Macroscopic Vascular Invasion Research Articles

Perioperative blood transfusion does not influence recurrence-free and overall survivals after curative resection for hepatocellular carcinoma: A Propensity Score Matching Analysis

Whether perioperative blood transfusions (PBTs) negatively impact oncologic outcomes after curative resection for HCC remains controversial. We aimed to identify the independent predictive factors of PBT for curative resection of hepatocellular carcinoma (HCC), and to investigate the impact of PBT on long-term recurrence and survivals after resection. Of 1103 patients who underwent curative liver resection for HCC between 1999 and 2010, 285 (25.8%) patients received PBT. Univariable and multivariable regression analyses were used to identify independent predictive factors of PBT. Propensity scores and Cox regression analyses were used to compare the overall survival (OS) and recurrence-free survival (RFS) between patients who did and did not receive PBT. Multivariable regression analysis revealed that performance status, preoperative hemoglobin, cirrhosis, portal hypertension, tumor rupture, tumor size, macroscopic vascular invasion, and intraoperative blood loss were independent predictive factors of PBT for HCC resection. Propensity score matching analysis created 234 pairs of patients. Before propensity matching, PBT was significantly associated with increased risks of OS (HR: 2.455, 95% CI: 2.077-2.901, p<0.001) and RFS (HR: 2.018, 95% CI: 1.718-2.370, p<0.001) in the entire cohort. After propensity matching, PBT was not significantly associated with increased risks of OS (HR: 1.229, 95% CI: 0.988-1.527, p=0.063) and RFS (HR: 1.188, 95% CI: 0.960-1.469, p=0.113). After adjustment for other prognostic variables in the propensity matched cohort, PBT was still found not to be associated with OS and RFS after HCC resection. The present study identified that PBT did not influence RFS and OS after curative resection of HCC.

Efficacy of radioembolization according to tumor morphology and portal vein thrombosis in intermediate-advanced hepatocellular carcinoma.

We analyzed overall survival (OS) following radioembolization according to macroscopic growth pattern (nodular vs infiltrative) and vascular invasion in intermediate-advanced hepatocellular carcinoma (HCC). Between September 2005 and November 2013, 104 patients (50.0% portal vein thrombosis [PVT], 29.8% infiltrative morphology) were treated. Median OS differed significantly between patients with segmental and lobar or main PVT (p = 0.031), but was 17 months in both those with patent vessels and segmental PVT. Median OS did not differ for infiltrative and nodular HCC. Median OS was prolonged in patients with a treatment response at 3 months (p = 0.023). Prior TACE was also a significant predictor of improved OS. A further indication for radioembolization might be infiltrative HCC, since OS was similar to nodular types.

A prognosis model for patients with hepatocellular carcinoma and portal vein tumor thrombus following hepatic resection.

The present study aimed to identify the risk factors influencing the survival of patients with hepatocellular carcinoma (HCC) affected by portal vein tumor thrombus (PVTT), following hepatic resection, and to establish a prognostic model. Between March 2001 and May 2008, 234 cases of HCC with PVTT that underwent hepatic resection were randomly divided into experimental or validation groups. The association between the clinicopathological factors and disease-free survival (DFS) and overall survival (OS) was analyzed, and the significant factors involved were used to establish a prognostic model, which was then validated. Tumor rupture, number of tumors and macroscopic vascular invasion were observed to be independent risk factors of DFS and OS. In the prognostic model, the DFS and OS of low-, medium- and high-risk patients in the experimental group were observed to be significantly different, compared to those in the validation group. In conclusion, the present study established a prognostic model for patients with HCC affected by PVTT following hepatectomy, and demonstrated that the model may be used to guide the treatment of these patients and predict their prognosis.

Clinical characteristics and outcome of hepatocellular carcinoma in alcohol related and cryptogenic cirrhosis: a prospective study

Non-alcoholic fatty liver disease (NAFLD) is becoming a leading cause of chronic liver disease. Hepatocellular carcinoma (HCC) is one of its complications. Although the pathophysiology is unclear, it is reasonable to expect that cryptogenic cirrhosis related HCC (cryptogenic HCC) behaves differently to other types of HCC. This study prospectively compared patients with cryptogenic HCC and those with HCC related to alcoholic cirrhosis. A total of 150 consecutive patients with HCC (89 cryptogenic HCC and 61 alcohol related HCC) referred to our unit over a 23-month period were studied. Their demographic data, liver function, tumor characteristics and outcomes were compared. Alcohol related HCC was seen only in males. Compared with cryptogenic HCC, alcohol related HCC had significantly higher aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio (1.7 vs 1.4, P=0.002), model for end-stage liver disease score (13 vs 11, P=0.018) and Child's score (7 vs 6, P=0.037). No significant difference was seen in platelet counts, serum sodium and AST to platelet ratio index. Single nodular tumors were more common in cryptogenic HCC, while diffuse type tumors and macroscopic vascular invasion were common in alcohol related HCC. In patients who could not be offered any treatment because of advanced tumors or poor liver function, alcohol related HCC had a significantly lower median survival (5.3 months) compared with cryptogenic HCC (9.3 months, P=0.034). Compared with cryptogenic HCC, alcohol related HCC had worse liver function and aggressive tumor morphology at presentation, and a higher proportion was untreatable. In patients who could not be treated, median survival was lower in patients with alcohol related HCC than in those with cryptogenic HCC.

Abstract 3612: Study of the functional importance of PPARγ in honokiol-induced apoptosis of hepatoma cells

Abstract Hepatocellular carcinoma (HCC) is the leading cause of death in male cancer patients in Asia. PPARγ exhibited an inhibitory role in hepatocarcinogenesis in vitro and in vivo. Recently, it was found that honokiol functions not only as a RXR agonist but also a PPARγ agonist, and is capable of potentiating the activation of PPARγ in the presence of PPARγ agonist rosiglitazone in HLE human hepatoma cells. It also has been reported that honokiol exerts inhibitory effects on the growth and migration in hepatoma cells. However, whether PPARγ overexpression modulates the honokiol-induced growth inhibition in hepatoma cells is not known. Firstly, we examined the expression of PPARγ in tumor samples from 83 HCC patients by immunohistochemical staining. Our results showed that 53 samples had no PPARγ and the clinical parameters including tumor number, stages, and macroscopic vascular invasion (MVI) showed significant negative correlation with PPARγ expression. However, the expression of PPARγ was not associated with disease free survival or overall survival of patients with HCC. Using PPARγ overexpressed SK-Hep1 cells (SK-Hep1-PPARγ) for in vitro analyses, we found that 40 μM honokiol treatment of SK-Hep1-PPARγ cells induced a 20% increase of growth inhibition at 48 hour as compared to vector control cells by MTT assay. This corresponded well with the 15% increase in G0/G1 phase after honokiol treatment at 24 hour compared to vector control cells. In addition, honokiol treatment resulted in decreased cyclin D1, increased p21 and KLF4 expressions in SK-Hep1-PPARγ cells. Moreover, miRNA array analyses showed that increased expression of miR-222, let-7i, miR-628-3p and miR-664 as well as decreased miR-1291, miR184 and miR1249 were observed in SK-Hep1-PPARγ cells. In conclusion, PPARγ is not only a biomarker for prognosis of patients with HCC but also play an important role in the honokiol-induced growth inhibition of hepatoma cells. The functional importance of PPARγ regulated miRNA is currently under further investigation. Citation Format: Chin-Wen Chi, Hui-Tzu Hsu, Jia-Dong Hou, Chih-Chun Lee, Ying-Ju Kuo, Hsin-Chen Lee, Cheng-Yuan Hsia. Study of the functional importance of PPARγ in honokiol-induced apoptosis of hepatoma cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3612. doi:10.1158/1538-7445.AM2015-3612

Significance of viral status on prognosis of hepatitis B-related hepatocellular carcinoma after curative resection in East Asia.

Tumor recurrence remains one major obstacle for further improving the prognosis of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) patients after curative liver resection. It has been widely reported that tumor size, positive surgical margin, macroscopic vascular invasion, tumor-node-metastasis stage and Edmondson's grade were significantly related to HCC recurrence. However, the association between HCC recurrence and important viral factors, including the HBV DNA levels, status of hepatitis B surface antigen and hepatitis B e-antigen, levels of cccDNA and hepatitis B core-related antigen, viral genotypes and specific viral sequence mutations remained controversial. Meanwhile, studies on the effect of postoperative adjuvant antiviral therapy on HCC recurrence have been relatively limited and have yielded conflicting results. Identification of certain viral risk factors for HCC recurrence and stratification of patient risk are very important to perform future surveillance programs. As a HBV hyperendemic region, the majority of HBV-related HCC patients develop in East Asia. In this article, we thus systematically reviewed the risk of important viral factors involved in recurrent carcinogenesis and the role of adjuvant antiviral therapy in preventing tumor recurrence in this area.

Vascular invasion in hepatitis B virus-related hepatocellular carcinoma with underlying cirrhosis: possible associations with ascites and hepatitis B viral factors?

Vascular invasion is one of the most important prognostic factors for patients with hepatocellular carcinoma (HCC). The objective of the current, retrospective study was to determine the associations of ascites and hepatitis B viral factors (HBeAg and anti-HBe status and HBV DNA levels), as well as tumor-related factors (size, tumor number, grade, and location) with micro- or macroscopic vascular invasion in patients with HCC that developed as a result of hepatitis B virus (HBV)-related cirrhosis. A total of 336 consecutive patients were included. Potential factors associated with micro- or macroscopic vascular invasion were analyzed by logistic regression. Ascites were more commonly detected in patients with micro- or macroscopic vascular invasion, and the presence of ascites was independently associated with vascular invasion. Among patients with mild-to-moderate or severe ascites, the odds ratio for macroscopic vascular invasion was 4.83 (95 % confidence interval [CI] 2.29-10.16) and 11.87 (95 % CI 4.53-31.07), respectively. Similarly, the presence of ascites was associated with microscopic vascular invasion (OR 5.00; 95 % CI 1.23-20.31). In contrast, hepatitis B viral factors were not significantly associated with vascular invasion. The presence of ascites was associated with vascular invasion in patients with HBV-related cirrhotic HCC. Thus, patients with ascites, vascular invasion should be considered and more frequent surveillance should be performed after curative treatment.

Anatomical versus non-anatomical resection for hepatocellular carcinoma.

The optimal surgical resection method in patients with HCC to minimize the risk of local recurrence has not yet been determined. The aim of this study was to compare the prognosis following anatomical versus non-anatomical hepatic resection for hepatocellular carcinoma (HCC). Consecutive patients with HCC without macroscopic vascular invasion, treated by curative resection between 1981 and 2012 at Osaka Medical Centre, were included in this retrospective study. The outcomes of patients selected by propensity score matching were compared. Some 1102 patients were included, 577 in the anatomical and 525 in the non-anatomical resection group. By propensity score matching, 329 patients were selected into each group. Demographic, preoperative and tumour variables were similar between the propensity score-matched groups, including tumour size, tumour multiplicity, α-fetoprotein level and 15-min indocyanine green retention rate at 15 min. The incidence of microvascular invasion was higher in the matched anatomical resection group (P = 0·048). Stratified analysis of recurrence-free and overall survival rates revealed no statistically significant differences between the two propensity score-matched groups (P = 0·704 and P = 0·381 respectively). There was also no significant difference in the early recurrence rate within 2 years after resection between these groups (P = 0·726). Subset analysis of the early recurrence-free survival rate in patients with and without microvascular invasion revealed no significant differences between the groups (P = 0·312 and P = 0·479 respectively). The resection method had no impact on the risk of HCC recurrence or survival.

Determinants of survival after sorafenib failure in patients with BCLC-C hepatocellular carcinoma in real-world practice.

Sorafenib may improve progression-free survival (PFS) and overall survival (OS) of advanced hepatocellular carcinoma (HCC). However, the survival benefit is short lived and survivals after progressive disease (PD) have not been well characterized. This study aimed to evaluate the survival predictors of OS and postprogression survival (PPS) in advanced HCC patients receiving sorafenib treatment. Consecutive 149 HCC patients receiving sorafenib under National Health Insurance were retrospectively enrolled. All patients fulfilled the reimbursement criteria: Barcelona Clinic Liver Cancer stage C HCC with macroscopic vascular invasion or extrahepatic metastasis (Mets), and Child-Pugh class A. Radiologic assessment was performed at a 2-month interval using modified Response Evaluation Criteria in Solid Tumors. Patients who maintained Eastern Cooperative Oncology Group ≤2 and Child-Pugh class A at PD were assumed to be candidates for second-line treatment. During the median follow-up period of 7.5 months (range, 1.1-18.5), PD developed in 120 (80.5%) patients and 96 (64.4%) deaths occurred. The median PFS, OS, and PPS were 2.5, 8.0, and 4.6 months, respectively. In general, patients with Mets only had better OS and PPS than those with portal vein invasion. Independent predictors of OS include baseline performance status (hazard ratio [HR] = 1.956), tumor size (HR = 1.597), alpha-fetoprotein (HR = 1.869), discontinuation of sorafenib due to liver function deterioration (LD) (HR = 6.142), or concurrent PD and LD (HR = 2.661) and PD within 4 months (HR = 5.164). Independent predictors of PPS include deteriorated performance status (HR = 7.680), deteriorated liver functions (HR = 5.603), bilirubin (HR = 2.114), early PD (HR = 6.109), and new extrahepatic lesion (HR = 1.804). In 46 candidates for second-line trials, development of new extrahepatic lesion independently predicts poorer PPS (HR = 3.669). In conclusion performance status, liver functions, early disease progression, and progression pattern are important determinants of survival after sorafenib failure. These factors should be considered in clinical practice and second-line trial designs for patients with sorafenib failure.

Predictors of survival in patients with advanced hepatocellular carcinoma who permanently discontinued sorafenib.

Treatment with sorafenib of patients with advanced hepatocellular carcinoma is challenged by anticipated discontinuation due to tumor progression, liver decompensation, or adverse effects. While postprogression survival is clearly determined by the pattern of tumor progression, understanding the factors that drive prognosis in patients who discontinued sorafenib for any reason may help to improve patient management and second-line trial design. Patients consecutively admitted to three referral centers who were receiving best supportive care following permanent discontinuation of sorafenib for any reason were included. Postsorafenib survival (PSS) was calculated from the last day of treatment to death or last visit available. Two hundred and sixty patients were included in this prospective study, aged 67 years, 60% with hepatitis C, 51% Child-Pugh A, 83% performance status (PS) ≥1, 41% with macroscopic vascular invasion, and 38% with extrahepatic tumor spread. Overall, median PSS was 4.1 (3.3-4.9) months, resulting from 4.6 (3.3-5.7) months for 123 progressors, 7.3 (6.0-10.0) months in 77 with adverse effects, and 1.8 (1.6-2.4) months in 60 decompensated patients (P < 0.001). Postsorafenib survival was independently predicted by PS, prothrombin time, extrahepatic tumor spread, macrovascular invasion, and reason for discontinuation. Two hundred patients potentially eligible for second-line therapy had a PSS of 5.3 (4.6-7.1) months, which was dependent on reasons of discontinuation (P = 0.004), PS (P < 0.001), macrovascular invasion (P < 0.001), and extrahepatic metastases (P < 0.002). Discontinuation due to adverse effects in the absence of macrovascular invasion, extrahepatic metastases, and deteriorated PS predicts the best PSS in compensated patients, thereby setting the stage for both improved patient counseling and selection for second-line therapy.

Efficacy and safety of nintedanib versus sorafenib in Asian patients with advanced hepatocellular carcinoma (HCC): A randomized phase II trial.

339 Background: Nintedanib (N) is an oral, triple angiokinase inhibitor of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF) receptors. This randomized, multicenter, open-label, Phase II study (NCT00987935; 1199.39) evaluated the efficacy and safety of N versus sorafenib (S) in Asian patients with advanced HCC. Preliminary analysis showed similar time to progression (TTP) by independent central review (ICR). Methods: Asian patients with unresectable advanced HCC, Child–Pugh score 5–6, ECOG-PS ≤2, and alanine/aspartate aminotransferase (ALT/AST) ≤2× upper limit of normal were enrolled. Patients were randomized 2:1 to N 200 mg bid or S 400 mg bid continuously in 28-day cycles, until intolerable adverse events (AEs) or disease progression (PD); treatment beyond PD was allowed if clinical benefit was perceived. Primary endpoint was TTP by ICR (RECIST 1.0) and secondary endpoints were overall survival (OS) and investigator-assessed (IA) TTP. Results: Patients (N=95) were randomized to receive N (n=63) or S (n=32); arms were balanced except for macroscopic vascular invasion (48% vs 31%). At the final cutoff date (16 Jul 14), 88% of patients had a TTP event, and 86% had an OS event; 1 patient was on treatment beyond PD. N and S had comparable IA TTP (median 2.8 vs 3.0 months; HR 1.39 [95% CI: 0.87–2.23]) and OS (median 10.2 vs 10.7 months; HR 0.94 [95% CI: 0.59–1.49]). ICR TTP data are pending. All but 1 patient reported an AE (CTCAE 3.0). More S-treated patients had Grade ≥3 AEs (56% vs 84%), serious AEs (46% vs 56%), and AEs leading to dose reduction (19% vs 59%) and drug discontinuation (24% vs 34%). Class-specific AEs of tyrosine kinase inhibitors in &gt;15% of S-treated patients were hypertension, hand-foot skin reaction, and thrombocytopenia; only anemia was higher with N. AEs previously observed and higher with N were vomiting and nausea; ALT/AST increases and diarrhea were higher with S. Rash was reported in &gt;15% of patients only with S. Conclusions: N shows similar efficacy to S for TTP and OS. N was better tolerated than S and AEs were generally manageable. Further studies of N in Asian patients with advanced HCC are warranted. Clinical trial information: NCT00987935.

Alteration of N-glycan profiles in patients with chronic hepatitis and hepatocellular carcinoma.

Most of the modification of N-glycosylation reported in cancers including hepatocellular carcinoma (HCC) were based on the examinations of a small number of patients or particular proteins. The aim of this study is to reveal changes in whole serum N-glycan profiles systematically during the process of hepatocarcinogenesis and to elucidate their clinical application. We analyzed sera from 105 patients with chronic hepatitis/liver cirrhosis (CH/LC) and age-/sex-matched healthy volunteers (HLT), as well as from 114 patients with HCC. Serum N-glycan profiles were measured comprehensively by a new, quantitative, high-throughput method and compared with clinical parameters. The total amount of N-glycan expression was significantly higher in patients with CH/LC than in HLT; however, no differences were observed between CH/LC and HCC patients. In HCC patients, multi-antennary glycans with fucose residues, particularly m/z 3195, were increased compared with CH/LC patients. The expression of m/z 3195 was high, especially in patients with a high number of intrahepatic lesions (>3), large tumor size (>3 cm), macroscopic vascular invasion or metastasis. The ratio of pairs of glycans on the same path of the biosynthesis pathway (m/z 3195/1914) showed a higher area under the receiver-operator curve of 0.810 than any other single glycan to distinguish HCC from CH/LC. We demonstrate the full spectrum of the alterations of serum N-glycans comprehensively in patients with liver disease, and elucidate the possible use of glycans as novel biomarkers of liver disease progression.

Do patients with small solitary hepatocellular carcinomas without macroscopically vascular invasion require anatomic resection? Propensity score analysis

The benefits of anatomic resection in patients with small (<5 cm), solitary hepatocellular carcinomas remain unclear. Outcomes were therefore evaluated in patients who underwent anatomic resection or nonanatomic resection of small solitary hepatocellular carcinomas. Factors affecting overall survival and disease-free survival were investigated in 330 patients who underwent curative hepatectomy for solitary (≤5 cm) hepatocellular carcinomas without macroscopic vascular invasion. In addition, a propensity score matching model with 330 patients was constructed to overcome bias, with subgroups analyzed by tumor diameter (<3 cm and 3-5 cm). ICG-R15 ≥25% was confirmed as being independently associated with poorer overall survival and disease-free survival. One-to-one matching of preoperative characteristics yielded 72 pairs of patients receiving anatomic resection and nonanatomic resection, with long-term outcomes, including overall survival and disease-free survival, being similar in these 2 groups. Subgroup analysis showed that, in patients with tumors <3 cm in diameter, short-term outcomes were better in the nonanatomic resection group than in the anatomic resection group, including significantly reduced operation time (P = .02), blood loss (P = .01), blood transfusion (P < .01), complications (particularly bile leakage and abdominal abscess) (P = .04), and postoperative hospital stay (P < .01). Anatomic resection was not superior to nonanatomic resection in survival outcomes in patients with solitary small hepatocellular carcinomas without macroscopic vascular invasion. Rather, postoperative short-term outcomes were more favorable with nonanatomic resection.

An updated meta-analysis of randomized controlled trials assessing the effect of sorafenib in advanced hepatocellular carcinoma.

BackgroundThe efficacy of sorafenib in the treatment of advanced hepatocellular carcinoma (HCC) remains controversial. Therefore, we conducted a meta-analysis to evaluate the efficacy and safety of sorafenib for treating patients with advanced HCC.MethodsThe PubMed, Embase, and Web of Science databases were searched. Eligible studies were randomized controlled trials (RCTs) that assessed sorafenib therapy in patients with advanced HCC. The outcomes included overall survival (OS), time to progression (TTP), overall response rate (ORR), and toxicities. Hazard ratio (HR) and risk ratio (RR) were used for the meta-analysis and were expressed with 95% confidence intervals (CIs).ResultsSeven RCTs, with a total of 3807 patients, were included in this meta-analysis. All patients received sorafenib alone, or with other chemotherapeutic regimens. Pooled estimates showed that sorafenib improved the OS (HR = 0.74, 95% CI: 0.61, 0.90; P = 0.002), or TTP outcomes (HR = 0.69, 95% CI: 0.55, 0.86; P = 0.001). Subgroup analysis revealed that sorafenib was more effective in the patients with an Eastern Cooperative Oncology Group performance status (ECOG PS) of 1–2 (HR = 0.77, 95% CI: 0.60, 1.0; P = 0.05), or macroscopic vascular invasion (MVI), and/or extrahepatic spread (EHS) (HR = 0.65, 95% CI: 0.46, 0.93; P = 0.02), in terms of OS. Patients who received sorafenib did not have a higher ORR (RR = 0.85, 95% CI: 0.65, 1.11; P = 0.10). In addition, there was a slight increase in toxicity in the sorafenib group.ConclusionTreatment with sorafenib significantly improved OS and TTP in patients with advanced HCC. Additional large-scale, well-designed RCTs are needed to evaluate the efficacy of sorafenib-based therapy in the treatment of advanced HCC.

Overexpression of platelet-derived growth factor receptor alpha promotes tumor progression and indicates poor prognosis in hepatocellular carcinoma.

Dysregulation of platelet-derived growth factor receptor alpha (PDGFRα) has been documented in various cancers. However, its role in hepatocellular carcinoma (HCC) remains unknown. We and others have examined that upregulation of PDGFRα might be involved in hepatocarcinogenesis. Here, we report that PDGFRα plays a critical role in HCC progression and prognosis. The expression of PDGFRα was markedly higher in human HCC compared to adjacent liver tissues. Although PDGFRA mRNA was decreased in HCC, PDGF-A mRNA was dramatically increased in HCC. Overexpression of PDGFRα was strongly correlated with microvessel density (MVD) of HCC (p<0.05), as well as macroscopic vascular invasion of the tumors (p<0.05). HCC patients with high PDGFRα expression displayed a shorter overall survival and a higher recurrence rate than those with low PDGFRα expression (p<0.05, respectively). Additionally, stable overexpression of PDGFRα in hepatoma cells promoted cell proliferation, migration, invasion and epithelial-mesenchymal transition in vitro. Similarly, an in vivo assay showed that PDGFRα overexpression in hepatoma cells exhibited remarkably tumorigenic potential in tumor size and weight in vivo, which displayed markedly elevated MVD than controls. Thus, our study provided the evidence that PDGFRα may serve as a candidate prognostic marker and a novel therapeutic target for HCC.

Clinical, pathologic, and immunohistochemical prognostic factors in dogs with thyroid carcinoma.

BackgroundPrognostic markers for dogs with thyroid tumors are limited.Hypothesis/ObjectivesTo identify clinical, pathologic, and immunohistochemical prognostic factors for dogs with thyroid tumors.AnimalsSeventy dogs with thyroid neoplasia.MethodsRetrospective study. Dogs with thyroid neoplasia were included when follow‐up information and formalin‐fixed paraffin‐embedded tumor samples were available. Immunohistochemistry (IHC) was performed for thyroglobulin, calcitonin, Ki‐67, and E‐cadherin. Correlation of tumor variables (diameter, volume, localization, scintigraphic uptake, thyroid function, IHC) with local invasiveness and metastatic disease was performed on all tumor samples. Forty‐four dogs treated by thyroidectomy were included in a survival analysis.ResultsFifty dogs (71%) had differentiated follicular cell thyroid carcinoma (dFTC) and 20 (29%) had medullary thyroid carcinoma (MTC). At diagnosis, tumor diameter (P = .007; P = .038), tumor volume (P = .020), tumor fixation (P = .002), ectopic location (P = .002), follicular cell origin (P = .044), and Ki‐67 (P = .038) were positively associated with local invasiveness; tumor diameter (P = .002), tumor volume (P = .023), and bilateral location (P = .012) were positively associated with presence of distant metastases. Forty‐four dogs (28 dFTC, 16 MTC; stage I–III) underwent thyroidectomy. Outcome was comparable between dogs with dFTC and MTC. Macroscopic (P = .007) and histologic (P = .046) vascular invasion were independent negative predictors for disease‐free survival. Although time to presentation, histologic vascular invasion and Ki‐67 were negatively associated with time to metastases, and time to presentation was negatively associated with time to recurrence, no independent predictors were found. E‐cadherin expression was not associated with outcome.Conclusions and Clinical ImportancePrognostic factors have been identified that provide relevant information for owners and clinicians.

Implication of Microscopic and Macroscopic Vascular Invasion for Liver Resection in Patients with Hepatocellular Carcinoma

Background and Aim: Long-term data after liver resection for hepatocellular carcinoma (HCC) with vascular invasion are rare for non-Asian patients. The aim of the present study was to analyze the long-term outcome of liver resection for HCC with vascular invasion and to compare the results of subgroups with micro- and macrovascular invasion. Methods: From January 2000 to September 2010, 288 patients without extrahepatic metastases underwent liver resection for HCC. In 107 out of 288 patients (37%), vascular invasion was found in the final pathological analysis. The long-term outcome as well as the perioperative course of these patients was analyzed using a prospective database. Results: The 1-, 3- and 5-year cumulative survival rate of HCC patients with vascular invasion was 64.3, 41.4 and 23.9%, respectively. The median survival was 19 months. In the multivariate analysis, the overall survival was not influenced by the type of vascular invasion (micro- vs. macrovascular invasion), however overall survival was significantly impaired in case of lymphatic vessel invasion, intraoperative blood transfusions, need of fresh frozen plasma application, prolonged ICU stay and elevated preoperative bilirubin levels. Conclusions: Acceptable survival rates can be achieved in selected patients with macrovascular invasion after surgical resection, which is not markedly different from those with microvascular invasion. In view of an otherwise poor prognosis, liver resection seems to be justified for selected HCC patients with macrovascular invasion, although this stands in contrast with the BCLC recommendations. However, it is in accordance for example with the guidelines of the Asia-Pacific Association for the Study of the Liver.

Short- and long-term outcomes of laparoscopic versus open hepatectomy for small malignant liver tumors: a single-center experience.

Laparoscopic hepatectomy (Lap-Hx) has been increasingly performed for patients with liver tumors as surgical techniques and devices have progressed. However, the long-term outcomes of Lap-Hx for malignant liver tumors are not oncologically guaranteed. This study compared the short- and long-term outcomes between Lap-Hx and open hepatectomy (Open-Hx) for malignant liver tumors by matched-pair analysis. The indications for Lap-Hx at our department are a tumor size of <5 cm and fewer than two lesions without macroscopic vascular invasion or the need for biliary reconstruction. In total, 135 patients underwent Lap-Hx for malignant liver tumors through December 2013. We compared the short- and long-term outcomes between Lap-Hx and Open-Hx in patients who met the above-mentioned indications. With respect to short-term outcomes, the operation time, blood loss, postoperative hospital stay, white blood cell count, and C-reactive protein level after Lap-Hx were significantly better than those after Open-Hx in both the patients who underwent partial resection and those who underwent lateral sectionectomy. In patients who underwent partial resection, the incidence of postoperative complications after Lap-Hx was significantly lower than that after Open-Hx; in particular, wound infection and respiratory complications were significantly lower. Furthermore, when the tumor was located in the posterosuperior segments, the operation time for Lap-Hx was not shorter than that for Open-Hx. With respect to long-term outcomes of hepatocellular carcinoma, neither overall nor disease-free survival differed between the two groups. With respect to long-term outcomes of colorectal liver metastases, the disease-free survival rate was similar between Lap-Hx and Open-Hx; however, the overall survival rate was significantly better for Lap-Hx than for Open-Hx. Lap-Hx is a good option for selected patients with malignant liver tumors. The short- and long-term outcomes of Lap-Hx also are considered to be acceptable.

Involvement of platelets in extrahepatic metastasis of hepatocellular carcinoma

Recently, a relationship between platelets and cancer metastasis has been reported. The aim of this study is to elucidate the risk factors for extrahepatic metastasis (EHM), with emphasis on association with platelets in patients, with hepatocellular carcinoma (HCC). We examined risk factors for EHM in 1613 consecutive, newly diagnosed HCC patients by logistic regression analysis (case-control study). We also examined the factors by Cox proportional hazard model in a retrospective cohort fashion in 803 patients who received non-curative treatment for HCC. In the case-control study, multivariate analysis revealed that high platelet counts (odds ratio [OR] = 4.84; 95% confidence interval [CI] = 1.29-29.54; P = 0.01), high tumor number and the presence of macroscopic vascular invasion were significantly associated with EHM. In the cohort study, EHM was diagnosed in 71 patients during the study period (mean observation time = 23.3 months). On multivariate analysis, high tumor number, high des-γ-carboxyprothrombin (DCP) and Child-Pugh class A were significantly correlated with EHM, and the patients with high platelet counts tended to develop EHM (OR = 1.73; 95% CI = 0.99-3.14; P = 0.055). HCC patients with high platelet counts, as well as large numbers of tumors, high serum DCP and Child-Pugh class A, are at risk for EHM.

Is resectable hepatocellular carcinoma a contraindication to liver transplantation? A novel decision model based on “number of patients needed to transplant” as measure of transplant benefit

Number-needed-to-treat is used in assessing the effectiveness of a health-care intervention, and reports the number of patients who need to be treated to prevent one additional bad outcome. Although largely used in medical literature, there are no studies measuring the benefit of liver transplantation (LT) over hepatic resection (HR) for hepatocellular carcinoma (HCC) in terms of "Number of patients needed to transplant (NTT)." Child-Turcotte-Pugh (CTP) Classes B-C, very large (>10 cm) and multi-nodular (>2 nodules) tumours, macroscopic vascular invasion and extra-hepatic metastases. 1028 HCC cirrhotic patients from one Eastern (n=441) and two Western (n=587) surgical units. Patient survival observed after HR by proportional hazard regression model was compared to that predicted after LT by the Metroticket calculator. The benefit obtainable from LT compared to resection was analysed in relationship with number of nodules (modelled as ordinal variable: single vs. oligonodular), size of largest nodule (modelled as a continuous variable), presence of microscopic vascular invasion (MVI), and time horizon from surgery (5-year vs. 10-year). 330 patients were beyond the Milan criteria (32%) and 597 (58%) had MVI. The prevalence of MVI was 52% in patients within Milan criteria and 71% in those beyond (p<0.0001). In the 5-year transplant benefit analysis, nodule size and HCC number were positive predictors of transplant benefit, while MVI had a strong negative impact on NTT. Transplantation performed as an effective therapy (NTT <5) only in oligonodular HCC with largest diameter >3cm (beyond conventional LT criteria) when MVI was absent. The 10-year scenario increased drastically the transplant benefit in all subgroups of resectable patients, and LT became an effective therapy (NTT <5) for all patients without MVI whenever tumor extension and for oligonodular HCC with MVI within conventional LT criteria. Based on NTT analysis, the adopted time horizon (5-year vs. 10-year scenario) is the main factor influencing the benefit of LT in patients with resectable HCC and Child A cirrhosis.