Radioembolisation of hepatocellular carcinoma: a primer.

Transarterial radioembolisation (TARE) has gained increasing acceptance as an additional/alternative locoregional treatment option for hepatocellular carcinoma, and colorectal hepatic metastases that present beyond potentially curative options. This is a catheter-based transarterial selective internal brachytherapy that involves injection of radioactive microspheres (usually Y-90) that are delivered selectively to the liver tumours. Owing to the combined radioactive and microembolic effect, the findings at follow-up imaging are significantly different from that seen with other transarterial treatment options. Considering increasing confidence among clinicians, refinement in techniques and increasing number of ongoing trials, TARE is expected to gain further acceptance and become an important tool in the armamentarium for the treatment of liver malignancies. So it is imperative that all radiologists involved in the management of liver malignancies are well versed with TARE to facilitate appropriate discussion at multidisciplinary meetings to direct further management. In this article, we provide a comprehensive review on various aspects of radioembolisation with Y-90 for hepatocellular carcinoma including the patient selection, treatment planning, radiation dosimetry and treatment, side effects, follow-up imaging and future direction.

Outcome after laparoscopic versus open wedge resection for suspected gastric gastrointestinal stromal tumors: A matched-pair case-control study.

BACKGROUND: Laparoscopic resection of gastric gastrointestinal stromal tumors (GISTs) has been shown by several retrospective studies to be technically feasible and associated with favorable outcomes when compared to the open approach. This study aims to mitigate potential selection bias by performing a case control study of laparoscopic (LWR) versus open wedge resection (OWR) matched by resection type, location and tumor size. METHODS: We retrospectively identified 50 consecutive patients who underwent LWR for a suspected gastric GIST from a prospective database and matched this cohort with 50 patients who underwent OWR. RESULTS: There was no statistical difference between the key baseline clinicopathological features of patients' who underwent LWR versus OWR. Patients who underwent LWR had longer operating times [150 (range, 65-270) minutes vs 92.5 (25-200) minutes, P < .001] but decreased median blood loss [0 (0-300) ml vs 0 (0-1200) ml, P = .015], decreased frequency of intraoperative or postoperative blood transfusion [1 (2%) vs 8 (16%), P = .031], decreased median time to liquid diet [2 (0-5) vs 3 (1-7) days, P < .001], decreased median time to solid diet [3 (1-6) vs 5 (2-11) days, P < .001] and decreased postoperative stay [4 (2-10) vs 4.5 (3-17), P < .001] compared to OWR. There was no difference in oncological outcomes such as frequency of close margins (≤ 1 mm) and recurrence-free survival. CONCLUSION: This matched case-control study provides supporting evidence that LWR results in superior perioperative outcomes compared to OWR without compromising on oncological outcomes.

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.

Systematic review of outcomes of liver resection for early hepatocellular carcinoma within the Milan criteria.

BACKGROUND: Long-term overall survival after liver resection in patients with hepatocellular carcinoma (HCC) within the Milan criteria has been reported to improve in recent years. This study systematically reviewed the outcomes of surgical resection for HCC in patients with good liver function and meeting the Milan criteria for early HCC, published in the past 10 years. METHODS: A literature search was conducted in PubMed for papers on outcomes of surgical resection for HCC published between January 2000 and December 2010. Cochrane systematic review methodology was used for this review. The primary outcome was overall survival. Secondary outcomes included operative mortality and disease-free survival. Studies that focused on geriatric populations, paediatric populations, a subset of the Milan criteria (such solitary tumours) or included patients with incidental tumours were excluded, as were case reports, conference abstracts, and studies with a large proportion of Child-Pugh grade C liver cirrhosis or unknown Child-Pugh status. RESULTS: Of 152 studies reviewed, two randomized clinical trials and 27 retrospective case series were eligible for inclusion. The 5-year overall survival rate after resection of HCC ranged from 27 to 81 (median 67) per cent, and the median disease-free survival rate from 21 to 57 (median 37) per cent. There was a trend towards improved overall survival in recent years. The operative mortality rate ranged from 0 to 5 (median 0·7) per cent. CONCLUSION: Surgical resection offers good overall survival for patients with HCC within the Milan criteria and with good liver function, although recurrence rates remain high. Outcomes have tended to improve in more recent years.

Computed tomography hepatic arteriography has a hepatic falciform artery detection rate that is much higher than that of digital subtraction angiography and 99mTc-MAA SPECT/CT: implications for planning 90Y radioembolization?

PURPOSE: To compare the hepatic falciform artery (HFA) detection rates of digital subtraction angiography (DSA), computed tomography hepatic arteriography (CTHA) and 99mTc-macroaggregated albumin (99mTc-MAA) single photon emission computed tomography with integrated CT (SPECT/CT) and to correlate HFA patency with complication rates of yttrium-90 (90Y) radioembolization. MATERIAL AND METHODS: From August 2008 to November 2010, 79 patients (range 23-83 years, mean 62.3 years; 67 male) underwent pre-treatment DSA, CTHA and 99mTc-MAA scintigraphy (planar/SPECT/CT) to assess suitability for radioembolization with 90Y resin microspheres. Thirty-seven patients were excluded from the study, because CTHA was performed with a catheter position that did not result in opacification of the liver parenchyma adjacent to the falciform ligament. DSA, CTHA and 99mTc-MAA SPECT/CT images and medical records were retrospectively reviewed. RESULTS: A patent HFA was detected in 22 of 42 patients (52.3%). The HFA detection rates of DSA, CTHA and 99mTc-MAA SPECT/CT were 11.9%, 52.3% and 13.3%, respectively (p<0.0001). An origin from the segment 4 artery was seen in 51.7% of HFAs. Prophylactic HFA coil-embolization prior to 90Y microspheres infusion was performed in 2 patients. Of the patients who underwent radioembolization with a patent HFA, none developed supra-umbilical radiation dermatitis. One patient experienced epigastric pain attributed to post-embolization syndrome and was managed conservatively. CONCLUSION: The HFA detection rate of CTHA is superior to that of DSA and 99mTc-MAA SPECT/CT. Complications related to non-target radiation of the HFA vascular territory rarely occur, even in patients undergoing radioembolization with a patent HFA.

Comparing the efficacy of sunitinib with sorafenib in xenograft models of human hepatocellular carcinoma: mechanistic explanation.

Hepatocellular carcinoma (HCC) is the fifth most common and third deadliest malignancy. Sorafenib has demonstrated 44% survival advantage over placebo and has emerged as a standard of care in advanced HCC. The therapeutic effects of sorafenib are however transient and hence additional treatment options are warranted. In this study, we aimed to compare the efficacy of sunitinib relative to sorafenib, two potent inhibitors of protein tyrosine kinases involved in tumor growth, metastasis, or angiogenesis. We reported that sorafenib and sunitinib suppressed tumor growth, angiogenesis, cell proliferation, and induced apoptosis in both orthotopic and ectopic models of HCC. However, the antitumor effect of 50 mg/kg sorafenib was greater than that of 40 mg/kg sunitinib. Sorafenib inhibited p-eIF4E Ser209, p-p38 Thr180/Tyr182 and reduced survivin expression. This was not seen with sunitinib. In addition, the antitumor and apoptotic effects of sorafenib, which are associated with upregulation of fast migrating Bim and ASK1 and downregulation of survivin, were greater than that of sunitinib. These observations explained in part the apparent superior anti-tumor activity of sorafenib compared to sunitinib. In conclusion, sunitinib demonstrated an inferior anti-tumor activity compared to sorafenib in ectopic and orthotopic models of human HCC. It remains to be seen whether such observations would be recapitulated in humans.

Randomised double-blind trial of megestrol acetate vs placebo in treatment-naive advanced hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide. We tested megestrol acetate (MA) against placebo in the treatment of advanced HCC. METHODS: From 2002 through 2007, this randomised double-blind trial enrolled 204 patients with treatment-naive advanced HCC (Eastern Cooperative Oncology Group (ECOG) performance rating of 0-3) from specialist care centres in six Asia-Pacific nations. Patients received placebo or MA (320 mg day(-1)). End points were overall survival (OS) and quality of life. RESULTS: An adverse but not statistically significant difference in OS was found for MA vs placebo: median values 1.88 and 2.14 months, respectively (hazard ratio (HR)=1.25, 95% CI=0.92-1.71, P=0.16). However, OS was similar among patients of good functional status (Child-Pugh A and ECOG 0, 1 or 2) (44.3%) in both treatment groups, with the adverse effect of MA confined to those of poor status. Megestrol acetate patients had a worse global health status (not statistically significant) but reduced levels of appetite loss and nausea/vomiting. CONCLUSION: Megestrol acetate has no role in prolonging OS in advanced treatment-naive HCC. Overall survival with placebo differed markedly from that in similar trials conducted elsewhere, suggesting therapeutic outcomes may be strongly dependent on ECOG status and Child-Pugh score.

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.

Thermoresponsive core-shell magnetic nanoparticles for combined modalities of cancer therapy.

Thermoresponsive polymer-coated magnetic nanoparticles loaded with anti-cancer drugs are of considerable interest for novel multi-modal cancer therapies. Such nanoparticles can be used for magnetic drug targeting followed by simultaneous hyperthermia and drug release. Gamma-Fe(2)O(3) iron oxide magnetic nanoparticles (MNP) with average sizes of 14, 19 and 43 nm were synthesized by high temperature decomposition. Composite magnetic nanoparticles (CNP) of 43 nm MNP coated with the thermoresponsive polymer poly-n-isopropylacrylamide (PNIPAM) were prepared by dispersion polymerization of n-isopropylacrylamide monomer in the presence of the MNP. In vitro drug release of doxorubicin-(dox) loaded dehydrated CNP at temperatures below and above the lower critical solution temperature of PNIPAM (34 degrees C) revealed a weak dependence of drug release on swelling behavior. The particles displayed Fickian diffusion release kinetics; the maximum dox release at 42 degrees C after 101 h was 41%. In vitro simultaneous hyperthermia and drug release of therapeutically relevant quantities of dox was achieved, 14.7% of loaded dox was released in 47 min at hyperthermia temperatures. In vivo magnetic targeting of dox-loaded CNP to hepatocellular carcinoma (HCC) in a buffalo rat model was studied by magnetic resonance imaging (MRI) and histology. In summary, the good in vitro and in vivo performance of the doxorubicin-loaded thermoresponsive polymer-coated magnetic nanoparticles suggests considerable promise for applications in multi-modal treatment of cancer.

2-[18F]-2-deoxy-D-glucose (FDG) uptake in human tumor cells is related to the expression of GLUT-1 and hexokinase II.

BACKGROUND: The uptake of 2-[18F]-2-deoxy-D-glucose ((18)F-FDG) is widely used as a marker of increased glucose metabolism to monitor progression of cancers with positron emission tomography (PET). Many tumors have been shown to overexpress facilitated glucose transporters, especially GLUT-1 and a glycolytic enzyme, hexokinase II. PURPOSE: To define whether a quantitative relationship exists between the expression levels of GLUT-1 and hexokinase II, and (18)F-FDG uptake in human cancer xenografts. MATERIAL AND METHODS: We determined the expression levels of both GLUT-1 and hexokinase II in normal cells and in five different human cancer cell lines (AGS, A431, A549, Colo 320 HSR, and HepG2) using Western blot analysis. In vitro assays of 18F-FDG uptake in cultures were performed, and subsequently representative cell lines were inoculated onto the flanks of severe combined immunodeficient (SCID) mice. To establish an orthotopic model of human hepatocellular carcinoma (HCC), cells were injected into the intraportal vein of SCID mice. (18)F-FDG uptake in vivo was assessed by subjecting mice to PET imaging. RESULTS: All cell lines were shown to express higher amounts of GLUT-1 and hexokinase II compared with fibroblast controls. Our results from in vitro (18)F-FDG uptake assays also correlated with the Western blot results. All xenografts gave highly positive results at microPET imaging, and a strong correlation (R(2)=0.88, P<0.001) was found between the maximum standardized uptake values (SUV(max)) and the expression of GLUT-1 proteins. CONCLUSION: Our data indicate that the expression levels of GLUT-1 and hexokinase II as well as in vitro assays of FDG uptake serve as good screening tests to evaluate the feasibility of cell lines to be further developed into xenograft cancer models for small-animal PET imaging.

Pathologic, radiologic and PET scan response of gastrointestinal stromal tumors after neoadjuvant treatment with imatinib mesylate.

AIM: The aim of this study is to review the radiologic, PET scan and pathologic response and the outcome of patients with advanced GIST treated with neoadjuvant IM followed by surgical resection. MATERIALS AND METHODS: We report a case and review 36 patients reported in MEDLINE with advanced GIST treated with neoadjuvant IM followed by surgical resection. RESULTS: Thirty-seven patients with a median age of 56 years (range, 32-76 years) at presentation were treated with neoadjuvant IM. Radiologic response accurately predicted pathological response in 31/36 patients, whereas PET scan was accurate in predicting treatment response in only 6/23 patients. CONCLUSION: This study demonstrates that the pathologic response of GIST to IM is usually incomplete and does not correlate with the complete response seen on PET scan. This finding suggests that surgical resection will continue to play a vital role in the treatment of patients with advanced disease responding to IM treatment.

Clinico-pathological features of cystic pancreatic endocrine neoplasms and a comparison with their solid counterparts.

AIM: Pancreatic endocrine neoplasms (PENs) may occasionally manifest as cystic lesions of the pancreas. The aim of this study is to report our experience with cystic PENs and to compare their clinico-pathological features with their solid counterparts. MATERIALS AND METHODS: From 1990 to 2004, 38 patients with PENs were reviewed. Six of these tumours appeared on radiological imaging as a cystic lesion of the pancreas. RESULTS: Of the 38 patients with a PEN, 21 of the patients were female and with a median age of 54.5 (range, 33-83) years. Sixteen patients had functional endocrine tumours of which insulinoma was the most common. The six patients with cystic PEN had a median age of 55.5 (range, 41-70) years and half were female. Cystic PENs were significantly larger [48 (range, 25-170) mm vs 19 (range, 3-120) mm, P = 0.013] and were less likely to be benign (0 vs 50%, P = 0.017) compared to their solid counterparts. There was no difference between cystic and solid PENs in terms of age, sex, presence of symptoms, proportion of functioning tumours and location of tumours within the pancreas. CONCLUSION: Cystic PENs share many clinico-pathological features with solid PENs. These differ only in the cystic appearance and tend to be of a larger size. Hence, these findings suggest that cystic and solid PENs are unlikely to be distinct pathological entities but are likely to be morphological variants of the same entity.

Cystic neoplasms of the pancreas with mucin-production.

AIM: To compare the clinico-pathological features of intraductal papillary mucinous cystic tumours (IPMT) and mucinous cystic tumours (MCT) of the pancreas. METHODS: Eighteen patients with IPMT and 18 with MCT who underwent surgical resection between 1990 and 2004 were retrospectively reviewed. Their clinico-pathological features were compared using univariate analysis. Statistical analyses of potential predictive factors of malignancy for each of these two groups were also conducted. RESULTS: Patients with IPMT were found to be older (64+/-10 vs 43+/-18 years, p<0.001) and were predominantly male (male:female ratio, 5:4 vs 1:17, p=0.003) as compared to patients with MCT. MCTs were found in the body-tail region (100%) whereas IPMTs were more evenly distributed (50% in the head) (p=0.001). Pathologically, IPMT was distinct from MCT in terms of size (3.8+/-3.2 vs 9.1+/-4.4 cm, p=0.001), association with secondary pancreatitis (50 vs 0%, p=0.011), communication with the pancreatic duct (94 vs 0%, p<0.001), presence of a dilated main pancreatic duct (61 vs 0%, p<0.001) and the presence of ovarian-type stroma (0 vs 44%, p=0.003). CONCLUSION: IPMT and MCT are distinct clinico-pathological entities. This distinction is important as management and outcome of these entities may differ.

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.

Management of inpatients exposed to an outbreak of severe acute respiratory syndrome (SARS).

This is a prospective observational study of a cohort of inpatients exposed to a severe acute respiratory syndrome (SARS) outbreak. Strict infection control policies were instituted. The 70 patients exposed to the SARS outbreak were isolated from the rest of the hospital. They were triaged, quarantined and cohorted in three open plan wards. Selective isolation was carried out immediately when symptoms and signs suspicious of SARS manifested clinically. The patients' ages ranged from 21 to 90 years and 56% had surgery before the quarantine. Sixteen patients with unexplained fever during the period of quarantine were isolated, seven of whom were eventually diagnosed with probable SARS. The crude incidence of SARS in our cohort was 10%. The SARS case fatality was 14%. No secondary transmission of the SARS virus within the cohort was observed. Strict infection control, together with appropriate triaging, cohorting and selective isolation, is an effective and practical model of intervention in cohorts exposed to a SARS outbreak. Such a management strategy eases the logistic constraints imposed by demands for large numbers of isolation facilities in the face of a massive outbreak.

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.

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.