Immune activation underlies a sustained clinical response to Yttrium-90 radioembolisation in hepatocellular carcinoma.

OBJECTIVES: Yttrium-90 (Y90)-radioembolisation (RE) significantly regresses locally advanced hepatocellular carcinoma and delays disease progression. The current study is designed to deeply interrogate the immunological impact of Y90-RE, which elicits a sustained therapeutic response. DESIGN: Time-of-flight mass cytometry and next-generation sequencing (NGS) were used to analyse the immune landscapes of tumour-infiltrating leucocytes (TILs), tumour tissues and peripheral blood mononuclear cells (PBMCs) at different time points before and after Y90-RE. RESULTS: TILs isolated after Y90-RE exhibited signs of local immune activation: higher expression of granzyme B (GB) and infiltration of CD8+ T cells, CD56+ NK cells and CD8+ CD56+ NKT cells. NGS confirmed the upregulation of genes involved in innate and adaptive immune activation in Y90-RE-treated tumours. Chemotactic pathways involving CCL5 and CXCL16 correlated with the recruitment of activated GB+CD8+ T cells to the Y90-RE-treated tumours. When comparing PBMCs before and after Y90-RE, we observed an increase in tumour necrosis factor-α on both the CD8+ and CD4+ T cells as well as an increase in percentage of antigen-presenting cells after Y90-RE, implying a systemic immune activation. Interestingly, a high percentage of PD-1+/Tim-3+CD8+ T cells coexpressing the homing receptors CCR5 and CXCR6 denoted Y90-RE responders. A prediction model was also built to identify sustained responders to Y90-RE based on the immune profiles from pretreatment PBMCs. CONCLUSION: High-dimensional analysis of tumour and systemic immune landscapes identified local and systemic immune activation that corresponded to the sustained response to Y90-RE. Potential biomarkers associated with a positive clinical response were identified and a prediction model was built to identify sustained responders prior to treatment.

Real-World Data on Clinical Outcomes of Patients with Liver Cancer: A Prospective Validation of the National Cancer Centre Singapore Consensus Guidelines for the Management of Hepatocellular Carcinoma.

INTRODUCTION: Real-world management of patients with hepatocellular carcinoma (HCC) is crucially challenging in the current rapidly evolving clinical environment which includes the need for respecting patient preferences and autonomy. In this context, regional/national treatment guidelines nuanced to local demographics have increasing importance in guiding disease management. We report here real-world data on clinical outcomes in HCC from a validation of the Consensus Guidelines for HCC at the National Cancer Centre Singapore (NCCS). METHOD: We evaluated the NCCS guidelines using prospectively collected real-world data, comparing the efficacy of treatment received using overall survival (OS) and progression-free survival (PFS). Treatment outcomes were also independently evaluated against 2 external sets of guidelines, the Barcelona Clinic Liver Cancer (BCLC) and Hong Kong Liver Cancer (HKLC). RESULTS: Overall treatment compliance to the NCCS guidelines was 79.2%. Superior median OS was observed in patients receiving treatment compliant with NCCS guidelines for early (nonestimable vs. 23.5 months p < 0.0001), locally advanced (28.1 vs. 22.2 months p = 0.0216) and locally advanced with macrovascular invasion (10.3 vs. 3.3 months p = 0.0013) but not for metastatic HCC (8.1 vs. 6.8 months p = 0.6300), but PFS was similar. Better clinical outcomes were seen in BCLC C patients who received treatment compliant with NCCS guidelines than in patients with treatment only allowed by BCLC guidelines (median OS 14.2 vs. 7.4 months p = 0.0002; median PFS 6.1 vs. 4.0 months p = 0.0286). Clinical outcomes were, however, similar for patients across all HKLC stages receiving NCCS-recommended treatment regardless of whether their treatment was allowed by HKLC. CONCLUSION: The high overall compliance rate and satisfactory clinical outcomes of patients managed according to the NCCS guidelines confirm its validity. This validation using real-world data considers patient and treating clinician preferences, thus providing a realistic analysis of the usefulness of the NCCS guidelines when applied in the clinics.

SIRveNIB: Selective Internal Radiation Therapy Versus Sorafenib in Asia-Pacific Patients With Hepatocellular Carcinoma.

Purpose Selective internal radiation therapy or radioembolization (RE) shows efficacy in unresectable hepatocellular carcinoma (HCC) limited to the liver. This study compared the safety and efficacy of RE and sorafenib in patients with locally advanced HCC. Patients and Methods SIRveNIB (selective internal radiation therapy v sorafenib), an open-label, investigator-initiated, phase III trial, compared yttrium-90 (90Y) resin microspheres RE with sorafenib 800 mg/d in patients with locally advanced HCC in a two-tailed study designed for superiority/detriment. Patients were randomly assigned 1:1 and stratified by center and presence of portal vein thrombosis. Primary end point was overall survival (OS). Efficacy analyses were performed in the intention-to-treat population and safety analyses in the treated population. Results A total of 360 patients were randomly assigned (RE, 182; sorafenib, 178) from 11 countries in the Asia-Pacific region. In the RE and sorafenib groups, 28.6% and 9.0%, respectively, failed to receive assigned therapy without significant cross-over to either group. Median OS was 8.8 and 10.0 months with RE and sorafenib, respectively (hazard ratio, 1.1; 95% CI, 0.9 to 1.4; P = .36). A total of 1,468 treatment-emergent adverse events (AEs) were reported (RE, 437; sorafenib, 1,031). Significantly fewer patients in the RE than sorafenib group had grade ≥ 3 AEs (36 of 130 [27.7%]) v 82 of 162 [50.6%]; P < .001). The most common grade ≥ 3 AEs were ascites (five of 130 [3.8%] v four of 162 [2.5%] patients), abdominal pain (three [2.3%] v two [1.2%] patients), anemia (zero v four [2.5%] patients), and radiation hepatitis (two [1.5%] v zero [0%] patients). Fewer patients in the RE group (27 of 130 [20.8%]) than in the sorafenib group (57 of 162 [35.2%]) had serious AEs. Conclusion In patients with locally advanced HCC, OS did not differ significantly between RE and sorafenib. The improved toxicity profile of RE may inform treatment choice in selected patients.

Image-guided radiofrequency ablation of liver malignancies: experience at Singapore General Hospital.

UNLABELLED: The aim of this paper was to study the efficacy, side effects and complications of radiofrequency (RF) ablation of primary and metastatic liver malignancies. MATERIALS AND METHODS: We retrospectively reviewed 57 patients (39 men, 18 women; mean age, 63 years; age range, 44 to 83 years) who underwent RF ablation for liver malignancies from January 2002 to December 2004. A total of 87 tumours were ablated - 71 (81.6%) hepatocellular carcinomas and 16 (18.4%) metastases (from primaries in the colon, stomach and pancreas). RF ablation was performed either percutaneously (n = 71) under conscious sedation or intraoperatively (n = 16) under general anaesthesia. Follow-up ranged from 1 month to 41 months (mean, 15.2) and included computed tomography (CT) 1 day, 1 month and 3 months after ablation, and half-yearly thereafter. Patients were observed for local tumour progression and for the emergence of new tumours. RESULTS: Four patients with a total of 5 tumours were lost to follow-up. Of the remaining 82 tumours treated, complete ablation was attained in 66 tumours after a single procedure, giving a primary effectiveness rate of 80.5%. Seven (8.5%) required 2 procedures to achieve complete ablation, giving a secondary effectiveness rate of 89% after 2 ablations. One tumour (1.2%) required 3 procedures to achieve complete ablation. One tumour required 4 procedures to date, with the latest follow-up CT still demonstrating incomplete ablation. Two tumours (2.4%) had an initial RF ablation and subsequent transarterial chemoembolisation (TACE). One tumour had an initial RF ablation followed by 32Phosphorus-biosilicon (BrachySil) injection, the latter as part of a Phase IIA trial. One tumour required 2 RF ablations and a subsequent TACE. Lastly, 3 tumours received initial RF ablation but subsequent local tumour progression was not treated as the patients were deemed unfit for repeat ablation. No procedure-related deaths or major complications were encountered. Minor complications were reported in 2 patients (3.8%) - subcapsular haematoma and thermal injury to the adjacent gastric antrum, both not necessitating surgical intervention. CONCLUSIONS: RF ablation is an effective, safe and relatively simple procedure for the treatment of unresectable liver malignancies.

Quantitative Study on the Effect of Abnormalities on Respiration-Induced Kidney Movement.

Respiration-induced movement of abdominal organs hampers the targeting accuracy of non-invasive surgical techniques such as focused ultrasound surgery and radiosurgery. Unaccounted organ movement can result in either under dosage or damage to intervening healthy tissues. The respiration-induced movement is known to be significantly large in kidneys; however, the impact of abnormalities such as tumors and cysts on kidney movement is poorly understood. In this study, we quantified the movement patterns of kidneys in 48 normal and 62 affected kidneys (43 calcified cysts, 11 angiomyolipomas, 4 renal cell carcinomas and 4 polycystic kidneys) using ultrasound and simultaneously tracked the respiratory movement patterns using a stereo camera system. The kidneys were localized from 2-D ultrasound sequences using a template matching technique. The average movements of the right and left kidneys were, respectively, 24.54 ± 6.4 and 17.06 ± 3.66 mm in the superior-inferior and 13.62 ± 3.71 and 9.80 ± 3.32 mm in the transverse directions. Average movement in the superior-inferior direction of normal kidneys was greater than that of affected kidneys for both right (26.9 ± 5.1 vs. 22.6 ± 3.3, p < 0.001) and left (17.8 ± 2.5 vs. 16.1 ± 4.2, p = 0.01) kidneys. On the basis of spatial extent of abnormality, affected kidneys were categorized as category A (<10 mm in 26 patients), category B (10-20 mm in 22 patients) and category C (>20 mm in 14 patients). Compared with normal patients, the extent of movement was significantly reduced in abnormal categories B (p < 0.001) and C (p < 0.001), but the change was not significant in category A (p = 0.04). Hysteresis plots of the kidneys revealed a maximum change of 12.3 mm. The movement patterns of the kidneys also closely correlated with the respiratory movement pattern (Pearson correlation = 0.89 [right] and 0.87 [left]). We expect that the movement pattern analyses and quantification carried out in this study would aid in developing movement adaptive surgical protocols for non-invasive treatment of kidney tumors/cancers.

National Cancer Centre Singapore Consensus Guidelines for Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the 6th most common cancer in the world, but the second most common cause of cancer death. There is no universally accepted consensus practice guidelines for HCC owing to rapid developments in new treatment modalities, the heterogeneous epidemiology and clinical presentation of HCC worldwide. However, a number of regional and national guidelines currently exist which reflect practice relevant to the epidemiology and collective experience of the consensus group. In 2014, clinicians at the multidisciplinary Comprehensive Liver Cancer Clinic (CLCC) at the National Cancer Centre Singapore (NCCS) reviewed the latest published scientific data and existing international and regional practice guidelines, such as those of the National Comprehensive Cancer Network, American Association for the Study of Liver Diseases and the Asian Pacific Association for the Study of the Liver, and modified them to reflect local practice. These would serve as a template by which treatment outcomes can be collated and benchmarked against international data. The NCCS Consensus Guidelines for HCC have been successfully implemented in the CLCC since their publication online on 26(th) September 2014, and the guidelines allow outcomes of treatment to be compared to international data. These guidelines will be reviewed periodically to incorporate new data.

Non-Target Activity Detection by Post-Radioembolization Yttrium-90 PET/CT: Image Assessment Technique and Case Examples.

High resolution yttrium-90 ((90)Y) imaging of post-radioembolization microsphere biodistribution may be achieved by conventional positron emission tomography with integrated computed tomography (PET/CT) scanners that have time-of-flight capability. However, reconstructed (90)Y PET/CT images have high background noise, making non-target activity detection technically challenging. This educational article describes our image assessment technique for non-target activity detection by (90)Y PET/CT, which qualitatively overcomes the problem of background noise. We present selected case examples of non-target activity in untargeted liver, stomach, gallbladder, chest wall, and kidney, supported by angiography and (90)Y bremsstrahlung single-photon emission computed tomography with integrated computed tomography (SPECT/CT) or technetium-99m macroaggregated albumin SPECT/CT.

Multicenter phase II study of sequential radioembolization-sorafenib therapy for inoperable hepatocellular carcinoma.

BACKGROUND: The safety and tolerability of sequential radioembolization-sorafenib therapy is unknown. An open-label, single arm, investigator-initiated Phase II study (NCT0071279) was conducted at four Asia-Pacific centers to evaluate the safety and efficacy of sequential radioembolization-sorafenib in patients with hepatocellular carcinoma (HCC) not amenable to curative therapies. METHODS: Sorafenib (400 mg twice-daily) was initiated 14 days post-radioembolization with yttrium-90 (90Y) resin microspheres given as a single procedure. The primary endpoints were safety and tolerability and best overall response rate (ORR) using RECIST v1.0.Secondary endpoints included: disease control rate (complete [CR] plus partial responses [PR] and stable disease [SD]) and overall survival (OS). RESULTS: Twenty-nine patients with Barcelona Clinic Liver Cancer (BCLC) stage B (38%) or C (62%) HCC received a median of 3.0 GBq (interquartile range, 1.0) 90Y-microspheres followed by sorafenib (median dose/day, 600.0 mg; median duration, 4.1 months). Twenty eight patients experienced ≥1 toxicity; 15 (52%) grade ≥3. Best ORR was 25%, including 2 (7%) CR and 5 (18%) PR, and 15 (54%) SD. Disease control was 100% and 65% in BCLC stage B and C, respectively. Two patients (7%) had sufficient response to enable radical therapy. Median survivals for BCLC stage B and C were 20.3 and 8.6 months, respectively. CONCLUSIONS: This study shows the potential efficacy and manageable toxicity of sequential radioembolization-sorafenib. TRIAL REGISTRATION: ClinicalTrials.gov NCT00712790.

Single centre experience of transjugular liver biopsy in 152 patients.

INTRODUCTION: Liver biopsy is considered the definitive investigation in the diagnosis and management of liver disease. This study describes the experience of performing transjugular liver biopsy (TJLB) over the last 9 years in a local single centre. MATERIALS AND METHODS: A retrospective review of consecutive TJLB procedures performed at our institution was conducted. A total of 152 patients (74 males and 78 females), with a mean age of 47.4 years (range, 13 to 83 years) underwent a total of 154 TJLB procedures at our institution between March 2003 and November 2011. The principal indication for TJLB was severe coagulopathy in over 80% of patients. The technical success, number of passes, histological adequacy and complication rates were analysed. RESULTS: The procedural success rate was 98.7% (152 out of 154 procedures). Adequate material for diagnosis was obtained in 149 out of 152 (98.0%) technically successful procedures. There was procedure related morbidity in 8 patients (5.2%) of which all but one were self-limiting requiring no further intervention. We also performed hepatic venous pressure gradient (HVPG) measurements in 19% of patients at the time of TJLB. CONCLUSION: TJLB performed at our institution is a safe and reliable technique in patients in whom traditional percutaneous liver biopsy may be hazardous. TJLB has a high technical success rate as well as a high diagnostic yield with a low complication rate. TJLB also has the added benefit of performing HVPG, which is of increasing importance in management and prognostication of chronic liver disease.

Primary hepatic artery embolization in pediatric blunt hepatic trauma.

Non-operative management of isolated blunt hepatic trauma is recommended except when hemodynamic instability requires immediate laparotomy. Hepatic artery angioembolization is increasingly used for hepatic injuries with ongoing bleeding as demonstrated by contrast extravasation on the CT scan. It is used primarily or after laparotomy to control ongoing hemorrhage. Hepatic angioembolization as part of multimodality management of hepatic trauma is reported mainly in adults, with few pediatric case reports. We describe our institution experience with primary pediatric hepatic angioembolization and review the literature with regard to indications and complications. Two cases (3 and 8 years old), with high-grade blunt hepatic injuries with contrast extravasation on the CT scan were successfully managed by emergency primary hepatic angioembolization with minimal morbidity and avoided laparotomy. To date, the only reports of pediatric hepatic angioembolization for trauma are 5 cases for acute bleeding and 15 delayed cases for pseudoaneurysm. The role of hepatic angioembolization in the presence of an arterial blush on CT in adults is accepted, but contested in a pediatric series, despite higher transfusion rate and mortality rate. We propose that hepatic angioembolization should be considered adjunct treatment, in lieu of, or in addition to emergency laparotomy for hemostasis in pediatric blunt hepatic injury.

Hepatic falciform ligament Tc-99m-macroaggregated albumin activity on SPECT/CT prior to Yttrium-90 microsphere radioembolization: prophylactic measures to prevent non-target microsphere localization via patent hepatic falciform arteries.

Yttrium-90 (Y-90) selective internal radiation therapy (SIRT) is increasingly used to treat inoperable hepatocellular carcinoma. We describe two patients where hepatic falciform ligament Technetium-99m-macroaggregated albumin (Tc-99m-MAA) activity was identified on single photon emission computed tomography with integrated low-dose CT (SPECT/CT) scan during pre-therapy planning, and the steps taken to prevent radiation dermatitis. The first patient underwent prophylactic coil embolization of the patent hepatic falciform artery; the second patient underwent super-selective infusion of Y-90 resin microspheres to avoid the patent hepatic falciform artery. The incidence of falciform ligament Tc-99m-MAA activity detected on SPECT/CT at our institution is 10%. Tc-99m-MAA SPECT/CT scan provides valuable diagnostic information for treatment planning prior to Y-90 SIRT.

Prophylactic embolization of hepatic artery pseudoaneurysm after blunt abdominal trauma in a child.

We describe a 10-year-old boy who developed a pseudoaneurysm in the territory of the left hepatic artery after blunt trauma to the abdomen, which was prophylactically embolized. He was discharged early and was able to return to activities of daily life. In view of the potentially fatal complication of severe hemorrhage from a missed hepatic pseudoaneurysm rupture, recognition and early embolization of a traumatic pseudoaneurysm of hepatic artery are recommended. This decreases morbidity, mortality, and length of hospital stay and allows for early mobilization especially in children who are difficult to restrain in bed.