We identified the studies by searching MEDLINE, Embase, Cochrane Library (CENTRAL) databases, Web of Science, ScienceDirect, the China Journal Full-text Database, and the National Institute of Health Clinical Trials Database (www. ClinicalTrials.gov) with the following keywords: “hepatocel- lular carcinoma” or “HCC” or “hepatic tumor” or “hepatic cancer” or “liver cancer” and “PVTT” or “portal vein tumor thrombi” or “portal vein tumor thrombosis” and “chemother- apy” and “TACE” or “chemoembolization” or “embolization” and “clinical trials” in the English language and in non-English languages (limits of the search period: from January 1990 to October 2014). The references of the retrieved literature were also screened. The search strategies are shown in Figure 1.
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A case of advanced multiple hepatocellular carcinomas (HCC) with portal vein tumor thrombosis successfully treated by oral tegafur/uracil is reported. A 69-year-old Japanese woman with advanced HCC with tumor thrombosis under- went transcatheter arterial infusion chemotherapy in April 2001. However, 1 year later, the patient experieced a recur- rence with advanced multiple HCC with portal vein tumor thrombosis and ascites. Treatment with oral tegafur/uracil was started in May 2002 and resulted in the partial response of liver tumors and the complete improvement of ascites. She remained in good health for about 6 years. This case strongly suggests that oral tegafur/uracil is an effective treatment for some cases of advanced HCC with portal vein tumor thrombosis.
The current study demonstrated that DCP <1000 mAu/mL at pretreatment and RT were independently related to OS, according to a Cox model in a PS analysis. The serum DCP level correlates with intrahepatic vas- cular invasion, and the DCP level might reflect expan- sion of macroscopic hepatic vascular invasion . These findings suggest that the first goal of therapy for advanced HCC with major PVTT should consist of intensive treatment to recanalize the PVTT. RT is more effective than sorafenib, because major PVTT is inten- sively irradiated by RT. In fact, the overall objective re- sponse rate (complete response plus partial response) for PVTT by RT reached 45%, and the response rate was even better in patients with C-P class A . In addition, 3D-CRT for PVTT can minimize liver-related AEs (Table 3). Almost all patients receiving sorafenib discontin- ued therapy (due to AEs or disease progression), while only one patient discontinued RT. Involvement of the main PVTT is associated with poor prognosis, possibly because of increased risk of tumor spread, elevated portal venous pressure causing variceal hemorrhage, and decreased portal flow resulting in ascites, jaundice, hepatic encephalopathy, and liver failure [7,9,23,26]. Sorafenib can compromise hepatic function by decreasing portal blood flow, as we pre- viously demonstrated that sorafenib induced significant vasoconstriction of the portal venous area and significantly reduced portal venous flow, according to Doppler ultrason- ography in patients with unresectable HCC . Other in- vestigators have used magnetic resonance imaging to show similar results . Therefore, we believe that sorafenib should be administered only after recanalization of major PVTT by other treatments .
Several limitations of this study should be noted. This study was retrospective, and the included samples were not random, thereby leading to selection bias in determining the treatment regimen, although the baseline characteristics were similar between the two groups, suggesting that the degree of bias might not have been large. A prospective randomized study should be conducted to evaluate the benefits of TACE among patients with HCC and PVTT. Second, the treatment regimens in the control group of this study were ununified, possibly affecting the OS. Third, the diagnosis and grades of PVTT were determined through enhanced CT scans or MRI without pathologic confirmation. Thrombogenesis tends to occur on the basis of PVTT, which can broaden the extent of portal vein occlusion, thereby influencing the accuracy of PVTT grading because accurate imaging modalities for PVTT grading could not be obtained.
Methods: Data on 62 patients with PVTT and endoscopically proven esophageal or gastric variceal bleeding from 2007 to 2012 were studied. In most cases, the varices were treated using endoscopic variceal band ligation (EVL). We assessed the patients ’ rebleeding-free and overall survival using the Kaplan-Meier method, and a Cox proportional hazard model was used to analyze effect of independent factors on rebleeding-free and overall survival times. Results: Most patients had decompensated cirrhosis and were classified as Child-Pugh class B (56 %) or C (36 %). A total of 35 patients (56 %) had PVTT in the main portal trunk. Among all patients, 58 (94 %) and 4 (6 %) had esophageal and gastric variceal bleeding, respectively. Bleeding was managed using EVL in all, but one patient (98 %) who was treated with a Sengstaken-Blakemore tube. A total of 24 patients (39.3 %) experienced rebleeding, and these patients had a median overall survival time of 36 days. A PVTT in the main portal trunk was predictive of rebleeding (hazard ratio 3.706, p = .0223), and α -fetoprotein-L3 levels <37.4 % (hazard ratio 0.464, p = 0.015) and Child-Pugh class A/B (hazard ratio 0.398, p = 0.007) were associated with overall survival. We observed 95 bleeding events in 62 patients. EVL achieved hemostasis in 92 of the 95 bleeding events, whereas seven immediate deaths occurred due to variceal bleeding (7/92, 7.6 %). All three bleeding events treated with modalities other than EVL resulted in immediate deaths. Conclusions: EVL is a safe and effective treatment of variceal ruptures in patients with HCC and PVTT. After successful hemostasis, alleviation of the underlying liver function impairment and tumor control are equally important for a good prognosis.
Most patients with HCC involving extensive PVTT have multiple intrahepatic metastases at the time of diagnosis and they are considered poor surgical candidates. If left untreated, patients with HCC involving PVTT have a me- dian overall survival (OS) of 2–4 months [16, 17]. PVTT is also a causative factor for intrahepatic tumor dissemin- ation, which primarily accounts for the poor prognosis in this group of patients [18, 19]. The most common staging system for HCC employed in American and European centers, the Barcelona Clinic Liver Cancer (BCLC) system, recommends against surgical resection in cases involving PVTT . In a previous series of patients who under- went hepatectomy and thrombectomy for HCC involving PVTT in the main portal trunk, the 1- and 3-year OS rates were 25 and 4 %, respectively, and the disease-free survival rates were 3 % and 0 %, respectively . How- ever, surgical resection is considered the only curative
The present study evaluated patients who had up to four small- sized to medium-sized (,10 cm) HCC lesions treated with conventional fractionated intensity-modulated radiotherapy (IMRT). None of the patients had PVTT and they were classi- fied as stage I–IIIA using the AJCC staging system. Because there was variation in the total dose and in the fraction dose, we used the biologically effective dose (BED) for analysis, and all patients received IMRT with a median RT dose of 67.1 Gy 10 BED. The results of the present study revealed one-year and 2-year actuarial local control rates of 81.6% and 69.5%, respectively, and one-year and 2-year overall survival rates of 90.0% and 71.1%, respectively. Although caution must be taken in interpreting clinical outcomes due to the heterogeneity of patient characteristics, these outcomes were more favorable compared with those of previous studies, which showed one-year and 2-year local control rates ranging from 77.9% to 100% and 61.1% to 93%, respectively, and one-year and 2-year overall survival rates ranging from 41.8% to 72.0% and 19.9% to 69.1%, respectively. 3,4,6–8,11,12,21,22 We
characteristic feature of highly aggressive tumors which means de novo generation of microvascular channels independent of endothelial cells. Therefore, DKK1 may enhance tumor growth via direct effect on cellular proliferation and/or indirectly through promoting tumoral angiogenesis or vasculogenic mimicry in the tumor microenvironment.
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The risk factors of PVT appeared to vary according to age and gender. In young patients aged <20 years, umbi- lical catheterization was the main risk which was similar to the study of 31 children with PVT in Italy , whereas in older adults (age 40-60 and >60), malignancy was the major etiology (69.1% and 86%, respectively). Only 1 case of cancer, i.e. hepatoblastoma, was found in a young patient with PVT. Abdominal infection such as omphalitis which causes thrombophlebitis of the umbili- cal vein and eventually the portal system was reported in most pediatric series [21,31] but was found in only 1 case in this study (7.7%). Almost half of our young patients had unidentifiable risks (46.2%) which could be attributed to truly idiopathic causes or incomplete thrombophilic investigations. Although the main limita- tion of this study is its retrospective nature and a com- plete set of thrombophilic investigations might not have been performed in some of these cases in the last 10 years, it should be noted that hereditary thrombophilic disorders such as Factor V Leiden, prothrombin gene G20210A mutation, protein C deficiency, protein S defi- ciency, antithrombin deficiency, and methylenetetrahy- drofolate reductase (MTFR) gene mutation are very rare in the Southeast Asian population [32,33]. A study of 61 patients with PVT from India reported only 1 case of Factor V Leiden and none with prothrombin gene G20210A mutation . A prospective study should be performed to further explain these unidentifiable causes. Regarding the impact of gender, men were more com- monly affected with cirrhosis and malignancies than women although both conditions remained the major risk factors in both genders.
Previous studies showed that the rate of portal vein re- canalization was significantly higher while the rate of thrombus progression was significantly lower in the anticoagulation group compared with the non- anticoagulation group. These results suggest that antic- oagulation, rather than “wait-and-see” strategy, should be actively employed to maximize the recanalization of thrombosed portal veins in liver cirrhosis. However, this recommendation should be cautiously applied for the following reasons. First, only a small number of studies were included in the two comparative analyses, and none of them was nonrandomized. Second, the role of
their portal flow with partial or complete recanalization during follow up. All four patients with cancer or cirrhosis and acute PVT (67%) who received anticoagulation ther- apy had partial or complete recanalization. Among such patients who did not receive anticoagulation therapy (n = 34), only 15% improved their portal flow and had any degree of spontaneous resolution of the thrombosis. Of patients with oesophageal varices (n = 48), 60% of the patients without, and (n = 12) 75% of patients with can- cer of cirrhosis were treated endoscopically with band ligation (VBL) and/or sclerotherapy, in 24% as primary prophylaxis. Forty-two percent of patients without and 17% of patients with cancer or cirrhosis were treated with β-blockers as primary prophylaxis. Of patients with one or more variceal bleeding episodes (n = 24), 92% of patients without and 80% with cancer or cirrhosis were treated with VBL or sclerotherapy, and 88% with and 90% with- out cancer or cirrhosis with β-blockers (24% of these also with long-acting nitrates) as secondary prophylaxis.
In cirrhosis patients, literature suggests that more than 70% of partial or nonocclusive PVTs spontaneously resolve when initially discovered on Doppler ultrasonography. This high rate of spontaneous resolution is likely due to the inherent weaknesses in Doppler techniques. Unlike the deep veins in the extremities, the deep veins of the abdomen are not externally compressible; thus, differentiating true thrombosis gish flow is difficult. For this reason, before therapeutic decisions can be made regarding PVT, diagnosis must be verified by contrast enhanced imaging such as CT or MRI. Importantly, malignant tumor thrombus, a common finding with hepatocellular carcinoma (HCC), does not
In acute pancreatitis, inflammation can cause damage to the vessels and lead to hepatic infarcts. However, in- farction remains a rare complication of portal vein thrombosis because of the arterial compensation . In our patient, several factors contributed to the un- favorable outcome: idiopathic cause of pancreatitis, which is an independent risk factor of mortality ; the absence of splanchnic venous thrombus regression; and the extension of venous intestinal ischemia despite anticoagulation. The clinical and biological evolution was unfavorable in the absence of possibility of liver transplant in our context.
More recently, thrombogenic and inflammatory risk factors have also been implicated in the pathogenesis of PVT. In selected populations, an association between plasma D-dimer level and an increased risk of PVT thrombosis has been proposed. Plasma D-dimer has an important role as a marker of thrombogenesis. It is a sensitive marker of fibrin turnover and allows the recognition of activated coagulation, which may be manifested in various clinical conditions. 50,51 The measurement may allow the specific
A 54-year-old man presented as an emergency with diffuse abdominal pain, nausea, and vomiting. The body mass index (BMI) of the patient was 42 kg/m2.He was smoker (one pack/day). He had undergone LSG 21 days prior to the index admission. The laboratory findings were insignificant, with only an increase in white cell count. Computerized tomography (CT) of the abdomen confirmed the diagnosis of portal vein thrombosis (Figure 3,4,5,6,7,8). He was admitted to the hospital, dehydrated, and was started on medical treatment with intravenous heparin infusion, fluid resuscitation. Thereafter he was shifted to warfarin, which was continued after discharge.
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Splenic and superior mesenteric veins together form the portal vein posterior to the pancreas. Portal vein thrombosis (PVT) is a significant clinicopathologic entity that all surgeons should be aware with. It has significant morbidity and mortality with 1% incidence in general population. The lifetime possibility of having portal vein thrombosis (PVT) is nearly 1%. PVT is being diagnosed more often as a result of the increasing usage of numerous advanced imaging modalities. Sonography, CT and magnetic resonance imaging are most used to diagnose PVT. Malignancy, inflammatory conditions of abdomen, trauma, surgery and hypercoagulable states are the most common risk factors causing PVT in surgical patients. PVT ultimately leads to the establishment of many collateral vessels nearby the thrombosed portal vein. First- line treatment for PVT is therapeutic anticoagulation-it helps prevent the spread of the thrombus. Other therapeutic preferences comprise surgery and interventional radiographic procedures.
It has been reported that multiple TACE treatments may lead to A-P shunts, thus it is recommended that chemoembolization should be abandoned if A-P shunts appear or the dose of embolic agents should be reduced . In the present study, some of the HCC cases con- tinued to progress after TACE; invasion of the tumor at the portal vein and development of tumor thrombus were found. These conditions lead to an increase of A-P shunt flow. In other cases, TACE treatment did not stop the growth of the existing tumor thrombus, resulting in an increase of A-P shunts. Therefore, embolization of the tumor thrombus should be performed if patients have satisfactory liver function. The embolization of the blood supply of tumor thrombus could reduce the flow of the A-P shunts.
In this study, we also found that BHMT, IVD, CRAT and arginase-1 were all down-regulated in cancer tis- sues of HCC without PVT and further deceased in the cancer tissues of HCC with PVT. BHMT is a cytosolic enzyme that catalyses the conversion of homocysteine to methionine. Teng et al. showed BHMT was important in one-carbon metabolism and lack of BHMT resulted in fatty liver and HCC in an animal model . Yan et all also showed that deficiency of BHMT leads to accumu- lation of homocysteine which impairs endothelial func- tion by compromising VEGF/Akt endothelial nitric oxide synthetase signaling and vascular complications . Isovaryl-CoA dehydrogenase is a mitochondrial matrix enzyme that catalyzes the third step in leucine metabo- lism. Clinically, reduced activity of IVD is a recessive autosomal disorder and cause isovaleric acidosis . Clinical symptom is presented as severe metabolic aci- dosis. Deficiency of IVD in HCC cells might cause accel- erate acidosis in the microenvironment of tumor which might exaggerate cancer to invade vessels and resistant to chemotherapy or radiotherapy. In this study, CRAT was also down-regulated in the cancer cells with PVT. Clinically, deficiency of CRAT is an autosomal recessive inborn error of mitochondrial fatty acid oxidation . Hypoglycemia is one of the clinical presentations. Imagi- nably, decreased level of glucose in the tumor microenvi- ronment might force cancer cells to invade vessel to get energy source.
All of the patients underwent extensive evaluation to exclude underlying or coexisting liver disease. We con- firmed that liver histology results were normal at the time of the procedure. Patients underwent Doppler ul- trasound evaluation of the mesenteric and portal venous systems. Magnetic resonance and computed tomo- graphic angiography were used as noninvasive ap- proaches to obtain accurate images of the intrahepatic veins before surgery. A standard hepatic-function panel, prothrombin time, and random nonfasting venous am- monia level were obtained at the time of initial evalua- tion.
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Our study was mainly focused on the diagnostic roles of ALB and GGT and systematically explored the prognostic roles of these biomarkers. We successfully established a novel and effective score model including ALB, GGT, PVTT, and tumor number, which were all independent prognostic predictors in our study. The Kaplan-Meier sur- vival analysis showed that patients with higher scores had worse outcomes. Our simple and practical model could predict the prognosis of HCC patients and could be used to guide clinical decision making.
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