We report two cases of hepato-venous fistulas between hepatic abscesses and hepatic/portal veins documented on abscessography during percutaneous drainage of liver abscesses, which resulted in severe sepsis and a stormy post drainage clinical course. Liver abscesses can rupture into the portal and hepatic veins causing worsening of systemic sepsis especially when they are in close proximity to each other. During percutaneous drainage, care must also be taken to avoid overinjection of the abscess, which can worsen the fistula. The ensuing sepsis is severe and requires aggressive intensive medical care and ventilatory support to tide the patient over the septic episode.

Diffusion weighted MR imaging in acute stroke: the SGH experience.

Cerebrovascular accident (CVA) is a leading cause of death and disability in many countries. Diffusion-weighted (DW) magnetic resonance (MR) imaging has been reported to be useful in the detection of acute strokes and as an investigative tool evaluating the therapeutic effects of neuroprotective and thrombolytic agents. The objectives of this study are to share our experience using the commercially available isotropic DW scan in imaging of acute stroke, assess its usefulness over conventional T2-weighted (T2W) scans in a busy clinical radiology unit and highlight it pitfalls. We found the rapid sub-minute DW technique well suited for ill and restless stroke patients and superior to T2W scans in many ways. It was highly sensitive to acute ischaemic lesions, made lesions easily identifiable and readily differentiated the acute lesion from a background of multiple chronic infarcts. However, there are potential pitfalls in the evaluation of small hyperacute posterior fossa strokes and venous infarcts. The major strength of this MR technique lies in its ability to diagnose hyperacute strokes and thence the potential for therapeutic thrombolysis, but unfortunately patients qualifying for the "therapeutic window" were a minority. More efforts need to be focused on public education in order for this powerful imaging modality to find its true value and contribute to viability of an effective thrombolytic programme.

MR imaging and MR spectroscopy of adenocarcinoma of the prostate.

INTRODUCTION: We examined the impact of magnetic resonance (MR) imaging and MR spectroscopy on the diagnosis and management of prostate cancer. METHODS: A Medline search was performed and the relevant articles reviewed. The salient points are discussed and summarised. RESULTS: MR imaging with phased-array and endorectal coils is not recommended for routine staging. It has a complementary role in improving the accuracy of local staging in patients with intermediate risk based on Partin's normogram. MR spectroscopy can be performed in conjunction with high-resolution anatomic MR imaging of the prostate. It exploits the increased choline and decreased citrate levels within malignant prostatic tissue compared with normal prostatic tissue, and can potentially improve the assessment of cancer location and extent within the prostate, as well as extracapsular spread in small retrospective studies. It also has the potential of providing a measure of the presence and extent of prostate cancer after therapy. CONCLUSION: MR imaging is indicated in staging patients with intermediate risk based on Partin's normogram. Combined MR imaging and MR spectroscopy of the prostate is a promising imaging tool which can contribute to the diagnosis and management of prostate cancer when combined with clinical, biochemical and histological data. Large prospective studies must be performed to ascertain the true clinical value of combined MR imaging/MR spectroscopy for the management of prostate cancer patients.

Current status in imaging of colorectal liver metastases.

Colorectal cancer is a common malignancy that often metastasizes to the liver. Evaluation of the liver for metastases is important for staging and prognosis. Resection of limited hepatic metastases can result in prolonged survival. Imaging is vital to select appropriate patients to avoid unnecessary surgery. A variety of modern imaging tools can be used to detect and characterise hepatic lesions. These include contrast enhanced helical computed tomography (CT), CT arterial portography, magnetic resonance imaging (MRI) and intraoperative ultrasound (IOUS). Each has their advantages as well as disadvantages. Besides accuracy, availability, cost and presence of expertise determine the optimal modality or combination of modalities to use. The appearance of metastases on imaging can be correlated with histopathological abnormalities. Though metastases can often be distinguished from benign lesions, their appearances are by no means pathognomonic. Follow-up imaging for interval change and for assessment of response is often required.

Clinical applications of MR cholangiopancreatography.

INTRODUCTION: We review the clinical applications of magnetic resonance cholangiopancreatography (MRCP) and illustrate them with clinical examples. METHODS: A literature search was performed in MedLine using the keywords "MR cholangiopancreatography" and "MRCP". The relevant articles were reviewed. The radiology information system was searched for MRCP examinations performed from July 1999 to December 2002. A surgical database of resected cases was also referenced. Illustrative cases were chosen in consultation with surgical authors to show the clinical applications of MRCP. RESULTS: MRCP is useful for assessment of choledocholithiasis, choledochal cysts, pancreas divisum, primary sclerosing cholangitis, pancreatitis and anatomical variation of the biliary ducts. When complemented with dynamic gadolinium-enhanced studies, MRCP is useful for assessment of ductal cholangiocarcinoma, pancreatic and gall bladder neoplasms. Illustrative cases are provided. CONCLUSION: MRCP is an important modality for the clinical assessment of biliary and pancreatic disorders.

Magnetic resonance imaging of brain metastases: magnetisation transfer or triple dose gadolinium?

Magnetic resonance (MR) imaging of brain metastases relies on the neovascularity of metastases and the associated breach of blood-brain barrier manifesting as enhancement on T1-weighted images. There are 2 main strategies to improve the detection of brain metastases. One may increase the dose of gadolinium and increase the signal of the lesion. Alternatively, one may also lower the signal of the background (by magnetisation transfer suppression), in which case the enhancing lesion is rendered more conspicuous without increasing the dose of gadolinium. We aim to compare the efficacy of single-dose conventional spin-echo T1 scans with magnetisation transfer (MT) suppression with triple-dose conventional spin-echo T1 scans in the detection of brain metastases in 18 patients undergoing imaging for brain metastases. An incremental dose technique was employed. After administration of a single dose of gadolinium, MT suppressed T1-weighted scans were obtained, followed by a conventional T1 scan. Two doses of gadolinium were subsequently given, achieving a cumulative triple-dose, and a conventional T1-weighted scan was then performed. We found single-dose MT suppressed and triple-dose scans performed equally well and detected 26 metastatic lesions. They detected 5 (5/26, 19%) more lesions than the conventional single-dose T1 scans. Five (5/21, 24%) questionable lesions on single-dose conventional scans were confidently diagnosed on the single-dose MT suppressed and the triple-dose conventional scan. We conclude that single-dose MT suppressed scans are a cost-effective technique of detecting brain metastases.

Computed tomographic appearance of colorectal hepatic metastases.

INTRODUCTION: This article reviews the various computed tomography (CT) appearances of hepatic metastases from colorectal primaries and assesses the frequency of occurrence of the various patterns. MATERIALS AND METHODS: This is a retrospective study of the CT appearances of histologically proven colorectal hepatic metastases in a group of 52 patients who had undergone surgical hepatic resection between January 1994 and December 2001. A total of 74 hepatic metastatic lesions were reviewed. All lesions were examined in the portal venous phase. RESULTS: A discernible rim was seen in 54 lesions (73%). Thick rim was present in 36 lesions (48.6%) and thin rim in 18 lesions (24.3%). Enhancement of the rim was present in 62 cases (83.8%). Increased central attenuation was seen in 38 lesions (51.4%). Of these, the centre was heterogeneous in 76.3% and scar-like in 23.7%. A non-enhancing rim was seen in 12 lesions (16.2%) which appeared as lesions with "bevelled edge". Thick enhancing rim with non-enhancing centre was the most common combination in 15 lesions (20.3%). CONCLUSION: An enhancing rim could be seen in 83.8% of lesions. Increased central attenuation was present in 51.4% of the lesions. Familiarity with the various CT appearances may facilitate identification and diagnosis of colorectal liver metastases.

Breath-hold fast recovery fast spin echo versus conventional non-breath-hold fast spin echo T2-weighted MR imaging of focal liver lesions.

INTRODUCTION: We compare the breath-hold fast recovery fast spin echo (BHFRFSE) T2-weighted and non-breath-hold fast spin echo (NBHFSE) T2-weighted sequences in image quality and lesion characterisation of focal liver lesions. MATERIALS AND METHODS: Fat-suppressed T2-weighted magnetic resonance (MR) images obtained with the 2 sequences (BHFRFSE and NBHFSE) in 79 patients with 113 liver lesions were analysed retrospectively. The image quality and nature of the lesions were evaluated by 2 experienced radiologists. RESULTS: Based on receiver operating characteristic curve analysis, lesion characterisation was comparable for both sequences. The image quality of BHFRFSE was significantly better than that of NBHFSE. The NBHFSE missed 4 malignant lesions while BHFRFSE missed 2 malignant lesions. CONCLUSION: BHFRFSE performs similarly to NBHFSE in image quality and liver lesion characterisation.